[Federal Register Volume 81, Number 1 (Monday, January 4, 2016)]
[Proposed Rules]
[Pages 42-44]
[FR Doc No: 2015-33011]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 172

[Docket No. FDA-2015-F-4317]

Center for Science in the Public Interest, Natural Resources
Defense Council, Center for Food Safety, Consumers Union, Improving
Kids' Environment, Center for Environmental Health, Environmental
Working Group, Environmental Defense Fund, and James Huff; Filing of
Food Additive Petition

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of petition.

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SUMMARY: The Food and Drug Administration (FDA or we) is announcing
that we have filed a petition, submitted by the Center for Science in
the Public Interest, Natural Resources Defense Council, Center for Food
Safety, Consumers Union, Improving Kids' Environment, Center for
Environmental Health, Environmental Working Group, Environmental
Defense Fund, and James Huff, proposing that the food additive
regulations be amended to no longer authorize the use of seven listed
synthetic flavoring food additives and to establish zero tolerances for
the additives.

DATES: The food additive petition was filed on August 17, 2015. Submit
either electronic or written comments by March 4, 2016.

ADDRESSES: You may submit comments as follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to http://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 http://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): Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Division of
Dockets Management, 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-2015-F-4317 for ``Center for Science in the Public Interest,
Natural Resources Defense Council, Center for Food Safety, Consumers
Union, Improving Kids' Environment, Center for Environmental Health,
Environmental Working Group, Environmental Defense Fund, and James
Huff; Filing of Food Additive Petition.''
    Received comments will be placed in the docket and, except for
those submitted as ``Confidential Submissions,'' publicly viewable at
http://www.regulations.gov or at the Division of Dockets Management
between 9 a.m. and 4 p.m., Monday through Friday.
     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 http://www.regulations.gov.
Submit both copies to the Division of Dockets Management. 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 http://www.fda.gov/regulatoryinformation/dockets/default.htm.
    Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to http://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 Division of Dockets Management, 5630 Fishers
Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Judith Kidwell, Center for Food Safety
and Applied Nutrition (HFS-265), Food and Drug Administration, 5100
Paint Branch Pkwy., College Park, MD 20740-3835,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

I. Background

    Under section 409(b)(5) of the Federal Food, Drug, and Cosmetic Act
(the FD&C Act) (21 U.S.C. 348(b)(5)), we are giving notice that we have
filed a food additive petition (FAP 5A4810) submitted by the Center for
Science in the Public Interest, Natural Resources Defense Council,
Center for Food Safety, Consumers Union, Improving Kids' Environment,
Center for Environmental Health, Environmental Working Group,
Environmental Defense Fund, and James Huff, c/o Thomas Neltner, 1875
Connecticut Ave. NW., Suite 600, Washington, DC 20009. The petition
proposes to amend Sec.  172.515 (21 CFR 172.515), Synthetic flavoring
substances and adjuvants, to no longer provide for the use of seven
listed synthetic flavoring food additives and to establish zero
tolerances for these additives.
    The seven food additives that are the subject of this petition are
as follows:

     Benzophenone (also known as diphenyl ketone) (CAS No.
119-61-9);
     Ethyl acrylate (CAS No. 140-88-5);
     Eugenyl methyl ether (also known as 4-allylveratrole or
methyl eugenol) (CAS No. 93-15-2);
     Myrcene (also known as 7-methyl-3-methylene-1,6-
octadiene) (CAS No. 123-35-3);
     Pulegone (also known as p-menth-4(8)-en-3-one) (CAS No.
89-82-7);
     Pyridine (CAS No. 110-86-1); and
     Styrene (CAS No. 100-42-5).

II. Amendment of Sec.  172.515

    In accordance with the procedures for amending or revoking a food
additive regulation in Sec.  171.130 (21 CFR 171.130), the petition
asks us to amend Sec.  172.515 to no longer provide for the use of
these seven food additives as synthetic flavoring substances.
Specifically, the petitioners contend that new data establish that
these substances are carcinogenic and are, therefore, not safe for use
in food under the Delaney Clause (section 409(c)(3)(A) of the FD&C
Act), which provides that no food additive shall be deemed to be safe
if it is found to induce cancer when ingested by man or animal, or if
it is found, after tests which are appropriate for the evaluation of
the safety of food additives, to induce cancer in man or animal. The
petitioners cite, as evidence, conclusions by the National Toxicology
Program, the International Agency for Research on Cancer, and the
California Environmental Protection Agency's Office of Environmental
Health Hazard Assessment. The petitioners also include results from an
observational epidemiology study in humans exposed to styrene and a
number of long-term, animal feeding studies conducted on each of the
seven additives to support their request. If we determine new data are
available that establish these food additives induce cancer, then FDA
will amend Sec.  172.515 to no longer provide for their use by
publishing an amendment to the regulation in the Federal Register, as
set forth in Sec. Sec.  171.130 and 171.100 (21 CFR 171.100).
    Although the petition proposes to amend only Sec.  172.515 to no
longer provide for the use of these seven synthetic flavoring
substances, our action in response to the petition could affect other
regulations which provide specifically for the use of these additives.
Specifically, benzophenone is also approved for use as an indirect food
additive, i.e., a plasticizer (21 CFR 177.2600(c)(4)(iv) diphenyl
ketone). We note that some of these flavoring substances (e.g., ethyl
acrylate, pyridine, styrene) are permitted for use by other food
additive regulations and food contact notifications as reactants or
manufacturing aids. Such uses are not the subject of these food
additive regulations and food contact notifications, and as such, may
not necessarily be affected if this petition results in a regulation.

III. Establish a Zero Tolerance

    The petition also requests that FDA explicitly establish a zero
tolerance for these seven substances in Sec.  172.515. There is no
statutory or regulatory provision for establishing a zero tolerance
standard for flavoring food additives in Sec.  172.515. We note,
however, that 21 CFR part 189 permits FDA to prohibit by rulemaking the
use of substances in human foods because of a determination that they
present a potential risk to the public health or have not been shown by
adequate scientific data to be safe for use in human foods. To the
extent that a rulemaking under part 189 to prohibit the use of these
seven substances in food satisfies the petitioner's request for a zero
tolerance, we will consider, to the extent appropriate, whether such a
rulemaking is necessary if this petition results in a regulation.
    We also are reviewing the potential environmental impact of the
petitioners' requested action. The petitioners have claimed a
categorical exclusion from preparing an environmental assessment or
environmental impact statement

under 21 CFR 25.32(m). In accordance with regulations issued under the
National Environmental Policy Act (40 CFR 1506.6(b)), we are placing
the environmental document submitted with the subject petition on
public display at the Division of Dockets Management (see ADDRESSES) so
that interested persons may review the document. If we determine that
the petitioners' claim of categorical exclusion is warranted and that
neither an environmental assessment nor an environmental impact
statement is required, we will announce our determination in the
Federal Register if this petition results in a regulation. If we
determine that the claim of categorical exclusion is not warranted, we
will place the environmental assessment on public display at the
Division of Dockets Management and provide notice in the Federal
Register announcing its availability for review and comment.

