
                                       
                    UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                               WASHINGTON, D.C.  20460
                                       
	OFFICE OF CHEMICAL SAFETY 
	AND POLLUTION PREVENTION
                                                                               


MEMORANDUM

DATE: 	01/23/14

SUBJECT: 	Zoxamide.  Petition for the Establishment of Permanent Tolerances for Use on Dry Onion Bulbs.  Summary of Analytical Chemistry and Residue Data.

PC Code: 101702
DP Barcode: D416653
Decision No.: 476622
Registration No.: 10163-6414
Petition No.: 3F8164
Regulatory Action: Section 3 Registration
Risk Assessment Type: NA
Case No.: NA
TXR No.: NA
CAS No.: 156052-68-5
MRID No.: 49067102
40 CFR: 180.567
		              									

FROM:	Meheret Negussie, Chemist			
		Risk Assessment Branch III
		Health Effects Division (HED 7509P)
		
		
THROUGH:	Steve Funk, Senior Chemist
		Christine Olinger, Branch Chief
		Risk Assessment Branch III
		Health Effects Division (HED 7509P)	
		
		
TO:		Marcel Howard/Hope Johnson, RM#21
		Fungicide Branch		
		Registration Division (7505P)

		



Executive Summary

Zoxamide is a broad-spectrum protectant fungicide registered for use on potatoes, grapes, tomatoes, and cucurbit vegetables. 

Tolerances for residues of zoxamide have been established under 40 CFR §180.567(a)(1) on  grapes at 3.0 ppm, grape raisins at 15.0 ppm, tomatoes at 2.0 ppm, and cucurbit vegetables at 1.0 ppm.  Tolerances are established under 40 CFR §180.567(a)(2) for the combined residues of zoxamide and its metabolites on potatoes at 0.06 ppm, potato flakes and chips at 0.30 ppm, and potato wet peel at 0.10 ppm.

Gowan Company (Gowan) has submitted a petition for the establishment of permanent tolerances for the residues of zoxamide [3,5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-4-methylbenzamide and its metabolites 3,5-dichloro-4-hydromethylbenzoic acid (RH-1452) and 2,6-dichlorobenzene-1,4-dicarboxylic acid (RH-1453) in/on dry bulb onions. Section F of the current petition proposes the establishment of permanent tolerances for residues of zoxamide and its metabolites in/on:

      Dry bulb Onion (Crop Group 3, Bulb Vegetables) .........................0.7 ppm

In conjunction with this petition, Gowan is requesting amended registration of the 75% water dispersible granule (WDG) formulation of zoxamide (Gavel(R) 75DF Fungicide) (EPA Reg. No. 10163-6414), to add uses on dry bulb onions.  Gavel 75 DF agricultural fungicide is a mixture of 8.3% zoxamide and 66.7% mancozeb. Only zoxamide is evaluated in this assessment.  The product is proposed for up to eight foliar applications at 0.12 - 0.17 lb ai/A/application for a total seasonal application rate of 1.33 lb ai/A, with a preharvest interval (PHI) of 7 days.

Adequate metabolism studies on potatoes, grapes, cucumbers, and tomatoes are available.  The residue of concern for tolerance setting and risk assessment is zoxamide for grapes, grape processed commodities, tomatoes, and cucumbers.   The residue of concern for tolerance setting and risk assessment is zoxamide and its metabolites (RH-1452 and RH-1455) in/on potatoes and processed potatoes.

There are no livestock feed items associated with this petition. 

Adequate analytical methods are available for enforcing zoxamide tolerances and collecting data on residues in plant commodities.  The analytical methods, gas chromatography with electron capture detection (GC/ECD) and GC with mass selective detection (GC/MSD) are available for tolerance enforcement for plant commodities as primary and confirmatory methods, respectively.  For the acid metabolites (RH-1452 and RH-1455), the GC/MSD is the primary method and the GC/ECD method is the confirmatory method.  

The methods have been adequately validated for the determination of residues of zoxamide in plant commodities.

Samples from the submitted crop field trials were analyzed for residues of zoxamide and its metabolites using an acceptable GC/MSD method.  The method was adequately validated prior to and/or in conjunction with the analysis of the field trial samples. The validated limit of quantitation (LOQ) was 0.02 ppm for each analyte in dry bulb onion. 

Adequate multiresidue methods testing data have been submitted.  The data indicate that the multiresidue methods are adequate for enforcement of tolerances for zoxamide only.

Adequate storage stability data are available to support storage conditions and intervals of samples from the onion bulb crop field trials.

