UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

	OFFICE OF PREVENTION, PESTICIDE

	AND TOXIC SUBSTANCES

  SEQ CHAPTER \h \r 1 MEMORANDUM

Date:  		March 18, 2009.

SUBJECT:	Cyazofamid. Amend Section 3 Registration to Add Uses on Fruiting Vegetables, Okra, Grape (East of the Rocky Mountains), and Greenhouse Vegetable Transplants.  Summary of Analytical Chemistry and Residue Data.

PC Code:  085651	DP Barcode:  357042

Decision No.:  399610	Registration No.:  71512-3

Petition No.:  8E7427	Regulatory Action:  Sec. 3 Registration

Risk Assessment Type:  NA	Case No.:  NA

TXR No.:  NA	CAS No.:  120116-88-3

MRID No.:  See MRID Summary Table	40 CFR:  180.601

	Ver.Apr.08

FROM:	Amelia M. Acierto, Chemist

		Risk Assessment Branch 3

		Health Effects Division (7509P)	  SEQ CHAPTER \h \r 1

THROUGH:	Stephen Funk, Senior Scientist

		Risk Assessment Branch 3

		Health Effects Division (7509P)

TO:		Barbara Madden, RM #5

		Risk Integration, Minor Use, and Emergency Response Branch

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

MRID Summary Table

MRID No.	Study Type	Comments

47528401	860.1500 Pepper	New DER; 47528401.der.doc

47528402	860.1500 Lettuce and tomato transplants	New DER; 47528402.der.doc

47532601	860.1100 Chemical Identity	Confidential Appendix

  SEQ CHAPTER \h \r 1 This document was originally prepared under contract by Dynamac Corporation (1901 Research Boulevard, Suite 220; Rockville, MD 20850) and has been reviewed by the Health Effects Division (HED) and revised to reflect current Office of Pesticide Programs (OPP) policies.

Executive Summary

  SEQ CHAPTER \h \r 1 Cyazofamid [4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-1H-imidazole-1-sulfona mide] is a fungicide which is currently registered to ISK Biosciences Corporation for use on potato, tomato, and the cucurbit vegetables group.  Under PP#8E7427, the Interregional Research Project No. 4 (IR-4), on behalf of the Agricultural Experiment Stations of AL, FL, MI, OH, and OK, has proposed the establishment of tolerances for the combined residues of cyazofamid, 4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-1H-imidazole-1-sulfonam ide and its metabolite CCIM, 4-chloro-5-(4-methylphenyl)-1H-imidazole-2-carbonitrile, expressed as cyazofamid, in/on the following commodities:

Vegetable, fruiting, group 8	0.80 ppm

Okra	0.80 ppm

Grape – East of the Rocky Mountains	1.5 ppm

Concomitantly, the petitioner has proposed to delete the established tolerances for the combined residues of cyazofamid and CCIM, in/on:

Tomato	0.20 ppm

Grape (import)	1.5 ppm

In conjunction with this petition,   SEQ CHAPTER \h \r 1 IR-4 is requesting amended registration of the ISK Biosciences end-use product, Ranman® 400SC (EPA Reg. No. 71512-3), a 3.33 lb ai/gal suspension concentrate (equivalent to a flowable concentrate; FlC) formulation, to add new uses on fruiting vegetables, okra, and grapes grown east of the Rocky Mountains; the product is currently registered for foliar application to cucurbit vegetables, potato, and tomato.  In addition, the petitioner wishes to include a greenhouse application of cyazofamid as a drench treatment to fruiting vegetables, okra, and cucurbit vegetables destined for transplantation to the field.  Foliar application is proposed for fruiting vegetables, okra, and grapes reflecting up to six applications at maximum seasonal rates of 0.455 lb ai/A for fruiting vegetables and 0.568 lb ai/A for grapes with 0- and 30-day preharvest intervals (PHIs), respectively.  For fruiting and cucurbit vegetable transplants, a single drench application is proposed, made at the time of seeding or any time thereafter up to 1 week prior to transplant, at 0.078 lb ai/A.

Tolerances for residues of cyazofamid are established under 40 CFR §180.601 and are expressed in terms of the combined residues of cyazofamid and its metabolite CCIM, expressed as cyazofamid.  Permanent tolerances are established under §180.601(a) in/on potato at 0.02 ppm, carrot roots at 0.09 ppm, cucurbit vegetable group 9 at 0.10 ppm, tomato at 0.20 ppm, and imported wine grapes (no domestic registrations) at 1.5 ppm.

The nature of the residues in plants is adequately understood for purposes of this petition based on previously submitted metabolism studies on grape, potato, and tomato.  HED has concluded that the residues of concern for tolerance setting and risk assessment purposes are the parent, cyazofamid, and the CCIM metabolite.

There are no livestock feedstuffs associated with the proposed uses on grape or fruiting or cucurbit vegetables; therefore, no livestock metabolism data, enforcement methods, storage stability data, or feeding studies are required to support this petition.

Adequate enforcement methodology is available to enforce the proposed tolerances.  Cyazofamid and metabolite CCIM are completely recovered (>80% recovery) using FDA’s Multiresidue Protocol D (without cleanup).  In addition, an acceptable HPLC/UV method is available for use as a single analyte confirmatory method.

Samples of peppers, leaf lettuce, and tomato from the submitted field trials were analyzed for residues of cyazofamid and its metabolite CCIM using acceptable LC/MS/MS  SEQ CHAPTER \h \r 1  methods.  The validated LOQ was 0.01 ppm for each analyte using both methods.  The methods were adequately validated prior to and/or concurrently with analysis of the field trial samples.

Adequate storage stability data are available or were submitted to support the crop field trial data submitted under this action.

The available European field trial data for grape are adequate to support the proposed use of the 3.3 lb ai/gal FlC formulation on grapes grown east of the Rocky Mountains.  No change in the established tolerance level for grapes is necessary; however, the tolerance must be moved to 180.601(c), for tolerances with regional registration.

