UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

	OFFICE OF PREVENTION, PESTICIDE

	AND TOXIC SUBSTANCES

  SEQ CHAPTER \h \r 1 MEMORANDUM

Date:  11/24/2008

SUBJECT:	Boscalid.  Amended Use Pattern Request for Banana.  Summary of Analytical Chemistry and Residue Data.

PC Code:  128008	DP Barcode:  D354687

Decision No.:  394534	Registration No.:  NA

Petition No.:  8E7366	Regulatory Action:  Amended Section 3

Risk Assessment Type:  NA	Case No.:  NA

TXR No.:  NA	CAS No.:  188425-85-6

MRID No.:  47353902	40 CFR:  §180.589

FROM:	Douglas Dotson, Ph.D., Chemist

		Registration Action Branch 2

		Health Effects Division (7509P)

			  SEQ CHAPTER \h \r 1

THROUGH:	Dennis McNeilly, Chemist

		Christina Swartz, Branch Chief

		Registration Action Branch 2

		Health Effects Division (7509P)

TO:		Bryant Crowe/Tony Kish, RM Team 22

		Fungicide Branch

		Registration Division (7505P)		  SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1

  SEQ CHAPTER \h \r 1 This document was originally prepared under contract by Dynamac Corporation (2275 Research Boulevard, Suite 300; Rockville, MD 20850.  The document has been reviewed by the Health Effects Division (HED) and revised to reflect current Office of Pesticide Programs (OPP) policies.

Executive Summary

Boscalid is a carboxamide (an anilide) fungicide that inhibits mitochondrial respiration, thereby inhibiting spore germination, germ tube elongation, mycelial growth, and sporulation of pathogenic fungi on the leaf surface.  Boscalid is currently registered to BASF Corporation as water dispersible granule (WDG) formulations for use on a wide variety of food/feed crops.

BASF Corporation has submitted bridging data (MRID 47353902) in support of a request to:  (i) allow use of Cumora® Fungicide on bananas grown in Central and South America; and (ii) amend the established import tolerance [40 CFR §180.589] for residues of boscalid in/on banana from 0.2 ppm to 0.5 ppm.  The current submission is part of a tolerance petition, PP#8E7366, which also includes an application to register and establish a boscalid tolerance on coffee.  This summary document only addresses the request for amended use pattern and tolerance for bananas.  The coffee data, along with HED’s regulatory conclusions and recommendations, will be addressed in a separate document.

Cumora® Fungicide is a 500 g/L suspension concentrate (SC) formulation of boscalid intended to control Black and Yellow Sigatoka on banana and plantain crops grown in Costa Rica, Ecuador, Colombia, Honduras, Panama, Guatemala, Belize, El Salvador, Nicaragua, Dominican Republic, Mexico, Argentina, Brazil, Philippines, and Martinique.  The product is proposed for a maximum of four broadcast foliar applications to established bananas at 0.134 lb ai/A per application for a total rate of 0.536 lb ai/A, with either a 0- or 1-day preharvest interval (PHI) depending on country.  The current import tolerance of 0.02 ppm for residues of boscalid in/on banana was established based on residue data reflecting use of a 50% WDG formulation applied at maximum seasonal rates of 0.52-0.56 lb ai/A and a 0-day PHI (DP# 322235, 11/3/05, D. Dotson  SEQ CHAPTER \h \r 1 ).

Boscalid tolerances for plant commodities are listed in 40 CFR §180.589 (a)(1) and are expressed in terms of residues of the fungicide boscalid [3-pyridinecarboxamide, 2-chloro-N-(4'-chloro[1,1'-biphenyl]-2-yl)].  Plant commodity tolerances range from 0.05 ppm in/on peanut and tuberous and corm vegetables (Crop Subgroup 1-C) to 60 ppm in/on leafy greens (Crop Subgroup 4-A), except head and leaf lettuce.

  SEQ CHAPTER \h \r 1 The nature of the residue in plants is adequately understood.  The HED Metabolism Assessment Review Committee (MARC) determined that, in target crops, the parent only is the residue of concern for risk assessment and tolerance expression.  This determination continues to be in effect.

There are no livestock feedstuffs associated with the proposed amended use pattern on bananas.  Therefore, no livestock metabolism data, enforcement methods, storage stability data, or feeding studies are required to support this petition.  The requirements for rotational crop data are also not relevant to this request because bananas are typically not rotated, and data for Guidelines 860.1850 and 860.1900 (confined and field accumulation in rotational crops) are not required to establish an import tolerance.

An adequate GC/MS   SEQ CHAPTER \h \r 1 method (Method D0008) is available for enforcing tolerances in plant commodities.  The method has been validated or approved by the Analytical Chemistry Branch of BEAD.  Residues in/on plant commodities from the banana field trials associated with this petition were determined using an LC/MS/MS data-collection method (BASF Method D9908, Version II).  This method was adequately validated in conjunction with the field trial analyses, and the validated limit of quantitation (LOQ) was 0.05 ppm for boscalid in all commodities tested.

The requirements for multiresidue methods (MRM) testing data are fulfilled.  Residues of boscalid and its hydroxy metabolite were not adequately recovered using the MRMs.  The MRM data have been forwarded to FDA for a future updating of PAM, Vol. I.

Adequate storage stability data are available demonstrating that residues of boscalid are reasonably stable under frozen conditions in/on diverse crop matrices for at least 24 months.  Samples from the crop field trials were stored for a maximum of ~6 months prior to residue analysis.  There are no storage stability issues or corrections that might need to be applied to the banana field studies discussed in this document.

Adequate field residue data on both bagged and unbagged bananas were provided along with data on banana pulp and peel.  These data reflect side-by-side trials reflecting both formulations at the maximum use pattern.  In the trials conducted using the WDG formulation, maximum residues of boscalid in/on unbagged whole bananas were 0.12 ppm at 0-day PHI and 0.19 ppm at 1-day PHI.  In the trials conducted using the SC formulation, maximum residues of boscalid in/on unbagged whole bananas were 0.28 ppm at 0-day PHI and 0.42 ppm at 1-day PHI.  In treated bagged bananas, the majority (22 of 24 samples) bore residues below the LOQ (LOQ = 0.05 ppm).

The Agency generally recommends that 12 field trials be submitted for imported bananas.  Twelve trials were originally submitted for the registration of the WDG formulation.  For the bridging study, the registrant submitted the results of 6 trials performed using each formulation.  In the bridging study, the residue levels resulting from the use of the two formulations were comparable.  The average field trial value for the WDG and SC formulations were 0.07 ppm and 0.11 ppm, respectively.  A value of ½ LOQ (0.025 ppm) was used for samples whose residue value was reported as <LOQ (0.05 ppm).  Although the average field trial values were relatively close, the maximum field trial value for the SC formulation was approximately twice as high as the maximum value for the WDG formulation (0.42 ppm as opposed to 0.19 ppm).  As the bridging study demonstrated that, in general, residues were comparable, the results of all banana field trials were used to determine the recommended tolerance.  All residue values for unbagged whole bananas were entered into the Agency’s Tolerance Generator for NAFTA-Harmonized Tolerances to determine an appropriate tolerance level; see Appendix I.  The tolerance spreadsheet recommends a RAC tolerance of 0.40 ppm.  This value is higher than the current 0.2 ppm tolerance for banana because the maximum residue values for the SC formulation ((0.28 and 0.42 ppm) were higher than any of the values from the WDG field trials.  The petitioner should submit a revised Section F to lower the proposed RAC tolerance from 0.5 ppm to 0.4 ppm.

HED does not require residue data for any processed commodities associated with banana.  Therefore, data requirements for processed food and feed are not relevant to this tolerance petition.

The Codex Alimentarius Commission has established a maximum residue limit (MRL) for residues of boscalid in or on banana at 0.2 ppm, which is equivalent to the current U.S. tolerance.  However, the recommended U.S. tolerance of 0.4 ppm will be higher than the Codex MRL.  Mexico has not established any MRLs for residues of boscalid in/on raw agricultural commodities.  Canadian MRLs have been established for a variety of crops but not for banana.

Analytical reference standards for boscalid are available at the EPA National Pesticide Standards Repository.

  SEQ CHAPTER \h \r 1 Regulatory Recommendations and Residue Chemistry Deficiencies

Pending submission of a revised Section F, there are no residue chemistry issues that would preclude granting a registration for the amended use pattern requested for boscalid on imported bananas.  Provided the forthcoming human health risk assessment does not identify any issues of concern, the submitted data support the following tolerance for residues of boscalid in/on:

Banana	0.40 ppm

860.1550 Proposed Tolerances

The petitioner should submit a revised Section F in which the proposed tolerance for banana is 0.40 ppm, rather than 0.5 ppm.

Other Considerations

HED notes that there are outstanding deficiencies/issues from an early boscalid petition, PP# 1F06313 (DP# 278385, 8/15/03, M. Nelson), which must still be addressed by the petitioner.  As a condition of registration, a date of submission should be confirmed.

	•	Submission of radiovalidation data demonstrating the efficiency of the hydrolysis step in the proposed tolerance enforcement method (DFG S19) for livestock matrices.  These radiovalidation data will also be used in support of the data collection method (471/0) for livestock matrices.

