[Federal Register Volume 88, Number 38 (Monday, February 27, 2023)]
[Proposed Rules]
[Pages 12273-12276]
[FR Doc No: 2023-03924]

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DEPARTMENT OF TRANSPORTATION

Federal Aviation Administration

14 CFR Part 39

[Docket No. FAA-2023-0421; Project Identifier MCAI-2022-01360-A]
RIN 2120-AA64

Airworthiness Directives; Pilatus Aircraft Ltd. 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 certain Pilatus Aircraft Ltd. (Pilatus) Model PC-12, PC-12/45, PC-
12/47, and PC-12/47E airplanes. This proposed AD was prompted by
mandatory continuing airworthiness information (MCAI) originated by an
aviation authority of another country to identify and correct an unsafe
condition on an aviation product. The MCAI identifies the unsafe
condition as insufficient grounding of the vapor cycle cooling system
(VCCS) compressor/condenser. This proposed AD would require inspecting
the power return and chassis grounding cable attachment points at frame
37, including the attachment parts, and depending on the inspection
results, corrective action. This proposed AD would also require
modifying the installation of the VCCS compressor/condenser power
return cables and installing an additional isolated VCCS chassis ground
cable. The FAA is proposing this AD to address the unsafe condition on
these products.

DATES: The FAA must receive comments on this NPRM by April 13, 2023.

ADDRESSES: You may send comments, using the procedures found in 14 CFR
11.43 and 11.45, by any of the following methods:
     Federal eRulemaking Portal: Go to regulations.gov. Follow
the instructions for submitting comments.
     Fax:<PHONE_NUMBER>.
     Mail: U.S. Department of Transportation, Docket
Operations, M-30, West Building Ground Floor, Room W12-140, 1200 New
Jersey Avenue SE, Washington, DC 20590.
     Hand Delivery: Deliver to Mail address above between 9
a.m. and 5 p.m., Monday through Friday, except Federal holidays.
    AD Docket: You may examine the AD docket at regulations.gov under
Docket No. FAA-2023-0421; or in person at Docket Operations between 9
a.m. and 5 p.m., Monday through Friday, except Federal holidays. The AD
docket

contains this NPRM, the MCAI, any comments received, and other
information. The street address for Docket Operations is listed above.
    Material Incorporated by Reference:
     For service information identified in this NPRM, contact
Pilatus Aircraft Ltd., Customer Support General Aviation, CH-6371
Stans, Switzerland; phone: +41 848 24 7 365; email:
aircraft.com">[email protected]aircraft.com; website: pilatus-aircraft.com.
     You may view this service information at the FAA,
Airworthiness Products Section, Operational Safety Branch, 901 Locust,
Kansas City, MO 64106. For information on the availability of this
material at the FAA, call<PHONE_NUMBER>.

FOR FURTHER INFORMATION CONTACT: Doug Rudolph, Aviation Safety
Engineer, General Aviation & Rotorcraft Section, International
Validation Branch, FAA, 901 Locust, Room 301, Kansas City, MO 64106;
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-2023-0421; Project Identifier
MCAI-2022-01360-A'' 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 Doug
Rudolph, Aviation Safety Engineer, FAA, General Aviation & Rotorcraft
Section, International Validation Branch, 901 Locust, Room 301, Kansas
City, MO 64106. Any commentary that the FAA receives which is not
specifically designated as CBI will be placed in the public docket for
this rulemaking.

Background

    The European Union Aviation Safety Agency (EASA), which is the
Technical Agent for the Member States of the European Union, has issued
EASA AD 2022-0212, dated October 18, 2022 (referred to after this as
``the MCAI''), to correct an unsafe condition on certain serial-
numbered Pilatus Model PC-12, PC-12/45, PC-12/47, and PC-12/47E
airplanes.
    The MCAI was prompted by a reported occurrence of a burning odor
coming from the air conditioning vents during the climb phase of a
Pilatus Model PC-12/47E airplane. An investigation identified that
insufficient grounding of the VCCS compressor/condenser at frame 37
resulted in severe heat damage to the baseplate and adjacent metal
support structure. It was determined that this condition may occur on
airplanes equipped in production with the large oxygen bottle installed
on the right-hand side of the rear fuselage.
    To address the unsafe condition, the MCAI requires a one-time
inspection of the power return and chassis grounding cable attachment
point at frame 37, including the attachment parts, and modification of
the installation of the VCCS.
    This condition, if not addressed, could, in the case of damage to
the oxygen supply line, lead to an uncontrolled fire with damage to the
airplane and injury to the occupants.
    You may examine the MCAI in the AD docket at regulations.gov under
Docket No. FAA-2023-0421.

Related Service Information Under 1 CFR Part 51

    The FAA reviewed Pilatus PC-12 Service Bulletin 21-016, dated
August 15, 2022, which specifies procedures for inspecting the power
return and chassis grounding cable attachment point on the airframe at
frame 37, including the attachment parts, modifying the installation of
the VCCS compressor/condenser power return cables, and installing an
additional isolated VCCS chassis ground cable. This service bulletin
also specifies contacting Pilatus if any damage is found.
    This service information is reasonably available because the
interested parties have access to it through their normal course of
business or by the means identified in ADDRESSES.

FAA's Determination

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

Proposed AD Requirements in This NPRM

    This proposed AD would require accomplishing the actions specified
in the MCAI, except as discussed under ``Differences Between this
Proposed AD and the MCAI.''

Differences Between This Proposed AD and the MCAI

    The MCAI requires contacting the manufacturer for approved
corrective action instructions if any discrepancy is found during the
inspection. This proposed AD would require contacting either the
Manager, International Validation Branch, FAA; or EASA; or Pilatus's
EASA Design Organization Approval (DOA). If approved by the DOA, the
approval must include the DOA-authorized signature.

Costs of Compliance

    The FAA estimates that this AD, if adopted as proposed, would
affect 8 airplanes of U.S. registry.
    The FAA estimates the following costs to comply with this proposed
AD:

                                                 Estimated Costs
----------------------------------------------------------------------------------------------------------------
                                                                                Cost per      Cost on U.S.
              Action                      Labor cost             Parts cost           product        operators
----------------------------------------------------------------------------------------------------------------
Inspect...........................  3 work-hours x $85     Not Applicable.......            $255          $2,040
                                     per hour = $255.
Modify............................  5 work-hours x $85     667..................           1,092           8,736
                                     per hour = $425.
----------------------------------------------------------------------------------------------------------------

    The repair instructions that may be needed as a result of the
inspection could vary significantly from airplane to airplane. The FAA
has no data to determine the costs to accomplish the repair or the
number of airplanes that would need this repair.

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:

Pilatus Aircraft Ltd.: Docket No. FAA-2023-0421; Project Identifier
MCAI-2022-01360-A.

(a) Comments Due Date

    The FAA must receive comments on this airworthiness directive
(AD) by April 13, 2023.

(b) Affected ADs

    None.

(c) Applicability

    This AD applies to Pilatus Aircraft Ltd. Model PC-12, PC-12/45,
PC-12/47, and PC-12/47E airplanes, serial numbers 466, 467, 725,
861, 1032, 1052, 1082, 1115, 1232, 1411, 1428, 1439, 1530, 1541,
1663, 1725, and 1802, certificated in any category.

 (d) Subject

    Joint Aircraft System Component (JASC) Code 2197, Air
Conditioning System Wiring.

 (e) Unsafe Condition

    This AD was prompted by mandatory continuing airworthiness
information (MCAI) originated by an aviation authority of another
country to identify and correct an unsafe condition on an aviation
product. The MCAI identifies the unsafe condition as insufficient
grounding of the vapor cycle cooling system (VCCS) compressor/
condenser. The FAA is issuing this AD to address this condition. The
unsafe condition, if not addressed, could, in the case of damage to
the oxygen supply line, lead to an uncontrolled fire with damage to
the airplane, and injury to the occupants.

(f) Compliance

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

(g) Required Actions

    (1) Within 2 months after the effective date of this AD, inspect
the power return and chassis grounding cable attachment points at
frame 37, including the attachment parts, for physical and heat
damage, de-lamination, and corrosion in accordance with steps (2)
through (6) of Section 3.B. of the Accomplishment Instructions in
Pilatus PC-12 Service Bulletin (SB) 21-016, dated August 15, 2022
(Pilatus PC-12 SB 21-016).
    (2) If, during the inspection required by paragraph (g)(1) of
this AD, any physical or heat damage, de-lamination, or corrosion as
identified in steps (2) through (6) of Section 3.B. of the
Accomplishment Instructions in Pilatus PC-12 SB 21-016 is detected,
before further flight, repair using a method approved by the
Manager, International Validation Branch, FAA; the European Union
Aviation Safety Agency (EASA); or Pilatus's EASA Design Organization
Approval (DOA). If approved by the DOA, the approval must include
the DOA-authorized signature.
    (3) Within 2 months after the effective date of this AD, modify
the installation of the VCCS compressor/condenser power return
cables and install an additional isolated VCCS chassis ground cable
in accordance with Section 3.C. of the Accomplishment Instructions
in Pilatus PC-12 SB 21-016. Where the service bulletin specifies
discarding the stop angle, this AD requires removing the stop angle
from service.

(h) Alternative Methods of Compliance (AMOCs)

    The Manager, International Validation Branch, FAA, has the
authority to approve AMOCs for this AD, if requested using the
procedures found in Sec.  39.19. In accordance with Sec.  39.19,
send your request to your principal inspector or local Flight
Standards District Office, as appropriate. If sending information
directly to the manager of the International Validation Branch, mail
it to the address identified in paragraph (i)(2) of this AD or email
to: [email protected]. If mailing information, also submit
information by email. Before using any approved AMOC, notify your
appropriate principal inspector, or lacking a principal inspector,
the manager of the local flight standards district office/
certificate holding district office.

