[Federal Register Volume 87, Number 207 (Thursday, October 27, 2022)]
[Proposed Rules]
[Pages 65018-65020]
[FR Doc No: 2022-22851]

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DEPARTMENT OF TRANSPORTATION

Federal Aviation Administration

14 CFR Part 39

[Docket No. FAA-2022-1305; Project Identifier AD-2022-00913-T]
RIN 2120-AA64

Airworthiness Directives; Gulfstream Aerospace Corporation
Airplanes

AGENCY: Federal Aviation Administration (FAA), DOT.

ACTION: Notice of proposed rulemaking (NPRM).

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SUMMARY: The FAA proposes to adopt a new airworthiness directive (AD)
for all Gulfstream Aerospace Corporation (Gulfstream) Model GV and GV-
SP airplanes. This proposed AD was prompted by the omission of a life
limit in the airworthiness limitations section (ALS) of the maintenance
manual for a certain main landing gear (MLG) trunnion pin. This AD
requires revising the ALS of the existing instructions for continued
airworthiness (ICA) or inspection program for the airplane to establish
a life limit for the affected MLG trunnion pin. The FAA is proposing
this AD to address the unsafe condition on these products.

DATES: The FAA must receive comments on this proposed AD by December
12, 2022.

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-2022-1305; 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, any comments received, and other
information. The street address for Docket Operations is listed above.

FOR FURTHER INFORMATION CONTACT: Miral Patel, Aerospace Engineer,
Systems and Equipment Section, FAA, Atlanta ACO Branch, 1701 Columbia
Avenue, College Park, GA 30337; phone:<PHONE_NUMBER>; 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-2022-1305; Project Identifier
AD-2022-00913-T'' 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 Miral
Patel, Aerospace Engineer, Systems and Equipment Section, FAA, Atlanta
ACO Branch, 1701 Columbia Avenue, College Park, GA 30337; phone: 404-
474-5590; email: [email protected]. 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 has received a report indicating a life limit for replacing
MLG trunnion pin part number (P/N) 1159SCL566-17 had been omitted from
the ALS of the maintenance manual for Models GV and GV-SP airplanes.
Gulfstream revised the ALS for the applicable airplanes to establish a
life limit of 20,000 flight cycles for the affected MLG trunnion pin. A
trunnion pin remaining in service beyond its life limit could lead to
fracture and failure of the trunnion pin. This condition, if
unaddressed, could result in MLG failure and could lead to a runway
excursion.

FAA's Determination

    The FAA is issuing this NPRM after determining that the unsafe
condition described previously is likely to exist or develop on other
products of the same type design.

Related Service Information

    The FAA reviewed Gulfstream GV Aircraft Maintenance Manual,
Revision 55, dated March 15, 2022; Gulfstream G550 Aircraft Maintenance
Manual, Revision 36, dated March 15, 2022; and Gulfstream G500-5000
Aircraft Maintenance Manual, Revision 36, dated March 15, 2022. The
service information adds a life limit for MLG trunnion pin P/N
1159SCL566-17.

Proposed AD Requirements in This NPRM

    This proposed AD would require revising the ALS of the existing ICA
or inspection program for the airplane to establish a life limit of
20,000 flight cycles for MLG trunnion pin P/N 1159SCL566-17.

Costs of Compliance

    The FAA estimates that this AD, if adopted as proposed, would
affect 582 airplanes of U.S. registry. The FAA estimates the following
costs to comply with this proposed AD:

                                                 Estimated Costs
----------------------------------------------------------------------------------------------------------------
                                                                                Cost on U.S.
                Action                         Labor cost           Parts cost     Cost/airplane     operators
----------------------------------------------------------------------------------------------------------------
Revise ALS............................  1 work-hr. x $85 = $85..             N/A             $85         $49,470
----------------------------------------------------------------------------------------------------------------

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 adding the following new airworthiness
directive:

Gulfstream Aerospace Corporation: Docket No. FAA-2022-1305; Project
Identifier AD-2022-00913-T.

 (a) Comments Due Date

    The FAA must receive comments on this airworthiness directive
(AD) by December 12, 2022.

(b) Affected ADs

    None.

 (c) Applicability

    This AD applies to Gulfstream Aerospace Corporation Model GV and
GV-SP airplanes, all serial numbers, certificated in any category.

    Note 1 to paragraph (c): Model GV-SP airplanes are also referred
to by the marketing designations G500, G550, and G500-5000.

(d) Subject

    Joint Aircraft System Component (JASC) Code 3200, Landing Gear
System.

(e) Unsafe Condition

    This AD was prompted by the omission of a life limit in the
airworthiness limitations section (ALS) for a certain main landing
gear (MLG) trunnion pin. The FAA is issuing this AD to prevent a MLG
trunnion pin from remaining in service beyond its fatigue life. This
unsafe condition, if not addressed, could result in MLG failure and
could lead to a runway excursion.

(f) Compliance

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

(g) Incorporation of ALS Revisions

    Within 12 months after the effective date of this AD, revise the
existing ALS of the instructions for continued airworthiness or
aircraft inspection program for your airplane by establishing a life
limit of 20,000 flight cycles for each MLG trunnion pin part number
(P/N) 1159SCL566-17.

    Note 2 to paragraph (g):  The life limit in paragraph (g) of
this AD is contained in table 5 in Section 05-10-10 of Gulfstream V
Aircraft Maintenance Manual, Revision 55, dated March 15, 2022;
table 4 in Section 05-10-10 of the Gulfstream G500-5000 Aircraft
Maintenance Manual, Revision 36, dated March 15, 2022; and table 4
in Section 05-10-10 of the Gulfstream G550 Aircraft Maintenance
Manual, Revision 36, dated March 15, 2022.

 (h) Alternative Methods of Compliance (AMOCs)

    (1) The Manager, Atlanta ACO 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 (i)(1) of this AD.
    (2) Before using any approved AMOC, notify your appropriate
principal inspector, or lacking a principal inspector, the manager
of the responsible Flight Standards Office.

 (i) Related Information

    (1) For more information about this AD, contact Miral Patel,
Aerospace Engineer, Systems and Equipment Section, FAA, Atlanta ACO
Branch, 1701 Columbia Avenue, College Park, GA 30337; phone: 404-
474-5590; email: [email protected].
    (2) For Gulfstream service information identified in this AD
that is not incorporated by reference, contact Gulfstream Aerospace
Corporation, Technical Publications Dept., P.O. Box 2206, Savannah,
GA 31402-2206; phone:<PHONE_NUMBER>; email: [email protected];
website: gulfstream.com/en/customer-support/. You may view this
service information at the FAA, Airworthiness Products Section,
Operational Safety Branch, 2200 South 216th St., Des Moines, WA. For
information on the availability of this material at the FAA, call
206-231-3195. You may view this service information at the FAA,
Airworthiness Products Section, Operational Safety Branch, 2200
South 216th St., Des Moines, WA. For information on the availability
of this material at the FAA, call<PHONE_NUMBER>.

(j) Material Incorporated by Reference

    None.