The submitted crop field trial data for dry onion bulb reflect the proposed use pattern and are acceptable.  The submitted data will support the proposed tolerances for dry onion bulb of 0.7 ppm.  Using the Organization of Economic Cooperation and Development (OECD) statistical calculation procedure, the recommended tolerance for onion bulb is 0.7 ppm, which is the same as the proposed tolerance.  HED recommends submitting a revised Section F to propose a tolerance on onion, bulb, subgroup 3-07A.  

The nature of the residue in rotational crops is understood based on adequate confined rotational crop studies.  HED has concluded that the residues of concern for rotational crops for risk assessment and tolerance setting purposes are the parent compound, and its metabolites RH-1455 and RH-1452.  The available data support the 30-day plant-back interval (PBI) specified on the label for rotated crops without primary uses of zoxamide.

There are no Codex or Canadian maximum residue limits (MRLs) established for residues of zoxamide in/on onion bulbs.  The US tolerance and Canadian MRL expressions are the same. The US and Canadian residue definitions include zoxamide for grapes and processed grapes and zoxamide and its metabolites for potatoes and processed potatoes.  The US and Codex residue definitions are not in harmony.  The Codex residue definition includes only zoxamide for all crops.  An International Residue Limit Status sheet is attached (Attachment II)

Regulatory Recommendations and Residue Chemistry Deficiencies

HED has examined the residue chemistry database for zoxamide.  Pending submission of revised Sections B and F and submittal of analytical standard, there are no residue chemistry issues that would preclude granting registration for the requested uses of zoxamide on dry bulb onion or establishment of the following tolerances for combined residues of zoxamide and its metabolites:
40 CFR §180.567 (a) (2):

            Onion, bulb, subgroup 3-07A	0.7 ppm

A human health risk assessment is forthcoming.

Note to PM:  According to HED's Interim Guidance on Tolerance Expressions (5/27/09, S. Knizner), the tolerance expressions for zoxamide should be revised as follow:

Under 40 CFR §180.567(a) (1):  "Tolerances are established for residues of zoxamide including is metabolites and degradates, in or on the commodities in the table below.  Compliance with the tolerance levels specified below is to be determined by measuring only zoxamide (3,5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-4-methylbenzamide).
   
Under 40 CFR §180.567 (a) (2):  "Tolerances are established for residues of zoxamide including is metabolites and degradates, in or on the commodities in the table below.  Compliance with the tolerance levels specified below is to be determined by measuring only the sum of zoxamide (3,5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-4-methylbenzamide) and its metabolites 3,5-dichloro-1,4-benzenedicarboxylic acid (RH-1455 and RH-141455) and 3,5-dichloro-4-hydroxymethylbenzoic acid (RH-1452 and RH-141452) calculated as the stoichiometric equivalent of zoxamide.

860.1200  Directions for Use

   * The proposed use directions for onions (dry bulb), garlic, and shallots should be revised to onions (dry bulb), garlic, and shallot bulbs. 
   
860.1550 Proposed Tolerances

   * The proposed tolerance of 0.70 ppm for "Dry bulb Onion (Crop Group 3, Bulb Vegetables)" should be revised to Onion, bulb, subgroup 3-07A at 0.7 ppm.
      
860.1650 Submittal of Analytical Reference Standards

   * The analytical reference standard for zoxamide is depleted.  A 5g standard needs to be supplied to the repository.

Background

The chemical names and structures of zoxamide and the acid metabolites RH-1452 and RH-1455 are presented in Table 1. The physicochemical properties of the technical grade of zoxamide are presented in Table 2.

Table  1.	Zoxamide Nomenclature.  
Chemical structure
--------------------------------------------------------------------------------

Common name
Zoxamide
Company experimental name
RH-7281
IUPAC name
(RS)-3,5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-p-toluamide
Molecular weight 
336.64 g/mol
CAS name
3,5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-4-methylbenzamide
CAS registry number
156052-68-5
End-use product (EP)
Gavel(R) 75DF Fungicide (EPA Reg. No. 10163-6414) (This product is a combination of zoxamide + mancozeb. Only zoxamide residues have been determined.)
Chemical structure
                                       
Common name
RH-141452
Company experimental name
RH-1452
Chemical name
3,5-dichloro-4-hydromethylbenzoic acid
Molecular weight 
221.04 g/mol
CAS Name
Not available
Chemical structure
                                       
Common name
RH-141455
Company experimental name
RH-1455
Chemical name
2,6-dichlorobenzene-1,4-dicarboxylic acid
Molecular weight 
235.02 g/mol
CAS Name
Not available