(i) Additional Information

    (1) Refer to EASA AD 2022-0212, dated October 18, 2022, for
related information. This EASA AD may be found in the AD docket at
regulations.gov under Docket No. FAA-2023-0421.
    (2) For more information about this AD, contact Doug Rudolph,
Aviation Safety Engineer, General Aviation & Rotorcraft Section,
International Validation Branch, FAA, 901 Locust, Room 301, Kansas
City, MO 64106; phone:<PHONE_NUMBER>; email: [email protected].

(j) Material Incorporated by Reference

    (1) The Director of the Federal Register approved the
incorporation by reference of the service information listed in this
paragraph under 5 U.S.C. 552(a) and 1 CFR part 51.
    (2) You must use this service information as applicable to do
the actions required by this AD, unless the AD specifies otherwise.
    (i) Pilatus PC-12 Service Bulletin 21-016, dated August 15,
2022.
    (ii) [Reserved]
    (3) For service information identified in this AD, contact
Pilatus Aircraft Ltd., Customer Support General Aviation, CH-6371
Stans, Switzerland; phone: +41 848 24 7 365; email:
aircraft.com">[email protected]aircraft.com; website: pilatus-aircraft.com.
    (4) You may view this service information at the FAA,
Airworthiness Products Section, Operational Safety Branch, 901
Locust, Kansas City, MO 64106. For information on the availability
of this material at the FAA, call<PHONE_NUMBER>.
    (5) You may view this service information that is incorporated
by reference at the National Archives and Records Administration
(NARA). For information on the availability of this material at
NARA, email [email protected], or go to: www.archives.gov/federal-register/cfr/ibr-locations.html.

    Issued on February 17, 2023.
Christina Underwood,
Acting Director, Compliance & Airworthiness Division, Aircraft
Certification Service.
[FR Doc. 2023-03924 Filed 2-24-23; 8:45 am]
BILLING CODE 4910-13-P


[Federal Register Volume 88, Number 234 (Thursday, December 7, 2023)]
[Rules and Regulations]
[Pages 85110-85111]
[FR Doc No: 2023-26844]

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DEPARTMENT OF HOMELAND SECURITY

Coast Guard

33 CFR Part 100

[USCG-2023-0899]

Special Local Regulations; Marine Events Within the Captain of
the Port Charleston

AGENCY: Coast Guard, Department of Homeland Security (DHS).

ACTION: Notification of enforcement of regulation.

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SUMMARY: The Coast Guard will enforce the special local regulation for
the Charleston Parade of Boats on December 9, 2023, to provide for the
safety of life on navigable waterways during this event. Our regulation
for marine events within the Captain of the Port Charleston identifies
the regulated area for this event in Charleston, SC. During the
enforcement period, no person or vessel may enter, transit through,
anchor in, or remain within the regulated area unless authorized by the
Coast Guard Patrol Commander or a designated representative.

DATES: The regulations in 33 CFR 100.704 will be enforced from 4 p.m.
through 8 p.m. on December 9, 2023, for the location identified in
paragraph (d), Item 10 in table 1 to Sec.  100.704.

FOR FURTHER INFORMATION CONTACT: If you have questions about this
notification of enforcement, call or email Lieutenant James Sullivan,
Sector Charleston Waterways Management Division, U.S. Coast Guard;
telephone<PHONE_NUMBER>, email [email protected].

SUPPLEMENTARY INFORMATION: The Coast Guard will enforce the special
local regulation in 33 CFR 100.704 for the Charleston Parade of Boats
regulated area identified in table 1 to Sec.  100.704, paragraph (d),
Item 10, from 4 p.m. until 8 p.m. on December 9, 2023. This action is
being taken to provide for the safety of life on navigable waterways
during this event. Our regulation for recurring marine events, Captain
of the Port Charleston, Sec.  100.704, paragraph (d), Item 10,
specifies the location of the regulated area for the Charleston Parade
of Boats, which encompasses portions of the Charleston Harbor located
in Charleston, SC, including Anchorage A, Shutes Folly, Bennis Reach,
Horse Reach, Hog Island Reach, Town Creek Lower Reach, and Ashley
River. Under the provisions of 33 CFR 100.704, all persons and vessels
are prohibited from entering the regulated area, except those persons
and vessels participating in the event, unless they receive permission
to do so from the Coast Guard Patrol Commander, or designated
representative.
    Spectator vessels may safely transit outside the regulated area,
but may not anchor, block, loiter in, impede the transit of festival
participants or official patrol vessels or enter the regulated area
without approval from the Coast Guard Patrol Commander or a designated
representative. The Coast Guard may be assisted by other Federal,
State, or local law enforcement agencies in enforcing this regulation.
In addition to this notice of enforcement in the Federal Register, the
Coast Guard will provide notice of the regulated area via Local Notice
to Mariners, Marine Safety Information Bulletins, Broadcast Notice to
Mariners, and on-scene designated representatives.

    Dated: November 27, 2023.
F.J. Delrosso,
Captain, U.S. Coast Guard, Captain of the Port Charleston.
[FR Doc. 2023-26844 Filed 12-6-23; 8:45 am]
BILLING CODE 9110-04-P


OFFICE OF PREVENTION, PESTICIDES, AND TOXIC SUBSTANCES UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 TXR No: 0050572 March 20, 2002 Memorandum SUBJECT: TEBUTHIURON (PC Code: 105501) Toxicology Disciplinary Chapter for the Tolerance Reassessment Eligibility Decision Document FROM: Robert Fricke, Ph. D. Reregistration Branch 2 Health Effects Division (7509C)

THRU: Alan Nielsen, Branch Senior Scientist Reregistration Branch 2 Health Effects Division (7509C)

TO: Paula Deschamp, Risk Assessor Reregistration Branch 2 Health Effects Division (7509C)

DP Barcode: D277101 Submission: S596544 Action Requested: Review toxicology studies submitted by the registrant and prepare the toxicology chapter to support Tolerance Reassessment Eligibility Decision (TRED) for tebuthiuron.

Attached is the updated toxicology chapter summarizing the findings of the toxicology studies. TEBUTHIURON PC Code: 105501 Toxicology Disciplinary Chapter for the Tolerance Reassessment Eligibility Decision (TRED) Document February 20, 2002 Prepared by: Robert F. Fricke, Ph. D. Reregistration Branch 2 Health Effects Division Mail Code 7509C Peer reviewed by: Yung Yang, Ph. D. Toxicology Branch Health Effects Division Mail Code 7509C Robert F. Fricke, Toxicologist Yung Yang, Toxicologist TABLE OF CONTENTS 1 HAZARD CHARACTERIZATION ........................................ 1 2 REQUIREMENTS .................................................... 2 3 DATA GAPS ......................................................... 3 4 HAZARD ASSESSMENT ............................................... 3 4.1 Acute Toxicity .................................................... 3 4.2 Subchronic Toxicity ............................................... 3 4.2.1 870.3100 90 Day Oral Toxicity  Rat ......................... 3 4.2.2 870.3150 90 Day Oral Toxicity  Dog ........................ 4 4.2.3 870.3200 21/ 28 Day Dermal Toxicity  Rabbit .................. 4 4.2.4 870.3250 90 Day Dermal Toxicity ........................... 4 4.2.5 870.4365 90 Day Inhalation Toxicity ......................... 5 4.3 Prenatal Developmental Toxicity ...................................... 5 4.3.1 870.3700a Prenatal Developmental Toxicity Study  Rat ........... 5 4.3.2 870.3700b Prenatal Developmental Toxicity Study  Rabbit ......... 6 4.4 Reproductive Toxicity .............................................. 7 4.4.1 870.3800 Two Generation Reproduction and Fertility Effects  Rat .. 7 4.5 Chronic Toxicity .................................................. 8 4.5.1 870.4300 Combined Chronic Toxicity/ Carcinogenicity StudyCD SD) BR Rats ................................. 8 4.5.2 870.4100b Chronic Toxicity  Dog ............................ 9 4.6 Carcinogenicity .................................................. 10 4.6.1 870.4200b Carcinogenicity Study  Crl: CD 1 (ICR) BR Mouse ..... 10 4.6.2 870.4300 Carcinogenicity Study CD( SD) BR Rats .............. 11 4.7 Mutagenicity .................................................... 11 4.8 Neurotoxicity ................................................... 13 4.8.1 870.6100 Delayed Neurotoxicity Study  Hen .................. 13 4.8.2 870.6200a Acute Neurotoxicity Screening Battery ............... 14 4.8.3 870.6200b Subchronic Neurotoxicity Screening Battery ........... 14 4.8.4 870.6300 Developmental Neurotoxicity Study ................. 14 4.9 Metabolism ..................................................... 14 4.9.1 870.7485 Metabolism  Rat ............................... 14 4.10 Special Studies .................................................. 14 5 TOXICITY ENDPOINT SELECTION .................................... 14 5.1 Dermal Absorption ............................................... 15 5.2 Classification of Carcinogenic Potential ................................ 15 5.2.1 Conclusions and Classification of Carcinogenic Potential ........... 15 5.2.2 Quantification of Carcinogenic Potential ........................ 15 6 FQPA CONSIDERATIONS ............................................ 15 6.1 Special Sensitivity to Infants and Children .............................. 15 6.2 Recommendation for a Developmental Neurotoxicity Study ................ 15 7 OTHER ISSUES ..................................................... 15 8 REFERENCES ...................................................... 15 9 APPENDICES ....................................................... 19 9.1 Toxicity Profile Summary Tables ..................................... 19 9.1.1 Acute Toxicity Table ....................................... 19 9.1.2 Subchronic, Chronic, and Other Toxicity Table ................... 19 9.2 Summary of Toxicological Dose and Endpoints for Tebuthiuron for Use in Human Risk Assessment ................................................. 22 Tebuthiuron (105501) RED Toxicology Chapter 1 1 HAZARD CHARACTERIZATION The toxicological database for tebuthiuron is not considered adequate for hazard characterization, however the database will support the Tolerance Reassessment Eligibility Decision (TRED) for the current registered uses. Hazard characterization was not possible because of datagaps which include a developmental toxicity study in rabbit, a chronic feeding/ carcinogenicity study in the rat and oncogenicity study in the mouse; all of these studies were found to be unacceptable. The requirement for a developmental neurotoxicity study is being held in reserve, pending submission of the rabbit developmental toxicity study. Additionally, the Health Effects Division's Hazard Identification Assessment Review Committee (HIARC) determined that a 28 day inhalation is required to provide better hazard characterization.

