                  UNITED STATES ENVIRONMENTAL PROTECTION AGENCY                             WASHINGTON, D.C.  20460                  UNITED STATES ENVIRONMENTAL PROTECTION AGENCY                             WASHINGTON, D.C.  20460

              OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION               OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

										February 19, 2015

MEMORANDUM

SUBJECT:	Drinking Water Assessment for IR4 New Uses of Spinosad and Spinetoram on Coffee, Berry/Low Growing Berry (Subgroup 13-07G), Berry/Small Fruit/Vine Climbing (Subgroup 07-07F), Bulb Vegetables (Subgroup 3-07B), Cottonseed (Subgroup 20C),  and Dow New Proposed Uses on the Control of Root Maggot on Cabbage Plant (Brassica (Cole) Leafy Vegetables, Subgroup 5).  		(PC 110003 - Spinosad, 110008/110009 - Spinetoram; DP Barcodes D415813, 415815)

FROM:	Larry Liu, Chemist, Ph.D. 		Environmental Risk Branch 5 		Environmental Fate and Effects Division (7507P)

THROUGH:	Mah T. Shamim, Ph.D., Branch Chief 		Environmental Risk Branch 5 		Environmental Fate and Effects Division (7509P) 									 TO:		Tom Bloem 		Health Effects Division (7509P)

		Barbara Madden; RM 05       Registration Division (7505P)

Summary

Currently proposed section 3 uses and the previously-modeled turf use of spinosad and spinetoram were modeled using the currently-released EFED models (SWCC for surface water and PRZM-GW for ground water).  The results of the modeling exercise indicate that turf use results in higher EDWCs than all the proposed new uses. Therefore, the revised EDWCs are as follows:

(a)	For spinosad concentrations in surface water: the acute 1-in-10 years peak EDWC is 25.0 ppb, the non-cancer/chronic 1-in-10 years annual mean EDWC is 21.7 and the 1-10-years overall mean cancer/chronic is 14.2 ppb.  For spinetoram concentrations in surface water: the acute 1-in-10 years peak EDWC is 8.6 ppb, the non-cancer/chronic 1-in-10 years annual mean EDWC is 5.9 and the 1-10-years overall mean cancer/chronic is 3.8 ppb.

(b)	Due to the extremely high adsorption of spinosad and spinetoram with soil, even using 100-year weather records and all available scenario (DELMARVA_STD.SCN, FLCITRUS_STD.SCN, FLPOTATO_STD.SCN, GACOASTAL_STD.SCN, NCCOASTAL_STD.SCN, WISANDS_STD.SCN) in PRZM-GW simulation, Post-Breakthrough Mean Concentration (PBT) and Simulation Average Breakthrough Time (BT) were not achieved (See Appendix E for further details).  Although the use on coffee resulted in the highest groundwater EDWCs in all proposed uses, these values are below detection limits

Introduction

The Environmental Fate and Effects Division (EFED) has completed its review of an IR-4 petition for the new uses of Spinosad (Reg. numbers 62719-266, 62719-497, and 62719-621) and Spinetoram (Reg. no. 62719-539, 62719-545, 62719-541) on coffee, berry/low growing berry (subgroup 13-07G), berry/small fruit/vine climbing (subgroup 07-07F), and bulb vegetables (subgroup 3-07B), and cottonseed (subgroup 20C).  The other actions associated with the subject data package codes are conversions of crop groups, which do not include new uses for evaluation, for berry subgroups 13-07A and B, citrus fruit group 10-10, pome fruit group 11-10, stone fruit group 12-12, tree nut group 14-12, onion subgroup 3-07A, and fruiting vegetable subgroup 8-10. Furthermore, Dow AgroSciences has requested the addition of new proposed use for the control of root maggot (Brassica (Cole) Leafy Vegetables, Subgroup 5) at the base of cabbage plants and adjacent soils by utilizing banded applications.

Uses of Characterization

Spinosad is an insecticide and currently registered on a variety of crops and non-crops in the US.  It controls many foliage feeding pests such as lepidopterous larvae (worms or caterpillars), leafminers, thrips, and red imported fire ants. This product's active ingredient, Spinosad, is biologically derived from the fermentation of Saccharopolyspora spinosa, and it is formulated as an SC (suspension concentrate). Table 1 summarizes the application rates from the product label for all proposed new uses of spinosad.

Table 1. Proposed New Uses of Spinosad Products Crop Single Appl. Rate (lb ai/A) Max # Appl./Year Minimum Appl. Interval (days) Max Appl. Rate/Year (lb ai/A) Appl. Methods Entrust SC(R) Insecticide

Coffee

0.064-0.164

6

5 0.45 Spray/ground, chemigation and aerial

Berry, Low Growing Berry (Subgroup 13-07G) except cranberry and lowbush berry

Berry, Small Fruit, Vine Climbing (Subgroup-13-07F) except fuzzy kiwifruit 0.064-0.096

0.064-0.120 5

5 3-7

5 0.45

0.45 Spray/ground, chemigation and aerial

Spray/ground, chemigation and aerial

Bulb Vegetables (Subgroup 3-07B) 0.040-0.120 5 4 0.45 Spray/ground, chemigation and aerial

Cottonseed (Subgroup 20C) 0.046-0.096 unspecified 5 0.45 Spray/ground, chemigation and aerial

Brassica (Cole) Leafy Vegetables, (Subgroup 5) for Control of Root Maggot on Cabbage Plant 0.078-0.156 6 4 0.45 Spray/ground

Spinetoram is an insecticide and currently registered on a variety of crops in the US. It controls or suppresses many foliage feeding pests such as lepidopterous larvae (worms, caterpillars), dipterous leafminers, thrips, and certain psyllids. This product's active ingredient, Spinetoram, is derived from the fermentation of Saccharopolyspora spinosa, and it is formulated as SC (suspension concentrate) and WG (dispersible granules). Table 2 summarizes the application rates from the various product labels for all proposed new uses of spinetoram.

Table 2.  Proposed New Uses of Spinetoram Products Crop Single Appl. Rate (lb ai/A) Max # Appl./Year Minimum Appl. Interval (days) Max Appl. Rate/Year (lb ai/A) Appl. Methods Delegate WG(R) Insecticide

Radiant SC(R) Insecticide

Coffee

0.032-0.080

6

5 0.305 Spray/ground, chemigation and aerial

Berry, Low Growing Berry (Subgroup 13-07G) except cranberry and lowbush berry

Berry, Small Fruit, Vine Climbing (Subgroup-13-07F) except fuzzy kiwifruit 0.048-0.080 5 3-4 0.305 Spray/ground, chemigation and aerial

Bulb Vegetables (Subgroup 3-07B) 0.040-0.080 5 4 0.234 Spray/ground, chemigation and aerial

Cottonseed (Subgroup 20C) 0.011-0.064 6 4 0.266 Spray/ground, chemigation and aerial

Brassica (Cole) Leafy Vegetables, (Subgroup 5) for Control of Root Maggot on Cabbage Plant 0.039-0.078 6 4 0.266 Spray/ground

General Physical-Chemical and Fate Properties

Spinosad

Spinosad (XDE-105) is a mixture of two active naturally occurring secondary degradates (Spinosad A and Spinosad D). Even though the two degradates have analogous fate properties (i.e., similar half-lives in hydrolysis, aqueous photolysis, soil photolysis, aerobic soil metabolism, etc), the key distinction between the two spinosad components is that Factor D consists of an extra methyl group at carbon 4 on the central ring. In addition, spinosad A is the major component in parent spinosad is at approximately an 85:15 ratio. Both spinosad A and D have similar molecular weight (732 vs 746 g/mol respectively). Spinosad A has a greater water solubility than spinosad D and as pH increases water solubility decreases. Table 3 presents a summary of physicochemical properties of the two spinosad components.

Table 3. Summary of Physicochemical Properties of Spinosad

Physical Property

Spinosad A

Spinosad D Structure

CAS Registry Number

131929-60-7

131929-63-0

Empirical Formula

C41H65NO10

C42H67NO10

Molecular Weight

731.976

745.988

Odor

Slightly stale water or earthy

Relative Density (20C)

0.512

Melting Point

84-99.5C

161.5-170C

Vapor Pressure (25C)

2.4E-10 mmHg 3E-11 kPa

1.6E-10 mm Hg 2E-11 kPa

Octanol/Water Partition Coefficient (log Kow)       pH 5       pH 7       pH 9       Distilled water

2.78 4.01 5.16 3.91

3.23 4.53 5.21 4.38

Dissociation Constant (pKa) (20C)

8.10

7.87

Water Solubility (20C)       pH 5       pH 7       pH 9       Distilled water

290 mg/L 235 mg/L 16 mg/L 89.4 mg/L

28.7 mg/l 0.332 mg/L 0.053 mg/L 0.495 mg/L

Spinosad A and spinosad D converted in an aerobic soil metabolism study to degradates that are very identical to the parent with half-lives of approximately 9-17 days. Similar degradates are formed under photolytic settings with a half-life of <1 day at pH 7 in sterile water and about 10 days in soil. Spinosad A has a low to moderate water solubility and a low to slight mobility in sandy soils, and is immobile in silt loam and clay loam soils. In terrestrial field dissipation studies with Spinosad A on bare ground plots, the half-life was <1 day, no leaching was observed, and 3.1% of the applied was recovered in runoff.

Spinosad has a high affinity for sediment and moves rapidly from the water to the sediment phases where it, together with its major degradates, is highly persistent. In anaerobic aquatic metabolism studies, spinosad had a half-life of 161-250 days. In an aquatic microcosm dissipation outdoor study, spinosad residues in the sediment peaked at 8 days and had an observed half-life of greater than 25 days (See Appendix A for details).

Spinetoram

Spinetoram (XDE-175) is a new second generation spinosyn insecticide consisting of a mixture of spinetoram J and spinetoram L at roughly 3:1 ratio. These two components are not isomers.  Furthermore, spinetoram J is the major component in the spinetoram mixture, and the distinction between both components is that spinetoram L contains an extra methyl group at carbon 4 on the central ring. Spinetoram L is slightly heavier (760 g/mol) than spinetoram J (748 g/mol), and spinetoram J has a lower water solubility than spinetoram L, that is, spinetoram L is more soluble in water at pH 5 and 7 (See Table 4).

Based on laboratory studies, both components of spinetoram dissipate rapidly by photolysis in pH 7 buffer solution, with half-lives of <1 day. Other major routes of dissipation are aerobic soil metabolism, with non-linear half-lives of 3-31 days, and photolysis in soil, with environmental half-lives of 19-88 days. In aerobic and anaerobic water/sediment systems, spinetoram rapidly associates with the sediment phase where dissipation proceeds more slowly. Half-lives in total aerobic water/sediment systems were 116-124 days, and in total anaerobic water/sediment systems were 385-1,386 days. In laboratory soil, spinetoram was generally immobile (Kd = 84 and Koc =8,570). Under terrestrial and aquatic field conditions, spinetoram dissipated rapidly, with observed half-lives of <=1 day. Leaching was not significant under terrestrial field conditions, and migration into sediments was not significant under aquatic field conditions.