    Issued on October 14, 2022.
Gaetano A. Sciortino,
Deputy Director for Strategic Initiatives, Compliance & Airworthiness
Division, Aircraft Certification Service.
[FR Doc. 2022-22851 Filed 10-26-22; 8:45 am]
BILLING CODE 4910-13-P


[Federal Register Volume 87, Number 115 (Wednesday, June 15, 2022)]
[Notices]
[Page 36197]
[FR Doc No: 2022-12838]

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SECURITIES AND EXCHANGE COMMISSION

[Release No. 34-95074; File No. SR-CboeBZX-2022-017]

Self-Regulatory Organizations; Cboe BZX Exchange, Inc.; Notice of
Withdrawal of Proposed Rule Change To Amend BZX Rule 11.17, Clearly
Erroneous Executions

June 9, 2022.
    On March 7, 2022, Cboe BZX Exchange, Inc. (the ``Exchange'') filed
with the Securities and Exchange Commission (``Commission''), pursuant
to Section 19(b)(1) of the Securities Exchange Act of 1934 (``Act'')
\1\ and Rule 19b-4 thereunder,\2\ a proposed rule change to (i) make
the current clearly erroneous execution (``CEE'') pilot program
permanent, and (ii) limit the circumstances where CEE reviews would
continue to be available during Regular Trading Hours. The proposed
rule change was published for comment in the Federal Register on March
11, 2022.\3\ On April 19, 2022, the Commission designated a longer
period for Commission action on the proposed rule change, until June 9,
2022.\4\ The Commission has received no comment letters on the
proposal.
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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. 94374 (March 7,
2022), 87 FR 14062.
    \4\ See Securities Exchange Act Release No. 94744, 87 FR 24351
(April 25, 2022).
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    On June 8, 2022, the Exchange withdrew the proposed rule change
(File No. SR-CboeBZX-2022-017).

    For the Commission, by the Division of Trading and Markets,
pursuant to delegated authority.\5\
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    \5\ 17 CFR 200.30-3(a)(12).
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J. Matthew DeLesDernier,
Assistant Secretary.
[FR Doc. 2022-12838 Filed 6-14-22; 8:45 am]
BILLING CODE 8011-01-P


[Federal Register Volume 83, Number 100 (Wednesday, May 23, 2018)]
[Notices]
[Pages 23956-23959]
[FR Doc No: 2018-10975]

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SECURITIES AND EXCHANGE COMMISSION

[Release No. 34-83274; File No. SR-MRX-2018-15]

Self-Regulatory Organizations; Nasdaq MRX, LLC; Notice of Filing
and Immediate Effectiveness of Proposed Rule Change To Amend
Supplementary Material .03 to Rule 804 To Enhance Anti-Internalization
Functionality

May 17, 2018.
    Pursuant to Section 19(b)(1) of the Securities Exchange Act of 1934
(``Act''),\1\ and Rule 19b-4 thereunder,\2\ notice is hereby given that
on May 2, 2018, Nasdaq MRX, LLC (``MRX'' or ``Exchange'') filed with
the Securities and Exchange Commission (``Commission'') the proposed
rule change as described in Items I, II, and III, below, which Items
have been prepared by the Exchange. The Commission is publishing this
notice to solicit comments on the proposed rule change from interested
persons.
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    \1\ 15 U.S.C. 78s(b)(1).
    \2\ 17 CFR 240.19b-4.
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I. Self-Regulatory Organization's Statement of the Terms of Substance
of the Proposed Rule Change

    The Exchange proposes to amend Supplementary Material .03 to Rule
804 to enhance anti-internalization functionality.
    The text of the proposed rule change is available on the Exchange's
website at http://nasdaqmrx.cchwallstreet.com/, at the principal office
of the Exchange, and at the Commission's Public Reference Room.

II. Self-Regulatory Organization's Statement of the Purpose of, and
Statutory Basis for, the Proposed Rule Change

    In its filing with the Commission, the Exchange included statements
concerning the purpose of and basis for the proposed rule change and
discussed

any comments it received on the proposed rule change. The text of these
statements may be examined at the places specified in Item IV below.
The Exchange has prepared summaries, set forth in sections A, B, and C
below, of the most significant aspects of such statements.

A. Self-Regulatory Organization's Statement of the Purpose of, and
Statutory Basis for, the Proposed Rule Change

1. Purpose
    The purpose of the proposed rule change is to enhance the anti-
internalization (``AIQ'') functionality provided to Market Makers on
the Exchange by giving members the flexibility to choose to have this
protection apply at the market participant identifier level (i.e.,
existing functionality),\3\ at the Exchange account level, or at the
member firm level. The Exchange believes that this enhancement will
provide helpful flexibility for Market Makers that wish to prevent
trading against all quotes and orders entered by their firm, or
Exchange account, instead of just quotes and orders that are entered
under the same market participant identifier. Similar functionality was
also recently introduced on the Exchange's affiliated exchanges, Nasdaq
PHLX LLC (``Phlx'') and NOM.\4\ The Exchange believes that introducing
this functionality now on MRX will ensure that MRX Market Makers on
will benefit from similar flexibility in applying this protection.
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    \3\ Currently, the rule uses the term ``member identifier'' for
this concept. The Exchange proposes to rename ``member identifier''
to ``market participant identifier'' to be consistent with
terminology used on the Nasdaq Options Market (``NOM'') and to avoid
member confusion that could result in using the similar terms
``member identifier'' and ``member firm identifier'' in this rule.
    \4\ See Phlx Rule 1080(p)(2); NOM Chapter VI, Sec. 10. See also
Securities Exchange Act Release Nos. 82012 (November 3, 3017), 82 FR
52082 (November 9, 2017) (SR-Phlx-2017-93); 81171 (July 19, 2017),
82 FR 34557 (July 25, 2017) (SR-Nasdaq-2017-069).
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    Currently, the Exchange provides mandatory AIQ functionality
whereby quotes and orders entered by Market Makers using the same
market participant identifier will not be executed against quotes and
orders entered on the opposite side of the market by the same Market
Maker using the same market participant identifier.\5\ When a quote or
order entered by a Market Maker would trade with other quotes or orders
from the same market participant identifier, the trading system cancels
the resting quote or order back to the entering party prior to
execution.\6\ This functionality shall not apply in any auction or with
respect to complex order transactions. AIQ assists Market Makers in
reducing trading costs from unwanted executions potentially resulting
from the interaction of executable buy and sell trading interest from
the same firm when performing the same market making function.
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    \5\ See Supplementary Material .03 to Rule 804. This
functionality shall not apply in any auction.
    \6\ Id. A quote or order entered by a Market Maker only triggers
AIQ when it would trade with other quotes or orders from the same
Market Maker. Thus, an incoming quote or order entered by a Market
Maker may interact with other interest with priority on the book
prior to triggering AIQ. After AIQ is triggered, the incoming quote
or order may continue to trade with resting interest from other
participants.
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    Today, this protection prevents Market Makers from trading against
their own quotes and orders at the market participant identifier level.
The proposed enhancement to this functionality would allow members to
choose to have this protection applied at the market participant
identifier level as implemented today, at the Exchange account level,
or at the member firm level. If members choose to have this protection
applied at the Exchange account level, AIQ would prohibit quotes and
orders from different market participant identifiers associated with
the same Exchange account from trading against one another. Similarly,
if the members choose to have this protection applied at the member
firm level, AIQ would prohibit quotes and orders from different market
participant identifiers within the member firm from trading against one
another. Members that do not select to have this protection applied at
the Exchange account level or member firm level will have their AIQ
protection defaulted to the market participant identifier level
protection applied today. The Exchange believes that the proposed AIQ
enhancement will provide members with more tailored self-trade
functionality that allows them to manage their trading as appropriate
based on the members' business needs. While the Exchange believes that
some firms will want to restrict AIQ to trading against interest from
the same market participant identifier--i.e., as implemented today--the
Exchange believes that other firms will find it helpful to be able to
configure AIQ to apply at the Exchange account level or at the member
firm level so that they are protected regardless of which market
participant identifier the order or quote originated from. Similar
flexibility is offered on the Exchange's affiliates, Phlx and NOM, and
also on the CBOE BZX Exchange, Inc. (``BZX''), which provides members
the ability to apply Match Trade Prevention (``MTP'') modifiers--i.e.,
BZX's version of self-trade protection--based on market participant,
Exchange Member, trading group, or Exchange Sponsored Participant
identifiers.\7\
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    \7\ See BZX Rule 21.1(g).
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    The examples below illustrate how AIQ would operate based on the
market participant identifier level protection, the Exchange account
level, or for members that choose to apply AIQ at the member firm
level:
Example 1
    1. Member ABC (market participant identifier 123A & 555B) with AIQ
configured at the market participant identifier level.
    2. 123A Quote: $1.00 (5) x $1.10 (20).
    3. 555B Buy Order entered for 10 contracts at $1.10.
    4. 555B Buy Order executes 10 contracts against 123A Quote. 123A
and 555B are not prevented by the system from trading against one
another because Member ABC has configured AIQ to apply at the market
participant identifier level. This is the same as existing
functionality.
Example 2
    1. Member ABC (Account 999 with market participant identifiers 123A
and 555B, and Account 888 with market participant identifier 789A) with
AIQ configured at the Exchange account level.
    2. 123A Quote: $1.00 (5) x $1.10 (20).
    3. 789A Quote: $1.05(10) x $1.10 (20).
    4. 555B Buy Order entered for 30 contracts at $1.10.
    5. 555B Buy Order executes against 789A Quote but 555B Buy Order
does not execute against 123A Quote. AIQ purges the 123A Quote and the
remaining contracts of the 555B Buy Order rests on the book at $1.10.
123A and 555B are not permitted trade against one another because
Member ABC has configured AIQ to apply at the Exchange account level.
This is new functionality as the member has opted to have AIQ operate
at the Exchange account level.
Example 3
    1. Same as Example 2 above but Member ABC has AIQ configured at the
member level.
    2. AIQ purges the 123A Quote and the 789A Quote and the 555B Buy
Order rests on the book at $1.10. This is new functionality as the
member has opted to have AIQ operate at the member level.

