UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                             WASHINGTON, DC  20460
                                       
                         OFFICE OF CHEMICAL SAFETY AND
                             POLLUTION PREVENTION

MEMORANDUM

DATE:	7 July 2014

SUBJECT:	Metrafenone.  Petition to Establish Permanent Tolerances (with Section 3 Registration) for Residues Resulting from Use of the Fungicide on Apricot, Cherry Subgroup 12-12A, Peach Subgroup 12-12B, Fruiting Vegetables Group 8-10, Small Vine Climbing Fruit Except Fuzzy Kiwifruit Subgroup 13-07F, Hops, Pome Fruits Group 11-10, and Cucurbit Vegetables Group 9; Evaluation of Conditional Data.  Summary of Analytical Chemistry and Residue Data.  

PC Code:  000325
DP Barcodes:  D407432, D411389, D414077, D416465, D417602
Decision Numbers:  472590, 476552, 480739, 484338
Registration Number:  7969-284
Petition Numbers:  3F8163, 3F8187, 3E8211
Regulatory Action:  Section 3 Registration
Risk Assessment Type:  NA
Case Number:  7052
TXR Number:  NA
CAS Number:  220899-03-6
MRID Numbers:  48981303, -04, -07 & -08; 49055901 & -02; 49119101 to -09; 49145401 to -08; 49267201 to -05
40 CFR:  §180.624

FROM: 	William T. Drew, Chemist
		Dennis McNeilly, Chemist
		Risk Assessment Branch II (RAB2)
		Health Effects Division (HED), 7509P

THRU:	Elizabeth Holman, Physical Scientist
		Michael Doherty, PhD, Senior Scientist
		RAB2/HED, 7509P

TO:		Tony Kish and Heather Garvie, RM Team 22
		Fungicide Branch (FB)
		Registration Division (RD), 7505P
			and
		Barbara Madden and Andrew Ertman, RM Team 5
		Risk Integration Minor Use, and Emergency Response Branch (RIMUERB)
		RD, 7505P
Table of Contents

1.0     Executive Summary	4
2.0     Regulatory Recommendations	7
2.1     Data Deficiencies/Data Needs	7
2.2     Tolerance Considerations	8
2.2.1      Enforcement Analytical Method/Multiresidue Methods	8
2.2.2      Recommended Tolerances	9
2.2.3      Revisions to Petitioned-For Tolerances	9
2.2.4      International Harmonization	9
2.3      Label Recommendations	10
2.4      Submittal of Analytical Reference Standards (860.1650)	10
3.0      Chemical Identity	10
3.1      Nomenclature	11
3.2      Physicochemical Characteristics	11
3.3      Pesticide Use Pattern/Directions for Use (860.1200)	12
4.0      Metabolite/Degradate Residue Profile	13
4.1      Nature of the Residue	19
4.1.1 	Summary of Plant and/or Livestock Metabolism (860.1300)	24
4.1.2	Summary of Confined Rotational Crops (860.l850)	27
4.1.3	Summary of Rat Metabolism	29
4.1.4	Summary of Environmental Degradation	29
5.0	Residue Profile	30
5.1       Residue Analytical Methods (860.1340)	30
5.1.1	Data Collection Methods	30
5.1.2	Multi-Residue Methods (860.1360)	33
5.1.3	Tolerance Enforcement Methods	34
5.2      Storage Stability (860.1380)	38
5.3      Residue Data	40
5.3.1	Crop Field Trials (860.1500)	40
5.3.2	Field Rotational Crops (860.1900)	55
5.3.3	Processed Food and Feed (860.1520)	55
5.3.4	Meat, Milk, Poultry and Eggs (860.1480)	60
5.3.5.	Food Handling (860.1460)	61
5.3.6	Water, Fish and Irrigated Crops (860.1400)	61
5.4      Food Residue Profile	61
6.0	Tolerance Derivation	62
References	63
Attachment 1:  International Residue Limit Status	65
Attachment 2:  OECD MRL (Tolerance) Assessment Calculations	66  



1.0	Executive Summary

Metrafenone (with CAS name (3-bromo-6-methoxy-2-methylphenyl)(2,3,4-trimethoxy-6-methylphenyl)methanone) is a benzophenone fungicide that has preventative properties for control of powdery mildew produced by assorted pathogens in various fruits and vegetables.  

In PP#3F8163, BASF Corporation has proposed the establishment of permanent tolerances for residues of the fungicide metrafenone in/on the following raw agricultural commodities (RACs), at the level listed below.  

      Fruits, pome group 11-10	1.5 ppm

In PP#3F8187, BASF Corporation has proposed the establishment of permanent tolerances for residues of the fungicide metrafenone in/on the following RACs, at the level listed below.  

      Vegetables, Fruiting, group 8-10	1.0 ppm

In PP#3E8211, Interregional Research Project Number 4 (IR-4) has proposed the establishment of permanent tolerances for residues of the fungicide metrafenone in/on the following RACs, at the levels listed below.  

      Apricot	0.7 ppm
      Cherry subgroup 12-12A	2 ppm
      Fruit, small, vine climbing, except fuzzy kiwifruit, 
      subgroup 13-07F	4.5 ppm
      Hop, dried cones 	70 ppm
      Peach subgroup 12-12B	0.7 ppm
      Vegetable, cucurbit, group 9	0.5 ppm

The nature of the residue in plants is adequately understood, based on acceptable grape and cucumber metabolism studies.  HED has previously determined that, for tolerance enforcement purposes, the residue of concern (ROC) in primary crops is parent metrafenone only.  HED also concluded previously that certain unidentified and tentatively identified residues from the grape metabolism study should be accounted for in the dietary risk assessment.  

In conjunction with PP#3F8163, BASF submitted a FIFRA Section 3 requesting registration of a suspension concentrate (SC) formulation (Vivando; EPA Registration #7969-284), containing 2.5 pounds of the active ingredient per gallon (lb ai/gal), for use on pome fruits group 11-10.  The product is proposed for up to 3 foliar applications to pome fruits at 0.2-0.3 lb ai per acre (lb ai/A) per application, with a maximum seasonal application rate of 0.9 lb ai/A, a minimum re-treatment interval (RTI) of 7 days, and a pre-harvest interval (PHI) of 7 days.  

In conjunction with PP#3F8187, BASF submitted a FIFRA Section 3 requesting registration of the SC formulation, Vivando, for use on fruiting vegetables group 8-10.  The product is proposed for up to 3 foliar applications to fruiting vegetables at 0.2-0.3 lb ai/A per application, with a maximum seasonal application rate of 0.9 lb ai/A, a minimum RTI of 7 days, and a PHI of 0 days.  

In conjunction with PP#3F8211, IR-4 submitted a FIFRA Section 3 requesting registration of the SC formulation, Vivando, for use on apricots, cherry subgroup 12-12A, peach subgroup 12-12B (up to 2 foliar applications at 0.2-0.3 lb ai/A per application, with a maximum seasonal application rate of 0.6 lb ai/A, a minimum RTI of 7 days, and a PHI of 7 days), hops (same use pattern, except a PHI of 3 days), cucurbit vegetables group 9 (up to 3 foliar applications at 0.2-0.3 lb ai/A per application, with a maximum seasonal application rate of 0.9 lb ai/A, a minimum RTI of 7 days, and a PHI of 0 days), and small vine-climbing fruit except fuzzy kiwifruit subgroup 13-07F (same use pattern, except a minimum RTI of 14 days, and a PHI of 14 days).  

Crop Field Trials:  The number and geographic distribution of the field trials are adequate, and the use patterns are consistent with the maximum proposed use pattern regarding application rate, PHI, and minimum RTIs.  

Adequate pome fruit field trial data were submitted in support of the proposed use.  The submitted data support the proposed tolerance of 1.5 ppm in pome fruits (group 11-10).  

Adequate fruiting vegetable field trial data were submitted in support of the proposed use.  The submitted data support a recommended tolerance of 0.90 ppm, rather than the proposed tolerance of 1.0 ppm, in fruiting vegetables (group 8-10).  

Adequate cucurbit vegetable field trial data were submitted in support of the proposed use.  The submitted data support the proposed tolerance of 0.5 ppm in cucurbit vegetables (group 9); HED recommends that the tolerance be established at 0.50 ppm.  

Adequate cherry field trial data were submitted in support of the proposed use.  The submitted data support the proposed tolerance of 2 ppm in the cherry subgroup (12-12A); HED recommends that the tolerance be established at 2.0 ppm.  

Adequate peach field trial data were submitted in support of the proposed use.  The submitted data support the proposed tolerance of 0.7 ppm in the peach subgroup (12-12B); HED recommends that the tolerance be established at 0.70 ppm.  

Adequate hops field trial data were submitted in support of the proposed use.  The submitted data support the proposed tolerance of 70 ppm in hops.  

The proposed tolerance of 4.5 ppm in small vine climbing fruits except fuzzy kiwifruit (subgroup 13-07F) is based upon existing data for grapes (the representative commodity for the subgroup).  Upon establishment of the tolerance in subgroup 13-07F, the existing tolerance in grapes should be removed.  

The proposed tolerance of 0.7 ppm in apricots is based upon the submitted data for peaches.  HED recommends that the tolerance be established at 0.70 ppm.  

Processing Studies:  The apple processing study data indicated that residues of metrafenone do not concentrate appreciably in any apple processed commodities, with the exception of apple sauce, in which the processing factor was 4.5X.  Processing factors ranged from <1X to 1.2X (average of 2 trials for each commodity) for the other processed commodities.  

The tomato processing study data indicated that residues of metrafenone do not concentrate in tomato processed commodities, with the exception of peel and wet pomace, in which residues concentrate, on average, by factors of 6.3X and 5.1X, respectively.  The mean transfer factor of tomato peel and wet pomace (>1) indicates that the metrafenone residues are mainly located in the tomato peels.  

Residue Analytical Methods:  There is an adequate enforcement method available for the quantitation of metrafenone in plant commodities (Method FAMS 105-01).  Additionally, BASF has proposed the QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) method as a new enforcement method for metrafenone residues in plant commodities, and DFG Method S19 (extended revision) as the new enforcement method for metrafenone residues in livestock commodities.  

Storage Stability:  Adequate storage stability data are available to support the storage durations and conditions of samples from the submitted field trial, metabolism and processing studies.  

Meat, Milk, Poultry and Eggs:  The only livestock feed item associated with the proposed new uses is apple wet pomace, and it is fed only to dairy cattle.  Based on the dietary burden to dairy cattle of metrafenone residues in apple wet pomace, and the results of the goat metabolism study, it is not expected that detectable residues would be found in cattle commodities.  Therefore, tolerances in livestock commodities are not required.  

Conditional Data:   Additional method validation data were requested for the analytical Method FAMS 105-01.  In addition, radiovalidation data were required to demonstrate that Method FAMS 105-01 adequately recovers weathered residues of metrafenone from grapes.  BASF submitted the information requested to satisfy the conditions of registration (MRIDs #48981305, 48981306 and 48981307).  

HED accepts the cucumber metabolism and other extraction efficiency data which show adequate extractability using the 4:1 n-heptane/acetone solvent.  This resolves HED concerns about the analytical Method FAMS 105-01 adequately recovering weathered residues of metrafenone from grapes, and the issue of accounting for aged residues in the grape metabolism study.   It also resolves the issue of the extraction solvent used in the data collection method, BASF Method 535/0, being different than that used in the proposed enforcement method.  

Therefore, all of HED's previously identified conditional data requirements have been sufficiently addressed.  

MRL Harmonization:  The proposed uses in IR-4's petition (PP#3E8211) are also being reviewed by Canada's Pest Management Regulatory Agency (PMRA).  EPA and PMRA have agreed to harmonize (wherever possible) the recommended tolerances and maximum residue limits (MRLs), based on use of the Organization for Economic Cooperation and Development (OECD) tolerance calculation procedure.  Harmonization of EPA's recommended tolerances with PMRA's recommended MRLs has been agreed upon for all commodities requested in PP#3E8211 except apricot.  PMRA has decided against translating the peach field trial data to apricot, and will therefore not be establishing an MRL in apricot.  


2.0	Regulatory Recommendations

HED has examined the residue chemistry database for metrafenone.  Pending submission of a revised Section F (to propose tolerance levels in accordance with those recommended by HED, and to correct some of the commodity definitions), there are no residue chemistry issues that would preclude establishing tolerances in the requested commodities.  HED recommends in favor of establishing tolerances for residues of metrafenone as specified in Section 2.2.2, below.

2.1	Data Deficiencies/Data Needs

No additional data are required to support HED's currently recommended tolerances in pome fruits, fruiting vegetables, cucurbit vegetables, the cherry subgroup (12-12A), the peach subgroup (12-12B), hops, small vine climbing fruits except fuzzy kiwifruit subgroup (13-07F), and apricots.  

HED previously recommended that the following actions be required as a condition of registration (D331685; D. McNeilly; 18 February 2010).  The conditional data (MRIDs #48981305, 48981306 and 48981307) were submitted in response to the data deficiencies listed below.  

         1. Additional method validation data should be submitted for Method FAMS 105-01 reflecting fortifications at 4.5 ppm for grapes, and at both 0.05 ppm, the limit of quantitation (LOQ), and 17 ppm for raisins.  
         
         2. Radiovalidation data are required to demonstrate that Method FAMS 105-01 adequately recovers weathered residues of metrafenone from grapes.  HED is willing to accept cucumber data currently being collected, as proposed by the registrant, provided such data show adequate extractability by the 4:1 n-heptane/acetone solvent mixture.  
         
         3. Because the extraction solvent used in the data collection method is different than that used in the proposed enforcement method, radiovalidation data are required to support the data collection method, BASF Method 535/0.  Samples from the cucumber metabolism study may also be used to generate these data.  

These conditional data submissions (D407462) have been reviewed, and have adequately resolved all of HED's previously identified issues.  

2.2	Tolerance Considerations

2.2.1	Enforcement Analytical Method/Multiresidue Methods

There is an adequate enforcement method available for the quantitation of metrafenone in plant commodities (Method FAMS 105-01).  Additionally, BASF has proposed the QuEChERS method as a new enforcement method for metrafenone that will cover fortifications at 4.5 ppm in grapes, and at both the LOQ (0.05 ppm) and 17 ppm in raisins.  QuEChERS stands for "Quick, Easy, Cheap, Effective, Rugged and Safe."  The method that was initially submitted for enforcement (Method FAMS 105-01) of metrafenone in grapes is an older gas chromatography (GC) method that was developed in 1998.  Although Method FAMS 105-01 performs adequately for metrafenone in grapes and raisins, it was decided that a more modern methodology was needed which could take advantage of current advances in sample clean-up and liquid chromatography with tandem mass spectrometric detection (LC/MS/MS) techniques.  The QuEChERS method was validated on eight diverse matrices (MRID #48981303) according to the OECD guidance document on pesticide analytical methods (ENV/JM/MONO(2007)17).  The method has also been subjected to an independent laboratory validation (ILV) by Sprecht Laboratories (MRID #48981304) in accordance with the OECD guidance document.  

Acceptable multiresidue methods testing data have previously been submitted for metrafenone in grapes.  The data indicate that multiresidue methods may be suitable for determining residues of metrafenone in grapes for tolerance enforcement.  

2.2.2	Recommended Tolerances

TABLE 2.2.2	Tolerance Summary for Metrafenone.  
                      Commodity as Proposed by Registrant
                           Proposed Tolerance (ppm)
                          Recommended Tolerance (ppm)
                    Comments; Correct Commodity Definition
Apricot
                                      0.7
                                     0.70
Based on submitted peach data.
Cherry subgroup 12-12A
                                       2
                                      2.0

Fruits, pome group 11-10
                                      1.5
                                      1.5
Fruit, pome, group 11-10
Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13-07F	
                                      4.5
                                     4.5*
Based on data supporting the existing tolerance in grape.
Hop, dried cones
                                      70
                                      70

Peach subgroup 12-12B
                                      0.7
                                     0.70

Vegetable, cucurbit, group 9
                                      0.5
                                     0.50

Vegetables, Fruiting, group 8-10
                                      1.0
                                     0.90
Vegetable, fruiting, group 8-10
*Upon establishment of the tolerance in subgroup 13-07F, the existing tolerance in grapes should be removed.  

2.2.3	Revisions to Petitioned-For Tolerances

Instead of the proposed tolerance in cucurbit vegetables (0.5 ppm), HED recommends establishing the tolerance at 0.50 ppm, in order to avoid the situation where a field sample containing residues significantly above the tolerance (0.54 ppm, for example) would be considered non-violative.  For the same reason, HED recommends that the proposed tolerances of 0.7 ppm in the peach subgroup (12-12B) and apricots be revised to 0.70 ppm.  Similarly, HED recommends that the proposed tolerance of 2 ppm in the cherry subgroup (12-12A) be revised to 2.0 ppm.  

Because HED determined that 2 of the 9 pepper field trials should be considered replicates, the OECD tolerance calculation procedure result for 8 trials was 0.9 ppm, instead of the 1 ppm result when 9 trial values were entered.  The tolerance calculation result for tomatoes was 0.6 ppm, which is in accordance with the Agency's guidelines for setting a crop group tolerance (within 5X of the result for peppers).  Since a crop group tolerance is set based on the representative commodity having the larger (or largest) tolerance calculation result, HED recommends that the tolerance in fruiting vegetables (group 8-10) be established at 0.90 ppm.  

2.2.4	International Harmonization

The proposed uses in IR-4's petition (PP#3E8211) are also being reviewed by Canada's PMRA.  EPA and PMRA have agreed to harmonize (wherever possible) the recommended tolerances and MRLs, based on use of the OECD tolerance calculation procedure.  Harmonization of EPA's recommended tolerances with PMRA's recommended MRLs has been agreed upon for all commodities requested in PP#3E8211 except apricot.  PMRA has decided against translating the peach field trial data to apricot, and will therefore not be establishing an MRL in apricot.  

2.3	Label Recommendations

None.

2.4	Submittal of Analytical Reference Standards (860.1650)

The analytical standard for metrafenone, with an expiration date of 1 August 2019, is currently available in the EPA's National Pesticide Standards Repository (NPSR), per Email communication from Theresa Cole of the Biological and Economic Analysis Division's (BEAD's) Analytical Chemistry Branch (ACB) on 7 January 2014.  The metrafenone metabolite is also currently available, with an expiration date of 1 November 2014.  The registrant is required to maintain reasonable amounts of the analytical reference standard for metrafenone in the NPSR.  However, as the metabolite is not included in the tolerance expression, it is not required to be stocked in the NPSR.  When necessary, a new reference standard, or updated certificate of analysis (COA), should be sent to the ACB, which is located at Fort Meade, MD.  It should be sent to the attention of either Theresa Cole or Thuy Nguyen at the address listed below, along with a letter of transmittal.  Please note that the full 9-digit ZIP Code is required, or the mail will be returned to the registrant.  

		USEPA
		National Pesticide Standards Repository
		Analytical Chemistry Branch/BEAD/OPP
		701 Mapes Road
		Fort George G. Meade, MD  20755-5350

The letter of transmittal should include the assay of the standard, name of the analytical method used, a statement of principal impurities, purification procedures employed, storage requirements, and special precautions for safe handling.  Replacement of standards may be required periodically if supplies are exhausted, if the standards expire, or if decomposition occurs during storage.  Material Safety Data Sheets (MSDSs) must accompany all analytical standards as specified in 29CFR§1910.1200 by the Occupational Safety and Health Administration (OSHA).  


3.0	Chemical Identity

Metrafenone is a benzophenone fungicide with preventative properties.  It is intended for the control of powdery mildew produced by Uncinula necator in grapes and Podosphaera in pome fruit.  The chemical structure and nomenclature of metrafenone are presented in Table 3.1, below.  The physicochemical properties of the technical grade of metrafenone are presented in Table 3.2, below.  

3.1	Nomenclature

TABLE 3.1	Metrafenone Nomenclature
Compound
                                       
Common name
Metrafenone
Company experimental names
BAS 560 F; AC 375839; CL 375839
Molecular formula
C19H21BrO5
Molecular weight
409.27
IUPAC name
3′-bromo-2,3,4,6′-tetramethoxy-2′,6-dimethylbenzophenone
CAS name
(3-bromo-6-methoxy-2-methylphenyl)(2,3,4-trimethoxy-6-methylphenyl)methanone
CAS registry number
220899-03-6
End-use product (EP)
Vivando Fungicide (2.5 lb ai/gal; EPA Registration #7969-284)

3.2	Physicochemical Characteristics

TABLE 3.2	 Physicochemical Properties of Metrafenone.
                                   Parameter
                                     Value
                                   Reference
Melting point/range
99.2-100.8ºC
Petition administrative materials (MRID 49055900)
pH
3.45 (1% aqueous suspension)

Density
1.45 g/cm[3] (20°C)

Water solubility

deionized
pH >5
pH 7
pH 9
                                     mg/L
                                     0.474
                                     0.552
                                     0.492
                                     0.457

Solvent solubility

acetone
acetonitrile
dichloromethane
ethyl acetate
n-hexane
methanol
toluene
                                      g/L
                                      403
                                      165
                                     1950
                                      261
                                      4.8
                                     26.1
                                      363

Vapor pressure
1.15 x 10[-6] mm Hg (20ºC)

Dissociation constant, pKa
No dissociation

Octanol/water partition coefficient, Log [KOW]
4.3 (25ºC, pH 4)

UV/visible absorption spectrum
Not available


Metrafenone is a solid under ambient conditions, and has low volatility.  The compound has a relatively low solubility in water, and moderate to high solubility in organic solvents.  Its octanol/water partition coefficient suggests that accumulation of metrafenone in fatty tissues is possible.  

3.3      Pesticide Use Pattern/Directions for Use (860.1200)

BASF submitted an undated draft label for the BASF 2.5 lb ai/gal formulation (Vivando, EPA Registration #7969-284).  A summary of the proposed use patterns is presented in Table 3.3, below.