	•	Submission of radiovalidation data demonstrating the efficiency of the microwave hydrolysis step in Method 476/0, which determines bound residues of boscalid in milk and liver.

	•	Data are required demonstrating the frozen storage stability of boscalid residues in processed grape juice (2 months).

Background

The chemical structure and nomenclature of boscalid are presented in Table 1.  The physicochemical properties of the technical grade of boscalid are presented in Table 2.

Table 1.   Boscalid Nomenclature.

Compound

Common name	Boscalid

Company experimental name	BAS 510 F

IUPAC name	2-chloro-N-(4'-chlorobiphenyl-2-yl)-nicotinamide

CAS name	3-pyridinecarboxamide,2-chloro-N-(4'-chloro[1,1'-biphenyl]-2-yl

CAS registry number	188425-85-6

End-use product (EPs) requested for registration	BAS 510 01F (Cantus® fungicide; 50% WDG)

BAS 510 05F (Cumora® 50 SC fungicide; 500 g/L SC)

TABLE 2.	Physicochemical Properties of Boscalid.

Parameter	Value	References

Melting point/range	142.8-143.8 C	MRIDs 45404802 and 45404804-45404809

pH	Does not dissociate in water.

	Relative Density (20ºC)	1.381g/cm3

	Water solubility (20ºC)	4.64 mg/L at pH 6

	Solvent solubility (g/100 mL at 20ºC)	acetone	16-20	ethyl acetate 6.7-8.0 methanol	4-5	2-propanol	<0.01 acetonitrile	4-5	dichloromethane 20-25 toluene 	2-5	n-heptane 	<0.01

1-octanol	<0.01	olive oil	2.9

N,N-DMF >25

	Vapor pressure (20ºC)	7 x 10-7 Pa

	Dissociation constant, pKa	None

	Octanol/water partition coefficient, Log(KOW)	2.96

	UV/visible absorption spectrum	molar extinction coefficient = 3.15 x104 L/mole/cm at 228 nm; 1.53 x103 at 290 nm

860.1200  Directions for Use

In support of the proposed import tolerance, the petitioner has submitted undated specimen labels with English translations for the 500 g/L suspension concentrate formulation (Cumora® 50 SC fungicide).  The specimen labels claim to be effective for control of Black/Yellow Sigatoka on banana and plantain crops grown in Central and South America.  A summary of the proposed use patterns was extracted from the various labels included in the petition’s Section B, and is summarized below in Table 3.

Table 3.	Summary of Directions for Use of Boscalid.

Applic. Timing, Type, and Equip.	Formulation	Applic. Rate

(lb ai/A)

[kg ai/ha]	Max. No. Applic. per Season	Max. Seasonal Applic. Rate

(lb ai/A)

[kg ai/ha]	PHI

(days)	Use Directions and Limitations

Banana (For Use in Costa Rica, Ecuador, Colombia, Honduras, Panama, Guatemala, Belize, El Salvador, Nicaragua, Dominican Republic, Mexico, Argentina, Brazil, Philippines, and Martinique)

Broadcast foliar

Ground or aerial	500 g/L SC	0.134

[0.150]	4	Implied:

0.536

[0.600]	0 (for Central America and Colombia)

1 (for Ecuador)	Applications are to be made with oil (7-10 L/ha) plus an emulsifier with a 10- to 15-day retreatment interval.

Conclusions.  The proposed use directions on banana are adequately described and sufficient to allow evaluation of the residue data relative to the proposed use.

860.1300 Nature of the Residue - Plants

Residue Chemistry Memo DP# 278385, 8/15/03, M. Nelson, (PP# 1F06313)

HED MARC Decision Memo DP# 286786, 1/9/03

  SEQ CHAPTER \h \r 1 The nature of boscalid residues in target (primary) crops is adequately understood based upon acceptable 14C metabolism studies conducted on grapes, lettuce, and beans.  These studies were reviewed in the initial boscalid petition, PP# 1F06313.  No significant metabolism of boscalid occurred in grapes or lettuce.  Unchanged parent was the only component identified, accounting for 92-98% and 99% TRR (total radioactive residues), respectively.  In bean plants, boscalid was metabolized slowly.  Unchanged parent was the major component identified, accounting for up to 72% TRR in/on bean dry seeds and 99% TRR in/on bean plants.  Cleavage products 1-(chlorophenyl)-2-aminobenzene and 2-chloronicotinic acid were present in small amounts, accounting for <1% and <10% TRR, respectively.

The HED MARC concluded that parent boscalid is the sole residue of concern for risk assessment and the tolerance expression for primary (target) crops.  The cleavage products were not included based on the limited cleavage which occurred and the low levels of their ingestion expected from dietary and environmental sources.  These conclusions continue to be in effect.

860.1300 Nature of the Residue – Livestock

Residue Chemistry Memo D278385, 8/15/03, M. Nelson, (PP# 1F06313)

HED MARC Decision Memo D286786, 1/9/03

≥10% of the TRR.  No amide bridge cleavage products were identified.  Based on the structural similarity of boscalid and M510F 01, and the fact that the enzymatic hydrolysis step in the proposed enforcement method will release M510F 02 back to free M510F 01, the MARC concluded that the combined residues of parent BAS 510 F, M510F 01, and M510F02 are the residues of concern for risk assessment and the tolerance expression in livestock matrices.  This conclusion continues to be in effect.

860.1340 Residue Analytical Methods

DER Reference List Reviewed in PP# 1F06313:

46351405.der (Data Collection Method, 445/0)

45405027.der (Data Collection Method, D9908)

45405028.der (Proposed Enforcement Method, D0008)

Residue Chemistry Memo D278385, 8/15/03, M. Nelson, (PP# 1F06313)

Residue Chemistry Memo D284510, 8/12/03, D. Swineford and E. Kolbe (PMV memo)

An adequate GC/MS method (Method D0008) is available for enforcing boscalid tolerances in plant commodities.  The Analytical Chemistry Branch in BEAD concluded that the method is acceptable for enforcement purposes in plants without the need for an EPA validation.

An adequate LC/MS/MS method (BASF Method D9908, Version II) is also available for collecting residue data on plant commodities.  Boscalid residues in all of the plant commodities associated with the current field trials were determined using this LC/MS/MS method.  According to the method, residues are extracted with methanol:water:2 N HCl (70:25:5, v:v:v), centrifuged, and an aliquot of the supernatant cleaned by partitioning between cyclohexane and 1 N HCl saturated with NaCl (5:1, v:v).  The cyclohexane phase is evaporated to dryness and reconstituted in a buffered methanol:water (80:20, v:v) solution.  Residues are determined by LC/MS/MS using the m/z 343→307 transition for detecting and quantifying boscalid.  Residues are quantified using an external calibration curve of boscalid standards.  The validated limit of quantitation is 0.05 ppm for boscalid in all commodities tested.  In conjunction with each field trial, the method was adequately validated using control samples of each plant matrix fortified with boscalid at levels ranging from 0.05 to 200 ppm.

860.1360 Multiresidue Methods

Residue Chemistry Memo D278385, 8/15/03, M. Nelson, (PP# 1F06313)

  SEQ CHAPTER \h \r 1 Residues of boscalid and its metabolite M510F01 were not adequately recovered using the multiresidue methods.  Protocol A was not applicable.  Protocol B was not applicable for boscalid and yielded inconsistent recoveries of M510F01.  Residues of boscalid and its hydroxy metabolite M510F01 had good responses with GC/ECD on a DB-1 column under Protocol C.  Neither analyte was recovered at ≥30% using Protocols D, E, and F.  The study has been forwarded to FDA for a future updating of PAM, Vol. I.

860.1380 Storage Stability

DER Reference List Reviewed in PP#s   SEQ CHAPTER \h \r 1 1F6313, 3E6791, 4F6875, & 5E6933:

  SEQ CHAPTER \h \r 1 46351404.der (Plant Matrices)

46160103.der (Tomato Paste)

Residue Chemistry Memo D322235, 11/3/05, D. Dotson (PP#s   SEQ CHAPTER \h \r 1 1F6313, 3E6791, 4F6875, & 5E6933)

 ≤-20ºC in/on fortified samples of cabbage (leafy vegetables), canola seed (oil seed), peach (fruit/fruiting vegetable), sugar beet roots (root crop), peas (legume vegetable), wheat grain (non-oily grain), wheat forage (foliage), and wheat straw (dry feed) for up to 24 months.  Data are also available indicating that boscalid is stable for up to 45 days in peanut oil and for up to 38.4 months in tomato paste stored at ≤-20ºC.  In the initial boscalid petition, PP# 1F06313, storage stability data for grape processed commodities were requested.  This data requirement remains outstanding.

The storage intervals and conditions for samples from the current crop field trials are presented in Table 4.

Table 4.   Summary of Storage Conditions and Intervals of Samples from Crop Field Trials.

Matrix 	Storage Temperature (°C)	Actual Storage Duration (Days) Interval of Demonstrated Storage Stability

Banana, whole fruit	Ambient at the field sites and during shipping

<-5°C at the analytical laboratory	100-166 days

(3.3-5.5 months)	Storage stability data are available demonstrating that boscalid is stable under frozen conditions in diverse crop matrices for at least 24 months.