Implementation
    The Exchange proposes to launch the AIQ functionality described in
this proposed rule change in either Q2 or Q4 2018. The Exchange will
announce the implementation date of this functionality in an Options
Trader Alert issued to members prior to the launch date.
2. Statutory Basis
    The Exchange believes that the proposed rule change is consistent
with the requirements of the Act and the rules and regulations
thereunder that are applicable to a national securities exchange, and,
in particular, with the requirements of Section 6(b) of the Act.\8\ In
particular, the proposal is consistent with Section 6(b)(5) of the
Act,\9\ because it is designed to promote just and equitable principles
of trade, remove impediments to and perfect the mechanisms of a free
and open market and a national market system and, in general, to
protect investors and the public interest.
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    \8\ 15 U.S.C. 78f(b).
    \9\ 15 U.S.C. 78f(b)(5).
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    The Exchange believes that the proposed rule change is consistent
with the protection of investors and the public interest as it is
designed to provide Market Makers with additional flexibility with
respect to how to implement self-trade protections provided by AIQ.
Currently, all Market Makers are provided functionality that prevents
quotes and orders from one market participant identifier from trading
with quotes and orders from the same market participant identifier.
This allows Market Makers to better manage their order flow and prevent
undesirable executions where the Market Maker, using the same market
participant identifier, would be on both sides of the trade. While this
functionality is helpful to our members, some members would prefer not
to trade with quotes and orders entered by different market participant
identifiers within the same Exchange account or member. Thus, the
Exchange is proposing to provide members with flexibility with respect
to how AIQ is implemented. While members that like the current
functionality can continue to use it, members who would prefer to
prevent self-trades across different market participant identifiers
within the same Exchange account or at the member level will now be
provided with functionality that lets them do this. Similar flexibility
is offered on Phlx and NOM, as well as BZX.\10\ The Exchange believes
that flexibility to apply AIQ at the Exchange account or member firm
level would be useful for the Exchange's members too. The Exchange
believes that the proposed rule change is designed to promote just and
equitable principles of trade and will remove impediments to and
perfect the mechanisms of a free and open market as it will further
enhance self-trade protections provided to Market Makers similar to
those protections provided on other markets. This functionality does
not relieve or otherwise modify the duty of best execution owed to
orders received from public customers.
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    \10\ See supra notes 4 and 7.
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B. Self-Regulatory Organization's Statement on Burden on Competition

    In accordance with Section 6(b)(8) of the Act,\11\ the Exchange
does not believe that the proposed rule change will impose any burden
on intermarket or intramarket competition that is not necessary or
appropriate in furtherance of the purposes of the Act. The proposed
rule change is designed to enhance AIQ functionality provided to
Exchange Market Makers, and will benefit members that wish to protect
their quotes and orders against trading with other quotes and orders
within the same Exchange account or member, rather than the more
limited market participant identifier standard applied today. The new
functionality, which provides similar flexibility to that offered on
Phlx, NOM, and BZX, is also completely voluntary, and members that wish
to use the current functionality can also continue to do so. The
Exchange does not believe that providing more flexibility to members
will have any significant impact on competition. In fact, the Exchange
believes that the proposed rule change is evidence of the competitive
environment in the options industry where exchanges must continually
improve their offerings to maintain competitive standing.
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    \11\ 15 U.S.C. 78f(b)(8).
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C. Self-Regulatory Organization's Statement on Comments on the Proposed
Rule Change Received From Members, Participants, or Others

    No written comments were either solicited or received.

III. Date of Effectiveness of the Proposed Rule Change and Timing for
Commission Action

    Because the foregoing proposed rule change does not: (i)
Significantly affect the protection of investors or the public
interest; (ii) impose any significant burden on competition; and (iii)
become operative for 30 days from the date on which it was filed, or
such shorter time as the Commission may designate, it has become
effective pursuant to Section 19(b)(3)(A)(iii) of the Act \12\ and
subparagraph (f)(6) of Rule 19b-4 thereunder.\13\
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    \12\ 15 U.S.C. 78s(b)(3)(A)(iii).
    \13\ 17 CFR 240.19b-4(f)(6). In addition, Rule 19b-4(f)(6)
requires a self-regulatory organization to give the Commission
written notice of its intent to file the proposed rule change at
least five business days prior to the date of filing of the proposed
rule change, or such shorter time as designated by the Commission.
The Exchange has satisfied this requirement.
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    At any time within 60 days of the filing of the proposed rule
change, the Commission summarily may temporarily suspend such rule
change if it appears to the Commission that such action is: (i)
Necessary or appropriate in the public interest; (ii) for the
protection of investors; or (iii) otherwise in furtherance of the
purposes of the Act. If the Commission takes such action, the
Commission shall institute proceedings to determine whether the
proposed rule should be approved or disapproved.

IV. Solicitation of Comments

    Interested persons are invited to submit written data, views, and
arguments concerning the foregoing, including whether the proposed rule
change is consistent with the Act. 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 protected]. Please include
File Number SR-MRX-2018-15 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-MRX-2018-15. 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 website (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 website 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. Persons submitting comments are cautioned that we do
not redact or edit personal identifying information from comment
submissions. You should submit only information that you wish to make
available publicly. All submissions should refer to File Number SR-MRX-
2018-15 and should be submitted on or before June 13, 2018.

    For the Commission, by the Division of Trading and Markets,
pursuant to delegated authority.\14\
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    \14\ 17 CFR 200.30-3(a)(12).
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Eduardo A. Aleman,
Assistant Secretary.
[FR Doc. 2018-10975 Filed 5-22-18; 8:45 am]
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[Federal Register: August 7, 2009 (Volume 74, Number 151)]
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DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

Combined Notice of Filings No. 1

July 31, 2009.
    Take notice that the Commission has received the following Natural
Gas Pipeline Rate and Refund Report filings:

    Docket Numbers: RP09-845-000.
    Applicants: TransColorado Gas Transmission Company LLC.