TABLE 3.3	Summary of Proposed Directions for Use of Metrafenone.  
                    Application Timing; Type; Equipment[1]
                                   Use Rate
                                   (lb ai/A)
                            Maximum Uses Per Season
                            Max. Seasonal Use Rate
                                   (lb ai/A)
                                 PHI[2] (Days)
              Use Directions, Application Timing, and Limitations
                            Pome Fruits Group 11-10
Prior to disease development; foliar; ground/aerial equipment.
                                   0.20-0.30
                                       3
                                     0.90
                                       7
Minimum RTI[3] of 7 days.  Apply in a minimum of 10 gallons of spray solution per acre (GPA) for aerial applications.  
                        Fruiting Vegetables Group 8-10
Prior to disease development; foliar; ground/aerial equipment.
                                   0.20-0.30
                                       3
                                     0.90
                                       0
Minimum RTI of 7 days.  Apply in a minimum of 10 GPA for aerial applications.  
                             Peach Subgroup 12-12B
Prior to disease development; foliar; ground/aerial equipment.
                                   0.20-0.30
                                       2
                                     0.60
                                       7
Minimum RTI of 7 days.  Apply in a minimum of 10 GPA for aerial applications.  
                                    Apricot
Prior to disease development; foliar; ground/aerial equipment.
                                   0.20-0.30
                                       2
                                     0.60
                                       7
Minimum RTI of 7 days.  Apply in a minimum of 10 GPA for aerial applications.  
                            Cherry Subgroup 12-12A
Prior to disease development; foliar; ground/aerial equipment.
                                   0.20-0.30
                                       2
                                     0.60
                                       7
Minimum RTI of 7 days.  Apply in a minimum of 10 GPA for aerial applications.  
                                     Hops
Prior to disease development; foliar; ground/aerial equipment.
                                   0.20-0.30
                                       2
                                     0.60
                                       3
Minimum RTI of 7 days.  Apply in a minimum of 10 GPA for aerial applications.  
                          Cucurbit Vegetables Group 9
Prior to disease development; foliar; ground/aerial equipment.
                                   0.20-0.30
                                       3
                                     0.90
                                       0
Minimum RTI of 7 days.  Apply in a minimum of 10 GPA for aerial applications.  
      Small Vine Climbing Fruit (Except Fuzzy Kiwifruit) Subgroup 13-07F
Prior to disease development; foliar; ground/aerial equipment.
                                   0.20-0.30
                                       3
                                     0.90
                                      14
Minimum RTI of 14 days.  Apply in a minimum of 10 GPA for aerial applications.  
1. The labels state that the product must be applied before visual symptoms of powdery mildew appear, as it has no curative properties, and will not control latent or established infections of powdery mildew.  Aerial applications may be made where the use of ground equipment is not possible.  Not to be applied via chemigation.  No more than 2 sequential applications may be made before alternating to a labeled fungicide with a different mode of action.  
2. PHI = Pre-Harvest Interval.  
3. RTI = Re-Treatment Interval.  

A 12-hour re-entry interval (REI) is specified.  

Discrepancies in the stated minimum RTI (7 versus 14 days) and minimum PHI (0 versus 7 days) for pome fruit were noted in various proposed master and supplemental labels for Vivando.  The registrant stated that the correct RTI and PHI are both 7 days for the use on pome fruit.  RD should ensure that the final label lists the correct RTI and PHI.  

Conclusions:  The proposed use directions are adequate to allow evaluation of the residue data relative to the requested uses.  The proposed maximum seasonal use rates, minimum RTIs, and minimum PHIs are supported by the submitted crop field trial data.


4.0	Metabolite/Degradate Residue Profile

Grape:  Based on the results of the grape metabolism study, the petitioner concluded that metrafenone is rapidly metabolized in grapes and grape vines to compounds more polar than the parent.  There was no evidence of cleavage of the methanone bridge between the two rings of the compound.  One metabolite that was tentatively identified in grape juice suggested a two-fold oxidation of the methyl group of the bromophenyl ring.  Two metabolites tentatively identified in the acetone surface wash of mature grape leaves appeared to have been formed by oxidation of the methyl group of the bromophenyl or trimethoxyphenyl ring (with lactone formation), and a third metabolite suggested de-halogenation of the bromophenyl ring in addition to oxidation.  The proposed metabolic profile in grapes is summarized in Figure 4.0.1, below.  

HED notes that the grape metabolism is only marginally adequate with respect to elucidation of all metabolites of concern, due to high percentages of unidentified residues.  HED has not required a new grape metabolism study since the data were considered acceptable for both tolerance enforcement and conducting an upper-bound dietary exposure assessment (D312307; D. McNeilly; 24 August 2006).  

Cucumber:  In the cucumber metabolism study, metrafenone accounted for 95.0% (6.076 ppm) of the total radioactive residues (TRR) in 0 days after treatment 1 (0-DAT1) foliage, 12.6% TRR (0.0021 ppm) in 14-DAT1 whole fruit, 42.4% TRR (0.0216 ppm) in 3 days after treatment 2 (3-DAT2) whole fruit, 6.5% TRR (0.0009 ppm) in 3-DAT2 pulp, 61.0% TRR (0.1607 ppm) in 3-DAT2 peel, and 80.4% TRR (7.084 ppm) in 3-DAT2 rest of the plant.  No other components were identified in cucumber matrices.  Remaining radioactivity consisted of multiple unknown components, characterized as polar, medium polar, or nonpolar.  Polar unknowns (4-6/matrix) accounted for 13.1-36.9% TRR (0.0041-0.0067 ppm) in whole fruit (both sampling intervals) and pulp, and for 0.82% TRR (0.0715 ppm) in the rest of the plant, with no single component accounting for >18.9% TRR or >0.0299 ppm.  Medium polar unknowns (4-20/matrix) accounted for 3.8-46.8% TRR (0.0062-1.2278 ppm) in all cucumber matrices, with no single component accounting for >12.2% TRR or >0.2742 ppm.

Based on the cucumber metabolism study, metrafenone is metabolized in cucumber and cucumber plant to more polar components.  The unchanged parent was the major residue component in most matrices; in pulp, where metrafenone was a minor component, some polar components were detected at concentrations similar to those of metrafenone; see the data evaluation record (DER) for MRID #48981307.
FIGURE 4.0.1		Proposed Metabolic Profile of Metrafenone in Grapes



Wheat:  Based on the results of the wheat metabolism study, the petitioner proposed that metrafenone initially undergoes Phase I biotransformations, beginning with a single oxidative de-methylation of the parent to form CL 434223, CL 376991 and CL 377160, followed by a second oxidative de-methylation to form CL 1500835 (see Figure 4.0.2, below).  The lactones CL 3000402 and CL 1500831 are formed by oxidation at each benzylic carbon followed by cyclization.  Oxidation of the methyl groups on either of the two phenyl rings gives rise to the aldehyde derivatives, CL 1500833, CL 1500834 and CL 1500837.  Aromatic oxidation and oxidative de-methylations can produce CL 1500832.  Additionally, CL 1500836 is formed by oxidation at the benzylic carbon of the bromophenyl-ring to an aldehyde followed by reductive de-bromination.  The oxidations are proposed to be either enzymatic and/or chemical (photolysis) in nature.  These Phase I processes are then followed by Phase II transformation reactions, which are enzymatic glucoside conjugation reactions to yield the conjugates CL 1500838 and CL 1500839 from their corresponding aglycones, CL 434223 and CL 376991.  These results show that the benzophenone backbone of metrafenone remains intact without cleavage at the carbonyl group.  Rather, the metabolites are derived from metrafenone through various reactions occurring on the ring systems (see the DER for MRID #49119101).  

FIGURE 4.0.2		Proposed Metabolic Profile of Metrafenone in Wheat



Goat:  Following oral dosing with [bromophenyl-6-[14]C]-metrafenone at 13 and 87 ppm in the diet for 5 consecutive days, TRR in the low and high dose groups, respectively, were <0.005 and 0.008-0.010 ppm in milk, 0.231 and 1.278 ppm in liver, 0.060 and 0.329 ppm in kidney, <0.005 and 0.008 ppm in muscle, and <0.005 and 0.015 ppm in fat.  Following oral dosing with [trimethoxyphenyl-U-[14]C]-metrafenone at 8 and 60 ppm in the diet for 5 consecutive days, TRR in the low and high dose groups, respectively, were <0.005 and <0.005-0.006 ppm in milk, 0.208 and 0.718 ppm in liver, 0.047 and 0.157 ppm in kidney, <0.005 and 0.006 ppm in muscle, and <0.005 and 0.022 ppm in fat.  Radioactivity in milk was generally stable throughout the dosing period.  Most of the administered dose was excreted (75.7-85.7%), with the majority (61.8-74.1%) excreted in the feces.  

Parent was the major residue in milk (24.12% TRR), and was the major and only identified residue component in fat, accounting for 60.00-85.32% TRR.  Metrafenone was a minor residue in liver (2.74-3.49% TRR) and kidney (3.25-4.35% TRR).  Region of interest 13 (ROI-13) was a major residue component in milk (10.67% TRR) and was the major residue component in liver and kidney, accounting for 14.77-21.05% TRR and 26.29-28.15% TRR, respectively.  ROI-9 was also a major component in liver and kidney, accounting for 9.89-13.23% TRR and 9.51-13.57% TRR, respectively; ROI-9 was a minor component in milk (2.83% TRR).  ROI-16 was a minor residue component in milk (3.8% TRR), liver (6.41-7.12% TRR), and kidney (1.46-4.19% TRR).  Remaining radioactivity was found to consist of up to 18 minor ROIs, together accounting for:  55.94% TRR in milk; 13.45-14.46% TRR in fat; 50.63-61.70% TRR in liver; and 48.81-55.08% TRR in kidney.  The single largest ROI accounted for 11.7% TRR in TMP-label liver, with the majority (10.86% TRR) found in the pepsin hydrolysate.  

Based on the submitted goat metabolism study, the registrant has proposed the following metabolic pathway for metrafenone in ruminants (see Figure 4.0.3, below).  Metabolism of metrafenone in lactating goat occurred at the methyl and methoxy groups on the rings.  Hydroxylation of the methyl groups yielded hydroxymethyl derivatives, whereas O-demethylation yielded hydroxyphenyl derivatives.  These hydroxylated metabolites underwent Phase II glucuronidation to produce various mono-O-glucuronides.  All of the prominent goat metabolites were identified as O-glucuronides (see the DER for MRID #49267201).  


FIGURE 4.0.3		Proposed Metabolic Profile of Metrafenone in Goats


Rat:  In the rat metabolism and pharmacokinetics study, excretion was 91-100 % after 168 hours, most of which was excreted in the feces within the first 48 hours.  The highest concentration of metrafenone was found in the liver.  Bile was the major excretion pathway, based on the results in bile duct-cannulated rats.  Six urinary and biliary metabolites were identified.  In urine, up to 21 other minor unknowns were found.  In bile, up to 24 minor unknowns were found.  The parent compound was not detected in urine or bile.  Most of the fecal radioactivity consisted of parent metrafenone, and an additional 12 fecal metabolites were 0.03-15% of administered dose.  There were up to 45 other fecal minor unknowns.  The absorbed material was metabolized by ortho-dealkylation, aliphatic oxidation, debromination, ring hydroxylation and conjugation reactions.  Primary excretion was as glucuronic acid conjugates in bile and urine.  Residues in feces were primarily as parent and aglycones of bile and urine conjugates (D354166; D. McNeilly; 1 March 2010).  

4.1	Nature of the Residue
	Residue Chemistry Summary D312307; D. McNeilly; 24 August 2006
	Metabolism DER for MRID #48981307 (Cucumber)
	Metabolism DER for MRID #49119101 (Wheat)
	Metabolism DER for MRID #49267201 (Goat)

Grape:  The nature of the residue in grapes is adequately understood.  Although the previously submitted metabolism study reflects treatment at roughly 0.5X the proposed maximum seasonal rate to grapes, sufficient radioactive residues were obtained in grapes to enable characterization/ identification of residues.  The ROC in grapes for risk assessment and tolerance enforcement is metrafenone.  For risk assessment purposes, HED's Residues of Concern Knowledge-based Subcommittee (ROCKS) concluded that the residues described as "acetone unknowns" and "juice" in the metabolism study should be included (D370903; G.F. Kramer; 18 Nov 2009).

The metabolite profile was very similar for both radiolabels.  Metrafenone was the only component of the residue that was conclusively identified in grapes and leaves.  Metrafenone accounted for 41-53% TRR in grapes harvested immediately following the last of five foliar applications of radiolabeled metrafenone, and it accounted for 23-25% TRR in grapes harvested 35 days after the final application.  

Based on the results of the study, metrafenone is rapidly metabolized in grapes and grape vines to more polar compounds.  There was no evidence of cleavage of the methanone bridge between the two rings of the compound.  One metabolite that was tentatively identified in grape juice suggested a two-fold oxidation of the methyl group of the bromophenyl ring.  Two metabolites tentatively identified in the acetone surface wash of mature grape leaves appeared to have been formed by oxidation of the methyl group of the bromophenyl or trimethoxyphenyl ring (with lactone formation), and the third metabolite suggested de-halogenation of the bromophenyl ring in addition to oxidation.  (See Tables C.2.2.1, C.2.2.2, C.2.3.1, C.2.3.2 and C.2.3.3 in the DER for MRID #46415749.)  

Cucumber:  BASF Corporation has submitted a study investigating the metabolism of uniformly ring-labeled [trimethoxyphenyl-U-[14]C]metrafenone (specific activity 6 MBq/mg) in cucumber.  The radiolabeled test substance was formulated as an SC, and applied to greenhouse-grown cucumber plants as two broadcast foliar applications at 0.18 lb ai/A/application (200 g ai/ha/application), for a total application of 0.36 lb ai/A (400 g ai/ha).  The applications were made at a 14-day RTI.  Samples of foliage were harvested immediately after the first application (0-DAT1), and samples of whole fruit were harvested 14 days after the first application (14-DAT1), immediately before the second application.  Samples of mature whole fruit, pulp, peel, and rest of plant were harvested 3 days after the second application (3-DAT2).
 
The TRR, determined by summing extractable and nonextractable radioactivity, were 6.397 and 0.016 ppm in 0-DAT1 foliage, and 14-DAT1 in whole fruit harvested following the first application at 0.18 lb ai/A; TRR were 0.051, 0.013, 0.263 and 8.807 ppm, respectively, in 3-DAT2 whole fruit, pulp, peel, and rest of plant harvested following two applications at 0.36 lb ai/A.  

Extraction with methanol released the majority of the radioactivity from cucumber matrices: ~99% TRR for 0-DAT1 foliage, ~88% for 14-DAT1 whole fruit, ~93% for 3-DAT2 whole fruit, ~91% for 3-DAT2 pulp and peel, and ~93% for 3-DAT2 rest of plant.  Extraction with water released an additional 0.3-3.2% TRR from all matrices.  Remaining nonextractable residues were, respectively, 0.9% TRR (0.058 ppm), 11.0% TRR (0.0018 ppm), 5.7% TRR (0.0029 ppm), 7.8% TRR (0.0010 ppm), 7.8% TRR (0.0205 ppm), and 4.2% TRR (0.374 ppm).  The extraction procedures adequately extracted the majority of residues from cucumber matrices.  Results were normalized; therefore, accountabilities were 100%.

Residues were identified and quantitated in cucumber matrices by high performance liquid chromatography with UV detection (HPLC/UV).  Identification of metrafenone was achieved by HPLC co-chromatography with an unlabeled reference standard in 0-DAT1 cucumber foliage, and 14-DAT1 whole fruit.  No other reference standards were included in the study.  Identification of metrafenone in the other samples was achieved by comparison of the retention times and the HPLC elution profiles with those of the extracts investigated by co-chromatography.  Confirmatory HPLC/UV analysis was conducted on all samples.  Samples were stored frozen (approximately -18°C) after collection, and were processed, extracted and subjected to initial analysis by HPLC for quantitation purposes within 67-86 days (2.2-2.8 months) of harvest.  Final analyses were completed within 80-203 days (2.6-6.7 months) of harvest.  Because samples were analyzed within roughly 4-6 months of harvest, no storage stability data are required to support the study.

Metrafenone accounted for 95.0% TRR (6.076 ppm) in 0-DAT1 foliage, 12.6% TRR (0.0021 ppm) in 14-DAT1 whole fruit, 42.4% TRR (0.0216 ppm) in 3-DAT2 whole fruit, 6.5% TRR (0.0009 ppm) in 3-DAT2 pulp, 61.0% TRR (0.1607 ppm) in 3-DAT2 peel, and 80.4% TRR (7.084 ppm) in 3-DAT2 rest of plant.  No other components were identified in cucumber matrices.  Remaining radioactivity consisted of multiple unknown components, characterized as polar, medium polar, or nonpolar.  Polar unknowns (4-6/matrix) accounted for 13.1-36.9% TRR (0.0041-0.0067 ppm) in whole fruit (both sampling intervals) and pulp, and for 0.82% TRR (0.0715 ppm) in the rest of the plant, with no single component accounting for >18.9% TRR or >0.0299 ppm.  Medium polar unknowns (4-20/matrix) accounted for 3.8-46.8% TRR (0.006-1.228 ppm) in all cucumber matrices, with no single component accounting for >12.2% TRR or >0.2742 ppm.  A single nonpolar component was detected in 3-DAT2 rest of plant at 0.02% TRR (0.0016 ppm).  (See Tables C.2.1, C.2.2.1, C.2.2.2, C.2.3.1 and C.2.3.2 in the DER for MRID #48981307.)  

Wheat:  BASF Corporation has submitted a study investigating the metabolism of [bromophenyl-6-[14]C]metrafenone (BP label; specific activity 20.30 uCi/mg) and uniformly ring-labeled [trimethoxyphenyl-U-[14]C]metrafenone (TP label; specific activity 18.16 uCi/mg) in wheat.  The radiolabeled test substances were formulated as emulsifiable concentrates (ECs), and applied to field-grown wheat plants as three broadcast foliar applications, the first two at nominal application rates of 0.268 lb ai/A (300 g ai/ha), and the third at 0.179 lb ai/A (200 g ai/ha).  The actual total application rates were 0.674 lb ai/A (756.0 g ai/ha) for the BP label, and 0.642 lb ai/A (719.3 g ai/ha) for the TP label.  Applications were made at 13- to 14-day RTIs.  Samples of immature whole plants were collected within roughly 3 hours of each application; forage (whole plant) was collected 3 days after the first application; hay was collected 14 days after the second application; and mature straw, chaff and grain were collected at maturity, 35 days after the third application.  The in-life phase of the study was conducted by Excel Research Services (Fresno, CA) and Qualls Agricultural Laboratory (Ephrata, WA), while the analytical phase of the study was conducted by BASF (Princeton, NJ).  

Following three broadcast foliar applications of [bromophenyl-6-[14]C]metrafenone or [trimethoxyphenyl-U-[14]C]metrafenone at total application rates of 0.674 lb ai/A (756 g ai/ha) for the BP label, and 0.642 lb ai/A (719.3 g ai/ha) for the TP label, TRR in immature wheat plants sampled immediately following applications 1, 2 and 3, respectively, were 7.275, 5.959 and 6.997 ppm in BP-label samples, and 9.890, 8.416 and 5.382 ppm in TP-label samples.  Although immature plants were subjected to further extraction and analysis procedures, results were not included in the submission, and these matrices are not discussed further herein.  TRR in remaining BP- and TP-label samples, respectively, were 8.167 and 5.265 ppm in forage, 7.784 and 8.498 ppm in hay, 8.914 and 8.248 ppm in straw, and 0.209 and 0.399 ppm in grain.  The higher TRR in hay and straw were attributed by the petitioner to dehydration of the samples.

Results were similar for both labels, although residues of parent were consistently higher in BP-label samples.  Metrafenone was the major identified residue in wheat forage, hay and straw, accounting for 58.9-64.4% TRR in forage, 12.7-26.0% TRR in hay, and 7.7-13.6% TRR in straw.   Metrafenone was the only identified residue in wheat grain, accounting for 3.1-7.7% TRR.  All remaining metabolites were identified in all samples of forage, hay and straw.  Metabolites CL 3000402, which was ROI 4, CL 1500838 (ROI 5), and CL 434223 (ROI 8) each accounted for 0.8-6.6% TRR.  Combined residues of the following metabolite pairs or groups each accounted for 1.5-6.5% TRR:  CL 1500837 + CL 1500836 (ROI 3), CL 1500839 + CL 1500832 (ROI 6), and CL 1500833 + CL 1500834 + CL 1500835 + CL 377160 + Unknown ROI 7C (ROI 7).  Two remaining metabolites, CL 376991 (ROI 9) and CL 1500831 (ROI 10), each accounted for <=1.8% TRR.  

No other components were identified in wheat matrices.  Polar unknowns ROI 1 and ROI 2, comprised of multiple minor components, each accounted for 3.1-4.3% TRR in forage, 11.5-17.4% TRR in hay, and 8.3-10.6% TRR in straw; one additional multicomponent unknown, ROI 11, accounted for <=1.7% TRR in forage, hay and straw.  Polar unknown ROI 1 accounted for 21.3-26.2% TRR in grain, while remaining unknowns together accounted for <2.0% TRR.  Although quantitative results were not reported for α-amylase hydrolysis of grain, ROI 1 comprised ~59% and 74%, respectively, of the recovered radioactivity following hydrolysis.  (See Tables C.2.1, C.2.2.1, C.2.2.2, C.2.2.3, C.2.3.1, C.2.3.2 and C.2.3.3 in the DER for MRID #49119101.)  

Goat:  BASF Corporation has submitted a study investigating the metabolism of [bromophenyl-6-[14]C]-metrafenone (BP label; specific activity 8.03 uCi/mg) or uniformly ring-labeled [trimethoxyphenyl-U-[14]C]-metrafenone (TMP label; specific activity 8.02 uCi/mg) in the lactating goat.  The test substances were administered orally via gelatin capsule to two lactating goats per label, once daily for 5 consecutive days, at 13 and 87 ppm in the feed for the BP label, and at 8 and 60 ppm in the feed for the TMP label.  A control goat received capsules containing carrier only.  Milk was collected twice daily, in the morning and afternoon, prior to dosing.  Goats were sacrificed approximately 21-23 hours after administration of the final dose, and the following tissues were collected:  Liver (entire), kidney (both), muscle (composite of loin and leg), and fat (omental).  The in-life phase of the study was conducted by Fort Dodge Animal Health, Division of American Home Products Corporation, Agricultural Research Center (Princeton, NJ), and the analytical phase of the study was conducted by BASF Agro Research (Princeton, NJ).  

TRR in BP-label milk and tissues from the low and high dose goats, respectively, were <0.005 and 0.008-0.010 ppm in milk, 0.231 and 1.278 ppm in liver, 0.060 and 0.329 ppm in kidney, <0.005 and 0.008 ppm in muscle, and <0.005 and 0.015 ppm in fat.  TRR in TMP-label samples from low and high dose goats, respectively, were <0.005 and <0.005-0.006 ppm in milk, 0.208 and 0.718 ppm in liver, 0.047 and 0.157 ppm in kidney, <0.005 and 0.006 ppm in muscle, and <0.005 and 0.022 ppm in fat.  In general TRR were higher in BP-label samples than in TMP-label samples.  Radioactivity in milk was generally stable throughout the dosing period.  Most of the administered dose was excreted (75.7-85.7%), with the majority (61.8-74.1%) excreted in the feces.  

The following samples from high dose goats were subjected to further extraction and analysis:  Day 5 BP-label milk, and BP- and TMP-label liver, kidney, and fat; samples of TMP-label Day 5 milk and muscle (both labels) were not were not analyzed further because TRR were <0.01 ppm.  The majority of the radioactivity in milk (98.9% TRR) was extracted with acetone.  Sequential extraction with acetonitrile (ACN), ACN/water, methanol/acetone/water/triethylamine (TEA), and methanol/water/trifluoroacetic acid (TFA) released the majority of the radioactivity in liver (59.2-68.9% TRR) and kidney (87.1-93.1% TRR).  The majority of the radioactivity in fat (~100% TRR) was extracted with methanol.  The nonextractable residues of liver and kidney were subjected to hydrolysis with pepsin, followed by extraction with acidic methanol, which together released an additional 25.9-37.6% TRR in liver, and 7.5-10.6% TRR in kidney.  Remaining nonextractable residues following extraction and hydrolysis procedures were 14.3% TRR (0.001 ppm) in milk, 5.3-7.5% TRR (0.054-0.068 ppm) in liver, 4.6-7.7% TRR (0.012-0.015 ppm) in kidney, and 6.0% TRR (0.0013 ppm) in TMP-label fat (nonextractable residues in BP-label fat were not reported).  The extraction procedures adequately extracted the majority of residues from goat milk and tissues.  Accountabilities were roughly 100-122%.  