The octanol/water partitioning coefficients for spinetoram J and spinetoram L are 12,303 and 30,903, respectively. Spinetoram (both components), does accumulate in fish. In rainbow trout exposed to spinetoram J, the bioconcentration factors (BCFs) for edible tissue, nonedible tissue, and whole fish were 11, 53, and 46 mL/g, respectively. In rainbow trout exposed to spinetoram L, the BCFs for edible tissue, nonedible tissue, and whole fish were 104, 330, and 344 mL/g, respectively (See Appendix B for details).    Table 4. Physical/Chemical and Fate Properties of Spinetoram

Spinetoram J Spinetoram L Chemical Structure

Molecular Weight (g/mol) 748 760 Water Solubility -pH 5 423 ppm 1630 ppm                             pH 7 11.3 ppm 46.7 ppm                             pH 9 8 ppm 2 ppm                            pH 10 6.3 ppm 0.7 ppm Log Kow 4.09 4.38 Vapor Pressure 5.3x10-5 Pa 2.1x10-5 PA Hydrolysis, pH 5 (half-life) Stable stable Hydrolysis, pH 7 (half-life) Stable stable Hydrolysis, pH 9 (half-life) Stable 158 days Aqueous Photolysis (pH 7) (half-life of parent) 0.5 day 0.2 day Soil Photolysis (half-life) 27.4 days 9.4 days Aerobic Soil Metabolism (half-life) 26.5 days (CA) 17.9 days (CA)

8.6 days (VA) 3.2 days (VA)

22.7 days (MS) 19.1 days (MS)

30.8 days (IA) 15.3 days (IA) Anaerobic Aquatic Metabolism (half-life) 385 days (total system) 1,386 days (total system) Aquatic Aerobic Metabolism (half-life) 116 days (total system) 124 days (total system) Kd/Koc (loamy sand) 14/1800 31/3936 Kd/Koc (silt loam) 271/24648 483/43873 Kd/Koc (sandy loam) 38/5490 92/13185 Kd/Koc (loam) 12/2344 24/4816 Terrestrial Field Dissipation (half-life) 23.7 days (CA)

6.1 days (VA)

< 1 day (ID)

< 1 day (Ontario, Canada)

< 1 day (Prince Edward Island, Canada) Aquatic Field Dissipation(half-life) < 1 day (GA)

1.3 days (IN) BCF (non-edible) 53/103 (low dose/high dose) 330/430 (low dose/high dose) BCF (edible) 11/43 (low dose/high dose) 104/214 (low dose/high dose) BCF (whole fish) 46/86 (low dose/high dose) 344/348 (low dose/high dose)

 Four major degradates were identified in spinetoram fate studies: N-demethyl-J, N-demethyl-L, O-demethyl-175-J, and O-demethyl-175-L (see Appendix C for details). The registrant has submitted absorption studies for two major degradates (N-demethyl-J and N-demethyl-L) detected in spinetoram assessments. Results suggest that N-demethyl-J and N-demethyl-L are classified as slightly mobile and hardy mobile, respectively (Table 5).    Table 5. Physical, chemical, and fate properties for two major degradates (N-demethyl-J and N-demethyl-L) detected in the fate studies for spinetoram J and spinetoram L

N-demethyl-J N-demethyl-L Chemical Structure

Molecular Weight (g/mol) 734 746 Kd/Koc (loamy sand) 16/2062 34/4270 Kd/Koc (silt loam) 133/12127 340/30918 Kd/Koc (sandy loam) 32/4642 81/11559 Kd/Koc (loam) 8/1631 19/3718 Average Kd/Koc 47/5116  119/12616

Drinking Water Assessment

Tier II models (SWCC and PRZM/GW) were used to estimate surface water and groundwater EDWCs, respectively, for the proposed uses of spinosad and spinetoram. A total residue method was used in estimating EDWCs. This is because the main ring structures in the transformation products which were tentatively characterized in the fate studies remain unchanged.  For example, spinetoram-J has a molecular weight (MW) of 748g/mol whereas as its degradate (N-demethyl-J) has a MW of 734, due to the loss of a small methyl group.  In the modeling, EFED assumed all the total spinosad and spinetoram residues (fully or partially identified) are stable under the aqueous photolysis, aerobic soil metabolism, aerobic aquatic metabolism, and anaerobic aquatic metabolism settings. Table 6 lists the input parameters used in modeling. Due to the high adsorption of spinosad and spinetoram with soil, EDWCs in groundwater are negligible. Table 6.  Summary of Input Parameters for Spinosad and Spinetoram in SWCC and PRZM/GW Input Parameter Spinosad Spinetoram Hydrolysis Stable Stable Aqueous Photolysis Stable Stable Aerobic Soil Metabolism Stable Stable Aerobic Aquatic Metabolism Stable Stable Anaerobic Aquatic Metabolism Stable Stable Koc 11,543 L/kg 12,511 L/kg Vapor Pressure 2.4x 10 -10 torr 1.6x 10 -7 torr Water Solubility 87.4 ppm 11.3 ppm Molecular Weight (g/mol) 734 760 Application Method Aerial Aerial

The use of spinosad and spinetoram on coffee resulted in the highest surface water EDWCs in all the proposed uses, results are presented in Table 7 (see Appendix D).   However, since much highest application rate on turf (i.e., 1.6 lb ai/A) in all proposed uses was modeled using FIRST in the 2002 spinosad DWA and the highest application rate on turf (i.e., 0.454 lb ai/A) was modeled using FIRST in the 2007 spinetoram DWA, in addition to the proposed new uses, EFED decided to use the recently released SWCC to generate EDWCs on the registered turf use.  Although the peak EDWC for coffee is slightly higher than that for turf, since the only available scenario for coffee is from Puerto Rico, EFED decided not to consider that those values and recommended to use EDWCs from turf use in the current DWA.

Due to the extremely high adsorption of spinosad and spinetoram with soil, even using 100-year weather records and all six available scenario (DELMARVA_STD.SCN, FLCITRUS_STD.SCN, FLPOTATO_STD.SCN, GACOASTAL_STD.SCN, NCCOASTAL_STD.SCN, WISANDS_STD.SCN) in PRZM-GW simulation, Post-Breakthrough Mean Concentration (PBT) and Simulation Average Breakthrough Time (BT) were not achieved (See Appendix E for further details).  Although the use on coffee resulted in the highest groundwater EDWCs in all proposed uses, these values are below detection limits (Table 8).

Table 7.  Surface Water EDWCs from the Proposed Crop Uses and the Registered Turf Use of Spinosad and Spinetoram. Crop (Registration Status) Estimated Environmental Concentrations (ppb) Spinosad  Spinetoram   Coffee (proposed) Peak (1-in-10 yr) 13.8 9.4

365-day Avg  (1-in-10 yr) 7.7 5.9

Entire Simulation Mean 5.7 4.6 Berry (proposed) Peak (1-in-10 yr) 6.9 4.4

365-day Avg  (1-in-10 yr) 5.7 3.6

Entire Simulation Mean 3.4 2.0 Bulb Vegetables (proposed) Peak (1-in-10 yr) 9.1 4.0

365-day Avg  (1-in-10 yr) 8.0 3.5

Entire Simulation Mean 4.6 2.0 Cottonseed (proposed) Peak (1-in-10 yr) 7.0 2.8

365-day Avg  (1-in-10 yr) 3.5 2.3

Entire Simulation Mean 2.6 1.7 Cabbage (proposed) Peak (1-in-10 yr) 13.0 7.3

365-day Avg  (1-in-10 yr) 6.1 3.4

Entire Simulation Mean 5.1 2.8 Turf (registered) Peak (1-in-10 yr) 25.0 8.6

365-day Avg  (1-in-10 yr) 21.7 5.9

Entire Simulation Mean 14.2 3.8

Table 8.  Groundwater EDWCs from the Proposed Crop Uses of Spinosad and Spinetoram.

Coffee

ChemicalID Scenario ID Peak(ppb) PBT Avg(ppb) SimAvg BT(d) spinosad DELMARVA_STD.SCN 1.42E-11 Incomplete 7.24E-13 Incomplete 0.0801 spinosad FLCITRUS_STD.SCN 0.000996 Incomplete 0.000117 Incomplete 0.0938 spinosad FLPOTATO_STD.SCN 1.37E-12 Incomplete 1.13E-13 Incomplete 0.0431 spinosad GACOASTAL_STD.SCN 0 Incomplete 0 Incomplete 0.0569 spinosad NCCOASTAL_STD.SCN 7.83E-09 Incomplete 4.66E-10 Incomplete 0.1008 spinosad WISANDS_STD.SCN 3.84E-18 Incomplete 1.65E-19 Incomplete 0.0698

Berry

ChemicalID Scenario ID Peak(ppb) PBT Avg(ppb) SimAvg BT(d) spinosad DELMARVA_STD.SCN 1.35E-11 Incomplete 6.90E-13 Incomplete 0.0801 spinosad FLCITRUS_STD.SCN 0.00094 Incomplete 0.000111 Incomplete 0.0938 spinosad FLPOTATO_STD.SCN 1.29E-12 Incomplete 1.06E-13 Incomplete 0.0431 spinosad GACOASTAL_STD.SCN 0 Incomplete 0 Incomplete 0.0569 spinosad NCCOASTAL_STD.SCN 7.32E-09 Incomplete 4.35E-10 Incomplete 0.1008 spinosad WISANDS_STD.SCN 3.60E-18 Incomplete 1.55E-19 Incomplete 0.0698

Bulb Vegetables

ChemicalID Scenario ID Peak(ppb) PBT Avg(ppb) SimAvg BT(d) spinosad DELMARVA_STD.SCN 1.35E-11 Incomplete 6.90E-13 Incomplete 0.0801 spinosad FLCITRUS_STD.SCN 9.40E-04 Incomplete 1.11E-04 Incomplete 0.0938 spinosad FLPOTATO_STD.SCN 1.29E-12 Incomplete 1.06E-13 Incomplete 0.0431 spinosad GACOASTAL_STD.SCN 0.00E+00 Incomplete 0.00E+00 Incomplete 0.0569 spinosad NCCOASTAL_STD.SCN 7.32E-09 Incomplete 4.35E-10 Incomplete 0.1008 spinosad WISANDS_STD.SCN 3.60E-18 Incomplete 1.55E-19 Incomplete 0.0698