Table  2.	Physicochemical Properties of Zoxamide.
                                   Parameter
                                     Value
                                   Reference
Melting point/range
159.5 - 160.5 °C (98.8% purity)
MRID 49067102
pH


Density
Relative Density 1.38 at 20 °C

Water solubility (at 20°C)
0.681 +- 0.017 mg/L

Solvent solubility (at 20°C)
Ethyl acetate: 20.0 g/L
Acetone: 55.7 g/L
Xylene: 1.56 g/L
n-Octanol: 6.49 g/L
n-Heptane: 0.038 g/L
1,2-Dichloroethane: 12.5 g/L

Vapor pressure (at 25, 35, and 45°C)
<1.3 x 10[-5] Pa

Dissociation constant, pKa
Not measurable by spectrophotometry, titration or conductivity.  Absorbance did not change in acidic, neutral, or basic conditions; Solubility was too low for titration; with decrease in concentration, no increase in reading was observed.

Octanol/water partition coefficient, KOW
Log Kow 3.76 +- 0.04 at ambient temp

UV/visible absorption spectrum
212 nm. ε = 46330


860.1200  Directions for Use

Gowan has submitted proposed use directions (Section B) for the 75% water dispersible granule (WG) formulation of zoxamide (Gavel(R) 75DF Fungicide) (EPA Reg. No. 10163-6414) on  dry bulb onions. Gavel 75 DF agricultural fungicide is a mixture of 8.3% zoxamide and 66.7% mancozeb.

The proposed use directions for onion bulb are presented in Table 3.

Table  3.	Summary of Directions for Use of Zoxamide
Applic. Timing, Type, and Equip.
                                Formulation[1]
                                [EPA Reg. No.]
                                 Applic. Rate 
                                   (lb ai/A)
                          Max. No. Applic. per Season
                          Max. Seasonal Applic. Rate
                                   (lb ai/A)
                                    PHI[1]
                                    (days)
                       Use Directions and Limitations[2]
                    Onions (dry bulb), garlic, and shallots
Broadcast, Foliar, 
Ground, aerial, or chemigation
                     (Gavel(R) 75DF Fungicide [10163-6414]
                                   0.12-0.17
                                       
                                  1.5 to 2.0
                                   (product)
                                       8
                                     1.33
                                       7
Follow a protective spray schedule starting when diseases are first reported in the area and repeat at 7-day intervals throughout the season.  
Do not allow spray or drift to contact bulbs after lifting from soil.
Do not apply to exposed bulb.
[1] PHI = Pre-harvest interval

For ground applications on potatoes, cucurbits, tomatoes, and dry bulb onions, the label recommends a spray volume of 2-3 gal/A; and 5 gal for vineyards.  The label specifies application in a minimum of 2 gallons of water per acre (GPA) using aerial equipment; in the state of CA a minimum of 5 GPA should be used.  Chemigation applications are to be made through sprinkler-type irrigation systems only.  The label recommends using agricultural surfactants and that zoxamide can be tank mixed with other registered fungicides.  The following crop restrictions appear on the registered label:  0-day PBI for any crop listed on the label and 30-day PBI for all other crops.

Note:  The Section B/label must be revised to indicate use on onions (dry bulb), garlic, and shallot, bulbs. 

Conclusions.  The submitted use directions are adequate to allow evaluation of the residue data relative to the proposed use.  The submitted field trial data for onion bulb reflect the maximum proposed use rates, the minimum retreatment intervals (RTIs), and the proposed PHIs.

860.1300 Nature of the Residue - Plants

Residue Chemistry Memo DP# 237892, 1/10/2001, A. Acierto 
Residue Chemistry Memo DP#s 266181, D268774, 4/02/2001, A. Acierto 

Adequate metabolism studies on potatoes, grapes, cucumbers, and tomatoes are available.

The HED's Metabolism Assessment Review Committee (MARC) has determined that the residue of concern for tolerance setting and risk assessment is zoxamide for grapes and grape processed commodities and is zoxamide and its metabolites (RH-1452 and RH-1455) in/on potatoes (Memo, A.M. Acierto & W.D. Wassell, 12/18/2000, D270797).  

The data concerning the metabolism of zoxamide in/on tomatoes and cucumbers were not presented to the MARC and HED had concluded the residue of concern in tomatoes and cucurbit vegetables for tolerances and risk assessment is zoxamide.

The nature of the residue of zoxamide on bulb onions is understood based on available metabolism studies.