To support the proposed use on the fruiting vegetables crop group, IR-4 submitted crop field trial data for bell and non-bell pepper.  In addition, the petitioner is relying on existing residue data for tomato.  The submitted pepper field trial data together with the available tomato field trial data are adequate to support the proposed use.  The data indicate that the proposed tolerance for the fruiting vegetable crop group is too high; a tolerance of 0.40 ppm is appropriate.

To support the proposed use on vegetables intended for transplant, IR-4 submitted residue data reflecting a greenhouse drench application to leaf lettuce and tomato seedlings that were subsequently transplanted to the field.  The data are adequate to support the proposed use on tomato.  Additional tests are needed to support the drench application on other crops to be transplanted: 2 tests each for bell pepper and non-bell pepper and 4 tests each for squash and cucumber.  No data is required for okra at this time since data may be translated from tomato and pepper to okra.

Tentatively acceptable confined rotational crop data have been submitted previously; field rotational crop data are not required.  HED previously concluded that the residue of concern in rotational crops is cyazofamid.  A 30-day plantback interval is established for all crops for which cyazofamid is not registered.

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

Pending submission of a revised Section B (see requirements under Directions for Use), submission of additional processing data for grapes (see requirements under Processed Food and Feed), and submission of a revised Section F (see requirements under Proposed Tolerances), there are no residue chemistry issues that would preclude granting:  conditional Section 3  registration for the requested use of cyazofamid on grapes east of the Rocky Mountains; full registration for the requested foliar, broadcast uses on fruiting vegetables, crop group 8, and drench/at transplant uses on tomato intended for transplant; and establishment of  tolerances for the combined residues of cyazofamid and its metabolite CCIM as follows::

	Tolerances to be established under 40 CFR §180.601(a):

Vegetable, fruiting, group 8	0.40 ppm

Okra	0.40 ppm

	Tolerances to be established under 40 CFR §180.601(c):

Grape	1.5 ppm

A human health risk assessment is forthcoming.

Note to PM:  On establishment of the recommended tolerances, the following tolerances should be removed from 40 CFR §180.601(a):

Grape, wine, *import	1.5 ppm

Tomato	0.20 ppm

Deficiencies

860.1200 Directions for Use

The maximum seasonal use rates for grapes, okra, fruiting vegetables, and cucurbits (excluding drench uses) in the Section B/label must be revised to reflect the total of the maximum number of applications at the maximum proposed use rate.  This corresponds to 0.43 lb ai/A for all crop types.

The Section B/label for cucurbit vegetables, fruiting vegetables, and okra must be amended: “3 fl oz/100 gallons of water (0.078 lb a.i./A)” should be clarified to indicate that the maximum gal water/A is 100.

.

The Section B/label must be revised to state that applications may be made to tomatoes in greenhouse transplant production but that no other greenhouse applications may be made.  The statement on the label “for use on all transplants” must be deleted.

 860.1550 Proposed Tolerances

The petitioner should submit a revised Section F reflecting the recommended tolerances and commodity definitions presented above and in Table 7.

Background

Cyazofamid is a broad-spectrum fungicide (Group 21; quinone inside inhibitor) active against oomycete fungi (such as Phytophthora, Plasmopara, Pseudoperonospora, and Pythium) and Plasmodiophoromycetes (Plasmodiospora brassicae).  It inhibits all stages of fungal development in the life cycle of Phytophthora infestans which causes late blight disease on potatoes and tomatoes, and inhibits the germination and formation of zoosporangia, germination of cytospores, zoospore mobility, and mycelial growth.  It controls downy mildew on cucurbit vegetables and grapes.

The chemical names and structures of cyazofamid and its major metabolite, CCIM, are shown in Table 1, and the physicochemical properties of the parent are summarized in Table 2.

Table 1.	Test Compound Nomenclature.

Compound	Chemical Structure

Common name	Cyazofamid

Company experimental name	N/A

IUPAC name	4-chloro-2-cyano-N, N-dimethyl-5-p-tolylimidazole-1-sulfonamide

CAS name 4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-1H-imidazole-1-sulfonam ide

CAS registry number	120116-88-3

End-use product (EP)	Ranman® 400SC Agricultural Fungicide (EPA Reg. No. 71512-3)

Compound	Chemical Structure of metabolite

Common name	CCIM

IUPAC name	4-chloro-5-p-tolylimidazole-2-carbonitrile

CAS name	4-chloro-5-(4-methylphenyl)-1H-imidazole-2-carbonitrile

Table 2.	Physicochemical Properties of the Technical Grade Cyazofamid.

Parameter	Value	Reference

Melting point (°C)	152.7	PMRA Regulatory Note REG2006-05 on Cyazofamid, 12/6/06

pH	4.9	e-Pesticide Manual, 13th Edition

Density at 20 °C (g/mL)	1.446

	Water solubility (at 20 °C)	pH	Solubility (mg/L)	REG2006-05

	5

7

9	0.121

0.107

0.109

	Solvent solubility (at 21.2°C)	Solvent	Solubility (g/L)

Acetone

Ethyl acetate

Methanol

Dichloromethane

Toluene

Hexane

n-Octanol

Acetonitrile

2-Propanol	43.1

16.19

1.74

94.82

6.0

0.03

0.04

29.446

0.43

	Vapor pressure at 25°C	<1.33 x 10-5 Pa

	Dissociation constant (pKa)	Does not dissociate in water. No pKa in the pH range of 2-12.