Cottonseed

ChemicalID Scenario ID Peak(ppb) PBT Avg(ppb) SimAvg BT(d) spinosad DELMARVA_STD.SCN 1.32E-11 Incomplete 6.74E-13 Incomplete 0.0801 spinosad FLCITRUS_STD.SCN 0.000944 Incomplete 0.000111 Incomplete 0.0938 spinosad FLPOTATO_STD.SCN 1.30E-12 Incomplete 1.07E-13 Incomplete 0.0431 spinosad GACOASTAL_STD.SCN 0 Incomplete 0 Incomplete 0.0569 spinosad NCCOASTAL_STD.SCN 7.52E-09 Incomplete 4.48E-10 Incomplete 0.1008 spinosad WISANDS_STD.SCN 3.71E-18 Incomplete 1.60E-19 Incomplete 0.0698

Cabbage

ChemicalID Scenario ID Peak(ppb) PBT Avg(ppb) SimAvg BT(d) spinosad DELMARVA_STD.SCN 1.39E-11 Incomplete 7.10E-13 Incomplete 0.0801 spinosad FLCITRUS_STD.SCN 0.000998 Incomplete 0.000118 Incomplete 0.0938 spinosad FLPOTATO_STD.SCN 1.38E-12 Incomplete 1.14E-13 Incomplete 0.0431 spinosad GACOASTAL_STD.SCN 0 Incomplete 0 Incomplete 0.0569 spinosad NCCOASTAL_STD.SCN 7.94E-09 Incomplete 4.73E-10 Incomplete 0.1008 spinosad WISANDS_STD.SCN 3.91E-18 Incomplete 1.68E-19 Incomplete 0.0698

Coffee

ChemicalID Scenario ID Peak(ppb) PBT Avg(ppb) SimAvg BT(d) spinetoram DELMARVA_STD.SCN 2.17E-12 Incomplete 1.09E-13 Incomplete 0.0739 spinetoram FLCITRUS_STD.SCN 0.000328 Incomplete 3.81E-05 Incomplete 0.0865 spinetoram FLPOTATO_STD.SCN 2.34E-13 Incomplete 1.92E-14 Incomplete 0.0398 spinetoram GACOASTAL_STD.SCN 0 Incomplete 0 Incomplete 0.0525 spinetoram NCCOASTAL_STD.SCN 1.21E-09 Incomplete 7.11E-11 Incomplete 0.0931 spinetoram WISANDS_STD.SCN 3.12E-19 Incomplete 1.30E-20 Incomplete 0.0645

Berry

ChemicalID Scenario ID Peak(ppb) PBT Avg(ppb) SimAvg BT(d) spinetoram DELMARVA_STD.SCN 2.06E-12 Incomplete 1.03E-13 Incomplete 0.0739 spinetoram FLCITRUS_STD.SCN 0.000327 Incomplete 3.80E-05 Incomplete 0.0865 spinetoram FLPOTATO_STD.SCN 2.35E-13 Incomplete 1.93E-14 Incomplete 0.0398 spinetoram GACOASTAL_STD.SCN 0 Incomplete 0 Incomplete 0.0525 spinetoram NCCOASTAL_STD.SCN 1.24E-09 Incomplete 7.28E-11 Incomplete 0.0931 spinetoram WISANDS_STD.SCN 3.20E-19 Incomplete 1.34E-20 Incomplete 0.0645

Bulb Vegetables

ChemicalID Scenario ID Peak(ppb) PBT Avg(ppb) SimAvg BT(d) spinetoram DELMARVA_STD.SCN 1.43E-12 Incomplete 7.14E-14 Incomplete 0.0739 spinetoram FLCITRUS_STD.SCN 2.26E-04 Incomplete 2.63E-05 Incomplete 0.0865 spinetoram FLPOTATO_STD.SCN 1.62E-13 Incomplete 1.33E-14 Incomplete 0.0398 spinetoram GACOASTAL_STD.SCN 0.00E+00 Incomplete 0.00E+00 Incomplete 0.0525 spinetoram NCCOASTAL_STD.SCN 8.54E-10 Incomplete 5.03E-11 Incomplete 0.0931 spinetoram WISANDS_STD.SCN 2.11E-19 Incomplete 7.90E-21 Incomplete 0.0645

Cottonseed

ChemicalID Scenario ID Peak(ppb) PBT Avg(ppb) SimAvg BT(d) spinetoram DELMARVA_STD.SCN 1.86E-12 Incomplete 9.36E-14 Incomplete 0.0739 spinetoram FLCITRUS_STD.SCN 0.000288 Incomplete 3.35E-05 Incomplete 0.0865 spinetoram FLPOTATO_STD.SCN 2.06E-13 Incomplete 1.69E-14 Incomplete 0.0398 spinetoram GACOASTAL_STD.SCN 0 Incomplete 0 Incomplete 0.0525 spinetoram NCCOASTAL_STD.SCN 1.08E-09 Incomplete 6.34E-11 Incomplete 0.0931 spinetoram WISANDS_STD.SCN 2.71E-19 Incomplete 1.06E-20 Incomplete 0.0645

Cabbage

ChemicalID Scenario ID Peak(ppb) PBT Avg(ppb) SimAvg spinetoram DELMARVA_STD.SCN 1.86E-12 Incomplete 9.36E-14 Incomplete 0.0739 spinetoram FLCITRUS_STD.SCN 0.000288 Incomplete 3.35E-05 Incomplete 0.0865 spinetoram FLPOTATO_STD.SCN 2.06E-13 Incomplete 1.69E-14 Incomplete 0.0398 spinetoram GACOASTAL_STD.SCN 0 Incomplete 0 Incomplete 0.0525 spinetoram NCCOASTAL_STD.SCN 1.08E-09 Incomplete 6.34E-11 Incomplete 0.0931 spinetoram WISANDS_STD.SCN 2.71E-19 Incomplete 1.06E-20 Incomplete 0.0645

Appendix A: Environmental Fate Properties of Spinosad

Degradation and Metabolism

Spinosad and Spinosad A and spinosad D were relatively stable in pH 5, 7, and 9 sterile aqueous buffer solutions that were incubated in the dark at 25°C (MRID 43507301).

In sterile buffered (pH 7) solutions, spinosad A and spinosad D phototransformed with half-lives of 0.8-0.9 days (MRID 43507302). The β-isomers of the 13,14-dihydro of the pseudoaglycone of spinosad A and of spinosad D were detected at a maximum of 20.2-24.9% of the applied at 48 hours (study termination). In alkaline (pH 9.2) pond water, spinosad A and spinosad D phototransformed rapidly with half-lives of 0.54-0.55 days. On soil, spinosad A and spinosad D had photodegradation half-life of 8.68-9.71 days (MRIDs 44597733 and 43507303). The only transformation present at >5 % of the applied was N-demethyl-A, which reached 14.8% of the applied at 18 days post-treatment. These studies were not long enough to determine the fate of the degradates.

In aerobic silt loam soil, spinosad A and spinosad D converted to degradates with initial half-lives of 17.3 and 14.5 days, respectively (MRIDs 44597733 and 43507303). Spinosad A converted to degradates with a half-life of 9.4 days in sandy loam soil incubated under similar conditions. Approximately 75-90% of the applied spinosad converted to degradates by 28 days. The major degradate of spinosad A was N-demethyl-A, which accumulated to a maximum 51-61% of the applied at 14-28 days post-treatment, then decreased to 12.27-21.72% at 9 months and 2.77-5.96% at 1 year. The major degradate of spinosad D was N-demethyl - D, which accumulated to a maximum 68% of the applied at 28 days post-treatment and approximately 50% at 6 months. Several minor degradates, each less than 10% of the applied, were isolated but not conclusively identified. The anaerobic soil metabolism of spinosad could not be evaluated because no studies were submitted.

In anaerobic flooded clay sediment, spinosad A and spinosad D converted to degradates with half-lives of 161 and 250 days (MRID 43507305). By 7 days post-treatment, >90% of the applied radioactivity was associated with the sediment fraction.  Three major degradates of spinosad A, each present at a maximum 8-12% of the applied were identified: N-demethyl-A, reversepseudoaglycone (806643), and ketoreversepseudoaglycone (814426). One major degradate of spinosad D, N-demethyl-D, was present at a maximum 6.5% of the applied.

The fate of spinosad under the aerobic aquatic environment is unknown. This is because the submitted study (MRID 46642701) is classified as unacceptable and is scientifically invalid because significant variability in the results between sampling intervals and between systems at the same sampling interval prevents any confident interpretation of the study results.  Because of poor results in the initial experiment, the data presented in this MRID are a compilation of analyses of selected test systems from four separate experimental sets for each test substance and system.  In addition, degradates comprising 10% of the applied may have been present and not identified.

Soil sorption and mobility

The mobility of spinosad A, at nominal concentrations of 0.04-5.0 ug/mL, was investigated in sand, loamy sand, sandy loam, silt loam, and clay loam soils (MRID 43507306).  Koc values were 2,862, 831, 4,237, 134,583, and 21,938, respectively.  Freundlich Kdes values for both desorption phases for the sand, loamy sand, sandy loam, and silt loam soils were 8.4-9.2, 6.6-8.2, 27-30, 288-357 and 292-296, respectively; corresponding 1/n values ranged from 0.826-0.921. Adsorption coefficients for spinosad A were used in modeling.

The mobility of N-demethyl-A, the major degradate of spinosad A, was investigated at 0.05-5.0 ug/mL in sand, loamy sand, sandy loam, and silt loam soils (MRID 43816602).  Koc values were 2,138, 662, 2,881, and 74,583, respectively.  Freundlich Kdes values for both desorption phases for the sand, loamy sand, sandy loam, and silt loam soils were 6.3-6.5, 5.3-6.3, 19-20, and 171-179, respectively; corresponding 1/n values ranged from 0.775-0.880.

Spinosad A and D are not volatile; vapor pressures (25°C) are 2.0 to 3.0 x 10[-11] kPa.  CO2 was the only volatile compound detected in metabolism studies.

Field dissipation

Radioactive spinosad A, formulated as an emulsifiable concentrate, degraded with half-lives of 0.5 days in bareground plots of silt loam soil in Mississippi and 0.3 days in loam soil in California (MRID 43714301).  Approximately 2-3% remained after 3-5 days.  The study did not include those major degradates detected in the laboratory fate studies as analytes. Spinosad A and its degradates were not detected below the 6-inch soil depth. Unextracted [[14]C] residues increased to a maximum of 34-58% by 38-40 days. At the Mississippi site, total radioactivity in the runoff accounted for 3.1% of the applied radioactivity.