860.1300 Nature of the Residue - Livestock

Residue Chemistry Memo DP# D277097, 12/18/2000, A. Acierto 
Residue Chemistry Memo DP# 237892, 1/10/2001, W. Wassell, A. Acierto

An acceptable metabolism study on goats is available.  The MARC did not determine the residue of concern in ruminants since HED has concluded that livestock tolerances are not needed at this time.  

HED has concluded that tolerances for secondary residues in milk and ruminant tissues are not required at this time and the uses can be considered category 3 of 40 CFR §180.6(a).  It is not possible to determine with certainty whether finite residues will be incurred, but there is no reasonable expectation of finite residues in milk and ruminant tissues.

Poultry:

A poultry metabolism study has not been submitted.  There are no poultry feed items associated with the registered/proposed uses of zoxamide.  Therefore, a poultry metabolism study is not required.  However, if any crops which have poultry feed items are added in the future, then a poultry metabolism study will be required.

860.1340 Residue Analytical Methods

Residue Chemistry Memo DP# 237892, 1/10/2001, A. Acierto 
Residue Chemistry Memo DP#s 266181, D268774, 4/02/2001, A. Acierto 

Plant commodity methods

Enforcement method: A gas chromatography using electron capture detection (GC/ECD) as the primary method and a GC with mass selective detection (GC/MSD) as the confirmatory method are available for tolerance enforcement for plant commodities.

Adequate method validation, radiovalidation, and independent method validation has been submitted for the primary and confirmatory methods.

For the two acid metabolites, RH-1452 and RH-1455, in/on potato tubers and potato processed fractions, the GC/MSD method is proposed as the primary method and the GC/ECD method as the confirmatory method.

The GC/ECD and GC/MSD methods were validated by the Analytical Chemistry Branch 
(ACB)/Biological and Economic Analysis Division (BEAD).  After validation by ACB, the enforcement methods were forwarded to FDA. (DP# D284394, D284396, D284398, and 
D28400).

 Data collection methods:  Samples of dry bulb onions from the submitted crop field trials were  analyzed for residues of zoxamide and its two acid metabolites (RH-1452 and RH-1455) using an acceptable GC/MSD method.  The method was adequately validated prior to and/or in conjunction with the analysis of the field trial.  The validated LOQs were 0.02 ppm for each analyte.

Briefly, residues in homogenized samples were extracted with acetonitrile (ACN): 2% sodium carbonate (80:20, v:v) and filtered.  The filtrates are combined and concentrated.  Residues in the concentrated extract are partitioned with 2% sodium carbonate solution and ethyl acetate (16:15, v:v).  The aqueous layer containing the sodium salts of RH-1452 and RH-1455 was re-partitioned with ethyl acetate.  The organic layers were combined and concentrated to dryness.  Residues were re-dissolved in hexane, sonicated, then subjected to Florisil solid phase extraction (SPE).  Residues of zoxamide were eluted with hexane:ethyl acetate (80:20, v:v), concentrated to dryness, and re-dissolved in hexane for further purification by Alumina-B SPE.  Zoxamide residues were eluted with hexane:ethyl acetate (80:20, v:v), concentrated to dryness, re-dissolved in ethyl acetate, and sonicated for analysis by GC/MSD.

For the aqueous layer, following liquid-liquid partitioning and after adjusting the pH to <=1, residues were partitioned with ethyl acetate.  The aqueous layer was re-partitioned with ethyl acetate; the remaining aqueous layer was discarded, and the organic layers were combined with sodium sulfate.  The solution was decanted, concentrated to dryness, re-dissolved in ethyl acetate, sonicated, and ethyl ether was added.  Residues of RH-1452 and RH-1455 were methylated with diazomethane.  The acid metabolites were esterified.  The methylated residues of RH-1452 (RH-7391) and RH-1455 (RH-7399) are concentrated to dryness and re-dissolved in hexane for further purification by Florisil column chromatography.  Residues were eluted with ethyl acetate, concentrated to dryness, and re-dissolved in ethyl acetate for analysis.  Residues of RH-7391 and RH-7399, methylated residue of the acid metabolites, were quantitated by GC/MSD.

Livestock commodity methods

The petitioner is not proposing tolerances for zoxamide residues in milk, eggs, and animal tissues.  Consequently, attempts to develop residue analytical methods for animal commodities were not pursued.  HED has concluded that, based on the proposed uses, residue analytical methods for animal commodities are not required for this petition.

Conclusions.  The residue analytical methods for plants are adequate.  Acceptable methods are available for tolerance enforcement purposes for the residues of concern in/on plant commodities, and samples of dry bulb onions from the submitted crop field trials were analyzed for residues of zoxamide and its metabolites using an acceptable data collection method.