	Octanol/water partition coefficient 	LogKOW = 3.2

Λmax (nm)

2

7

10	285

279

287

860.1100 Chemical Identity

DER Reference:  47532601 (no DER; MRID reviewed herein; see Confidential Appendix, Appendix II)

To support the proposed uses for cyazofamid on grapes in the U.S., IR-4 is relying on European field trial data submitted to establish the current import tolerance for cyazofamid residues in/on wine grapes (PP#1F06305).  ChemSAC considered this request (see minutes of 8/29/07 meeting) and concluded that the residue data may be used to support application of cyazofamid to grapes grown east of the Rocky Mountains, provided that the petitioner addresses the following issues:  (i) the maximum U.S. application rate should be equal to or less than the rate used in the European trials; (ii) the U.S. preharvest and reapplication intervals should match the European trials; and (iii) the petition needs to address any differences in formulation and inert ingredients between that used in the European trials and that proposed in the U.S.  In evaluating a similar request for translation of European residue data on grapes for uses of cymoxanil and famoxadone east of the Rocky Mountains, ChemSAC noted (see minutes of 4/7/04 meeting) that if the U.S. product contained an inert ingredient which could significantly increase the adherence or stability of the residues, the data translation would not likely be accepted.

In response to the third requirement, ISK Biosciences Corporation has submitted a product chemistry discussion and data comparing the composition of the 3.33 lb ai/gal FlC formulation (Ranman 400SC; EPA Reg. No. 71512-3) proposed for use on grapes east of the Rocky Mountains in the U.S. and the 0.208 lb ai/gal FlC formulation (Mildicut 25SC) used in the European field trials.  The comparison of the two formulations was presented in a Confidential Appendix.

Conclusions.  Based on the product chemistry data provided by ISK Biosciences Corporation, the two formulations are comparable (ChemSAC meeting, 3/18/2009).

860.1200 Directions for Use

IR-4 has submitted Section B specifying the proposed uses of the 3.33 lb ai/gal FlC formulation of cyazofamid (Ranman® 400SC; EPA Reg. No. 71512-3) on grapes east of the Rocky Mountains, okra and fruiting vegetables, and cucurbit vegetables, along with a specimen label (dated 2/6/07) reflecting general use directions.  HED notes that the specimen label is essentially identical to the accepted label (dated 12/1/06) except that fewer tank mix partners are listed.  A summary of the proposed use directions for cyazofamid is presented below in Table 3.

Table 3.	Summary of Directions for Use of Cyazofamid.

Applic. Timing, Type, and Equip.	Formulation

[EPA Reg. No.]	Applic. Rate

(lb ai/A)	Max. No. Applic. per Season	Max. Seasonal Applic. Rate

(lb ai/A)	PHI

(days)	Use Directions and

Limitations1, 2

Grapes (East of the Rocky Mountains)

Foliar, Broadcast,

Ground or aerial	3.33 lb ai/gal FlC

in ≥100 gal/A or by air in ≥ 5 gal/A at a 10- to 14-day retreatment interval (RTI).  Use of any surfactant is prohibited.

Okra and Crop Group 8, includes all members of Fruiting Vegetables:  tomato, ground cherry, tomatillo, pepper (including bell pepper, chili pepper, cooking pepper, pimento, sweet pepper), eggplant, and pepino

Foliar,

Broadcast,

Ground or aerial	3.33 lb ai/gal FlC

[71512-3]	0.054-0.071	6	0.455	0	Applications are to be made beginning at flower initiation or when conditions are favorable for disease development at a 7- to 10-day RTI.3

At transplant,

directed to the base of the plant or in transplant water	3.33 lb ai/gal FlC

[71512-3]	0.054-0.071

(0.071 in trans-plant water)	1	0.455	0	Initial application is to be made at transplant to the base of the plants or in transplant water in ≥50 gal/A.  Additional applications are to be made when conditions are favorable for disease development at a 7- to 10-day RTI.

+

Foliar,

Broadcast,

Ground or aerial

	+

5

(implied)

	Drench to seedling tray at the time of seeding or any time thereafter up to 1 week prior to transplant	3.33 lb ai/gal FlC

[71512-3]	0.078 lb ai/

100 gal	1	0.078 lb ai/

100 gal	0	Greenhouse transplant production.  Use of any surfactant is prohibited.

Crop Group 9, includes all members of Cucurbit Vegetables:  cantaloupe, chayote, Chinese-waxgourd, citron melon, cucumbers, gherkin, gourds, honeydew melons, Momordica spp., muskmelon, watermelon, pumpkin, squash, and zucchini

Registered uses4

Foliar,

Broadcast,

Ground or aerial	3.33 lb ai/gal FlC

[71512-3]	0.054-0.071	6	0.429	0	Applications are to be made beginning at flower initiation or when conditions are favorable for disease development at a 7- to 10-day RTI.

Foliar,

Broadcast,

Ground or aerial

0.071	6

	Applications are to be made beginning when conditions are favorable for disease development at weekly intervals

Proposed uses4

At transplant,

directed to the base of the plant or in transplant water	3.33 lb ai/gal FlC

[71512-3]	0.054-0.071

(0.071 in trans-plant water)	1	0.429	0	Initial application is to be made at transplant to the base of the plants or in transplant water in ≥50 gal/A.  Additional applications are to be made when conditions are favorable for disease development at a 7- to 10-day RTI.

 +

Foliar,

Broadcast,

Ground or aerial

	+

5

(implied)

	Drench to seedling tray at the time of seeding or any time thereafter up to 1 week prior to transplant	3.33 lb ai/gal FlC

[71512-3]	0.078 lb ai/

100 gal	1	0.078 lb ai/

100 gal

 (0.078 lb ai/A)	0	Greenhouse transplant production.  Use of any surfactant is prohibited.

1 The use directions specify the following resistance management restriction for all listed crops:  Do not make more than three consecutive applications of the 3.33 lb ai/gal FlC formulation followed by at least three applications of fungicides having different modes of action before making additional applications of the 3.33 lb ai/gal FlC formulation.

2 For foliar applications to fruiting and cucurbit vegetables:  use of an organosilicone and/or nonionic surfactant is recommended for applications made in volumes up to 60 gal/A; application may be made through sprinkler irrigation equipment.