Pond water (pH 7.6, ca. surface area 2.2 m[2], depth 47.5-50 cm) and clay loam sediment (ca. depth 5.5-6 cm) maintained in outdoor tanks were treated once with a broadcast-spray application of the suspension concentrate at 100 g/ha to the water surface (MRID 43848803). Spinosad (including spinosad A and D) dissipated rapidly from the water with a calculated half-life of 1.5 days, and total spinosad residues dissipated from the water with a calculated half-life of 4 days. In the water, the degradates N-demethyl-A and N-demethyl-D were detected at maximums of 2.3 ppb (8 hours) and 3.6 ppb (0 hour), respectively, and were <0.5 ppb at 15 days.  In the sediment, spinosad A was detected at a maximum average 14.9 ppb at 4 days and was 14.3 ppb at 35 days. N-demethyl-A was detected at a maximum average 11.1 at 15 days and was <=9.4 ppb at 35 days. Spinosad D was <=4.2 ppb and N-demethyl-D was not detected (LOD 11.3 ppb) at any interval in the sediment. Total spinosad residues in the water had an observed half-life of <1 days. Spinosad residues (parent and its degradates) in the sediment reached a maximum concentration at 8 days post-treatment and had decreased by approximately 25% by 35 days. These field studies need to be re-evaluated because the half-lives may reflect the transformation of the parent to other degradates similar to the parent. Also the dissipation half-lives reflect the movement of the parent and degradates from one media to another and do not show degradation of the product.

Accumulation

[[14]C]Spinosad A and D accumulated in rainbow trout held under laboratory flow-through conditions for up to 28 days (MRIDs 44537734 and 43557601). In the high concentration experiments (19.0 ng/L for spinosad A and 33.0 ng/L for spinosad D), maximum BCFs for spinosad A were 28.8 mL/g (at Day 28) for the nonedible tissue, 7.5 mL/g (at Day 25) for the edible tissue, and 21.1 mL/g (at Day 7) for the whole fish tissue; and for spinosad D were 42 mL/g (at Day 11) for the nonedible tissue, 20.5 mL/g (at Day 11) for the edible tissue, and 41.9 mL/g (at Day 7) for the whole fish tissue.  Registrant-calculated BCFs for total [[14]C]residues were 103-152, 16-47, and 84-115 mL/g for the nonedible, edible, and whole fish tissues, respectively.

In fish exposed to spinosad A, parent accounted for 68.34% of the HPLC distribution in whole fish extracts on exposure day 1, and <=29.74% at later sampling intervals. Spinosad J was present at 125 ng/g in day 25 nonedible extracts and day 28 whole fish extracts; all other degradates were each <50 ng/g.  In fish exposed to spinosad D, parent accounted for 83.43% of the HPLC distribution in whole fish tissue on exposure day 1, 48.80% on day 7, 42.19% on day 14, and 35.44% on day 28.  In the whole fish tissues, 15-Pk4 and 20-Pk4 [N-monomethylated, O-demethylated Spinosad Factor D] was a maximum of 134 ng/g; 15-Pk6 and 20-Pk6 [N-monomethylated, O-demethylated Spinosad Factor D]  was a maximum of 230 ng/g; Spinosad Factor L was a maximum of 229 ng/g; Spinosad Factor O was a maximum of 173 ng/g; and N-demethyl-D was a maximum of 544 ng/g.  All other degradates were <50 ng/g.

Spinosad (i.e., spinosad A and D) has a relatively low bioconcentration factor (BCF's of the parent ranged from 8-20,X, 29-42X, and 21-42X for muscle, viscera, and whole fish, respectively), and a relatively rapid rate of depuration (half-life of about one day). These factors generally would prevent substantial bioconcentration of the material in the food web.

Appendix B: Environmental Fate Properties of Spinetoram

Degradation and Metabolism

 The total residue method was used in estimating EECs in the ecological risk assessment. This is because the main ring structures in the degradates, which were tentatively identified or partially characterized in the fate studies, are essentially the same as the parent. In the modeling of spinetoram, EFED used the same toxicity for spinetoram J and spinetoram L and the persistence of the spinetoram residues (including parent and its degradates) under the aqueous photolysis, soil photolysis, aerobic soil metabolism, and anaerobic aquatic metabolism conditions.

Spinetoram is expected to dissipate relatively rapidly under most environmentally relevant conditions with the apparent primary route of dissipation being via photolysis in water and soil, and aerobic metabolism in soil.  However, it should be noted that most of the degradates detected in the laboratory studies  still contain the major complicated ring structures. Parent spinetoram is stable to hydrolysis and persistent under aerobic and anaerobic aquatic environments in the laboratory, but dissipates rapidly in terrestrial and aquatic field environments. Also, leaching and migration into sediments under field conditions was not significant.

Spinetoram was stable to hydrolysis at pH 5, and 7, and had <10% decline over 30 days at pH 9 (MRID 46695023).  The photodegradation half-life in pH 7 buffer solutions for spinetoram J and spinetoram L was 12 and 5 hours, respectively (MRID 46695022). In moist loam soil, the photodegradation half-life for spinetoram J and spinetoram L was 27.4 and 9.4 days, respectively (MRID 46695024).  In VA loam, MS loam, sandy loam and silt loam soils, spinetoram J dissipated with nonlinear half-lives of 9, 23, 27 and 31, respectively; spinetoram L dissipated with nonlinear half-lives of 3, 19, 18 and 15 days, respectively (MRID 46695025).

In aerobic aquatic conditions, the half-life in water could not be determined as dissipation from the water phase was very rapid, with both test substances rapidly associating with the sediment; spinetoram J and spinetoram L degraded in the sediment with nonlinear half-lives of 126 and 114 days, respectively; and from the total system with half-lives of 116 and 124 days, respectively (MRID 46695027).  In anaerobic aquatic conditions, both test substances again associated rapidly with the sediment; spinetoram J and spinetoram L degraded in the sediment with half-lives of 408 and 1,386 days, respectively; and in the total system with half-lives of 385 and 1,386 days, respectively (MRID 46695026).

The proposed transformation pathway involves spinetoram J and spinetoram L degrading due to photolysis and/or microbial metabolism by de-methylation to yield N-demethyl-J and N-demethyl-L, respectively (O-demethyl-J and O-demethyl-L, respectively, under anaerobic aquatic conditions), and several minor unidentified compounds. Further degradation occurs to form numerous increasingly polar compounds over time, and ultimately mineralization to CO2.

Soil Sorption and Mobility

Spinetoram is expected to be generally immobile in soil (MRID 46695028). Spinetoram J and spinetoram-L were classified as having low mobility to being immobile according to McCall's Relative Mobility classification system in loamy sand, silt loam, sandy loam and loam soils from the U.S., with a Koc of 1800 to 43873 mL/g.

Field Dissipation

Under terrestrial field conditions, the half-life for spinetoram (-J + -L) in loam and sandy loam soil was 23.7 days and 6.1 days, respectively, while the observed half-life was <=1 day in each soil (MRIDs 46695029 and 47072901).  Spinetoram was not detected below the 0-15 cm soil depth at any sampling intervals. Under aquatic field conditions, spinetoram dissipated very quickly in water (MRID 46695030), with no partitioning of residues into the sediment. Total spinetoram residues (spinetoram J + spinetoram L) dissipated in the water with half-lives of 18.1 to 20.4 hours.  No residues of spinetoram J or spinetoram L were detected in any pre- or post-application sediment samples.

Accumulation

Since the octanol/water partitioning coefficients for spinetoram J and spinetoram L are high (12,303 and 30,903, respectively), these two components are expected to bioconcentrate in fish.  In rainbow trout exposed to spinetoram J at 17.3 ng/mL, the bioconcentration factors (BCFs) for edible tissue, nonedible tissue, and whole fish were 11, 53, and 46 mL/g, respectively (MRID 46695128). After 1 day of depuration, total [[14]C] residues in the whole fish had decreased by 28.2%.  After 21 days of depuration, total [[14]C] residues had decreased by 88.7%. The elimination half-lives for [[14]C] residues in edible tissue, nonedible tissue, and whole fish were 2.3, and 4.1, and 4.6 days, respectively. In rainbow trout exposed to spinetoram L at 22.3 ng/mL, the BCFs for edible tissue, nonedible tissue, and whole fish were 104, 330, and 344 mL/g, respectively (MRID 46695129). After 1 day of depuration, total [[14]C] residues in the whole fish had steadily decreased by 9.5%. After 14 days of depuration, total [[14]C] residues had decreased by 87.4%. The elimination half-lives for [[14]C] residues in whole fish, edible tissue, and nonedible tissue were 4.5, 3.9, and 4.1 days, respectively. Spinetoram J and spinetoram L rapidly metabolized, yielding 2-4 more polar degradates; correspondingly, N-demethyl-J and N-demethyl-L were positively identified, along with 3'-O-deethyl-XDE-175-L.

Appendix C: Summary of Degradates in the Environmental Fate Studies for Spinetoram

Degradate (Name) Maximum Degradate Concentration (% of applied) and Time (days) to Maximum Concentration in Study: Degradates Analyzed in Study:

Hydrolysis (161-1) Aqueous Photo. (161-2) Soil Photo. (161-3) Aerobic Soil (162-1) Anaerobic Aquatic (162-3) Aerobic Aquatic (162-4) Field Diss. (164-1) Aquatic Diss.  (164-2) Fish Study (165-4) N-demethyl-J 6.7% @ 30 d 6.6% @ 0.33 d Not Analyzed 68.1% @ 125 d Not Analyzed 8.9% @ 16 d 0.0590 mg/kg @ 26 d 0.373 ug/L @ 1 h 7.141 mg/kg @ 21 d  N-demethyl-L 11.9% @ 30 d 12.2% @ 0.17 d Not Analyzed 41.0% @ 32 d  Not Analyzed 9.6% @ 21 d (0.0039 mg/kg @ 0 d) [2] 0.060 ug/L @ 0.5 h  Not Reported[1] N-demethyl-J + N-demethyl-L Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Analyzed 0.410 ug/L @ 6 h[1] Not Analyzed O-demethyl-175-J Not Analyzed Not Analyzed Not Analyzed Not Analyzed 26.7% @ 365 d 2.8% @ 30 d Not Analyzed Not Analyzed Not Analyzed O-demethyl-175-L Not Analyzed Not Analyzed Not Analyzed Not Analyzed 10.4% @ 365 d Not Analyzed Not Analyzed Not Analyzed Not Analyzed 3'-O-deethyl-175-J Not Analyzed Not Detected Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Detected 3'-O-deethyl-175-L Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Reported[1] N-demethyl-175-L +  3'-O-deethyl-175-L Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Analyzed 16.034 mg/kg @ 28 d N-formyl-175-J Not Analyzed Not Detected Not Analyzed Not Detected Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Detected Aglycone-175-J Not Analyzed Not Detected Not Analyzed Not Detected Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Detected C9-pseudoaglycone-175-J Not Analyzed Not Detected Not Analyzed Not Detected Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Detected C9-pseudoaglycone-175-L Not Analyzed Not Detected Not Analyzed Not Detected Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Detected C9-ketopseudoaglycone-175-J Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Detected C9-ketopseudoaglycone-175-L Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Detected C17-pseudoaglycone-175-J Not Analyzed Not Detected Not Analyzed Not Detected Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Detected C17-pseudoaglycone-175-L Not Analyzed Not Detected Not Analyzed Not Detected Not Analyzed Not Analyzed Not Analyzed Not Analyzed Not Detected Carbon dioxide Not Analyzed Not Analyzed 3.5% @ 18 d  spinetoram J: from 5.0% @ 366 d (CA) to  35.2% @ 276 d (VA)

spinetoram-L: From 12.50% @ 276 d (CA) to  36.2% @ 365 d (VA) 0.2% @ 90 d 0.7% @ 2 d Not Analyzed Not Analyzed Not Analyzed Nonextractable residues Not Analyzed Not Analyzed 15.6% @ 18 d 37.9% @ 276 d 12.1% @ 365 d 11.0% @ 21 d Not Analyzed Not Analyzed Not Analyzed 1 Data from identified degradates reported as a combined number. 2 Maximum concentration was <LOQ.