Banana , pulp

123-168 days

(4.0-5.5 months)

	Banana, peel

128-173 days

(4.2-5.7 months)

Conclusions.  Adequate storage stability data are available demonstrating that residues of boscalid are stable under frozen conditions in/on diverse crop matrices for at least 24 months.  Samples from the crop field trials were stored for a maximum of 5.7 months prior to residue analysis.  There are no storage stability issues or corrections that might need to be applied to the various residue studies relevant to the crop commodities discussed in this document.

860.1480 Meat, Milk, Poultry, and Eggs

There are no livestock feedstuffs associated with the proposed use on banana.  Therefore, data requirements pertaining to meat, milk, poultry, and eggs are not relevant to this tolerance petition.

860.1500 Crop Field Trials

Banana

An import tolerance of 0.02 ppm is currently established in 40 CFR §180.589 for residues of boscalid on banana.  The residue data used to establish the import tolerance were generated using the 50% WDG formulation and were reviewed in PP#s   SEQ CHAPTER \h \r 1 1F6313, 3E6791, 4F6875, and 5E6933 (DP# 322235, 11/3/05, D. Dotson).    SEQ CHAPTER \h \r 1 The petitioner is now proposing to amend the registered uses of boscalid on bananas to include the use of a 500 g/L SC (Cumora® Fungicide) formulation.  In support of the proposal to amend the use pattern, BASF has submitted revised Sections B and F along with a bridging study (MRID 47353902).  The proposed new use pattern for banana is presented in Table 3.  In the revised Section F, the petitioner proposes an increase in the existing tolerance level for banana, from 0.2 ppm to 0.5 ppm.

The Executive Summary of the bridging study DER (MRID 47353902) is reproduced below.  For the purpose of completeness, the previous study DER (MRID 46537101) from the initial petition is also reproduced below.

MRID 47353902

DER Reference:	47353902.der.doc

Six side-by-side banana field trials were conducted during the 2006-2007 growing season in Costa Rica (1 trial), Ecuador (1 trial), Colombia (1 trial), Honduras (1 trial), Guatemala (1 trial) and the French West Indies (1 trial).  Each trial site consisted of one untreated plot and two treated plots.  At each treated plot, four foliar broadcast applications of either the 50% water dispersible granules (WDG) or 500 g/L suspension concentrate (SC) formulation of boscalid were made at ~0.135 lb ai/A per application (~0.15 kg ai/ha per application), with a 9- to 11-day retreatment interval, for a total seasonal rate of ~0.54 lb ai/A (~0.60 kg ai/ha; ~1x the maximum proposed seasonal rate).  All applications were made using ground equipment from above the canopy to simulate aerial application in ~3 gal/A (25-30 L/ha) spray volumes; an adjuvant was added to the spray mixture (spray oil at 2.5-3 L/ha, plus emulsifier).  Bagged and unbagged bananas were harvested 0 and 1 day after the last application (DALA).

Samples of banana whole fruit, pulp, and peel were analyzed for residues of boscalid using an LC/MS/MS method, BASF Analytical Method Number D9908 (Version II).  The validated limit of quantitation (LOQ) was 0.05 ppm for boscalid in each banana matrix.  The method was adequate for data collection based on acceptable concurrent recoveries.

Whole banana fruit was stored frozen (<-5°C) for a maximum of 166 days (5.5 months), banana pulp was stored for a maximum of 168 days (5.5 months), and banana peel was stored for a maximum of 173 days (5.7 months).  Adequate storage stability data are available to support the conditions and durations for banana samples.

The results of the banana side-by-side trials are summarized in Table 5.  Following the last of four foliar broadcast applications of the 50% WDG formulation to banana at a total rate of ~0.54 lb ai/A (0.60 kg ai/ha) with a 0-day PHI, maximum residues of boscalid were 0.12 ppm in/on unbagged whole fruit, 0.08 ppm in/on unbagged pulp, and 0.31 ppm in/on unbagged peel.  Residues of boscalid were below the method LOQ (<0.05 ppm) in/on bagged whole fruit, pulp, and peel.  At the 1-day PHI, maximum residues of boscalid were 0.06 ppm in/on bagged whole fruit, 0.19 ppm in/on unbagged whole fruit, and 0.47 ppm in/on unbagged peel.  Residues of boscalid were below the method LOQ (<0.05 ppm) in/on bagged pulp and peel and in/on unbagged pulp.

In the side-by side trials, following the last of four foliar broadcast applications of the 500 g/L SC formulation to banana at a total rate of ~0.54 lb ai/A (~0.60 kg ai/ha) with a 0-day PHI, maximum residues of boscalid were 0.07 ppm in/on bagged whole fruit, 0.28 ppm in/on unbagged whole fruit, and 0.56 ppm in/on unbagged peel.  Residues of boscalid were below the method LOQ (<0.05 ppm) in/on bagged pulp and peel and in/on unbagged pulp.  At the 1-day PHI, maximum residues of boscalid after use of this formulation were 0.42 ppm in/on unbagged whole fruit and 0.93 ppm in/on unbagged peel.  Residues of boscalid were below the method LOQ (<0.05 ppm) in/on bagged whole fruit, pulp, and peel, and in/on unbagged pulp.

The results of this study indicate that there is no discernible difference between the residues in bananas obtained using the WDG and SC formulation of boscalid.  Peel is not considered a significant food/feed item of banana; therefore, the data are presented for informational purposes only.

MRID 46537101

DER Reference	46537101.der.doc

Residue Chemistry Memo D322235, 11/3/05, D. Dotson (PP#s   SEQ CHAPTER \h \r 1 1F6313, 3E6791, 4F6875, & 5E6933)

Twelve field trials were conducted on banana during the 2003-2004 growing season in Costa Rica (2 trials), Colombia (2 trials), Ecuador (2 trials), Guatemala (1 trial), Honduras (2 trials), Martinique (2 trials), and Mexico (1 trial).  At each test location four broadcast foliar applications of boscalid (50% WDG) were made to bananas at 0.125-0.144 lb ai/A/application.  The total seasonal application rate ranged from 0.52-0.56 lb ai/A (~1x the maximum proposed seasonal rate).  The RTI was 10-13 days.  Applications were made using ground equipment, simulating aerial application above the plant canopy, in spray volumes of approximately 3 gal/A of water.  An adjuvant (spray oil plus emulsifier) was added to the spray mixture for all applications.  Mature banana RAC samples were harvested at 0 DALA.

The residues of boscalid in/on banana samples (unbagged and bagged, whole fruit RAC and pulp) were quantitated using a validated LC/MS/MS method, BASF Analytical Method D9908, the data collection method for plant matrices.  Acceptable concurrent method validation data for banana commodities were obtained for boscalid.  The validated LOQ was 0.05 ppm for residues of boscalid in/on banana whole fruit and pulp.  The LOD was 0.005 ppm.

The field residue samples were stored frozen (<-10ºC) a maximum of 4 months from harvest to analysis.  The available storage stability data indicate that residues of boscalid are stable under frozen conditions in/on diverse crop matrices for at least 24 months.

The results of the banana trials (MRID 46537101) are summarized in Table 5.  In the banana field trials residues of boscalid ranged from <0.05 ppm to 0.18 ppm in/on 12 samples of unbagged whole bananas harvested immediately (0-day PHI) after the last of four applications of boscalid (50% WDG) totaling 0.52-0.56 lb ai/A/season.  Boscalid residues were <0.05 ppm in/on all 12 treated bagged whole banana samples.  The residue levels of boscalid in treated pulp samples, both bagged and unbagged (n=24), were <0.05 ppm (<LOQ).

Table 5.	Summary of Residue Data from Banana Field Trials with Boscalid.

Crop matrix

[MRID]	Total Applic. Rate

(lb ai/A)	PHI (days)	Residue Levels (ppm)

	n	Min.	Max.	HAFT1	Median	Mean	Std. Dev.