3 This use pattern is identical to the registered use on tomato.

4 Section B of the petition refers to the cucurbits section of the label for the 3.33 lb ai/gal FlC formulation for further directions and restrictions.

≥5 gal/A; and (3) application through sprinkler irrigation systems is not recommended unless specific directions are given for a crop.

The following rotational crop restriction is specified:  “Crops on this label may be planted immediately after the last treatment.  Do not plant other crops not registered for this product within 30 days after the last application.”

The specimen/accepted label states that the 3.33 lb ai/gal FlC formulation is not to be used for disease control on tomatoes or cucurbit vegetables grown for fruit production in greenhouses.

Conclusions.  The submitted use directions are sufficient to allow evaluation of the submitted residue data relative to the proposed uses.  For grapes, the maximum rates and PHIs in the relevant field trials are adequate.  The available data represent application rates >1x the proposed maximum seasonal rate for use in the U.S., similar retreatment intervals, and a shorter PHI (21/22 days) than the proposed U.S. PHI of 30 days.  For peppers (bell and non-bell) and tomato, the use patterns in the submitted field trials reflected the proposed use.

The maximum seasonal use rates for grapes, okra, fruiting vegetables, and cucurbits (excluding drench uses) must be revised in the Section B/label to reflect the total of the maximum number of applications at the maximum proposed use rate, which corresponds to 0.43 lb ai/A for all crop types.

The Section B/label for cucurbit vegetables, fruiting vegetables, and okra must be amended:“3 fl oz/100 gallons of water (0.078 lb a.i./A)” should be clarified to indicate that the maximum gal water/A is 100.

The Section B/label must be revised to state that applications may be made to tomatoes in greenhouse transplant production but that no other greenhouse transplant applications may be made.  The statement on the label “for use on all transplants” must be deleted.

860.1300 Nature of the Residue - Plants

Residue Chemistry Memo DP# 323339, 2/8/07, A. Acierto (PP#1F06305)

Residue Chemistry Memo DP# 285680, 2/20/04, A. Acierto (PP#1F06305)

No new plant metabolism studies were submitted with this petition.  Adequate plant metabolism studies with cyazofamid on grape, potato, and tomato were submitted in conjunction with PP#1F06305.  In each study, the cyazofamid test substances were radiolabeled in either the phenyl ring ([benzene-14C]cyazofamid) or in the fourth position of the imidazole ring ([imidazole-14C]cyazofamid).  The principal residue component identified in whole grapes, potatoes, and tomatoes was the unchanged parent cyazofamid; metabolite CCIM was identified at much lower levels.  Comparison of the metabolic profile of the initial extract with that of fortified stored samples demonstrated that cyazofamid in potato degraded by ~24% over the 6-month storage period, with a corresponding increase in the metabolite CCIM; fortified residues remained relatively unchanged in tomato for 9-9.5 months under frozen conditions.

The nature of the residue in plants is adequately understood for the purposes of this petition.  HED previously concluded that for risk assessment and tolerance expression, the parent, cyazofamid, and the CCIM metabolite are the residues of concern in plants.

860.1300 Nature of the Residue - Livestock

There are no livestock feedstuffs associated with the proposed/amended use on grape or fruiting or cucurbit vegetables; therefore, data requirements for livestock metabolism are not relevant to this tolerance petition.

860.1340 Residue Analytical Methods

Residue Chemistry Memo DP# 323339, 2/8/07, A. Acierto (PP#1F06305)

Residue Chemistry Memo DP# 285680, 2/20/04, A. Acierto (PP#1F06305)

Enforcement Method:  Adequate enforcement methodology is available to enforce the proposed tolerances.  Cyazofamid and metabolite CCIM are completely recovered (>80% recovery) using FDA’s Multiresidue Protocol D (without cleanup).  In addition, an acceptable HPLC/UV method is available for use as a single analyte confirmatory method.

Data Collection Methods:  Samples of peppers from the submitted field trials were analyzed for residues of cyazofamid and its metabolite CCIM using an LC/MS/MS  SEQ CHAPTER \h \r 1  method.  Briefly,  SEQ CHAPTER \h \r 1  samples were extracted with acetonitrile (ACN):water, each containing 2% acetic acid (1:1, v:v), then filtered.  The filtrate was evaporated to near dryness, reconstituted in 2% sodium sulfate solution, and then partitioned twice with methylene chloride.  The resulting organic phase was evaporated to dryness, redissolved in ACN:water, each containing 0.5% acetic acid (1:1, v:v), and analyzed for cyazofamid and CCIM using LC/MS/MS.  The validated LOQ was 0.01 ppm for each analyte.

Samples of leaf lettuce and tomato were analyzed for residues of cyazofamid and its metabolite CCIM using an LC/MS/MS  SEQ CHAPTER \h \r 1  method referenced by the petitioner as “Independent Laboratory Validation of the Residue Method for IKF-916 and CCIM in Tomatoes,” with minor modifications.  Briefly,  SEQ CHAPTER \h \r 1  samples were extracted with ACN followed by ACN:water (95:5, v:v) and vacuum filtered.  The filtrate was partitioned with hexane, and the resulting ACN phase was concentrated and dissolved in ACN:water (20:80, v:v), and then subjected to cleanup via solid phase extraction on a polymeric column; residues were eluted with ACN:water (60:40, v:v).  The eluate was concentrated with nitrogen or diluted with ACN/water (50:50, v:v) as necessary, filtered, and analyzed for cyazofamid and CCIM using LC/MS/MS.  The validated LOQ, based on the lower limit of method validation (LLMV), was 0.01 ppm for each analyte.

The methods were adequately validated prior to and/or concurrently with analysis of the field samples.  Acceptable recoveries were obtained from untreated crop samples fortified with each analyte at ~0.01-0.5 ppm.  Fortification levels included the LOQ and bracketed residue levels found in treated samples.

Conclusions.  The submitted residue analytical methods data are adequate to satisfy data requirements for the subject action.  Acceptable enforcement methodology is available for tolerance enforcement purposes for the proposed uses, and adequate LC/MS/MS methods were used for data collection in the submitted field trial studies.