    Dated: December 29, 2015.
Dennis M. Keefe,
Director, Office of Food Additive Safety, Center for Food Safety and
Applied Nutrition.
[FR Doc. 2015-33011 Filed 12-31-15; 8:45 am]
 BILLING CODE 4164-01-P


[Federal Register Volume 80, Number 164 (Tuesday, August 25, 2015)]
[Notices]
[Pages 51642-51644]
[FR Doc No: 2015-20935]

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SECURITIES AND EXCHANGE COMMISSION

[Release No. 34-75736; File No. SR-CBOE-2015-045]

Self-Regulatory Organizations; Chicago Board Options Exchange,
Incorporated; Order Instituting Proceedings To Determine Whether To
Approve or Disapprove a Proposed Rule Change, as Modified by Amendment
No. 1, Relating to Rule 6.53C and Complex Orders on the Hybrid System

August 19, 2015.

I. Introduction

    On May 12, 2015, Chicago Board Options Exchange, Incorporated (the
``Exchange'' or ``CBOE'') filed with the Securities and Exchange
Commission (the ``Commission''), pursuant to Section 19(b)(1) of the
Securities Exchange Act of 1934 (the ``Exchange Act'' or ``Act''),\1\
and Rule 19b-4 thereunder,\2\ a proposed rule change to modify CBOE
Rule 6.53C, Complex Orders on the Hybrid System, regarding eligibility
for participation in the Complex Order Book (``COB'') and the Complex
Order Auction (``COA''). The proposed rule change was published for
comment in the Federal Register on May 27, 2015.\3\ On June 3, 2015,
CBOE filed Amendment No.1 to the proposed rule change.\4\ On July 6,
2015, the Commission extended the time period within which to approve
the proposed rule change, disapprove the proposed rule change, or
institute proceedings to determine whether to disapprove the proposed
rule change, to August 25, 2015.\5\ The Commission has received no
comments on the proposed rule change. This order institutes proceedings
under Section 19(b)(2)(B) of the Act \6\ to

determine whether to approve or disapprove the proposed rule change.
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    \1\ 15 U.S.C. 78s(b)(1).
    \2\ 17 CFR 240.19b-4.
    \3\ See Securities Exchange Act Release No. 75003 (May 20,
2015), 80 FR 30306 (``Notice'').
    \4\ Amendment No. 1 to the proposed rule change amended the
statutory basis and burden on competition sections regarding
distinguishing between Professional and non-Professional orders for
purposes of determining eligibility for COA.
    \5\ See Securities Exchange Act Release No. 75359 (July 6,
2015), 80 FR 39821 (July 10, 2015).
    \6\ 15 U.S.C. 78s(b)(2)(B).
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II. Description of the Proposal

    The Exchange seeks to modify CBOE Rule 6.53C to allow the Exchange
to further distinguish between the complex order origin types that are
eligible for the COB and COA.\7\ Currently, under CBOE Rule 6.53C, the
Exchange may determine whether orders from non-broker dealer public
customers, broker-dealers that are not Market-Makers or specialists on
an options exchange, and/or Market-Makers or specialists on an options
exchange are eligible for entry into the COB or COA. Under these
current COA and COB eligibility parameters, there is no distinction
between professional public customers and non-professional public
customers.
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    \7\ The COA is a feature within CBOE's Hybrid System that
exposes eligible complex orders for price improvement. In classes
where the COA is activated, eligible orders are electronically
exposed for an exposure period. At the conclusion of the COA
process, the order is then allocated or, to the extent not executed,
sent to the COB or routed. See Notice, 80 FR at 15264.
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    The Exchange proposes to modify CBOE Rule 6.53C so that it could
determine whether the following two additional types of market
participants are eligible for entry into the COB and the COA: (i) Non-
broker-dealer public customers that are Voluntary Professional
Customers or Professional Customers (herein, ``Professionals'') and
(ii) non-broker-dealer public customers that are not Voluntary
Professional Customers or Professional Customers.
    CBOE states that it is proposing this change so that it may prevent
orders from Professionals from triggering a COA. According to the
Exchange, CBOE participants currently may cancel and replace their
complex orders as often as they wish without incurring any cancellation
fees. Each order that meets the eligibility requirements detailed in
CBOE Rule 6.53C,\8\ including cancellations and replacements, generates
a new COA. The Exchange states that few of the complex orders entered
by Professional Customers that trigger a COA actually execute in the
auction process.\9\ Accordingly, CBOE believes that allowing COA
eligibility to be determined by origin code (e.g., by whether the order
comes from a Professional), which permits CBOE to prevent orders from
Professionals from triggering a COA, will ``eliminate the clutter of
unnecessary Professional COA messages, as well as increase the
likelihood of executions for public customers.'' \10\ The Exchange
further believes that allowing Professionals to participate in the COA
can be detrimental to non-professional public customer order flow.\11\
The Exchange also believes that ``removing unnecessary Professional COA
messages may encourage more participants to provide auction responses
(ultimately increasing the likelihood of executions for public
customers . . .) because fewer unnecessary COA messages will most
likely increase the proportion of responses that lead to an
execution.'' \12\
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    \8\ A COA-eligible order is a complex order that, as determined
by the Exchange on a class-by-class basis, is eligible for COA
considering the order's marketability (defined as a number of ticks
away from the current market), size, complex order type, and complex
order origin type. See Rule 6.53C(d)(1). This proposed rule change
would change the term ``complex order origin type'' to ``complex
order origin code.''
    \9\ For example, in Amendment No. 1, the Exchange notes that
orders for Professionals made up 52% of COA auctions but resulted in
0.62% of COA executions in the month of February 2015. The Exchange
states that this is a representative example of Professional orders
participation and execution rates in the COA.
    \10\ See Notice, 80 FR at 30307.
    \11\ See id.
    \12\ See Amendment No. 1 at 4.
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III. Proceedings To Determine Whether To Approve or Disapprove SR-CBOE-
2015-045 and Grounds for Disapproval Under Consideration