Banana (proposed use = 0.536 lb ai/A total application rate, 0/1-day PHI)

50% WDG Formulation

Whole fruit, bagged [46537101]	0.52-0.56	0	12	<0.05	<0.05	<0.05	<0.05 <0.05	--

Whole fruit, unbagged

[46537101]

	12	<0.05	0.18	0.18	0.07	0.08	0.04

Whole fruit, both

[46537101]

	24	<0.05	0.18	0.18	<0.05	0.07	0.03

Pulp

[46537101]	0.52-0.56	0	24	<0.05	<0.05	<0.05	<0.05	<0.05	--

Whole fruit, bagged

[47353902]	0.534-0.538	0	6	<0.05	<0.05	0.05	0.05	0.05	--

Pulp, bagged

[47353902]

0	6	<0.05	<0.05	0.05	0.05	0.05	--

Peel, bagged

[47353902]

0	6	<0.05	<0.05	0.05	0.05	0.05	--

Whole fruit, unbagged

[47353902]

0	6	<0.05	0.12	0.12	0.06	0.07	0.029

Pulp, unbagged

[47353902]

0	6	<0.05	0.08	0.08	0.05	0.06	0.012

Peel, unbagged

[47353902]

0	6	0.07	0.31	0.31	0.23	0.21	0.103

Whole fruit, bagged

[47353902]	0.534-0.538	1	6	<0.05	0.06	0.06	0.05	0.05	0.004

Pulp, bagged

[47353902]

1	6	<0.05	<0.05	0.05	0.05	0.05	--

Peel, bagged

[47353902]

1	6	<0.05	<0.05	0.05	0.05	0.05	--

Whole fruit, unbagged

[47353902]

1	6	<0.05	0.19	0.19	0.08	0.09	0.05

Pulp, unbagged

[47353902]

1	6	<0.05	<0.05	0.05	0.05	0.05	--

Peel, unbagged

[47353902]

1	6	<0.05	0.47	0.47	0.10	0.15	0.158

500 g/L SC Formulation

Whole fruit, bagged

[47353902]	0.533-0.539	0	6	<0.05	0.07	0.07	0.05	0.05	0.008

Pulp, bagged

[47353902]

0	6	<0.05	<0.05	0.05	0.05	0.05	--

Peel, bagged

[47353902]

0	6	<0.05	<0.05	0.05	0.05	0.05	--

Whole fruit, unbagged

[47353902]

0	6	<0.05	0.28	0.28	0.09	0.12	0.094

Pulp, unbagged

[47353902]

0	6	<0.05	<0.05	0.05	0.05	0.05	--

Peel, unbagged

[47353902]

0	6	0.06	0.56	0.56	0.23	0.25	0.198

Whole fruit, bagged

[47353902]	0.533-0.539	1	6	<0.05	<0.05	0.05	0.05	0.05	--

Pulp, bagged

[47353902]

1	6	<0.05	<0.05	0.05	0.05	0.05	--

Peel, bagged

[47353902]

1	6	<0.05	<0.05	0.05	0.05	0.05	--

Whole fruit, unbagged

[47353902]

1	6	<0.05	0.42	0.42	0.05	0.12	0.148

Pulp, unbagged

[47353902]

1	6	<0.05	<0.05	0.05	0.05	0.05	--

Peel, unbagged

[47353902]

1	6	<0.05	0.93	0.93	0.19	0.30	0.329

1  HAFT = Highest average field trial result.

Conclusions.  The submitted and available residue data for banana are adequate, and the trials conducted reflect the proposed use pattern for banana.  The number and locations of field trials are adequate for the purpose of amending the import tolerance on bananas.  An acceptable method was used for the quantitation of residues of boscalid, and the studies are supported by adequate storage stability data.

The Agency generally recommends that twelve field trials be submitted for imported bananas (NAFTA Guidance Document on Data Requirements for Tolerances on Imported Commodities, 4/2003).  Twelve trials were originally submitted for the registration of the WDG formulation.  For the bridging study, the registrant submitted the results of six trials performed using each formulation.  In the bridging study, the residue levels resulting from the use of the two formulations were comparable.  The average field trial value for the WDG and SC formulations were 0.07 ppm and 0.11 ppm, respectively.  A value of ½ LOQ (0.025 ppm) was used for samples whose residue value was reported as <LOQ (0.05 ppm).  Although the average field trial values were relatively close, the maximum field trial value for the SC formulation was approximately twice as high as the maximum value for the WDG formulation (0.42 ppm as opposed to 0.19 ppm).  As the bridging study demonstrated that, in general, residues were comparable, the results of all banana field trials were used to determine the recommended tolerance.  Also, the SC formulation will be used in addition to the WDG formulation currently being used.  It is not meant to replace the WDG formulation.  All residue values for unbagged whole bananas were entered into the Agency’s tolerance spreadsheet to determine an appropriate tolerance level (see Appendix I).  The tolerance spreadsheet recommends a RAC tolerance of 0.40 ppm.  This value is higher than the current 0.2 ppm tolerance for banana because the maximum residue values for the SC formulation (0.28 and 0.42 ppm) were higher than any of the values from the WDG field trials.  The petitioner should submit a revised Section F to lower the proposed RAC tolerance from 0.5 ppm to 0.4 ppm.

860.1520 Processed Food and Feed

HED does not require residue data for any processed commodities associated with banana.  Therefore, data requirements for processed food and feed are not relevant to this tolerance petition.

  SEQ CHAPTER \h \r 1 860.1650 Submittal of Analytical Reference Standards

Analytical standards for boscalid (with an expiration date of 4/1/2014) are currently available in the EPA National Pesticide Standards Repository (electronic communication, D. Wright, ACB/BEAD, 10/17/08).  The analytical reference standard for boscalid must be recertified or replenished as requested by the Repository.  The reference standards should be sent to the Analytical Chemistry Lab, which is located at Fort Meade, to the attention of Theresa Cole at the following address:

	USEPA

	National Pesticide Standards Repository/Analytical Chemistry Branch/OPP

	701 Mapes Road

	Fort George G. Meade, MD  20755-5350

(Note that the mail will be returned if the extended zip code is not used.)

860.1850 and 860.1900 Confined and Field Accumulation in Rotational Crops

As the proposed uses on banana do not include rotational crops, these guideline requirements are not relevant to the current petition.

860.1550 Proposed Tolerances

The residue of concern in plants is boscalid per se for the purposes of risk assessment and tolerance expression.  Boscalid tolerances for plant commodities are listed in 40 CFR §180.589 (a)(1) and are expressed in terms of residues of the fungicide boscalid [3-pyridinecarboxamide, 2-chloro-N-(4'-chloro[1,1'-biphenyl]-2-yl)].  The tolerance expression proposed by BASF in PP#8E7366 is consistent with the tolerance definition for plant commodities listed in 40 CFR §180.589 (a)(1).

The submitted banana side-by-side field trial data for the WDG and SC formulations, along with the data previously submitted for banana using the WDG formulation are adequate.  The field trial data for both formulations were entered into the Agency’s tolerance spreadsheet as specified by the Guidance for Setting Pesticide Tolerances Based on Field Trial Data SOP (version dated 2/2008) to determine an appropriate tolerance level (see Appendix I).  Based on the output from the tolerance spreadsheet, HED recommends establishment of an import tolerance of 0.40 ppm for banana.

The Codex Alimentarius Commission has established a MRL for residues of boscalid in or on banana at 0.2 ppm, which is equivalent to the current U.S. tolerance.  However, the recommended U.S. tolerance is higher than the Codex MRL.  Mexico has not established any MRLs for residues of boscalid in/on raw agricultural commodities.  Canadian MRLs have been established for a variety of crops but not for banana.

A tolerance summary is presented below in Table 6.

Table 6.   Tolerance Summary for Boscalid.

Commodity	Current §180.589

Tolerance (ppm)	Proposed §180.589

Tolerance (ppm)	Recommended §180.589

Tolerance (ppm)	Comments;

Correct Commodity Definition

Banana	0.2 1	0.5	0.40

	1 Import tolerance, no current U.S. registration

References

PP#1F06313.  BAS 510 F (Common Name: Boscalid), New Fungicide Active Ingredient.  Residue Chemistry Summary Document, 278385, M. Nelson, 08/15/03

  SEQ CHAPTER \h \r 1 PP#s 1F6313, 3E6791, 4F6875, and 5E6933:  Boscalid, Registrant’s Response to Deficiencies Cited in Tolerance Petition 1F6313.  Summary of Analytical Chemistry and Residue Data for Rotational Root Crops, Direct Uses on Celery, Spinach, Bananas, Strawberries, Almonds, and Potatoes, and Seed Treatment Uses on Bulb Vegetables, Brassica Leafy Vegetables, Legume Vegetables, Peanuts, and Sunflowers, 322235, D. Dotson, 11/3/05

NAFTA Guidance Document on Data Requirements for Tolerances on Imported Commodities, USEPA (OPP), Canada (PMRA), and Mexico (CICOPLAFEST), 4/2003

  SEQ CHAPTER \h \r 1 Attachments:

International Residue Limit Status sheet

Appendix I - Tolerance Assessment Calculations

INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name:  3-pyridinecarboxamide, 2-chloro-N-(4'-chloro[1,1'-biphenyl]-2-yl	Common Name:  Boscalid

	X Proposed tolerance

 Reevaluated tolerance

 Other	Date:  8/26/08

Codex Status (Maximum Residue Limits)	U. S. Tolerances

 No Codex proposal step 6 or above

 No Codex proposal step 6 or above for the crops requested	Petition Number:  PP#8E7366

DP#:  355200

Other Identifier:

Residue definition (step 8/CXL):  Boscalid	Reviewer/Branch:  C. Swartz/D. Dotson/RAB2

	Residue definition:  Boscalid

Crop (s)	MRL (mg/kg)	Crop(s) 	Tolerance (ppm)

Banana	0.2	Banana	0.5

Limits for Canada	Limits for Mexico

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 No Limits for the crops requested

Residue definition:  2-chloro-N-(4'-chloro[1,1'-

biphenyl]-2-yl)-3-pyridinecarboxamide

	Residue definition:  N/A

Crop(s)	MRL (mg/kg)	Crop(s)	MRL (mg/kg)

	Notes/Special Instructions:

S. Funk, 08/26/08

Appendix I.  Tolerance Assessment Calculations.