860.1360 Multiresidue Methods

Residue Chemistry Memo DP# 285680, 2/20/04, A. Acierto (PP#1F06305)

Adequate multiresidue method data for cyazofamid and its metabolites were submitted previously in conjunction with PP#1F06305.

Conclusions.  The Agency previously concluded that the FDA Multiresidue Method designated Protocol D (without cleanup) meets the requirement of the Residue Chemistry Test Guideline 860.1360 to enforce tolerances for non-fatty commodities and recommended its use as the enforcement method for residues of cyazofamid and CCIM in grape, tomato, the cucurbit vegetable group, and potato (Memo dated 10/22/03, E. Kolbe, ACB, BEAD).

860.1380 Storage Stability

Residue Chemistry Memo DP# 285680, 2/20/04, A. Acierto (PP#1F06305)

Storage stability data submitted previously demonstrated that cyazofamid and its metabolite CCIM were reasonably stable for up to ~36 months in tomatoes.

A concurrent storage stability study was conducted with the leaf lettuce and tomato transplant study.  The data indicated that residues of cyazofamid and CCIM were stable in/on leaf lettuce and tomato stored frozen for up to 20.9 and 19.6 months, respectively; however, no 0-day data were provided.

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

Table 4.	Summary of Storage Conditions and Durations of Samples from Crop Field Trial Studies.

Matrix 	Storage Temperature

 (°C)	Actual Storage Duration	Interval of Demonstrated Storage Stability

Pepper	-28.7 to -14.7	158-272 days

(5.2-8.9 months)	Residues of cyazofamid and CCIM were reasonably stable in/on tomato stored frozen for up to ~36 months.

Lettuce, leaf	-40 to -5	210-611 days

(6.9-20.1 months)	Concurrent storage stability data indicate that residues of cyazofamid and CCIM are stable for up to 634 days in/on leaf lettuce and 596 days in/on tomato.  Additional data indicate that residues of cyazofamid and CCIM were reasonably stable in/on tomato stored frozen for up to ~36 months.

Tomato	-40 to -5	198-583 days

(6.5-19.2 months)

Conclusions.  The available storage stability data for tomato may be translated to support the storage durations and conditions of samples of peppers from the submitted crop field trial studies.  The available and concurrent storage stability studies are adequate to support the storage durations and conditions of samples of tomato and leaf lettuce from the submitted transplant study.  No corrections for potential decline during storage are needed for any of the residue studies.

Zero-day data were not provided with the concurrent storage stability study on leaf lettuce and tomato; IR-4 is reminded that storage stability studies should always include a 0-day sampling interval to establish the residue levels present at the time samples are placed into storage [see OPPTS 860.1380(d)(6)(i)].

860.1400 Water, Fish, and Irrigated Crops

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

860.1460 Food Handling

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

860.1480 Meat, Milk, Poultry, and Eggs

There are no livestock feedstuffs associated with the proposed use on grape or fruiting or cucurbit vegetable; therefore, data requirements pertaining to meat, milk, poultry, and eggs are not relevant to this tolerance petition.

860.1500 Crop Field Trials

DER Reference:	47528401.der.doc (Pepper)

		47528402.der.doc (Lettuce and tomato transplants)

Residue Chemistry Memo DP# 285680, 10/1/04, A. Acierto (PP#1F06305)

Residue Chemistry Memo DP# 285680, 2/20/04, A. Acierto (PP#1F06305)

Grape

No new grape field trial data were submitted with this petition.  To support the proposed uses for cyazofamid on grapes in the U.S. east of the Rocky Mountains, IR-4 is relying on European field trial data submitted to establish the current import tolerance for cyazofamid residues in/on wine grapes (PP#1F06305).  ChemSAC considered this request (see minutes of 8/29/2007 meeting) and concluded that the European residue data may be used to support application of cyazofamid to grapes grown east of the Rocky Mountains, provided that the petitioner addresses the following issues:  (i) the maximum U.S. application rate should be equal to or less than the rate used in the European trials; (ii) the U.S. preharvest and reapplication intervals should match the European trials; and (iii) the petitioner needs to address any differences in formulation and inert ingredients between the product(s) used in the European trials and the product(s) proposed for use in the U.S.  The petitioner’s response to the third requirement is addressed under 860.1100.

IR-4 is proposing the 3.3 lb ai/gal FlC formulation of cyazofamid for up to six broadcast foliar applications to grapes grown east of the Rocky Mountains at 0.054-0.071 lb ai/A/application, for a maximum seasonal rate of 0.568 lb ai/A, with a 10- to 14-day RTI and a 30-day PHI.  HED notes that based on the proposed use pattern, the proposed maximum seasonal rate must be reduced to 0.429 lb ai/A.

IR-4 has submitted (in Section G of the petition) summaries of the grape field trial data reviewed in conjunction with PP#1F06305 for imported grapes (DP#285680; refer to the DER for MRID 45409026 for a complete summary of the grape field trial data).

Ten trials were conducted with wine varieties of grapes   SEQ CHAPTER \h \r 1 in France (4 trials), Germany (2 trials), Italy (2 trials), Portugal (1 trial), and Spain (1 trial) during the 1999 growing season.  In addition, three trials were conducted in the United States in Region 10, and one trial each was conducted in Argentina and Mexico.

At most test locations, a total of eight broadcast foliar applications of the 0.208 lb ai/gal FlC formulation were made to grape vines at ~0.089 lb ai/A/application.  Applications were made with 10- to 16-day retreatment intervals for total seasonal rates of 0.689-0.732 lb ai/A (1.6-1.7x the maximum proposed seasonal rate for the current petition).  Grapes at one trial conducted in Northern France received nine applications for at total rate of 0.803 lb ai/A (1.9x); grape vines at the Portugal and Spain trials received eight applications at ~0.067 and 0.076 lb ai/A/application, respectively, for total rates of 0.529 and 0.621 lb ai/A (1.2-1.4x).  Mature grapes were harvested 21/22 days following the last application.

