Task Force June 14, 2002 P. O. Box 331, Miflwood, VA 22646 ( 540) 837 1602 Charles M. Auer Environmental Protection Agency 1200 Pennsylvania Avenue, NW Room 4146 A Washington, DC 20004 Re: ~

Dear Mr. Auer:

The HAP Task Force has addressed the technical issues raised in your March 1, 2002 letter. To resolve these remaining technical issues, a meeting was held at the recent Society of Toxicology ( SOT) meeting in Nashville between EPA scientists and our contractor. As a consequence, appropriate changes and additions have b~ ee~~~ made to Appendix C and additional references regarding the PBPK modeling have been added. These are enclosed.

With these changes, I look forward to seeing a final draft ofthe enforceable consent agreement ( ECA) for ethylene dichioride.

Enclosure S incer ly your~

nIA1 / 1~ ~

Peter E. Voytek, PhD Manager cc: W. C, Norman, Esq. RECEIVED OPPT NCIC 2003 MAR11 5: 03PM OPPT 2003 0010 0052 APPENDIX C PK/ MECH PROCEDURES AND ROUTE TO ROUTE EXTRAPOLATION REPORTING FOR ETHYLENE DICHLORIDE This Appendix contains detailed procedures for the kinetic studies and route to route extrapolations to be conducted for ethylene dichioride, and is organized into the following sections:

C. 1 Pharmacokinetic Studies for F344 Rats C. 2 Subchronic Toxicity C. 3 Subchronic Neurotoxicity C. 4 Reproductive Toxicity C, 5 PBPK Model Description and Coding C, 6 General Outline for Route to Route Extrapolation Reports C:\ WINDOWS\ Temporary Internet Files\ ContentJE5\ 4EAADOIJA\ edc AppC_ rev. wpd April 24, 2002 C.!. Pharmacokinetic Studies for F344 Rats A total of4 pharmacokinetic studies ( designated Study 1, Study 2, Study 3 and Study 4) will be conducted to support PBPK modeling activities for ethylene dichloride, as described in this section ( C. 1.). It is anticipated that the pharmacokinetic studies will start one year after the ECAis signed, with an interim report generated six months later, and the final report submitted three months later ( see Appendix A for complete schedule).

Demonstration ofPeriodicity Following Repeated Inhalation Exposures Dose( s) Route Exposure Frequency Observations ProDosed Rat F344 Young adult 132 animals ( 3 controls at beginning ( t =

0) and 3 at end ofexposure ( t = 6 ix) on days 1, 3, and 5; 3 exposed animals at the beginning of exposure ( t 0) on days 3 and 5, 3 exposed animals/ time point at t 0.25, 0.5, 6.25 and 16 hr during and after exposure on days 1, 3, and 5, and 6 exposed animals/ time point at t = 1, 3, 6, and 8 hr during and after exposure on days 1, 3, 5) To be determined Inhalation 6 hrs/ day, 5 consecutive days Liver and lung GSH in controls ( n 3) at beginning and end ofexposure ( 0 and 6 hrs) on days 1 ,3 and 5. Lung and liver GSH in exposed animals ( n 3) at beginning of exposure on days 3 and 5. Venous blood concentrations ofEDC ( n 3) at 0.25, 0.5, 6.25, and 16 hrs after exposure starts on days 1, 3, and 5. Venous blood concentrations ofEDC ( n = 6) and lung and liver GSH concentrations ( n 3) at 1, 3, 6, and 8 hours after exposure starts on days 1, 3, and 5. Parameter Species Strain Age Number of animals C:\ WINDOWS\ Temporary hiternet Fi1es\ Content. IE5\ 4EAADO~ JA\ edc AppCrev. wpd April 24, 2002 Kinetic studies wifi be conducted for demonstrating periodicity in the rat following inhalation exposures with EDC. Measurements ofEDC in blood and tissue: blood partition coefficients are anticipated to be sufficient to describe tissue concentration time courses ofEDC based onthe results ofSpreafico eta!. ( 1980) where concentrations in brain, kidney, spleen, liver, lung, andadiposetissue were found to parallel the concentrations in blood ofrats exposed to EDC byiv, oral, and inhalation routes. Measurements oflung and liver GSH will be used to further calibrate and validate the GSHdepletion portion ofthe PBPK model. These data will allow the model to compute the flux through both metabolism pathways that are dependent onGSH conjugation ( see section C. 5). The depletion ofGSH in various tissues has been used to determine and validate the kinetic constants for GSH conjugation reactions for a number ofchemicals and their metabolites. These include vinylidene chloride ( D'Souzaand Andersen, 1988), EDC ( D'Souza eta!., 1988), ethyl acrylate ( Frederick eta!., 1992), ethylene oxide ( Krishnan et al., 1992) and ally! chloride ( Clewell and Andersen, 1994). In contrast, elimination ofEDC metabolites via the GSH pathway, measured as urinary thiodiglycolic acid ( TDGA) is not anoptimal biomarker ofGSH metabolism. Departures from a linear relationship between dose and 24 hour TDGAmay be observed as doseincreases ( Payan et a!., 1993) in therange ofdoses used in existing toxicity studies ( e. g., NCI, 1978). A possible lag in urinary elimination as TDGA, extending > 24 hours after dosing, would compromise use ofthis biomarker as validation for GSH metabolism during a repeated dosing study.

Air concentrations should be measured hourly. Blood samples will be drawn on days 1, 3, and 5. Blood samples ( from 3 or 6 animals) and liver and lung of3 animals ( for glutathione determination) will be collected immediately following sacrifice. Blood samples will be drawn from 6 animals only at sampling times where lung and liver GSH are also being measured ( 3 animals' lungs and livers for GSH, 3 for freezing). Lung, liver, kidney, brain, adrenal gland, and thyroid will be frozen for possible further analysis. A positive control ( spiked storage sample) wifi be required to demonstrate the recovery ofEDC in tissues following freezing. Tissues wifi be stored until after the Tier I Program Review.

C:\ WINDOWS\ TemporaryInternet FiIes\ Content. IE5\ 4EAADO~ JA\ edc AppCrev. wpd April 24, 2002 Demonstration of Periodicity Following Repeated Oral Exposures to Ethylene Dichioride by Corn Oil Gavage Parameter Species Strain Age Number ofanimals Dose( s) Route Exposure Frequency Observations Pronosed Rat F344 Young adult 132 animals ( 3 controls at dosing ( t = 0) and 3 after dosing ( t = 2 6 ix) on days 1, 3, and 5; 3 exposed animals prior to dosing ( t = 0) on days 3 and 5; 3 exposed animals at t = 0.25, 4, 16, and 24 hrs after dosing on days 1, 3, and 5; and 6 exposed animals/ time point 0.5, 1, 2, and 8 hrs after dosing on days 1, 3, 5) 150 mg/ kg Corn oil gavage 1 x/ day, 5 consecutive days Liver and lung GSH in controls ( n = 3) prior to dosing ( at 0 hrs) and at 8 hrs after dosing. Liver and lung GSH in previously dosed animals ( n = 3) prior to dosing ofremaining animals ( t = 0) on days 3 and 5. Venous blood concentrations ofEDC ( n= 3) at 0.25, 4, 16, and 24 hrs after dosing on days 1, 3, and 5. Venous blood concentrations of EDC ( n 6) and lung and liver GSH concentrations ( n = 3) at 0.5, 1, 2, and 8 hours after exposure starts on days 1, 3, and 5 Kinetic studies will be conducted for demonstrating periodicity in the rat following corn oil gavage with EDC. Measurements ofEDC in blood and tissue: blood partition coefficients are anticipated to be sufficient to describe tissue concentration time courses ofEDC based on the results ofSpreafico et al. ( 1980) where concentrations in brain, kidney, spleen, liver, lung, and adipose tissue were found to parallel the concentrations in blood of rats exposed to EDC by iv, oral, and inhalation routes. Measurements oflung and liver GSH wifi be usedto further calibrate and validate theGSH depletion portion ofthe PBPK model. These data wifi allow the model to compute the flux through both metabolism pathways that are dependent on GSH conjugation ( see section C. 5). The depletion of GSH in various tissues has been used to determine and validate the kinetic constants for GSH conjugation reactions for a number of chemicals and their metabolites. These include vinylidene C:\ WINDOWS\ TemporaryInternet Files\ Content. 1E5\ 4EAADO4JA\ edc AppC_ rev. wpd April 24, 2002 chloride ( D'Souza and Andersen, 1988), EDC ( D'Souza et al., 1988), ethyl acrylate ( Frederick et a!., 1992), ethylene oxide ( Krishnan et al., 1992) and allyl chloride ( Clewell and Andersen, 1994). In contrast, elimination ofEDC metabolites via the GSH pathway, measured as urinary thiodiglycolic acid ( TDGA) is not an optimal biomarker ofGSH metabolism, Departures from a linear relationship between dose and 24 hourTDGA maybe observed as dose increases ( Payan et aL, 1993) in the range ofdoses used in existing toxicity studies ( e. g., NCI, 1978). A possible lag in urinary elimination as TDGA, extending > 24 hours after dosing, would compromise use ofthis biomarker as validation for GSH metabolism during a repeated dosing study.