The dataset used to establish a tolerance for boscalid on imported banana consisted of field trial data for unbagged whole banana.  For unbagged whole banana, the data entered reflect application rates of 0.52-0.60 lb ai/A (4 applications at 0.125-0.144 lb ai/A per application) using the WDG and SC formulation with either a 0- or 1-day PHI.  As specified by the Guidance for Setting Pesticide Tolerances Based on Field Trial Data SOP (version dated 2/2008), the field trial application rates and PHIs are within 25% of the maximum label application rate and minimum label PHI, respectively.  Table I-1 lists the residue data for unbagged bananas sorted by formulation.  The residue values that were entered into the tolerance spreadsheet in Table I-1 are the aggregates of all data submitted for unbagged bananas using both formulations and approximating the proposed use pattern.

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Dximum likelihood estimation (MLE) procedures were needed to impute censored values.  In Table I-1, “(MLE)” is used to designate he imputed values.  Visual inspection of the lognormal probability plot (Figure I-1) and the results from the approximate Shapiro-Francia test statistic (Figure I-2) indicated that the dataset was reasonably lognormal.

As the field trial data for boscalid on unbagged banana represent a large dataset (i.e., more than 15 samples) and are reasonably lognormal, the minimum of the 95% upper confidence limit (UCL) on the 95th percentile and the point estimate of the 99th percentile should be selected as the tolerance value.  Using the rounding procedure as outlined in the SOP, the 95% UCL on the 95th percentile rounds to the value 0.40 ppm and the point estimate of the 99th percentile rounds to the value 0.45 ppm (Figure I-2).  Because the 0.40-ppm value was the minimum value, 0.40 ppm is the recommended tolerance level for boscalid on banana.

Table I-1.	Residue data used to calculate tolerance for boscalid on banana.

Regulator:	EPA	EPA	EPA	EPA

Chemical:	Boscalid (WDG)	Boscalid (WDG)	Boscalid (SC)	Boscalid (WDG & SC)

Crop:	Banana, whole fruit, unbagged	Banana, whole fruit, unbagged Banana, whole fruit, unbagged	Banana, whole fruit, unbagged (MLE)

PHI:	0 Days	0-1 Days	0-1 Days	0-1 Days

Total App. Rate:	0.52-0.56 lb ai/A	0.53-0.54 lb ai/A	0.60 lb ai/A 0.52-0.60 lb ai/A

Submitter:	BASF Corporation	BASF Corporation	BASF Corporation	BASF Corporation

MRID Citation:	MRID 446537101	MRID 47353902	MRID 47353902	MRIDs 446537101 and 47353902

	Residues of Boscalid (ppm)

	0.050	0.120	0.120	0.050

	0.100	0.190	<0.05	0.100

	<0.05	<0.05	<0.05	0.015 (MLE)

	0.100	<0.05	<0.05	0.100

	<0.05	<0.05	0.180	0.017 (MLE)

	0.180	0.080	0.120	0.180

	<0.05	<0.05	<0.05	0.020 (MLE)

	0.070	<0.05	<0.05	0.070

	0.090	0.060	0.280	0.090

	0.110	0.080	0.420	0.110

	0.070	0.090	0.050	0.070

	<0.05	0.080	<0.05	0.022 (MLE)

0.120

0.190

0.024 (MLE)

0.026 (MLE)

0.028 (MLE)

0.080

0.030 (MLE)

0.032 (MLE)

0.060

0.080

0.090

0.080

0.120

0.034 (MLE)

0.036 (MLE)

0.039 (MLE)

0.180

0.120

0.041 (MLE)

0.043 (MLE)

0.280

0.420

0.050

0.048 (MLE)

Figure I-   SEQ Figure_II- \* ARABIC  1 .  Lognormal probability plot of boscalid field trial data for banana.

Figure I- 2.  Tolerance spreadsheet summary of boscalid field trial data for banana.

Page   PAGE  1  of   NUMPAGES  19

Boscalid	Summary of Analytical Chemistry and Residue Data	DP#: 354687


[Federal Register Volume 86, Number 72 (Friday, April 16, 2021)]
[Notices]
[Pages 20225-20228]
[FR Doc No: 2021-07786]

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SECURITIES AND EXCHANGE COMMISSION

[Release No. 34-91529; File No. SR-NYSEAMER-2021-17]

Self-Regulatory Organizations; NYSE American LLC; Notice of
Filing and Immediate Effectiveness of Proposed Rule Change To Amend
Rule 7.37E

April 12, 2021.
    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 1, 2021, NYSE American LLC (``NYSE American'' or
the ``Exchange'') 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 Rule 7.37E to specify when the
Exchange may adjust its calculation of the PBBO. The proposed rule
change is available on the Exchange's website 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

Purpose
    The Exchange proposes to amend Rule 7.37E to specify when the
Exchange may adjust its calculation of the PBBO.\4\
---------------------------------------------------------------------------

    \4\ The term ``PBBO'' is defined in Rule 1.1E to mean the Best
Protected Bid and the Best Protected Offer, which in turn mean the
highest Protected Bid and the lowest Protected Offer, which refer to
quotations in an NMS stock that is (i) displayed by an Automated
Trading Center; (ii) disseminated pursuant to an effective national
market system plan; and (iii) an Automated Quotation that is the
best bid or best offer of a national securities exchange or the best
bid or best offer of a national securities association. The term
NBBO is defined to mean the national best bid and offer. The
Exchange notes that the NBBO may differ from the PBBO because the
NBBO includes Manual Quotations, which are defined as any quotation
other than an automated quotation. 17 CFR 242.600(b)(37).
---------------------------------------------------------------------------

    Generally, the Exchange updates both the PBBO and NBBO based on
quote updates received from data feeds from Away Markets, which are
disclosed in Rule 7.37E(d).\5\ In 2015, the Exchange described in a
rule filing that when it routes interest to a protected quotation, the
Exchange adjusts the PBBO.\6\ The Exchange proposes to amend its rules
to include that description in Rule 7.37E and provide additional
specificity of when it may adjust its calculation of the PBBO.
---------------------------------------------------------------------------

    \5\ The Exchange proposes non-substantive amendments to Rule
7.37E(d) to update the names of the exchanges listed in the table by
replacing the term ``Bats'' with ``Cboe,'' replacing the term
``NASDAQ'' with ``Nasdaq,'' removing reference to ``OMX'' for Nasdaq
BX, Inc. and Nasdaq PHLX LLC, adding reference to ``Inc.'' for
Nasdaq BX, Inc., and deleting an extraneous ``LLC''.
    \6\ See Securities Exchange Act Release No. 74408 (March 2,
2015), 80 FR 12225 (March 6, 2015) (SR-NYSEMKT-2015-11) (Notice of
filing and immediate effectiveness of proposed rule change)
(``Datafeed Filing'').
---------------------------------------------------------------------------

    As proposed, new paragraph (d)(1) of Rule 7.37E would provide:

    The Exchange may adjust its calculation of the PBBO based on
information about orders it sends to Away Markets with protected
quotations, execution reports received from those Away Markets, and
certain orders received by the Exchange.

    This proposed rule text is consistent with the Exchange's
disclosure in the Datafeed Filing and adds specificity that the
Exchange may adjust its calculation of the PBBO based on execution
reports received from Away Markets and certain orders received by the
Exchange.\7\
---------------------------------------------------------------------------

    \7\ The Exchange does not adjust its calculation of the NBBO
based on information about orders sent to Away Markets, execution
reports from Away Markets, or certain orders received by the
Exchange.
---------------------------------------------------------------------------

    Proposed Rule 7.37E(d)(1) is based on MEMX LLC (``MEMX'') Rule
13.4(b) with two non-substantive differences.\8\ First, the Exchange
proposes to use the term ``PBBO,'' which is the term used in the
Exchange's rules for the best-priced protected quotations, instead of
``NBBO.'' Second, the Exchange proposes to refer to ``Away Markets,''
which is a defined term in Rule 1.1E, instead of ``other venues.''
---------------------------------------------------------------------------

    \8\ MEMX Rule 13.4(b) provides: ``The Exchange may adjust its
calculation of the NBBO based on information about orders sent to
other venues with protected quotations, execution reports received
from those venues, and certain orders received by the Exchange.''
---------------------------------------------------------------------------

    MEMX has not disclosed circumstances when ``certain orders received
by the Exchange'' would result in an adjustment to its calculation of
the PBBO, but the Exchange believes that when MEMX receives an ISO with
a Day time in force (``Day ISO''), it adjusts its calculation of the
PBBO. The Exchange proposes that it would also adjust its calculation
of the PBBO based on receipt of a Day ISO, which is consistent with how
Nasdaq Stock Market LLC (``Nasdaq'') \9\ and Cboe BZX Exchange, Inc.
(``BZX'') \10\ function.
---------------------------------------------------------------------------