Residues were quantitated in milk and tissues by HPLC/UV.  Metrafenone was identified in milk, liver and fat by co-chromatography.  Three ROIs, ROI-9, -13 and -16, were major residue components in milk, liver and/or kidney.  Individual components of these ROIs were identified primarily in liver by LC/MS, in conjunction with hydrolysis via beta-glucuronidase.  The three ROIs were found to include O-glucuronide conjugates of metabolites.  ROI-9 was comprised of metabolites CL 1023361, CL 1023362 and CL 1500702; ROI-13 was comprised of metabolites CL 1500698, CL 1023363 and a minor unknown; and ROI-16 was comprised of metabolites CL 1500701, CL 1500699 and a minor unknown.  The metabolite profiles were similar for both labels, and the metabolite profiles in liver and kidney were similar.  

Parent was the major residue in milk (24.12% TRR, 0.0024 ppm), and was the major and only identified residue component in fat, accounting for 60.00-85.32% TRR (0.0090-0.0188 ppm).  Metrafenone was a minor residue in liver (2.74-3.49% TRR; 0.025-0.035 ppm) and kidney (3.25-4.35% TRR; 0.005-0.014 ppm).  ROI-13 was a major residue component in milk (10.67% TRR, 0.001 ppm), and was the major residue component in liver and kidney, accounting for 14.77-21.05% TRR (0.106-0.269 ppm) and 26.29-28.15% TRR (0.044-0.086 ppm), respectively.  ROI-9 was also a major component in liver and kidney, accounting for 9.89-13.23% TRR (0.071-0.169 ppm) and 9.51-13.57% TRR (0.021-0.031 ppm), respectively; ROI-9 was a minor component in milk (2.83% TRR).  ROI-16 was a minor residue component in milk (3.8% TRR), liver (6.41-7.12% TRR), and kidney (1.46-4.19% TRR).  Remaining radioactivity was found to consist of up to 18 minor ROIs, together accounting for 55.94% TRR (0.0056 ppm) in milk, 13.45-14.46% TRR (0.0022-0.0030 ppm) in fat, 50.63-61.70% TRR (0.443-0.647 ppm) in liver, and 48.81-55.08% TRR (0.077-0.181 ppm) in kidney.  The single largest ROI accounted for 11.7% TRR (0.084 ppm) in TMP-label liver, with the majority (10.86% TRR) found in the pepsin hydrolysate.  

Based on the submitted goat metabolism study, the registrant has proposed the following metabolic pathway for metrafenone in ruminants.  Metabolism of metrafenone in lactating goat occurred at the methyl and methoxy groups on the rings.  Hydroxylation of the methyl groups yielded hydroxymethyl derivatives, whereas O-demethylation yielded hydroxyphenyl derivatives.  These hydroxylated metabolites underwent Phase II glucuronidation to produce various mono-O-glucuronides. All of the prominent goat metabolites were identified as O-glucuronides.  (See Tables 8a, 8b, 8c, 8d, 8e, 8f and 8g in the DER for MRID #49267201.)  

Conclusions:  Based on the wheat, cucumber and grape metabolism studies, metrafenone is metabolized in plants to more polar components.  The unchanged parent was the major residue component in most matrices; in cucumber pulp, where metrafenone was a minor component, some polar components were detected at low concentrations similar to those of metrafenone.  All of the prominent goat metabolites were identified as O-glucuronides.

4.1.1	Summary of Plant and/or Livestock Metabolism (860.1300)
	ROCKS Memo D370903; G.F. Kramer; 18 Nov 2009
	Residue Chemistry Summary D312307; D. McNeilly; 24 August 2006
	Metabolism DER for MRID #48981307 (Cucumber)
	Metabolism DER for MRID #49119101 (Wheat)

Data have been submitted and reviewed depicting the metabolism/degradation of metrafenone in numerous crops and the environment.  HED has determined the plant and livestock ROCs for purposes of tolerance enforcement and risk assessment (see Table 4.1.1.1, below).  

TABLE 4.1.1.1	Summary of Metrafenone Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression.
                                    Matrix
                     Residues Included in Risk Assessment
                   Residues Included in Tolerance Expression
Plants
Primary crops 
Metrafenone + acetone unknowns + juice (correction factor derived from grape metabolism study)
Metrafenone

Rotational crops
Not Applicable
Not applicable
Livestock
Ruminants
Not Applicable
Not applicable

Poultry
Not Applicable
Not applicable
Drinking water
Metrafenone + total extractable residues
Not applicable

For primary crops, metrafenone parent serves as an adequate measure of misuse based on its percentage of the TRR in the metabolism studies, and the significant residues seen in crop field trials.  For dietary risk assessment purposes, HED concludes that some of the significant amounts of tentatively identified and unidentified material in the grape metabolism study need to be included.  The tentatively identified metabolites in the "acetone unknowns" and "juice" fractions retain the dual ring structure of the parent compound.  Such residues may be of comparable toxicity to the parent, metrafenone.  At this time, the residues described as "acetone unknowns" and "juice" should be included along with the parent for assessing dietary risk.  This approach would account for 93% and 77% of the TRR in grapes harvested after the fifth application of the BP-labeled metrafenone ([bromophenyl-6-[14]C]metrafenone) and TMP labeled metrafenone ([trimethoxyphenyl-U-[14]C]metrafenone), respectively.

Data from the metrafenone grape and cucumber metabolism studies were used to derive a dietary exposure adjustment factor by dividing residues (as a percent of the TRR) of the parent plus the "acetone unknowns" and "juice" fractions by the residue of parent only in the grape metabolism study.  Conducting this evaluation for both radiolabels, and both harvesting intervals resulted in a maximum ratio of 2.1, and an average ratio of 1.9.  HED decided to use a dietary exposure ratio factor of 2.0.  This adjustment factor was then used to convert tolerance levels for the parent to residues of parent plus the "acetone unknowns" and "juice" fractions (see ROCKS Memo, D370903; G. Kramer; 19 November 2009).  

The wheat metabolism study was classified as marginally scientifically acceptable.  Insufficient attempts were made to characterize/identify radioactivity in the nonextractable residues of wheat hay and straw, which accounted for 20.8-23.0% TRR (1.615-1.952 ppm) in hay and at least 27.7-38.1% TRR (2.465-3.139 ppm) in straw.  In addition, insufficient quantitative data were provided concerning the characterization of radioactivity in the nonextractable residues of grain for HED to ascertain whether these residues were sufficiently characterized.  

In addition, the study was missing much of the data supporting the limited characterization attempts that were described.  However, the finding that metrafenone is the major residue of concern in wheat is consistent with the previous plant metabolism studies, and the European Food Safety Authority (EFSA) has accepted the results of this study in conjunction with the other metabolism studies in establishing MRLs.   Also, the progression of residue distribution from forage to hay and straw in terms of the relative amounts of extractable and nonextractable residues, and the consistency of the metabolite profile across these matrices are mitigating factors.  It is likely that the nonextractable residues of hay and straw are comprised of further breakdown products incorporated into natural components (conjugates), which are not considered toxic.  Furthermore, previous metabolism studies (in grape, cucumber and rat) have demonstrated that metrafenone tends to be broken down into a multitude of metabolites, many of which were ultimately unidentified.  

Because there are no current or proposed uses on cereal grains at this time, data from the wheat metabolism study were not included in calculation of the dietary exposure adjustment factor.  Should the registrant submit any future petition requesting the use of metrafenone on cereal grain(s), the derivation and calculation of this adjustment factor will need to be revisited.  Ideally, a new metabolism study in a cereal grain would be conducted, with a more thorough attempt to identify many of the resulting metabolites.  Otherwise, an adjustment factor of 6 (as calculated in Table 4.1.1.2, below) would need to be included for cereal grain commodities in the column for adjustment factor 2 in the dietary exposure assessment.  

TABLE 4.1.1.2	Metrafenone Metabolism Adjustment Factor.
                                       
                                   BP Label
                                   TMP Label
                           Maximum/Average Ratio[1]
                                     Grape
                                    Residue
                                    %TRR[2]
                                       
                                   0 DALT[3]
                                    35 DALT
                                    0 DALT
                                    35 DALT
                                       
Metrafenone
53.3%
24.7%
40.7%
22.8%

"Acetone Unknown"
32.6%
--
23.5%
--

"TRR in Juice fraction"
7.1%
18%
12.5%
25.3%

Ratio
1.74
1.73
1.88
2.11
2.1/1.9
                            Cucumber (Whole fruit)
                                    Residue
%TRR	(Note:  Only one ring was labeled in the cucumber metabolism study.)
				14 DAT1[5]                3 DAT2
Metrafenone


12.6%
42.4%

Polar unknowns


24.0%
13.1%

Medium polar unknowns


41.3%
23.4%

Ratio


6.0[4]
2.0
2.0

                            Wheat (Grain), 35 DAT3
                                    Residue
                                     %TRR
                                      ppm
                                     %TRR
                                      ppm
                                       
Metrafenone
7.7%
0.016
3.1%
0.013

Unknown ROI
15.1%
0.032
20.2%
0.081

Unknowns ROI 2-11
<2%
<0.004
<2%
<0.004

Ratio
3.22

8.16

8.16/5.69
                            Wheat (Forage), 3 DAT1
                                    Residue
                                     %TRR
                                      ppm
                                     %TRR
                                      ppm
                                       
Metrafenone
64.4%
5.261
58.9%
3.101

All metabolites and unknowns in extract
27.3%
2.228
27.6%
1.444

Ratio
1.42

1.47

1.47/1.45
                             Wheat (Hay), 14 DAT2
                                    Residue
                                     %TRR
                                      ppm
                                     %TRR
                                      ppm
                                       
Metrafenone
26.0%
2.021
12.7%
1.078

All metabolites and unknowns in extract
50.0%
3.905
59.8%
5.095

Ratio
2.92

5.71

5.71/4.32
                            Wheat (Straw), 35 DAT3
                                    Residue
                                     %TRR
                                      ppm
                                     %TRR
                                      ppm
                                       
Metrafenone
13.6%
1.215
7.7%
0.635

All metabolites and unknowns in extract
39.1%
3.511
44.9%
3.702

Ratio
3.88

6.83

6.83/5.36
1. Ratio = [parent + other ROC]/parent.
2. TRR= Total Radioactive Residues
3. DALT = Days After Last Treatment.  
4. While the percentages of these fractions are high, the actual TRR is less than 0.005 ppm and therefore, were not used in the calculation of the correction factor.  
5. (#) DAT(#) = (number of) Days After Treatment (treatment number).  

To obtain dietary exposure residue values for all commodities, a factor of 2.0 was entered into the column for adjustment factor 2 in the dietary exposure assessment (D371367; D. McNeilly; 18 February 2010).  

Conclusions:  The nature of the residue in plants and animals has been adequately delineated.  

4.1.2	Summary of Confined Rotational Crops (860.l850)
	Confined Accumulation in Rotational Crops DER for MRID #49119105

BASF Corporation has submitted a confined rotational crop study with [bromophenyl-6-[14]C]metrafenone (BP label; specific activity 10.15 uCi/mg) and [trimethoxyphenyl-U-[14]C]metrafeneone (TP label; specific activity 8.97 uCi/mg).  The radiolabeled test substances were formulated as ECs, and applied to bare sandy loam soil in outdoor plots at a rate equivalent to 0.558 lb ai/A (625 g ai/ha).  Rotational crops (lettuce, radish and canola) were planted at plant-back intervals (PBIs) of 30, 60, 90 and 365 days after soil treatment.  Immature and mature lettuce, mature radish roots and tops, and canola straw, seed and whole plant were harvested.  The in-life phase of the study was conducted by Excel Research Services at the Qualls Agricultural Laboratory (Ephrata, WA), and the analytical phase of the study was conducted by BASF Corporation (Princeton, NJ).
	
Following a single foliar broadcast application of [bromophenyl-6-[14]C]metrafenone or [trimethoxyphenyl-U-[14]C]metrafenone at 0.558 lb ai/A, TRR, determined by combustion/LSC, accumulated at >=0.01 ppm in immature lettuce at the 90-day PBI (both labels), radish tops at the 30-, 60- (TP label only) and 90-day PBIs, radish root at the 30-, 60- and 90-day PBIs (BP label only), canola seed at the 90-day PBI (BP label only), and canola straw at the 30-, 60-, 90- and 365-day PBIs (both labels).  The petitioner also analyzed samples where TRR were <0.01 ppm, but greater than the reported LOQ (0.004 ppm), which included mature lettuce at the 30-day PBI (both labels), radish tops at the 60-day PBI (BP label only), radish roots at the 90-day PBI (TP label only), and canola (whole plant) at the 60-day PBI (both labels).  TRR were below the LOQ in mature lettuce at the 60- and 365-day PBI (both labels).  TRR in 365-day samples were <=0.008 ppm in all matrices, and were not further analyzed with the exception of 365-day canola straw (0.023-0.029 ppm).  TRR were generally highest in 30-day PBI matrices, ranging from 0.005 ppm in mature lettuce to 0.048 ppm in canola straw.  For lettuce, higher residues of 0.030-0.034 ppm were detected at the 90-day PBI; however, the petitioner attributed the increase in residues to harvesting the crop at an immature stage due to late planting.  TRR generally decreased at the 60-day PBI, ranging from <0.004 ppm in mature lettuce to 0.027 ppm in canola straw, but residues increased slightly at the 60-day PBI in radish tops (0.018 ppm).  TRR increased at the 90-day PBI in radish tops, and canola straw and seed, ranging from 0.010 ppm in canola seed to 0.033 ppm in canola straw, and decreased slightly in 90-day radish root (0.009-0.010 ppm).

Extraction with MeOH/water released the majority of the radioactivity, 62.1-85.2% TRR, in 30- and 90-day lettuce, 30-, 60- and 90-day radish tops and roots, 30-, 60-, 90- and 365-day canola straw, and 60-day canola whole plant (BP label only).  Extraction with hexane released the majority of radioactivity, 51.6-86.2% TRR, in 30- and 90-day canola seed (BP label only) and 60-day canola seed (TP label only); extraction with hexane released 41.9% TRR in 60-day canola seed samples (BP label), and 45.6-47.9% TRR in 30- and 90-day canola seed samples (TP label).  Samples of 90-day immature lettuce, 30-day radish tops, 60-day radish roots, and 30-, 60-, 90- and 365-day canola straw were subjected to additional extraction procedures to release bound residues.  Extraction with MeOH/2% HCl released 5.9-19.9% TRR from immature lettuce, radish tops and roots, and canola straw.  

Remaining nonextractable residues in the matrices that were subjected to additional extraction procedures to release bound residues were 18.7-19.6% TRR (0.006 ppm) in immature lettuce, 17.6-20.8% TRR (0.003-0.005 ppm) in radish tops, 25.0-31.8% TRR (0.005 ppm) in radish roots, and 11.8-29.4% TRR (0.004-0.008 ppm) in canola straw.  For the remaining matrices, nonextractable residues were 17.7% TRR (0.001 ppm) in 30-day mature lettuce, 14.8-36.0% TRR (0.002-0.006 ppm) in 60- and 90-day radish tops, 19.8-31.2% TRR (0.003-0.005 ppm) in 30- and 90-day radish roots, 13.8-58.1% TRR (0.001-0.005 ppm) in 30-, 60- and 90-day canola seed, and 23.9-100% TRR (0.001-0.006 ppm) in 60-day canola whole plant.  Initial extraction results were normalized; therefore, accountabilities were approximately 100%.

Select sample extracts were analyzed by HPLC/UV.  All samples of rotational crop commodities were analyzed within 205-740 days (6.7-24.3 months) of harvest.  No storage stability data were submitted.  However, a 2012 storage stability study (MRID #48981308) reviewed in conjunction with the recent pome fruit petition (PP#3F8163) supports the sample storage conditions and durations of samples in this rotational crop study. 

Metrafenone was identified by HPLC co-chromatography with reference standards.  Additional ROIs were characterized on the basis of HPLC fractionation profiles.  HPLC analysis of the MeOH/water extracts showed multiple unknown peaks in each sample.  Metrafenone was identified at 6.2-11.1% TRR (<0.001-0.004 ppm) in 30-day and 90-day (BP label only) lettuce samples, and 3.9-27.7% TRR (<0.001-0.004 ppm) in 30-, 60- and 90-day radish roots.  The most abundant residue in the majority of samples was the polar ROI 1, which accounted for 8.1-17.3% TRR (0.001-0.003 ppm) in 30- and 90-day lettuce, 15.3-43.7% TRR (0.001-0.01 ppm) in 60- and 90- radish tops (BP label), 10.3-17.9% TRR (0.002-0.003 ppm) in 30-, 60- and 90-day radish tops (TP label), 16.6-26.5% TRR (0.002-0.004 ppm) in 30-, 60- and 90-day radish roots, and 25.1-42.4% TRR (0.007-0.015 ppm) in canola straw, all PBIs.  A second ROI, ROI 2, was present at 11.9% TRR (0.004 ppm) in 90-day immature lettuce (TP label only), 8.8-20.0% TRR (<0.001-0.005 ppm) in 60- and 90-day radish tops (BP label only), 12.8% TRR (0.002 ppm) in 60-day radish roots (TP label only), 9.6-12.4% TRR (0.003-0.005 ppm) in 30- and 90-day (BP label only) canola straw.  These peaks were not further investigated in any matrix.  

Because only parent was identified in the submitted confined rotational crop study, a metabolic profile was not provided.  

Conclusions:  The results from the confined rotational crop study indicated that there is no expected accumulation of metrafenone or its degradation products in the parts of plants used for human food or animal feed consumption.  The levels of individual metabolites were below 0.01 ppm.  Owing to the low concentrations of metrafenone and related residues in subsequent rotated crops, no field rotational crop trials are required.  Plant-back restrictions are not necessary for metrafenone.  

4.1.3	Summary of Rat Metabolism
	Risk Assessment D354166; D. McNeilly; 1 March 2010

In a rat metabolism and pharmacokinetics study, excretion was 91-100% after 168 hours.  Most radioactivity was excreted within the first 48 hours (84-99% in feces, 0.5-4.8% in urine).  The highest concentration was in the liver.  Bile was the major excretion pathway.  In bile duct-cannulated rats, total recovery was 97-100% at 72 hours.  At the low dose, bile recovery was 85-90%; at the high dose, feces had 80-82%, with bile having 15-17% (indicating absorption was saturated).  Six urinary and biliary metabolites were found.  In urine, up to 21 other minor unknowns were found.  In bile, up to 24 minor unknowns were found (21-24% for the low dose, and 3-4% for the high dose).  The parent compound was not detected in urine or bile.  Twelve fecal metabolites along with the parent were found.  Most of the fecal radioactivity was contained in parent metrafenone.  Fecal metabolites were 0.03-15% of the administered dose.  There were up to 45 other fecal minor unknowns.  In feces of bile duct-cannulated animals, metabolites plus parent were identified.  The parent accounted for most of the activity; however, there were up to 17 minor unknowns.  The absorbed material was metabolized by ortho-dealkylation, aliphatic oxidation, debromination, ring hydroxylation, and conjugation.  Primary excretion was as glucuronic acid conjugates in bile and urine.  Residues in feces were primarily as parent and aglycones of bile and urine conjugates.  

4.1.4	Summary of Environmental Degradation
	EFED Drinking Water Memo D411540, D414403, D416312; J.A. Hetrick; 25 November 2013

The only positively identified major degradate of metrafenone in the environmental fate studies was CL 377160 (3-bromo-6-methoxy-2-methylphenyl)(3-hydroxy-2,4-dimethoxy-6-methylphenyl)-methanone).  CL 377160 was formed through soil photolysis at up to 18.9% of the applied radioactivity (AR), and through anaerobic aquatic metabolism at up to 10.8% AR in the total system.  It was also formed as a minor degradate through aquatic photolysis, and aerobic aquatic metabolism.  

In one anaerobic aquatic metabolism study, another six degradates were formed at >9%, but these were either unidentified or only tentatively identified.  These included TN (tentatively identified as a lactone compound at maximums of 3.3%, 26.9% and 28.0% in the water layer, sediment and total system, respectively), MB (tentatively identified as a hydroxylation product of TN at maximums of 1.1%, 11.6% and 11.7% in the water layer, sediment and total system, respectively), and four unidentified degradates formed in the total system at 9.3% to 13% AR.  

Carbon dioxide was also a major degradate, formed through aquatic photolysis at up to 25% AR, and through all other measured processes as a minor degradate.  
 
 Most processes also resulted in formation of a substantial amount of minor degradates, some individually measured and identified, but most not.  Although all of these degradates were present at less than 10%, and some at very low levels, they still may be of exposure concern because of the large overall amounts.  In some cases, minor degradates, mostly unidentified, made up more than 50% of the AR in a single sampling event.  In addition, based on the structure of the parent compound, and the proposed degradation pathways, many of the minor degradates may have a high degree of structural similarity to each other and/or the parent, and so may have toxic properties similar to those of the parent.  


5.0	Residue Profile

5.1	Residue Analytical Methods (860.1340)

5.1.1	Data Collection Methods

QuEChERS:  The hops (NAFTA trials), pome fruit, fruiting vegetable, cucurbit, cherry and peach RAC samples, and apple processed commodities were analyzed for residues of metrafenone using an LC/MS/MS method which is described in Metrafenone (BAS 560 F): Validation of the Multi-Residue Enforcement Method QuEChERS for the Determination of Residues in Plant Matrices using LC/MS/MS (BASF Study #398340).  A QuEChERS method uses dispersive solid phase extraction (dSPE) to prepare the sample for analysis.  The method detects parent metrafenone, which has been determined to be the ROC for tolerance enforcement purposes in primary crops, based on plant metabolism studies.  A summary of the methodology used to analyze the samples follows.

Briefly, metrafenone residues in RAC samples are extracted by shaking with a buffered solution of water and ACN in the presence of salts (Supelco 55227-u mixture, containing sodium chloride, magnesium sulfate, and citrate buffering agents) and centrifuged.  An aliquot of the supernatant is further purified on a dSPE clean-up tube (Restek 26215, containing magnesium sulfate to remove residual water,  and primary secondary amine sorbent to remove sugars and fatty acids) and centrifuged.  An aliquot of the extract is diluted with an acidified solution of ACN and water (0.1% formic acid in 1:1 ACN/water) prior to analysis by LC/MS/MS.   Metrafenone is quantitated via MS/MS detection using the positive ionization mode monitoring ion transitions from m/z 409-->209 for quantitation, and m/z 409-->227 for confirmation.  Quantitation was obtained using an external calibration curve of metrafenone standards.  