    Description: TransColorado Gas Transmission Company LLC submits
Second Revised Sheet No 1 et al. FERC Gas Tariff, Second Revised Volume
No 1.
    Filed Date: 07/29/2009.
    Accession Number: 20090730-0136.
    Comment Date: 5 p.m. Eastern Time on Monday, August 10, 2009.

    Docket Numbers: RP09-846-000.
    Applicants: Northwest Pipeline GP.
    Description: Northwest Pipeline GP submits Third Revised Sheet No 5
et al. to its FERC Gas Tariff, Fourth Revised Volume No 1.
    Filed Date: 07/29/2009.
    Accession Number: 20090730-0135.
    Comment Date: 5 p.m. Eastern Time on Monday, August 10, 2009.

    Docket Numbers: RP09-847-000.
    Applicants: Kern River Gas Transmission Company.
    Description: Kern River Gas Transmission Co submits Second Revised
Sheet No. 492 to FERC Gas Tariff, Second Revised Volume No. 1.
    Filed Date: 07/29/2009.
    Accession Number: 20090730-0133.
    Comment Date: 5 p.m. Eastern Time on Monday, August 10, 2009.

    Docket Numbers: RP09-848-000.
    Applicants: Kern River Gas Transmission Company.
    Description: Kern River Gas Transmission Company submits Seventh
Revised Sheet 490 et al. of its FERC Gas Tariff. Second Revised Volume
1, to be effective 9/2/09.
    Filed Date: 07/30/2009.
    Accession Number: 20090730-0242.
    Comment Date: 5 p.m. Eastern Time on Tuesday, August 11, 2009.

    Docket Numbers: RP09-849-000.
    Applicants: Ozark Gas Transmission, LLC.
    Description: Ozark Gas Transmission, LLC submits First Revised
Sheet No 178 to its FERC Gas Tariff, First Revised Volume No 1.
    Filed Date: 07/30/2009.
    Accession Number: 20090730-0245.
    Comment Date: 5 p.m. Eastern Time on Tuesday, August 11, 2009.

    Docket Numbers: RP09-850-000.
    Applicants: Mojave Pipeline Company.
    Description: Mojave Pipeline Company submits Twenty Sixth Revised
Sheet 11 to its FERC Gas Tariff, Second Revised Volume 1, to be
effective 9/1/09.
    Filed Date: 07/30/2009.
    Accession Number: 20090730-0147.
    Comment Date: 5 p.m. Eastern Time on Tuesday, August 11, 2009.

    Docket Numbers: RP09-851-000.
    Applicants: Transcontinental Gas Pipe Line Company.
    Description: Transcontinental Gas Pipe Line Company submits First
Revised Sheet 171 et al. to FERC Gas Tariff, Fourth Revised Volume 1,
to be effective 8/30/09.
    Filed Date: 07/30/2009.
    Accession Number: 20090731-0086.
    Comment Date: 5 p.m. Eastern Time on Tuesday, August 11, 2009.

    Any person desiring to intervene or to protest in any of the above
proceedings must file in accordance with Rules 211 and 214 of the
Commission's Rules of Practice and Procedure (18 CFR 385.211 and
385.214) on or before 5 p.m. Eastern time on the specified comment
date. It is not necessary to separately intervene again in a subdocket
related to a compliance filing if you have previously intervened in the
same docket. Protests will be considered by the Commission in
determining the appropriate action to be taken, but will not serve to
make protestants parties to the proceeding. Anyone filing a motion to
intervene or protest must serve a copy of that document on the
Applicant. In reference to filings initiating a new proceeding,
interventions or protests submitted on or before the comment deadline
need not be served on persons other than the Applicant.
    The Commission encourages electronic submission of protests and
interventions in lieu of paper, using the FERC Online links at http://
www.ferc.gov. To facilitate electronic service, persons with Internet
access who will eFile a document and/or be listed as a contact for an
intervenor must create and validate an eRegistration account using the
eRegistration link. Select the eFiling link to log on and submit the
intervention or protests.
    Persons unable to file electronically should submit an original and
14 copies of the intervention or protest to the Federal Energy
Regulatory Commission, 888 First St., NE., Washington, DC 20426.
    The filings in the above proceedings are accessible in the
Commission's eLibrary system by clicking on the appropriate link in the
above list. They are also available for review in the Commission's
Public Reference Room in Washington, DC. There is an eSubscription link
on the Web site that enables subscribers to receive e-mail notification
when a document is added to a subscribed docket(s). For assistance with
any FERC Online service, please e-mail<EMAIL_ADDRESS>or
call<PHONE_NUMBER> (toll free). For TTY, call<PHONE_NUMBER>.

Nathaniel J. Davis, Sr.,
Deputy Secretary.
[FR Doc. E9-18922 Filed 8-6-09; 8:45 am]

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[Federal Register: January 16, 2007 (Volume 72, Number 9)]
[
Notices]
[Page 1712]
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DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Docket No. PR06-19-002]

Cypress Gas Pipeline, LLC; Notice of Compliance Filing

January 8, 2007.
    Take notice that on December 20, 2006, Cypress Gas Pipeline, LLC
filed a revised Statement of Operating Conditions in compliance with
the Commission's letter order issued on December 6, 2006, in Docket
Nos. PR06-19-000 and PR06-19-001.
    Any person desiring to protest this filing must file in accordance
with Rule 211 of the Commission's Rules of Practice and Procedure (18
CFR 385.211). Protests to this filing will be considered by the
Commission in determining the appropriate action to be taken, but will
not serve to make protestants parties to the proceeding. Such protests
must be filed on or before the date as indicated below. Anyone filing a
protest must serve a copy of that document on all the parties to the
proceeding.
    The Commission encourages electronic submission of protests in lieu
of paper using the ``eFiling'' link at http://www.ferc.gov. Persons

unable to file electronically should submit an original and 14 copies
of the protest to the Federal Energy Regulatory Commission, 888 First
Street, NE., Washington, DC 20426.
    This filing is accessible on-line at http://www.ferc.gov, using the

``eLibrary'' link and is available for review in the Commission's
Public Reference Room in Washington, DC. There is an ``eSubscription''
link on the Web site that enables subscribers to receive email
notification when a document is added to a subscribed docket(s). For
assistance with any FERC Online service, please email

<EMAIL_ADDRESS>or call<PHONE_NUMBER> (toll free). For

TTY, call<PHONE_NUMBER>.
    Protest Date: 5 p.m. Eastern Time on January 23, 2007.

Magalie R. Salas,
Secretary.
 [FR Doc. E7-439 Filed 1-12-07; 8:45 am]

BILLING CODE 6717-01-P


SAP Minutes No. 2003 03 October 28 and 29, 2003 FIFRA Scientific Advisory Panel Meeting, Held at the Holiday Inn Hotel, Arlington, Virginia A Set of Scientific Issues Being Considered by the Environmental Protection Agency Regarding:

Ensuring Data Quality for In Vitro Tests Used as Alternatives to Animal Studies for Regulatory Purposes: A Consultation Myrta R. Christian, M. S. Steven G. Heeringa, Ph. D. Designated Federal Official FIFRA SAP, Session Chair FIFRA Scientific Advisory Panel FIFRA Scientific Advisory Panel Date: December 22, 2003 Date: December 22, 2003 2 of 22 NOTICE These meeting minutes have been written as part of the activities of the Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA), Scientific Advisory Panel ( SAP). These meeting minutes represent the views and recommendations of the FIFRA SAP, not the United States Environmental Protection Agency ( Agency). The content of these meeting minutes do not represent information approved or disseminated by the Agency. These meeting minutes have not been reviewed for approval by the Agency and, hence, the contents of this report do not necessarily represent the views and policies of the Agency, nor of other agencies in the Executive Branch of the Federal government, nor does mention of trade names or commercial products constitute a recommendation for use.