    \9\ See Nasdaq Rule 4703(j) (``Upon receipt of an ISO, the
System will consider the stated price of the ISO to be available for
other Orders to be entered at that price, unless the ISO is not
itself accepted at that price level (for example, a Post-Only Order
that has its price adjusted to avoid executing against an Order on
the Nasdaq Book) or the ISO is not Displayed.'') and Securities
Exchange Act Release No. 74558 (March 20, 2015) 80 FR 16050, 16068
(March 26, 2015) (SR-Nasdaq-2015-024) (Notice).
    \10\ See Securities Exchange Act Release No. 74074 (January 15,
2015), 80 FR 3679, 3680 (January 23, 2015) (SR-BATS-2015-04) (Notice
of filing and immediate effectiveness of proposed rule change to
clarify the use of certain data feeds) (``The Exchange's [matching
engine] will update the NBBO upon receipt of a Day ISO. When a Day
ISO is posted on the BATS Book, the [matching engine] uses the
receipt of a Day ISO as evidence that the protected quotes have been
cleared, and the ME does not check away markets for equal or better-
priced protected quotes. . . . In determining whether to route an
order and to which venue(s) it should be routed, the [routing
engine] makes its own calculation of the NBBO. . . . The [routing
engine] does not utilize Day ISO Feedback in constructing the NBBO;
however, because all orders initially flow through the [matching
engine], to the extent Day ISO Feedback has updated the [matching
engine's] calculation of the NBBO, all orders processed by the
[routing engine] do take Day ISO Feedback into account.'') (``BZX
Filing'').
---------------------------------------------------------------------------

    Specifically, the Exchange proposes that it would adjust its
calculation of the PBBO upon receipt of a Day ISO Order that the
Exchange displays. As described in Rule 7.37E(e)(3)(C), a Day ISO is
eligible for the exception to locking or crossing a protected quotation
because the member organization simultaneously routes an ISO to execute
against the full size of any locked or crossed protection quotations,
i.e., the member organization routes ISOs to trade with contra-side
protected quotations on Away Markets that are priced equal to or better
than the arriving Day ISO on the Exchange. Because receipt of a Day ISO
informs the Exchange that the member organization has routed ISOs to
trade with Away Market contra-side protected quotations priced equal to
or better than the Day ISO, upon receipt and displaying of a Day ISO,
the Exchange proposes to adjust its calculation of the PBBO to exclude
any contra-side protected quotations that are priced equal to or better
than the Day ISO.
     For example, if the best protected bid is 10.00, Exchange
A is displaying a protected offer at 10.05, and Exchange B is
displaying a protected offer at 10.09, the Exchange's calculation of
the PBBO would be 10.00 x 10.05. If the Exchange receives a Day ISO for
100 shares to buy priced at 10.05 that is displayed on the Exchange at
10.05, the Exchange would adjust its calculation of the PBBO to be
10.05 x 10.09 and would use this updated PBBO for execution, routing,
and re-pricing determinations.
    If a Day ISO is displayed on the Exchange at a price less
aggressive than its limit price (e.g., a Day ISO ALO that, if displayed
at its limit price, would lock displayed interest on the Exchange), the
Day ISO still informs the Exchange that the member organization has
routed ISOs to trade with contra-side protected quotations on Away
Markets that are priced equal to or better than the limit price of
arriving Day ISO on the Exchange. The Exchange would therefore use the
limit price of the Day ISO ALO to determine how to adjust its
calculation of the contra-side Away Market PBBO, provided that contra-
side displayed interest on the Exchange equal to the limit price of the
Day ISO ALO would not be considered cleared. The price at which the
arriving Day ISO ALO would be displayed would be the price that informs
the Exchange's calculation of the same-side PBBO.

    For example, when the best protected bid is 10.00 and Exchange A is
displaying a protected offer at 10.05 and the Exchange's best displayed
offer is 10.07, the Exchange's calculation of the PBBO would be 10.00 x
10.05, then:
     If the Exchange receives ALO ``1'' to buy at 10.06, it
would be displayed at 10.04 and be assigned a working price of 10.05,
which is the PBO (displayed on Exchange A),\11\ and the Exchange would
adjust the PBBO to be 10.04 x 10.05.
---------------------------------------------------------------------------

    \11\ See Rule 7.31E(e)(2)(B)(i).
---------------------------------------------------------------------------

     If next, the Exchange receives Day ISO ALO ``2'' to buy at
10.07, the Exchange would be permitted to display that order at a price
that crosses Exchange A's PBO because it is a Day ISO. However, because
it locks the Exchange's best displayed offer, due to its ALO modifier,
the Exchange would display Day ISO ALO ``2'' at 10.06 and it would have
a working price of 10.06.\12\ In this scenario, the Exchange proposes
to adjust its calculation of the PBBO to be 10.06 x 10.07 and use this
updated PBBO for execution, routing, and re-pricing determinations,
including repricing the ALO ``1'' to buy to both work and display at
its limit price of 10.06.
---------------------------------------------------------------------------

    \12\ See Rule 7.31E(e)(3)(D)(ii). Currently, the Exchange would
display such Day ISO ALO ``2'' at 10.06 and would adjust its
calculation of the same-side PBBO and reprice same-side resting
orders to the Day ISO price, but would not adjust its calculation of
the contra-side PBBO for purposes of routing and execution
determinations of new orders.
---------------------------------------------------------------------------

    The Exchange believes that adjusting the PBBO in this manner is
consistent with Regulation NMS because the member organization that
submitted the Day ISO ALO to buy priced at 10.07 has represented that
it has sent ISOs to trade with protected offers on other exchanges
priced at 10.07 or lower. The only reason that such order would not be
displayed at 10.07 on the Exchange is because it has an ALO modifier
and cannot trade with the Exchange's displayed offer of 10.07. However,
there is no restriction on that Day ISO ALO being displayed at 10.06,
which crosses the Away Market PBO of 10.05. The Exchange believes in
this circumstance, it is consistent with Regulation NMS for the
Exchange to consider that any Away Market protected offers priced 10.07
or below have been cleared and therefore adjust its calculation of the
contra-side Away Market PBBO for purposes of execution, routing, and
repricing determinations based on the limit price of the Day ISO ALO.
    The Exchange believes that the proposed amendments to Rule 7.37-
E(d) would promote clarity and transparency in the Exchange's rules
regarding circumstances when the Exchange may adjust its calculation of
the PBBO. The Exchange does not believe this proposed rule change is
novel. Rather, the Exchange believes that other equity exchanges that
accept Day ISOs similarly adjust their calculation of the best
protected bid and best protected offer for purposes of making
execution, routing, and repricing determinations based on the receipt
of Day ISOs, as described above. The Exchange anticipates that it will
implement the technology change to how it calculates the PBBO in May
2021.
2. Statutory Basis
    The Exchange believes that the proposal is consistent with Section
6(b) of the Act,\13\ in general, and furthers the objectives of
Sections 6(b)(5) of the Act,\14\ in particular, because 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 and because it is not
designed to permit unfair discrimination between customers, issuers,
brokers, or dealers.
---------------------------------------------------------------------------

    \13\ 15 U.S.C. 78f(b).
    \14\ 15 U.S.C. 78f(b)(5).
---------------------------------------------------------------------------

    The Exchange believes that the proposed rule change would remove
impediments to and perfect the mechanism of a free and open market and
a national market system because it is designed to promote clarity and
transparency in Exchange rules of when the Exchange may adjust its
calculation of the PBBO. The Exchange believes that adjusting its
calculation of the PBBO based on receipt of a Day ISO is consistent
with Regulation NMS because the member organization that entered such
Day ISO has also sent ISOs to Away Markets to trade with contra-side
protected quotations priced equal to or better than the Day ISO. For
the same reasons that displaying a Day ISO at a price that locks or
crosses the PBBO is consistent with Regulation NMS, the Exchange
believes that adjusting its calculation of the PBBO based on receipt
and display of a Day ISO for purposes of making execution, routing, and
repricing determinations for other orders is also consistent with
Regulation NMS. The Exchange further notes that the proposed rule text
is not novel and is based on MEMX Rule 13.4(b) and is consistent with
Nasdaq rules and the BZX Filing.

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

    In accordance with Section 6(b)(8) of the Act,\15\ the Exchange
believes that the proposed rule change would not impose any burden on
competition that is not necessary or appropriate in furtherance of the
purposes of the Act. The proposed rule changes are designed to promote
transparency and clarity in Exchange rules regarding when the Exchange
may adjust its calculation of the PBBO. The Exchange believes that the
proposed rule change would promote competition because the Exchange
proposes to adjust its calculation of the PBBO under similar
circumstances that other equity exchanges adjust their calculation of
the PBBO, including MEMX, Nasdaq, and BZX.
---------------------------------------------------------------------------

    \15\ 15 U.S.C. 78f(b)(8).
---------------------------------------------------------------------------

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 Exchange has filed the proposed rule change pursuant to Section
19(b)(3)(A)(iii) of the Act \16\ and Rule 19b-4(f)(6) thereunder.\17\
Because the 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 prior to
30 days from the date on which it was filed, or such shorter time as
the Commission may designate, if consistent with the protection of
investors and the public interest, the proposed rule change has become
effective pursuant to Section 19(b)(3)(A) of the Act and Rule 19b-
4(f)(6)(iii) thereunder.
---------------------------------------------------------------------------

    \16\ 15 U.S.C. 78s(b)(3)(A)(iii).
    \17\ 17 CFR 240.19b-4(f)(6).
---------------------------------------------------------------------------

    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) \18\ of the Act to determine
whether the proposed rule change should be approved or disapproved.
---------------------------------------------------------------------------

    \18\ 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-NYSEAMER-2021-17 on the subject line.