The test dose was selected based on the doses administeredto rats in the high dose group for the 90 day study conducted by Daniel et al. ( 1994). Blood samples will be drawn on days 1, 3, and 5. Blood samples ( from 3 or 6 animals) and liver and lung of3 animals ( for glutathione determination) will be collected immediately following sacrifice. Lung, liver, kidney, brain, adrenal gland, and thyroid will be frozen for possible further analysis. A positive control ( spiked storage sample) will be required to demonstrate the recoveryofEDC in tissues following freezing. Tissues wifi be stored until after the Tier I Program Review.

C:\ WINDOWS\ Ten iporary InternetFiles\ Content. 1E5\ 4EAADO~ JA\ edc AppCrev. wpd April 24, 2002 Demonstration of Periodicity ~ ridebAueousGavae Parameter Following Repeated Oral Exposures to Ethylene Proposed Species Rat Strain F344 Age Young adult Number of animals 132 animals ( 3 controls at dosing ( t = 0) and 3 after dosing ( t 2 6 ix) on days 1, 3, and 5; 3 exposed animals prior to dosing ( t = 0) on days 3 and 5; 3 exposed animals at t 0.25, 4, 16, and 24 hrs after dosing on days 1, 3, and 5; and 6 exposed animals/ time point 0.5, 1, 2, and 8 hrs after dosing on days 1, 3, 5) Doses < 43 mg/ kg day Route Aqueous gavage Exposure Frequency ix/ day, 5 consecutive days Observations Liver and lung GSH in controls ( n = 3) prior to dosing ( at 0 hrs) and at 8 hrs after dosing. Liver and lung GSH in previously dosed animals ( n 3) prior to dosing ofremaining animals ( t 0) on days 3 and 5. Venous blood concentrations ofEDC ( n'= 3) at 0.25, 4, 16, and 24 hrs after dosing on days 1, 3, and 5. Venous blood concentrations of EDC ( n 6) and lung and liver GSH concentrations ( n = 3) at 0.5, 1, 2, and 8 hours after exposure starts on days 1, 3, and 5 Kinetic studies will be conducted for demonstrating periodicity in the rat following aqueous gavage with EDC. Measurements ofEDC in blood and tissue: blood partition coefficients are anticipated to be sufficient to describe tissue concentration time courses ofEDC based on the results ofSpreafico et al. ( 1980) where concentrationsin brain, kidney, spleen, liver, lung, and adipose tissue were found to parallel the concentrations in blood ofrats exposed to EDC by iv, oral, and inhalation routes. Measurements oflung and liver GSH will be used to further calibrate and validate the GSH depletion portion of the PBPK model. These data will allow the model to compute the flux through both metabolism pathways that are dependent on GSH conjugation ( see section C. 5). The depletion of GSH in various tissues has been used to determine and validate the kinetic constants for GSH conjugation reactions for a number of chemicals and their metabolites. These include vinylidene chloride ( D'Souza and Andersen, 1988), EDC ( D' Souza et aL, 1988), ethyl acrylate ( Fredericket al.,

C:\ WJNDOWS\ Temporary Internet Files\ ContenLlE5\ 4EAADO6JA\ ede" AppC_ rev. wpd April 24, 2002 1992), ethylene oxide ( Krishnan et al., 1992) and allyl chloride ( Clewell and Andersen, 1994). In contrast, elimination ofEDC metabolites via the GSH pathway, measured as urinary thiodiglycolic acid ( TDGA) is not anoptimal biomarker ofGSHmetabolism. Departures from a linear relationship betweendose and 24 hourTDGA may be observed as doseincreases ( Payan et al., 1993) in the range ofdoses used in existing toxicity studies ( e. g., NCI, 1978). A possible lag in urinary elimination as TDGA, extending > 24 hours after dosing, would compromise use ofthis biomarker as validation for GSH metabolism during a repeated dosing study. The rate constant for oral absorption from a gavage dose of EDC in water ( to be determined via PBPK modeling) wifi be considered appropriate for modeling oftoxicity studies in whichEDC wasingested via adlibitum access to drinkingwater ( e. g., O'Flaherty, 1996).

The test dose will be selected based on the water solubility and dosing volume. The water solubility of EDC is 8.7 mg/ niL, and the dosing volume for a rat should be no more than 5 nil/ kg, for a maximum dose of 43 mg/ kg/ d. The actual dose will be set based on the ability of the lab to consistently, homogeneously solubilize the test article. Blood samples wifi be drawn on days 1, 3, and 5. Blood samples ( from 3 or 6 animals) and liver and lung of 3 animals ( for glutathione determination) will be collected immediately following sacrifice. Lung, liver, kidney, brain, adrenal gland, and thyroid will be frozen for possible further analysis. A positive control ( spiked storage sample) will be required to demonstrate the recovery ofEDC in tissues following freezing. Tissues will be stored until after the Tier I Program Review.

C:\ WINDOWS\ Temporary Internet Files\ Content. 1E5\ 4EAADdVJA\ edc AppCrev. wpd April 24, 2002 Study 4: Determination ofPartition Coefficients The rat brain: air, kidney: air, testes: air, and ovary: air partition coefficients will be determined using the vial equilibration technique described by Gargas et al. ( 1989, Toxicol. Appl. Pharmacol. 98, 87 99).

A total of 5 rats will be used, ifpartition coefficients are determined individually. A higher number ofanimals may be required if composite samples are used. It is preferred that partition coefficients be determined for individual animals, however if tissue volumes are insufficient to measure individually a composite sample may be used.

C:\ WTNDOWS\ Temporary Internet Files\ Content. 1E5\ 4EAAI) O& A\ edc AppCrev. wpd April 24, 2002 C. 2 Subchronic Toxicity Route To Route Extrapolation The NOAEL/ LOAEL values obtained from the existing subchronic study ofDaniel et al. ( 1994) will be extrapolated from the oral route to the inhalation route using a PBPK model ( Appendix C. 5). The internal dose metric ( e. g., peak concentration or average concentration ofEDC, or amount ofEDC metabolized) used to perform this extrapolation will be determined based on a consideration ofthe effects observed and a plausible mechanism ofaction.

C:\ WINDOWS\ Temporary Internet Files\ Content. 1E5\ 4EAADO9JA\ edc AppC_ rev. wpd April 24, 2002 C. 3 Subchronic Neurotoxicity ~ To RouteExtraolation The NOAEL/ LOAEL values obtained from the subchronic neurotoxicity testing will be extrapolated from the oral route to the inhalation route using a PBPK model ( Appendix C. 5). The internal dose metric ( e. g., peak concentration or average concentration ofEDC, or amount ofEDC metabolized) used to perform this extrapolation will be determined based on a consideration ofany neurological effects observed and a plausible mechanism ofaction.

C:\ WINDOWS\ Temporary Internet Files\ Content. IE5\ 4EAADdI~ lA\ ede AppCrev. wpd April 24, 2002 C. 4 Reproductive Toxicity ~ To RouteExtraolation TheNOAEL/ LOAELvalues obtained from the reproductive toxicity testing willbe extrapolatedfrom the oral route to the inhalation route using a PBPK model ( Appendix C. 5). The results ofAlumot et al. ( 1976), Rao et al. ( 1980) and Lane et al. ( 1982) will also be compared to the current reproductive toxicity testing. The internal dose metric ( e. g., peak concentration or average concentration ofEDC, or amount ofEDC metabolized) used to perform this extrapolation will be determined based on a consideration ofany reproductive effects observed and a plausible mechanism ofaction.

C:\ WINDOWS\ Temporary Internet Files\ Content. 1E5\ 4EAADdII1A\ ede'AppCrev. wpd April 24, 2002 C. 5 PBPK Model Description and Coding The preliminary PBPK model ( to be refined as part ofthis ECA) is a modification ofD'Souza et al. ( 1987, 1988) to include periodic consumption ofdrinking water. Rat physiology is represented by five tissue groups ( lung, liver, richly perfused tissues, slowly perfused tissues, and adipose tissues). Because conjugation of EDC with glutathione in the lung and liver is an important pathway of elimination, the model includes normal synthesis and breakdown ofglutathione in the lung and liver and a time delayed compensatory increase in glutathione synthesis when glutathione concentrations are less than steady state values. The oxidative metabolite ofEDC is assumed to stay within the tissue in which it was produced ( lung or liver) and its production ( from EDC) and further reactions ( GSH conjugation and other reactions) are described. The metabolic scheme is depicted below.