Adequate storage stability data submitted in support of the grape field trials indicated that residues of cyazofamid and CCIM were reasonably stable in grapes for up to 12 months and 6 months, respectively, but declined by an average of 50% after 24 months of freezer storage.  Grape samples from some of the field trials, including trials conducted in France, Germany, and Italy, were stored for >12 months prior to analysis; therefore, the residue values from the affected samples were adjusted for residue decline on storage as needed.

Based on these data, HED recommended an import tolerance of 1.5 ppm for grapes.  The tolerance recommendation was based on maximum combined residues of cyazofamid and CCIM, corrected for decline on storage, of 1.17 ppm in/on grapes from a trial conducted in Italy at an application rate of 0.714 lb ai/A.  The Tolerance/MRL Harmonization Spreadsheet was not used in calculating the tolerance.

Conclusions.  The available European grape field trial data are adequate to support the proposed use of the 3.33 lb ai/gal FlC formulation in the U.S. on grapes grown east of the Rocky Mountains.  The available data represent application rates >1x the proposed maximum seasonal rate for use in the U.S., similar retreatment intervals, and a shorter PHI (21/22 days) than the proposed U.S. PHI of 30 days.  In addition, the formulation used in the European trials and that proposed for use in the U.S. are comparable (refer to 860.1100).

The available data will support a tolerance with regional registration for combined residues of cyazofamid and CCIM in/on grapes at 1.5 ppm.

Vegetable, Fruiting (Crop Group 8) and Okra

A tolerance is established for the combined residues of cyazofamid and its metabolite CCIM in/on tomato at 0.20 ppm [40 CFR §180.601(a)].  To support the proposed use of cyazofamid on fruiting vegetables, crop group 8, and okra, IR-4 has submitted field trial data for pepper (bell and non-bell) and referenced tomato field trials previously submitted by ISK Biosciences in support of the established tolerance on tomato.  The representative commodities of the fruiting vegetable group are tomato, bell pepper, and non-bell pepper.

Pepper

IR-4 has submitted field trial data for cyazofamid on pepper (bell and non-bell).  Nine field trials were conducted on peppers in the United States during the 2006 growing season:  six bell pepper trials were conducted in Zones 2 (NC; 1 trial), 3 (FL; 1 trial), 5 (ND; 1 trial), 6 (OK; 1 trial), and 10 (CA; 2 trials); and three non-bell pepper trials were conducted in Zones 5 (ND), 8 (OK), and 10 (CA).

Each test site included one control plot and one treated plot.  At each test location, the treated plots received six broadcast foliar applications of a 3.33 lb ai/gal FlC formulation of cyazofamid at a rate of 0.067-0.075 lb ai/A per application, with a 6- to 8-day retreatment interval, for a total seasonal rate of 0.418-0.429 lb ai/A (~1x the adjusted maximum proposed seasonal application rate).  Applications were made in spray volumes of ~19-31 gal/A using ground equipment, with an organosilicone surfactant.  Samples of mature peppers were harvested on the day of the last application (0-day PHI).  At one field trial (ND; bell pepper), additional samples were collected 1, 3, and 7 days after the last application to address residue decline.

Samples of peppers were analyzed for residues of cyazofamid and its metabolite CCIM using an adequate LC/MS/MS  SEQ CHAPTER \h \r 1  method; the validated LOQ was 0.01 ppm for each analyte.  Sample storage intervals and conditions are reported in Table 4.  Adequate storage stability data are available to support the study.

The results of the pepper field trials are summarized in Table 5.  In samples of bell pepper harvested at a 0-day PHI following six applications of the 3.33 lb ai/gal FlC formulation at a total rate of 0.418-0.429 lb ai/A, maximum respective residues of cyazofamid and CCIM were 0.283 and 0.014 ppm; maximum combined residues were 0.297 ppm.  In non-bell pepper, maximum respective residues of cyazofamid and CCIM were 0.317 ppm and 0.017 ppm; maximum combined residues were 0.331 ppm.

In the residue decline trial, residues of cyazofamid declined with increasing sampling interval in/on bell pepper; residues of CCIM were <LOQ in/on all bell pepper samples from all sampling intervals.

Tomato

ISK Biosciences Corporation previously submitted residue data for cyazofamid and CCIM on tomato under PP#1F06305 (DP# 285680; refer to the 860.1500 DER for MRID 45409031 for a complete summary of the tomato field trial data).  The available tomato field trial data reflect application of the 3.33 lb ai/gal FlC formulation according to a use pattern identical to that proposed for fruiting vegetables with respect to maximum individual and seasonal application rates (~0.071 and 0.429 lb ai/A, respectively), maximum number of seasonal applications (six), and minimum RTI (7 days).  Separate trials were conducted in 1999 reflecting a 7-day PHI and use of an organosilicone surfactant and in 2000-2001 reflecting a 0-day PHI and no adjuvant, except at one site where a side-by-side trial was conducted with and without surfactant.  Two residue decline trials conducted in 1999 also included a 0-day PHI.

RAB3 previously concluded that the tomato field trial data were adequate.  The existing tolerance for tomatoes was established using data reflecting the 7-day PHI; however, IR-4 is proposing a 0-day PHI for use on fruiting vegetables.  For purposes of the subject petition, only the tomato field trial data reflecting a 0-day PHI are summarized herein.  These data are re-evaluated in conjunction with the submitted pepper field trial data in support of the proposed use on fruiting vegetables and okra.

Thirteen field trials were conducted on tomatoes in the United States during the 2000-2001 growing seasons in Zones 1 (1 trial; NY), 3 (2 trials; FL), 4 (1 trial; AR), and 10 (9 trials; CA), and two trials were conducted during the 1999 growing season in Zones 2 (1 trial; NC) and 10 (1 trial; CA).  A third FL trial conducted in 2000 is not included in this summary because the seasonal application rate was only 0.271 lb ai/A (0.6x the maximum proposed seasonal application rate) due to a calculation error.