The acute toxicity studies indicate that tebuthiuron, technical, is more toxic for oral (Toxicity Category II) exposure than for either dermal (Toxicity Category IV) or inhalation (Toxicity Category III). Tebuthiuron is not an eye or skin irritant and not a skin sensitizer.

In the 21 day dermal toxicity study in rabbits, no dermal or systemic toxicity was observed at 1000 mg/ kg/ day (limit dose).

Although the most consistent toxicological effect was decreased body weight, histopathological changes in the pancreas were observed in both the subchronic and chronic toxicity studies in the rat. Pancreatic acinar cells of both sexes showed vacuolation, which was described as generally slight or affecting only a few cells; males also had increased relative spleen and prostate gland weights. In a rat developmental study, however, pancreatic tissue appeared normal.

Subchronic and chronic toxicity studies were available for the dog. In a subchronic study, anorexia, with resulting weight loss, and clinical chemistry effects (increased blood urea nitrogen and alkaline phosphatase) were observed at 50 mg/ kg/ day. In a chronic (1 year) study clinical signs of toxicity (emesis anorexia, and diarrhea ), decreased body weight, increased ALT and ALP (males only), increased absolute and relative liver weights, and increased relative kidney (females only) thyroid (males only) weights.

At the doses tested, neither the rat nor mouse showed any treatment related increase in the incidence of neoplasms. However, the HIARC (TXR No. 0050450, dated February 5, 2002) concluded that the dose levels were too low to assess the carcinogenic potential of tebuthiuron.

Tebuthiuron was not mutagenic in bacteria or in cultured mammalian cells. There was also no indication of a clastogenic effect up to toxic doses in vivo.

Results from the rat developmental and reproductive toxicity studies indicated that there was no evidence (qualitative or quantitative) for increased susceptibility following in utero and/ or pre post natal exposure. The rabbit developmental toxicity study was found to be unacceptable; susceptibility can not be evaluated in rabbits.

In a rat metabolism study with 14 C tebuthiuron, absorption was complete; excretion was rapid both sexes, but was delayed during the first 12 hours post dose, indicating saturation of Tebuthiuron (105501) RED Toxicology Chapter 2 biotransformation or excretion. At termination, no significant amounts of residual radioactivity in any tissue examined, but the skin showed the highest amounts relative to other tissues. Six metabolites of tebuthiuron were identified. The major urinary metabolite was identified as hydroxylated tebuthiuron metabolites.

2 REQUIREMENTS The requirements (CFR §158.340, revised as of July 1, 1999) for Food and Non Food Use for tebuthiuron, technical, are summarized in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Study Required Satisfied 870.1100 Acute Oral Toxicity ....................... 870.1200 Acute Dermal Toxicity ..................... 870.1300 Acute Inhalation Toxicity ................... 870.2400 Primary Eye Irritation ..................... 870.2500 Primary Dermal Irritation ................... 870.2600 Dermal Sensitization ...................... Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 870.3100 Oral Subchronic (Rodent) ................... 870.3150 Oral Subchronic (Non Rodent) ............... 870.3200 21 Day Dermal ........................... 870.3250 90 Day Dermal ........................... 870.3465 28 Day inhalation 870.3465 90 Day Inhalation ........................ Yes Yes Yes No Yes No Yes Yes Yes

No a

870.3700a Developmental Toxicity (Rodent) ............. 870.3700b Developmental Toxicity( Non rodent) ......... 870.3800 Reproduction ............................ Yes Yes Yes Yes No a Yes 870.4100a Chronic Toxicity (Rodent) ................... 870.4100b Chronic Toxicity (Non rodent) ................ 870.4200a Oncogenicity (Rat) ......................... 870.4200b Oncogenicity (Mouse) ...................... 870.4300 Chronic/ Oncogenicity ...................... Yes Yes Yes Yes Yes No a Yes No a No a No a 870.5100 Mutagenicity— Gene Mutation  bacterial ....... 870.5300 Mutagenicity— Gene Mutation  mammalian ..... 870.5375 Mutagenicity– in vitro cytogenicity 870.5385 Mutagenicity— Mammalian bone marrow chromosomal aberration test ................. 870.5550 Mutagenicity— UDS in Mammalian cells in vitro 870.5900 In vitro sister chromatid exchange assay ........ Yes Yes Yes No Yes Yes Yes Yes Yes

Yes Yes 870.6100a Acute Delayed Neurotox. (Hen) ............... 870.6100b 90 Day Neurotoxicity (Hen) .................. 870.6200a Acute Neurotox. Screening Battery (Rat) ........ 870.6200b 90 Day Neuro. Screening Battery (Rat) ......... 870.6300 Developmental Neurotoxicity ................. No No No No Yes b

No a 870.7485 General Metabolism ........................ 870.7600 Dermal Penetration ........................ Yes No Yes Yes a The HIARC determined that these studies must be repeated b The HIARC determined that this study is held in reserve pending submission of a rabbit developmental toxicity study Tebuthiuron (105501) RED Toxicology Chapter 3 3 DATA GAPS 28 day inhalation study in the rat (870.3465) Developmental toxicity study in the rabbit (870.3700b) Chronic feeding/ oncogenicity study in the rat (870.4300) Oncogenicity study in the mouse (870.4200) Developmental neurotoxicity study (870.6300) (held in reserve)

4 HAZARD ASSESSMENT 4.1 Acute Toxicity Adequacy of data base for acute toxicity: The database for acute toxicity is considered adequate. The acute toxicity studies indicate that tebuthiuron, technical, is more toxic for oral (Toxicity Category II) exposure than for either dermal (Toxicity Category IV) or inhalation (Toxicity Category III). The primary eye and skin irritation studies were both Toxicity Category IV; no dermal sensitization occurred with tebuthiuron in guinea pigs.

Acute Toxicity of Tebuthiuron, Technical Guideline No. Study Type MRID No. Results Toxicity Category 870.1100 Acute Oral (Rat) 40583901 LD50 =477.5 mg/ kg (%%) 387.5 mg/ kg (&&) II 870.1200 Acute Dermal (Rabbit) 40583902 LD50 => 5000 mg/ kg (%%and &&) IV 870.1300 Acute Inhalation (Rat) 00155730 LC50 = 3.696 mg/ L III 870.2400 Primary Eye Irritation 40583903 Slight irritation IV 870.2500 Primary Skin Irritation 40583902 Non irritating IV 870.2600 Dermal Sensitization 40583904 Non sensitizer

4.2 Subchronic Toxicity Adequacy of data base for subchronic toxicity: With the exception of the 28 day inhalation study, the database for subchronic toxicity is considered adequate. Subchronic studies in both the rat and dog, as well as a 28 dy dermal toxicity study, were considered to be acceptable.

4.2.1 870.3100 90 Day Oral Toxicity  Rat Executive Summary: In a subchronic toxicity study (MRID 00020662), Harlan SpragueDawley rats (10/ sex/ dose) were fed diets containing tebuthiuron (purity not given) at 0, 400, 1000 or 2500 ppm (0, 20, 50 or 125 mg/ kg/ day) for three months. High dose males and females showed decreased body weights, increased relative liver, kidney, gonad Tebuthiuron (105501) RED Toxicology Chapter 4 weights; males also had increased relative weights for spleen, prostate gland and moderate vacuolization of the pancreatic acinar cells.

The LOAEL was established at 125 mg/ kg/ day, based on increased relative organ weights and increased incidence of vacuolization of the pancreatic acinar cells; the NOAEL was established at 50 mg/ kg/ day.

This study is classified as Acceptable/ Guideline and satisfies the requirements for a subchronic toxicity study [870.3100 (§ 82 1a)] in rats.

4.2.2 870.3150 90 Day Oral Toxicity  Dog Executive Summary: In a subchronic toxicity study (MRID 00020663), beagle dogs (2/ sex/ dose) were dosed (capsule) with tebuthiuron (purity not given) at 0, 12.5, 25 or 50 mg/ kg/ day for 90 days. Clinical signs were limited to high dose dogs, which had anorexia; all animals survived to terminal sacrifice. High dose females had body weight losses of 5%. Transient increases (up to 4 fold) in alkaline phosphatase activity were observed in high dose animals; other clinical chemistry parameters were unaffected by treatment. Relative liver weights were slightly increased in one male and female in the high dose group, however, gross and histopathological observations did not show any treatmentrelated effects in these animals.

The LOAEL was established at 50 mg/ kg/ day, based on decreased body weight and increased alkaline phosphatase activity; the NOAEL was established at 25 mg/ kg/ day.

This study is classified as Acceptable/ Guideline and satisfies the requirements for a subchronic toxicity study [870.3150 (§ 82 1b)] in dogs.