Ethylene dichioride Oxidative metabolism + H cl~ cl~ 0 I ( VmaxL, Km) ( KGSM) I + GSH I ( KGS) OH ( KFEE)

CI~~

Macromolecules, other reactions The PBPK model for repeated exposure to EDC, to be refined based on the studies described in C. 1, will also be validated against other relevant, existing pharmacokinetic data for single exposures to EDC ( e. g., Reitz et aL, 1982, Spreafico et al., 1980, D'Souza et al., 1987, 1988).

The model code is provided below.

PROGRAM: GLUTATHIONE DEPLETION MODEL FOR EDC ( EDC GSH. CSL) ` Initial parameter values for the rat ( DSouza et al. 1987, 1988)' ` Retyped, documentation modified by LMS 7/ 19/ 0 1'

INITIAL ` SPECIAL FLOW RATES'

C:\ WINDOWS\ Ternporary Internet Files\ ContenLlE5\ 4EAADdI2A\ edc AppCrev. wpd April 24,2002 CONSTANT QPC'~= l5 $` alveolar ventilationrate L/ hr/ kg" 0.74'

CONSTANT QCC= 15 $` Cardiac output L/ hr/ kgt' 0.74'

` FRACTIONAL BLOOD FLOW TO TISSUES' CONSTANT QLC = 0.07 $` Fractional blood flow to liver' CONSTANT QFC = 0.05 $` Fractional blood flow to fat' CONSTANT QRC = 0.64 $` Fractional blood flow to rapid' CONSTANT QSC = 0.24 $` Fractional blood flowto slow'

` BODY WEIGHT' CONSTANT BW = 0.22 $` Body weight ( kg)'

` FRACTIONAL TISSUE VOLUMES' CONSTANT VPC = 0.004 $` Fraction lung tissue' CONSTANT VLC = 0.04 $` Fraction liver tissue' CONSTANT VFC = 0.07 $` Fraction fat tissue' CONSTANT VRC = 0.316 $` Fraction rapid tissue' CONSTANT VSC = 0.42 $` Fraction slow tissue'

` PARTITION COEFFICIENTS' CONSTANT PP = 1.1 $` Lung/ blood partition coefficient' CONSTANT PL = 1.1 $` Liver/ blood partition coefficient' CONSTANT PF = 12.2 $` Fat/ blood partition coefficient' CONSTANT PS = 0.8 $` Slowly perfused tissue/ blood partition coefficient' CONSTANT PR = 1.1 $` Richly perfused tissue/ blood partition coefficient' CONSTANT PB = 27.6 $` Bloodlair partition coefficient'

CONSTANT MW = 98.96 $` Molecular weight ( g/ mol)'

` KINETIC CONSTANTS' CONSTANT VMAX1C = 3.15 $` Maximum velocity ofmetabolism ( mg/ hr kg" 0.7)' CONSTANT VMAXpC = 3.15 $` Maximum velocity ofmetabolism ( mg/ hr kgt' 0.7)' CONSTANT KM = 0.25 $` Michaelis Menten constant ( mg/ L)'

CONSTANT KGSC=' 0.0012 $` conj rate const w parent( l/( uM ix kg'~' 0.7))' CONSTANT KGSMC = 0.15 $` conj rate const w metab ( l/( uM hr kg'~ 0.7))' CONSTANT KFEEC= 4500 $` conj rate const w non gsh ( l/( hr kg'~' 0.7))' CONSTANT KOalC = 3.8 $` GSH synthase synthesis liv( umol/ hr/ hr/ kg'~ 0.7)' CONSTANT KOapC = 0.22 $` GSH synthase synthesis lu( umol/ hr/ hr/ kgt' 0.7)' CONSTANT K1CO. 1 16 $` GSH breakdown ( 1/ hr/ kg" 0.7)' CONSTANT Ki aC' 0.095 $` GSH synthase breakdown( 1 / hr/ kg" O. 7)' CONSTANT KS = 1000 $` Maximum GSH induction ( uM)' CONSTANT TD = 1.5 $` Time delay ( ix)'

C:\ WINDOWS\ TemporaryInternet Files\ Content. 1E5\ 4EAADdI3A\ edc AppC rev. wpd April 24, 2002 CONSTANT GSO1 = 7000 $` Initial GSH concentration ( uM)' CONSTANT GSOp = 1200 $` Initial GSH concentration ( uM)' CONSTANT PLRATIOO. 14 $` MFO ratio lung/ liver' CONSTANT KOOl = 11.254 $` liver ( umo] Ihr)' CONSTANT KOOp = 11.254 $` liver ( umol/ hr)'

DOSING INFO' CONSTANT CONC = 10 $ Inhaled concentration ( ppm)'

` Periodic drinking water exposure section' ` assume t= 0 is 7 am for reference' INTEGER I $ I'= l $` Counter for drinking arrays' CONSTANT DRCONC= 0.0 $` Conc ofEDC in water ( mg/ L)' CONSTANT KA = S $ rate const absorp EDC from stomach' ARRAY DRTIME( 6) $` store drinking times in array' ARRAY DRPCT( 6) $` store drinking percentages' CONSTANT DRTIME= 1.0,5.0,9.0,13.0,17.0,21,0 CONSTANT DRPCT= 0.233,0. 1,0.1,0.1,0.233,0.234 ` Assume 70 kg man drinks 2 liters/ day, calc rodent allometrically' DRVOL = 0. 102* BW** 0.7 $` calc vol water drunk from BW' DRDOSE = DRVOL* DRCONC $` total dose from water each day ( mg)' ODOSE = 0.0 $` to calculate input to stom ( mg)' NEWDAY = 0,0 $` to reset arrays each 24 hrs'

` TIMTNG PARAMETERS' CONSTANT TSTART = 48. $` Start ofexposure ( hrs)' CONSTANT TPER= 24 CONSTANT TSTOP= l20 CONSTANT POINTS= 1200 $` Number ofpoints in plot' CINT = TSTOP/ POINTS $` Commun' tion interval' TCHNG= 6 ` SCALED PARAMETERS' QC = QCC* BW** 0.74 QP = QPC* BW** 0.74 QL = QLC* QC QF = QFC* QC QS = QSC* QC QR= QRC* QC VP = VPC* BW VL = VLC* BW VF = VFC* BW C:\ WINDOWS\ TemporaryInternet Files\ Content, 1E5\ 4EAADdI4A\ edc AppC rev. wpd April 24, 2002 VS = 0.82* BW~ VF VR = 0,09* BW~ VL ` Liver metabolism' VMAX1= VMAXIC* BW** 07 KOal ~ r~ K0alC* BW** 0.7 Kgs KgsC* bw**(~ 0.3) Kgsm KgsmC* bw**(~ 0.3) Kfee = KfeeC* BW**(~ 0.3) Ki = K1C* BW**(~ 0.3) Kia K1aC* BW**(~ 0,3) AGSOI= GSO1* VL ` Lung metabolism VMAXp= PLRATIO* VMAXpC* BW** 0.7 KOap = KOapC* BW** 0,7 AGSOpGSOp* VP P1= 0 P1R= 0 P2= 0 P2R= 0 P3= 100 P3R= 100 END $` End ofinitial'

DYNAMIC ALGORITHM IALG'= 2 $~ Gearmethod for stiff systems'

DERIVATIVE ` CI= Concentration in inhaled air ( mg/ l)' CI= MW/ 24450* CONC* pulse( tstart, tper, tchng)

` Algebraic solution for CAl after gas exchange' CA1= ( QC* CV + QP* CI)/( QC + QP/ PB) CX = CAl/ PB ` Mass balance for the lung tissue compartment' RAP = QC*( CA1~ CA) RAMp AP = INTEG( RAP, 0.0) CP = AP/ VP AUCP= INTEG( CP, 0.0) CA= CP/ PP C:\ WINDOWS\ Temporary Internet Files\ ContenLJE5\ 4EAADdI5A\ edc AppCrev. wpd April 24, 2002 AUCB= INTEG( CA, 0.0)

` UPTAKE BY ORAL ROUTE' RSTOM = ~ KA* STOM $` dSTOM/ dT' STOM = INTEG( RSTOM, 0.0) + ODOSE $` amount in stomach ( mg)'

` AS = Amount in slowly perfused tissues ( mg)' RAS = QS*( CA~ CVS) AS = INTEG( RAS, 0.0) CVS = AS/( VS* PS) CS = AS/ VS ` AR= Amount in richly perfused tissues ( mg)' RAR = QR*( CA~ CVR) AR = INTEG( RAR, 0.0) CVR = AR/( VR* PR) CR = ARIVR ` ÀY = Amount in fat tissues ( mg)' RAF = QF*( CA~ CVF) AF = INTEG( RAF, 0.0) CVF = AF/( VF* PF) CF = AF/ VF CV = Mixed venous blood concentration ( mg/ l)' CV = ( QF* CVF + QL* CVL + QS* CVS + QR* CVR)/ QC ` LIVER METABOLISM' ` AL = Amount in liver tissue ( mg)' RAL = QL*( CA~ CVL)~ RAMl + KA* STOM AL = INTEG( RAL, 0.0) CVL = AL/( VL* PL) CL = AL/ VL AUCL = INTEG( CL, 0.)