The FIFRA SAP is a Federal advisory committee operating in accordance with the Federal Advisory Committee Act and was established under the provisions of FIFRA, as amended by the Food Quality Protection Act FQPA of 1996. The FIFRA SAP provides advice, information, and recommendations to the Agency Administrator on pesticides and pesticide related issues regarding the impact of regulatory actions on health and the environment. The Panel serves as the primary scientific peer review mechanism of the EPA, Office of Pesticide Programs ( OPP) and is structured to provide balanced expert assessment of pesticide and pesticide related matters facing the Agency. Food Quality Protection Act Science Review Board members serve the FIFRA SAP on an ad hoc basis to assist in reviews conducted by the FIFRA SAP. Further information about FIFRA SAP reports and activities can be obtained from its website at http:// www. epa. gov/ scipoly/ sap/ or the OPP Docket at ( 703) 305 5805. Interested persons are invited to contact Larry Dorsey, SAP Executive Secretary, via e mail at dorsey. <EMAIL_ADDRESS>epa. gov.

In preparing these meeting minutes, the Panel carefully considered all information provided and presented by the Agency presenters. This document addresses the information provided and presented within the structure of the charge by the Agency. 3 of 22 CONTENTS PARTICIPANTS........................................................................................................... 4 INTRODUCTION......................................................................................................... 6 CHARGE ...................................................................................................................... 7 PANEL DELIBERATIONS AND RESPONSE TO CHARGE .................................. 9 REFERENCES............................................................................................................ 20 4 of 22 Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel Meeting October 28 and 29, 2003 Ensuring Data Quality for In Vitro Tests Used as Alternatives to Animal Studies for Regulatory Purposes: A Consultation PARTICIPANTS FIFRA SAP, Session Chair Steven G. Heeringa, Ph. D., Research Scientist & Director for Statistical Design, University of Michigan, Institute for Social Research, Ann Arbor, MI Designated Federal Official Mrs. Myrta R. Christian, FIFRA Scientific Advisory Panel Staff, Office of Science Coordination and Policy, EPA FIFRA Scientific Advisory Panel Members Stephen M. Roberts, Ph. D. ( FIFRA SAP Chair), Professor & Program Director, University of Florida, Center for Environmental & Human Toxicology, Gainesville, FL Stuart Handwerger, M. D., Director, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH Gary E. Isom, Ph. D., Professor of Toxicology, School of Pharmacy and Pharmacological Sciences, Purdue University, West Lafayette, IN Mary Anna Thrall, D. V. M., Professor, Department of Pathology, College of Veterinary & Biomedical Sciences, Colorado State University, Fort Collins, CO FQPA Science Review Board Members Joseph P. Bressler, Ph. D., Department of Neurobiology, The Kennedy Krieger Research Institute, Baltimore, MD George L. DeGeorge, Ph. D., Chief Scientific Officer, MB Research Laboratories, Spinnerstown, PA James Freeman, Ph. D., ExxonMobil Biomedical Sciences, Inc., Annandale, New Jersey Michael Luster, Ph. D., Chief, Toxicology and Molecular Biology Branch, National Institute for Occupational Safety and Health, Morgantown, WV 5 of 22 James F. McCormack, Ph. D., Director of Nonclinical Laboratory Compliance, Food & Drug Administration, Rockville, MD Kenneth Portier, Ph. D., Associate Professor of Statistics, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, FL Gregory A. Reed, Ph. D., Associate Professor, Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS 6 of 22 INTRODUCTION The Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA), Scientific Advisory Panel ( SAP) has completed its review of the set of scientific issues being considered by the Agency pertaining to the processes for regulatory acceptance of and ensuring the quality of data from in vitro tests used as alternatives to animal studies for regulatory purposes. Advance notice of the meeting was published in the Federal Register on September 22, 2003. The review was conducted in an open Panel meeting held in Arlington, Virginia, on October 28 and 29, 2003. Dr. Steven G. Heeringa chaired the meeting. Mrs. Myrta R. Christian served as the Designated Federal Official.

The FIFRA SAP was asked to review issues concerned with processes for regulatory acceptance of and ensuring the quality of data from in vitro tests used as alternatives to animal studies for regulatory purposes, including performance standards, essential test method components, and quality control of test methods, in the context of three new in vitro assays for dermal corrosivity which will be incorporated into its OPTS 870.2500 test guideline for Acute Dermal Irritation.

In preparing these meeting minutes, the Panel carefully considered all information provided and presented by the Agency presenters, as well as information presented by public commenters. These meeting minutes address the information provided and presented at the meeting, especially the response to the charge by the Agency. 7 of 22 CHARGE Performance Standards The Agency plans to adopt the Performance Standards developed by the Interagency Coordinating Committee on the Validation of Alternative Methods ( ICCVAM) as a means of communicating the basis by which each of three validated in vitro test methods, Corrositex ® , EPISKIN   / EpiDerm   , and Transcutaneous Electrical Resistance ( TER), are deemed acceptable for providing dermal corrosivity data. Performance Standards consist of descriptions of ( 1) essential test method components, which are the essential structural, functional, and procedural elements of a validated test method that should be included in the protocol of a proposed mechanistically and functionally similar test method; ( 2) a minimum list of Reference Chemicals, which is used to assess the accuracy and reliability of the similar test method; and ( 3) comparable accuracy and reliability values that should be achieved by the proposed test method when evaluated using the minimum set of Reference Chemicals.

Question 1 Please comment on the provisions in the Performance Standards for each of the three methods to demonstrate mechanistic similarity of " me too" methods. Do the essential test method components for each method adequately describe the unique characteristics of the method necessary to determine whether a test is mechanistically and functionally similar?

Question 2 In its evaluation of any mechanistically similar test system, the Agency plans to use the generic criteria used by ICCVAM for selecting subsets of the Reference Chemicals for all three ICCVAM Performance Standards documents. The criteria specify that chemicals should be selected in such a way that the subset: includes representatives of applicable chemical classes, measures a range of corrosive strengths, includes well defined chemicals that are currently available commercially, and has unequivocal animal or other in vivo evidence. Please comment on the strengths or weaknesses of this approach and identify and discuss any modifications to the criteria that should be considered.

Question 3 The ICCVAM approach for demonstrating functional similarity of " me too" test methods to validated methods includes the use of well characterized Reference Chemicals and specifies the accuracy and reliability that should be achieved by " me too" test systems when tested in intra and inter laboratory studies. Please comment on whether " me too" test systems should be demonstrated to be effective for evaluating the testing endpoint for all of the chemicals in the Performance Standard. Please comment on the value of including chemicals with range of potencies in the Performance Standard. Under what circumstances might testing of " me too" systems within one laboratory ever be sufficient to demonstrate functional equivalence? 8 of 22 Quality Control The Agency is proposing quality control measures that should be considered when evaluating the reliability of test kits for regulatory purposes. Please address the following specific issues.

Question 4 Subsets of the Reference Chemicals used in test method validation may be used as training or calibration sets by testing laboratories using in vitro systems. Please discuss the utility of and necessity for training or calibration sets in assuring data quality. Please comment on the chemicals selected by ICCVAM for use as a calibration set for TER for this purpose. Please comment on the ranges of chemical classes and potencies of these chemicals. How might other chemicals be selected for possible use in the calibration sets? Please comment on the value of identifying chemicals that might be used by laboratories as training sets to demonstrate proficiency in performing the test.

Question 5 Anticipating the use of systems using tissue constructs, ex vivo systems, microarrays or genetically modified cells, please discuss aspects of the quality control criteria that are necessary for assuring the integrity of such systems over time and from lot to lot. Please comment on whether and how the type of system  tissue constructs, ex vivo systems, or genetically modified cells or animals  should affect the criteria for quality control for assuring the integrity of such systems, both over time and from lot to lot.