Appendix D: Surface Water Modeling of Spinosad and USEPA Standard Reservoir

Estimated Environmental Concentrations for spinosad are presented in Table 1 for the USEPA standard reservoir with the FLturfSTD field scenario. A graphical presentation of the year-to-year peaks is presented in Figure 1. These values were generated with the Surface Water Concentration Calculator (SWCC Version 1.106). Critical input values for the model are summarized in Tables 2 and 3. This model estimates that about 0.77% of spinosad applied to the field eventually reaches the water body. The main mechanism of transport from the field to the water body is by spray drift (63.7% of the total transport), followed by runoff (30.3%) and erosion (6.05%). In the water body, pesticide dissipates with an effective water column half-life of 551.8 days. (This value does not include dissipation by transport to the benthic region; it includes only processes that result in removal of pesticide from the complete system.) The main source of dissipation in the water column is washout (effective average half-life = 551.9 days) followed by volatilization (4767521 days). In the benthic region, pesticide is stable.  The vast majority of the pesticide in the benthic region (99.92%) is sorbed to sediment rather than in the pore water.

Table 1. Estimated Environmental Concentrations (ppb) for spinosad. Peak (1-in-10 yr) 25.0 4-day Avg (1-in-10 yr) 24.0 21-day Avg (1-in-10 yr) 23.3 60-day Avg (1-in-10 yr) 22.5 365-day Avg (1-in-10 yr) 21.7 Entire Simulation Mean 14.2

Table 2. Summary of Model Inputs for spinosad. Scenario FLturfSTD Cropped Area Fraction 1.0 Koc (ml/g) 11543 Water Half-Life (days) @ 25 °C 0 Benthic Half-Life (days) @ 25 °C 0 Photolysis Half-Life (days) @ 25 °Lat 0 Hydrolysis Half-Life (days) 0 Soil Half-Life (days) @ 25 °C 0 Foliar Half-Life (days) 35 Molecular Wt 734 Vapor Pressure (torr) 0.00000001 Solubility (mg/l) 87.4

Table 3. Application Schedule for spinosad. Date (Mon/Day) Type Amount (kg/ha) Eff. Drift 6/1 Foliar 0.448 0.95 0.16 6/8 Foliar 0.448 0.95 0.16 6/15 Foliar 0.448 0.95 0.16 6/22 Foliar 0.448 0.95 0.16

Figure 1. Yearly Peak Concentrations

Appendix E.  Groundwater Analysis for spinosad and the Wisconsin Corn - WI Central Sands Scenario Estimated groundwater concentrations and breakthrough times for spinosad are presented in Table 1 for the Wisconsin Corn - WI Central Sands groundwater scenario. A graphical presentation of the daily concentrations in the aquifer is presented in Figure 1. These values were generated with the PRZM-GW (Version 1.07). Critical input values for the model are summarized in Tables 2 and 3.

Table 1. Groundwater Results for spinosad and the Wisconsin Corn - WI Central Sands Scenario. Peak Concentration (ppb) 3.84E-18 Post-Breakthrough Mean Concentration (ppb) Incomplete Entire Simulation Mean Concentration (ppb) 1.65E-19 Average Breakthrough Time (days) Incomplete Throughputs 0.06983208

Table 2. Chemical Properties for Groundwater Modeling of spinosad. Koc (ml/g) 11543 Surface Soil Half Life (days) 0 Hydrolysis Half Life (days) 0 Diffusion Coefficint Air (cm2/day) 0.0 Henry's Constant 0.0 Enthalpy (kcal/mol) 0.0

Table 3. Pesticide application scheme used for spinosad.  This application scheme was applied every year of the simulation. Application Date (Month/Day) Application Method Application Rate (kg/ha) 6/1 Above canopy application 0.089 6/6 Above canopy application 0.089 6/11 Above canopy application 0.089 6/16 Above canopy application 0.089 6/21 Above canopy application 0.089 6/26 Above canopy application 0.089

Figure 1. Aquifer Breakthrough Curve for spinosad and the Wisconsin Corn - WI Central Sands Scenario


"King, Heidi R."<EMAIL_ADDRESS> 01/08/2008 09:31 AM

To

Ron Evans/RTP/USEPA/US@EPA

cc

Subject

RE: follow-up to your phone call  RESEND

Ron, would it be possible to move Friday's meeting to 11:30?  Art can

join us at 11:30 -

heidi

-----Original Message-----

From<EMAIL_ADDRESS><EMAIL_ADDRESS> Sent: Monday, January 07, 2008 3:33 PM

To: King, Heidi R.

Cc<EMAIL_ADDRESS> Subject: RE: follow-up to your phone call RESEND

OK, lets review the bidding........

o     meeting on baseline set for 11:00 on Friday

o     I will talk to Kathy about setting up the Pb NAAQS RIA meeting

tomorrow

o     I would like to expand our conversation on the energy EO to

include Nathalie Simon of OPEI since they are the keepers of the Agency

guidance on EOs like this one.  If you can give me a few times which you

are available over the next few days I will coordinate with Nathalie to

arrange a conference call.

             "King, Heidi R."

             <Heidi_R._King@o

             mb.eop.gov>                                             To

                                      Ron Evans/RTP/USEPA/US@EPA

             01/07/2008 03:13                                        cc

             PM                       Allen Basala/RTP/USEPA/US@EPA,

                                      Bryan Hubbell/RTP/USEPA/US@EPA,

                                      Darryl

                                      Weatherhead/RTP/USEPA/US@EPA,

                                      David

                                      Misenheimer/RTP/USEPA/US@EPA,

                                      Janet Cakir/RTP/USEPA/US@EPA,

                                      Kathy Kaufman/RTP/USEPA/US@EPA,

                                      Ken Adler/DC/USEPA/US@EPA, Lydia

                                      Wegman/RTP/USEPA/US@EPA,

                                      "Johansson, Robert"

<EMAIL_ADDRESS>                                       , Rosalina

                                      Rodriguez/RTP/USEPA/US@EPA

                                                                Subject

                                      RE: follow-up to your phone call

                                      RESEND

Heidi

I will arrange for this baseline discussion to get on Lydia and our

control strategy experts calendars; I will also arrange for a conference

call line.  Who else will be joining us?

>> Thanks, Ron, I've included Art and Rob.

As to the Energy EO discussion, it may be best for you and I to chat via

phone so I can understand what your (or DOE) concerns are prior to

setting up a meeting.  As you can see from the writeup, the conclusion

is not so much a function of economic analysis as applicable scope.

Since this writeup was accepted during prior NAAQS RIA interagency

reviews, I would like a clearer understand of what is different here

prior to setting up a larger meeting.  Please give me a call at your

convenience.

>> That's a great idea!  I'm not sure there are concerns so much as an

opportunity to make sure we're on the same page.  We'll need to have the

interagency discussion anyway, as I want the group to be aligned on the

guidance document available at the link below, but it will be a good

chance for us to review EPA's thoughts reflected in the NPRM language.

As you are probably aware, OIRA bears the responsibility of designating

whether a regulation is a significant energy action, and the Statement

of Energy Effects would follow similar guidance to the RIA so that there

is likely not a need for additional modeling above what satisfies the

RIA.

http://www.whitehouse.gov/omb/memoranda/m01-27.html

As to the broader discussion about the Pb NAAQS RIA, I will check in

with Kathy Kaufman tomorrow on when she will be ready.  She is out at a

conference this afternoon and will not be back until the morning.  Have

you discussed a specific list of pending topics with Kathy ?

>> I would like to begin to introduce the interagency group to the Pb

RIA, in part to control expectations that this will not be as complex as

the Ozone NAAQS RIA, and also to give other agencies a chance to suggest

additional data which they might be able to contribute given the short

timelines and derth of data available to support this analysis.  I trust

that your group has done a thorough review, but given the data and

timeline constraints, I'd like to make sure we have as a group taken the

opportunity to welcome additional information while there is still time

to incorporate such contributions.  It seems particularly important

given the multi-media nature of Pb.

Thanks for your time Ron,

heidi

-----Original Message-----

From<EMAIL_ADDRESS><EMAIL_ADDRESS> Sent: Monday, January 07, 2008 2:42 PM

To: King, Heidi R.

Cc<EMAIL_ADDRESS><EMAIL_ADDRESS> <EMAIL_ADDRESS><EMAIL_ADDRESS> <EMAIL_ADDRESS><EMAIL_ADDRESS> <EMAIL_ADDRESS><EMAIL_ADDRESS>Johansson,

Robert<EMAIL_ADDRESS> Subject: RE: follow-up to your phone call RESEND

Heidi

Got it!  Thanks

I will arrange for this baseline discussion to get on Lydia and our

control strategy experts calendars; I will also arrange for a conference

call line.  Who else will be joining us?

As to the Energy EO discussion, it may be best for you and I to chat via

phone so I can understand what your (or DOE) concerns are prior to

setting up a meeting.  As you can see from the writeup, the conclusion

is not so much a function of economic analysis as applicable scope.

Since this writeup was accepted during prior NAAQS RIA interagency

reviews, I would like a clearer understand of what is different here

prior to setting up a larger meeting.  Please give me a call at your

convenience.

As to the broader discussion about the Pb NAAQS RIA, I will check in

with Kathy Kaufman tomorrow on when she will be ready.  She is out at a

conference this afternoon and will not be back until the morning.  Have

you discussed a specific list of pending topics with Kathy ?

Ron

             "King, Heidi R."

             <Heidi_R._King@o

             mb.eop.gov>                                             To

                                      Ron Evans/RTP/USEPA/US@EPA

             01/07/2008 02:20                                        cc

             PM                       Janet Cakir/RTP/USEPA/US@EPA, Ken

                                      Adler/DC/USEPA/US@EPA, Lydia

                                      Wegman/RTP/USEPA/US@EPA, David

                                      Misenheimer/RTP/USEPA/US@EPA,

                                      Darryl

                                      Weatherhead/RTP/USEPA/US@EPA,

                                      Kathy Kaufman/RTP/USEPA/US@EPA,

                                      Allen Basala/RTP/USEPA/US@EPA,

                                      Bryan Hubbell/RTP/USEPA/US@EPA,

                                      Rosalina

                                      Rodriguez/RTP/USEPA/US@EPA,

                                      "Johansson, Robert"

<EMAIL_ADDRESS>                                                                 Subject

                                      RE: follow-up to your phone call

                                      RESEND

Hi Ron,

Thanks for your response.  Email addresses were the same from both of

your emails, so I hope this reaches you and I'll follow up with a phone

call to make sure.