` AM = Amount metabolized liver ( mg)' RAM1=( VMAX1* CVL)/( KM+ CVL)+ RACPG1* MW/ I000 AMI= INTEG( RAM1,0.) AMPI= AM1* 1000/ MW RAMP1= RAML* 1000/ MW ` CMl= OXIDATIVE METABOLITE LIVER mg/ L)' RAMMl=( VMAX1* CVL)/( KM+ CVL)~ RACMGl* MW/ l000~ RACMEEl* MW/ 1000 C:\ WINDOWS\ Ternporary Internet Files\ ContenLlES\ 4EAADdl~ A\ edc~ AppC_ rev. wpd April 24, 2002 AMM1= INTEG( RAMM1,0.) CML= AMMI/ VL ` GSl = GLUTAHIONE LIVER ( uM)' GSHtdl = DELAY( GSI* 1 , GS1, TD, 10000) $` Time delayed GSH levels' RK0I~~ K0al*( GSOl+ KS)/( GSHtdl + KS) K1A* K0l KOl= INTEG( RKOL, KOOl) RAMGS1= KOl K1 * GS1* VL. RACMG1.. RACPGI AMGS1= INTEG( RAMGS1, AGSO1) GS1= AMGS1/ VL ` ACMGlAMT METABOLITE CONJUGATED WITH GSH LIVER ( uMOLES)' RACMGI= KGSM* GS1* CMI* 1000/ MW ACMG1= INTEG( RACMGI, 0.0)

` ACMEEI= AMT METABOLITE CONJUGATED WITH EVERYTHING ELSE LIVER' ` uMOLES' RACMEEI= KFEE* VL* CM1* 1 000/ MW ACMEEI= INTEG( RACMEE1,0.)

` ACPGI = AMT PARENT CONJUGATED WITH GSH LIVER ( uMOLES)' RACPG1= KGS* GS1* CVL* VL* 1000/ MW ACPG1= INTEG( RACPG1,0.)

` LUNG METABOLISM' ` AMp= Amount metabolized lung ( mg)' RAMp=( VMAXp* CA)/( KM+ CA)+ RACPGp* MW/ i000 AMp" INTEG( RAMp, O.) AMPp= AMp* 1000./ MW pJ~= p~ J~ 4p* i 000./ MW ` CMpOXIDATIVE METABOLITE ( mg/ L)' RAMMp=( VMAXp* CA)/( KM+ CA)~ RACMGp* MW/ 1 000~ RACMEEp* MW/ i000 AMMp= INTEG( RAMMp, 0.) CMpAMMp/ VP ` GSpGLUTAHIONE LUNG ( uM)' GSHtdp= DELAY( GSp* 1 , GSp, TD, 1 0000)$' Time delayed GSH levels' RK0p= K0AP*( GSOp+ KS)/( GSHtdp+ KS)~ KlA* KOp KOpINTEG( RKOp, KOOp) RAMGSp'KOp Kl* GSp* Vp.. RACMGpRACpGp AMGSp='~ NTEG( RAMGSp, AGSOp) GSp= AMGSp/ VP C:\ WINDOWS\ TemporaryInternet Files\ Conient. 1E5\ 4EAADdI7A\ edc AppCrev. wpd April 24, 2002 ` ACMGp= AMT METABOLITE CONJUGATED WITH GSH LUNG ( uMOLES)' RACMGp= KGSM* GSp* CMp* VP* 1000/ MW ACMGp= INTEG( RACMGp, 0.)

` ACMEEpAMT METABOLITE CONJUGATED WITH EVERYTHING ELSE LUNG ( uMOLES)' RACMEEp= KFEE* VP* CMp* 1000/ MW ACMEEp= INTEG( RACMEEp, 0.)

` ACPGpAMT PARENT CONJUGATED WITH GSH LUNG ( uMOLES)' RACPGp= KGS* GSp* CP* VP* 1000/ MW ACPGPp= INTEG( RACPGp, 0.)

` PCTGSH PERCENT GSH COMPARED TO CONTROL' PCTGSHP= GSp/ GSOp* 100 TERMT( T. GE. TSTOP)

PROCEDURAL ( P1 , P 1R= AMP, RAMP)

IF( T. LT.( DRTIME( I)+ NEWDAY)) GO TO SKIP2 ODOSE=( ODOSE+ DRPCT( I)* DRDOSE)* PULSE( TSTART, TPER, TPER) 1= 1+ 1 IF( I. LT. 7) GO TO SKIP2 1= 1 6 NEWDAY= NEWDAY+ 24.0 SKIP2.. CONTINUE IF ( AMIN1 ( AMP1, RAMP1, ACMG1, RACMG1, ACMEE1, RACMEE1). LT. 1 E 9) GOTO OUT ` Pl= PERCENT PARENT METABOLISM THROUGH GSH' P1 = ACPG1IAMP1* 100 P1 R= RACPGJIRAMP1* 100 ` P2= PERCENT METABOLITE CONJUGATED WITH GSH' P2= ACMGII( ACMG1+ ACMEE1)* 100 P2R= RACMGI1( RACMGH~ RACMEEl)* 100 P3= 100 P2 P3R= 100 P2R OUT. . CONTINUE END $` End ofprocedural'

C~\ WINDOWS\ TempararyInternet Files\ ContentilE5\ 4EAADd1&\ edc AppCrev. wpd April 24, 2002 END $` End of derivative' END $` End ofdynamic' END $` End of program'

C:\ WINDOWS\ Ternporaiy Internet Files\ Content. lE5\ 4EAADd19A\ edc Appcrev. wpd April 24, 2002 C. 6 General Outline for Route to Route Extrapolation Reports A total ofthree route to route extrapolation reports will be generated for EDC, one for each ofthe following endpoints: subchronic toxicity, subchronic neurotoxicity, and reproductive toxicity. At a minimum, each ofthese reports will follow the general outline presented below.

1.0 Introduction Statement of objectives for a specific endpoint route to route extrapolation relevant to the HAPs testing for EDC Application ofthe PBPK Model for EDC relevant to specific endpoint 2.0 Summary ofKey Study ( ies)

For subchronic toxicity, the design and results of( Daniel et al., 1994) will be summarized relevant to the route to route extrapolation and results from Tier I Program Review Testing.

For subehronic neurotoxicity, the design and results ofthe Tier II testing will be summarized relevant to the route to route extrapolation and results from Tier I Program Review Testing.

For reproductive toxicity, the design and results ofthe Tier II testing wifi be summarized and the results of Alumot et al. ( 1976), Rao et al. ( 1980) and Lane et al. ( 1982) will be summarized relevant to the route to route extrapolation and results from Tier I Program Review Testing.

3.0 Selection of Critical Endpoints and Dose Measure( s)

Forsubchronic toxicity, subchronic neurotoxicityandreproductive toxicity, theendpo ints and dose measures will be determined from the Tier II testing.

4~~ 0 Route to Route Extrapolation Results Quantitative calculationofinhalation NOAEL/ LOAEL values for corresponding oral values.

5~ 0 Sensitivity Analysis Assessment ofthe contribution ofvariability/ uncertainty in each parameter to PK modeling results.