860.1360 Multiresidue Methods

Residue Chemistry Memo DP# 237892, 1/10/2001, A. Acierto 

The petitioner has previously submitted data pertaining to the multiresidue methods testing of zoxamide and its metabolites (RH-1452 and RH-1455) in conjunction with PP#9F05058.  The
multiresidue methods data indicate that zoxamide was successfully recovered using Protocols D and E, while none of the protocols successfully recovered either of the metabolites. The MRMs are adequate for enforcement of zoxamide tolerances. The submission has been forwarded to FDA for complete evaluation in conjunction with the earlier petition (D255783, N. Dodd, 7/20/99).

860.1380 Storage Stability

Residue Chemistry Memo DP# 237892, 1/10/2001, A. Acierto 

Based upon available data, residues of zoxamide in/on potatoes are stable during frozen storage for a period of 11.3 months.  Based on the results of a successful radiovalidation study, residues of the acid metabolites in/on potato, tubers are stable under frozen storage conditions for up to 29 months.  Potato crop field trial samples were stored frozen for a period of 12 to 23 months prior to analysis and potato processed commodities were stored frozen for a period of 12 months prior to analysis.  Previously, adjustment of the potato processing data for storage degradation prior to analysis was not required.

The storage durations and conditions of samples from the submitted crop field trials are presented in Table 4.

            Table  4.	Summary of Storage Conditions and Durations of Samples from Crop Field Trial and Processing Studies.  
Matrix 
                                    Storage
                                  Temperature
                                     (°C)
                            Actual Storage Duration
                  Interval of Demonstrated Storage Stability
Dry bulb onions
~-25-10
40-343 days ( 1.3-11.4 months)
Residues of zoxamide are stable during frozen storage in/on potatoes for up to 11.3 months and its metabolites are stable up to 29 months.

Conclusions.  The available storage stability data for zoxamide on potatoes are adequate to support the storage durations and conditions of samples of dry bulb onion raw agricultural commodities from the submitted crop field trials.  

860.1400 Water, Fish, and Irrigated Crops

This guideline requirement is not relevant to the current petitions as there are no aquatic uses currently proposed for zoxamide.

860.1460 Food Handling

This guideline requirement is not relevant to the current petitions as there are no food handling uses being proposed for zoxamide.

860.1480 Meat, Milk, Poultry, and Eggs

There are no livestock feedstuffs associated with the proposed use of zoxamide on onion bulbs.  

860.1500 Crop Field Trials

DER References:	49067102.der.doc 
		
Table  6.	Summary of Residue Data from Dry Bulb Onion Crop Field Trials with Zoxamide.
Commodity
                                    Analyte
                                  Total Rate 
                                    lb ai/A
                                  (kg ai/ha)
                                      PHI
                                    (days)
                            Residue Levels (ppm)[1]
                                       
                                       
                                       

                                       n
                                  Sample Min.
                                  Sample Max.
                                    LAFT[2]
                                    HAFT[2]
                                    Median
                                     Mean
                                   Std. Dev.
Dry bulb onion
                                   Zoxamide
                                   1.32-1.34
                                  (1.48-1.51)
                                      6-7
                                      12
                                   <0.02
                                     0.443
                                   <0.020
                                     0.435
                                     0.172
                                     0.163
                                     0.115

                                    RH-1455
                                       
                                       
                                      12
                                   <0.02
                                   <0.02
                                   <0.02
                                   <0.02
                                     0.02
                                     0.02
                                      N/A

                                    RH-1452
                                       
                                       
                                      12
                                   <0.02
                                     0.053
                                   <0.02
                                     0.049
                                     0.023
                                     0.028
                                     0.010

                                   Combined
                                       
                                       
                                      12
                                   <0.062
                                   <0.483
                                   <0.063
                                   <0.475
                                     0.221
                                     0.211
                                     0.113
[1]  Except for sample min/max, values reflect per trial averages; n = no. of field trials.
[2]  LAFT = lowest average field trial; HAFT = highest average field trial.

Onion bulb

Gowan has submitted field trial data for zoxamide on dry bulb onion.  Twelve field trials were conducted in the United States and Canada during the 2011 and 2012 growing seasons in the North American Free Trade Agreement (NAFTA) Growing Zones 1 (NY; 1 trial), 5 (ON; 2 trials and MI, WI, and IA; 1 trial each), 6 (TX; 1 trial), 8 (KS; 1 trial), 10 (CA; 2 trials), 11 (ID; 1 trial), and 12 (OR; 1 trial).