Question 6 Please comment on the advantages and disadvantages of including concurrent positive and negative controls with in vitro assays when used as alternatives to animal testing. What are the important characteristics of positive and negative controls for in vitro studies? What aspects of positive control characteristics allow them to be used as part of the quality control process? When might confirmation that positive controls are performing within expected or historical limits be sufficient to demonstrate that the Proprietary Test Method or non proprietary assay system is functioning properly? When might additional quality control measures be needed?

Question 7 Does the Panel agree that the benchmark controls serve a useful purpose to demonstrate the level of response that can be expected for each chemical class for each lot of Proprietary Test Method assays? Can the Panel suggest criteria for choice of appropriate benchmark controls? 9 of 22 PANEL DELIBERATIONS AND RESPONSE TO CHARGE The specific issues addressed by the Panel are keyed to the Agency's background documents, and the Agency's charge questions.

Response to Charge I. Performance Standards The Agency plans to adopt the Performance Standards developed by the Interagency Coordinating Committee on the Validation of Alternative Methods ( ICCVAM) as a means of communicating the basis by which each of three validated in vitro test methods, Corrositex ® , EPISKIN   / EpiDerm   , and Transcutaneous Electrical Resistance ( TER), are deemed acceptable for providing dermal corrosivity data. Performance Standards consist of descriptions of ( 1) essential test method components, which are the essential structural, functional, and procedural elements of a validated test method that should be included in the protocol of a proposed mechanistically and functionally similar test method; ( 2) a minimum list of Reference Chemicals, which is used to assess the accuracy and reliability of the similar test method; and ( 3) comparable accuracy and reliability values that should be achieved by the proposed test method when evaluated using the minimum set of Reference Chemicals.

Question 1   Please comment on the provisions in the Performance Standards for each of the three methods to demonstrate mechanistic similarity of " me too" methods. Do the essential test method components for each method adequately describe the unique characteristics of the method necessary to determine whether a test is mechanistically and functionally similar?

Panel's comments:

The Panel endorsed the Performance Standards ( PS) approach to identify and validate " metoo and " unique" in vitro assays. The following paragraphs summarize the Panel's response for each of the three major components of the ICCVAM performance standards for in vitro tests.

Structural/ functional components:

The Panel concurred that the PS prepared by ICCVAM are very well described for each of the three tests, and the information should provide a basis to determine whether a test is mechanistically and functionally similar to a validated in vitro test method. The Panel stated that it would be helpful for the submitting laboratories if the Agency provided examples of what they would consider as a " me too" assay or a new assay, based upon the essential structural and functional elements ( e. g., human skin TER vs. rat skin TER). There was some concern among the Panel members that identification of a " me too" 10 of 22 assay could be a somewhat subjective process rather than one based entirely on objective criteria. However, with the limited tests that have been evaluated to date ( one " me too" and three unique), there was consensus that this approach of using structural and functional equivalence to determine a " me too" test is conceptually feasible.

Reference Chemicals:

The Panel recommended that NIEHS/ EPA ( thru ICCVAM) develop a standard list of reference chemicals for validating in vitro tests and establish a chemical repository for reference samples/ positive controls available to laboratories for developing/ conducting in vitro skin studies. The reference panel should contain sufficient numbers of different chemical classes ( with a range of potency, solubility, etc.) to establish reasonable performance of that specific test for those particular classes of chemicals.

For the three validated test methods, members of the Panel recommended that the laboratories be allowed to determine their own positive control( s) and suggested that the PS not suggest specific examples such as NaOH pellets and 10 N HCl. The Panel felt that these particular examples may be too corrosive, and if suggested by the Agency as a positive control, could become the " gold standard." In lieu of citing specific examples for positive controls, the Panel suggested that the Agency PS provide general requirements ( e. g., well characterized, results in a low to intermediate response, etc.) wanted in a positive control for a validated test.

For all three validated tests, the Agency PS would benefit from a more thorough discussion of appropriate benchmark controls ( range of severity, classes of chemicals) and also how benchmark controls would be considered in the validation studies of the assay. The Panel also recommends that minimum replicate requirements be specified for positive, negative and benchmark controls, and that the PS be unambiguously stated.

Concordance and reliability values:

The Panel suggested that the Agency provide clear guidance on requirements necessary to establish test reliability for the PS for each validated in vitro test ( how many labs for the interlaboratory reliability and how many intra laboratory replications?). The Panel also recommended that the Agency better define what is meant by comparable concordance for test accuracy   will this be statistically based? The Panel expressed the view that the PS should include specific guidelines for minimum achieved sensitivity and specificity of the test when applied to the reference chemical set.

One Panel member expressed the view that if there is no appreciable difference in performance, an in vitro assay should be recommended as the preferred alternative testing method for use over an ex vivo assay ( e. g., rat skin TER) as the former more directly addresses the goal of animal replacement.

Question 2 11 of 22   In its evaluation of any mechanistically similar test system, the Agency plans to use the generic criteria used by ICCVAM for selecting subsets of the Reference Chemicals for all three ICCVAM Performance Standards documents. The criteria specify that chemicals should be selected in such a way that the subset includes representatives of applicable chemical classes, measures a range of corrosive strengths, includes well defined chemicals that are currently available commercially, and has unequivocal animal or other in vivo evidence. Please comment on the strengths or weaknesses of this approach and identify and discuss any modifications to the criteria that should be considered.

Panel's comments:

The Panel expressed the view that the strength of the PS approach to validating a new or " me too" in vitro test derives from the stated selection criteria for the Reference Chemical set. By including a range of chemical classes in the Reference Chemical set the general applicability of the test is supported. Choosing Reference Chemicals exhibiting a broad range of corrosive strengths provides insight into the quantitative value of the test. This could be important for assignment of corrosive agents to packing groups. In addition, the inclusion of mildly corrosive agents supports estimation of the sensitivity of the test. The use of well defined agents with unequivocal animal or other in vivo evidence in regard to skin corrosivity anchors the Reference Chemicals as valid " real world" representatives and allows for validated comparisons between the in vitro findings and the potential effects of actual environmental or occupational exposures. Limiting the Reference Chemical set to commercially available chemicals allows for the widespread use of this testing regimen.

The Panel identified a weakness of the approach in that it may be difficult to include a sufficient number of Reference Chemicals in each class, both corrosive and non corrosive, which meet all of these criteria. The Episkin/ Epiderm Reference Chemical set comes closest, with 6 of 8 classes containing both corrosive and non corrosive agents. Although numerous classes of potentially corrosive chemicals are included in the various Reference Chemical sets, some classes are missing. This includes inorganic salts, such as FeCl3, which was reported by ECVAM to be corrosive. Also the Panel noted that hydrocarbons and halogenated hydrocarbons are common solvents and diluents for pesticides, and that these chemicals might be included for study either as individual agents or in combination with other chemicals. The question of how many " classes" the test methods ( or " me too" tests) are validated with, versus the number of classes which the test may be approved for, remains unanswered.

The Panel pointed out that a second weakness of the PS Reference Chemical descriptions for the validated in vitro tests is the lack of standardization of the list. Different groups of specific chemical agents are employed ( or recommended) for the different in vitro tests. While this may not affect the validation of individual test systems, it does impact on comparisons between the available and proposed test systems.

Question 3 12 of 22   The ICCVAM approach for demonstrating functional similarity of " me too" test methods to validated methods includes the use of well characterized Reference Chemicals and specifies the accuracy and reliability that should be achieved by " me too" test systems when tested in intra and inter laboratory studies. Please comment on whether " me too" test systems should be demonstrated to be effective for evaluating the testing endpoint for all of the chemicals in the Performance Standard. Please comment on the value of including chemicals with range of potencies in the Performance Standard. Under what circumstances might testing of " me too" systems within one laboratory ever be sufficient to demonstrate functional equivalence?