4.2.3 870.3200 21/ 28 Day Dermal Toxicity  Rabbit Executive Summary: In a dermal toxicity study (MRID 00149733, 00160796) New Zealand White rabbits were treated for 21 days with tebuthiuron (purity not given) at 0 or 1000 (limit dose) mg/ kg/ day. No treatment related toxicity was observed.

The LOAEL was not established; the NOAEL was established at 1000 mg/ kg/ day (limit dose)

This study is classified as Acceptable/ Guideline and satisfies the requirements for a 21 day dermal toxicity study [870.3200 (§ 82 2)] in rabbits.

4.2.4 870.3250 90 Day Dermal Toxicity No study available, not required 4.2.5 870.4365 90 Day Inhalation Toxicity Tebuthiuron (105501) RED Toxicology Chapter 5 No study available. A 28 day inhalation study has been identified as a data gap by the HIARC.

4.3 Prenatal Developmental Toxicity Adequacy of data base for Prenatal Developmental Toxicity: The data base for prenatal developmental toxicity is not complete. The developmental toxicity study in the rabbit was found to be unacceptable; the requirement for a developmental neurotoxicity study is being held in reserve pending submission of this study. In the rat developmental toxicity study, no qualitative/ quantitative evidence of increased susceptibility was observed.

4.3.1 870.3700a Prenatal Developmental Toxicity Study  Rat Executive Summary: In a developmental toxicity study (MRID 00020803, 40485801), 25 presumed pregnant Harlan rats per group were administered tebuthiuron (purity not given; Lot No. 1093 316A 259) at dietary concentrations of 0, 600, 1200, or 1800 ppm (0, 37, 72, or 110 mg/ kg/ day, respectively) on gestation days (GD) 6 15, inclusive. On GD 20, dams were sacrificed and subjected to gross necropsy; pancreatic tissue was saved from 10 females/ group for histopathological examination. Fetal sex, weight, and viability were determined and each fetus was examined for external abnormalities. Approximately onethird of all fetuses were fixed in Bouin's solution for subsequent visceral examination and the remainder were cleared for skeletal examination.

All dams survived to terminal sacrifice. No treatment related clinical signs of toxicity were observed in any group. Body weights, body weight gains, and food consumption by the low and mid dose groups were similar to the controls throughout the study. No treatment related lesions were observed in any dam at necropsy. Pancreatic tissue, as evaluated by both gross and microscopic examination, appeared normal.

For the high dose group, absolute body weights were slightly reduced on GD 16 to 93% of the control level due to reduced body weight gains during the entire treatment interval. Body weight gains by the high dose dams were 21% of the control level during GD 6 10 and 57% of the control level during GD 11 15. During the treatment interval, food consumption by the high dose group was 71% of the control amount for GD 6 10 and 95% of the control amount for GD 11 15. Compensatory weight gain and food consumption was observed in the high dose group during the post treatment interval.

The maternal toxicity LOAEL is 1800 ppm (110 mg/ kg/ day) based on decreased body weight gains and food consumption. The maternal toxicity NOAEL is 1200 ppm (72 mg/ kg/ day).

No differences were observed between the treated and control groups for pregnancy rate, number of corpora lutea/ dam, number of implantation sites/ dam, pre or post implantation losses, number of fetuses/ litter, fetal body weights, or fetal sex ratios. No dead fetuses were observed. Tebuthiuron (105501) RED Toxicology Chapter 6 The total number of fetuses( litters) available for examination for malformations/ variations in the control, low, mid, and high dose groups was 259( 23), 263( 21), 300( 23), and 258( 21), respectively. No treatment related abnormalities were found in any fetus. In the control, low, mid, and high dose groups, the total number of fetuses( litters) with external, visceral, or skeletal malformations/ variations was 3( 2), 4( 4), 11( 7), and 4( 3), respectively. Hydronephrosis was a common finding in fetuses from control and treated groups.

The developmental toxicity NOAEL is $ $1800 ppm (110 mg/ kg/ day) and the developmental toxicity LOAEL was not identified.

This study is classified as Acceptable/ Guideline and satisfies the requirements for a developmental toxicity study [870.3700 (§ 83 3a)] in rats.

4.3.2 870.3700b Prenatal Developmental Toxicity Study  Rabbit Executive Summary: In a developmental toxicity study (MRID 00020644), 15 presumed pregnant Dutch belted rabbits per group were administered tebuthiuron (96.5% a. i.; Lot No.: B30 23 149) by gavage at doses of 0, 10, or 25 mg/ kg/ day on gestation days (GD) 6 18, inclusive. Details of the purity and composition and of the insemination procedure were given in MRID 41122401. On GD 28, all surviving does were sacrificed and examined grossly. Litters were weighed and each fetus examined for viability, sex, and external malformations/ variations. The fetuses were killed, examined viscerally by fresh dissection (including the brain), and the carcasses processed for skeletal examination.

Doses for the study were selected on the basis of a preliminary range finding study (MRID 40776301). In this study, mated rabbits (4/ group) were administered 5, 10, 20, 25, 50, or 100 mg/ kg/ day on GD 6 18. Three animals in the 100 mg/ kg/ day group died or were killed moribund on GD 8 10. Overall body weight changes for the treated groups were 140, 5, 37, 72, 103, and 480 g, respectively. From the range finding study, the percentage of resorptions in the 25, 50, and 100 mg/ kg/ day groups was 68.8, 66.7, and 100%..

In the main study, premature deaths of several animals were considered incidental to treatment. No clinical signs of toxicity were observed in any animal. No effects on body weights, body weight changes, or food consumption were noted for the treated groups as compared with the controls. No treatment related lesions were found at gross necropsy.

The maternal toxicity NOAEL was established at 25 mg/ kg/ day; the LOAEL for maternal toxicity was not established.

No differences between the treated and control groups were noted for pregnancy rate or numbers of corpora lutea, implantations, fetuses/ litter, or resorptions. Although the mean fetal body weights in the high dose group were significantly lower than the control value, the decreases were attributed to increased liter size. Tebuthiuron (105501) RED Toxicology Chapter 7 The total number of fetuses( litters) examined in the control, low, and high dose groups was 48( 11), 58( 11), and 68( 12), respectively. No treatment related external, visceral, or skeletal malformations/ variations were observed in this study.

The developmental toxicity NOAEL is established at 25 mg/ kg/ day; the LOAEL was not established.

This study is classified as Unacceptable/ Guideline and does not satisfy the guideline requirements for a developmental toxicity study [870.3700 (§ 83 3b)] in rabbits.

4.4 Reproductive Toxicity Adequacy of data base for Reproductive Toxicity: The data base for reproductive toxicity is considered complete and no additional studies are required at this time.

4.4.1 870.3800 Two Generation Reproduction and Fertility Effects  Rat Executive Summary: In a two generation reproduction study (MRID 00090108), tebuthiuron (Lot No. 00880 1L 1, X 35920, 98.0% a. i.) was fed to groups of 25 male and 25 female Wistar rats per dose at dietary concentrations of 0, 100, 200, and 400 ppm. The dietary levels corresponded to doses of 6 7, 13 14, and 26 28 mg/ kg/ day, respectively, for F0 and F1 males and 7 8, 14 15, and 30 31 mg/ kg/ day, respectively, for F0 and F1 females averaged over the premating period only. Adult rats of both generation were fed the treated or control diets during the premating period (98 days for F0 and 124 days for F1 rats) and during mating, gestation, and lactation of two litters per generation. Pups from the F1a litters were selected to parent the F2 generation.

No treatment related deaths, clinical signs of toxicity, gross lesions, or microscopic lesions were observed in adult rats of either generation. No treatment related effects were observed on body weight, body weight gain, food consumption, or food efficiency in F0 male rats, F1 male rats, or F0 female rats fed any dose at any time during the study including the premating, mating, gestation, and lactation periods. F1 females in the 200 and 400 ppm groups had mean weekly body weights 7 9% (not biologically significant) and 8 13% (p< 0.01 or <0.05), respectively, less than the control group throughout the premating period starting with day 21 for the 200 ppm group and day 7 for the 400 ppm group. Weight gain over the entire premating period was 7% (N. S.) less than controls for 200 ppm group F1 females and 14% (p< 0.05) less for the 400 ppm group. Cumulative food consumption was not significantly affected, but food efficiency was reduced by 13% (p< 0.01) for 400 ppm group F1 females. The decreased body weights and weight gain did not extend into the gestation or lactation period for F2a litters.

The parental systemic LOAEL was established at 400 ppm (30 mg/ kg/ day) for female rats based on deceases in body weight and weight gain; NOAEL was established at 200 ppm (14 mg/ kg/ day). Parental effect levels were not established for adult male rats in this study. Tebuthiuron (105501) RED Toxicology Chapter 8 No effects were observed on reproductive parameters as measured by sperm morphology, fertility index for females, and the number of litters produced.

A reproductive LOAEL was not established; the NOAEL was established at 400 ppm (30 mg/ kg/ day).

The F1a , F1b , F2a , or F2b offspring/ litters were not affected by treatment with tebuthiuron in the diet. The mean litter size at birth, litter size throughout lactation, survival indices (live birth, viability, and lactation), and pup weights and pup weight gain throughout lactation were not statistically different between treated and control groups. Dosing was considered to be barely adequate for assessing reproductive and offspring toxicity.

The offspring LOAEL was not established; the NOAEL was established at 400 ppm (30 mg/ kg/ day).

This study is classified Acceptable/ Guideline and satisfies the guideline requirement for a two generation reproductive study (OPPTS 870.3800, §83 4) in the rat.

4.5 Chronic Toxicity Adequacy of data base for chronic toxicity: The data base for chronic toxicity is not complete; datagaps include a chronic feeding/ carcinogenicity study in the rat.