    The Commission is instituting proceedings pursuant to Section
19(b)(2)(B) of the Act \13\ to determine whether the proposed rule
change, as modified by Amendment No. 1, should be approved or
disapproved. Institution of such proceedings is appropriate at this
time in view of the legal and policy issues raised by the proposed rule
change, as discussed below. Institution of proceedings does not
indicate that the Commission has reached any conclusions with respect
to any of the issues involved.
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    \13\ 15 U.S.C. 78s(b)(2)(B).
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    Pursuant to Section 19(b)(2)(B) of the Act,\14\ the Commission is
providing notice of the grounds for disapproval under consideration.
The Commission is instituting proceedings to allow for additional
analysis of, and comment on, whether the proposed rule change is
consistent with: Section 6(b)(5) of the Act,\15\ which requires that
the rules of a national securities exchange be designed, among other
things, to prevent fraudulent and manipulative acts and practices, to
promote just and equitable principles of trade, to remove impediments
to and perfect the mechanism of a free and open market and a national
market system and, in general, to protect investors and the public
interest, and are not designed to permit unfair discrimination between
customers, issuers, brokers, or dealers; and Section 6(b)(8) of the
Act,\16\ which requires that the rules of a national securities
exchange not impose any burden on competition not necessary or
appropriate in furtherance of the purposes of the Act.
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    \14\ 15 U.S.C. 78s(b)(2)(B). Section 19(b)(2)(B) of the Exchange
Act also provides that proceedings to determine whether to
disapprove a proposed rule change must be concluded within 180 days
of the date of publication of notice of the filing of the proposed
rule change. See id. The time for conclusion of the proceedings may
be extended for up to 60 days if the Commission finds good cause for
such extension and publishes its reasons for so finding. See id.
    \15\ 15 U.S.C. 78f(b)(5).
    \16\ 15 U.S.C. 78f(b)(8).
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    The Exchange's proposed rule change would provide the Exchange
discretion to determine whether two additional groups of market
participants are eligible for entry into the COA and COB: (i)
Professionals and (ii) non-broker-dealer public customers that are not
Professionals.\17\ The Commission believes that the proposal raises
important issues that warrant further public comment and Commission
consideration regarding whether the proposal would result in unfair
discrimination or would impose an unnecessary and or inappropriate
burden on competition to the extent the Exchange exercises its proposed
discretion and excludes either of the two categories of market
participants discussed above from the COA and COB.
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    \17\ Under the current Rule, CBOE already may determine that
Broker-dealers that are not Market-Makers or specialists on an
options exchange and Market-Makers or specialists on an options
exchange are not eligible for entry into the COA and COB pursuant to
CBOE Rule 6.53C.
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    In light of these issues and concerns, the Commission believes that
questions arise regarding whether the proposal is consistent with the
requirements of Sections 6(b)(5) and 6(b)(8) of the Act. As the
Commission continues to evaluate the issues presented by the proposal,
the Commission solicits comment on whether the proposal is consistent
with the Act and whether the Exchange has met its burden in presenting
a statutory analysis of how its proposal is consistent with the Act. In
particular, the grounds for disapproval under consideration include
whether the Exchange's proposal is consistent with Sections 6(b)(5)
\18\ and 6(b)(8) \19\ of the Act.
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    \18\ 15 U.S.C. 78f(b)(5).
    \19\ 15 U.S.C. 78f(b)(8).
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    In addition, under the Commission's rules of procedure, a self-
regulatory organization that proposes to amend its rules bears the
burden of demonstrating

that its proposal is consistent with the Act.\20\ In this regard:
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    \20\ Rule 700(b)(3), 17 CFR 201.700(b)(3).

the description of the proposed rule change, its purpose and
operation, its effect, and a legal analysis of its consistency with
applicable requirements must all be sufficiently detailed and
specific to support an affirmative Commission finding. Any failure
of the self-regulatory organization to provide the information
elicited by Form 19b-4 may result in the Commission not having a
sufficient basis to make an affirmative finding that a proposed rule
change is consistent with the Exchange Act and the rules and
regulations thereunder that are applicable to the self-regulatory
organization.\21\
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    \21\ Id.

IV. Procedure: Request for Written Comments

    The Commission requests that interested persons provide written
submissions of their views, data and arguments with respect to the
concerns identified above, as well as any other concerns they may have
with the proposed rule change. In particular, the Commission invites
the written views of interested persons concerning whether the proposal
is consistent with Sections 6(b)(5) and 6(b)(8) \22\ or any other
provision of the Act, or the rules and regulations thereunder. Although
there do not appear to be any issues relevant to approval or
disapproval which would be facilitated by an oral presentation of
views, data, and arguments, the Commission will consider, pursuant to
Rule 19b-4 under the Act,\23\ any request for an opportunity to make an
oral presentation.\24\
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    \22\ 15 U.S.C. 78f(b)(5) and (b)(8).
    \23\ 17 CFR 240.19b-4.
    \24\ Section 19(b)(2) of the Act, as amended by the Securities
Act Amendments of 1975, Public Law 94-29 (June 4, 1975), grants to
the Commission flexibility to determine what type of proceeding--
either oral or notice and opportunity for written comments--is
appropriate for consideration of a particular proposal by a self-
regulatory organization. See Securities Act Amendments of 1975,
Senate Comm. on Banking, Housing & Urban Affairs, S. Rep. No. 75,
94th Cong., 1st Sess. 30 (1975).
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    Interested persons are invited to submit written data, views, and
arguments regarding whether the proposal should be approved or
disapproved by September 15, 2015. Any person who wishes to file a
rebuttal to any other person's submission must file that rebuttal by
September 29, 2015. In light of the concerns raised by the proposed
rule change, as discussed above, the Commission invites additional
comment on the proposed rule change as the Commission continues its
analysis of whether the proposed rule change is consistent with Section
6(b)(5),\25\ Section 6(b)(8),\26\ and all other provision of the Act,
or the rules and regulations thereunder. The Commission asks that
commenters address the sufficiency and merit of the Exchange's
statements in support of the proposed rule change, in addition to any
other comments they may wish to submit about the proposed rule change.
In particular, the Commission invites comment on the following:
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    \25\ 15 U.S.C. 78f(b)(5).
    \26\ 15 U.S.C. 78f(b)(8).
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    1. Would excluding orders submitted by Professionals from entry
into the COA or COB adversely affect the ability of Professionals to
execute their orders? Why or why not?
    2. Do commenters agree with the Exchange that there are an
excessive number of Professional COA messages that adversely affect the
likelihood of executions for non-broker-dealer public customers that
are not Professionals? Would excluding Professionals orders from the
COA increase the likelihood of, or otherwise impact, executions for
non-broker-dealer public customers that are not Professionals? If so,
how?
    3. Is the volume of auction messages generated by Professionals
disruptive to the auction process? If so, how?
    4. Are there other methods that involve less potential for unfair
discrimination that could be used to reduce the volume of messages?
    5. Do Professionals want their orders to be eligible for entry into
the COA or the COB? Why or why not?
    6. Although the Exchange states that the proposal is intended to
allow the Exchange to prevent Professionals from entry into the COB or
COA, the proposed rule change, as drafted, would also allow the
Exchange to determine that non-broker-dealer public customers that are
not Professionals Customers are not eligible for entry into both the
COA and the COB. Do commenters believe that excluding non-broker-dealer
public customers that are not Professionals from the COA and COB is
consistent with the Act? Is so, why? If not, why not?
    Comments may be submitted by any of the following methods:

Electronic Comments

     Use the Commission's Internet comment form (http://www.sec.gov/rules/sro.shtml); or
     Send an email to<EMAIL_ADDRESS>Please include
File Number SR-CBOE-2015-045 on the subject line.