Paper Comments

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

All submissions should refer to File Number SR-NYSEAMER-2021-17. 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-NYSEAMER-2021-17, and should be
submitted on or before May 7, 2021.

    For the Commission, by the Division of Trading and Markets,
pursuant to delegated authority.\19\
---------------------------------------------------------------------------

    \19\ 17 CFR 200.30-3(a)(12).
---------------------------------------------------------------------------

J. Matthew DeLesDernier,
Assistant Secretary.
[FR Doc. 2021-07786 Filed 4-15-21; 8:45 am]
BILLING CODE 8011-01-P


[Federal Register Volume 88, Number 227 (Tuesday, November 28, 2023)]
[Notices]
[Pages 83136-83138]
[FR Doc No: 2023-26106]

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

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2022-E-2101]

Determination of Regulatory Review Period for Purposes of Patent
Extension; Korsuva

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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

SUMMARY: The Food and Drug Administration (FDA or the Agency) has
determined the regulatory review period for Korsuva and is publishing
this notice of that determination as required by law. FDA has made the
determination because of the submission of an application to the
Director of the U.S. Patent and Trademark Office (USPTO), Department of
Commerce, for the extension of a patent which claims that human drug
product.

DATES: Anyone with knowledge that any of the dates as published (see
SUPPLEMENTARY INFORMATION) are incorrect may submit either electronic
or written comments and ask for a redetermination by January 29, 2024.
Furthermore, any interested person may petition FDA for a determination
regarding whether the applicant for extension acted with due diligence
during the regulatory review period by May 28, 2024. See ``Petitions''
in the SUPPLEMENTARY INFORMATION section for more information.

ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. The https://www.regulations.gov electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of January 29, 2024. Comments
received by mail/hand delivery/courier (for written/paper submissions)
will be considered timely if they are received on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No.
FDA-2022-E-2101 for ``Determination of Regulatory Review Period for
Purposes of Patent Extension; KORSUVA.'' Received comments, those filed
in a timely manner (see ADDRESSES), will be placed in the docket and,
except for those submitted as ``Confidential Submissions,'' publicly
viewable at https://www.regulations.gov or at the Dockets Management
Staff between 9 a.m. and 4 p.m., Monday through Friday,<PHONE_NUMBER>.
     Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with Sec.  10.20 (21 CFR 10.20) and
other applicable disclosure law. For more information about FDA's
posting of comments to public dockets, see 80 FR 56469, September 18,
2015, or access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852,<PHONE_NUMBER>.

FOR FURTHER INFORMATION CONTACT: Beverly Friedman, Office of Regulatory
Policy, Food and Drug Administration, 10903 New Hampshire Ave., Bldg.
51, Rm. 6250, Silver Spring, MD 20993,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

I. Background

    The Drug Price Competition and Patent Term Restoration Act of 1984
(Pub. L. 98-417) and the Generic Animal Drug and Patent Term
Restoration Act (Pub. L. 100-670) generally provide that a patent may
be extended for a period of up to 5 years so long as the patented item
(human drug or biologic product, animal drug product, medical device,
food additive, or color additive) was subject to regulatory review by
FDA before the item was marketed. Under these acts, a product's
regulatory review period forms the basis for determining the amount of
extension an applicant may receive.
    A regulatory review period consists of two periods of time: a
testing phase and an approval phase. For human drug products, the
testing phase begins when the exemption to permit the clinical
investigations of the drug becomes effective and runs until the
approval phase begins. The approval phase starts with the initial
submission of an application to market the human drug product and
continues until FDA grants permission to market the drug product.
Although only a portion of a regulatory review period may count toward
the actual amount of extension that the Director of USPTO may award
(for example, half the testing phase must be subtracted as well as any
time that may have occurred before the patent was issued), FDA's
determination of the length of a regulatory review period for a human
drug product will include all of the testing phase and approval phase
as specified in 35 U.S.C. 156(g)(1)(B).
    FDA has approved for marketing the human drug product, Korsuva
(difelikefalin acetate). Korsuva is indicated for the treatment of
moderate-to-severe pruritus associated with chronic kidney disease in
adults undergoing hemodialysis. Subsequent to this approval, the USPTO
received a patent term restoration application for Korsuva (U.S. Patent
No. 7,402,564) from Cara Therapeutics, Inc., and the USPTO requested
FDA's assistance in determining the patent's eligibility for patent
term restoration. In a letter dated September 28, 2022, FDA advised the
USPTO that this human drug product had undergone a regulatory review
period and that the approval of Korsuva represented the first permitted

commercial marketing or use of the product. Thereafter, the USPTO
requested that FDA determine the product's regulatory review period.

II. Determination of Regulatory Review Period

    FDA has determined that the applicable regulatory review period for
Korsuva is 4,625 days. Of this time, 4,381 days occurred during the
testing phase of the regulatory review period, while 244 days occurred
during the approval phase. These periods of time were derived from the
following dates:
    1. The date an exemption under section 505(i) of the Federal Food,
Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(i)) became effective:
December 26, 2008. The applicant claims January 16, 2009, as the date
the investigational new drug application (IND) became effective.
However, FDA records indicate that the IND effective date was December
26, 2008, which was 30 days after FDA receipt of the IND.
    2. The date the application was initially submitted with respect to
the human drug product under section 505 of the FD&C Act: December 23,
2020. FDA has verified the applicant's claim that the new drug
application (NDA) for Korsuva (NDA 214916) was initially submitted on
December 23, 2020.
    3. The date the application was approved: August 23, 2021. FDA has
verified the applicant's claim that NDA 214916 was approved on August
23, 2021.
    This determination of the regulatory review period establishes the
maximum potential length of a patent extension. However, the USPTO
applies several statutory limitations in its calculations of the actual
period for patent extension. In its application for patent extension,
this applicant seeks 1,827 days of patent term extension.

III. Petitions

    Anyone with knowledge that any of the dates as published are
incorrect may submit either electronic or written comments and, under
21 CFR 60.24, ask for a redetermination (see DATES). Furthermore, as
specified in Sec.  60.30 (21 CFR 60.30), any interested person may
petition FDA for a determination regarding whether the applicant for
extension acted with due diligence during the regulatory review period.
To meet its burden, the petition must comply with all the requirements
of Sec.  60.30, including but not limited to: must be timely (see
DATES), must be filed in accordance with Sec.  10.20, must contain
sufficient facts to merit an FDA investigation, and must certify that a
true and complete copy of the petition has been served upon the patent
applicant. (See H. Rept. 857, part 1, 98th Cong., 2d sess., pp. 41-42,
1984.) Petitions should be in the format specified in 21 CFR 10.30.
    Submit petitions electronically to https://www.regulations.gov at
Docket No. FDA-2013-S-0610. Submit written petitions (two copies are
required) to the Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

    Dated: November 21, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023-26106 Filed 11-27-23; 8:45 am]
BILLING CODE 4164-01-P


Guidance for FDA Staff and

Industry

Compliance Policy Guides Manual

Sec. 608.400

Compounding of Drugs for Use in Animals

Submit written comments regarding this guidance document identified with
Docket No. 2003D-0290 to the Dockets Management Branch (HFA-305), 5630
Fishers Lane, rm. 1061, Rockville, MD 20852.

Additional copies of this document may be obtained by sending a request
to the Division of Compliance Policy (HFC-230, Food and Drug
Administration, 5600 Fishers Lane, Rockville, MD 20857, or from the
Internet at:   HYPERLINK
"http://www.fda.gov/ora/compliance_ref/cpg/default.htm"
http://www.fda.gov/ora/compliance_ref/cpg/default.htm   or     HYPERLINK
"http://www.fda.gov/OHRMS/DOCKETS/98fr/03d-0290-gdl0001.pdf"
http://www.fda.gov/OHRMS/DOCKETS/98fr/03d-0290-gdl0001.pdf

U.S. Department of Health and Human Services

Food and Drug Administration

Office of Regulatory Affairs

Center for Veterinary Medicine

July 2003

Compliance Policy Guide

Compliance Policy Guidance for FDA Staff and Industry

CHAPTER – 6

SUBCHAPTER - 600

Sec. 608.400 - Compounding of Drugs for Use in Animals

This compliance policy guidance is intended to provide guidance and
instructions to FDA staff, industry, and the public for obtaining
information to help fulfill the Agency’s plans regarding the
compounding of drugs for use in animals.  The compliance policy guidance
does not create or confer any rights for or on any person and does not
operate to bind the Food and Drug Administration (FDA) or the public.
An alternative approach may be used if such approach satisfies the
requirements of the applicable statute and regulations.  It is intended
for FDA personnel, industry, and the public and is available
electronically to the public.