Panel's comments:

The Panel agreed that a minimum number of Reference Chemicals ( subset of the entire list) should be specified in the PS, to be used for validation procedures of existing alternative test methods, as well as " me too" tests. It was noted, for example, that there was a large range in the number of Reference Chemicals used among the three test systems presented, with a low of 12 to a high of 122, depending upon the test method under consideration. Although the use of the entire original Reference Chemical set for a validated test method for validation of a " me too" test might be considered excessive, it is nonetheless important to carry out a sufficiently broad characterization of a new test to validate its performance.

The approach of specifying a known level of accuracy and reliability for a " me too" test to be considered equivalent to the validated test system was accepted by the Panel. Panel members suggested that Reference Chemicals be limited to those that have been tested with sufficient replication, such that the reliability and accuracy estimates themselves are considered sufficiently precise. The Panel recommended that the concordance of results from " me too" tests be established by comparison to the unequivocal properties of the test chemicals in human or animal tests, rather than by comparison to an alternative test method. It was recognized that other alternative tests may have less than 100% accuracy ( sensitivity and specificity) that would cloud the meaning of " me too" test " accuracy" or concordance.

One Panel member considered it essential that if as few as 12 chemicals ( or in any case less than 20) are specified in the PS ( as was the EC's specification in the case of Corrositex ® ) then 100% concordance with in vivo test results should be required to demonstrate test equivalence and assure the public safety. Lower percentage concordance would be acceptable if a large enough subset of the Reference Chemicals were tested so as to include more than one chemical from all classes originally validated, with a range of potencies or responses for each class.

While recognizing that the validated test provides the history ( that is, the empirical criteria for acceptable sensitivity, selectivity, etc.), it remains questionable whether this is an appropriate " bright line." There may be important statistical or practical considerations to the choice of the subset of Reference Chemicals to be included in the PS. One Panel member queried 13 of 22 whether the decision point for qualitative judgment of corrosive agents is sensitive enough to detect even weakly corrosive agents, stating that the judgment of sensitivity cannot be made without validation using known weakly corrosive agents. Thus, the " Performance Standard" should include: 1) a stated minimum number of diverse test chemicals, from all relevant chemical classes; ( 2) a requirement for Reference Chemicals with varying potencies, efficacies, or range of response, ideally within each chemical class; and 3) minimum standards for reliability and accuracy/ concordance in the " me too" test system results when compared to the known properties of the test chemicals for in vivo tests.

A majority of the Panel agreed that validation of a " me too" test in a single laboratory should be acceptable, if that single laboratory is the only practitioner of the method. The criteria for acceptance should be as rigid as that for a multi laboratory validation. This would involve at least a sufficient number of independent, repeated tests using the Reference Chemicals to establish the concordance of the " me too" test with a validated test, and to determine the intra laboratory test reliability of the " me too" test.

The Panel noted the importance of using good experimental design in intra and interlaboratory studies, being concerned that there was little discussion of batch to batch ( or peltto pelt in the case of TER) variability in any of the test method protocols, data, or results. The implication is that this is a very small source of variability for these test systems, which may not be the case in future systems. The general procedures for evaluating " me too" systems should take this into account.

II. Quality Control The Agency is proposing quality control measures that should be considered when evaluating the reliability of test kits for regulatory purposes. Please address the following specific issues.

Question 4   Subsets of the Reference Chemicals used in test method validation may be used as training or calibration sets by testing laboratories using in vitro systems. Please discuss the utility of and necessity for training or calibration sets in assuring data quality. Please comment on the chemicals selected by ICCVAM for use as a calibration set for TER for this purpose. Please comment on the ranges of chemical classes and potencies of these chemicals. How might other chemicals be selected for possible use in the calibration sets? Please comment on the value of identifying chemicals that might be used by laboratories as training sets to demonstrate proficiency in performing the test.

Panel's comments: 14 of 22 Given the nature of these in vitro systems, particularly in regard to lot to lot and day to day variability, the Panel felt it essential that test system performance be established and understood. A simple positive and negative control may not be sufficient to represent the range of responses and the sensitivity required for detection of weakly corrosive agents. In the case of the Corrositex ® test the twelve Reference Chemicals suggested by ICCVAM meet the criterion of including strongly and weakly corrosive and non corrosive agents. However, 12 chemicals constitute a limited test set. It also is incomplete; missing are potentially corrosive inorganic salts like Fe( Cl) 3, which is noted in the 60 chemical ECVAM list. Further, the ECVAM " 60" list does not completely reflect the classes of chemicals that are important with regard to pesticide registration. Hydrocarbon solvents, for example, find use as diluents but are not included in the list. While most of these solvents are complex mixtures, toxicity profiles can be established both for the mixture and for suitable single chemical surrogates ( e. g., toluene, decane, etc). Clearly a balance must be struck between maintaining a manageable number of Reference Chemicals and assuring that all relevant mechanistic and chemical classes are included.

While the background documents discuss the need for a range of potencies for chemicals, it is important that Reference Chemicals that represent a range of implementation difficulties be included as well. Part of the calibration process for testing laboratories is that the technicians learn to be consistent in application so that reproducible results will be obtained for the Reference Chemicals over time. The potency of a chemical may not be the best measure of how difficult it is for a technician to get consistent results with that chemical. The Reference Chemical set should include some chemicals that are difficult to work with, thereby challenging the technical skill of the staff and forcing them to " stay skilled." Further, some chemicals ( e. g., solvents) may destroy the test system; knowledge of this is important if such a chemical is tested in a formulated product.

The Panel noted that training in the use of the validated test is required to be documented under GLPs, presumably with Reference Chemicals. One panel member expressed caution regarding the use of the terms proficiency and calibration set. Proficiency implies a precision and accuracy as may be required by independent accreditation. The training to meet this objective is a laboratory management function. The term, " calibration set" implies traceability to some standard, e. g., a national standard. In the context of the Panel's discussion, Reference Chemicals are identified that can be used as control or benchmark chemicals to help standardize or validate a method in a laboratory and monitor its performance but may not, in the strictest sense, be a true calibration of the test results.

For a training set of chemicals to be used either initially or at some set intervals for the validation of an assay and its performance in a given laboratory, this balance between number of chemicals and inclusivity shifts to a higher number of individual chemicals. Whereas twelve might be an appropriate number for regular " calibration" a training and validation set could easily be 2 3 times this number. This would ensure coverage of relevant classes and potencies for corrosive agents and better test the abilities of a given laboratory to perform the assay accurately. 15 of 22 The Panel expressed the view that Reference Chemical testing:

  Provides relevant training and documentation of training as required by GLPs;   Provides a means to evaluate technician competency for the test method;   Permits comparison to a validation database and assessment of variability among labs;   Identifies relative strengths/ weaknesses of the lab and whether additional training is needed.

Question 5   Anticipating the use of systems using tissue constructs, ex vivo systems, microarrays or genetically modified cells, please discuss aspects of the quality control criteria that are necessary for assuring the integrity of such systems over time and from lot to lot. Please comment on whether and how the type of system  tissue constructs, ex vivo systems, or genetically modified cells or animals  should affect the criteria for quality control for assuring the integrity of such systems, both over time and from lot to lot.

Panel's comments:

The use of PS, positive controls, negative controls and benchmark controls will provide the opportunity to achieve a degree of control over the quality of Proprietary Test Methods ( PTMs). Two issues that have not been addressed in the PS are how drift in the PTMs will be monitored and how information about problems that arise from the use of these controls will be assimilated and evaluated by the vendor. Individual test facilities may detect failures or out of specification performance of the PTM and proceed according to their operating procedures, but the lack of GMP like regulatory authority does not require these failures to be reported to and addressed by the vendor.