Paper Comments

     Send paper comments in triplicate to Secretary, Securities
and Exchange Commission, 100 F Street NE., Washington, DC 20549-1090.

All submissions should refer to File Number SR-CBOE-2015-045. This file
number should be included on the subject line if email is used. To help
the Commission process and review your comments more efficiently,
please use only one method. The Commission will post all comments on
the Commission's Internet Web site (http://www.sec.gov/rules/sro.shtml). Copies of the submission, all subsequent amendments, all
written statements with respect to the proposed rule change that are
filed with the Commission, and all written communications relating to
the proposed rule change between the Commission and any person, other
than those that may be withheld from the public in accordance with the
provisions of 5 U.S.C. 552, will be available for Web site viewing and
printing in the Commission's Public Reference Room, 100 F Street NE.,
Washington, DC 20549 on official business days between the hours of
10:00 a.m. and 3:00 p.m. Copies of the filing also will be available
for inspection and copying at the principal office of the Exchange. All
comments received will be posted without change; the Commission does
not edit personal identifying information from submissions. You should
submit only information that you wish to make available publicly. All
submissions should refer to File Number SR-CBOE-2015-045 and should be
submitted by September 15, 2015. Rebuttal comments should be submitted
by September 29, 2015.

    For the Commission, by the Division of Trading and Markets,
pursuant to delegated authority.\27\
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    \27\ 17 CFR 200.30-3(a)(57).
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Jill M. Peterson,
Assistant Secretary.
[FR Doc. 2015-20935 Filed 8-24-15; 8:45 am]
BILLING CODE 8011-01-P


[Federal Register Volume 88, Number 144 (Friday, July 28, 2023)]
[Notices]
[Pages 48878-48881]
[FR Doc No: 2023-15909]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2023-N-2895]

Outsourcing Facility Fee Rates for Fiscal Year 2024

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing the
fiscal year (FY) 2024 rates for the establishment and reinspection fees
related to entities that compound human drugs and elect to register as
outsourcing facilities under the Federal Food, Drug, and Cosmetic Act
(FD&C Act). The FD&C Act authorizes FDA to assess and collect an annual
establishment fee from outsourcing facilities, as well as a
reinspection fee for each reinspection of an outsourcing facility. This
document establishes the FY 2024 rates for the small business
establishment fee ($6,196), the non-small business establishment fee
($20,036), and the reinspection fee ($18,588) for outsourcing
facilities; provides information on how the fees for FY 2024 were
determined; and describes the payment procedures outsourcing facilities
should follow.

DATES: These fee rates are effective October 1, 2023, and will remain
in effect through September 30, 2024.

ADDRESSES: Office of Financial Management, Food and Drug
Administration, 4041 Powder Mill Rd., Rm. 61075, Beltsville, MD 20705-
4304.

FOR FURTHER INFORMATION CONTACT: For more information on human drug
compounding and outsourcing facility fees, visit FDA's website at:
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/human-drug-compounding.
    For questions relating to this notice: Olufunmilayo Ariyo, Office
of Financial Management, Food and Drug Administration, 4041 Powder Mill
Rd., Beltsville, MD 20705-4304,<PHONE_NUMBER>; or the User Fee Support
Staff at [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    Under section 503B of the FD&C Act (21 U.S.C. 353b), a human drug
compounder can register with FDA as an ``outsourcing facility.''
Outsourcing facilities, as defined in section 503B(d)(4), are
facilities that meet all the conditions described in section 503B(a),
including registering with FDA as an outsourcing facility and paying an
annual establishment fee. If the conditions of section 503B are met, a
drug compounded by or under the direct supervision of a licensed
pharmacist in an outsourcing facility is exempt from three sections of
the FD&C Act: (1) section 502(f)(1) (21 U.S.C. 352(f)(1)), concerning
the labeling of drugs with adequate directions for use; (2) section 505
(21 U.S.C. 355), concerning the approval of human drug products under
new drug applications or abbreviated new drug applications; and (3)
section 582 (21 U.S.C. 360eee-1), concerning drug supply chain security
requirements. Drugs compounded in outsourcing facilities are not exempt
from the requirements of section 501(a)(2)(B) of the FD&C Act (21
U.S.C. 351(a)(2)(B)), concerning current good manufacturing practice
requirements for drugs.
    Section 744K of the FD&C Act (21 U.S.C. 379j-62) authorizes FDA to
assess and collect the following fees associated with outsourcing
facilities: (1) an annual establishment fee from each outsourcing
facility and (2) a reinspection fee from each outsourcing facility
subject to a reinspection (see section 744K(a)(1) of the FD&C Act).
Under statutorily defined conditions, a qualified applicant may pay a
reduced

small business establishment fee (see section 744K(c)(4) of the FD&C
Act).
    FDA announced in the Federal Register of November 24, 2014 (79 FR
69856), the availability of a final guidance for industry entitled
``Fees for Human Drug Compounding Outsourcing Facilities Under Sections
503B and 744K of the FD&C Act.'' The guidance provides additional
information on the annual fees for outsourcing facilities and
adjustments required by law, reinspection fees, how to submit payment,
the effect of failure to pay fees, and how to qualify as a small
business to obtain a reduction of the annual establishment fee. This
guidance can be accessed on FDA's website at: https://www.fda.gov/media/136683/download.

II. Fees for FY 2024

A. Methodology for Calculating FY 2024 Adjustment Factors

1. Inflation Adjustment Factor
    Section 744K(c)(2) of the FD&C Act specifies the annual inflation
adjustment for outsourcing facility fees. The inflation adjustment has
two components: one based on FDA's payroll costs and one based on FDA's
non-payroll costs for the first 3 of the 4 previous fiscal years. The
payroll component of the annual inflation adjustment is calculated by
taking the average change in FDA's per full-time equivalent (FTE)
personnel compensation and benefits (PC&B) in the first 3 of the 4
previous fiscal years (see section 744K(c)(2)(A)(ii) of the FD&C Act).
FDA's total annual spending on PC&B is divided by the total number of
FTEs per fiscal year to determine the average PC&B per FTE.
    Table 1 summarizes the actual cost and FTE data for the specified
fiscal years and provides the percent change from the previous fiscal
year and the average percent change over the first 3 of the 4 fiscal
years preceding FY 2024. The 3-year average is 3.9280 percent.