It should be noted that initial review of the carcinogenicity studies in the rat and mouse by the RfD Committee on August 28, 1992 did not consider the doses to be adequate based on the absence of systemic effects. On February 25, 1993, however, the RfD Committee (Second RfD/ Peer review report of Tebuthiuron, memo dated March 1, 1993) reconvened and found the rat carcinogenicity study to be acceptable; the committee felt that the doses were considered adequate, or at least approaching an adequate dose, for carcinogenicity testing in rats based on body weight gain decrease. Even though the Committee found the mouse carcinogenicity study to be unacceptable (inadequate dose levels), they concluded that treatment did not seem to alter the tumor profile for this strain of mouse and indicated that there would be no need for another study.

4.5.1 870.4300 Combined Chronic Toxicity/ Carcinogenicity Study CD( SD) BR Rats Executive Summary: In a chronic toxicity/ carcinogenicity study (MRID 00020714), tebuthiuron (> 97% a. i., lot number, 6SG43 and B30 23 149) was administered to male and female Wistar rats (40/ group/ sex) at dietary concentrations of 400, 800, or 1600 ppm (20, 40, and 80 mg/ kg/ day, based on the default food factor of 0.05). Two control groups of 60 male and 60 female Wistar rats administered untreated basal diet. No interim sacrifice was conducted for this study. Two replicate studies were carried out.

No treatment related effects were reported for clinical signs, mortality, or clinical pathology in male or female rats receiving any dose of the test material. The mortality rates for all groups was high. During the first year of treatment, 10 19% of males died Tebuthiuron (105501) RED Toxicology Chapter 9 while at the end on the study, only 26% of all rats remained alive. Pneumonia affected the majority of animals in all groups at various times during the study; antibiotic treatment was required during one episode. Absolute body weights presented graphically indicated that high dose males and females weighed less than controls throughout most of the study. The magnitude of the reduction in absolute body weight could not be determined for assessment of statistical or toxicologic significance. A 15% reductions in body weight in high dose females was observed at study termination. Food consumption was measured but not reported.

Relative kidney weights were depressed in high dose male rats, but no histopathological correlates were observed. Each animal was necropsied, but gross findings were not tabulated. Vacuolization of pancreatic acinar cells (generally slight or affecting only a few cells) was observed in 11 males and 13 females receiving the high dose and in none of the controls of either sex. Only selected histopathological data were presented in the summary tables of the study report; therefore, a complete assessment of histopathological findings could not be conducted. No treatment related neoplasms were reported; common neoplasms included pituitary adenomas and mammary fibroadenomas in female rats. The microscopic findings in the pancreatic acinar cells were generally slight, affected only a few cells, and caused no physiological effect on glucose levels.

Based on the results of this study (decreased terminal body weight in females), the LOAEL for systemic toxicity was established at 80 mg/ kg/ day; a LOAEL was not established im males. The NOAEL was established at 40 mg/ kg/ day in females at 80 mg/ k/ day in females.

The HIARC (TXR No. 0050450, dated February 5, 2002) determined that doses used in this study were not considered to be adequate for the evaluation of the carcinogenic potential of tebuthiuron.

This chronic toxicity/ carcinogenicity study in the rat is Unacceptable/ Guideline and does not satisfy the guideline requirement for a chronic toxicity/ carcinogenicity oral study [OPPTS 870.4300 (§ 83 5)] in the rat.

4.5.2 870.4100b Chronic Toxicity  Dog Executive Summary: In a one year chronic toxicity study, tebuthiuron (98.9% a. i., Batch No. X 35920) was administered daily by capsule to groups of 4 male and 4 female beagle dogs at doses of 0, 12.5, 25.0, or 50.0 mg/ kg/ day (MRID 00146801).

All animals survived to scheduled termination. Clinical signs of toxicity in high dose animals included anorexia, emesis, and diarrhea. Absolute body weights for females and food consumption for males and females were not affected by treatment. Body weights of the high dose males were less than those of the controls throughout most of the study with statistical significance attained occasionally. Overall weight gains by the high dose males and females were 67% and 82%, respectively, of the control levels. No treatment related ophthalmological lesions, changes in urinalysis parameters, or microscopic lesions were Tebuthiuron (105501) RED Toxicology Chapter 10 noted and gross necropsy was unremarkable.

Thrombocyte counts were significantly (p # 0.05) increased in high dose males at 6 and 12 months as compared with the controls. Alanine aminotransferase (ALT) levels were increased in males after 1 month and in females after 3 months to 186 529% and 228 407%, respectively, of the control group levels. In addition, alkaline phosphatase (AP) levels in males were increased to 283 408% of the control levels at 6 and 12 months. Statistical significance was not attained at all timepoints for the increases in enzyme levels due to large variability between individual animals.

Absolute liver weights were significantly (p # 0.05) increased in the high dose males and females. No other differences in absolute organ weights were found. Also for the highdose groups, significant (p # 0.05) differences in organ weights relative to final body weight included increased relative liver weights in males and females, increased relative kidney weights in females, and increased relative thyroid weights in males.

The LOAEL was established at 50 mg/ kg/ day based on clinical signs (anorexia, emesis, and diarrhea), decreased body weight gains, increased alanine aminotransferase and alkaline phosphatase (males only) levels, increased absolute and relative liver weights, increased relative kidney weights (females only), and increased relative thyroid weights (males only). The NOAEL was established at 25 mg/ kg/ day.

This study is classified as Acceptable/ Guideline and satisfies the guideline requirements for a chronic toxicity study in dogs [OPPTS 870.4100 (83 1b)] .

4.6 Carcinogenicity Adequacy of data base for Carcinogenicity: The database for carcinogenicity is considered inadequate. The HIARC (TXR No. 0050450, dated February 5, 2002) reevaluated the classification and concluded that the carcinogenic potential of tebuthiuron can not be determined due to inadequate carcinogenicity studies.

4.6.1 870.4200b Carcinogenicity Study  Crl: CD 1 (ICR) BR Mouse Executive Summary: In a carcinogenicity study (MRID 00020717) Tebuthiuron (> 97% a. i., lot # B30 23 149) was administered to groups of 80 Harlan ICR mice/ sex/ dose in pelleted diet at dose levels of 400, 800, or 1600 ppm (60, 120, or 240 mg/ kg /day based on the default food factor of 0.15) for 2 years. The control group, consisting of 120 males and 120 females was fed untreated pelleted diet. Animals were equally subdivided by dose and sex into two substudies; the second substudy was started 1 week after the first. It should be noted that animals were not assigned by body weight.

Although there was a statistically significant decrease (32.4 g, 12%) in the terminal body weights of high dose females in one of the substudies (M9153), this is likely due to the higher body weight (36.7 g) of the control females in this substudy. The terminal body Tebuthiuron (105501) RED Toxicology Chapter 11 weight of the control females in the other substudy was 34.1 g.

There were no compound related effects on mortality, clinical signs, hematology or clinical chemistry, organ weights, or gross or microscopic pathology.

The LOAEL for systemic toxicity was not established. The NOAEL was established at 1600 ppm (240 mg/ kg/ day).

At the doses tested, there was no treatment related increase in tumor incidence when compared to that of controls. Dosing was not considered adequate based on the absence of systemic effects.

This carcinogenicity study in Unacceptable/ Guideline and does not satisfy guideline requirements for a carcinogenicity study in the rat.

4.6.2 870.4300 Carcinogenicity Study CD( SD) BR Rats Executive Summary: See section 4.5.1 (870.4300).

Adequacy of the Dose Levels Tested: At the doses tested, there was no treatment related increase in tumor incidence when compared to that of controls. Dosing was not considered adequate based on the absence of systemic effects.

4.7 Mutagenicity Adequacy of data base for Mutagenicity: The database for mutagenicity is considered adequate. The submitted test battery satisfies the Pre 1991 mutagenicity initial testing battery guidelines. There is no evidence of gene mutations in bacteria or mammalian cells, chromosome aberrations in mammalian cells or unscheduled DNA syntheses in cultured rat hepatocytes. No further testing is required at this time.

Gene Mutation 870.5100 Bacterial reverse gene mutation assay MRID 00141691 Acceptable/ Guideline In a reverse gene mutation assay in bacteria, S. typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538 were exposed to Tebuthiuron (98.0%, lot number X 35920) in dimethylsulfoxide (DMSO) at concentrations of 100, 500, 1000, 2500, or 5000 :g/ plate in the presence and absence of mammalian metabolic activation (S9 mix). Triplicate plates were utilized for each test concentration. Tebuthiuron was tested up to the limit dose. No increase in mutant frequency was noted in any strain with or without metabolic activation. The solvent and positive control values were appropriate in the respective strains. There was no evidence of induced mutant colonies over background in strains TA98, TA100, TA1535, TA1537 and TA1538 with or without S9 activation. Tebuthiuron (105501) RED Toxicology Chapter 12 870.5100 Bacterial reverse gene mutation assay MRID 00141690 Acceptable/ Guideline In a reverse gene mutation assay in bacteria, S. typhimurium strains G46, TA1535, TA100, C3076, TA1537, D3052, TA1538, and TA98 and E. coli strains WP2 and WP2 uvrA were exposed to tebuthiuron (98.0%, lot number X 35920) in dimethylsulfoxide (DMSO) over a concentration range of 0.1 to 1000 :g/ mL, in a gradient plate assay, in the presence and absence of mammalian metabolic activation (S9 mix). No increase in mutant frequency was noted in any S. typhimurium or E. coli tester strain with or without metabolic activation. The solvent and positive control values were appropriate in the respective strains. There was no evidence of induced mutant colonies over background in S. typhimurium strains G46, TA1535, TA100, C3076, TA1537, D3052, TA1538, and TA98 and E. coli strains WP2 and WP2 uvrA with or without S9 activation.