Other facilities may then use an inadequate/ under performing PTM or lot of PTM without benefit of the experiences of the first facility. There should be some consideration that PTM performance reports be compiled by the vendor and reported to purchasers of the PTM. Similar mechanisms are used by computer software vendors to alert purchasers of their products of problems or issues with their products.

The answer to the second part of this question goes beyond the immediate concerns of the Panel, which were in vitro tests for corrosive chemicals. Rather, the answer discusses general considerations for future in vitro tests that will incorporate the newest advances that are being made in molecular biology. All testing systems require quality control for assuring reproducibility, sensitivity, and specificity. Otherwise, results from the same test repeated in the same laboratory, or in different laboratories, could not be compared. Incorporating positive and negative controls, as well as benchmark samples, monitors quality control. The specific types of controls, the number of controls, the frequency of inserting these controls 16 of 22 and the benchmark samples, however, will likely be different for different types of assays. The number of controls would be expected to increase in highly variable systems ( e. g. those that require animals) but must be limited because of cost considerations. Hence, the development of newer testing systems that limit variability would have substantial benefit.

An example of the concern for variability is an ex vivo system, in which tissue is excised from a donor and cultured as either organ culture, explants, or dissociated cells. There will be variability in each type of culture because of variability in the donor animals. In primary cultures, however, the variability can be greatly limited if large batches of cells are prepared from several animals and frozen. New testing systems for screening different types of toxic chemicals will likely be developed using genetically modified cell lines. The Ames assay is one example of an already established test that uses genetically modified bacteria to screen for mutagens, which are possible carcinogens. A more complex test system could be developed to establish tissue constructs. For example, a testing system might be developed that uses genetically modified skin stem cell lines that differentiate into skin. The currently available tissue construct uses skin epithelial cells from donors. The advantage of the stem cell line is that the lot to lot variability would be reduced because the source of variability, donor tissue, would be reduced.

Microarrays ( gene arrays) are powerful endpoint assays that measure changes in the expression of hundreds or thousands of genes and will likely be used in different types of testing systems. One such use would be in classifying xenobiotics according to the patterns of genes that they induce. The pattern of gene expression has been termed a gene fingerprint, and testing systems might be developed for screening xenobiotics by measuring gene fingerprints. In measuring gene fingerprints, rather than one or two specific genes, the testing system has more power for statistical analysis and will likely produce more consistent data. Gene arrays also have the potential of reducing the number of required controls. For example, testing systems for determining gene fingerprints for xenobiotics must use cell lines that express enzymes that metabolize xenobiotics. Positive controls should be incorporated in the testing systems for screening xenobiotics to validate the presence of these enzymes. In using gene arrays, the positive controls might not be necessary because the expression of the activating enzymes, as well as the gene fingerprints, would be determined in the same gene array.

The Panel noted that microarrays and other related systems seem to have a long way to go toward producing reproducible responses among true replicates. In fact, very little true replication is being done, primarily due to the expense of each replicate. As the state of the art in microarray use becomes mature, true replication with demonstrated repeatability may become the standard. When that is truly the case, test systems based on this technology should provide useful tools for risk evaluations. As these new tests are put into practice, more attention must be focused on how drift in performance test standards will be monitored and how information about these problems will be assimilated and evaluated by the vendor.

Question 6 17 of 22   Please comment on the advantages and disadvantages of including concurrent positive and negative controls with in vitro assays when used as alternatives to animal testing. What are the important characteristics of positive and negative controls for in vitro studies? What aspects of positive control characteristics allow them to be used as part of the quality control process? When might confirmation that positive controls are performing within expected or historical limits be sufficient to demonstrate that the Proprietary Test Method or non proprietary assay system is functioning properly? When might additional quality control measures be needed?

Panel's comments:

The Panel commented that insufficient controls may preclude meaningful interpretation of in vitro test results. Despite the fact that positive and negative controls are not often used in in vivo studies, they are routinely included in in vitro studies and it is clearly advantageous and desirable that they be used in the test systems being discussed here. Positive and negative ( and vehicle) controls provide needed checks within a study that tell the investigator that the test system appears to be intact and functional. Positive controls help identify performance variability between technicians, between laboratories and between lots of test system. Appropriate controls will likely be needed for some length of time until the Agency and practitioners are satisfied with the performance of the test over time and across laboratories. From a quality control perspective, temporal monitoring of controls across studies and laboratories will help establish consistency of response for the test system.

The Panel again pointed out that a single positive control per assay may not be sufficient and that it may be desirable to include positive control chemicals for one or more of the classification severities. At least one Panel member queried as to what actions should be taken when a negative control produces a positive response or a positive control produces a negative response. The answer will depend on the degree of replication assigned to controls and the specified minimum accuracy or concordance for the test system. Clearly, the developers of the test system should incorporate into the recommended protocols guidance on the degree of replication needed for controls, and what actions should be taken when unexpected results are observed with controls. The degree of replication should be based upon the expected variability and the levels of specificity and sensitivity displayed by the test systems for the Reference Chemicals used as controls. With adequate replication, the fact that positive controls ( and negative and vehicle controls, for that matter) are performing within expected limits should be sufficient to demonstrate that the test system is functioning properly.

Question 7   Does the Panel agree that the benchmark controls serve a useful purpose to demonstrate 18 of 22 the level of response that can be expected for each chemical class for each lot of Proprietary Test Method assays? Can the Panel suggest criteria for choice of appropriate benchmark controls?

Panel's comments:

The Panel agrees that benchmark controls are an important mechanism to assess both the adequacy of the method as well as lot to lot variability and should be considered as a standard component of these test methods. Benchmark controls, as well as positive and negative controls, should be tested in each new lot to determine the viability and usability of each lot. Control charts could assess variability among lots, and provide a basis for acceptance/ rejection. The Panel suggests that benchmark controls include several " classic" responders from different chemical classes/ mode of actions.

Variability between different lots is a major concern of the Panel and must be assessed with negative and positive controls as well as benchmark samples. The number of controls and samples depends on several factors; many of which will be defined by the specific test. Certain tests are very consistent and require fewer positive controls and benchmark samples for assessing lot to variability whereas other tests are less consistent. The Panel agreed that there is concern regarding whether the lots are large enough to accommodate these types of controls. To address this concern, the Panel suggests that EPA establish the necessary controls and benchmark samples in the individual tests and consults with the manufacturer of the test. Accordingly, the manufacturer would be encouraged to change production so that the size of lots are sufficient for allowing adequate controls and benchmarks.

Appropriate benchmark controls should have the following properties:

  Consistent and reliable source( s) for the chemical   Structural and functional similarity to the class of article being tested   Known physical/ chemical characteristics   Supporting data on known effects in animal models   Known potency in the range of response ( including moderate response)

One Panel member stated that benchmark controls can serve a very useful purpose, especially in the situation where the test system demonstrates significant batch to batch variability in response. But this variability has not been directly addressed for the test systems being discussed here. If we assume that such variability is quite low, the benefit of re running benchmark controls for each batch is reduced. In this case, the use of benchmark controls might be relegated to a supplier QC role with periodic running of benchmark chemical to ensure continued consistency of response over time. On the other hand, if the test system does demonstrate significant batch to batch variability, it would be important to run benchmark controls more often. Finally, it would seem that benchmark controls would be more important in calibrating a formal dose response model. The need for these controls then depends on the level of precision needed in the final model. 19 of 22 20 of 22 REFERENCES 1. Interagency Coordinating Committee for Validation of Alternative Methods. 2003. ICCVAM Guidelines for the Nomination and Submission of New, Revised and Alternative Test Methods. NIH Publication 03 4508. September 2003.

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