                                 Table 1--FDA PC&Bs Each Year and Percent Change
----------------------------------------------------------------------------------------------------------------
                                               FY 2020           FY 2021           FY 2022       3-Year average
----------------------------------------------------------------------------------------------------------------
Total PC&B..............................    $2,875,592,000    $3,039,513,000    $3,165,477,000  ................
Total FTE...............................           $17,535           $18,501           $18,474  ................
PC&B per FTE............................          $163,992          $164,289          $171,348  ................
Percent Change From Previous Year.......           7.3063%           0.1811%           4.2967%           3.9280%
----------------------------------------------------------------------------------------------------------------

    Section 744K(c)(2)(A)(ii) of the FD&C Act specifies that this
3.9280 percent should be multiplied by the proportion of PC&B to total
costs of an average FDA FTE for the same 3 fiscal years.

                      Table 2--FDA PC&Bs as a Percent of FDA Total Costs of an Average FTE
----------------------------------------------------------------------------------------------------------------
                                               FY 2020           FY 2021           FY 2022       3-Year average
----------------------------------------------------------------------------------------------------------------
Total PC&B..............................    $2,875,592,000    $3,039,513,000    $3,165,477,000  ................
Total Costs.............................    $6,039,320,747    $6,105,480,000    $6,251,981,000  ................
PC&B Percent............................          47.6145%          49.7834%          50.6316%          49.3432%
----------------------------------------------------------------------------------------------------------------

    The payroll adjustment is 3.9280 percent multiplied by 49.3432
percent, or 1.9382 percent.
    Section 744K(c)(2)(A)(iii) of the FD&C Act specifies that the
portion of the inflation adjustment for non-payroll costs for FY 2024
is equal to the average annual percent change in the Consumer Price
Index (CPI) for urban consumers (U.S. City Average; Not Seasonally
Adjusted; All items; Annual Index) for the first 3 years of the
preceding 4 years of available data, multiplied by the proportion of
all non-PC&B costs to total costs of an average FDA FTE for the same
period.
    Table 2 provides the summary data for the percent change in the
specified CPI for U.S. cities. These data are published by the Bureau
of Labor Statistics and can be found on its website: https://data.bls.gov/cgi-bin/surveymost?cu. The data can be viewed by checking
the box marked ``U.S. city average, All items--CUUR0000SA0'' and then
selecting ``Retrieve Data.''

                   Table 3--Annual and 3-Year Average Percent Change in U.S. City Average CPI
----------------------------------------------------------------------------------------------------------------
                                               FY 2020           FY 2021           FY 2022       3-Year average
----------------------------------------------------------------------------------------------------------------
Annual CPI..............................            258.81            270.97            292.66  ................
Annual Percent Change...................           1.2337%           4.6980%           8.0027%           4.6448%
----------------------------------------------------------------------------------------------------------------

    Section 744K(c)(2)(A)(iii) of the FD&C Act specifies that this
4.6448 percent should be multiplied by the proportion of all non-PC&B
costs to total costs of an average FTE for the same 3 fiscal years. The
proportion of all non-PC&B costs to total costs of an average FDA FTE
for FYs 2019 to 2021 is 50.6568 percent (100 percent minus 49.3432
percent equals 50.6568 percent). Therefore, the non-pay adjustment is
4.6448 percent times 50.6568 percent, or 2.3529 percent.
    The PC&B component (1.9382 percent) is added to the non-PC&B
component (2.3529 percent), for a total inflation adjustment of 4.2911
percent (rounded). Section 744K(c)(2)(A)(i) of the FD&C Act specifies
that one is added to that figure, making the inflation adjustment
1.042911.
    Section 744K(c)(2)(B) of the FD&C Act provides for this inflation
adjustment to be compounded after FY 2015. This factor for FY 2024
(4.2911 percent) is compounded by adding one to it, and then
multiplying it by one plus the inflation adjustment factor for FY 2023
(18.8227 percent), as published in the