The method was validated before the analysis of any treated pome fruit samples by fortifying untreated control apple fruit samples at 0.010 and 0.10 ppm.  Concurrently with the analysis of field trial samples, the method was also validated using samples of untreated pome fruits fortified with metrafenone at 0.01, 0.10 and 1.0 ppm.  Additionally, the method was validated, before the analysis of any treated apple processed commodities, by fortifying untreated control dried apple samples at 0.01 and 0.10 ppm.  Concurrently with the analysis of processed commodities, the method was also validated using samples of untreated apple RAC and processed commodities fortified with metrafenone at 0.01 to 10 ppm.  

The method was validated before the analysis of any treated tomato samples by fortifying untreated control tomato fruit samples at 0.01, 0.10 and 1.0 ppm.  Concurrently with the analysis of field trial samples, the method was also validated using samples of untreated tomatoes fortified with metrafenone at 0.01 and 0.10 ppm.  

The method was validated before the analysis of any treated pepper samples by fortifying untreated control pepper fruit samples at 0.01, 0.10, and 3.0 ppm.  Concurrently with the analysis of field trial samples, the method was also validated using samples of untreated peppers fortified with metrafenone at 0.01 and 0.10 ppm.  

The method was validated before the analysis of any treated cucurbit samples by fortifying untreated control samples of cantaloupe and summer squash at 0.01, 0.10 and 1.0 ppm, and untreated cucumber samples 0.01 and 0.10 ppm.  Concurrently with the analysis of field trial samples, the method was also validated using samples of untreated cantaloupes, cucumbers and summer squash fortified with metrafenone at 0.01 and 1.0 ppm.  

The method was validated before the analysis of any treated cherry samples by fortifying untreated control cherry fruit samples at 0.01, 0.10 and 1.0 ppm.  Concurrently with the analysis of field trial samples, the method was also validated using samples of untreated cherries fortified with metrafenone at 0.01, 0.10 and 1.0 ppm.  

The method was validated before the analysis of any treated peach samples by fortifying untreated control peach fruit samples at 0.01, 0.10, 1.0 and 2.0 ppm.  Concurrently with the analysis of field trial samples, the method was also validated using samples of untreated peaches fortified with metrafenone at 0.01, 0.10 and 1.0 ppm.  

The method was validated before the analysis of any treated hops cone samples (reported in MRID #49145403) by fortifying untreated control samples of dried and fresh hops cones at 0.01-200 and 0.01-1.00 ppm, respectively.  Concurrently with the analysis of field trial samples, the method was also validated using samples of untreated dried and fresh hops cones fortified with metrafenone at 0.01-200 and 0.01-50 ppm, respectively.  

QuEChERS Conclusions:  The metrafenone residues in hops (NAFTA trials), pome fruit, fruiting vegetable, cucurbit, cherry and peach RAC samples, and apple processed commodities were quantitated using an LC/MS/MS multi-residue QuEChERS method (BASF Study #398340).  The method was successfully validated for all these commodities in conjunction with the studies prior to analysis of the field trial samples.  Acceptable concurrent method recovery data in all matrices were also obtained for metrafenone.  The validated LOQ for residues of metrafenone in pome fruits RAC and processed commodity samples was 0.01 ppm; the method limit of detection (LOD) was 0.003 ppm.  The validated LOQ for residues of metrafenone in fruiting vegetable samples was 0.01 ppm; the estimated method LOD was reported as 0.001 ppm, or approximately 10% of the LOQ.  The validated LOQ was 0.01 ppm for metrafenone in dried and fresh hops cones; the calculated LODs were 0.0034 and 0.0035 ppm in dried and fresh hops cones, respectively.  The validated LOQ was 0.01 ppm for metrafenone in all cucurbit matrices; the reported LOD in cucumber was 0.001 ppm (10% LOQ).   The LOQ was 0.01 ppm for metrafenone in cherries.  The LOQ was 0.01 ppm for metrafenone in peaches; the calculated LOD was 0.0041 ppm. No additional data are required in support of this data collection method.

BASF Methods #535/1 and #535/3:  The hops (German trials) RAC samples were analyzed for residues of metrafenone using BASF Methods #535/1 (L0076/01) and #535/3 (L0076/03).  The tomato processed commodities were analyzed for residues of metrafenone using BASF Method #535/1 (L0076/01).  

The two methods are essentially identical.  Briefly, samples were extracted with methanol/water/2N HCl (14:5:1, v/v/v), and centrifuged.  The supernatant was partitioned with cyclohexane/0.2N NaOH (5:1, v/v), and the organic phase was evaporated to dryness, then reconstituted in methanol/water (1:1, v/v) for LC/MS/MS analysis.  The method monitors two ion transitions for determination of metrafenone, m/z 411-->209 for quantitation, and m/z 411-->229 for confirmation.  

BASF Methods #535/1 and #535/3 were validated before the analysis of any treated hops cone samples (reported in MRIDs #49145407 and 49145408) by fortifying untreated control samples of dried and fresh hops cones at 0.01-200 and 0.01-1.00 ppm, respectively.  Concurrently with the analysis of field trial samples, the methods were also validated using samples of untreated dried and fresh hops cones fortified with metrafenone at 0.01-200 and 0.01-50 ppm, respectively.  

Concurrently with the analysis of tomato RAC and processed commodity samples, BASF Method #535/1 was validated using samples of untreated control tomato RAC and processed commodity samples (washed fruit, vegetable stock, paste, wet pomace, and peel) fortified with metrafenone at 0.01, 0.10, 1.0 and 5.0 ppm.  

BASF Methods #535/1 and #535/3 Conclusions:  The hops (German trials) RAC samples were analyzed for residues of metrafenone using BASF Methods #535/1 and #535/3.  The tomato processed commodities were analyzed for residues of metrafenone using BASF Method #535/1.  The methods were successfully validated for these commodities in conjunction with the studies prior to analysis of the field trial samples.  Acceptable concurrent method recovery data in all matrices were also obtained for metrafenone.  The validated LOQ was 0.01 ppm for metrafenone in tomato RAC and processed commodity samples; the method LOD was not specified.  The validated LOQ was 0.01 ppm for metrafenone in fresh hops cones, dried hops cones, and the hops processed commodities; the method LOD was not specified.  No additional data are required in support of these data collection methods.

5.1.2	Multi-Residue Methods (860.1360)
	Multi-Residue Methods DER for MRID #46857701

BASF Corporation previously submitted multiresidue method testing data for metrafenone with PP#4E6884.  Multiresidue method testing data were submitted for metrafenone and its metabolites CL 376991, CL 434223, and CL 3000402.  Metabolite CL 3000402 corresponds to a metabolite identified in the grape metabolism study as surface rinse metabolite 2; the other two metabolites appear to have been identified in cereal grains (data not submitted to EPA).  The test substances were analyzed according to the Food and Drug Administration (FDA)  Multiresidue Method Test guidelines in PAM Vol. I.  Metrafenone and its metabolites were tested through Protocols A, B, C, D, E and F; the compounds were not tested under Protocol G because they are not substituted ureas.  The study was conducted by Maxim Technologies (Middleport, NY).

The test substances do not have N-methylcarbamate structures and were not found to be naturally fluorescent in testing under Protocol A.  In Protocol B testing, metrafenone, CL 376991, and CL 434223 were completely recovered from grapes fortified at 0.05 and 0.50 ppm, and metrafenone and CL 376991 were partially recovered from peanuts fortified at 0.05 and 0.50 ppm; low recoveries were obtained for CL 434223.  CL 3000402 was not recovered in Protocol B testing due to matrix interferences in both grapes and peanuts.   

Protocol C testing of the compounds indicated that further testing using Protocols D, E and F was required for all test substances.  The Protocol C results indicated that all analytes were detected using an electron capture detector (ECD).  

Metrafenone was recovered from grapes fortified at 0.05 and 0.50 ppm using Protocols D and E (mixed ether and methylene chloride elution systems), and from peanuts fortified at 0.05 and 0.50 ppm using Protocol F.  CL 376991, CL 434223, and CL 3000402 were also recovered using Protocol D (without Florisil cleanup).  CL 376991, CL 434223, and CL 3000402 were not recovered from the Florisil column in Protocol E and F testing.  

These data indicate that FDA multiresidue methods Protocols D, E and F may be suitable for determining residues of metrafenone in grapes and peanuts.
  
Conclusions:  The submitted multiresidue methods test data are adequate.  The data indicate that multiresidue methods are probably suitable for determining residues of metrafenone in grapes for tolerance enforcement.  These results were previously submitted to FDA.  

5.1.3	Tolerance Enforcement Methods
	Residue Analytical Method DER for MRIDs #48981303 and 48981304
	Residue Analytical Method DER for MRIDs #49267202 and 49267203

QuEChERS:  BASF has submitted the QuEChERS method as the new enforcement method for metrafenone residues in plant commodities.  The data previously requested regarding fortification at tolerance levels for the previous tolerance enforcement method (FAMS 105-01 for grape, and FAMS 106-01 for wine) are no longer relevant.  This conditional data issue is considered resolved, and the new enforcement method and supporting ILV are discussed and reviewed below, and in the supporting DER for MRIDs #48981303 and 48981304.  

Briefly, homogenized samples are extracted with ACN.  A mixture of magnesium sulfate, sodium chloride, and citrate salts is added to buffer the solution to pH 5-5.5, and after shaking, the mixture is centrifuged to separate the phases.  An aliquot of the ACN phase is cleaned-up by dSPE on primary secondary amine sorbent for analysis using LC/MS/MS.  Two parent-daughter ion transitions are monitored, one for quantitation (m/z 409-->209), and the other for confirmation (m/z 411-->209 for dried hop cones, m/z 409-->227 for all other matrices).  Based on the lowest level of method validation (LLMV), the validated LOQ is 0.01 ppm for metrafenone.

The method was adequately validated using samples of dry bean seed, cucumber, dried hops cones, lemon, rapeseed, and wheat forage, grain and straw.  Samples were fortified with metrafenone at the LOQ (0.01 ppm) and 10X the LOQ (0.1 ppm) for dry bean seed and rapeseed; at 0.01, 0.10 and 0.50 ppm for wheat grain; at 0.01, 0.10, and 5.0 ppm for cucumber, lemon, wheat forage, and wheat straw; and at 0.01, 0.10, and 20 ppm for dried hop cones.  For samples fortified at the LOQ, recoveries ranged from 79-91% (average of 86% and standard deviation of 4.9%) for dry bean seed; 102-105% (average of 104% and standard deviation of 1.2%) for cucumber; 97-101% (average of 99% and standard deviation of 1.8%) for dried hop cones; 96-108% (average of 104% and standard deviation of 4.6%) for lemon; 94-99% (average of 97% and standard deviation of 2.0%) for rapeseed; 96-102% (average of 100% and standard deviation of 2.5%) for wheat forage; 102-105% (average of 104% and standard deviation of 1.1%) for wheat grain; and 96-105% (average of 100% and standard deviation of 3.4%) for wheat straw.  Individual recoveries at each fortification level were within the acceptable range of 70-120% and coefficients of variance ranged from 0.9-6.6%.  

The QuEChERS method is proposed as an enforcement method for metrafenone residues in plant commodities.  Because the method includes monitoring of two parent-daughter ion transitions, a separate confirmatory method is not required.  An adequate ILV study was submitted for the method (with dry bean seed, cucumber, dried hop cones, lemon, rapeseed, and wheat forage, grain and straw) at fortification levels including the LOQ and 10X the LOQ.  

No radiovalidation data were submitted.  However, the cucumber metabolism study conducted with metrafenone included data demonstrating the ability of ACN to extract incurred residues from treated crop matrices.  Ergo, no radiovalidation data are required.  

Because the QuEChERS method is a German multi-residue method, Agency method validation is not required.  

DFG Method S19:  BASF has submitted DFG Method S19 (extended revision) as the new enforcement method for metrafenone residues in livestock commodities.  The new enforcement method and supporting ILV are discussed and reviewed below, and in the supporting DER for MRIDs #49267202 and 49267203.  

Briefly, the samples are extracted with acetone/water (2:1, v:v), and the extracts are partitioned with ethyl acetate/cyclohexane (1:1, v:v).  An aliquot of the organic phase is evaporated to near dryness, and the residue is re-dissolved in ethyl acetate.  A salt mixture and cyclohexane are added to the residue and mixed.  The samples are cleaned up through gel permeation chromatography (GPC), and residues are eluted with ethyl acetate/cyclohexane (1:1, v:v).  The eluate is concentrated, and dissolved in ethyl acetate for analysis.  The LOQ is 0.01 ppm in milk, and 0.05 ppm in meat and eggs.  The LOD is 0.002 ppm in milk, and 0.01 ppm in meat and eggs.  

The method was adequately validated using samples of milk fortified with metrafenone at 0.010 and 0.10 ppm, and samples of meat and eggs fortified with metrafenone at 0.05 and 0.50 ppm.  Overall mean recoveries were 69-97%, with relative standard deviations of less than 20%, from each matrix tested.  

An ILV study was also conducted using samples of milk fortified with metrafenone at 0.010 and 0.1 ppm, and samples of meat and eggs fortified with metrafenone at 0.05 and 0.50 ppm.  Acceptable mean recoveries ranging from 76% to 101%, with relative standard deviations of less than 20%, were found from each matrix tested.  

No confirmatory procedures, or radiovalidation data were included in the submission.  Because this method monitors multiple ions for the determination of metrafenone, no confirmatory procedures are needed.  No radiovalidation data are required for the method because the solvent systems utilized in method DFG S 19 should efficiently extract metrafenone residues in meat, milk and eggs based on similar polarity of the solvents used in the goat metabolism study with metrafenone (refer to the DER for MRID #49267201).  


Conditional Data - Method Validation/Radiovalidation:  Additional method validation data were requested in the previous HED Risk assessment (D354166; D. McNeilly; 1 March 2010) for the analytical Method FAMS 105-01, reflecting fortifications at 4.5 ppm for grapes, and at both the LOQ (0.05 ppm) and 17 ppm for raisins.  In addition, radiovalidation data were also required to demonstrate that Method FAMS 105-01 adequately recovers weathered residues of metrafenone from grapes.  Since a new enforcement analytical method has been submitted these two issues related to the previous enforcement method are no longer relevant.  It should be noted that the registrant did provide data showing adequate extractability using the 4:1 n-heptane/acetone extraction approach.  HED notes that the cucumber data demonstrate adequate extractability using 4:1 n-heptane/acetone.  

Conditional Data - Data Collection Method Radiovalidation:  The extraction solvent used in the data collection method for grapes was different from that used in the proposed enforcement method, and radiovalidation data were required to support the data collection method, BASF Method 535/0.  Samples from the grape field trial and processing studies submitted with PP#8F7371 were analyzed for residues of metrafenone using an LC/MS/MS method, BASF method 535/0.  Briefly, samples of grape commodities were extracted with methanol/water/2N HCl (14:5:1, v/v/v), and centrifuged.  The supernatant was partitioned against cyclohexane under alkaline conditions, evaporated to dryness, and reconstituted in methanol/water (1:1, v/v) for LC/MS/MS determination of residues of metrafenone.  

This conditional data issue is considered resolved by the data extraction efficiency data discussed below, and summarized in Tables 5.1.3.1 and 5.1.3.2, below.  These data compare the extraction efficiency for the Method 535/0 together with the extraction efficiency for the extraction system used in the cucumber and grape metabolism studies.  The data demonstrate a high extraction efficiency for the methanol/water/HCl system.  All the cucumber fruit samples had extraction efficiencies equal to or greater than 88%.  

Conditional Data  -  Extraction Efficiencies Using Different Solvent Systems:  Cucumber plants were treated with two applications of radio-labeled metrafenone (labeled in the trimethoxyphenyl ring) at a rate of 200 g ai/ha (total seasonal application rate of 400 g ai/ha).  There was a 14-day interval between treatments.  Leaf samples were collected directly after the first application, and three days after the second application.  Whole fruit samples were harvested 14 days after the first application, and three days after the second application.  

The whole fruit was divided into pulp and peel samples.  The samples were homogenized and then extracted with the solvent systems listed in the table below.  Radioactivity was determined by liquid scintillation counting.  

TABLE 5.1.3.1	Extractability of 14C-Metrafenone in Cucumber Matrices (%TRR[1]).
                           Sample Matrix (Timing[2])
                             Metabolism Extraction
                                  Method 535
                                 Method 105-01
                                  S19 Method
                                       
                                  3X Methanol
                             Followed by 2X Water
                                Methanol/Water/
                                 HCl (70/25/5)
                          n-Heptane/ Acetone (80/20)
                                   Acetone/
                                  Water (2/1)
                           Cucumber Fruit (14-DAT1)
                                     87.5
                                      1.6
                                     87.6
                                     71.0
                                     86.2
                            Cucumber Fruit (3-DAT2)
                                     92.9
                                      1.4
                                     95.3
                                     85.4
                                     93.4
                            Cucumber Pulp (2-DAT2)
                                     91.1
                                      1.1
                                     93.5
                                     56.2
                                     91.0
                            Cucumber Fruit (3-DAT2)
                                     91.2
                                      1.1
                                     94.0
                                     84.0
                                     93.6
                            Cucumber Fruit (0-DAT1)
                                     98.8
                                      0.3
                                     94.2
                                     95.8
                                     96.8
                            Cucumber Fruit (3-DAT2)
                                     92.6
                                      3.2
                                     91.9
                                     85.3
                                     90.3
1. DAT = Days After first Treatment.  
2. TRR = Total Radioactive Residues.  

The recoveries for metrafenone using the extraction profile in the cucumber metabolism study are similar to the other three extraction profiles tested, except for one cucumber pulp sample which did have low recovery.  The extractability of radioactive residues from cucumber peel in the metabolism study was very high, 92.2% of the TRR from pulp, and 99.1% of the TRR from cucumber leaves.  Most of the radioactive residue was extracted with methanol.  The additional extraction with water released very low amounts of the TRR (1.1%).  

The extractability with solvents was tested for all cucumber matrices (leaf, fruit, pulp, peel and the rest of the plant).  Three one-step extraction methods were investigated:  methanol/water/2N HCl (14:5:1, v/v/v/), n-heptane/acetone (4:1, v/v), and acetone/water (2:1, v/v).  The results of the extractability tests are summarized in the table below.  

TABLE 5.1.3.2	Extractability of Cucumber Whole Fruit Samples with Different Solvent Systems.
                                    Sample
                                    Matrix
                                    DAT[1]
                                    Solvent
                                    ERR[2]
                            Mg/Kg             %TRR
                                    RRR[3]
                            Mg/Kg             %TRR
                                  Whole Fruit
                                      14
                 3X Methanol, 2X water (metabolism extraction)
                                     0.015
                                     89.0
                                     0.002
                                     11.0
                                       
                                       
                     Methanol/Water/2N HCl (Method 535/1)
                                     0.011
                                     87.6
                                     0.002
                                     12.4
                                       
                                       
                               n-Heptane/Acetone
                                (Method 105-01)
                                     0.004
                                     71.0
                                     0.002
                                     29.0
                                       
                                       
                          Acetone/Water (S-19 Method)
                                     0.012
                                     86.2
                                     0.002
                                     13.8
                                  Whole Fruit
                                      17
                             3X Methanol, 2X water
                                     0.048
                                     94.3
                                     0.003
                                      5.7
                                       
                                       
                             Methanol/Water/2N HCl
                                     0.042
                                     95.3
                                     0.002
                                      4.7
                                       
                                       
                               n-Heptane/Acetone
                                     0.038
                                     85.4
                                     0.007
                                     14.6
                                       
                                       
                                 Acetone/Water
                                     0.045
                                     93.4
                                     0.003
                                      6.6
1. DAT = Days After first Treatment.  
2. ERR = Extracted Radioactive Residues.  
3. RRR = Remaining or bound Radioactive Residues.  

Conclusions:  Radiovalidation data are no longer required to demonstrate that Method FAMS 105-01 and BASF Method 535 adequately recover weathered residues of metrafenone from grapes.  HED agrees that the cucumber data, and other extraction efficiency data conducted as a part of the cucumber metabolism study, adequately demonstrate the extractability of metrafenone residues using 4:1 n-heptane/acetone solvent and methanol/water/2N HCl (70:25:5, v/v/v) solvent systems.  No additional data are required to satisfy the conditional data requirements that were previously identified by HED.  

Method validation and ILV data submitted for the QuEChERS method (MRIDs #48981303 and 48981304) demonstrate that it is adequate as the new tolerance enforcement method for metrafenone.  

Method validation and ILV data submitted for the QuEChERS method (MRIDs #48981303 and 48981304) demonstrate that it is adequate as the new tolerance enforcement method for metrafenone.  

5.2	Storage Stability (860.1380)
	Residue Chemistry Summary D312307; D. McNeilly; 24 August 2006
	Storage Stability DER for MRID #48981308

BASF submitted the results of a storage stability study with metrafenone in wheat (whole plant, grain, and straw), grape, tomato, dried pea, and soybean seed (MRID #48981308).  These crops meet the OECD requirement for stability in five diverse crops, including high-water, high-oil, high-protein, high-starch and high-acid.  Untreated samples were fortified with metrafenone at 0.10 ppm, and stored frozen at roughly -20°C, followed by analysis at intervals of 0, 28-31, 55, 84, 85, 174-178, 358-360, 455, and/or 726-739 days.  

Samples were analyzed for residues of metrafenone using an LC/MS/MS method, BASF Method #535/1 (L0076/01).  This method was adequate for data collection, based on acceptable concurrent recovery data.  The LOQ, determined as the LLMV, was 0.01 ppm in each sample matrix.  It was not reported whether concurrent recoveries and recoveries in stored samples were corrected for apparent residues in controls.  

The study results indicate that residues of metrafenone are stable in wheat (whole plant, grain, and straw), grape, tomato, dried pea, and soybean seed stored frozen (roughly -20°C) for intervals of up to 726-739 days (approximately 2 years).