At each test location, a total of six broadcast foliar applications of the 3.33 lb ai/gal SC formulation were made to tomato plants at ~0.071 lb ai/A/application.  Applications were made with 2- to 12-day retreatment intervals for total seasonal rates of 0.413-0.434 lb ai/A (0.9-1x the adjusted maximum proposed seasonal application rate).  All applications were made in ~9-44 gal/A of water, except at two 2001 CA trials, where spray volumes were ~75-120 gal/A.  No surfactant was added to the application solutions except at the two 1999 trials and at one 2000 trial site in CA, in which a side-by-side trial was conducted with and without adjuvant (an organosilicone surfactant was used).  Mature tomatoes were harvested on the day of the last application (0-day PHI).

Samples of tomatoes were analyzed for residues of cyazofamid and its metabolite CCIM using an adequate HPLC/UV method with a validated limit of quantitation of 0.01 ppm for each analyte.  Adequate storage stability data were submitted to support the study.

The results of the tomato field trials reflecting a 0-day PHI are summarized in Table 5.  Following six applications of the 3.33 lb ai/gal FlC formulation at a total rate of 0.413-0.434 lb ai/A, maximum respective residues of cyazofamid and CCIM were 0.16 and 0.02 ppm; maximum combined residues were <0.17 ppm.

  SEQ CHAPTER \h \r 1 Data from the single side-by-side trial reflecting use of a surfactant suggested that addition of a surfactant to the spray mixture may result in slightly higher residues of cyazofamid; residues of CCIM were <0.01 ppm in all samples.  In two samples each of tomatoes harvested 0 and 7 days following application without a surfactant, residues of cyazofamid were 0.02 and 0.05 ppm (0-day PHI) and 0.02 and 0.03 ppm (7-day PHI); in samples harvested following application with a surfactant, residues of cyazofamid were 0.03 and 0.05 ppm (0-day PHI) and 0.04 and 0.06 ppm (7-day PHI).

Table 5.	Summary of Residue Data from Fruiting Vegetables Crop Field Trials with Cyazofamid.

Commodity

(MRID)	Total Applic. Rate1

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

n	Min.	Max.	HAFT2	Median	Mean	Std. Dev.

Proposed use = 0.429 lb ai/A total application rate, 0-day PHI3

Pepper, bell

(47528401)	0.418-0.429	0	Cyazofamid	12	0.037	0.283	0.224	0.064	0.091 0.071

	CCIM	12	<0.01	0.014	0.012	0.01	0.010	0.001

	Combined	12	<0.047	0.297	<0.236	0.074	0.101	0.072

Pepper, non-bell

(47528401)	0.419-0.426	0	Cyazofamid	6	0.211	0.317	0.307	0.263	0.266 0.038

	CCIM	6	<0.01	0.017	0.014	0.014	0.013	0.003

	Combined	6	<0.221	0.331	0.321	0.277	0.279	0.040

Tomato

(45409031, 45638507, 45638508) 	0.413-0.434	0	Cyazofamid	32	<0.01	0.16 0.145	0.05	0.05	0.03

	CCIM	32	<0.01	0.02	0.015	0.01	0.01	0.01

	Combined	32	<0.02	<0.17	<0.16	0.06	0.06	0.04

1  All pepper field trial data reflect use of a surfactant; the tomato field trial data include results from 3 trials with surfactant and 10 trials without surfactant; data from both parts of the side-by-side trial reflecting application with and without a surfactant are included.

2  HAFT = Highest Average Field Trial.

3  Maximum proposed seasonal rate reflects adjustment recommended by HED (total of the maximum proposed number of applications at the maximum proposed single application rate).

Okra

No residue data were submitted to support the proposed use on okra.  IR-4 is proposing to translate the existing and submitted fruiting vegetable data (pepper and tomato) to okra.  The proposed use on okra is identical to the proposed use on the fruiting vegetables crop group.  HED has approved adding okra to the fruiting vegetable crop group (see minutes of the ChemSAC meeting of 10/18/06).  Until 40 CFR §180.41 is updated, a separate tolerance must be established for okra.

Conclusions.  The submitted/available data for bell and non-bell pepper and tomato are adequate to fulfill data requirements.  The number and locations of the trials are in accordance with OPPTS Guideline 860.1500 for bell and non-bell pepper and tomato as representative commodities of the fruiting vegetables, group 8, and the trials reflect the proposed use pattern.  In addition, the same formulation of cyazofamid was used for both sets of trials.  Samples were analyzed for residues of cyazofamid and CCIM using an acceptable method, and the studies are supported by adequate storage stability data.

Although the proposed use pattern recommends use of a spray adjuvant for applications to fruiting vegetables, and the majority of the relevant tomato field trial data do not reflect use of a spray adjuvant, no additional field trial data for tomato are required.  In the single side-by-side trial evaluating use of an adjuvant, the data suggest that residues will increase only slightly with use of an adjuvant.  Furthermore, on examination of the available data for bell and non-bell peppers and tomato, RAB3 has concluded that it is unlikely that residues in/on tomato following applications made with a spray adjuvant will exceed the maximum combined residues observed in/on bell pepper at 0.297 ppm and non-bell pepper at 0.331 ppm; average residues in/on bell and non-bell pepper were also significantly higher (0.101 and 0.279 ppm, respectively) than those in/on tomato (0.06 ppm).

Based on residue data and the Tolerance/MRL Harmonization Spreadsheet, the recommended tolerances for bell pepper, non-bell pepper, and tomato would be 0.35, 0.40, and 0.20 ppm, respectively.  Because these values differ by a factor of <5x, the data suggest that a group tolerance of 0.40 ppm is appropriate for fruiting vegetable group 8.