Federal Register on July 28, 2022 (87 FR 45335). The result of this
multiplication of the inflation factors for the 8 years since FY 2015
(1.042922 x 1.239215) becomes the inflation adjustment for FY 2024. For
FY 2024, the inflation adjustment is 12.39215 percent (rounded). We
then add one, making the FY 2024 inflation adjustment factor 1.1239215.
2. Small Business Adjustment Factor
    Section 744K(c)(3) of the FD&C Act specifies that in addition to
the inflation adjustment factor, the establishment fee for non-small
businesses is to be further adjusted for a small business adjustment
factor. Section 744K(c)(3)(B) of the FD&C Act provides that the small
business adjustment factor is the adjustment to the establishment fee
for non-small businesses that is necessary to achieve total fees
equaling the amount that FDA would have collected if no entity
qualified for the small business exception in section 744K(c)(4) of the
FD&C Act. Additionally, section 744K(c)(5)(A) states that in
establishing the small business adjustment factor for a fiscal year,
FDA shall provide for the crediting of fees from the previous year to
the next year if FDA overestimated the amount of the small business
adjustment factor for such previous fiscal year.
    Therefore, to calculate the small business adjustment to the
establishment fee for non-small businesses for FY 2024, FDA must
estimate: (1) the number of outsourcing facilities that will pay the
reduced fee for small businesses for FY 2024 and (2) the total fee
revenue it would have collected if no entity had qualified for the
small business exception (i.e., if each entity that registers as an
outsourcing facility for FY 2024 were to pay the inflation-adjusted fee
amount of $18,588).
    With respect to (1), FDA estimates that 10 entities will qualify
for small business exceptions and will pay the reduced fee for FY 2024.
With respect to (2), to estimate the total number of entities that will
register as outsourcing facilities for FY 2024, FDA used data submitted
by outsourcing facilities through the voluntary registration process,
which began in December 2013. Accordingly, FDA estimates that 79
outsourcing facilities, including 10 small businesses, will be
registered with FDA in FY 2024.
    If the projected 79 outsourcing facilities paid the full inflation-
adjusted fee of $18,588, this would result in total revenue of
$1,468,452 in FY 2024 ($18,588 x 79). However, 10 of the entities that
are expected to register as outsourcing facilities for FY 2024 are
projected to qualify for the small business exception and to pay one-
third of the full fee ($6,196 x 10), totaling $61,960 instead of paying
the full fee ($18,588 x 10), which would total $185,880. This would
leave a potential shortfall of $123,920 ($185,880 minus $61,960).
    Additionally, section 744K(c)(5)(A) of the FD&C Act states that in
establishing the small business adjustment factor for a fiscal year,
FDA shall provide for the crediting of fees from the previous year to
the next year if FDA overestimated the amount of the small business
adjustment factor for such previous fiscal year. FDA has determined
that it is appropriate to credit excess fees collected from the last
completed fiscal year, due to the inability to conclusively determine
the amount of excess fees from the fiscal year that is in progress at
the time this calculation is made. This crediting is done by comparing
the small business adjustment factor for the last completed fiscal
year, FY 2022 ($2,056), to what would have been the small business
adjustment factor for FY 2022 ($1,731) if FDA had estimated perfectly.
    The calculation for what the small business adjustment would have
been if FDA had estimated perfectly begins by determining the total
target collections (15,000 x [inflation adjustment factor] x [number of
registrants]). For the most recent complete fiscal year, FY 2022, this
was $1,485,120 ($17,472 x 85). The actual FY 2022 revenue from the 85
total registrants (i.e., 74 registrants paying FY 2022 non-small
business establishment fee and 11 small business registrants) paying
establishment fees is $1,356,992. $1,356,992 is calculated as follows:
(FY 2022 Non-Small Business Establishment Fee adjusted for inflation
only) x (total number of registrants in FY 2022 paying Non-Small
Business Establishment Fee) + (FY 2022 Small Business Establishment
Fee) x (total number of small business registrants in FY 2022 paying
Small Business Establishment Fee). $17,472 x 74 + $5,824 x 11 =
$1,356,992. This left a shortfall of $128,128 from the estimated total
target collection amount ($1,485,120 minus $1,356,992). This amount
($128,128) divided by the total number of registrants in FY 2022 paying
Standard Establishment Fee (74) equals $1,731.
    The difference between the small business adjustment factor used in
FY 2022 and the small business adjustment factor that would have been
used had FDA estimated perfectly is $325 ($2,056 minus $1,731). The
$325 (rounded to the nearest dollar) is then multiplied by the number
of actual registrants who paid the standard fee for FY 2022 (74), which
provides us a total excess collection of $24,050 in FY 2022.
    Therefore, to calculate the small business adjustment factor for FY
2024, FDA subtracts $24,050 from the projected shortfall of $123,920
for FY 2024 to arrive at the numerator for the small business
adjustment amount, which equals $99,870. This number divided by 69 (the
number of expected non-small businesses for FY 2024) is the small
business adjustment amount for FY 2024, which is $1,447 (rounded to the
nearest dollar).

B. FY 2024 Rates for Small Business Establishment Fee, Non-Small
Business Establishment Fee, and Reinspection Fee

1. Establishment Fee for Qualified Small Businesses \1\
---------------------------------------------------------------------------

    \1\ To qualify for a small business reduction of the FY 2024
establishment fee, entities had to submit their exception requests
by April 30, 2023. See section 744K(c)(4)(B) of the FD&C Act. The
time for requesting a small business exception for FY 2024 has now
passed. An entity that wishes to request a small business exception
for FY 2025 should consult section 744K(c)(4) of the FD& C Act and
section III.D of FDA's guidance for industry entitled ``Fees for
Human Drug Compounding Outsourcing Facilities Under Sections 503B
and 744K of the FD&C Act,'' which can be accessed on FDA's website
at https://www.fda.gov/media/136683/download.
---------------------------------------------------------------------------

    The amount of the establishment fee for a qualified small business
is equal to $15,000 multiplied by the inflation adjustment factor for
that fiscal year, divided by 3 (see section 744K(c)(4)(A) and (c)(1)(A)
of the FD&C Act). The inflation adjustment factor for FY 2024 is
1.239215. See section II.A.1 of this document for the methodology used
to calculate the FY 2024 inflation adjustment factor. Therefore, the
establishment fee for a qualified small business for FY 2024 is one
third of $18,588, which equals $6,196 (rounded to the nearest dollar).
2. Establishment Fee for Non-Small Businesses
    Under section 744K(c) of the FD&C Act, the amount of the
establishment fee for a non-small business is equal to $15,000
multiplied by the inflation adjustment factor for that fiscal year,
plus the small business adjustment factor for that fiscal year, and
plus or minus an adjustment factor to account for over or under
collections due to the small business adjustment factor in the prior
year. The inflation adjustment factor for FY 2024 is 1.239215. The
small business adjustment amount for FY 2024 is $1,447. See section
II.A.2 of this document for the methodology used

to calculate the small business adjustment factor for FY 2024.
Therefore, the establishment fee for a non-small business for FY 2024
is $15,000 multiplied by 1.239215 plus $1,447, which equals $20,036
(rounded to the nearest dollar).
3. Reinspection Fee
    Section 744K(c)(1)(B) of the FD&C Act provides that the amount of
the FY 2024 reinspection fee is equal to $15,000, multiplied by the
inflation adjustment factor for that fiscal year. The inflation
adjustment factor for FY 2024 is 1.239215. Therefore, the reinspection
fee for FY 2024 is $15,000 multiplied by 1.239215, which equals $18,588
(rounded to the nearest dollar). There is no reduction in this fee for
small businesses.

C. Summary of FY 2024 Fee Rates

                   Table 4--Outsourcing Facility Fees
------------------------------------------------------------------------

------------------------------------------------------------------------
Qualified Small Business Establishment Fee..................   $6,196.00
Non-Small Business Establishment Fee........................   20,036.00
Reinspection Fee............................................   18,588.00
------------------------------------------------------------------------

III. Fee Payment Options and Procedures

A. Establishment Fee

    Once an entity submits registration information and FDA has
determined that the information is complete, the entity will incur the
annual establishment fee. FDA will send an invoice to the entity, via
email to the email address indicated in the registration file. The
invoice will contain information regarding the obligation incurred, the
amount owed, and payment procedures. A facility will not be registered
as an outsourcing facility until it has paid the annual establishment
fee under section 744K of the FD&C Act. Accordingly, it is important
that facilities seeking to operate as outsourcing facilities pay all
fees immediately upon receiving an invoice. If an entity does not pay
the full invoiced amount within 15 calendar days after FDA issues the
invoice, FDA will consider the submission of registration information
to have been withdrawn and adjust the invoice to reflect that no fee is
due.
    Outsourcing facilities that registered in FY 2023 and wish to
maintain their status as an outsourcing facility in FY 2024 must
register during the annual registration period that lasts from October
1, 2023, to December 31, 2023. Failure to register and complete payment
by December 31, 2023, will result in a loss of status as an outsourcing
facility on January 1, 2024. Entities should submit their registration
information no later than December 10, 2023, to allow enough time for
review of the registration information, invoicing, and payment of fees
before the end of the registration period.