TABLE 5.2	Storage Stability of Metrafenone in Wheat, Grape, Tomato, Dried Pea, and Soybean.
                                   Commodity
                                    Spike 
                                     Level
                                     (ppm)
                               Storage Interval
                                    (Days)
                           Recovered Residues (ppm)
                       Mean Recovered Residues[1] (ppm)
                               Mean Recovery (%)
                           Corrected Recovery (%)[2]
Wheat, Whole Plant
                                     0.10
                                       0
                                 0.085, 0.087
                                     0.086
                                      86
                                      --
                                       
                                       
                                      31
                                 0.074, 0.072
                                     0.073
                                      73
                                      94
                                       
                                       
                                      178
                                 0.083, 0.083
                                     0.083
                                      83
                                      96
                                       
                                       
                                      360
                                 0.081, 0.079
                                     0.080
                                      80
                                      100
                                       
                                       
                                      732
                                 0.081, 0.089
                                     0.085
                                      85
                                      86
Wheat, Grain
                                     0.10
                                       0
                                 0.105, 0.109
                                     0.107
                                      107
                                      --
                                       
                                       
                                      31
                                 0.079, 0.078
                                     0.079
                                      79
                                      87
                                       
                                       
                                      178
                                 0.083, 0.083
                                     0.083
                                      83
                                      85
                                       
                                       
                                      360
                                 0.085, 0.084
                                     0.085
                                      85
                                      83
                                       
                                       
                                      726
                                 0.077, 0.077
                                     0.077
                                      77
                                      86
Wheat, Straw
                                     0.10
                                       0
                                 0.091, 0.091
                                     0.091
                                      91
                                      --
                                       
                                       
                                      29
                                 0.090, 0.091
                                     0.091
                                      91
                                      100
                                       
                                       
                                      176
                                 0.083, 0.086
                                     0.085
                                      85
                                      95
                                       
                                       
                                      358
                                 0.089, 0.093
                                     0.091
                                      91
                                      96
                                       
                                       
                                      732
                                 0.077, 0.079
                                     0.078
                                      78
                                      100
Grape
                                     0.10
                                       0
                                 0.088, 0.090
                                     0.089
                                      89
                                      --

                                       
                                      30
                                 0.075, 0.079
                                     0.077
                                      77
                                      95

                                       
                                      176
                                 0.095, 0.099
                                     0.097
                                      97
                                      98

                                       
                                      358
                                 0.107, 0.105
                                     0.106
                                      106
                                      110

                                       
                                      730
                                 0.078, 0.088
                                     0.083
                                      83
                                      99
Tomato
                                     0.10
                                       0
                                 0.088, 0.089
                                     0.089
                                      89
                                      --

                                       
                                      29
                                 0.088, 0.087
                                     0.088
                                      88
                                      97

                                       
                                      174
                                 0.101, 0.101
                                     0.101
                                      101
                                      100

                                       
                                      358
                                 0.074, 0.076
                                     0.075
                                      75
                                      77

                                       
                                      455
                                 0.076, 0.076
                                     0.076
                                      76
                                      98

                                       
                                      726
                                 0.092, 0.100
                                     0.096
                                      96
                                      106
Dried Pea
                                     0.10
                                       0
                                 0.104, 0.104
                                     0.104
                                      104
                                      --

                                       
                                      29
                                 0.087, 0.093
                                     0.090
                                      90
                                      94

                                       
                                      176
                                 0.095, 0.097
                                     0.096
                                      96
                                      92

                                       
                                      358
                                 0.089, 0.091
                                     0.090
                                      90
                                      90

                                       
                                      730
                                 0.077, 0.090
                                     0.084
                                      84
                                      87
Soybean, Seed
                                     0.10
                                       0
                                 0.098, 0.098
                                     0.098
                                      98
                                      --

                                       
                                      28
                                 0.071, 0.072
                                     0.072
                                      72
                                      75

                                       
                                      55
                                 0.078, 0.079
                                     0.079
                                      79
                                      84

                                       
                                      84
                                 0.089, 0.090
                                     0.090
                                      90
                                      84

                                       
                                      85
                                 0.085, 0.079
                                     0.082
                                      82
                                      81

                                       
                                      176
                                 0.057, 0.062
                                     0.060
                                      60
                                      60

                                       
                                      358
                                 0.070, 0.073
                                     0.072
                                      72
                                      72

                                       
                                      739
                                 0.096, 0.100
                                     0.098
                                      98
                                      95
1. Mean recovered residues were determined by the study reviewer.
2. Corrected for mean concurrent recovery.

Storage stability data for grapes and wine were previously submitted and reviewed with PP#4E6884.  Those data indicate that residues of metrafenone are stable under frozen storage conditions for intervals of up to 18 months in grapes and wine (D312307; D. McNeilly; 24 August 2006).  

Conclusions:  The storage stability data are adequate and demonstrate that residues of metrafenone are stable in wheat (whole plant, grain, and straw), grape, tomato, dried pea, and soybean seed stored frozen (at approximately -20°C) for up to 726-739 days (roughly 2 years).  The submitted and available storage stability data are adequate to support the storage conditions and durations of samples from the submitted crop field trial and processing studies.  

5.3	Residue Data

5.3.1	Crop Field Trials (860.1500)

Pome Fruit (MRID #49055901):  BASF has submitted field trial data for metrafenone on representative crops (apple and pear) of the pome fruits crop group 11-10.  A total of 18 field trials were conducted on pome fruits during the 2010 growing season in North American Free Trade Agreement (NAFTA) Growing Zones:  twelve trials on apple in Zones 1 (NY, two trials; PA, one trial), 2 (VA, one trial), 5 (MI, WI, one trial each), 9 (UT, one trial), 10 (CA, one trial), and 11 (ID, WA, two trials each), and six trials on pear in Zones 1 (NY, one trial), 10 (CA, two trials), and 11 (ID, two trials; WA, one trial).

At 14 of the test sites (nine apple/five pear), one untreated control and one treated plot (Treatment 2) were established, with the treated plot receiving applications consisting of either concentrated or dilute spray volumes of 50-100 or 100-400 gallons per acre (GPA), respectively.  At the four remaining test sites (three apple and one pear), which were located in zones where only one trial per crop was to be conducted, one untreated control and side-by-side treated plots were established, with the treated plots receiving either the concentrate (Treatment 2) or dilute (Treatment 3) spray volume regime, described above.

At each site, the treated plots received three foliar airblast applications of metrafenone (2.5 lb ai/gal SC, BASF formulation code BAS 560 03 F) targeting roughly 0.3 lb ai/A/application (0.336 kg ai/ha/application), with a nominal 7-day RTI, resulting in a total rate of roughly 0.9 lb ai/A (1.0 kg ai/ha/season).  The actual application rate ranged from 0.29-0.31 lb ai/A/application, with 5- to 9-day RTIs, for a total rate of 0.89-0.92 lb ai/A (1.00-1.03 kg ai/ha/season).  The applications were made in approximately 59-86 GPA of water (552-804 L/ha) for concentrate spray volumes and approximately 101-257 GPA of water (945-2404 L/ha) for dilute spray volumes using ground (airblast) equipment.  An adjuvant (non-ionic surfactant) was included in the spray mixture for each application.  Single control and duplicate treated apple and pear RAC samples (fruit) were harvested at normal crop maturity 6- to 7- and 13- to 16-day PHIs at all test sites.  At one pear and two apple test sites, additional treated samples were collected at PHIs of 0, 3-4, and 21 days to examine residue decline.  

TABLE 5.3.1.1	Summary of Residue Data from Pome Fruit Field Trials with Metrafenone.
                                    Matrix
                             Total Use Rate +- 5%
                              kg ai/ha (lb ai/A)
                                 Spray Volume
                                     (GPA)
                                  PHI (Days)
                            Residue Levels (ppm)[1]
                                       
                                       
                                       
                                       
                                       n
                                     Min.
                                     Max.
                                    LAFT[2]
                                    HAFT[2]
                                    Median
                                       
                                     Mean
                                       
                                     Std.
                                     Dev.
                                     Apple
                                    (Fruit)
                                      1.0
                                     (0.9)
                                  (50-100)[3]
                                      6-7
                                       7
                                     0.07
                                     0.85
                                     0.08
                                     0.76
                                     0.23
                                     0.31
                                     0.23
                                       
                                       
                                       
                                     13-16
                                       7
                                     0.04
                                     0.57
                                     0.05
                                     0.54
                                     0.20
                                     0.22
                                     0.16
                                       
                                      1.0
                                     (0.9)
                                 (100-400)[4]
                                      6-7
                                       8
                                     0.13
                                     0.60
                                     0.14
                                     0.54
                                     0.29
                                     0.31
                                     0.15
                                       
                                       
                                       
                                     13-15
                                       8
                                     0.09
                                     0.49
                                     0.10
                                     0.45
                                     0.25
                                     0.27
                                     0.13
                                       
                                      1.0
                                     (0.9)
                                     Both
                                   (50-400)
                                      6-7
                                      15
                                     0.07
                                     0.85
                                     0.08
                                     0.76
                                     0.23
                                     0.31
                                     0.19
                                       
                                       
                                       
                                     13-16
                                      15
                                     0.04
                                     0.57
                                     0.05
                                     0.54
                                     0.20
                                     0.25
                                     0.14
                                     Pear
                                    (Fruit)
                                      1.0
                                     (0.9)
                                  (50-100)[3]
                                      6-7
                                       4
                                     0.13
                                     0.43
                                     0.16
                                     0.41
                                     0.29
                                     0.29
                                     0.13
                                       
                                       
                                       
                                     13-14
                                       4
                                     0.08
                                     0.36
                                     0.10
                                     0.33
                                     0.22
                                     0.22
                                     0.12
                                       
                                      1.0
                                     (0.9)
                                 (100-400)[4]
                                       7
                                       3
                                     0.12
                                     0.52
                                     0.14
                                     0.48
                                     0.41
                                     0.34
                                     0.18
                                       
                                       
                                       
                                      14
                                       3
                                     0.09
                                     0.43
                                     0.09
                                     0.37
                                     0.28
                                     0.25
                                     0.14
                                       
                                      1.0
                                     (0.9)
                                     Both
                                   (50-400)
                                      6-7
                                       7
                                     0.12
                                     0.52
                                     0.14
                                     0.48
                                     0.39
                                     0.31
                                     0.14
                                       
                                       
                                       
                                     13-14
                                       7
                                     0.08
                                     0.43
                                     0.09
                                     0.37
                                     0.28
                                     0.23
                                     0.12
                                All Pome Fruits
                                      1.0
                                     (0.9)
                                     Both
                                   (50-400)
                                      6-7
                                      22
                                     0.07
                                     0.85
                                     0.08
                                     0.76
                                     0.27
                                     0.31
                                     0.17
                                       
                                       
                                       
                                     13-16
                                      22
                                     0.04
                                     0.57
                                     0.05
                                     0.54
                                     0.21
                                     0.24
                                     0.13
1. Except for sample min/max, values reflect per trial averages; n = number of field trials.  
2. LAFT = Lowest Average Field Trial value; HAFT = Highest Average Field Trial value.  
3. Concentrate spray.  
4. Dilute spray.  

The residues of parent metrafenone in apple and pear RAC samples were quantitated using an LC/MS/MS multi-residue QuEChERS method (BASF Study #398340).  The method was successfully validated on apples in conjunction with this study prior to analysis of the field samples.  Acceptable concurrent method recovery data for pome fruit RAC samples were also obtained for metrafenone.  The validated LOQ for residues of metrafenone in pome fruits RAC samples was 0.01 ppm.  The LOD was 0.003 ppm.

The pome fruits RAC samples were stored frozen for a maximum of 734 days (24 months) from collection to extraction for analysis.  The interval between extraction and analysis was 0-1 day.  Adequate storage stability data for metrafenone are available to support the storage conditions and intervals incurred by the pome fruit residue samples in this study.

The results from these trials are summarized in Table 5.3.1.1, above, and show that following the last of three foliar airblast applications of metrafenone at roughly 0.3 lb ai/A/application, with 5- to 9-day RTIs, residues of metrafenone (and per trial averages) were 0.07-0.85 (0.08-0.76) ppm (concentrate spray) and 0.13-0.60 (0.14-0.54) ppm (dilute spray) in 30 treated apple samples harvested at a 6- or 7-day PHI.  At the same treatment rate and RTIs, metrafenone residues (and per trial averages) were 0.04-0.57 (0.05-0.54) ppm (concentrate spray) and 0.09-0.49 (0.10-0.45) ppm (dilute spray) in 30 treated apple samples collected at a 13- to 16-day PHI.

After three foliar airblast applications of metrafenone at roughly 0.3 lb ai/A/application, with 7- to 8-day RTIs, residues of metrafenone (and per trial averages) were 0.13-0.43 (0.16-0.41) ppm (concentrate spray) and 0.12-0.52 (0.14-0.48) ppm (dilute spray) in 14 treated pear samples harvested at a 6- or 7-day PHI.  At the same treatment rate and RTIs, metrafenone residues (and per trial averages) were 0.08-0.36 (0.10-0.33) ppm (concentrate spray) and 0.09-0.43 (0.09-0.37) ppm (dilute spray) in 14 treated pear samples collected at a 13- or 14-day PHI.

No substantial differences in metrafenone residues were observed between the concentrate and dilute spray applications.  Data from the residue decline sites indicate that metrafenone residues in pome fruits declined with increasing PHIs (results not shown here; see the DER for MRID #49055901 for further details).  

Pome Fruit Conclusions:  The results have shown that the maximum residues of metrafenone in pome fruits (apple and pear fruit RAC samples) following three foliar airblast applications of the 2.5 lb ai/gal SC formulation using dilute or concentrate spray volumes and totaling roughly 0.9 lb ai/A/season were 0.85 ppm at a 6- to 7-day PHI and 0.57 ppm at a 13- to 16-day PHI.  There were no substantial differences in the residues of metrafenone between the application spray volume treatments.  Data from the residue decline tests indicated that metrafenone residues in pome fruits declined with increasing PHIs.  The maximum metrafenone residues in pome fruits are within a factor of 5 of each other (0.85 and 0.52 ppm for apple and pear, respectively, at the targeted 7+-1 day PHI); therefore, the residues are within the EPA guidelines for the establishment of a group tolerance in crop group 11-10 (pome fruits). 

An acceptable method was used for residue quantitation, and adequate storage stability data are available to support the sample storage conditions and durations.  

Fruiting Vegetables, Tomato (MRID #49119108):  BASF has submitted field trial data for metrafenone (BAS 560 F) on tomato from a total of 18 trials conducted during the 2010-2011 growing seasons in NAFTA Growing Zones 1 (NY, one trial), 2 (GA, NC, one trial each), 3 (FL, two trials), 5 (OH, MI, one trial each), and 10 (NM and AZ, one trial each; CA, nine trials).  HED has determined that one trial pair (-CA123 and  - CA127) should be considered replicates; the above field trial distribution incorporates this conclusion.  

Each test location included one treated and one untreated plot.  At each site, the treated plot received three broadcast or directed foliar applications (except as noted below for the trial located in AZ) of metrafenone (2.5 lb ai/gal SC, BASF formulation code BAS 560 03 F) targeting 0.30 lb ai/A/application (0.336 kg ai/ha/application), with a nominal 7-day RTI, resulting in a total rate of 0.90 lb ai/A (1.0 kg ai/ha/season).  The actual application rate was 0.29-0.33 lb ai/A/application, with a 6- to 8-day RTI, for a total rate of 0.89-0.95 lb ai/A (0.999-1.066 kg ai/ha/season).  At the trial in AZ, in order to allow the fruit to develop further and provide adequate samples for residue analysis, four foliar sprays of metrafenone at 0.30-0.32 lb ai/A/application were made, with a 7- or 8-day RTI, totalling 1.23 lb ai/A (1.38 kg ai/ha/season).  All applications were made in approximately 31-90 GPA of water (286-841 L/ha) using ground equipment.  An adjuvant was included in the spray mixture for each application.  At all test sites tomato RAC samples (fruit) were harvested at normal crop maturity, at a 0 day PHI, after the spray had dried on the fruit, and again at a 6-8 day PHI.  At two test sites (Trial CA124 and FL38), additional treated samples were collected 1, 3, 9-10 and 12-14 day PHI to examine residue decline.  

The residues of parent metrafenone in tomato RAC samples were quantitated using an LC/MS/MS multi-residue QuEChERS method (BASF Study #398340).  Sample analysis was conducted by Pyxant Labs (Colorado Springs, CO).  The method was successfully validated on tomato in conjunction with this study prior to analysis of the field samples.  Acceptable concurrent method recovery data for tomato RAC samples were also obtained for metrafenone.  The validated LOQ for residues of metrafenone in tomato RAC samples was 0.01 ppm.  The estimated method LOD was reported as 0.001 ppm, or approximately 10% of the LOQ.  The calculated LOD and LOQ for metrafenone in tomato fruit were 0.001 and 0.004 ppm, respectively.

The tomato RAC samples were stored frozen for 303-730 days (approximately 10-24 months) from collection to extraction for analysis.  Adequate storage stability data for metrafenone are available to support the storage conditions and durations incurred by the tomato residue samples in this study.

As summarized in Table 5.3.1.2, below, the results from these trials show that following the last of three or four foliar applications of metrafenone at roughly 0.3 lb ai/A/application, with 6- to 8-day RTIs, residues of metrafenone (and per trial averages) were 0.041-0.452 (0.069-0.427) ppm in 38 treated tomato samples harvested at a 0-day PHI and <0.01-0.188 (<0.011-0.163) ppm in 38 treated tomato samples harvested at a 6-8 day PHI.  Data from the residue decline sites indicate that metrafenone residues in tomato generally declined with increasing PHIs. 

TABLE 5.3.1.2	Summary of Residue Data from Tomato Field Trials with Metrafenone
                                   Commodity
                                Total Use Rate
                               lb ai/A (g ai/ha)
                                 PHI (Days)[2]
                            Residue Levels (ppm)[1]
                                       
                                       
                                       
                                     n[3]
                                     Min.
                                     Max.
                                    LAFT[4]
                                    HAFT[4]
                                    Median
                                     Mean
                                   Std. Dev.
                                    Tomato
                                    (Fruit)
                                  0.891-1.234
                                  (999-1383)
                                       0
                                      18
                                    0.0409
                                     0.452
                                    0.0694
                                     0.427
                                     0.110
                                     0.164
                                     0.094
                                       
                                  0.910-0.922
                                (1020-1033)[5]
                                       1
                                       2
                                    0.0427
                                    0.0865
                                    0.0541
                                    0.0721
                                    0.0631
                                    0.0631
                                     NA[6]
                                       
                                       
                                       3
                                       2
                                    0.0512
                                    0.0830
                                    0.0572
                                    0.0748
                                    0.0660
                                    0.0660
                                      NA
                                       
                                  0.891-1.234
                                  (999-1383)
                                      6-8
                                      18
                                   <0.01
                                     0.188
                                  <0.0107
                                     0.163
                                    0.0860
                                    0.0770
                                    0.0446
                                       
                                  0.910-0.922
                                (1020-1033)[5]
                                     9, 10
                                       2
                                    0.0149
                                    0.0719
                                    0.0187
                                    0.0536
                                    0.0362
                                    0.0362
                                      NA
                                       
                                       
                                    12, 14
                                       2
                                    0.0138
                                    0.0327
                                    0.0166
                                    0.0247
                                    0.0207
                                    0.0207
                                      NA
      1. Except for sample min/max, values reflect per trial averages.
2. The first harvest was on the day of the last application (0-day PHI) at all trials.  The second harvest was 6 to 8 days after the last application (6- to 8-day PHI) at all trials, except field trials  - CA124 and  - FL38.  At field trial  - CA124, a decline study was conducted with the last application 0, 1, 3, 6, 10 and 12 days before harvest (0- to 12-day PHI). At field trial  - FL38, a decline study was conducted with the last application 0, 1, 3, 7, 9 and 14 days before harvest (0- to 14-day PHI).
3. n = number of field trials.
      4. LAFT = Lowest Average Field Trial value; HAFT = Highest Average Field Trial value.
      5. Data from the two residue decline trials.
      6. NA = Not Applicable.

Fruiting Vegetables, Pepper (MRID #49119107):  BASF has submitted field trial data for metrafenone (BAS 560 F) on pepper from a total of eight trials conducted during the 2010 growing season:  five on bell pepper varieties in NAFTA Growing Zones 2 (GA, one trial), 3 (FL, one trial), 5 (IL, one trial), 6 (OK, one trial) and 10 (CA, one trial) and three on non-bell pepper varieties in NAFTA Growing Zones 2 (GA, one trial), 8 (KS, one trial) and 10 (CA, one trial).  HED has determined that one trial pair (R100014 and R100019) should be considered replicates; the above field trial distribution incorporates this conclusion. 

Each test location included one treated and one untreated plot.  At each site, the treated plot received three broadcast foliar applications of metrafenone as an SC formulation, targeting 0.30 lb ai/A/application (0.336 kg ai/ha/application), with a nominal 7-day RTI, resulting in a total rate of 0.90 lb ai/A (1.0 kg ai/ha/season).  The actual application rate was 0.29-0.31 lb ai/A/application, with a 7-day RTI, for a total rate of 0.88-0.91 lb ai/A (0.991-1.017 kg ai/ha/season).  The applications were made in approximately 21-31 GPA of water (200-286 L/ha) using ground equipment.  A nonionic surfactant (NIS) adjuvant was included in the spray mixture for each application.  

Pepper RAC samples (fruit) were harvested at normal crop maturity, at a 0-day PHI at all test sites, after the spray had dried on the fruit, and again at a 7 day PHI.  At one test site (Trial R100014, CA), additional treated samples were collected at 3, 10 and 14 day PHIs to examine residue decline.  

The residues of parent metrafenone in pepper RAC samples were quantitated using an LC/MS/MS multi-residue QuEChERS method (BASF Study #398340, reported as Method #R00033).  Sample analysis was conducted by Pyxant Labs (Colorado Springs, CO).  The method was successfully validated on pepper in conjunction with this study prior to analysis of the field samples.  Acceptable concurrent method recovery data for pepper RAC samples were also obtained for metrafenone.  The validated LOQ for residues of metrafenone in pepper RAC samples was 0.01 ppm.  The method LOD was reported as 0.001 ppm, or 10% of the LOQ.  

The pepper RAC samples were stored frozen for 671-764 days (approximately 22-25 months) from collection to extraction for analysis, and were analyzed within 16 days of extraction.  Adequate storage stability data for metrafenone are available to support the storage conditions and durations incurred by the pepper residue samples in this study.

As summarized in Table 5.3.1.3, below, the results from these trials show that following the last of three foliar applications of metrafenone at roughly 0.3 lb ai/A/application, with 7-day RTIs, residues of metrafenone (and per trial averages) were 0.067-0.667 (0.081-0.498) ppm in 18 treated pepper samples harvested at a 0-day PHI and were 0.062-0.296 (0.065-0.295) ppm in 18 treated pepper samples harvested at a 7-day PHI.  

The maximum residues were observed in the non-bell pepper cultivars, but were at relatively similar levels to those observed in the bell-pepper cultivars:  Maximum metrafenone residues (and maximum per trial averages) for bell pepper varieties were 0.508 (0.417) ppm at the 0-day PHI and 0.271 (0.221) ppm at the 7-day PHI, and for non-bell pepper varieties, 0.667 (0.498) ppm at the 0-day PHI and 0.296 (0.295) ppm at the 7-day PHI.  Data from the residue decline site indicate that metrafenone residues in pepper declined with increasing pre-harvest intervals (results not shown here; see the DER for MRID #49119107 for further details). 