6.0 Conclusions 7.0 References C:\ WINDOWS\ Temporary Internet Files\ Content. IE5\ 4EAAD~ 0A\ edc AppC_ rev. wpd April 24, 2002


[Federal Register Volume 87, Number 247 (Tuesday, December 27, 2022)]
[Notices]
[Pages 79406-79408]
[FR Doc No: 2022-28086]

-----------------------------------------------------------------------

SECURITIES AND EXCHANGE COMMISSION

[Release No. 34-96551; File No. SR-PEARL-2022-57]

Self-Regulatory Organizations; Notice of Filing and Immediate
Effectiveness of a Proposed Rule Change by MIAX PEARL, LLC To Amend
Exchange Rule 519C Mass Cancellation of Trading Interest

December 20, 2022.
    Pursuant to section 19(b)(1) of the Securities Exchange Act of 1934
(the ``Act''),\1\ and Rule 19b-4 thereunder,\2\ notice is hereby given
that on December 8, 2022, MIAX PEARL, LLC (``MIAX Pearl'' 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.
---------------------------------------------------------------------------

    \1\ 15 U.S.C. 78s(b)(1).
    \2\ 17 CFR 240.19b-4.
---------------------------------------------------------------------------

I. Self-Regulatory Organization's Statement of the Terms of Substance
of the Proposed Rule Change

    The Exchange is filing a proposal to amend Exchange Rule 519C.
    The text of the proposed rule change is available on the Exchange's
website at http://www.miaxoptions.com/rule-filings/pearl at MIAX
Pearl's principal office, 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 Exchange proposes to amend Interpretations and Policies .01 of
Exchange Rule 519C, Mass Cancellation of Trading Interest, to provide
Members \3\ the option of having the Exchange cancel all orders,
including GTC Orders,\4\ if the Exchange detects a loss of
communication on a FIX Order Interface (``FOI'') Session.
---------------------------------------------------------------------------

    \3\ The term ``Member'' means an individual or organization
approved to exercise the trading rights associated with a Trading
Permit. Members are deemed ``members'' under the Exchange Act. See
Exchange Rule 100.
    \4\ A Good `til Cancelled or ``GTC'' Order is an order to buy or
sell which remains in effect until it is either executed, cancelled
or the underlying option expires. See Exchange Rule 516(i).
---------------------------------------------------------------------------

    MIAX PEARL Members may connect to the System using the MEO
Interface \5\ and/or the FIX Interface. These two connection protocols
are not mutually exclusive and Members, specifically Market Makers
(``MMs'') \6\ on the Exchange, primarily use the MEO Interface for
providing liquidity to the Exchange via their Market Making activities,
while Electronic Exchange Members (``EEMs'') \7\ primarily use the FIX
Interface for submitting orders.\8\
---------------------------------------------------------------------------

    \5\ The term ``MEO Interface'' means a binary order interface
used for submitting certain order types (as set forth in MIAX PEARL
Rule 516) to the MIAX Pearl System. See Exchange Rule 100.
    \6\ The term ``Market Maker'' or ``MM'' means a Member
registered with the Exchange for the purpose of making markets in
options contracts traded on the Exchange and that is vested with the
rights and responsibilities specified in Chapter VI of MIAX Pearl
Rules. See Exchange Rule 100.
    \7\ The term ``Electronic Exchange Member'' or ``EEM'' means the
holder of a Trading Permit who is a Member representing as agent
Public Customer Orders or Non-Customer Orders on the Exchange and
those non-Market Maker Members conducting proprietary trading.
Electronic Exchange Members are deemed ``members'' under the
Exchange Act. See Exchange Rule 100.
    \8\ The term ``order'' means a firm commitment to buy or sell
option contracts. See Exchange Rule 100.
---------------------------------------------------------------------------

    These interface ports provide the mechanism by which Members
maintain a connection to the Exchange and through which a Member
communicates its quotes and/or orders to the System.\9\ Market Makers
may submit quotes \10\ to the Exchange from one or more MEO ports.
Similarly, Members may submit orders to the Exchange from one or more
FIX ports.
---------------------------------------------------------------------------

    \9\ The term ``System'' means the automated trading system used
by the Exchange for the trading of securities. See Exchange Rule
100.
    \10\ The term ``quote'' or ``quotation'' means a bid or offer
entered by a Market Maker as a firm order that updates the Market
Maker's previous bid or offer, if any. When the term order is used
in these Rules and a bid or offer is entered by the Market Maker in
the option series to which such Market Maker is registered, such
order shall, as applicable, constitute a quote or quotation for
purposes of these Rules. See Exchange Rule 100.
---------------------------------------------------------------------------

FIX Connections
    Members connect to their assigned FIX port using the MIAX PEARL FIX
Orders Interface (``FOI'') which is a flexible interface that uses the
FIX protocol for both application and session level messages. As per
the FIX protocol, a connection is established by the Member submitting
a logon message to the Exchange. This logon message establishes the
Heartbeat interval that will be used by the session. The Exchange
relies on heartbeat \11\ messages to determine the status of the
connection to ensure bi-directional communication remains intact. Upon
missing a single heartbeat, FOI will send a Test Request message \12\
to the Member to check the status of the connection. Upon missing a
certain number of heartbeats,\13\ FOI will send a logout message and
terminate the connection. The Exchange currently offers Members certain
order handling risk protection options in this scenario.
---------------------------------------------------------------------------

    \11\ A ``Heartbeat'' message is a communication which acts as a
virtual pulse between the Exchange System and the Member's system.
The Heartbeat message sent by the Member and received by the
Exchange allows the Exchange to continually monitor its connection
with the Member. See Interpretations and Policies .02(i) of Exchange
Rule 519C.
    \12\ The test request message is a FIX Protocol message that
forces a heartbeat from the opposing application. The test request
message checks sequence numbers or verifies communication line
status. The opposite application responds to the Test Request with a
Heartbeat containing the Test Request ID. Financial Information
Exchange Protocol (FIX), Version 4.2 with errata. May 1, 2001.
    \13\ The Exchange notes that the current System setting is two
(2) heartbeats, and that any change to this setting will be
determined by the Exchange and communicated to Members via
Regulatory Circular.
---------------------------------------------------------------------------

    Specifically, when a Loss of Communication is detected on a FOI
connection the System will logoff the Member's session and (i) cancel
all eligible orders for the FIX Session if instructed by the Member
upon login, or (ii) cancel all eligible orders identified by the
Member. Following a disconnection, a reconnection will not be permitted
for a certain period of time (``yy'' seconds). The Exchange shall
determine the appropriate period of (``yy'' seconds) and shall notify
Members of the value of ``yy'' seconds via Regulatory Circular. In no
event shall ``yy'' be less than one (1) second or greater than ten (10)
seconds.\14\
---------------------------------------------------------------------------

    \14\ See Exchange Rule 519C(c)(2).
---------------------------------------------------------------------------

    At the time the Exchange adopted this functionality the Exchange
created an exception for Good `Til Cancel Orders in Interpretations and
Policies .01, which stated, Good `Til Cancelled (``GTC'') orders, as
defined in Rule 516 and PRIME Orders, as defined in Rule 515A, are not
eligible for automatic cancellation under paragraph (c) of Rule
519C.\15\
---------------------------------------------------------------------------

    \15\ See Interpretations and Policies .01 of Exchange Rule 519C.

---------------------------------------------------------------------------

Proposal
    The Exchange now proposes to amend Interpretations and Policies .01
to allow GTC orders to also be eligible for cancellation when the
Exchange detects a Loss of Communication.
    As proposed, if the Exchange determines that there is a Loss of
Communication, the Exchange will cancel the orders as described above,
additionally, if elected, the Exchange proposes to cancel all GTC
orders submitted through that FIX Session. As proposed, Members would
need to contact the Exchange's Help Desk,\16\ in a form and manner to
be determined by the Exchange and communicated via Regulatory Circular,
to have this optional order protection (cancellation of GTC orders)
configured.
---------------------------------------------------------------------------

    \16\ The term ``Help Desk'' means the Exchange's control room
consisting of Exchange staff authorized to make certain trading
determinations on behalf of the Exchange. The Help Desk shall report
to and be supervised by a senior executive officer of the Exchange.
See Exchange Rule 100.
---------------------------------------------------------------------------

2. Statutory Basis
    The Exchange believes that its proposed rule change is consistent
with section 6(b) of the Act \17\ in general, and furthers the
objectives of section 6(b)(5) of the Act \18\ in particular, in that it
is designed to prevent fraudulent and manipulative acts and practices,
to promote just and equitable principles of trade, to foster
cooperation and coordination with persons engaged in regulating,
clearing, settling, processing information with respect to, and
facilitating transactions in securities, to 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.
---------------------------------------------------------------------------

    \17\ 15 U.S.C. 78f(b).
    \18\ 15 U.S.C. 78f(b)(5).
---------------------------------------------------------------------------