B. Reinspection Fee

    FDA will issue invoices for each reinspection after the conclusion
of the reinspection, via email to the email address indicated in the
registration file or via regular mail if email is not an option.
Payments must be made within 30 days of the invoice date.

C. Fee Payment Procedures

    1. The preferred payment method is online using electronic check
(Automated Clearing House (ACH) also known as eCheck) or credit card
(Discover, VISA, MasterCard, American Express). Secure electronic
payments can be submitted using the User Fees Payment Portal at https://userfees.fda.gov/pay. (Note: only full payments are accepted. No
partial payments can be made online.) Once you search for your invoice,
click ``Pay Now'' to be redirected to Pay.gov. Electronic payment
options are based on the balance due. Payment by credit card is
available for balances less than $25,000. If the balance exceeds this
amount, only the ACH option is available. Payments must be made using
U.S. bank accounts as well as U.S. credit cards.
    2. If a check, bank draft, or postal money order is submitted, make
it payable to the order of the Food and Drug Administration and include
the user fee ID number to ensure that the payment is applied to the
correct fee(s). Payments can be mailed to: Food and Drug
Administration, P.O. Box 979107, St. Louis, MO 63197-9000. If a check,
bank draft, or money order is to be sent by a courier that requests a
street address, the courier should deliver your payment to: U.S. Bank,
Attention: Government Lockbox 979107, 1005 Convention Plaza, St. Louis,
MO 63101. (Note: This U.S. Bank address is for courier delivery only.
If you have any questions concerning courier delivery, contact the U.S.
Bank at<PHONE_NUMBER>. This telephone number is only for questions about
courier delivery.) Please make sure that the FDA post office box number
(P.O. Box 979107) is written on the check, bank draft, or postal money
order.
    3. For payments made by wire transfer, the invoice number must be
included. Without the invoice number the payment may not be applied.
Regarding reinspection fees, if the payment amount is not applied, the
invoice amount will be referred to collections. The originating
financial institution may charge a wire transfer fee. If the financial
institution charges a wire transfer fee, it is required that the
outsourcing facility add that amount to the payment to ensure that the
invoice is paid in full. Use the following account information when
sending a wire transfer: U.S. Dept of the Treasury, TREAS NYC, 33
Liberty St., New York, NY 10045, Acct. No. 75060099, Routing No.
021030004, SWIFT: FRNYUS33. If needed, FDA's tax identification number
is 53-0196965.

    Dated: July 24, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023-15909 Filed 7-27-23; 8:45 am]
BILLING CODE 4164-01-P


Evaluation of the Common Mechanism of Action of Pyrethroid Pesticides

Charge to the Panel

Pyrethroids are a class of synthetic insecticides which are structurally
based on the pyrethrins, botanical insecticides extracted from
Chrysanthemum cinerariaefolium. Pyrethroid exposure can occur from food,
water, or non-occupational settings. Potential exposure of the general
public to pyrethroid pesticides has increased over the past decade, due
in part to a shift in usage away from the organophosphate and N-methyl
carbamate pesticides.

Pyrethroids are scheduled for re-evaluation under the Office of
Pesticide Program’s registration review program as required under the
Federal Insecticide, Fungicide, Rodenticide Act (FIFRA). Background
information on the program is provided at: http://www.epa.gov/
oppsrrd1/registration review/. The current schedule is available at:
http://www.epa.gov/oppsrrd1/registration_review/schedule.htm. An
explanation of the schedule is at:   HYPERLINK
"http://www.epa.gov/oppsrrd1/registration_review/explanation.htm"
http://www.epa.gov/oppsrrd1/registration_review/explanation.htm .

With the passage of the FQPA (1996), EPA was required to consider
available information concerning the cumulative effects on human health
resulting from aggregate exposure to multiple chemicals that have a
common mechanism of toxicity. At this time, although some uncertainties
still exist, the Office of Pesticide Programs (OPP) believes that there
is sufficient scientific evidence to demonstrate that the pyrethrins and
synthetic pyrethroids share a common mechanism of action. The Agency’s
analysis and preliminary conclusions are provided in the document
titled: “Draft Science Policy Paper: Common Mechanism Grouping for the
Pyrethrins and Synthetic Pyrethroid Pesticides.” This draft issue
paper was developed by the Health Effects Division (HED) of OPP with
support from EPA’s Office of Research and Development (ORD).
Specifically, OPP is proposing that the naturally occurring pyrethrins
and synthetic pyrethroids form a common mechanism grouping based on 1)
shared structural characteristics; and 2) shared ability to interact
with voltage-gated sodium channels (VGSC), resulting in disruption of
membrane excitability in the nervous system, and ultimately
neurotoxicity characterized by two different toxicity syndromes. As
described in more detail below, OPP is further proposing to subgroup the
pyrethroid CMG into two subgroups representing Type I and II pyrethroids
based on differences in structure, sodium channel perturbations, and
neurobehavioral effects.

The Agency is soliciting comments from the Panel on science issues
related to the common toxicity pathway for pyrethroids, remaining
uncertainties, and the proposal to separate the pyrethroids into two
subgroups (Type I and II) 1. Pending the outcome of the June, 2009 peer
review, the pyrethroid pesticides are expected to be subject to
cumulative risk assessment during the forthcoming registration review.

1. Common pathway to neurotoxicity:

a.	OPP is proposing that the naturally occurring and synthetic
pyrethroids share the ability to interact with voltage-gated sodium
channels (VGSC) resulting in disruption of membrane excitability in the
nervous system, and ultimately neurotoxicity. The shared ability
provides the initial and common key event in the pathway to pyrethroid
neurotoxicity and thus provides a basis for forming a common mechanism
group. As described in Section 4.0 of the draft paper, the Agency has
determined that interaction with the VGSC is an initial and common key
event in the pathway to pyrethroid neurotoxicity.

Unlike the cholinesterase inhibiting organophosphorous and N-methyl
carbamate pesticides, pyrethroids lack a readily measurable in vivo
biomarker for the initial key event (i.e., sodium channel interaction).
Despite this, the scientific evidence correlating pyrethroid-induced
changes in VGSC function with neurotoxicity for purposes of forming a
common mechanism grouping is substantial. Given the availability of
extensive studies on the mechanism of toxicity and toxic effects of
pyrethroids, the lack of an in vivo biomarker does not preclude grouping
via a common mechanism.