TABLE 5.3.1.3	Summary of Residue Data from Pepper Field Trials with Metrafenone
                                   Commodity
                               Total Appl. Rate
                               lb ai/A (g ai/ha)
                                  PHI (days)
                            Residue Levels (ppm)[1]
                                       
                                       
                                       
                                       n
                                     Min.
                                     Max.
                                    LAFT[2]
                                    HAFT[2]
                                    Median
                                     Mean
                                   Std. Dev.
                                  Bell Pepper
                                    (Fruit)
                                  0.884-0.907
                                  (991-1017)
                                       0
                                       5
                                     0.112
                                     0.508
                                     0.148
                                     0.417
                                     0.270
                                     0.297
                                     0.113
                                       
                                       
                                       7
                                       5
                                    0.0828
                                     0.271
                                    0.0991
                                     0.221
                                     0.163
                                     0.158
                                    0.0506
                            Non-bell Pepper (Fruit)
                                       
                                       0
                                       3
                                    0.0665
                                     0.667
                                    0.0813
                                     0.498
                                     0.353
                                     0.311
                                     0.212
                                       
                                       
                                       7
                                       3
                                    0.0622
                                     0.296
                                    0.0649
                                     0.295
                                     0.144
                                     0.168
                                     0.117
                            Combined Pepper (Fruit)
                                       
                                       0
                                       8
                                    0.0665
                                     0.667
                                    0.0813
                                     0.498
                                     0.312
                                     0.302
                                     0.142
                                       
                                       
                                       7
                                       8
                                    0.0622
                                     0.296
                                    0.0649
                                     0.295
                                     0.154
                                     0.162
                                    0.0734
      1. Except for sample min/max, values reflect per trial averages; n = number of field trials
      2. LAFT = Lowest Average Field Trial Value; HAFT = Highest Average Field Trial value.

Fruiting Vegetables Conclusions:  The results have shown that the maximum residues of metrafenone in fruiting vegetables (tomato and pepper RAC samples) following three foliar broadcast applications of the 2.5 lb ai/gal SC formulation totaling roughly 0.9 lb ai/A/season were 0.667 ppm at a 0-day PHI.  Data from the residue decline tests indicated that metrafenone residues in fruiting vegetables declined with increasing PHIs.  The maximum metrafenone residues in fruiting vegetables are within a factor of 5 of each other (0.452 and 0.667 ppm for tomato and pepper, respectively, at the targeted 0-day PHI); therefore, the residues are within the EPA guidelines for the establishment of a group tolerance in crop group 8-10 (fruiting vegetables).  

An acceptable method was used for residue quantitation, and adequate storage stability data are available to support the sample storage conditions and durations.  

Cherry (MRID #49145402):  IR-4 submitted field trial residue data for metrafenone on cherry.  Fourteen cherry field trials (9 sweet cherry trials, and 5 tart cherry trials) were conducted in the United States and Canada during the 2010 growing season in NAFTA Growing Zones 1 (NY; 1 trial), 5A (MI; 2 trials), 5 (ON; 3 trials), 9 (CO; 1 trial), 10 (CA; 2 trials) and 11 (ID, WA, and BC; 5 trials).  HED has concluded that three trials conducted in Zone 5 should be considered replicates for purposes of OCSPP Residue Chemistry Test Guideline 860.1500 data requirements.  The above field trial distribution incorporates this conclusion.  

Each trial consisted of one untreated and one treated plot.  At each trial location, the treated plot received two foliar directed applications of a 2.5 lb ai/gal SC formulation of metrafenone (BAS560 03 F SC) at 0.286-0.314 lb ai/A/application (321-352 g ai/ha/application) for a total seasonal rate of 0.575-0.626 lb ai/A (645-702 g ai/ha).  Applications were made at 6- to 9-day RTIs using ground equipment (airblast sprayer) in spray volumes of 105-189 GPA (984-1767 L/ha), except at the NY trial, where higher than normal temperatures accelerated maturation, and required that applications be initiated earlier than anticipated; the first application at this trial was made in a spray volume of 60.7 GPA (568 L/ha).  An NIS, methylated seed oil (MSO), crop oil concentrate (COC), or organo-silicone surfactant (OSS) was added to the spray mixtures for all applications.  Samples of cherries were harvested from all trial sites at PHIs of 6-8 and 13-15 days.  Additional cherry samples were collected from two trials at PHIs of 0, 3, 17 and 21 days to generate residue decline data.  

Samples of cherries were analyzed for residues of metrafenone using an LC/MS/MS method derived from QuEChERS Method #R00033.  The LOQ, determined as the LLMV, was 0.01 ppm.  The method was adequate for data collection, based on acceptable method validation and concurrent recovery data.  The fortification levels used in concurrent method recovery were adequate to bracket expected residue levels.  Concurrent recoveries were corrected for apparent residues in controls; residues in treated samples were not corrected for residues in controls.

Samples of cherries were transferred to a sample preparation facility for homogenization prior to shipment to the analytical laboratory.  Samples were stored frozen (-31 to -3°C at the field sites, <=-5°C at the sample preparation facility, and temperature unspecified at the analytical laboratory) from collection to analysis for 676-784 days (22.2-25.8 months).  Samples were analyzed within 2-9 days of extraction.  Adequate storage stability data are available to support the sample storage conditions and durations.

The results from these trials are summarized in Table 5.3.1.4, below.  Following two foliar directed applications of a 2.5 lb ai/gal SC formulation of metrafenone at a total rate of 0.575-0.626 lb ai/A (645-702 g ai/ha), residues (and per trial averages) of metrafenone in cherries harvested at PHIs of 6-8 days and 13-15 days, respectively, were 0.280-1.17 (0.317-1.16) and 0.117-0.704 (0.144-0.608) ppm.  It was noted that the highest residues in cherries harvested at the 6- to 8-day PHI were observed in samples from the NY trial, where the first application was made in a lower than targeted spray volume, and the highest residues in cherries harvested at the 13- to 15-day PHI were observed in samples from one of the replicate MI trials, where adjuvant rates were lower than expected.  At the residue decline trials, residues of metrafenone generally declined with increasing PHI in cherries (results not shown here; see the DER for MRID #49145402 for further details).  

TABLE 5.3.1.4	Summary of Residue Data from Cherry Field Trials with Metrafenone.
                                   Commodity
                                  Total Rate
                                    lb ai/A
                                   (g ai/ha)
                                  PHI (days)
                           Residue Levels  (ppm)[1]
                                       
                                       
                                       
                                       n
                                     Min.
                                     Max.
                                    LAFT[2]
                                    HAFT[2]
                                    Median
                                     Mean
                                   Std. Dev.
Cherry
                                  0.575-0.626
                                   (645-702)
                                      6-8
                                      14
                                     0.280
                                     1.17
                                     0.317
                                     1.16
                                     0.493
                                     0.547
                                     0.221


                                     13-15
                                      14
                                     0.117
                                     0.704
                                     0.144
                                     0.608
                                     0.340
                                     0.370
                                     0.146
1. Except for sample min/max, values reflect per trial averages; n = number of distinct field trials. 
2. LAFT = Lowest Average Field Trial; HAFT = Highest Average Field Trial.

Cherry Conclusions:  The submitted cherry field trial data are scientifically acceptable.  Following two foliar directed applications of a 2.5 lb ai/gal SC formulation of metrafenone at a total rate of 0.575-0.626 lb ai/A (645-702 g ai/ha), residues (and per trial averages) of metrafenone in cherries harvested at PHIs of 6-8 days and 13-15 days, respectively, were 0.280-1.17 (0.317-1.16) and 0.117-0.704 (0.144-0.608) ppm.  At the residue decline trials, residues of metrafenone generally decreased with increasing PHIs in cherries.  

An acceptable method was used for residue quantitation, and adequate storage stability data are available to support the sample storage conditions and durations.  

Hops (MRID #49145403):  IR-4 submitted field trial data for metrafenone on hops.  Five hops field trials were conducted in the United States and Canada during the 2010 growing season in NAFTA Growing Zones 5 (ON 1 trial), 5B (QC; 1 trial), 11 (ID and WA; 2 trials) and 12 (OR; 1 trial).  Examination of the field trial records indicates that there were sufficient differences between the trials that each trial constitutes a separate trial for purposes of OCSPP Residue Chemistry Test Guideline 860.1500 data requirements.   

Each trial consisted of one untreated plot and one treated plot.  At each trial location, the treated plot received two foliar directed applications of a 2.5 lb ai/gal SC formulation of metrafenone (BAS560 03 F SC) at 0.304-0.319 lb ai/A/application (341-358 g ai/ha/application) for a total seasonal rate of 0.609-0.635 lb ai/A (683-712 g ai/ha).  Applications were made at 6- to 8-day RTIs, except at the ON trial, where the second application was delayed due to a hurricane (10-day RTI).  Applications were made using ground equipment in spray volumes of 84.6-173.8 GPA (791-1626 L/ha).  An NIS, MSO, COC or OSS was added to the spray mixtures for all applications.  Samples of fresh hops cones were harvested by hand at maturity from all trials at a PHI of 1-4 days.  Samples designated for dried hops cones were dried per normal cultural practices at or near the field sites.  To assess residue decline in dried hops cones, additional samples were collected at PHIs of 0, 4, 7 and 14 days from the WA trial.  Additional samples were also collected at the ON trial at 0- and 1-day PHIs for a residue decline study that was terminated due to low yields.  

Samples were analyzed for residues of metrafenone using an LC/MS/MS method derived from QuEChERS Method #R00033.  The LOQ, determined as the LLMV, was 0.01 ppm in dried and fresh hops cones.  The analytical method was adequate for data collection, based on acceptable method validation and concurrent recovery data.  The fortification levels used in method validation and concurrent method recovery were adequate to bracket expected residue levels.  Concurrent recoveries were corrected for apparent residues in controls; residues in treated samples were not corrected for residues in controls.  

Samples were transferred to a sample preparation facility for homogenization prior to shipment to the analytical laboratory.  Samples were stored frozen (-42 to 4.2°F at the field sites, <=5°C at the preparation facility, and -29 to - 17°C at the analytical laboratory) from harvest to analysis for 754-819 days (24.8-26.9 months) for dried hops cones, and 752-778 days (24.7-25.6 months) for fresh hops cones.  Samples were analyzed within 1-7 days of extraction.  Adequate storage stability data are available to support the sample storage conditions and durations for residues of metrafenone.

The results from these trials are summarized in Table 5.3.1.5, below.  Following two foliar directed applications of the 2.5 lb ai/gal SC formulation of metrafenone at 0.609-0.635 lb ai/A (683-712 g ai/ha), residues (and per trial averages) of metrafenone in dried hops cones and fresh hops cones, respectively, harvested at 1- to 4-day PHIs were 15.72-158.8 (16.87-131.9) and 5.51-31.36 ppm.  It was noted that the highest residues in dried hops cones were observed in samples from the ON trial where the second application was delayed due to a hurricane and where, according to the petitioner, half of the crop was destroyed by insects between applications.  Excluding results for the ON trial (because the hops cones were not of commercial quality), the highest average residues observed were 23.52 ppm.  At the WA residue decline trial, residues of metrafenone in dried hops cones decreased with increasing PHI.  At the ON decline trial, residues decreased from the 0- to 1-day PHI, but the highest residues were observed in samples from the 2-day PHI (results not shown here; see the DER for MRID #49145403 for further details).  

It was noted that the highest residues in dried hops cones were observed in samples from the ON trial, where the second application was delayed due to a hurricane and where, according to the petitioner, half of the crop was destroyed by insects between applications.  There were several communications with the petitioner (IR-4) regarding the ON trial, and an outlier analysis (Grubbs test) was submitted by IR-4.  The outlier analysis was evaluated by HED (D421923; Bayazid Sarkar; 21 August 2014).  HED used a different approach for analyzing the data (the Grubbs test was conducted on transformed data because there was sufficient evidence to reject the assumption of normality), and ultimately concurred that the residue value obtained from the ON field trial constituted an outlier.  The results of the HED analysis were shared with the PMRA reviewers, who then agreed to exclude that residue value from the dataset input to the OECD tolerance calculation procedure.  Excluding results for the ON trial (the outlier), the highest average residue observed was 23.52 ppm.  On a final note regarding hops, HED's recommended tolerance includes the results from European field trials, even though the North American field trial data were adequate.  Using the combined data sets results in a greater likelihood that any future European and Canadian MRLs, and US tolerances will all be harmonized.

TABLE 5.3.1.5	Summary of Residue Data from Hops Field Trials with Metrafenone (MRID #49145403).
                                   Commodity
                                  Total Rate
                               lb ai/A (g ai/ha)
                                  PHI (days)
                      Metrafenone Residue Levels (ppm)[1]
                                       
                                       
                                       
                                       n
                                     Min.
                                     Max.
                                    LAFT[2]
                                    HAFT[2]
                                    Median
                                     Mean
                                  Std.  Dev.
Hops cones, dried
                                  0.609-0.635
                                   (683-712)
                                      1-2
                                       5
                                     15.72
                                     158.8
                                     16.87
                                     131.9
                                     21.50
                                     43.07
                                     48.59
Hops cones, fresh
                                  0.609-0.635
                                   (683-712)
                                      2-4
                                       5
                                    5.51[3]
                                   31.36[3]
                                    5.51[3]
                                   31.36[3]
                                    6.17[3]
                                   11.76[3]
                                   11.08[3]
1. Except for sample min/max, values reflect per trial averages; n = number of field trials. 
2. LAFT = Lowest Average Field Trial; HAFT = Highest Average Field Trial.
3. Only one sample per trial was analyzed; therefore sample min = LAFT, and sample max = HAFT. Statistical data are therefore reflective of individual sample residues rather than per trial mean residue values.

Hops (MRID #49145403) Conclusions:  The submitted hops field trial data are scientifically acceptable.  Following two foliar directed applications of the 2.5 lb ai/gal SC formulation of metrafenone at 0.609-0.635 lb ai/A (683-712 g ai/ha), residues (and per trial averages) of metrafenone in dried hops cones and fresh hops cones, respectively, harvested at 1- to 4-day PHIs were 15.72-158.8 (16.87-131.9) and 5.51-31.36 ppm.  It was noted that the highest residues in dried hops cones were observed in samples from the ON trial, where the second application was delayed due to a hurricane and where, according to the petitioner, half of the crop was destroyed by insects between applications.  Excluding results for the ON trial (because the hops cones were not of commercial quality, and the average residue from the trial was deemed an outlier via the Grubbs test), the highest average residues observed were 23.52 ppm.  At the WA residue decline trial, residues of metrafenone in dried hops cones decreased with increasing PHI.  At the ON decline trial, residues decreased from the 0- to 1-day PHI, but the highest residues were observed in samples from the 2-day PHI.

An acceptable method was used for residue quantitation, and the study is supported by adequate storage stability data.  

Hops (MRIDs #49145407 & -08):  IR-4 submitted crop field trial and processing study data for metrafenone on hops.  Six field trials were conducted in Germany during the 2009 (four trials; MRID #49145407) and 2010 (two trials; MRID #49145408) growing seasons.  Both studies reflected collection of fresh (green) and dried hops cones.  In the 2009 study dried hops cones from three trials were processed to yield the following processed commodities:  beer, brewer's yeast, extracted hops, and hops draff.  Because the processed commodities of hops are not considered significant food/feed commodities in the US, the results of the processing study are presented herein but are not discussed in detail.  

Each trial consisted of one untreated plot and one treated plot.  At each trial location, the treated plot received two foliar directed applications of a 4 lb ai/gal (500 g ai/L) SC formulation of metrafenone (BAS 560 02 F) at 0.279-0.321 lb ai/A/application (313-360 g ai/ha/application) for a total seasonal rate of 0.580-0.633 lb ai/A (650-710 g ai/ha).  Applications were made at 6- to 8-day RTIs using ground equipment in spray volumes of 335-388 GPA (3133-3625 L/ha) without an adjuvant.  Samples of fresh (green) hops cones were harvested at PHIs of 0, 1, 2-4, and 7-8 days.  Additional samples of green hops cones designated for dried hops cones were collected from the 2- to 4-day PHIs at each site and were dried in hops kilns. 

Samples were analyzed for residues of metrafenone using LC/MS/MS via BASF methods #535/1 (L0076/01) and #535/3 (L0076/03).  The methods are essentially identical.  The LOQ, determined as the LLMV, was 0.01 ppm in all sample matrices.  The analytical methods were adequate for data collection, based on acceptable method validation and concurrent recovery data.  The fortification levels used in method validation and concurrent method recovery were adequate to bracket expected residue levels.  Recoveries were corrected for apparent residues in controls; residues in treated samples were not corrected for residues in controls.  

Samples were stored frozen (<=-18°C at the field sites, preparation facility, and analytical laboratories) from harvest to analysis for 147-242 days (4.8-8.0 months) for green hops cones and 151-236 days (5.0-7.8 months) for dried hops cones.  Samples were analyzed within 1-2 days of extraction.  Adequate storage stability data are available to support the sample storage durations and conditions for residues of metrafenone.

The results from these trials are summarized in Table 5.3.1.6, below.  Following two foliar directed applications of the 4 lb ai/gal (500 g ai/L) SC formulation of metrafenone at 0.580-0.633 lb ai/A (650-710 g ai/ha), residues (and per trial averages) of metrafenone in green hops cones and dried hops cones, respectively, harvested at a 2- to 4-day PHI were 1.78-8.50 (1.78-8.50) and 13.3-34.4 (13.3-34.4) ppm.  At the residue decline trials, residues of metrafenone in green hops cones generally declined with increasing PHI in four of the six trials, but remained relatively stable in two trials from the 0-day PHI to 7-day PHI (results not shown here; see the DER for MRIDs #49145407 and -08 for further details).  

TABLE 5.3.1.6	Summary of Residue Data from Hops Field Trials with Metrafenone (MRIDs #49145407 & 49145408).
                                   Commodity
                                  Total Rate
                                    lb ai/A
                                   (g ai/ha)
                                  PHI (days)
                      Metrafenone Residue Levels (ppm)[1]
                                       
                                       
                                       
                                       n
                                     Min.
                                     Max.
                                    LAFT[2]
                                    HAFT[2]
                                    Median
                                     Mean
                                  Std.  Dev.
Hops cones, green
                                  0.580-0.633
                                   (650-710)
                                      2-4
                                       6
                                     1.78
                                     8.50
                                     1.78
                                     8.50
                                     3.57
                                     4.16
                                     2.31
Hops cones, dried
                                       
                                      2-4
                                       6
                                     13.3
                                     34.4
                                     13.3
                                     34.4
                                     22.8
                                     24.7
                                     8.98
1. Except for sample min/max, values reflect per trial averages; n = number of field trials. 
2. LAFT = Lowest Average Field Trial; HAFT = Highest Average Field Trial.

Hops (MRID #49145407 & -08) Conclusions:  Following two foliar directed applications of the 4 lb ai/gal (500 g ai/L) SC formulation of metrafenone at 0.580-0.633 lb ai/A (650-710 g ai/ha), residues (and per trial averages) of metrafenone in green hops cones and dried hops cones, respectively, harvested at a 2- to 4-day PHI were 1.78-8.50 (1.78-8.50) and 13.3-34.4 (13.3-34.4) ppm.  In the residue decline trials, residues of metrafenone in green hops cones generally declined with increasing PHI in four of the six trials, but remained relatively stable in two trials from the 0-day PHI to 7-day PHI.

Acceptable methods were used for quantitation of residues, and the study is supported by adequate storage stability data.  

Peach (MRID #49145401):  IR-4 submitted field trial residue data for metrafenone on peach.  Fourteen peach field trials were conducted in the United States and Canada during the 2011 growing season in NAFTA Growing Zones 1 (NY; 1 trial), 2 (NJ and NC; 4 trials), 4 (AR; 1 trial), 5A (MI; 1 trial), 5 (ON; 2 trials), 6 (TX; 1 trial), 10 (CA; 3 trials) and 11 (BC; 1 trial). HED has determined that two Zone 10 and two Zone 5 peach trials should be considered replicates for purposes of OCSPP Residue Chemistry Test Guideline 860.1500 data requirements.  The above field trial distribution incorporates this conclusion.

Each trial consisted of one untreated plot and one treated plot. At each trial location, the treated plot received two foliar directed applications of a 2.5 lb ai/gal SC formulation of metrafenone (BAS560 03 F SC) at 0.291-0.307 lb ai/A/application (326.2-344.2 g ai/ha/application) for a total seasonal rate of 0.583-0.610 lb ai/A (653.6-683.9 g ai/ha).  Applications were made at 6- to 8-day RTIs using ground equipment in spray volumes of 104-182 GPA (973-1701 L/ha).  An NIS, COC or OSS was added to the spray mixtures for all applications.  Samples of peaches were harvested at PHIs of 6-8 days and 13-15 days at all trial sites.  Additional samples of peaches were collected from two trials at PHIs of 0, 3, 15/17 and 17/21 days to generate residue decline data.

Samples of peaches were analyzed for residues of metrafenone using an LC/MS/MS method derived from a QuEChERS Method #R00033. The LOQ, determined as the LLMV, was 0.01 ppm.  The method was adequate for data collection, based on acceptable method validation and concurrent recovery data.  The fortification levels used in method validation and concurrent method recovery were adequate to bracket expected residue levels.  Concurrent recoveries and residues in the treated samples were not corrected for residues in controls.  

Samples were transferred to a sample preparation facility for homogenization prior to shipment to the analytical laboratory.  Samples were stored frozen (frozen at the field sites, <=-5°C at the sample preparation facility, and temperature unspecified at the analytical laboratory) from collection to analysis for 297-397 days (9.8-13.1 months).  Samples were analyzed within 0-15 days of extraction.  Adequate storage stability data are available to support the sample storage conditions and durations.

The results from these trials are summarized in Table 5.3.1.7, below.  Following two foliar directed applications of the 2.5 lb ai/gal SC formulation of metrafenone at 0.583-0.610 lb ai/A (653.6-683.9 g ai/ha), residues (and per trial averages) of metrafenone in peaches harvested at PHIs of 6-8 days and 13-15 days, respectively, were 0.041-0.520 (0.051-0.489) and 0.029-0.394 (0.035-0.355) ppm.  At the residue decline trials, residues of metrafenone in peaches declined with increasing PHI in peaches (results not shown here; see the DER for MRID #49145401 for further details).   

TABLE 5.3.1.7	Summary of Residue Data from Peach Field Trials with Metrafenone.
                                   Commodity
                                  Total Rate
                               lb ai/A (g ai/ha)
                                  PHI (days)
                            Residue Levels (ppm)[1]
                                       
                                       
                                       
                                       n
                                     Min.
                                     Max.
                                    LAFT[2]
                                    HAFT[2]
                                    Median
                                     Mean
                                  Std.  Dev.
Peach
                                  0.583-0.610
                                 (653.6-683.9)
                                      6-8
                                      14
                                     0.041
                                     0.520
                                     0.051
                                     0.489
                                     0.208
                                     0.211
                                     0.098

                                       
                                     13-15
                                      14
                                     0.029
                                     0.394
                                     0.035
                                     0.355
                                     0.142
                                     0.143
                                     0.075
1. Except for sample min/max, values reflect per trial averages; n = number of distinct field trials. 
2. LAFT = Lowest Average Field Trial; HAFT = Highest Average Field Trial.

Peach Conclusions:  Following two foliar directed applications of the 2.5 lb ai/gal SC formulation of metrafenone at 0.583-0.610 lb ai/A (653.6-683.9 g ai/ha), residues (and per trial averages) of metrafenone in peaches harvested at PHIs of 6-8 days and 13-15 days, respectively, were 0.041-0.520 (0.051-0.489) and 0.029-0.394 (0.035-0.355) ppm.  At the residue decline trials, residues of metrafenone in peaches declined with increasing PHI in peaches.

An acceptable method was used for residue quantitation, and adequate storage stability data are available to support the sample storage conditions and durations.  