Each trial consisted of one untreated plot and one treated plot.  At each trial location, the treated plot received eight foliar broadcast applications of a 75% water dispersible granule (WG) formulation of zoxamide (Gavel(R) 75DF Fungicide) at 0.160-0.174 lb ai/A/application (0.179-0.195 kg ai/ha/application) for a total seasonal rate of 1.32-1.34 lb ai/A (1.48-1.51 kg ai/ha).  Applications were made at 6- to 8-day retreatment intervals (RTIs).  Applications were made using ground equipment in spray volumes of 15-39 gal/A (140-365 L/ha).  A nonionic surfactant (NIS) was added to the spray mixtures at all trial sites.  Samples of dry bulb onions were harvested at a 6- to 7-day preharvest interval (PHI).  Additional dry bulb onion samples were harvested from one trial (MI; TCI-11-319-04) at PHIs of 0, 3, 10, and 14 days to assess residue decline.

Samples were analyzed for residues of zoxamide and its acid metabolites RH-1452 and RH-1455 using a gas chromatography method with mass selective detection (GC/MSD), entitled "Tolerance Enforcement Method for Parent RH-7281 and its Two Acid Metabolites, RH-1452 and RH-1455, in Potato Peel Waste," dated June 1, 2000, with Morse Laboratories method modifications dated June 25, 2012.  The limit of quantitation (LOQ; determined as the lowest level of method validation, LLMV) was 0.02 ppm for each analyte in dry bulb onion.  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.  Quantifiable residues of RH-1455 and RH-1452 were converted to parent equivalents by the petitioner using molecular weight conversion factors of 1.43 for RH-1455 and 1.52 for RH-1452.

Dry bulb onion samples were stored frozen (frozen at the field sites and -25 to -10 °C at the analytical laboratory) from collection to analysis for 40-343 days (1.3-11.4 months).  Samples were analyzed within 0-9 days of extraction.  Adequate storage stability data are available to support the storage durations and conditions of samples from the submitted field trials.

Following eight foliar broadcast applications of the 75% WG formulation of zoxamide at 1.32-1.34 lb ai/A, residues (and per trial averages) of zoxamide, RH-1452, and combined residues, respectively, in/on bulb onions harvested at a 6- to 7-day PHI were <0.02-0.443 (<0.020-0.435), <0.02-0.053 (<0.02-0.049), and <0.062-<0.483 (<0.063-<0.475) ppm; residues of RH-1455 were <LOQ (0.02 ppm) in/on all samples of dry bulb onion.

In the residue decline trial, average residues of zoxamide were 0.333, 0.339, 0.264, 0.293, and 0.167 ppm at the 0-, 3-, 7-, 10-, and 14-day PHIs, respectively, indicating an overall decline in residues with increasing PHIs.  Average residues of RH-1452 as parent equivalents were 0.0266, 0.0309, 0.0263, <0.0260, and 0.0266 ppm at the 0-, 3-, 7-, 10-, and 14-day PHIs, respectively, indicating that residues were fairly stable over the sampling period.  Residues of RH-1455 were <LOQ in/on all samples; therefore, residue decline could not be assessed.  Average combined residues were <0.379, <0.390, <0.310, <0.338, and <0.213 ppm at the 0-, 3-, 7-, 10-, and 14-day PHIs, respectively, indicating a general overall decline in residues with increasing PHIs.

Conclusions.  Provided the directions for use and the proposed tolerances are revised, the submitted onion bulb field trial studies are acceptable and reflect the proposed use patterns.  Samples were analyzed for residues of zoxamide and it is metabolites using acceptable methods, and the studies are supported by adequate storage stability data. 
The average field trial values for bulb onions were entered into the OECD spreadsheet to determine an appropriate tolerance level.  Refer to Appendix I for the tolerance calculations.  The OECD tolerance calculation procedure recommends a tolerance of 0.7 ppm for dry bulb onions.  The recommended tolerance level is the same as proposed by the petitioner.  HED recommends submitting a revised Section F to propose a tolerance on onion, bulb, subgroup 3-07A.  

860.1520 Processed Food and Feed

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

860.1650 Submittal of Analytical Reference Standards

The analytical reference standard for zoxamide is depleted.  A 5g standard needs to be supplied to the repository.  Metabolites of zoxamide are currently available in the EPA National Pesticide Standards Repository (personal communication with Theresa Cole, ACB, 12/12/13), with expiration dates of 03/01/2015 (RH-12452) and 02/07/2015 (RH-1455).