870.5300 In vitro mammalian cell gene mutation MRID 00145041 Acceptable/ Guideline In a mammalian cell gene mutation assay in vitro, cultures of mouse lymphoma L5178Y TK+/ cells were exposed to Tebuthiuron (98.0%, lot No. X 35920) in dimethylsulfoxide at concentrations of 100, 200, 300, 400, 500, 600, 700, or 800 :g/ mL in an initial assay the absence of mammalian metabolic activation (S9 mix), and at concentrations of 10, 100, 200, 300, 400, 500, 750, or 1000 :g/ mL in an initial assay in the presence of S9 mix. Due to cytotoxicity, the nonactivated assay was repeated at concentrations of 10, 100, 200, 400, 500, 600, 700, and 800 :g/ mL, and the activated assay was repeated at concentrations of 1, 10, 100, 200, 400, 500, 600, or 700 :g/ mL. Tebuthiuron technical was tested up to concentrations limited by cytotoxicity. Relative growth ranged from 57% to 13% (at 100 to 800 :g/ mL) in the absence of metabolic activation in the initial assay and from 28% to 6% (at 10 to 750 :g/ mL) in the presence of metabolic activation in the initial assay. In the initial nonactivated assay, mutation indices of 2.0 and 2.4 were detected at 700 and 800 :g/ mL, respectively. In a repeat nonactivated assay, mutation indices of 2.0, 2.0, and 2.7 occurred at 200, 400, and 500 :g/ mL, respectively. Mutations were not induced at any concentration with activation. The ethyl methane sulfonate (without S9) and 3 methylcholanthrene (with S9 mix) positive controls responded appropriately. Tebuthiuron was considered weakly mutagenic in the absence of metabolic activation. No evidence of an increased mutant frequency was observed in the presence of metabolic activation. Tebuthiuron (105501) RED Toxicology Chapter 13 Cytogenetics 870.5375 In vitro mammalian cell chromosome aberration MRID 41134101 Acceptable/ Guideline In a mammalian chromosome aberration assay, Chinese Hamster Ovary (CHO) cell cultures were exposed to Tebuthiuron (99.08%, lot number 729AS7) in dimethylsulfoxide at concentrations of 0, 1650, 1800, or 1950 :g/ mL for 4 hours in the absence of exogenous metabolic activation (S9 mix) or to 1350, 1450, or 1550 :g/ mL for 4 hours in the presence of activation (followed by an additional 19 hour incubation in fresh medium). Tebuthiuron was tested up to concentrations limited by cytotoxicity. A preliminary cytotoxicity test showed survival ranging from 15% at 2285 :g/ mL to 115% at 1000 :g/ mL under nonactivated conditions and 39% at 1750 :g/ mL and 55% at 1500 :g/ mL. A significant (p< 0.01) increase in the percent of cells with aberrations was noted in nonactivated cultures at 1950 :g/ mL (15 &19% for treated duplicate cultures vs. 5% for vehicle controls) and activated cultures at 1550 :g/ mL (15 &18% for treated duplicate cultures vs. 5 6% for vehicle controls). The predominant types of aberrations were chromosome and chromatid breaks. No significant increases were observed at lower concentrations; however, rare complex aberrations, such as triradials, quadriradials and complex rearrangements were noted, providing further support for clastogenicity. Positive control values were acceptable. There was evidence of an increase in structural chromosomal aberrations over background in the presence and absence of metabolic activation.

Other Genotoxicity 870.5550 Unscheduled DNA synthesis in mammalian cell culture MRID 40750901 Acceptable/ Guideline In an unscheduled DNA synthesis assay, primary rat hepatocyte cultures were exposed to Tebuthiuron (99.1% a. i.; Lot No. 729AS7) in dimethylsulfoxide at eight concentrations ranging from 300 to 800 :g/ mL for 20 hours. Tebuthiuron was tested to the limit of cytotoxicity (cytotoxicity was observed at $900 :g/ mL). UDS activity was evaluated at concentrations up to 800 :g/ mL and there was no evidence of induction of UDS. The solvent (1% DMSO) and positive control (N methyl N' nitrosoguanidine 1 :g/ mL and 2 acetoaminofluorene 0.05 :g/ mL) values were appropriate. There was no evidence that unscheduled DNA synthesis, as determined by radioactive tracer procedures [nuclear silver grain counts] was induced.

4.8 Neurotoxicity Adequacy of data base for Neurotoxicity: No acute or subchronic neurotoxicity studies on Tebuthiuron are available. Evaluation of subchronic, chronic and reproduction toxicity, did not reveal any treatment related effects on the central or peripheral nervous system of mice, rats, or rabbits. No changes in clinical signs, brain weights, gross necropsy results or histopathological results suggested any part of the nervous system as a target organ. However, the HIARC meeting on December 13, 2001 and January 17, 2002 determined that a developmental neurotoxicity study should be held in reserve, pending submission of a developmental toxicity study in the rabbit (TXR No. 0050450, dated Tebuthiuron (105501) RED Toxicology Chapter 14 February 5, 2002).

4.8.1 870.6100 Delayed Neurotoxicity Study  Hen This study is not required.

4.8.2 870.6200a Acute Neurotoxicity Screening Battery This study is not required.

4.8.3 870.6200b Subchronic Neurotoxicity Screening Battery This study is not required.

4.8.4 870.6300 Developmental Neurotoxicity Study The requirement for this study is being held in reserve.

4.9 Metabolism Adequacy of data base for metabolism: The data base for metabolism is considered complete and no additional studies are required at this time.

4.9.1 870.7485 Metabolism  Rat Executive Summary: In a metabolism study (MRID 42711701, 43129701), male and female Fischer 344 rats were dose with 14 C tebuthiuron at a single low oral dose (10 mg/ kg), a repeated low oral dose (10 mg/ kg x 14 days), or a single high dose (100 mg/ kg). Absorption was complete at both the low and high dose. Terminal distribution data showed no significant amounts of residual radioactivity in any tissue examined, but the skin showed the highest amounts relative to other tissues. Excretion was rapid at both the low and high dose levels in both sexes, but was delayed during the first 12 hours postdose indicating saturation of biotransformation or excretion. From HPLC and mass spectral analysis of urine samples, 6 metabolites of tebuthiuron were identified. The major metabolite was identified as 109OH and/ or 104 OH, both hydroxylated metabolites of tebuthiuron. This metabolite composed between 39.6 60.3% of the administered dose in 0 24 hour urine of male and female rats. The second most abundant metabolite was identified as metabolite 106 of tebuthiuron. This comprised between 9 15% of the administered dose in 0 24 hour urine of low dose rats, and between 55.6% and 57.3% of the administered dose for male and female rats, respectively. Two other metabolites identified, 104/ 109 and 103 OH, comprised between 2 10% of the administered dose in male and female 0 24 hour urine. Feces contained minor amounts of 104 OH and 109 OH, accounting for an average of 3.5% of the administered dose.

4.10 Special Studies None 5 TOXICITY ENDPOINT SELECTION Tebuthiuron (105501) RED Toxicology Chapter 15 See Section 9.2 for Endpoint Selection Table 5.1 Dermal Absorption No study available.

5.2 Classification of Carcinogenic Potential 5.2.1 Conclusions and Classification of Carcinogenic Potential The HIARC (TXR No. 0050450, dated February 5, 2002) reevaluated the classification and concluded that the carcinogenic potential of tebuthiuron can not be determined due to inadequate carcinogenicity studies.

5.2.2 Quantification of Carcinogenic Potential Not applicable 6 FQPA CONSIDERATIONS 6.1 Special Sensitivity to Infants and Children The toxicological database is inadequate for FQPA assessment. The developmental toxicity study in the rabbit is unacceptable for the determination of susceptibility to the fetuses due to in utero tebuthiuron exposure. However, there is an adequate developmental toxicity study in the rat and a two generation reproductive toxicity study in the rat to assess the susceptibility of fetuses/ offspring to tebuthiuron. There is no qualitative/ quantitative evidence of increased susceptibility in 2 generation reproduction study in the rat or the developmental toxicity study in the rat. In the developmental toxicity study in the rabbit, no maternal or developmental toxicity was observed at the highest dose tested. Because there was no toxicity observed at the highest dose tested, susceptibility could not be ascertained and the HIARC concluded that a new developmental toxicity in the rabbit is needed..

6.2 Recommendation for a Developmental Neurotoxicity Study The FQPA Committee reserved the requirement of a developmental neurotoxicity study pending submission of a developmental toxicity study in rabbits.

7 OTHER ISSUES None 8 REFERENCES 00020662 Todd, G. C.; Gibson, W. R.; Kiplinger, G. F. (1972) The Toxicological Evaluation of EL 103 in Rats for 3 Months. (Unpublished study received Mar 13, 1973 under 1471 97; submitted by Elanco Products Co., Div. of Eli Lilly and Co., Tebuthiuron (105501) RED Toxicology Chapter 16 Indianapolis, Ind.; CDL: 006422 G)

00020663 Todd, G. C.; Gibson, W. R.; Kiplinger, G. F. (1972) The Toxicological Evaluation of EL 103 in Dogs for 3 Months. (Unpublished study received Mar 13, 1973 under 1471 97; submitted by Elanco Products Co., Div. of Eli Lilly and Co., Indianapolis, Ind.; CDL: 006422 H)

00020644 Todd, G. C., Markham, J. K., Adams, E. R., Owen, N. V., Gossett, F. O., and Morton, D. M. (1975) A teratology study with EL 103 in the rabbit. Toxicology Division, Lilly Research Laboratories, Greenfield, IN. Study No. B 7014. April 1975. Unpublished.