Ozone NAAQS RIA baseline for analysis:

Your first option works well, Friday 1/11 at 11am.  I have a couple of

solutions to propose, and I trust you to include the appropriate folks

on your end including Lydia and/or others.

Energy EO for Ozone NAAQS:

Let's have the meeting to review the analysis supporing the conclusion

from the NPRM as soon as possible.  Agenda: Let's review the

requirements of the EO and make sure we are all reading from the same

guidance.  While we of course all read this language from the proposal,

elements of the RIA would imply that OMB guidance might require further

Energy EO analysis, and this meeting is the opportunity to gain

alignment on requirements and expectations.

Energy EO for Pb NAAQS:

Again, let's have the meeting, but let's include additional RIA topics

in this meeting (we are due for another conversation on this RIA).  I

would like to make sure that all parties are on the same page with

respect to OMB's guidance on implementing the requirements of this EO,

and how it relates to this particular rulemaking, but I suspect this

will be a shorter conversation than the Ozone conversation.

Thanks, Ron  --

Heidi

Heidi R. King

OMB/OIRA

(202) 395-4551

 ******************************

Heidi, I got your voicemail about setting up a few meetings.   You

requested discussions on both the Energy E.O. analysis for ozone and Pb

plus a conversation on the baseline issue for the ozone RIA.   I am

going to take up the baseline issue first.

BASELINE    I presume this will be our opportunity to get Lydia and Art

together to talk per our previous conversation that this issue was ready

to raise up the management chain.   The ideal time will be from 11:00 to

12:00 this Friday the 11th.   I already have this time blocked on

Lydia's calendar for another meeting so I have high confidence that she

will be available.  She is also available after 3:30 on Friday.  Lydia

is also available from 4 to 5 on Thursday: however, I personally would

only be available until 4:45.  I would suggest this as a 3rd fallback

time.   We will have control strategy people from OAQPS and OTAQ on the

line to address any technical questions that Art may have during the

discussions.  Let me know if one of these times would work for you.

Energy EO Analysis  You indicated that DOE was interested in how our

energy impacts analysis is carried out.  I have reproduced the

discussion from the ozone NAAQS proposal RIA below.  As you can see from

the writeup, it is our determination that the setting of the NAAQS

standard is not a significant energy action as defined by the EO.  This

language is consistent with that which appeared in the PM NAAQS RIA and

was accepted as part of the Interagency review process.  Based on this I

don't believe that there is a need for a discussion.  Please let me know

if you have questions about this.

9.8 Executive Order 13211: Actions that Significantly Affect Energy

Supply, Distribution or Use  (from page 9-4)

This proposed rule is not a "significant energy action" as defined in

Executive Order 13211, "Actions Concerning Regulations That

Significantly Affect Energy Supply, Distribution, or Use"

(66 FR 28355 (May 22, 2001)) because in the Agency's judgment it is not

likely to have a significant adverse effect on the supply, distribution,

or use of energy. The purpose of this rule is to establish revised NAAQS

for ozone. The rule does not prescribe specific pollution control

strategies by which these ambient standards will be met. Such strategies

will be developed by States on a case-by-case basis, and EPA cannot

predict whether the control options selected by States will include

regulations on energy suppliers, distributors, or users. Thus, EPA

concludes that this rule is not likely to have any adverse energy

effects and does not constitute a significant energy action as defined

in Executive Order 13211.

-----Original Message-----

From<EMAIL_ADDRESS><EMAIL_ADDRESS> Sent: Monday, January 07, 2008 1:48 PM

To: King, Heidi R.

Cc<EMAIL_ADDRESS><EMAIL_ADDRESS> <EMAIL_ADDRESS><EMAIL_ADDRESS> <EMAIL_ADDRESS><EMAIL_ADDRESS> <EMAIL_ADDRESS><EMAIL_ADDRESS> <EMAIL_ADDRESS> Subject: follow-up to your phone call RESEND

Importance: High

Heidi, I was working within a different e-mail base when I sent this

e-mail a moment ago.  Please respond to this e-mail instead of the

previous one, the other comes from an archive database which means that

when you respond I will not see the e-mail come in.  Sorry for the

confusion.

Ron Evans

Leader, Air Benefit & Cost Group

HEID/OAQPS/OAR/EPA

Mail Drop C-439-02

919-541-5488

919-541-0839 fax

----- Forwarded by Ron Evans/RTP/USEPA/US on 01/07/2008 01:43 PM -----

             Ron

             Evans/RTP/USEPA/

             US                                                      To

                                      "King, Heidi R."

             01/07/2008 01:42<EMAIL_ADDRESS>              PM                                                      cc

                                      Janet Cakir/RTP/USEPA/US@EPA, Ken

                                      Adler/DC/USEPA/US@EPA, Lydia

                                      Wegman, David

                                      Misenheimer/RTP/USEPA/US@EPA,

                                      darryl weatherhead, Kathy

                                      Kaufman/RTP/USEPA/US@EPA, Allen

                                      Basala, Bryan Hubbell, rosalina

                                      rodriguez

                                                                Subject

                                      follow-up to your phone call

Heidi, I got your voicemail about setting up a few meetings.   You

requested discussions on both the Energy E.O. analysis for ozone and Pb

plus a conversation on the baseline issue for the ozone RIA.   I am

going to take up the baseline issue first.

BASELINE    I presume this will be our opportunity to get Lydia and Art

together to talk per our previous conversation that this issue was ready

to raise up the management chain.   The ideal time will be from 11:00 to

12:00 this Friday the 11th.   I already have this time blocked on

Lydia's calendar for another meeting so I have high confidence that she

will be available.  She is also available after 3:30 on Friday.  Lydia

is also available from 4 to 5 on Thursday: however, I personally would

only be available until 4:45.  I would suggest this as a 3rd fallback

time.   We will have control strategy people from OAQPS and OTAQ on the

line to address any technical questions that Art may have during the

discussions.  Let me know if one of these times would work for you.

Energy EO Analysis  You indicated that DOE was interested in how our

energy impacts analysis is carried out.  I have reproduced the

discussion from the ozone NAAQS proposal RIA below.  As you can see from

the writeup, it is our determination that the setting of the NAAQS

standard is not a significant energy action as defined by the EO.  This

language is consistent with that which appeared in the PM NAAQS RIA and

was accepted as part of the Interagency review process.  Based on this I

don't believe that there is a need for a discussion.  Please let me know

if you have questions about this.

9.8 Executive Order 13211: Actions that Significantly Affect Energy

Supply, Distribution or Use  (from page 9-4)

This proposed rule is not a "significant energy action" as defined in

Executive Order 13211, "Actions Concerning Regulations That

Significantly Affect Energy Supply, Distribution, or Use"

(66 FR 28355 (May 22, 2001)) because in the Agency's judgment it is not

likely to have a significant adverse effect on the supply, distribution,

or use of energy. The purpose of this rule is to establish revised NAAQS

for ozone. The rule does not prescribe specific pollution control

strategies by which these ambient standards will be met. Such strategies

will be developed by States on a case-by-case basis, and EPA cannot

predict whether the control options selected by States will include

regulations on energy suppliers, distributors, or users. Thus, EPA

concludes that this rule is not likely to have any adverse energy

effects and does not constitute a significant energy action as defined

in Executive Order 13211.

Ron Evans


[Federal Register Volume 78, Number 99 (Wednesday, May 22, 2013)]
[Notices]
[Pages 30313-30317]
[FR Doc No: 2013-12124]

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

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2013-N-0502]

Standardizing and Evaluating Risk Evaluation and Mitigation
Strategies; Notice of Public Meeting; Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of public meeting; request for comments.

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

SUMMARY: The Food and Drug Administration (FDA) is announcing a 2-day
public meeting to obtain input on issues and challenges associated with
the standardization and assessment of risk evaluation and mitigation
strategies (REMS) for drug and biological products. As part of the
reauthorization of the Prescription Drug User Fee Act (PDUFA), FDA has
committed to standardizing REMS to better integrate them into, and
reduce their burden to, the existing and evolving health care system.
As part of the PDUFA commitments, FDA will also seek to develop
evidence-based methodologies for assessing the effectiveness of REMS.
    To obtain input from stakeholders about REMS standardization and
evaluation, FDA will hold a public meeting to give stakeholders,
including health care providers, prescribers, patients, pharmacists,
distributors, drug manufacturers, vendors, researchers, standards
development organizations, and the public an opportunity to provide
input on ways to standardize and assess REMS.

DATES: The meeting will be held on July 25 and 26, 2013, from 8:30 a.m.
to 4:30 p.m. Individuals who wish to present at the meeting must
register by July 10, 2013. See section IV of this document for
information on how to register to speak at the meeting.

ADDRESSES: The public meeting will be held at FDA's White Oak Campus,
10903 New Hampshire Ave., Building 31 Conference Center, the Great Room
(Rm. 1503), Silver Spring, MD 20993. Submit electronic comments to
http://www.regulations.gov. Submit written comments to the Division of
Dockets Management (HFA-305), Food and Drug Administration, 5630
Fishers Lane, Rm. 1061, Rockville, MD 20852. Identify each set of
comments with the corresponding docket number for the public meeting as
follows: ``Docket No. FDA-2013-N-0502, ``Standardization and Evaluation
of Risk Evaluation and Mitigation Strategies, Public Meeting.''