Cucurbits (MRIDs #49145404, -05 & -06):  IR-4 has submitted field trial residue data for metrafenone on cantaloupe, cucumber and summer squash, the representative commodities of the cucurbit vegetable group 9, from 32 crop field trials conducted in the United States and Canada during the 2010 growing season.  Twelve cantaloupe trials were conducted in NAFTA Growing Zones 2 (GA and MD; 2 trials), 5 (OH and ON; 2 trials); 5B (QC; 1 trial), 6 (TX; 2 trials) and 10 (AZ, CA, and NM; 5 trials); six cucumber trials were conducted in Zones 2 (GA; 2 trials), 3 (FL, 1 trial), 5 (IA and MN; 2 trials) and 6 (OK; 1 trial); and fourteen squash trials were conducted in Zones 1 (NY; 1 trial), 2 (MD, NC, and SC; 3 trials), 3 (FL; 1 trial), 5 (ON; 2 trials), 5B (QC; 1 trial), 6 (TX; 2 trials), 10 (AZ and CA; 2 trials), 11 (WA; 1 trial) and 12 (BC; 1 trial).  Examination of the field trial records indicates that there were sufficient differences between the trials that each trial constitutes a separate trial for purposes of OCSPP Residue Chemistry Test Guideline 860.1500 data requirements.

Each trial consisted of one untreated and one treated plot.  At each trial location, the treated plot received three foliar broadcast or directed applications of a 2.5 lb ai/gal SC formulation of metrafenone (BAS560 03 F SC) at 0.286-0.316 lb ai/A/application (0.321-0.354 kg ai/ha/application) for a total seasonal rate of 0.884-0.936 lb ai/A (0.993-1.049 kg ai/ha).  Applications were made at 6-to 9-day RTIs using ground equipment in spray volumes of 29.2-74.2 GPA (273-693 L/ha).  At one ON squash trial, the first application was made in error at half the target application rate (0.124 lb ai/A; 0.139 kg ai/ha); therefore, the test substance was re-applied 3 days later at 0.312 lb ai/A (0.350 kg ai/ha), and the remaining two applications were made according to the study protocol.  This trial received a total of four applications for a total rate of 1.042 lb ai/A (1.168 kg ai/ha).  An NIS, MSO, COC or OSS was added to the spray mixtures for all applications.  Samples of cantaloupe, cucumber and summer squash were harvested at a PHI of 0 days.  Additional samples were collected from two trials for cantaloupe at PHIs of 1, 3, 7, 10/11 and 13/15 days, one trial for cucumber at PHIs of 1, 3, 7 and 10 days, and one trial for summer squash at PHIs of 1, 4, 6, 9 and 13 days to generate residue decline data.

Samples were analyzed for residues of metrafenone using an LC/MS/MS method derived from QuEChERS Method #R00033.  The LOQ, determined as the LLMV, was 0.01 ppm for metrafenone in all crop matrices.  The method was adequate for data collection, based on acceptable method validation and concurrent recovery data.  The fortification levels used in method validation and concurrent method recovery were adequate to bracket expected residue levels.  Concurrent recoveries were corrected for apparent residues in controls for cantaloupe and summer squash, but recoveries were not corrected for apparent residues in controls for cucumber.  Residues in treated samples were not corrected for residues in controls.

Samples of cucurbit vegetables were transferred to a sample preparation facility for homogenization prior to shipment to the analytical laboratory.  Samples of cucurbit vegetables were stored frozen (frozen at the field sites, <-10 or -5°C at the sample preparation facility, and -29 to -10°C at the analytical laboratories) from collection to analysis for 450-842 days (14.8-27.7 months).  Samples were analyzed within 0-2 days of extraction.  Adequate storage stability data are available to support the sample storage conditions and durations.

The results from these trials are summarized in Table 5.3.1.8, below.  Following three (or four) foliar broadcast or directed applications of a 2.5 lb ai/gal SC formulation of metrafenone (BAS560 03 F SC) at a total seasonal rate of 0.884-1.042 lb ai/A (0.993-1.168 kg ai/ha), residues (and per trial averages) of metrafenone in cantaloupe, cucumber and summer squash harvested at a 0-day PHI, were 0.038-0.332 (0.038-0.282), 0.046-0.168 (0.053-0.157), and 0.067-0.357 (0.072-0.305) ppm, respectively.  It was noted that at the one summer squash trial in which four applications were made for a total seasonal rate of 1.042 lb ai/A, residues were consistent with those observed at other trials, and are included in the values reported above.  At the residue decline studies, residues of metrafenone generally declined with increasing PHI in cantaloupe, cucumbers and summer squash (results not shown here; see the DER for MRIDs #4914540, -05 and -06 for further details).  

TABLE 5.3.1.8	Summary of Residue Data from Cuburbit Field Trials with Metrafenone.
                                   Commodity
                                  Total Rate,
                                    lb ai/A
                                  (kg ai/ha)
                                  PHI (days)
                               Residues (ppm)[1]
                                       
                                       
                                       
                                       n
                                     Min.
                                     Max.
                                    LAFT[2]
                                    HAFT[2]
                                    Median
                                     Mean
                                   Std. Dev.
Cantaloupe
                                  0.886-0.936
                                 (0.993-1.049)
                                       0
                                      12
                                     0.038
                                     0.332
                                     0.038
                                     0.282
                                     0.143
                                     0.152
                                     0.068
Cucumber
                                  0.894-0.920
                                 (1.002-1.035)
                                       
                                       6
                                     0.046
                                     0.168
                                     0.053
                                     0.157
                                     0.099
                                     0.105
                                     0.038
Summer squash
                                  0.884-1.042
                                 (0.993-1.168)
                                       
                                      14
                                     0.067
                                     0.357
                                     0.072
                                     0.305
                                     0.127
                                     0.162
                                     0.079
1. Except for sample min/max, values reflect per trial averages; n = number of field trials. 
2. LAFT = Lowest Average Field Trial; HAFT = Highest Average Field Trial.

Cucurbits Conclusions:  The submitted cucurbit vegetable field trial data are scientifically acceptable.  Following three (or four) foliar broadcast or directed applications of a 2.5 lb ai/gal SC formulation of metrafenone (BAS560 03 F SC) at a total seasonal rate of 0.884-1.042 lb ai/A (0.993-1.168 kg ai/ha), residues (and per trial averages) of metrafenone in cantaloupe, cucumber and summer squash harvested at a 0-day PHI, were 0.038-0.332 (0.038-0.282), 0.046-0.168 (0.053-0.157), and 0.067-0.357 (0.072-0.305) ppm, respectively.  It was noted that residues at the one summer squash trial in which four applications were made for a total seasonal rate of 1.042 lb ai/A, residues were consistent with those observed at other trials, and are included in the values reported above.  In the residue decline studies, residues of metrafenone generally declined with increasing PHI in cantaloupe, cucumbers and summer squash.

An acceptable method was used for residue quantitation, and the study is supported by adequate storage stability data.

5.3.2	Field Rotational Crops (860.1900)

A study investigating field accumulation in rotational crops has not been conducted with metrafenone, and is not required.  

5.3.3	Processed Food and Feed (860.1520)

Apple (MRID #49055902):  An apple processing study was conducted to determine the potential for concentration of residues of metrafenone in apple processed fractions.  Two trials were conducted to generate samples for processing in NAFTA Growing Zones 1 (NY, one trial) and 11 (ID, one trial) during the 2010 growing season.

At each test location, one untreated control and one treated plot were established.  The treated plots received three foliar airblast applications of metrafenone (2.5 lb ai/gal SC) applying at roughly 1.68 kg ai/ha/application (1.5 lb ai/A/application), with a nominal 7-day RTI, resulting in a total exaggerated rate of roughly 5.0 kg ai/ha (4.5 lb ai/A/season).  The actual application rates were 1.67-1.71 kg ai/ha/application (1.49-1.53 lb ai/A/application), with 6- or 7-day RTIs, for a total rate of 5.1 kg ai/ha/season (4.52-4.53 lb ai/A/season).  The applications were made in 80-102 GPA of water (748-954 L/ha) using ground equipment (airblast sprayers).  An NIS adjuvant was added to the spray mixture for all applications.  

At each site, one untreated control and one treated bulk apple RAC sample were harvested at normal crop maturity, at a 6- or 7-day PHI.  The samples were shipped to the processing facility, ACDS Research (North Rose, NY), where they were processed, according to simulated commercial procedures, into processed apple commodities (juice, wet pomace, apple sauce, canned apples, and dried apples).  Adequate descriptions of the processing procedures were provided, including material balance summaries.

The residues of parent metrafenone in apple RAC and processed commodity samples were quantitated using an LC/MS/MS multi-residue QuEChERS method (BASF Study #398340).  The method was successfully validated on dried apples in conjunction with this study prior to analysis of the field samples.  Acceptable concurrent method recovery data for each apple matrix were also obtained for metrafenone.  The validated LOQ for metrafenone residues in apple RAC and processed commodity samples was 0.01 ppm.  The method LOD was 0.003 ppm.

The processing residue results are summarized in Table 5.3.3.1, below.  After three exaggerated rate applications of metrafenone (2.5 lb ai/gal SC) to apples at a rate of 1.68 kg ai/ha/application (roughly 5.0 kg ai/ha/season), metrafenone residues were 1.46 ppm (New York) and 2.17 ppm (Idaho) in two treated apple RAC samples (whole fruit) harvested at a 6- or 7-day PHI.  The apple RAC samples were separately processed, using simulated commercial processing procedures, into the currently EPA-regulated commodities of apple, wet pomace and juice.  Apple sauce, canned apples, and dried apples were also generated and collected for analysis.

Metrafenone residues were 0.28 ppm in juice, 1.88 ppm in wet pomace, 7.01 ppm in apple sauce, 0.20 ppm in canned apples, and 1.05 ppm in dried apples collected from New York.  Metrafenone residues were 0.49 ppm in juice, 2.37 ppm in wet pomace, 8.94 ppm in apple sauce, 0.23 ppm in canned apples, and 0.85 ppm in dried apples collected from Idaho.

A comparison of the residues in the RAC samples with those in each processed fraction indicated that metrafenone residues do not concentrate (processing factors <1X to 1.2X, average of two trials) in any apple processed commodities, with the exception of apple sauce, in which the processing factor was 4.5X on average, with individual results of 4.8X and 4.1X calculated from the samples collected at the sites in New York and Idaho, respectively.  

The processing factors calculated in this study were less than the maximum theoretical concentration factor of >14X for apples (based on the maximum theoretical/experimental concentration factor; OCSPP 860.1520, Table 1), and 14X for apple pomace (based on the maximum observed experimental concentration factor; OCSPP 860.1520, Table 4).
 
The apple RAC and processed commodity samples were stored frozen for a maximum of 683 days (roughly 22 months) from collection to extraction for analysis.  Samples were analyzed on the day of extraction.  Processing was completed within 4 days of harvest.

Table 5.3.3.1	Metrafenone Residues in Apple Processed Fractions.
                                   Trial ID
                              (City, State/Year)
                                Total Use Rate
                                    lb ai/A
                                  (kg ai/ha)
                                      PHI
                                    (days)
                                   Processed
                                   Commodity
                                  Metrafenone
                                Residues (ppm)
                                  Processing
                                   Factor[1]
                                    Average
                               Processing Factor
R080753
(Alton, NY/2010)

4.52
(5.06)

                                       7
                               Whole Fresh Fruit
                                     1.46
                                     NA[2]
                                       

                                       
                                       
                                  Juice (raw)
                                     0.276
                                     0.189
                                  <1 (0.2)

                                       
                                       
                                  Wet Pomace
                                     1.88
                                     1.29
                                      1.2

                                       
                                       
                                  Apple Sauce
                                     7.01
                                     4.80
                                      4.5

                                       
                                       
                                 Canned Apples
                                     0.204
                                     0.140
                                  <1 (0.1)

                                       
                                       
                                 Dried Apples
                                     1.05
                                     0.719
                                  <1 (0.6)
R080754
(Weiser, ID/2010)

4.53
(5.07)
                                       6
                               Whole Fresh Fruit
                                     2.17
                                      NA
                                       
                                       
                                       
                                       
                                  Juice (raw)
                                     0.489
                                     0.225
                                       
                                       
                                       
                                       
                                  Wet Pomace
                                     2.37
                                     1.09
                                       
                                       
                                       
                                       
                                  Apple Sauce
                                     8.94
                                     4.12
                                       
                                       
                                       
                                       
                                 Canned Apples
                                     0.226
                                     0.104
                                       
                                       
                                       
                                       
                                 Dried Apples
                                     0.851
                                     0.392
                                       
1. The processing factor was calculated by dividing the residue in the apple processed commodity by the residue in the apple RAC sample (LOQ = 0.01 ppm).  
2. NA = Not Applicable (whole fresh fruit, the representative apple RAC sample).  

Apple Conclusions:  A comparison of the residues in the RAC with those in each processed fraction indicated that metrafenone residues do not concentrate appreciably (<1X to 1.2X on average) in any apple processed commodities, with the exception of apple sauce, in which the processing factor was 4.5X on average.  The observed concentration factors were less than the theoretical concentration factors.

An acceptable method was used for residue quantitation, and the study is supported by adequate storage stability data.  

Tomato (MRID #49119109):  Tomato processing studies were conducted to determine the potential for concentration of residues of metrafenone (BAS 560 F) in the processed fractions of tomato.

During the 2010 growing season, four tomato field trials were conducted in Germany at 04668 Motterwitz, Saxony; 04827 Gerichshain, Saxony; 19348 Düpow, Brandenburg; and 16248 Oderberg, Brandenburg.  At each location a treated plot was established; two of the trials also included an untreated control plot.  

The treated plots received two foliar applications of metrafenone (4.2 lb ai/gal SC, formulation code BAS 560 02 F) targeting 0.60 lb ai/A/application (0.675 kg ai/ha/application) with a nominal 7-day RTI, resulting in a total rate of 1.2 lb ai/A (1.35 kg ai/ha/season).  The actual application rates were 0.54-0.65 lb ai/A/application (0.61-0.73 kg ai/ha/application), with 6-8 day RTIs, resulting in a total rate of 1.18-1.28 lb ai/A/season (1.32-1.44 kg ai/ha/season).  The applications were made in 48-58 GPA of water (450-544 L/ha) using ground equipment, and no adjuvant was added to the spray mixtures.

At each location, tomato RAC samples (fruit) were harvested at PHIs of 0 and 3 or 4 days.  The bulk tomato samples collected at 3- or 4-day PHIs at each site were promptly processed, according to simulated commercial procedures, into tomato processed fractions.  

The tomato RAC and processed commodity samples were analyzed for residues of metrafenone by SGS Institut Fresenius GmbH, Taunusstein, Germany, using BASF Method Number 535/1 (L0076/01).  Acceptable concurrent method recovery data for tomato RAC and processed commodity samples were obtained for metrafenone.  The validated LOQ for residues of metrafenone in tomato RAC and processed commodity samples was 0.01 ppm.  

As summarized below in Table 5.3.3.2, the results from the processing study show that after two applications of metrafenone targeting 0.60 lb ai/A/application (0.675 kg ai/ha/application), metrafenone in treated tomato RAC samples (unwashed whole fruit) collected at 0- and 3- to 4-day PHIs were 0.675-1.189 ppm and 0.40-0.78 ppm, respectively (n=4 for each sampling interval).  

A total of four separate treated bulk samples were processed for a total of four processing tests.  The treated bulk tomato RAC samples harvested at 3- or 4-day PHIs and bearing quantifiable metrafenone residues (levels discussed above) were separately processed using simulated commercial processing procedures into paste and puree, the currently EPA-regulated commodities of tomato.  In addition, blanched tomatoes, blanching water, canned tomatoes, peeled tomatoes, wash water, tomato peel, wet pomace, washed tomatoes, raw juice, ketchup after pasteurization, and vegetable stock were collected for analysis.  A comparison of the residues in the RAC with those in each processed fraction indicates that residues of metrafenone do not concentrate in tomato processed commodities with the exception of peel and wet pomace, in which residues concentrate, on average, by factors of 6.3X (range, 3.51-7.86X, n=4) and 5.1X (range, 3.31-6.16X, n=4), respectively.

The processing factors calculated in this study were greater than the maximum theoretical concentration factors of 1.4X for tomato puree and 5.5X for tomato paste (based on loss of water; OCSPP 860.1520, Table 2) and 1.4X for tomato juice (based on separation into components; OCSPP 860.1520, Table 3).

The tomato RAC and processed commodity samples were stored frozen for a maximum of 165 days (5.4 months) from collection to analysis for residues of metrafenone.  

TABLE 5.3.3.2	Metrafenone Residues in Tomato Processed Fractions
                                Trial Location
                             (City, Country/ Year)
                                  Total Rate
                                   lbs ai/A
                                  (kg ai/ha)
                                   Processed
                                   Commodity
                                      PHI
                                   (Days)[1]
                                  Metrafenone
                             Processing Factor[2]
04668 Motterwitz, Saxony, Germany/2010 (L100261)
1.26 (1.41)
                                Fruit, 0 PHI[3]
                                       0
                                     0.675
                                      ---

                                       
                                Fruit, 3 PHI[3]
                                       3
                                     0.401
                                      ---

                                       
                                 Fruit, RAC[4]
                                       
                                     0.423
                                      1.0

                                       
                               Blanched tomatoes
                                       
                                     0.353
                                     0.83

                                       
                                Blanching water
                                       
                                   < 0.01
                                     0.02

                                       
                                Canned tomatoes
                                       
                                   < 0.01
                                     0.02

                                       
                                Peeled tomatoes
                                       
                                   < 0.01
                                     0.02

                                       
                                  Wash water
                                       
                                     0.066
                                     0.16

                                       
                                  Tomato peel
                                       
                                     3.184
                                     7.53

                                       
                                  Wet pomace
                                       
                                     2.034
                                     4.81

                                       
                                Washed tomatoes
                                       
                                     0.382
                                     0.90

                                       
                                   Raw juice
                                       
                                     0.168
                                     0.40

                                       
                         Ketchup after pasteurization
                                       
                                     0.177
                                     0.42

                                       
                                     Paste
                                       
                                     0.225
                                     0.53

                                       
                                     Puree
                                       
                                     0.335
                                     0.79

                                       
                                Vegetable stock
                                       
                                   < 0.01
                                     0.02
04827 Gerichshain, Saxony, Germany/2010 (L100262)
1.28 (1.44)
                                Fruit, 0 PHI[3]
                                       0
                                     0.962
                                      ---

                                       
                                Fruit, 3 PHI[3]
                                       3
                                     0.778
                                      ---

                                       
                                 Fruit, RAC[4]
                                       
                                     0.775
                                      1.0

                                       
                               Blanched tomatoes
                                       
                                     0.352
                                     0.45

                                       
                                Blanching water
                                       
                                     0.013
                                     0.02

                                       
                                Canned tomatoes
                                       
                                     0.015
                                     0.02

                                       
                                Peeled tomatoes
                                       
                                   < 0.01
                                     0.01

                                       
                                  Wash water
                                       
                                     0.507
                                     0.65

                                       
                                  Tomato peel
                                       
                                     4.807
                                     6.20

                                       
                                  Wet pomace
                                       
                                     2.567
                                     3.31

                                       
                                Washed tomatoes
                                       
                                     0.477
                                     0.62

                                       
                                   Raw juice
                                       
                                     0.198
                                     0.26

                                       
                         Ketchup after pasteurization
                                       
                                     0.327
                                     0.42

                                       
                                     Paste
                                       
                                     0.207
                                     0.27

                                       
                                     Puree
                                       
                                     0.501
                                     0.65

                                       
                                Vegetable stock
                                       
                                   < 0.01
                                     0.01
19348 Düpow, Brandenburg, Germany/2010 (L100263)
1.18 (1.32)
                                Fruit, 0 PHI[3]
                                       0
                                     1.189
                                      ---

                                       
                                Fruit, 4 PHI[3]
                                       4
                                     0.782
                                      ---

                                       
                                 Fruit, RAC[4]
                                       
                                     0.583
                                      1.0

                                       
                               Blanched tomatoes
                                       
                                     0.528
                                     0.91

                                       
                                Blanching water
                                       
                                     0.017
                                     0.03

                                       
                                Canned tomatoes
                                       
                                   < 0.01
                                     0.02

                                       
                                Peeled tomatoes
                                       
                                     0.013
                                     0.02

                                       
                                  Wash water
                                       
                                     0.218
                                     0.37

                                       
                                  Tomato peel
                                       
                                     4.585
                                     7.86

                                       
                                  Wet pomace
                                       
                                     3.592
                                     6.16

                                       
                                Washed tomatoes
                                       
                                     0.488
                                     0.84

                                       
                                   Raw juice
                                       
                                     0.194
                                     0.33

                                       
                         Ketchup after pasteurization
                                       
                                     0.219
                                     0.38

                                       
                                     Paste
                                       
                                     0.174
                                     0.30

                                       
                                     Puree
                                       
                                     0.487
                                     0.84

                                       
                                Vegetable stock
                                       
                                   < 0.01
                                     0.02
16248 Oderberg, Brandenburg, Germany/2010 (L100264)
1.18 (1.32)
                                Fruit, 0 PHI[3]
                                       0
                                     0.925
                                      ---
                                       
                                       
                                Fruit, 3 PHI[3]
                                       3
                                     0.435
                                      ---
                                       
                                       
                                 Fruit, RAC[4]
                                       
                                     0.452
                                      1.0
                                       
                                       
                               Blanched tomatoes
                                       
                                     0.398
                                     0.88
                                       
                                       
                                Blanching water
                                       
                                     0.012
                                     0.03
                                       
                                       
                                Canned tomatoes
                                       
                                   < 0.01
                                     0.02
                                       
                                       
                                Peeled tomatoes
                                       
                                     0.01
                                     0.02
                                       
                                       
                                  Wash water
                                       
                                     0.152
                                     0.34
                                       
                                       
                                  Tomato peel
                                       
                                     1.588
                                     3.51
                                       
                                       
                                  Wet pomace
                                       
                                     2.679
                                     5.93
                                       
                                       
                                Washed tomatoes
                                       
                                     0.242
                                     0.54
                                       
                                       
                                   Raw juice
                                       
                                     0.149
                                     0.33
                                       
                                       
                         Ketchup after pasteurization
                                       
                                     0.211
                                     0.47
                                       
                                       
                                     Paste
                                       
                                     0.201
                                     0.44
                                       
                                       
                                     Puree
                                       
                                     0.478
                                     1.06
                                       
                                       
                                Vegetable stock
                                       
                                   < 0.01
                                     0.02
1. The pre-harvest interval (PHI) for the bulk tomato RAC sample.  
2. The processing factor is calculated by dividing the residue in the processed fraction by the mean residue in the tomato RAC sample.  Processing factor  is equivalent to "transfer factor".  
3. Result from the analysis of the smaller tomato fruit RAC sample.  
4. Result from the representative "fresh fruit" sample collected at the processing facility.  

Tomato Conclusions:  A comparison of the residues in the RAC with those in each processed fraction indicated that residues of metrafenone do not concentrate in tomato processed commodities with the exception of peel and wet pomace, in which residues concentrate, on average, by factors of 6.3X and 5.1X, respectively.  The mean transfer factor of tomato peel and wet pomace (>1) indicates that the metrafenone residues are mainly located in the peel of the tomatoes.  