00020714 Todd, G., W. Gibson, D. Hoffman, et al. 1976. The toxicological evaluation of tebuthiuron (EL 103) in rats for two years. Studies R 603 and R 613. Toxicology Division, Lilly Research Laboratories, Greenfield, IN, November, 1976. Unpublished.

00020717 Todd, G. C.; Gibson, W. R.; Hoffman, D. G.; et al. (1976) The Toxicological Evaluation of Tebuthiuron (EL 103) in Mice for Two Years: Toxicology Report # 8. (Unpublished study received Dec 1, 1976 under 1471 EX 43; submitted by Elanco Products Co., Div. of Eli Lilly and Co., Indianapolis, Ind.; CDL: 230139 D)

00020803 Todd, G. C., Markham, J. K., Adams, E. R., Owen, N. V., Gibson, W. R., and Kiplinger, G. F. (1972) Rat teratology study with EL 103. The Lilly Toxicology Laboratories, Eli Lilly and Company, Greenfield, IN. Laboratory Study No. R632 September, 1972. Unpublished.

00090108 Adams, E. R., N. Owen, and J. Hoyt. 1981. A two generation reproduction study with tebuthiuron (Compound 75503) in the Wistar rat. Lilly Research Laboratories, Greenfield, IN. November, 1981. Study numbers R03780 and R08780. Unpublished 00141691 Rexroat, M. A., Todd, G. C. (1984). The effect of Tebuthiuron (Lilly Compound 75503) on the induction of reverse mutations in Salmonella typhimurium using the Ames test. Lilly Research Laboratories, Greenfield, IN. Study No. 840326AMS655. April, 1984. Unpublished 00145041 Oberly, T. J, Bewsey, B. J., Todd, G. C. (1984). The effect of Tebuthiuron (Lilly Compound 75503) on the induction of forward mutation at the thymidine kinase locus of L5178Y mouse lymphoma cells. Lilly Research Laboratories, Greenfield, IN. Study Nos. 840410 MLA655, 84060MLA655, 840612MLA655. Unpublished.

00146801 Todd, G. (1985). The toxicity evaluation of tebuthiuron (Lilly compound 75503) to Beagle dogs for one year. Lilly Research Laboratories, Greenfield, IN. Laboratory Study No. D04283. February 1985. MRID. Unpublished.

00149733 Brown, G. (1985) Subchronic (21 Day) Dermal Toxicity Study in New Zealand White Rabbits with Technical Tebuthiuron: Study B01484. Unpublished study Tebuthiuron (105501) RED Toxicology Chapter 17 prepared by Lilly Research Laboratories. 211 p.

00160796 Negilski, D.; McGrath, J.; Young, S. (1986) Reply to U. S. EPA Recommendation To Upgrade the Current 21 day Dermal Toxicity Study (BO1484) of Technical Tebuthiuron with Additional Doses to Establish a Systemic No effect Level. Unpublished study prepared by Eli Lilly and Co. 18 p.

40485801 Todd, G. C. and Higdon, G. L. (1972) A supplementary report of a rat teratology study with tebuthiuron (EL 103, compound 75503). Toxicology Division, Lilly Research Laboratories, Greenfield, IN. Laboratory Study No. R 632. September, 1972. Unpublished.

40750901 Negilski. D. S, Garriot, M. L., Yount, D. J. (1988) . The effect of Tebuthiuron (EL 103, Compound 75503) on the induction of DNA synthesis in primary cultures of adult rat hepatocytes. Eli Lilly and Company, Greenfield, IN. Study Nos. 880510UDS0655 and 880517 UDS0655. Unpublished.

40776301 Negilski, D. S. and Higdon, G. L. (1988) A supplementary report in support of a teratology study with tebuthiuron (EL 103, Compound 75503) in the rabbit. Toxicology Division, Lilly Research Laboratories, Greenfield, IN. Study No. B7014 June 8, 1988. Unpublished.

40870101 Negilski, D.; Todd, G. (1988) A Supplemental Inventory of Selected Tissues from Rats Given Diets Containing Tebuthiuron (...) for Two Years: Project ID: R 603 and R 613. Unpublished study prepared by Lilly Research Laboratories. 10 p.

41122401 Megilski, D. S., Rutherford, B. S., and Higdon, G. L. (1989) A supplementary report for a rabbit teratology study (B 7014) with tebuthiuron (EL 103, Compound 75503)  A response to the U. S. EPA's request for certain additional information to upgrade the rabbit teratology study from core supplementary to core minimum. Toxicology Division, Lilly Research Laboratories, Greenfield, IN. Study No. B 7014. March 8, 1989. Unpublished.

41134101 Negilski, D. S., Garriot, M. L., Kindig, D. E. F. (1989) The effect of tebuthiuron (EL 103, Compound 075503) on the in vitro induction of chromosomal aberrations in Chinese Hamster Ovary cells. Lilly Research Laboratories, Greenfield, IN, Study Nos. 890111CTX655, 890125CTX655, 890201CAB655, 890228CAB655. April 12, 1989. Unpublished.

42711701 Eschbach, J.; Hackett, D. (1993) Absorption, Distribution and Elimination of (Carbon 14) Tebuthiuron in Rats: Lab Project Number: DR 0189 9383 001. Unpublished study prepared by Bio/ dynamics, Inc. 107 p.

43129701 Eschbach, J.; Hackett, D. (1994) Absorption, Distribution and Elimination of (carbon 14) Tebuthiuron in Rats: Addendum: Lab Project Number: DR/ 0189/ 9383/ 001. Unpublished study prepared by Bio/ dynamics, Inc. 10 p.

USEPA Memorandum: Tebuthiuron oncogenicity studies, HED Project No. 9 0927, Tebuthiuron (105501) RED Toxicology Chapter 18 Caswell No. 366AA. From Quang Q. Bui, Head, Review Section I, Tox BranchHFAS HED to Robert Taylor, PM, # 25, Registration Division, November 30, 1988 (TXR No.: 007374)

USEPA Memorandum: Tebuthiuron: Report of the Hazard Identification Assessment Review Committee, February 5, 2002 (TXR No 0050450)

USEPA Memorandum: Tebuthiuron: Report of the FQPA Safety Factor Committee, February 12, 2002 (TXR No. 0050466) Tebuthiuron (105501) RED Toxicology Chapter 19 9 APPENDICES  Tables for Use in Risk Assessment 9.1 Toxicity Profile Summary Tables 9.1.1 Acute Toxicity Table  See Section 4.1 9.1.2 Subchronic, Chronic, and Other Toxicity Table Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 870.3100 90 Day oral toxicityrat 00020662 (1972) Acceptable/ Guideline 0, 20, 50, 125 mg/ kg/ day NOAEL = 50 mg/ kg/ day LOAEL = 125 mg/ kg/ day, based on decreased body weight, increased relative liver, kidney, gonads, spleen (males only), and prostate and slight vacuolization of pancreatic acinar cells.

870.3150 90 Day oral toxicitydog 00020663 (1972) Acceptable/ Guideline 0, 12.5, 25, 50 NOAEL = 25 mg/ kg/ day LOAEL = 50 mg/ kg/ day, based on decrease in body weight and increased alkaline phosphatase activity.

870.3200 21/ 28 Day dermal toxicity rabbit 00149733 (1985) 00160796 (1986) Acceptable/ Guideline 0, 1000 mg/ kg/ day NOAEL = 1000 mg/ kg/ day (limit dose)

870.3250 90 Day dermal toxicity No study available N/ A 870.3465 90 Day inhalation toxicity No study available N/ A 870.4100 [83 1( b)] 1 Year Feeding Study  Dog 00146801 (1985) Acceptable/ Guideline 0, 12.5, 25, 50 mg/ kg/ day NOAEL= 25 mg/ kg/ day LOAEL = 50 mg/ kg/ day based on clinical signs, decreased body wt, increased ALT and ALP (males only), increased absolute and relative livers and relative thyroid wt, (males only) wt, and increased absolute liver wt.

870.4200 [83 2 (b)]

Oncogenicity Study  Mouse 00020717 (1986)

Unacceptable/ Guideline 0, 60, 120, 240 mg/ kg/ day NOAEL= 240 mg/ kg/ day LOAEL = Not achieved Histopathology: None observed at doses tested, doses not high enough to assess carcinogenicity. Tebuthiuron (105501) RED Toxicology Chapter 20 Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 870.4300 [83 5( a)]

Combined Chronic Toxicity/ Carcinogenicity Study  Rat 00020714 (1976) 00098190 (1981) 40870101 (1988)

Unacceptable/ Guideline 0, 20, 40, 80 mg/ kg/ day NOAEL = 40 mg/ kg/ day, females 80 mg/ kg/ day males LOAEL = 80 mg/ kg/ day, based on decreased terminal body weight in females not established in males Histopathology: None observed at doses tested, doses not high enough to assess carcinogenicity.

870.3700 [83 3( a)]

Developmental Toxicity Study  Rat 00020803 (1972) 40485801 (1972)

Acceptable/ Guideline 0, 37, 72, 110 mg/ kg/ day Maternal Systemic NOAEL= 72 mg/ kg/ day LOAEL = 110 mg/ kg/ day) based on decreased body weight gains and food consumption.

Developmental NOAEL = 110 mg/ kg/ day LOAEL = not established 870.3700 [83 3( b)]

Developmental Toxicity  Rabbit 00020644 (1975) 40776301 (1988) 41122401 (1989)

Unacceptable/ Guideline 0, 10, or 25mg/ kg/ day Maternal Systemic NOAEL= 25 mg/ kg/ day LOAEL = not established Developmental NOAEL = 25 mg/ kg/ day LOAEL = not established 870.3800 [83 4] 2 Generation Reproduction  Rat 00090108 (1981)

Acceptable/ Guideline %% 0, 7, 14, and 26 mg/ kg/ day && 7, 14, and 30 mg/ kg/ day, Systemic NOAEL= 14 mg/ kg/ day LOAEL = 30 mg/ kg/ day, based on deceased in body weight and weight gain in F1 females. Parental effect levels were not established for adult male rats in this study.