The new standard should be sent to the Analytical Chemistry Lab (located at Fort Meade), to the attention of Theresa Cole, at the following address:

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

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

860.1850 Confined Accumulation in Rotational Crops

Residue Chemistry Memo DP# 237892, 1/10/2001, A. Acierto 
Residue Chemistry Memo DP#s 266181, D268774, 4/02/20013, A. Acierto 

Acceptable confined rotational crop studies were reviewed in conjunction with PP#9F05058 on representative crops of mustard greens (leafy vegetable), radishes and turnips (root vegetables), sorghum and wheat (cereal grains) and soybeans (legume/oil seed).

The parent compound was not identified in any rotational crop commodity at any plantback interval.  The metabolite RH-1452 was tentatively identified at <1-7% of TRR (ND-0.011 ppm) except in 30-day PBI soybean forage where it accounted for 25% of TRR (0.023 ppm).  Based on the results of the reviewed confined rotational crop study, it was concluded that there is no indication that zoxamide would be detected in rotational crops planted more than 30 days after the application of zoxamide. 

A 30-day plant-back interval (PBI) specified on the label for rotated crops without primary uses of zoxamide is adequate.

860.1900 Field Accumulation in Rotational Crops

Residue Chemistry Memo DP# 237892, 1/10/2001, A. Acierto 
Residue Chemistry Memo DP#s 266181, D268774, 4/02/2001, A. Acierto 

Based on the results of the reviewed confined rotational crop study and the data requirements specified in OPPTS 860.1850, field accumulation studies are not required.

860.1550 Proposed Tolerances

Tolerances for residues of zoxamide have been established under 40 CFR §180.567(a)(1) on  grapes at 3.0 ppm, grape raisins at 15.0 ppm, tomatoes at 2.0 ppm, and cucurbit vegetables at 1.0 ppm.  Tolerances are established under 40 CFR §180.567(a)(2) for the combined residues of zoxamide and its metabolites on potatoes at 0.06 ppm, potato flakes and chips at 0.30 ppm, and potato wet peel at 0.10 ppm.

The OECD tolerance calculation procedure was utilized in determining appropriate tolerance levels for dry bulb onions.  Based on the tolerance spreadsheet, the proposed tolerance of 0.7 ppm for dry bulb onion is appropriate.  The tolerance proposed by Gowan is listed in Table 10, along with the tolerance levels and revised commodity definitions recommended by HED.  
  
Pending submission of revised sections B and F, and submittal of analytical standard, adequate field trial data reflecting the proposed use patterns are available for purposes of establishing tolerances on dry bulb onions. 

Note to PM:  According to HED's Interim Guidance on Tolerance Expressions (5/27/09, S. Knizner), the tolerance expressions for zoxamide should be revised as follow:

Under 40 CFR §180.567(a) (1):  "Tolerances are established for residues of zoxamide including is metabolites and degradates, in or on the commodities in the table below.  Compliance with the tolerance levels specified below is to be determined by measuring only zoxamide (3,5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-4-methylbenzamide).
   
Under 40 CFR §180.567 (a) (2):  "Tolerances are established for residues of zoxamide including is metabolites and degradates, in or on the commodities in the table below.  Compliance with the tolerance levels specified below is to be determined by measuring only the sum of zoxamide (3,5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-4-methylbenzamide) and its metabolites 3,5-dichloro-1,4-benzenedicarboxylic acid (RH-1455 and RH-141455) and 3,5-dichloro-4-hydroxymethylbenzoic acid (RH-1452 and RH-141452) calculated as the stoichiometric equivalent of zoxamide.

Table 10. 	Tolerance Summary for zoxamide.
Commodity
                                Tolerance (ppm)
Comments; Correct Commodity Definition

                                   Proposed
                                  Recommended

40 CFR §180.609(a)(2)
Onion, bulb
                                      0.7
                                      0.7
                          Onion, bulb, subgroup 3-07A


References
DP#:	277097
Subject:	PP#9F05058; Zoxamide in/on Potato and Grapes.  Conclusions of the 11/14/2000 Meeting of the Metabolism Assessment Review Committee.
From:	A. Acierto
To:	G. Kramer
Dated:	12/18/2000

DP#s:	237892
Subject:	 PP#9F05058.  Zoxamide in/on Grapes and Potatoes.  Review of Analytical Methods and Residue Data.  First Food Use Review.
From:	A. Acierto
To:	Rose Kearns/Cynthia Giles-Parker
Dated:	1/10/2001