An acceptable method was used for residue quantitation, and the study is supported by adequate storage stability data.  

5.3.4	Meat, Milk, Poultry and Eggs (860.1480)
	Metabolism DER for MRID #49267201 (Goat)

The only livestock feed item associated with the proposed metrafenone new uses is apple wet pomace, and it is fed only to dairy cattle, at a mazimum of 10% of the diet.  Twelve apple field trials were conducted, with a HAFT value of 0.760 ppm.  An average processing factor of 1.2 was determined for apple wet pomace in the apple processing study (MRID #49055902).  Therefore, the adjusted metrafenone residues in apple pomace are 0.760 ppm x 1.2 PF = 0.912 ppm.  

When goats in the metabolism study were dosed at 87 ppm in the feed, the highest metrafenone residue in tissues was in liver at 0.269 ppm.  Scaling down to the anticipated dietary burden to dairy cattle of 0.228 mg/kg in feed, anticipated metrafenone residues are not expected to exceed 0.000705 ppm in liver, well below the LOD.  Residues would occur at lower levels in muscle, fat and milk.  Ergo, there is no reasonable expectation of residues above the LOQ of 0.01 ppm in the milk or tissues of ruminant animals.  

TABLE 5.3.4	Dietary Burden to Dairy Cattle from Metrafenone.
                                   Feedstuff
                               Feedstuff Type[1]
                                % Dry Matter 2
                                   % Diet[2]
                              Feeding Level (ppm)
                         Dietary Contribution (ppm)[3]
                                 Dairy Cattle
                               Apple wet pomace
                                      CC
                                      40
                                      10
                                     0.912
                                     0.228
                                 TOTAL BURDEN
                                      --
                                      --
                                     10[4]
                                     0.912
                                     0.228
1. CC = Carbohydrate Concentrate.  
2. OCSPP Residue Chemistry Test Guideline 860.1000, Table 1 Feedstuffs (30 June 2008).  
3. Contribution = (tolerance / % DM x % diet) for beef and dairy cattle.  
4. The remainder of the diet will be composed of feedstuffs (roughage and protein concentrate sources) derived from crops that do not have registered metrafenone uses or tolerances.  

Conclusions:  Based on the dietary burden to dairy cattle of metrafenone residues in apple wet pomace, and the results of the goat metabolism study, it is not expected that detectable residues would be found in cattle commodities.  Therefore, tolerances in livestock commodities are not required, nor is a livestock feeding study required.  

5.3.5	Food Handling (860.1460)

There are no proposed uses that are relevant to this guideline topic.  

5.3.6	Water, Fish, and Irrigated Crops (860.1400)

There are no proposed uses that are relevant to this guideline topic.  

5.4	Food Residue Profile

Residues of metrafenone from the new uses proposed in the current action are expected to vary from low (up to 0.70 ppm in apricot and peaches) to high levels (up to 70 ppm in dried hops cones).  


6.0	  Tolerance Derivation

Adequate pome fruit field trial data were submitted in support of the proposed use.  The submitted data support the proposed tolerance of 1.5 ppm in pome fruits (group 11-10).  

Adequate fruiting vegetable field trial data were submitted in support of the proposed use.  The submitted data support a recommended tolerance of 0.90 ppm, rather than the proposed tolerance of 1.0 ppm, in fruiting vegetables (group 8-10).  

Adequate cucurbit vegetable field trial data were submitted in support of the proposed use.  The submitted data support the proposed tolerance of 0.5 ppm in cucurbit vegetables (group 9); HED recommends that the tolerance be established at 0.50 ppm.  

Adequate cherry field trial data were submitted in support of the proposed use.  The submitted data support the proposed tolerance of 2 ppm in the cherry subgroup (12-12A); HED recommends that the tolerance be established at 2.0 ppm.  

Adequate peach field trial data were submitted in support of the proposed use.  The submitted data support the proposed tolerance of 0.7 ppm in the peach subgroup (12-12B); HED recommends that the tolerance be established at 0.70 ppm.  

Adequate hops field trial data were submitted in support of the proposed use.  The submitted data support the proposed tolerance of 70 ppm in hops.  

The proposed tolerance of 4.5 ppm in small vine climbing fruits except fuzzy kiwifruit (subgroup 13-07F) is based upon existing data for grapes (the representative commodity for the subgroup).  Upon establishment of the tolerance in subgroup 13-07F, the existing tolerance in grapes should be removed.  

The proposed tolerance of 0.7 ppm in apricots is based upon the submitted data for peaches.  HED recommends that the tolerance be established at 0.70 ppm.  

The rationales for the establishment and concurrent removal of tolerances associated with the current action are listed in Table 6, below.  

An International Residue Limit Status sheet is appended as Attachment 1.  Data sets and results from the OECD tolerance calculation procedure for the various commodities are appended as Attachment 2.  

TABLE 6	Tolerance Summary for Metrafenone (40CFR §624[a]).  
                                   Commodity
                           Existing Tolerance (ppm)
                          Recommended Tolerance (ppm)
                                   Rationale
Apricot
                                     None
                                     0.70
Based on submitted peach data.  
Cherry subgroup 12-12A
                                     None
                                      2.0
Based on submitted cherry data.  
Fruit, pome, group 11-10
                                     None
                                      1.5
Based on submitted pome fruits data.  
Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13-07F	
                                     None
                                      4.5
Based on data supporting the existing tolerance in grape.  
Grape
                                      4.5
                                    Remove
Covered by the subgroup 13-07F tolerance to be established.  
Hop, dried cones
                                     None
                                      70
Based on submitted hops data.  
Peach subgroup 12-12B
                                     None
                                     0.70
Based on submitted peach data.  
Vegetable, cucurbit, group 9
                                     None
                                     0.50
Based on submitted cucurbit data.  
Vegetable, fruiting, group 8-10
                                     None
                                     0.90
Based on submitted fruiting vegetable data.  


References

Metrafenone.  Petition for the Establishment of Tolerances on Imported Grapes.  Summary of Analytical Chemistry and Residue Data.  PP#4E6884.; D312307; D. McNeilly.  24 August 2006.  

Metrafenone:  Human Health Risk Assessment for Foliar Use on Grapes.; D354166; D. McNeilly; 1 March 2010.  

Metrafenone.  Report of the Residues of Concern Knowledgebase Subcommittee (ROCKS).; D370903; G.F. Kramer; 18 Nov 2009.  

Metrafenone: Chronic Aggregate Dietary Exposure (Food and Drinking Water) and Risk Assessment for the Section 3 Registration on Grapes.; D371367; D. McNeilly; 18 February 2010.  

Metrafenone.  Application for Section 3 Registration for Use on Grape.  Summary of Analytical Chemistry and Residue Data.; D331685; D. McNeilly; 18 February 2010.  
 
PP#4E6884.  New Chemical, Food Use of Metrafenone on Table and Wine Grapes.  Request for Petition Method Validation (PMV) of the Proposed Tolerance Enforcement Methods.; D331185; D. McNeilly; 3 August 2006.  

Review of Proposed Tolerance Enforcement Method for Metrafenone.; ACB Project #B06-38. D. Wright, D. McNeilly; 29 September 2008.  

Drinking Water Assessment for the Proposed Uses of Metrafenone [(3-bromo-6-methyoxy-2-methylphenyl) (2,3,4-trimethoxy-6-methylphenyl) methanone] on Pome Fruits, Fruiting Vegetables, Peach Subgroup 12-12B, Apricot, Cherry Subgroup 12-12A, Cucurbit Vegetables (Group 9), and Fruit, Small, Vine Climbing (except Fuzzy Kiwifruit) Subgroup 13-07F; D411540, D414403, D416312; J.A. Hetrick; 25 November 2013.  

Metrafenone.  Review of Residue Data from Hops Field Trials  -  Statistical Test for Outlier.; D421923; Bayazid Sarkar; 21 August 2014.  


Attachments

Attachment 1:  International Residue Limit Status sheet.  
Attachment 2:  OECD MRL (Tolerance) Assessment Calculations.


Attachment 1:  International Residue Limit Status

                         Metrafenone (PC Code 000325)
      Summary of US Tolerances and International Maximum Residue Limits.
                              Residue Definitions
                             US (40CFR §180.624)
                                    Canada
                                     Codex
Plants:  Metrafenone (3-bromo-6-methoxy-2-methylphenyl)(2,3,4-trimethoxy-6-methylphenyl)methanone.  
Metrafenone (3-bromo-6-methoxy-2-methylphenyl)(2,3,4-trimethoxy-6-methylphenyl)methanone.  

                                 Commodity[2]
                              Tolerance (ppm)[3]
                                   Commodity
                                  MRL (mg/kg)
                                   Commodity
                                  MRL (mg/kg)
Apricot
                                     0.70

                                       

                                       
Cherry subgroup 12-12A
                                      2.0

                                       

                                       
Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13-07F
                                      4.5
Grapes
Raisins
                                      4.5
                                      17

                                       
Fruits, pome, group 11-10
                                      1.5

                                       

                                       
Hop, cones, dried
                                      70

                                       

                                       
Peach subgroup 12-12B
                                     0.70

                                       

                                       
Vegetable, cucurbit, group 9
                                     0.50

                                       

                                       
Vegetables, fruiting, group 8-10
                                     0.90

                                       

                                       

                                       

                                       

                                       

                                       

                                       

                                       

                                       

                                       

                                       

                                       

                                       

                                       

                                       

                                       

                                       

                                       

                                       

                                       
Completed:  M. Negussie, 12 November 2013.  
1. Mexico adopts US tolerances, and/or Codex MRLs, for its export purposes.  
2. Includes only commodities of interest for this action.  
3. Tolerance values are those recommended by HED, not those proposed by the petitioner.  


Attachment 2:  OECD MRL (Tolerance) Assessment Calculations.  

Apple

Residues (mg/kg)
                                     0.218
                                     0.158
                                     0.492
                                     0.446
                                     0.360
                                     0.230
                                     0.214
                                     0.314
                                     0.141
                                     0.155
                                     0.165
                                     0.078
                                     0.536
                                     0.760
                                     0.392



 
 
 
 
 
                                  Metrafenone
                                       
 
                                     Apple
                                       
 
                                      USA
                                       
 
                            0.90 lb ai/A, 7-day PHI
                                       
 
 
 
 
 
Total number of data (n)
                                      15
                                       
 
Percentage of censored data
                                      0%
                                       
 
Number of non-censored data
                                      15
                                       
 
Lowest residue
                                     0.078
                                       
 
Highest residue
                                     0.760
                                       
 
Median residue
                                     0.230
                                       
 
Mean
                                     0.311
                                       
 
Standard deviation (SD)
                                     0.187
                                       
 
Correction factor for censoring (CF)
                                     1.000
                                       
 
 
                                       
                                       
 
Proposed MRL estimate
 
 
 
 
                                       
 
 
- Highest residue
                                     0.760
 
 
- Mean + 4 SD
                                     1.058
 
 
- CF x 3 Mean
                                     0.932
 
 
Unrounded MRL
                                     1.058
                                       
 
 
                                       
 
 
Rounded MRL
                                      1.5
                                       
 
 
 
 


Pear

Residues (mg/kg)
                                     0.405
                                     0.409
                                     0.189
                                     0.141
                                     0.160
                                     0.477
                                     0.392

 
 
 
 
 
                                  Metrafenone
                                       
 
                                     Pear
                                       
 
                                      USA
                                       
 
                            0.90 lb ai/A, 7-day PHI
                                       
 
 
 
 
 
Total number of data (n)
                                       7
                                       
 
Percentage of censored data
                                      0%
                                       
 
Number of non-censored data
                                       7
                                       
 
Lowest residue
                                     0.141
                                       
 
Highest residue
                                     0.477
                                       
 
Median residue
                                     0.392
                                       
 
Mean
                                     0.310
                                       
 
Standard deviation (SD)
                                     0.141
                                       
 
Correction factor for censoring (CF)
                                     1.000
                                       
 
 
                                       
                                       
 
Proposed MRL estimate
 
 
 
 
                                       
 
 
- Highest residue
                                     0.477
 
 
- Mean + 4 SD
                                     0.874
 
 
- CF x 3 Mean
                                     0.931
 
 
Unrounded MRL
                                     0.931
                                       
 
 
                                       
 
 
Rounded MRL
                                       1
                                       
 
 
                                       
                                       
 
 High uncertainty of MRL estimate.
                                       
 
[Small dataset]
 
 
 
 
 


Tomato

Residues (mg/kg)
                                     0.101
                                     0.228
                                     0.079
                                     0.110
                                     0.170
                                     0.105
                                     0.176
                                     0.246
                                     0.088
                                     0.285
                                     0.109
                                     0.095
                                     0.103
                                     0.234
                                     0.427
                                     0.099
                                     0.041
                                     0.222



 
 
 
 
 
                                  Metrafenone
                                       
 
                                   Tomatoes
                                       
 
                                      USA
                                       
 
                            0.90 lb ai/A, 0-day PHI
                                       
 
 
 
 
 
Total number of data (n)
                                      18
                                       
 
Percentage of censored data
                                      0%
                                       
 
Number of non-censored data
                                      18
                                       
 
Lowest residue
                                     0.041
                                       
 
Highest residue
                                     0.427
                                       
 
Median residue
                                     0.110
                                       
 
Mean
                                     0.162
                                       
 
Standard deviation (SD)
                                     0.096
                                       
 
Correction factor for censoring (CF)
                                     1.000
                                       
 
 
                                       
                                       
 
Proposed MRL estimate
 
 
 
 
                                       
 
 
- Highest residue
                                     0.427
 
 
- Mean + 4 SD
                                     0.547
 
 
- CF x 3 Mean
                                     0.486
 
 
Unrounded MRL
                                     0.547
                                       
 
 
                                       
 
 
Rounded MRL
                                      0.6
                                       
 
 
                                       
                                       
 
 
                                       
 
 
 
 
 
 
 


Pepper

Residues (mg/kg)
                                     0.417
                                     0.402
                                     0.148
                                     0.248
                                     0.270
                                     0.353
                                     0.081
                                     0.498

 
 
 
 
 
                                  Metrafenone
                                       
 
                             Bell/non-bell peppers
                                       
 
                                      USA
                                       
 
                            0.90 lb ai/A, 0-day PHI
                                       
 
 
 
 
 
Total number of data (n)
                                       8
                                       
 
Percentage of censored data
                                      0%
                                       
 
Number of non-censored data
                                       8
                                       
 
Lowest residue
                                     0.081
                                       
 
Highest residue
                                     0.498
                                       
 
Median residue
                                     0.312
                                       
 
Mean
                                     0.302
                                       
 
Standard deviation (SD)
                                     0.142
                                       
 
Correction factor for censoring (CF)
                                     1.000
                                       
 
 
                                       
                                       
 
Proposed MRL estimate
 
 
 
 
                                       
 
 
- Highest residue
                                     0.498
 
 
- Mean + 4 SD
                                     0.869
 
 
- CF x 3 Mean
                                     0.906
 
 
Unrounded MRL
                                     0.906
                                       
 
 
                                       
 
 
Rounded MRL
                                      0.9
                                       
 
 
                                       
                                       
 
 
                                       
 
 
 
 
 
 
 


Cherry

Residues (mg/kg)
                                     0.699
                                     0.393
                                     0.429
                                     0.494
                                     0.317
                                     0.738
                                     0.368
                                     0.438
                                     1.160
                                     0.492
                                     0.334
                                     0.596
                                     0.647
                                     0.547

 
                                  Metrafenone
                                       
 
                                    Cherry
                                       
 
                                      USA
                                       
 
                            0.60 lb ai/A, 7-day PHI
                                       
 
 
 
 
 
Total number of data (n)
                                      14
                                       
 
Percentage of censored data
                                      0%
                                       
 
Number of non-censored data
                                      14
                                       
 
Lowest residue
                                     0.317
                                       
 
Highest residue
                                     1.160
                                       
 
Median residue
                                     0.493
                                       
 
Mean
                                     0.547
                                       
 
Standard deviation (SD)
                                     0.221
                                       
 
Correction factor for censoring (CF)
                                     1.000
                                       
 
 
                                       
                                       
 
Proposed MRL estimate
 
 
 
 
                                       
 
 
- Highest residue
                                     1.160
 
 
- Mean + 4 SD
                                     1.430
 
 
- CF x 3 Mean
                                     1.640
 
 
Unrounded MRL
                                     1.640
                                       
 
 
                                       
 
 
Rounded MRL
                                       2
                                       

Hops

Residues (mg/kg)
                                    16.870
                                    21.890
                                    21.120
                                    23.520
                                    21.300
                                    22.800
                                    13.300
                                    19.700
                                    34.400
                                    33.100


 
 
 
 
 
                                  Metrafenone
                                       
 
                                     Hops
                                       
 
                                      USA
                                       
 
                            0.60 lb ai/A, 3-day PHI
                                       
 
 
 
 
 
Total number of data (n)
                                      10
                                       
 
Percentage of censored data
                                      0%
                                       
 
Number of non-censored data
                                      10
                                       
 
Lowest residue
                                    13.300
                                       
 
Highest residue
                                    34.400
                                       
 
Median residue
                                    21.595
                                       
 
Mean
                                    22.800
                                       
 
Standard deviation (SD)
                                     6.516
                                       
 
Correction factor for censoring (CF)
                                     1.000
                                       
 
 
                                       
                                       
 
Proposed MRL estimate
 
 
 
 
                                       
 
 
- Highest residue
                                    34.400
 
 
- Mean + 4 SD
                                    48.863
 
 
- CF x 3 Mean
                                    68.400
 
 
Unrounded MRL
                                    68.400
                                       
 
 
                                       
 
 
Rounded MRL
                                      70
                                       
 
 
 
 


Peach

Residues (mg/kg)
                                     0.211
                                     0.247
                                     0.227
                                     0.185
                                     0.166
                                     0.489
                                     0.208
                                     0.139
                                     0.208
                                     0.136
                                     0.051
                                     0.289
                                     0.222
                                     0.186



 
 
 
 
 
                                  Metrafenone
                                       
 
                                     Peach
                                       
 
                                      USA
                                       
 
                            0.60 lb ai/A, 7-day PHI
                                       
 
 
 
 
 
Total number of data (n)
                                      14
                                       
 
Percentage of censored data
                                      0%
                                       
 
Number of non-censored data
                                      14
                                       
 
Lowest residue
                                     0.051
                                       
 
Highest residue
                                     0.489
                                       
 
Median residue
                                     0.208
                                       
 
Mean
                                     0.212
                                       
 
Standard deviation (SD)
                                     0.098
                                       
 
Correction factor for censoring (CF)
                                     1.000
                                       
 
 
                                       
                                       
 
Proposed MRL estimate
 
 
 
 
                                       
 
 
- Highest residue
                                     0.489
 
 
- Mean + 4 SD
                                     0.604
 
 
- CF x 3 Mean
                                     0.635
 
 
Unrounded MRL
                                     0.635
                                       
 
 
                                       
 
 
Rounded MRL
                                      0.7
                                       
 
 
                                       
                                       
 
 
                                       
 
 
 
 
 
 
 


Cantaloupe

Residues (mg/kg)
                                     0.154
                                     0.226
                                     0.133
                                     0.088
                                     0.282
                                     0.177
                                     0.132
                                     0.038
                                     0.132
                                     0.209
                                     0.178
                                     0.080

 
 
 
 
 
                                  Metrafenone
                                       
 
                                  Cantaloupe
                                       
 
                                      USA
                                       
 
                            0.90 lb ai/A, 0-day PHI
                                       
 
 
 
 
 
Total number of data (n)
                                      12
                                       
 
Percentage of censored data
                                      0%
                                       
 
Number of non-censored data
                                      12
                                       
 
Lowest residue
                                     0.038
                                       
 
Highest residue
                                     0.282
                                       
 
Median residue
                                     0.144
                                       
 
Mean
                                     0.152
                                       
 
Standard deviation (SD)
                                     0.068
                                       
 
Correction factor for censoring (CF)
                                     1.000
                                       
 
 
                                       
                                       
 
Proposed MRL estimate
 
 
 
 
                                       
 
 
- Highest residue
                                     0.282
 
 
- Mean + 4 SD
                                     0.423
 
 
- CF x 3 Mean
                                     0.457
 
 
Unrounded MRL
                                     0.457
                                       
 
 
                                       
 
 
Rounded MRL
                                      0.5
                                       
 
 
 
 

Cucumber

Residues (mg/kg)
                                     0.100
                                     0.142
                                     0.084
                                     0.157
                                     0.053
                                     0.097

 
 
 
 
 
                                  Metrafenone
                                       
 
                                   Cucumber
                                       
 
                                      USA
                                       
 
                            0.90 lb ai/A, 0-day PHI
                                       
 
 
 
 
 
Total number of data (n)
                                       6
                                       
 
Percentage of censored data
                                      0%
                                       
 
Number of non-censored data
                                       6
                                       
 
Lowest residue
                                     0.053
                                       
 
Highest residue
                                     0.157
                                       
 
Median residue
                                     0.099
                                       
 
Mean
                                     0.106
                                       
 
Standard deviation (SD)
                                     0.038
                                       
 
Correction factor for censoring (CF)
                                     1.000
                                       
 
 
                                       
                                       
 
Proposed MRL estimate
 
 
 
 
                                       
 
 
- Highest residue
                                     0.157
 
 
- Mean + 4 SD
                                     0.258
 
 
- CF x 3 Mean
                                     0.317
 
 
Unrounded MRL
                                     0.317
                                       
 
 
                                       
 
 
Rounded MRL
                                      0.4
                                       
 
 
                                       
                                       
 
 High uncertainty of MRL estimate.
                                       
 
[Small dataset]
 
 
 
 
 


Summer Squash

Residues (mg/kg)
                                     0.305
                                     0.294
                                     0.125
                                     0.129
                                     0.101
                                     0.174
                                     0.072
                                     0.137
                                     0.216
                                     0.105
                                     0.100
                                     0.113
                                     0.277
                                     0.124

 
                                  Metrafenone
                                       
 
                                 Summer squash
                                       
 
                                      USA
                                       
 
                            0.90 lb ai/A, 0-day PHI
                                       
 
 
 
 
 
Total number of data (n)
                                      14
                                       
 
Percentage of censored data
                                      0%
                                       
 
Number of non-censored data
                                      14
                                       
 
Lowest residue
                                     0.072
                                       
 
Highest residue
                                     0.305
                                       
 
Median residue
                                     0.127
                                       
 
Mean
                                     0.162
                                       
 
Standard deviation (SD)
                                     0.079
                                       
 
Correction factor for censoring (CF)
                                     1.000
                                       
 
 
                                       
                                       
 
Proposed MRL estimate
 
 
 
 
                                       
 
 
- Highest residue
                                     0.305
 
 
- Mean + 4 SD
                                     0.476
 
 
- CF x 3 Mean
                                     0.487
 
 
Unrounded MRL
                                     0.487
                                       
 
 
                                       
 
 
Rounded MRL
                                      0.5
                                       