Reproductive NOAEL = 30 mg/ kg/ day LOAEL = not established Offspring NOAEL = 30 mg/ kg/ day LOAEL = not established 870.7600 (85 2) Dermal Penetration Rat No study available N/ A Tebuthiuron (105501) RED Toxicology Chapter 21 Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 870.7485 (85 1) Metabolism Study Rat 42711701 (1993) 43129701 (1994) Acceptable/ Guideline 10 or 100 mg/ kg, 1 day 10 mg/ kg/ day for 14 days Terminal distribution data showed no significant amounts of residual radioactivity in any tissue examined, but the skin showed the highest amounts relative to other tissues. Excretion was rapid at both the low and high dose levels in both sexes, but was delayed during the first 12 hours post dose, indicating saturation of biotransformation or excretion. Six metabolites of tebuthiuron were identified. The major metabolite in 0 24 hour urine of male (58.3%) and female (62.1%) rats was identified as hydroxylated tebuthiuron metabolites (# 109 OH and /or #104 OH). The second most abundant metabolite was identified as metabolite 106 of tebuthiuron. This comprised between 9 15% of the administered dose in 0 24 hour urine of low dose rats, and between 1  10% of the administered dose in high dose rats. Two other metabolites identified, 104/ 109 and 103 OH, .comprised between 2 10% of the administered dose in male and female 0 24 hour urine. Feces contained minor amounts of 104 OH and 109 OH, accounting for an average of 3.5% of the administered dose. Tebuthiuron (105501) RED Toxicology Chapter 22 aPAD aRfD FQPA SF = cPAD cRfD FQPA SF = 9.2 Summary of Toxicological Dose and Endpoints for Tebuthiuron for Use in Human Risk Assessment Exposure Scenario Dose Used in Risk Assessment, UF 1 FQPA SF and Endpoint for Risk Assessment Study and Toxicological Effects Acute Dietary females 13 50 years of age NOAEL = 25 mg/ kg/ day UF = 100 Acute RfD = 0.25 mg/ kg/ day FQPA SF 2 =3 = 0.083 mg/ kg/ day Developmental Toxicity Study Rabbit NOAEL of 25 mg/ kg/ day. LOAEL not established A range finding study showed increased early resorptions at 50 mg/ kg/ day Acute Dietary general population including infants and children N/ A N/ A No appropriate effects attributed to a single exposure was identified.

Chronic Dietary all populations NOAEL= 14 mg/ kg/ day UF = 100 Chronic RfD = 0.14 mg/ kg/ day FQPA SF 3 = 1 = 0.14 mg/ kg/ day Two generation reproduction study in the rat LOAEL = 30 mg/ kg/ day, based on decreased body weight and feed consumption in F1 females Toxicological endpoints for occupational/ residential exposure risk assessments were not selected since tebuthiuron is scheduled for a Tolerance Reassessment Eligibility Decision (TRED)

1 UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic) RfD = reference dose 2 Because there is a data gap for assessing susceptibility of fetuses following in utero exposure a FQPA safety factor of 3x will be used.

3 Because there was no susceptibility identified in the 2 generation rat reproduction study (a long term study). the FQPA safety factor will be removed (1x).


[Federal Register Volume 84, Number 112 (Tuesday, June 11, 2019)]
[Notices]
[Pages 27136-27137]
[FR Doc No: 2019-12256]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2019-N-2039]

Development of Best Practices in Physiologically Based
Pharmacokinetic Modeling To Support Clinical Pharmacology Regulatory
Decision-Making; Public Workshop

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of public workshop.

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SUMMARY: The Food and Drug Administration (FDA) Center for Drug
Evaluation and Research (CDER), in collaboration with the Center for
Biologics Evaluation and Research (CBER), is announcing a public
workshop entitled ``Development of Best Practices in Physiologically
Based Pharmacokinetic Modeling to Support Clinical Pharmacology
Regulatory Decision-Making.'' The purpose of this public workshop is to
discuss best practices and evidentiary criteria in the use of
physiologically based pharmacokinetic (PBPK) modeling approaches to
support regulatory decision-making; share experiences and cases where
applying PBPK modeling and simulation highlight the opportunities and
limitations of this approach; obtain input from stakeholders on when,
where, how, and with what limitations PBPK modeling and simulation may
be applied in regulatory decision-making; and discuss the knowledge
gaps and research needed to advance PBPK modeling sciences in drug
development to support regulatory decisions. This public workshop is
also being conducted to satisfy one of FDA's performance goals included
in the sixth reauthorization of the Prescription Drug User Fee
Amendments (PDUFA VI), part of the FDA Reauthorization Act of 2017
(FDARA), to hold a series of workshops related to model-informed drug
development (MIDD).

DATES: The public workshop will be held on November 18, 2019, from 8
a.m. to 5 p.m., Eastern Time. See the SUPPLEMENTARY INFORMATION section
for registration date and information.

ADDRESSES: The public workshop will be held at FDA White Oak Campus,
10903 New Hampshire Ave., Bldg. 31 Conference Center, the Great Room
(Rm. 1503, B and C), Silver Spring, MD 20993-0002. Entrance for public
workshop participants (non-FDA employees) is through Building 1 where
routine security procedures will be performed. For parking and security
information, please refer to: http://www.fda.gov/AboutFDA/WorkingatFDA/BuildingsandFacilities/WhiteOakCampusInformation/ucm241740.htm.

FOR FURTHER INFORMATION CONTACT: Lauren Milligan, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 3159, Silver Spring, MD 20993-0002, 240-
402-6421, email<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION:

I. Background

    Under FDARA, and in accordance with section I, part J of the PDUFA
VI Performance Goals, FDA agreed to convene a series of workshops to
identify best practices for MIDD (https://www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM511438.pdf at 27). FDA
is conducting this workshop as part of the MIDD workshop series.
    PBPK modeling is a drug development tool that mathematically
integrates physiological, physicochemical, and drug-dependent
preclinical and clinical information to predict an investigational
drug's absorption, distribution, metabolism, excretion, and
pharmacokinetics (PK). Over the past several decades, there has been
extensive research using PBPK modeling and simulation to address a wide
range of clinical questions, such as exploring the effects of extrinsic
factors (e.g., concomitant medications, food intake) and intrinsic
factors (e.g., age, organ dysfunction, disease status, genetics) on
drug exposures.
    FDA notes that PBPK modeling and simulation approaches are
extensively used in regulatory submissions to predict the potential for
drug-drug interactions and to support dosing recommendations for
certain drugs when they are co-administered with metabolic enzyme
modulators. However, challenges and knowledge gaps prevent PBPK
modeling from being routinely used for specific regulatory decisions.
Given the current limitations of the approach, it is important that the
scientific community explore when, where, and how PBPK modeling and
simulation may be applied in regulatory decision-making.

II. Objectives

    The objectives of the workshop are to:

    1. Discuss ``best practices'' in integrating in vitro and in
vivo data to develop PBPK models and developing evidentiary criteria

for PBPK models to be used for regulatory decision-making.
    2. Share experiences and cases applying PBPK modeling and
simulation that highlight the opportunities and limitations of this
approach.
    3. Obtain input from the stakeholders on when, where, how, and
with what limitations PBPK modeling and simulation may be applied in
regulatory decision-making.
    4. Discuss the knowledge gaps and research needs to advance PBPK
modeling sciences in drug development and regulatory evaluation.

    A detailed agenda will be posted in advance of the workshop at
https://www.fda.gov/Drugs/NewsEvents/ucm633778.htm.

III. Participating in the Public Workshop

    Registration: Persons interested in attending this public workshop
must register online by November 8, 2019, at https://www.eventbrite.com/e/pbpk-modeling-to-support-clinical-pharmacology-regulatory-decision-making-tickets-59005519096. Please provide complete
contact information for each attendee.
    Registration is free and based on space availability, with priority
given to early registrants. Early registration is recommended because
seating is limited. FDA may limit the number of participants from each
organization. Registrants will receive confirmation when they have been
accepted. If time and space permit, onsite registration on the day of
the public workshop will be provided beginning at 8 a.m.
    If you need special accommodations due to a disability, please
contact Lauren Milligan (see FOR FURTHER INFORMATION CONTACT) no later
than November 8, 2019.
    Streaming Webcast of the Public Workshop: This public workshop will
also be webcast. A live webcast of this workshop will be available at
https://www.fda.gov/Drugs/NewsEvents/ucm633778.htm on the day of the
workshop. If you have never attended a Connect Pro event before, test
your connection at https://collaboration.fda.gov/common/help/en/support/meeting_test.htm. To get a quick overview of the Connect Pro
program, visit https://www.adobe.com/go/connectpro_overview. FDA has
verified the website addresses in this document, as of the date this
document publishes in the Federal Register, but websites are subject to
change over time.
    Transcripts: Please be advised that as soon as a transcript of the
public workshop is available, it will be accessible at https://www.fda.gov/Drugs/NewsEvents/ucm633778.htm. It may be viewed at the
Dockets Management Staff (HFA-305), Food and Drug Administration, 5630
Fishers Lane, Rm. 1061, Rockville, MD 20852. A link to the transcript
will be available on the internet at https://www.fda.gov/Drugs/NewsEvents/ucm633778.htm.

    Dated: June 6, 2019.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2019-12256 Filed 6-10-19; 8:45 am]
 BILLING CODE 4164-01-P