INTRODUCTION

This document provides guidance to drug compounders, veterinarians, and
the staff of the Food and Drug Administration (FDA) on how the Agency
intends to address compounding of drugs intended for use in animals.
This guidance describes FDA’s current thinking on what types of
compounding might be subject to enforcement action.

BACKGROUND

FDA announced the availability of Compliance Policy Guide (CPG) section
608.400 entitled “Compounding of Drugs for Use in Animals” on July
3, 1996 (61 FR 34849), to provide guidance to FDA’s field and
headquarters staff with regard to the compounding of animal drugs by
veterinarians and pharmacists for use in animals.  There is a potential
for causing harm to public health and to animals when drug products are
compounded, distributed, and used in the absence of adequate and
well-controlled safety and effectiveness data or adherence to the
principles of contemporary pharmaceutical chemistry and current good
manufacturing practices.  Use of compounded drugs in animals can result
in adverse reactions and animal deaths.  Furthermore, because the
pharmacokinetics and depletion times for residues from compounded
products intended for use in food-producing animals are not known, the
assignment of an extemporaneous withdrawal time may result in
potentially harmful residues in food.  Inactive ingredients, such as
excipients and vehicles, from unapproved or unknown origins may also
pose additional risk (e.g., Freunds adjuvant, a carcinogen).

FDA is updating this guidance to be consistent, to the extent
practicable, with the scope of compounding permitted under regulations
implementing the Animal Medicinal Drug Use Clarification Act of 1994, to
describe what factors FDA will consider in exercising its enforcement
discretion regarding compounding of drugs intended for use in animals,
and to ensure the consistency of its policies with regard to compounding
of drugs intended for use in humans and in animals.

DISCUSSION

The Federal Food, Drug, and Cosmetic Act (the Act) does not distinguish
compounding from manufacturing or other processing of drugs for use in
animals.  FDA acknowledges the use of compounding within certain areas
of veterinary practice.  The current state of veterinary medicine
requires products to treat many conditions in a number of different
species, some of which are known to have unique physiological
characteristics.  Furthermore, FDA regulations specifically permit the
compounding of products from approved animal or human drugs under the
conditions set forth in 21 CFR 530.13.  This activity is not the subject
of this guidance.

However, FDA is greatly concerned about veterinarians and pharmacies
that are engaged in manufacturing and distributing unapproved new animal
drugs in a manner that is clearly outside the bounds of traditional
pharmacy practice and that violates the Act (e.g., compounding that is
intended to circumvent the drug approval process and provide for the
mass marketing of products that have been produced with little or no
quality control or manufacturing standards to ensure the purity,
potency, and stability of the product).  These activities are the focus
of this guidance.  Pharmacies and veterinarians who engage in activities
analogous to manufacturing and distributing drugs for use in animals may
be held to the same provisions of the Act as manufacturers.

With regard to compounding from bulk drug substances, two Federal
Appeals Court decisions, United States v. Algon Chemical Inc., 879 F.2d
1154 (3d Cir. 1989) and United States v. 9/1 Kg. Containers, 854 F.2d
173 (7th Cir. 1988), affirmed the FDA position that the Act does not
permit veterinarians to compound unapproved finished drug products from
bulk drug substances, unless the finished drug is not a new animal drug.
 The principle established by the court applies equally to compounding
by pharmacists.

Neither the Act nor its implementing regulations exempt veterinarians or
pharmacists from the approval requirements in the new animal drug
provisions of the Act, 21 U.S.C. Section 360b.  In the absence of an
approved new animal drug application, the compounding of a new animal
drug from any unapproved drug or from bulk drug substances results in an
adulterated new animal drug in violation of section 21 U.S.C. Section
351(a)(5).  The compounding of a new animal drug from an approved human
or animal drug also results in an adulterated new animal drug in
violation of 21 U.S.C. Section 351(a)(5), unless the conditions set
forth in 21 CFR 530.13(b) are met.

DEFINITIONS

“Bulk drug substance,” as defined in 21 CFR 207.3(a)(4), means any
substance that is represented for use in a drug and that, when used in
the manufacturing, processing, or packaging of a drug, becomes an active
ingredient or a finished dosage form of the drug, but the term does not
include intermediates used in the synthesis of such substances.

“Compounding” does not include mixing, reconstituting, or other such
acts that are performed in accordance with directions contained in
approved labeling provided by the product's manufacturer and other
manufacturer directions consistent with that labeling

A “valid veterinarian-client-patient relationship” (valid VCPR), as
defined in 21 CFR 530.3(i), is one in which:

A veterinarian has assumed the responsibility for making medical
judgments regarding the health of (an) animal(s) and the need for
medical treatment, and the client (the owner of the animal or animals or
other caretaker) has agreed to follow the instructions of the
veterinarian;

There is sufficient knowledge of the animal(s) by the veterinarian to
initiate at least a general or preliminary diagnosis of the medical
condition of the animal(s); and

The practicing veterinarian is readily available for follow-up in case
of adverse reactions or failure of the regimen of therapy.  Such a
relationship can exist only when the veterinarian has recently seen and
is personally acquainted with the keeping and care of the animal(s) by
virtue of examination of the animal(s), and/or by medically appropriate
and timely visits to the premises where the animal(s) are kept.

POLICY:

Generally, FDA will defer to state authorities regarding the day-to-day
regulation of compounding by veterinarians and pharmacists of animal and
human drugs that are intended for use in animals.  FDA anticipates that,
in such cases, cooperative efforts between the states and the Agency
will result in coordinated investigations, referrals, and follow-up
actions by the states.

However, when the scope and nature of activities of veterinarians and
pharmacists raise the kinds of concerns normally associated with a drug
manufacturer and result in significant violations of the new animal
drug, adulteration, or misbranding provisions of the Act, FDA has
determined that it will seriously consider enforcement action.  In
determining whether to initiate such an action, the Agency will consider
whether the veterinarian or pharmacist engages in any of the following
acts:

Compounding of drugs for use in situations (a) where the health of the
animal is not threatened; and (b) where suffering or death of the animal
is not likely to result from failure to treat.

Compounding of drugs in anticipation of receiving prescriptions, except
in very limited quantities in relation to the amounts of drugs
compounded after receiving prescriptions issued within the confines of a
valid VCPR.

Compounding of drugs that are prohibited for extralabel use in
food-producing or nonfood-producing animals, under 21 CFR 530.41(a) and
(b) respectively, because the drugs present a risk to the public health.

Compounding finished drugs from human or animal drugs that are not the
subject of an approved application, or from bulk drug substances, other
than those specifically addressed for regulatory discretion by the FDA,
Center for Veterinary Medicine, e.g., antidotes (see Appendix A).
Inquiries about compounding from unapproved drugs or bulk drug
substances should be directed to CVM, Division of Compliance,
301-827-1168.

Compounding from approved human drugs for which FDA has implemented a
restricted distribution system.

Using commercial scale manufacturing equipment for compounding drug
products.

Compounding drugs for third parties who resell to individual patients,
or offering compounded drug products at wholesale to other state
licensed persons or commercial entities for resale.

Failing to operate in conformance with applicable state law regulating
the practice of pharmacy.

Compounding of drugs for use in animals where an approved new animal
drug or approved new human drug used as labeled or in conformity with 21
CFR Part 530 will, in the available dosage form and concentration,
appropriately treat the condition diagnosed.

Compounding from a human drug for use in food-producing animals if an
approved animal drug can be used for the compounding.

Instances where illegal residues occur in meat, milk, eggs, honey,
aquaculture, or other food-producing animal products, and such residues
were caused by the use of a compounded drug.

Labeling a compounded drug with a withdrawal time established by the
pharmacist instead of the prescribing veterinarian.

Labeling of compounded drugs without sufficient information, such as
withdrawal times for drugs for food-producing animals or other
categories of information that are described in 21 CFR 530.12.

The foregoing list of factors is not intended to be all inclusive.
Other factors may be appropriate for consideration in a particular case.

REGULATORY ACTION GUIDANCE:

District offices are encouraged to consult with state regulatory
authorities to assure coherent application of this guidance to
establishments that are operating outside of the traditional practice of
pharmacy.

Follow FDA’s laws and procedures prior to sharing non-public
information with the public, or federal, state, local, and foreign
government officials.

FDA-initiated regulatory action may include issuing a warning letter,
seizure, injunction, and/or prosecution. Charges may include, but need
not be limited to, violations of 21 U.S.C. Sections 351(a)(2)(B),
351(a)(5), 352(a), 352(f)(1), and 352(o) of the Act.  Tissue residue
violations are covered under 21 U.S.C. Section 342(a)(2)(C)(ii) of the
Act.

Issued: 6/26/1996 (7/3/1996 Federal Register)

Revised:  7/8/2003 (7/14/2003 FR)

 APPENDIX A

LIST OF BULK DRUG SUBSTANCES FOR COMPOUNDING AND SUBSEQUENT USE IN
ANIMALS TO WHICH CVM WOULD NOT ORDINARILY OBJECT

Ammonium molybdate

Ammonium tetrathiomolybdate

Ferric ferrocyanide

Methylene blue

Picrotoxin

Pilocarpine

Sodium nitrite

Sodium thiosulfate

Tannic acid

 PAGE

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