    The disconnect feature of FIX connections is mandatory, however
Members have the option to enable the cancellation of all orders for an
entire session or select orders for cancellation on an order-by-order
basis, which would result in the cancellation of orders submitted over
a FIX Session when such session disconnects. The Exchange believes it
is appropriate to offer an additional option for Members to have the
Exchange cancel GTC orders from the order book when there is a
communication issue between the Member and the Exchange, as a
communication issue may or may not be quickly resolved.
    Offering to cancel all orders (including GTC orders) allows the
Member to customize Exchange risk protection functionality to align to
a Member's business needs. Offering this type of order cancellation
functionality to Members is consistent with the Act because it enables
Members to have greater control over the execution of their orders in
the event there is a communication issue with the Exchange. The
proposed order cancellation functionality is designed to mitigate the
risk of a missed execution associated with a loss of communication with
the Exchange. The proposed rule change is not unfairly discriminatory
among market participants, as it is available equally to all market
participants utilizing a FOI connection to the Exchange.
    The Exchange believes that the proposed rule change will assist
with the maintenance of a fair and orderly market by providing Members
with greater control over their resting orders. The Exchange's proposal
is consistent with the Act because it will mitigate the risk of
potential erroneous or unintended executions associated with a loss of
communication which protects investors and the public interest.
Additionally, the proposed rule adds another level of risk protection
for Members and protects investors and the public interest by
increasing the risk protection options available to Members of the
Exchange.

B. Self-Regulatory Organization's Statement on Burden on Competition

    The Exchange does not believe that the proposed rule change will
impose any burden on competition that is not necessary or appropriate
in furtherance of the purposes of the Act.
    The Exchange does not believe that the proposed rule change to
provide an additional risk protection imposes any burden on intra-
market competition that is not necessary or appropriate in furtherance
of the purposes of the Act. The Exchange believes that adding an
optional risk protection benefits all Members on the Exchange that use
a FOI connection as any Member with a FOI connection can elect to use
the risk protection described in the proposed rule.
    The Exchange does not believe the proposed rule change will impose
any burden on inter-market competition that is not necessary or
appropriate in furtherance of the purposes of the Act. For all the
reasons stated, the Exchange does not believe that the proposed rule
change will impose any burden on competition not necessary or
appropriate in furtherance of the purposes of the Act.

C. Self-Regulatory Organization's Statement on Comments on the Proposed
Rule Change Received From Members, Participants, or Others

    Written comments were neither solicited nor 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 after the date of the filing, or such
shorter time as the Commission may designate, it has become effective
pursuant to 19(b)(3)(A) of the Act \19\ and Rule 19b-4(f)(6) \20\
thereunder.
---------------------------------------------------------------------------

    \19\ 15 U.S.C. 78s(b)(3)(A).
    \20\ 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.
---------------------------------------------------------------------------

    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 necessary or
appropriate in the public interest, for the protection of investors, or
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-PEARL-2022-57.

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-PEARL-2022-57. 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-
PEARL-2022-57, and should be submitted on or before January 17, 2023.

    For the Commission, by the Division of Trading and Markets,
pursuant to delegated authority.\21\
---------------------------------------------------------------------------

    \21\ 17 CFR 200.30-3(a)(12).
---------------------------------------------------------------------------

Sherry R. Haywood,
Assistant Secretary.
[FR Doc. 2022-28086 Filed 12-23-22; 8:45 am]
BILLING CODE 8011-01-P


            UNITED STATES OF AMERICA

    DEPARTMENT OF TRANSPORTATION

            OFFICE OF THE SECRETARY

                     WASHINGTON, DC

Posted 9/21/2004, 4:00pm				  Served: September 21, 2004

In the Matter of

2005/2006 U.S.-CHINA AIR SERVICES

CASE AND DESIGNATIONS

Docket OST-2004-19077

NOTICE SHORTENING ANSWER PERIOD

By Order 2004-9-5, the Department issued an order instituting the
2005/2006 U.S.-China Air Services Case and invited interested U.S.
carriers to file applications for authority to serve the U.S.-China
market and for allocations of frequencies effective March 25, 2005, and
March 25, 2006.  The Order established a procedural schedule requiring
the incumbent carriers (Federal Express, Northwest, United, and UPS) to
file information responses by September 10, 2004.  All the incumbent
carriers filed submissions on September 10.

On September 17, 2004, Federal Express Corporation filed a motion in the
captioned proceeding requesting that the Department (1) compel
Northwest, United and UPS to “fully and completely” respond to the
Information Request by providing the complete itinerary for the subject
flights, including the flight number, each flight’s complete routing,
each flight’s day(s) of operation, and each flight’s departure and
arrival times; and (2) shorten the answer period for filing answers to
this motion from seven to one business day.  Under the Department’s
regulations (14 CFR 302.6) answers to the motion would normally be due
September 28, 2004.

Federal Express polled all parties served with the application and
notified the Department that United and UPS have objected to Federal
Express’ request for a shortened answer period.

As the resolution of this matter will have a bearing on the preparation
of Direct Exhibits, due October 13, we have decided to grant, in part,
Federal Express’ request to for a shortened answer period.

Therefore, acting under authority assigned in 14 CFR 385.3, we will
shorten the answer period and require that answers be filed no later
than noon on

September 23, 2004, and replies to any answers be filed by noon on

September 24, 2004.  We believe this revision strikes a proper balance
between the needs of all interested parties and will not prejudice any
party to the proceeding.

										2

We will serve this notice by electronic mail and facsimile on all
parties to this proceeding, and hereby authorize service of documents by
facsimile and by electronic mail.

By:

PAUL L. GRETCH

Director

Office of International Aviation

(SEAL)

Dated: September 21, 2004

An electronic version of this notice is available on the World Wide Web
at:

  HYPERLINK "http://dms.dot.gov//reports/reports_aviation.asp"
http://dms.dot.gov//reports/reports_aviation.asp

 Federal Express’ Motion at 4.


[Federal Register Volume 78, Number 89 (Wednesday, May 8, 2013)]
[Notices]
[Pages 26836-26837]
[FR Doc No: 2013-10902]

-----------------------------------------------------------------------

SECURITIES AND EXCHANGE COMMISSION

[Release No. 34-69503; File No. SR-NYSEArca-2013-44]

Self-Regulatory Organizations; NYSE Arca, Inc.; Notice of Filing
and Immediate Effectiveness of Proposed Rule Change Amending Its
Schedule of Fees and Charges for Exchange Services To Amend Step Up
Tier 2 to Reduce the Volume Threshold Requirements Needed To Be
Eligible for The Tier

May 2, 2013.
    Pursuant to Section 19(b)(1) \1\ of the Securities Exchange Act of
1934 (the ``Act'') \2\ and Rule 19b-4 thereunder,\3\ notice is hereby
given that, on April 22, 2013, NYSE Arca, Inc. (the ``Exchange'' or
``NYSE Arca'') filed with the Securities and Exchange Commission (the
``Commission'') the proposed rule change as described in Items I, II,
and III below, which Items have been prepared by the self-regulatory
organization. The Commission is publishing this notice to solicit
comments on the proposed rule change from interested persons.
---------------------------------------------------------------------------

    \1\ 15 U.S.C. 78s(b)(1).
    \2\ 15 U.S.C. 78a.
    \3\ 17 CFR 240.19b-4.
---------------------------------------------------------------------------

I. Self-Regulatory Organization's Statement of the Terms of Substance
of the Proposed Rule Change

    The Exchange proposes to amend its Schedule of Fees and Charges for
Exchange Services (``Fee Schedule'') to amend Step Up Tier 2 to reduce
the volume threshold requirements needed to be eligible for the tier.
The Exchange proposes to implement the changes on May 1, 2013. The text
of the proposed rule change is available on the Exchange's Web site at
www.nyse.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 self-regulatory organization
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 those 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 parts of such statements.