Please comment on the evidence which does and does not support the
Agency’s proposal that sodium channel interaction provides the initial
and common toxic event in the pathway to neurotoxicity for the synthetic
pyrethroids and pyrethrins. As part of your response, please comment on
the uncertainty associated with lack of a readily measurable in vivo
biomarker for sodium channel interaction.

b. 	The Agency is aware of studies which show that pyrethroids can bind
to other sites such as the calcium, chloride channels and ligand-gated
chloride channels currents. The Agency acknowledges that interaction
between the pyrethroids and these sites may mediate their potency.
However, the data which support interactions with the calcium, chloride,
and ligand-gated chloride channels are not sufficiently robust for
purposes of common mechanism grouping under the FQPA. Therefore, these
pathways do not provide the basis for establishing their binding as a
common key event leading to neurotoxicity. The Agency has concluded that
the evidence on pyrethroid interaction with the calcium and chloride
channels and ligand-gated chloride channels currents is limited and
inconsistent. The Agency has therefore concluded that the evidence does
not support characterizing these interactions as a common key event in
the pathway to neurotoxicity by the pyrethrins and synthetic pyrethroids
(Section 4.2.5). Please comment on the evidence which does and does not
support this determination.

2. Sodium channel structural heterogeneity:

Briefly, mammalian sodium channels are comprised of α and β subunits
that exist in multiple isoforms, giving rise to tissue, regional and
lifestage heterogeneity in sodium channel expression (Goldin 2001;
Plummer and Meisler 1999). Mammalian neurons typically express multiple
isoforms of both α and β subunits, making it difficult to determine
the composition of subunits comprising sodium channel currents in native
neurons. Evaluation of specific alpha- and beta-subunits (either alone
or in combination) may be interesting for purposes of evaluating species
differences, potential population pharmacodynamic variability, and
lifestage differences. With respect to the proposal to form a CMG,
however, incomplete knowledge of the role of the α and β subunits in
pyrethroid toxicity does not discount the role of sodium channel
interaction as a key event in pyrethroid toxicity. As described in
Sections 4.2 and 5.0, the Agency has concluded that although there is
heterogeneity among the subunit combinations, the pathway of toxicity
remains the same---namely that sodium channel interaction as a critical
and initial key event in toxicity of pyrethroids. Please comment on the
scientific support for and against the Agency’s conclusions with
respect to the sodium channel structural heterogeneity information.

3. Sub-grouping the Type I and II pyrethroids:

a.	The Agency has proposed to separate the pyrethrins and synthetic
pyrethroids into Type I and Type II subgroups as discussed in detail in
Section 5.0 of the Draft Science Policy Paper. Briefly, this proposal is
based on the structural difference in Type I and Type II pyrethroids,
i.e, the absence or presence of an α-cyano group, respectively1. This
structural difference is correlated with length of time the sodium
channel is inactivated (-CN=shorter; +CN=longer) which in turn
corresponds with the 2 distinct toxicity syndromes (-CN=T syndrome;
+CN=CS syndrome). This separation is based on a weight of the evidence
evaluation that considered both historical and newer studies from in
vitro (i.e., intact and transected sodium channels and microelectrode
array) and in vivo studies (i.e., motor activity and functional
observational battery).

Please comment on the evidence which does and does not support this
determination.

b.  	With respect to assigning the pyrethroids to sub-groups;

The Agency’s preliminary designation for 11 pyrethroids and pyrethrin
is based on a weight of the evidence assessment utilizing three key
lines of evidence:  presence/absence of the alpha-cyano group, effects
on sodium channel kinetics, and in vivo toxicity syndromes.

Five additional pyrethroids are being characterized in a special FOB
study.  For these five the structure is also known.  Thus for
tetramethrin, cyphenothrin, imiprothrin, phenothrin, and prallethrin,
information from two lines of evidence will be available (structure,
toxicity syndrome) for assigning these.

Tralomethrin is metabolized to deltamethrin in vivo and is also
converted in the environment to deltamethrin.  As such, given the
presence of the alpha-cyano group and its relationship to deltamethrin,
the Agency expects tralomethrin to be assigned a designation of Type II.

Cinerin and jasmolin are naturally occurring pyrethrins and do not have
the alpha-cyano group on their structure.  Thus, the Agency expects
cinerin and jasmolin to be assigned a designation of Type I.

Two other pyrethroids, metofluthrin (non-cyano) and fluvalinate (cyano)
have scant databases.  With respect to their toxicity, the Agency is
unaware of detailed characterization of their profiles which would allow
designation.  Moreover, the Agency is unaware of studies describing
their interactions with sodium channels.   The Agency expects
metofluthrin and fluvalinate to be designated as Type I and Type II
compounds, respectively, based on structure.

Please comment on the Agency’s approach to assigning the pyrethroids
to the Type I and Type II sub-groups.  Please include in your comments
consideration for those without special FOB information and for which
structure will be the major determinant in their designation.

Two pyrethroids, fenpropathrin and esfenvalerate, exhibit
characteristics of Type I and Type II compounds (i.e., “mixed”
Type).  In the anticipated cumulative risk assessment, the Agency must
determine the appropriate approach for these two.  In performing
exposure assessment and ultimately in estimating human risk, several
options have been identified—include fenpropathrin and esfenvalerate
in the Type I sub-group, in the Type II subgroup, or in both subgroups.

Please comment on these possible options and any others identified by
the Panel.

4. Evaluation of Dose-Addition of pyrethroids

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萏Ũ葞Ũ摧絘°ሀ 4.4, there are a limited number of mixture studies
on pyrethroids. Electrophysiological studies have evaluated mixtures of
two pyrethroids but used excessive doses and/or lack robust study
designs and statistical analyses. As such, these studies preclude
thorough evaluation of dose or effect addition. More recent studies
include Wolansky et al (2009) and Shafer et al (in prep) which evaluate
motor activity in vivo and micro electrode arrays, a newer assay for
mammalian neural networks, in vitro. The Wolansky et al (2009) and
Shafer et al (in prep) studies were specifically designed to test dose
additivity but endpoints measured in both studies lack in their ability
to establish dose additivity specifically at the level of the sodium
channel. Please comment on additional research which could be undertaken
to evaluate the assumption of dose-addition as it relates to the
proposed common mechanism pathway.

1The Agency acknowledges that at least two pyrethroids (esfenvalerate
and fenpropathrin) appear to exhibit characteristics of both Type I and
Type II. In the coming months and as the Agency moves into developing
the preliminary cumulative hazard and exposure assessments, the Agency
will make a determination as to how to handle these two pyrethroids in
the actual cumulative risk assessment. The public will have
opportunities to comment on this issue in the future.