FOR FURTHER INFORMATION CONTACT: Adam Kroetsch, Food and Drug
Administration, Center for Drug Evaluation and Research, 10903 New
Hampshire Ave., Bldg. 51, Rm. 1192, Silver Spring, MD 20993, 301-796-
3842, FAX:<PHONE_NUMBER>, email<EMAIL_ADDRESS>
I. Background

    This meeting builds upon prior stakeholder feedback on and input
into the design, implementation, and assessment of REMS. In July 2010,
FDA held a public meeting to obtain input on issues associated with the
development and implementation of REMS. In June 2012, FDA held a public
workshop to discuss survey methodologies and instruments that can be
used to evaluate patients' and health care providers' knowledge about
the risks of drugs marketed with an approved REMS. In addition, the
Food and Drug Administration Amendments Act of 2007 (Pub. L. 110-85)
requires FDA to bring, at least annually, one or more drugs with REMS
with elements to assure safe use (ETASU) before the Drug Safety and
Risk Management Advisory Committee. FDA also regularly discusses both
pre- and postapproval REMS with ETASUs with various FDA advisory
committees in the context of specific applications.
    This meeting also builds on FDA's internal efforts to improve the
design, implementation and assessment of REMS. In 2011, FDA created the
REMS Integration Initiative, designed to evaluate and improve its
implementation of REMS authorities. More information about the REMS
Integration Initiative can be found at (http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm350852.htm). As part of this
effort, FDA seeks to improve future REMS assessments and incorporate
the latest methodologies in the evolving science of risk management. In
its February 2013 report, ``FDA Lacks Comprehensive Data to Determine
Whether Risk Evaluation and Mitigation Strategies Improve Drug
Safety,'' the Department of Health and Human Services Office of the
Inspector General affirmed the need to identify and implement reliable
methods to assess the effectiveness of REMS and REMS components. This
report is available at https://oig.hhs.gov/oei/reports/oei-04-11-00510.pdf.
    This public meeting is intended to meet performance goals included
in the fifth reauthorization of the Prescription Drug User Fee Act
(PDUFA V). This reauthorization, part of the Food and Drug
Administration Safety and Innovation Act (FDASIA) (Pub. L. 112-144)
signed by the President on July 9, 2012, includes a number of
performance goals and procedures that are documented in the PDUFA V

Commitment Letter. (See ``PDUFA Reauthorization Performance Goals and
Procedures Fiscal Years 2013 Through 2017,'' which is available at
http://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm270412.pdf.)
    FDA developed the performance goals and procedures for PDUFA V in
consultation with drug industry representatives, patient and consumer
advocates, health care professionals, and other public stakeholders
from July 2010 through May 2011. Title XI of the letter, ``Enhancement
and Modernization of the FDA Drug Safety System,'' states that FDA user
fees will be used to enhance REMS by measuring the effectiveness of
REMS and evaluating, with stakeholder input, appropriate ways to better
integrate them into the existing and evolving health care system. (See
``PDUFA Reauthorization Performance Goals and Procedures Fiscal Years
2013 through 2017'' at http://www.fda.gov/downloads/ForIndustry/
UserFees/PrescriptionDrugUserFee/UCM270412.pdf).
    Toward that end, the PDUFA V Commitment Letter identified a number
of specific goals, including holding one or more public meetings to
explore strategies to standardize REMS and reduce the burden of
implementing REMS on practitioners, patients, and others in various
health care settings and on methodologies for assessing whether REMS
are mitigating the risks they purport to mitigate and for assessing the
effectiveness and impact of REMS, including methods for assessing the
effect on patient access, individual practitioners, and the overall
burden on the health care delivery system. FDA also committed to
issuing a report of its findings regarding standardizing REMS; the
report will identify priority projects in four areas (pharmacy systems,
prescriber education, providing benefit/risk information to patients,
and practice settings). FDA also committed to issuing guidance on
methodologies for assessing REMS, specifically, methodologies for
determining whether a specific REMS with ETASU is commensurate with the
specific serious risk listed in the labeling of the drug and
considering the observed risk, not unduly burdensome on patient access
to the drug. For details on specific FDA commitments, see the PDUFA
Reauthorization Performance Goals and Procedures Fiscal Years 2013
Through 2017, Section XI, ``Enhancement and Modernization of the FDA
Drug Safety System,'' Parts A2, A3, which is available at http://www.fda.gov/downloads/forindustry/userfees/prescriptiondruguserfee/ucm270412.pdf.

II. Purpose and Scope of Meeting

    The purpose of this public meeting is to obtain feedback from
stakeholders on: (1) Issues and challenges associated with
standardizing and assessing REMS for drug and biological products and
(2) identifying potential projects that will help standardize REMS and
integrate them into the health care delivery system. FDA is seeking
information and comments from a broad range of stakeholders, including
interested health care providers, prescribers, patients, pharmacists,
distributors, drug manufacturers, vendors, researchers, standards
development organizations, and the public.
    To promote greater standardization and improved assessment of REMS,
FDA is seeking feedback on how to reduce any unnecessary variation in
REMS and, in the process, to make REMS elements and associated tools
less burdensome to stakeholders, better integrated into the health care
system, more effective, and easier to assess. FDA recognizes that the
REMS elements and associated tools found in existing REMS programs have
varied. In some cases, these variations are appropriate, because REMS
are designed to address specific risks posed by particular drugs in a
wide range of patient populations and health care settings. However,
FDA may be able to establish standards to reduce unnecessary variation
and to make REMS more predictable and simpler to understand, implement,
and measure. The establishment of standards also presents the
opportunity to improve upon the design of REMS elements and associated
tools and assessment methodologies in the future.
    After this meeting, FDA will issue a report to the public that
identifies REMS standardization projects in the four areas specified in
the PDUFA V commitment letter: Prescriber education, pharmacy systems,
practice settings, and providing benefit/risk information to patients.
FDA welcomes stakeholder input to help identify high-quality projects
that could offer FDA and stakeholders the opportunity to develop, test,
and implement new approaches to standardizing REMS and integrating them
into the health care system. The scope of such projects might include
research studies, demonstration projects, and the development of new
REMS tools using, for example, emerging information technologies or
existing controls in the health care system. These projects might be
carried out by FDA alone or in collaboration with stakeholders and
outside experts.

III. Scope of Public Input Requested

    FDA is particularly interested in obtaining information and public
comment on the following areas:

A. Prescriber-Directed REMS Tools

    REMS programs use a number of tools to educate prescribers and/or
ensure that they carry out REMS requirements, including screening,
monitoring, and counseling patients. These tools have included risk
communications to prescribers, prescriber training, and instruments to
help prescribers prescribe the drug safely--for example, counseling
guides and checklists.
    1. Many REMS with elements to assure safe use provide for
prescriber training on the risks of the drug and how to use the drug
safely. In some REMS, the completion of this training is required
before a person can become a certified prescriber of the drug. Sponsors
provide REMS training in a variety of formats, including in-person,
online, and through printed materials. FDA is interested in input on
which formats and training approaches are most effective for prescriber
training; how frequently prescribers should be asked to take REMS
training and whether a single training is sufficient; what additional
tools could be used to reinforce what prescribers learn during the
training and help them apply what they have learned; and how REMS
training could be incorporated into continuing medical education
programs.
    2. Prescriber training often includes knowledge assessments that
prescribers must successfully complete as part of the training. These
knowledge assessments, which typically take the form of multiple-choice
questions, are designed to ensure that the prescriber understands the
training material; they also serve to reinforce key messages from the
training. (Knowledge assessments should not be confused with the
surveys of knowledge that drug manufacturers may conduct as part of
their REMS assessments.) FDA is interested in input on when knowledge
assessments should be included in REMS and whether they should be
included in all REMS that include prescriber training. In addition, FDA
requests input on how knowledge assessments can be designed to ensure
accurate measurement of prescribers' knowledge and how knowledge
assessments can be designed to measure or predict prescribers' ability
to apply what they have learned in their practice.
    3. Once prescribers have met all requirements for certification
under the

REMS (e.g., completed training), they generally must complete an
enrollment form to be recognized as certified and able to prescribe the
drug. Generally, by completing, signing, and submitting the enrollment
form, prescribers acknowledge their understanding of the drug's risks
and the REMS requirements. In some REMS, the enrollment form also is
used to share information about the risks of the drug and how to use
the drug safely. FDA is interested in stakeholder input on whether the
information and agreements included in current REMS prescriber
enrollment forms are presented in a way that is easy for prescribers to
understand. Also, what, if anything, should be done to standardize,
simplify, or streamline prescriber enrollment forms and the overall
prescriber enrollment process?
    4. What else can be done to improve the effectiveness of existing
prescriber-directed REMS tools, to standardize them, to reduce their
burden, and/or to better integrate them into the health care delivery
system?
    5. What tools and technologies not currently used in REMS could be
incorporated into REMS to help educate prescribers and ensure that they
carry out REMS requirements? What evidence exists to support the
effectiveness of these tools and technologies?
    6. What projects could be carried out to standardize the provision
of prescriber education in REMS?
    7. What projects could be carried out to better integrate REMS into
prescriber practice settings?
    8. What methodologies exist or might be developed to assess the
effectiveness of prescriber-directed REMS tools, the tools' burden on
the health care delivery system, and the effect of these tools on
patient access?

B. Patient-Directed REMS Tools

    REMS programs may use a number of tools to educate and counsel
patients, provide patients with information about the risks of the
drug, and help to ensure that patients use the drug safely. These tools
may include patient enrollment in the REMS, patient monitoring,
counseling by health care professionals, Medication Guides, and other
patient-directed educational materials.
    1. REMS use a range of written materials to help educate and
counsel patients, including Medication Guides. In some cases, health
care practitioners give these materials to patients to read on their
own, and in other cases health care providers are asked to review these
materials with patients and use them in patient counseling.
    2. In REMS that include patient education, what would make written
educational materials more effective? What other materials, tools, and
technologies, (e.g., reference materials, checklists, smartphone
applications) might be used to help educate patients and reinforce what
they have learned?
    3. How could the provision of information to patients be
standardized, and what are the most efficient ways of providing
information to patients given the variety of patient information needs
and learning styles?
    4. In many REMS, patients receive counseling that may include a
discussion of the benefits and risks of the drug as well as
instructions on how to use the drug safely. In the majority of such
REMS, prescribers are called upon to counsel patients, but other health
care practitioners, including pharmacists and nurses, may also play a
role in counseling patients. What are ways to improve current REMS
approach to counseling patients? How should the timing and frequency of
patient counseling be determined? Under what circumstances is it
appropriate for prescribers to provide patient counseling in a REMS,
when should other providers play a role in counseling patients in a
REMS, and how can patient counseling in REMS be integrated into
pharmacists' existing medication therapy management practices?
    5. Many REMS with elements to assure safe use include prescriber-
patient agreements. These agreements are used to document that an
informed discussion of the drug's benefits and risks took place and
that the patient understood the risks. Prescriber-patient agreements
may also support patient counseling by providing information for
prescribers to review with patients. Some REMS require that these
agreements be signed by the prescriber and patient and submitted to the
drug manufacturer. Are the information and agreements included in
prescriber-patient agreements presented in a way that is easy for
patients to understand and act upon? What, if anything, should be done
to standardize, simplify, or streamline prescriber-patient agreement
forms and the overall agreement process?
    6. What else can be done to improve the effectiveness of existing
patient-directed tools, to standardize them, to reduce their burden,
and/or to better integrate them into the existing and evolving health
care delivery system?
    7. What tools and technologies not currently used in REMS could be
incorporated into REMS to help counsel patients, to provide them with
information on the risks of the drug, and to ensure that they use the
drug safely? What evidence exists to support the effectiveness of these
tools and technologies?
    8. What projects could be carried out to standardize the provision
of benefit-risk information to patients?
    9. What methodologies exist or might be developed to assess the
effectiveness of patient-directed REMS tools, the tools' burden on the
health care delivery system, and the effect of these tools on patient
access?