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

1. Purpose
    The Exchange proposes to amend its Fee Schedule to amend Step Up
Tier 2 to reduce the volume threshold requirements needed to be
eligible for the tier. The Exchange proposes to implement the changes
on May 1, 2013.
    Currently, in order to qualify for Step Up Tier 2, an ETP Holder on
a daily basis, measured monthly, must directly execute providing volume
on NYSE Arca in an amount that is an increase of no less than 0.12% of
U.S. consolidated average daily volume (``US CADV'') in Tape A, Tape B,
and Tape C securities for that month over the ETP Holder's average
daily providing volume in June 2011 (the ``Baseline Month''), subject
to a minimum increase of 12 million average daily providing shares. The
Exchange proposes to reduce the eligibility requirement for Step Up
Tier 2 to no less than 0.10% of US CADV for the month over the ETP
Holder's average daily providing volume in the Baseline Month, subject
to a minimum increase of 10 million average daily providing shares. The
Exchange does not propose to amend the credits for Step Up Tier 2.
    By way of example, if an ETP Holder executed an average daily
providing volume of 5 million shares in the Baseline Month, then to
qualify for Step Up Tier 2 in a month where US CADV is 11 billion
shares, that ETP Holder would need to increase its average daily
providing volume by at least 11 million shares, or 0.10% of that
month's US CADV, for a total average daily providing volume of at least
16 million shares.\4\
---------------------------------------------------------------------------

    \4\ In addition, those ETP Holders that did not directly provide
volume to NYSE Arca in the Baseline Month will be treated as having
an average daily providing volume of zero for the Baseline Month.
With respect to the increased percentage of US CADV, the volume
requirements to reach Step Up Tier 2's pricing levels will adjust
each calendar month based on the US CADV for that given month.
---------------------------------------------------------------------------

    The Exchange notes that the proposed fee change will reverse the
Step Up Tier 2 fee changes that became operative on April 1, 2013.\5\
The Exchange is proposing the Step Up Tier 2 fee change because the
previous fee change did not result in the anticipated increase in
orders sent to the Exchange. As previously explained,\6\ the goal of
the Step Up Tiers is to incent ETP Holders to increase the orders sent
directly to the Exchange and therefore provide liquidity that supports
the quality of price discovery and promotes market transparency. In the
Step Up Tiers Release, the Exchange explained that the Step Up Tiers
were expected to benefit ETP Holders whose increased order flow
provided added levels of liquidity (thereby contributing to the depth
and market quality on the Exchange) but who are still not eligible for
Tier 1, 2 or 3, or Investor Tier 1 or 2.\7\ For similar reasons, the
Exchange believes that lowering the volume requirements needed to be
eligible for Step Up Tier 2 will allow a greater number of ETP Holders
to qualify for the tier, which will in turn incent ETP Holders to
increase the orders sent directly to the Exchange and therefore provide
liquidity that supports the quality of price discovery and promotes
market transparency. The Exchange believes that this especially is the
case given that the $0.0029 credit for providing liquidity in Tape A
and Tape C securities under Step Up Tier 2 is substantially higher than
the credits for Tape A and Tape C securities under the Basic Rates
($0.0021) and Tier 3 ($0.0025).
---------------------------------------------------------------------------

    \5\ See Securities Exchange Act Release No. 69305 (April 4,
2013), 78 FR 21443 (April 10, 2013) (SR-NYSEArca-2013-32).
    \6\ See Securities Exchange Act Release No. 64820 (July 6,
2011), 76 FR 40974 (July 12, 2011) (SR-NYSEArca-2011-41) (``Step Up
Tiers Release'').
    \7\ Id. at 76 FR 40975.
---------------------------------------------------------------------------

    The proposed changes are not otherwise intended to address any
other problem, and the Exchange is not aware of any significant problem
that the affected market participants would have in complying with the
proposed changes.
2. Statutory Basis
    The Exchange believes that the proposed rule change is consistent
with

Section 6(b) of the Act,\8\ in general, and furthers the objectives of
Sections 6(b)(4) and 6(b)(5) of the Act,\9\ in particular, because it
provides for the equitable allocation of reasonable dues, fees, and
other charges among its members, issuers and other persons using its
facilities and does not unfairly discriminate between customers,
issuers, brokers or dealers.
---------------------------------------------------------------------------

    \8\ 15 U.S.C. 78f(b).
    \9\ 15 U.S.C. 78f(b)(4) and (5).
---------------------------------------------------------------------------

    The Exchange believes that the proposed amendment to Step Up Tier 2
that lowers the volume requirements needed to be eligible for the tier
is reasonable because the proposed change is designed to further incent
ETP Holders to increase the orders sent directly to the Exchange and
therefore provide liquidity that supports the quality of price
discovery and promotes market transparency. The Exchange believes that
this is especially the case given that the $0.0029 credit for providing
liquidity in Tape A and Tape C securities is substantially higher than
the credits for Tape A and Tape C securities under the Basic Rates
($0.0021) and Tier 3 ($0.0025). In addition, the proposed change is
reasonable because it is reverting to the volume thresholds that were
previously in place at the Exchange.\10\ The Exchange further believes
that the proposed amendment is equitable and not unfairly
discriminatory because it will allow a greater number of ETP Holders to
qualify for the tier, which will in turn incent ETP Holders to increase
order flow and provide added levels of liquidity (thereby contributing
to the depth and market quality on the Exchange), even if they may not
be eligible for Tier 1, 2 or 3, or Investor Tier 1 or 2. Moreover, Step
Up Tier 2 is available for all ETP Holders to satisfy.
---------------------------------------------------------------------------

    \10\ See supra n.5.
---------------------------------------------------------------------------

B. Self-Regulatory Organization's Statement on Burden on Competition

    The Exchange does not believe that the proposed rule change will
impose any burden on competition that is not necessary or appropriate
in furtherance of the purposes of the Act. In particular, the proposed
amendment to Step Up Tier 2 that lowers the volume requirement needed
to be eligible for the tier is designed to incent ETP Holders and
Market Makers to increase the volume of orders sent directly to the
Exchange and therefore provide liquidity that supports the quality of
price discovery and promotes market transparency.
    The Exchange notes that it operates in a highly competitive market
in which market participants can readily favor competing venues. In
such an environment, the Exchange must continually review, and consider
adjusting, its fees and credits to remain competitive with other
exchanges. For the reasons described above, the Exchange believes that
the proposed change reflects this competitive environment.

C. Self-Regulatory Organization's Statement on Comments on the Proposed
Rule Change Received From Members, Participants, or Others

    No written comments were solicited or received with respect to the
proposed rule change.

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

    The foregoing rule change is effective upon filing pursuant to
Section 19(b)(3)(A) \11\ of the Act and subparagraph (f)(2) of Rule
19b-4 \12\ thereunder, because it establishes a due, fee, or other
charge imposed by the Exchange.
---------------------------------------------------------------------------

    \11\ 15 U.S.C. 78s(b)(3)(A).
    \12\ 17 CFR 240.19b-4(f)(2).
---------------------------------------------------------------------------

    At any time within 60 days of the filing of such proposed rule
change, the Commission summarily may temporarily suspend such rule
change if it appears to the Commission that such action is necessary or
appropriate in the public interest, for the protection of investors, or
otherwise in furtherance of the purposes of the Act. If the Commission
takes such action, the Commission shall institute proceedings under
Section 19(b)(2)(B) \13\ of the Act to determine whether the proposed
rule change should be approved or disapproved.
---------------------------------------------------------------------------

    \13\ 15 U.S.C. 78s(b)(2)(B).
---------------------------------------------------------------------------

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_ADDRESS>Please include
File Number SR-NYSEArca-2013-44 on the subject line.

Paper Comments

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

All submissions should refer to File Number SR-NYSEArca-2013-44. This
file number should be included on the subject line if email is used. To
help the Commission process and review your comments more efficiently,
please use only one method. The Commission will post all comments on
the Commission's Internet Web site (http://www.sec.gov/rules/sro.shtml). Copies of the submission, all subsequent amendments, all
written statements with respect to the proposed rule change that are
filed with the Commission, and all written communications relating to
the proposed rule change between the Commission and any person, other
than those that may be withheld from the public in accordance with the
provisions of 5 U.S.C. 552, will be available for Web site viewing and
printing in the Commission's Public Reference Room, 100 F Street NE.,
Washington, DC 20549, on official business days between the hours of
10:00 a.m. and 3:00 p.m. Copies of such filing also will be available
for inspection and copying at the principal office of the Exchange. All
comments received will be posted without change; the Commission does
not edit personal identifying information from submissions. You should
submit only information that you wish to make publicly available. All
submissions should refer to File Number SR-NYSEArca-2013-44 and should
be submitted on or before May 29, 2013.