DP#s:	266181 and 268774
Subject:	PP#0F06093.  Zoxamide in/onTomatoes and Cucurbits.  Review of Analytical Methods and Residue Data.
From:	A. Acierto
To:	Rose Kearns/Cynthia Giles-Parker
Dated:	4/2/2001
MRIDs:	45012103 to  45012118

DP#:	276323
Subject:	 PP# 9F05058. ID# 000707-00271 & ID# 000707-00272: Zoxamide in/on Grapes and Potatoes.  
From:	A. Acierto
To:	Rose Kearns/Cynthia Giles-Parker
Dated:	5/10/2003
MRIDs:	45437802, 45499801, 45461402, and 45461403



Attachments:  
International Residue Limit Status sheet
Appendix I - Tolerance Assessment Calculations

Template Version April 2008





International Residue Limits 

                     Zoxamide (PC Code 101702; 12/04/2013)
Summary of US and International Tolerances and Maximum Residue Limits 
Residue Definition: 
US
Canada
Mexico[2]
Codex[3]
40 CFR 180. 567 (a)General 

(1) 3,5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-
oxopropyl)-4-methylbenzamide
 (2) combined residues of zoxamide and its metabolites 3,5-dichloro-1,4-benzenedicarboxylic acid (RH-1455 and RH-141455) and 3,5-dichloro-4-hydroxymethylbenzoic acid (RH-1452 and RH-141452) 
Grapes and raisins: 3,5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-
oxopropyl)-4-methylbenzamide

Potatoes, potato processed fractions (chips, flakes and granules): 
3,5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-
oxopropyl)-4-methylbenzamide, including the
metabolites 3,5-dichloro-1,4-benzene-dicarboxylic
acid and 3,5-dichloro-4-hydroxymethyl
benzoic acid

Zoxamide
Commodity[1]
Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US
Canada
Mexico[2]
Codex[3]
Onion, bulb, subgroup 3-07A 
0.7























Completed:  M. Negussie; 12/04/2013
[1] Includes only commodities of interest for this action.  Tolerance values should be the HED recommendations and not those proposed by the applicant.
2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains.  PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.















Appendix I.  Tolerance Assessment Calculations.

The OECD statistical calculation procedure was used for calculating recommended tolerance on onion bulb.  As specified in the OECD document, the average residue value from each field trial was used.  

Onion Bulb

The dataset used to establish tolerances for zoxamide and its metabolites consisted of field trial data representing application rates of 1.32-1.34 lb ai/A (8 applications at 0.16-0.17 lb ai/A/application) with a 6- to 8-day PHI.  The field trials reflect the proposed application rate and samples were collected at the proposed pre-harvest intervals.  The residue values entered into the tolerance spreadsheet are provided in Table I-1.

Using the OECD statistical calculation procedure the recommended tolerance for onion bulb is 0.7 ppm.

Table I-1.	Residue data used to calculate tolerances for zoxamide on onion bulb.
Regulator:
EPA
Chemical:
Zoxamide
Crop:
Onion bulb
PHI:
6-8 days
App. Rate:
1.32-1.34 lb ai/A
Submitter:
Gowan
MRID Citation:
MRID 49067102
               Combined residues of zoxamide and its metabolites

0.218

0.475

0.261

0.310

0.244

0.063

0.140

0.073

0.128

0.160

0.242

0.223








Figure I-1.  Tolerance spreadsheet summary of zoxamide field trial data for dry onion bulb.

 
 
 
 
 
                                   Zoxamide
                                       
 
                                Dry,onion bulb
                                       
 
                                      EPA
                                       
 
                               1.32-1.34 lb ai/A
                                       
 
 
 
 
 
Total number of data (n)
                                      12
                                       
 
Percentage of censored data
                                      0%
                                       
 
Number of non-censored data
                                      12
                                       
 
Lowest residue
                                     0.063
                                       
 
Highest residue
                                     0.475
                                       
 
Median residue
                                     0.221
                                       
 
Mean
                                     0.211
                                       
 
Standard deviation (SD)
                                     0.113
                                       
 
Correction factor for censoring (CF)
                                     1.000
                                       
 
 
                                       
                                       
 
Proposed MRL estimate
 
 
 
 
                                       
 
 
- Highest residue
                                     0.475
 
 
- Mean + 4 SD
                                     0.662
 
 
- CF x 3 Mean
                                     0.634
 
 
Unrounded MRL
                                     0.662
                                       
 
 
                                       
 
 
Rounded MRL
                                      0.7
                                       
 
 
                                       
                                       
 
 
                                       
 
 
 
 
 
 
 