C. REMS Tools in Drug Dispensing Settings

    Drug dispensing settings, such as prescribers' offices, hospitals,
pharmacies (e.g., specialty, retail, and mail-order), integrated health
care delivery systems, and infusion centers, often play a significant
role in REMS. This is a challenging area to address because of the wide
range of health care settings involved and because dispensers are
frequently called upon to coordinate care across a range of health care
settings and practitioners and to reinforce the tools that have been
used by other health care practitioners. Specific dispensing settings
may be required to obtain certification under a REMS, and, like
prescribers, the health care practitioners who dispense a drug
(authorized dispensers) may be required to complete training, counsel
patients, and provide patients with educational materials, including
Medication Guides. In addition, dispensers may be required to document
that certain safe-use conditions are met before dispensing (e.g., by
ordering/checking lab tests or completing a form or checklist).
    Many REMS with elements to assure safe use require that specific
health care settings be certified to be able to dispense the drug. To
certify the health care setting, REMS typically require a
representative of that health care setting to agree that the health
care setting will meet all REMS requirements, including the completion
of any necessary training.
    1. Under what circumstances should individual practitioners within
a health care setting (e.g., pharmacists, as opposed to pharmacies) be
certified, instead of the health care setting? How could this
effectively be accomplished while minimizing the burden on the health
care system?
    2. In most REMS that include dispenser certification, each
dispensing site is certified individually. Under what circumstances
would it be appropriate to use a single certification for a health care
setting with multiple dispensing sites such as a pharmacy

chain, an integrated health care system, or a hospital system?
    3. In what ways can the implementation of REMS tools in different
dispensing settings be standardized, and under what circumstances might
the implementation approach need to vary to accommodate the different
types of dispensing settings that can be part of a REMS?
    4. What obstacles have made it difficult for authorized dispensers
to obtain drugs under existing REMS, and how can these be overcome?
    5. How can REMS be made more compatible with existing systems for
the procurement and distribution of drugs? How can REMS be integrated
into any future electronic track and trace systems?
    6. What else can be done to improve the effectiveness of existing
REMS tools in drug dispensing settings, to standardize them, to reduce
their burden, and/or to better integrate them into the existing and
evolving health care delivery system?
    7. What tools and technologies not currently used in REMS could be
incorporated into REMS to help train and certify authorized dispensers,
ensure that only certified dispensers can obtain the drug, and ensure
that any safe-use conditions are met before a drug is dispensed? What
evidence exists to support the effectiveness of these tools and
technologies?
    8. What projects could be carried out to integrate REMS tools into
pharmacy systems?
    9. What projects could be carried out to integrate REMS tools into
other drug dispensing settings, such as hospitals, pharmacies, long-
term care facilities, and integrated health care delivery systems?
    10. What methodologies exist or might be developed to assess the
effectiveness of REMS tools across the range of dispensing settings,
the tools' burden on the health care delivery system, and the effect of
these tools on patient access?

D. Approaches to Standardizing REMS Tools

    Many stakeholders have asked FDA to standardize specific REMS tools
like stakeholder enrollments, Web sites, and educational materials.
Standardizing REMS tools will require ongoing collaboration among FDA,
drug manufacturers, stakeholders, scientific experts, and others. To
ensure that standardized tools are effective and minimally burdensome,
they should be developed in an open and inclusive process that
incorporates the feedback of all relevant stakeholders as well as the
latest science and best practices from across the health care system.
To ensure the continued success of these tools, they must be updated
regularly as best practices evolve.
    1. What opportunities and barriers exist for the development and
implementation of standardized REMS tools? What are some ways that FDA
can collaborate with third parties such as standards development
organizations, industry groups, professional societies, and
accreditation organizations to develop standardized REMS tools and
ensure their adoption?
    2. How might health information technologies such as electronic
health records, pharmacy management systems and electronic prescribing
systems be used to integrate REMS into existing health care settings?
What role might health information technologies play in REMS in the
future? How can these technologies be used to inform practitioners and
patients about REMS, monitor patients, and document that any safe-use
conditions are met? Could the integration of REMS into health
information systems ever reduce or eliminate the need for other REMS
tools, such as provider education?
    3. Many stakeholders have suggested that a single Web portal should
be established to act as a repository for standardized REMS tools and
materials and to serve as a central information or reference source for
REMS stakeholders. What barriers exist for the development of a single
REMS Web portal? Who would be responsible for developing and
maintaining the Web portal, and what role would FDA play?

E. Approaches To Assessing the Impact of REMS

    Drug manufacturers are required to submit assessments of their REMS
on a regular basis. To date, these assessments have tried to evaluate
the effectiveness of the REMS by measuring the frequency of adverse
outcomes of interest, the knowledge of stakeholders, and the compliance
of stakeholders with certain REMS requirements. To accomplish this,
drug manufacturers have relied on spontaneous adverse event reporting,
knowledge surveys, and systems that track stakeholder completion of
certain activities, such as enrollment and documentation of safe use
conditions. To improve how REMS are assessed, FDA is considering
additional areas for measurement and additional methods to measure the
impact of REMS.
    1. Should FDA routinely ask sponsors to assess the overall impact
of their REMS on prescriber, dispenser, and patient burden, and/or
access to the drug? If so, how could drug manufacturers assess the REMS
impact on access and burden?
    2. What methods might be used to separate the impact of a REMS
program from that of other related risk management activities? Without
having a control group, how should FDA interpret and act on REMS
assessment information?
    3. It is possible to interpret evidence of sustained REMS
effectiveness to mean that the REMS should be maintained indefinitely,
but such evidence may also suggest that safe use of the drug is now
ingrained in the health care system and that the REMS can be modified
or eliminated. What evidence could help FDA determine whether a drug
would continue to be used safely if the REMS were modified or released?

IV. Attendance and Registration

    The FDA Conference Center at the White Oak location is a federal
facility with security procedures and limited seating. Attendance is
free and will be on a first come, first served basis. Individuals who
wish to present at the public meeting must register on or before July
10, 2013, through http://remsmeeting.eventbrite.com and provide
complete contact information, including name, title, affiliation,
address, email, and phone number. In section III of this document, FDA
has included questions for comment. You should identify the questions
you wish to address in your presentation, so that FDA can consider that
in organizing the presentations. FDA will do its best to accommodate
requests to speak, and will determine the amount of time allotted to
each presenter and the approximate time that each oral presentation is
scheduled to begin. An agenda will be available approximately 2 weeks
before the meeting at http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm351029.htm.
    If you need special accommodations because of disability, please
contact Adam Kroetsch (see FOR FURTHER INFORMATION CONTACT) at least 7
days before the meeting.
    A live Web cast of this meeting will be viewable at https://collaboration.fda.gov/remsjuly2013/ on the day of the meeting. A video
record of the meeting will be available at the same Web address for 1
year.

V. Comments

    Interested persons may submit either electronic comments regarding
this document to http://www.regulations.gov

or written comments to the Division of Dockets Management (see
ADDRESSES). It is only necessary to send one set of comments. Identify
comments with the docket number found in brackets in the heading of
this document. To ensure consideration, submit comment by (see DATES).
Received comments may be seen in the Division of Dockets Management
between 9 a.m. and 4 p.m., Monday through Friday, and will be posted to
the docket at http://www.regulations.gov.

VI. Transcripts

    Please be advised that as soon as a transcript is available, it
will be accessible at http://www.regulations.gov. It may be viewed at
the Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD. A
transcript will also be available in either hardcopy or on CD-ROM,
after submission of a Freedom of Information request. Written requests
are to be sent to the Division of Freedom of Information (ELEM-1029),
Food and Drug Administration, 12420 Parklawn Dr., Element Bldg.,
Rockville, MD 20857.

    Dated: May 16, 2013.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2013-12124 Filed 5-21-13; 8:45 am]
BILLING CODE 4160-01-P


[Federal Register: September 15, 2009 (Volume 74, Number 177)]
[Notices]
[Page 47235]
[DOCID:fr15se09-60]

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

DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Project No. 13567-000]

City of Guttenberg, IA; Notice of Preliminary Permit Application
Accepted for Filing and Soliciting Comments, Motions To Intervene, and
Competing Applications

September 8, 2009.
    On August 12, 2009, City of Guttenberg, Iowa filed an application,
pursuant to section 4(f) of the Federal Power Act, proposing to study
the feasibility of the Guttenberg Water Power Project (Guttenberg
Project). The Guttenberg Project would be located at the U.S. Army
Corps of Engineers' (Corps) Mississippi River Lock and Dam No. 10,
located at River Mile 615.0 on the Mississippi River in Clayton County,
Iowa, and Grant County, Wisconsin, adjacent to the City of Guttenberg.
    The proposed Guttenberg Project would be installed within the
existing and unused auxiliary lock adjacent to the 600-foot-long
primary, operating lock which is adjacent to the existing 5,747-foot-
long Corps Lock & Dam No. 10.
    The proposed project would consist of: (1) Nine 485-kilowatt
generator-turbine units totaling 4.365 megawatts (MW) that would be
arrayed within the auxiliary lock on a frame module structure; (2) a
new 69-kilovolt transmission line connected to an existing above-ground
local distribution system; and (3) appurtenant facilities. The project
would have an estimated average annual generation of 27,000 megawatt-
hours.
    Applicant Contact: Mr. Barry Dykhuizen, City Manager, City of
Guttenberg, P.O. Box 580, 502 S. 1st St., Guttenberg, IA 52052-0580,
(563) 252-1161 ext. 109.
    FERC Contact: Patrick Murphy,<PHONE_NUMBER>.
    Deadline for filing comments, motions to intervene, competing
applications (without notices of intent), or notices of intent to file
competing applications: 60 days from the issuance of this notice.
Comments, motions to intervene, notices of intent, and competing
applications may be filed electronically via the Internet. See 18 CFR
385.2001(a)(1)(iii) and the instructions on the Commission's Web site
under the ``e-Filing'' link. If unable to be filed electronically,
documents may be paper-filed. To paper-file, an original and eight
copies should be mailed to: Kimberly D. Bose, Secretary, Federal Energy
Regulatory Commission, 888 First Street, NE., Washington, DC 20426. For
more information on how to submit these types of filings please go to
the Commission's Web site located at http://www.ferc.gov/filing-
comments.asp. More information about this project can be viewed or
printed on the ``eLibrary'' link of Commission's Web site at http://
www.ferc.gov/docs-filing/elibrary.asp. Enter the docket number (P-
13567) in the docket number field to access the document. For
assistance, call toll-free 1-866-208-3372.

Kimberly D. Bose,
Secretary.
[FR Doc. E9-22099 Filed 9-14-09; 8:45 am]

BILLING CODE 6717-01-P