    For the Commission, by the Division of Trading and Markets,
pursuant to delegated authority.\14\
---------------------------------------------------------------------------

    \14\ 17 CFR 200.30-3(a)(12).
---------------------------------------------------------------------------

Kevin M. O'Neill,
Deputy Secretary.
[FR Doc. 2013-10902 Filed 5-7-13; 8:45 am]
BILLING CODE 8011-01-P


[Federal Register Volume 83, Number 204 (Monday, October 22, 2018)]
[Notices]
[Page 53357]
[FR Doc No: 2018-23011]

-----------------------------------------------------------------------

DEPARTMENT OF TRANSPORTATION

Federal Aviation Administration

Notice of Intent To Rule on Disposal of Aeronautical Property at
Murfreesboro Municipal Airport, Murfreesboro, TN

AGENCY: Federal Aviation Administration (FAA), DOT.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Federal Aviation Administration is requesting public
comment on a request by the City of Murfreesboro, to release
approximately 1.28 acres of land at the Murfreesboro Municipal Airport
from federal obligations. The request consists of 1.28 acres of parcel
``1'' as shown on the Approved Exhibit A property map. The parcel is
situated westward from the terminal area, lying along the south side of
the main access road to the airport from Memorial Boulevard (US Highway
231). Parcel ``1'' was acquired by the City of Murfreeboro by Deed
dated May 26, 1947, which included 237.25 acres of the original
airport. This request will release 1.28 acres of this property from
federal obligations.

DATES: Comments must be received on or before November 21, 2018.

ADDRESSES: Comments on this notice may be mailed or delivered in
triplicate to the FAA at the following address: Memphis Airports
District Office, Attn: Jamal Stovall, Community Planner, 2600 Thousand
Oaks Boulevard, Suite 2250, Memphis, TN 38118.
    In addition, one copy of any comments submitted to the FAA must be
mailed or delivered to Mr. Chad L. Gehrke, Airport Manager,
Murfreesboro Municipal Airport at the following address: Murfreesboro
Municipal Airport, 1930 Municipal Boulevard, Murfreesboro, TN 37129.

FOR FURTHER INFORMATION CONTACT: Mr. Jamal Stovall, Community Planner,
Federal Aviation Administration, Memphis Airports District Office, 2600
Thousand Oaks Boulevard, Suite 2250, Memphis, TN 38118-2482. The
application may be reviewed in person at this same location, by
appointment.

SUPPLEMENTARY INFORMATION: The FAA proposes to rule and invites public
comment on the request to release property for disposal at the
Murfreesboro Municipal Airport, 1930 Memorial Boulevard, Murfreesboro,
TN 37129, under the provisions of 49 U.S.C. 47107(h)(2). The FAA
determined that the request to release property at the Murfreesboro
Municipal Airport, (MBT) submitted by the Sponsor meets the procedural
requirements of the Federal Aviation Administration and the release of
the property does not and will not impact future aviation needs at the
airport. The FAA may approve the request, in whole or in part, no
sooner than thirty days after the publication of this notice.
    The following is a brief overview of the request:
    The City of Murfreesboro is releasing approximately 1.28 acres of
property fronting U.S. Highway 231 (Memorial Boulevard) and Airport
Road. This request will release this property from federal obligations.
    Any person may inspect the request in person at the FAA office
listed above under FOR FURTHER INFORMATION CONTACT.
    In addition, any person may, upon request, inspect the request,
notice and other documents germane to the request in person at the
Murfreesboro Municipal Airport, 1930 Memorial Boulevard, Murfreesboro,
TN 37129.
    This action is taken under the provisions of 49 U.S.C. 47107(h)(2).

    Issued in Memphis, Tennessee on October 16, 2018.
Phillip J. Braden,
Manager, Memphis Airports District Office, Southern Region.
[FR Doc. 2018-23011 Filed 10-19-18; 8:45 am]
 BILLING CODE 4910-13-P


[Federal Register Volume 76, Number 244 (Tuesday, December 20, 2011)]
[Proposed Rules]
[Page 78872]
[FR Doc No: 2011-32630]

-----------------------------------------------------------------------

ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 63

[EPA-HQ-OAR-2010-1042; FRL-9609-1]
RIN 2060-AQ90

National Emission Standards for Hazardous Air Pollutants for Wool
Fiberglass Manufacturing

AGENCY: Environmental Protection Agency (EPA).

ACTION: Proposed rule; notice of public hearings and extension of
public comment period.

-----------------------------------------------------------------------

SUMMARY: The EPA published in the Federal Register on November 25,
2011, the proposed rules, ``National Emission Standards for Hazardous
Air Pollutants: Mineral Wool Production and Wool Fiberglass
Manufacturing.'' The EPA was asked to hold a public hearing only on the
wool fiberglass rule. Therefore, EPA is making two announcements:
first, a public hearing for the proposed Wool Fiberglass Manufacturing
rule will be held on January 4, 2012 in Kansas City Kansas, and second,
the comment period for the Wool Fiberglass Manufacturing proposed rules
will be extended until February 3, 2012.

DATES: The public hearing will be held on January 4, 2012. Comments
must be received by February 3, 2012.

ADDRESSES: The public hearing to be held on January 4, 2012, will be
held at the Hilton Garden Inn, 520 Minnesota Avenue, Kansas City,
Kansas 66101; telephone:<PHONE_NUMBER>.
    The public hearing will convene at 2 p.m. and will continue until 8
p.m. A dinner break is scheduled from 5 p.m. until 6:30 p.m. The EPA
will make every effort to accommodate all speakers that arrive and
register before 8 p.m. The EPA's Web site for the rulemaking, which
includes the proposal and information about the hearings, can be found
at: http://www.epa.gov/ttn/atw/rrisk/rtrpg.html.

FOR FURTHER INFORMATION CONTACT: If you would like to present oral
testimony at the public hearing, please contact Ms. Pamela Garrett,
U.S. Environmental Protection Agency, Office of Air Quality Planning
and Standards, Sector Policies and Programs Division (D243-01),
Research Triangle Park, North Carolina 27711; telephone: (919) 541-
7966; fax number:<PHONE_NUMBER>; email address<EMAIL_ADDRESS>(preferred method for registering). The last day to register to present
oral testimony in advance will be Friday, December 30, 2011. If using
email, please provide the following information: the time you wish to
speak (afternoon or evening), name, affiliation, address, email address
and telephone and fax numbers. Time slot preferences will be given in
the order requests are received. Requests to speak will be taken the
day of each of the hearings at the hearing registration desk, although
preferences on speaking times may not be able to be fulfilled. If you
will require the service of a translator, please let us know at the
time of registration.
    Questions concerning the November 25, 2011, proposed rule should be
addressed to Susan Fairchild, Office of Air Quality Planning and
Standards, Sector Policies and Programs Division (D 243-04),
Environmental Protection Agency, Research Triangle Park, North Carolina
27711; telephone number:<PHONE_NUMBER>; facsimile number: (919) 541-
3207; email address<EMAIL_ADDRESS>    Public hearing: The proposal for which the EPA is holding the
public hearing was published in the Federal Register on November 25,
2011, and is available at: http://www.epa.gov/ttn/atw/rrisk/rtrpg.html
and also in the docket identified below. The public hearing will
provide interested parties the opportunity to present oral comments
regarding the EPA's proposed standards, including data, views or
arguments concerning the proposal. The EPA may ask clarifying questions
during the oral presentations, but will not respond to the
presentations at that time. Written statements and supporting
information submitted during the comment period will be considered with
the same weight as any oral comments and supporting information
presented at the public hearing.
    Commenters should notify Ms. Garrett if they will need specific
equipment or if there are other special needs related to providing
comments at the public hearing. The EPA will provide equipment for
commenters to make computerized slide presentations if we receive
special requests in advance. Oral testimony will be limited to 5
minutes for each commenter. The EPA encourages commenters to bring a
copy of their oral testimony along with any other information
supporting their statements in electronic (via email or CD) or in hard
copy form. A recorder will be present during the public hearing to
record oral statements. All information submitted to the EPA during the
public hearing and a transcribed copy of the oral statements will be
entered into the docket.
    The public hearing schedule, including lists of speakers, will be
posted on the EPA's Web site at http://www.epa.gov/ttn/atw/rrisk/rtrpg.html. Verbatim transcripts of the hearing and written statements
will be included in the docket for the rulemaking. The EPA will make
every effort to follow the schedule as closely as possible on the day
of the hearing; however, please plan for the hearing to run either
ahead of schedule or behind schedule.

How can I get copies of this document and other related information?

    The EPA has established a docket for the proposed rule, ``National
Emission Standards for Hazardous Air Pollutants: Wool Fiberglass
Manufacturing Risk and Technology Review,'' under No. EPA-HQ-OAR-2010-
1042, available at www.regulations.gov.

List of Subjects in 40 CFR Part 63

    Environmental protection, Administrative practice and procedure,
Air pollution control, Hazardous substances, Intergovernmental
relations, Reporting and recordkeeping requirements.

    Dated: December 15, 2011.
Mary E. Henigin,
Acting Director, Office of Air Quality Planning and Standards.
[FR Doc. 2011-32630 Filed 12-19-11; 8:45 a.m.]
BILLING CODE 6560-50-P