The available data for the fruiting vegetable crop group may be used to support the proposed tolerance for okra.  The tolerance should be established at the same level as the fruiting vegetable group tolerance, 0.40 ppm.

Vegetable transplants from the greenhouse to the field

Under the current action, IR-4 is proposing use of cyazofamid on fruiting and cucurbit vegetables that are to be transplanted from the greenhouse to the field.

In support of the proposed use, IR-4 has submitted magnitude of the residue data for cyazofamid reflecting greenhouse application to leaf lettuce and tomato to be transplanted, with tomatoes harvested at the one-inch size to provide a worst-case sampling of marketable crop.  Eight trials were conducted at four test locations in the United States during the 2005 and 2006 growing seasons.  One trial each was conducted for leaf lettuce and tomato in Zones 2 (MD), 3 (FL), 6 (TX), and 9 (NM).  Leaf lettuce and tomato were selected by the petitioner as representative of all vegetable transplants.

Each trial reflected one set of untreated plants and five sets of treated plants.  For each trial a single drench application of the 3.33 lb ai/gal FlC formulation was made at a rate of ~0.78 lb ai/100 gal (equivalent to 0.78 lb ai/A; 10x the maximum proposed application rate for vegetables to be transplanted) to seedlings grown in transplant trays in the greenhouse in an amount sufficient to wet the entire root zone; no adjuvant was used.  Following application, plants were transplanted to field plots according to the following schedule:

Treatment 01 = Untreated control

Treatment 02 = Application made 1 day prior to transplanting

Treatment 03 = Application made 7 ± 1 days prior to transplanting

Treatment 04 = Application made 14 ± 2 days prior to transplanting

Treatment 05 = Application made 21 ± 3 days prior to transplanting

Treatment 06 = Application made 28 ± 3 days prior to transplanting

Samples of leaf lettuce were collected at maturity, 21-53 days after transplanting, and samples of green, 1-inch tomatoes were collected 46-71 days after transplanting, respectively.  The harvest dates corresponded to preharvest intervals (PHIs) of 22-81 days for leaf lettuce and 47-99 days for tomato.

Samples were analyzed for residues of cyazofamid and its metabolite CCIM using an adequate LC/MS/MS method; the validated LOQ was 0.01 ppm for each analyte.  Sample storage intervals and conditions are reported in Table 4.  Adequate storage stability data are available to support the study.

The results of the vegetable transplant trials are summarized in Table 6.  Following a single drench application of the 3.33 lb ai/gal FLC formulation at a rate of ~0.78 lb ai/100 gal, residues of cyazofamid and CCIM were each below the LLMV (<0.01 ppm) in/on all samples of tomato following treatment 1, 7, 14, 21, or 28 days prior to transplanting, for combined residues <0.02 ppm.  Quantifiable residues of cyazofamid were observed in/on samples of mature leaf lettuce for all transplant intervals, while residues of CCIM were below the LLMV (<0.01 ppm) in/on leaf lettuce for all transplant intervals.  Maximum combined residues of cyazofamid and CCIM in/on leaf lettuce were:  (i) <0.230 ppm for plants treated 1 day prior to transplanting (PHI = 22-54 days); (ii) <0.055 ppm for plants treated 7 ± 1 days prior to transplanting (PHI = 29-60 days); (iii) <0.078 ppm for plants treated 14 ± 2 days prior to transplanting (PHI = 36-67 days); (iv) <0.044 ppm for plants treated 21 ± 3 days prior to transplanting (PHI = 43-74 days); and (v) <0.057 ppm for plants treated 28 ± 3 days prior to transplanting (PHI = 50-81 days).

Table 6.	Summary of Residue Data from Vegetable Transplant Field Trials with Cyazofamid Following Application of 10x the Proposed Rate.

Commodity	Total Applic. Rate

 (lb ai/100 gal)	PHI (days)	Treatment

(days before transplant)	Residue Levels1

 (ppm)

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

Proposed use =  0.078 lb ai/100 gal as single drench application up to 1 week prior to transplant

Cyazofamid

Lettuce, leaf	0.77-0.78	22-54	1	8	0.013	0.220	0.143	0.039	0.061	0.070

29-60	7 ± 1	8	<0.01	0.045	0.038	0.011	0.018	0.013

36-67	14 ± 2	8	<0.01	0.068	0.040	0.012	0.022	0.020

43-74	21 ± 3	8	<0.01	0.034	0.029	0.013	0.018	0.010

50-81	28 ± 3	8	<0.01	0.047	0.033	0.014	0.021	0.014

Tomato	0.77-0.80	47-72	1	8	<0.01	<0.01	<0.01	0.01	0.01	--

54-79	7 ± 1	8	<0.01	<0.01	<0.01	0.01	0.01	--

61-86	14 ± 2	8	<0.01	<0.01	<0.01	0.01	0.01	--

68-93	21 ± 3	8	<0.01	<0.01	<0.01	0.01	0.01	--

75-99	28 ± 3	8	<0.01	<0.01	<0.01	0.01	0.01	--

CCIM

Lettuce, leaf	0.77-0.78	22-54	1	8	<0.01	<0.01	<0.01	0.01	0.01	--

29-60	7 ± 1	8	<0.01	<0.01	<0.01	0.01	0.01	--

36-67	14 ± 2	8	<0.01	<0.01	<0.01	0.01	0.01	--

43-74	21 ± 3	8	<0.01	<0.01	<0.01	0.01	0.01	--

50-81	28 ± 3	8	<0.01	<0.01	<0.01	0.01	0.01	--

Tomato	0.77-0.80	47-72	1	8	<0.01	<0.01	<0.01	0.01	0.01	--

54-79	7 ± 1	8	<0.01	<0.01	<0.01	0.01	0.01	--

61-86	14 ± 2	8	<0.01	<0.01	<0.01	0.01	0.01	--

68-93	21 ± 3	8	<0.01	<0.01	<0.01	0.01	0.01	--

75-99	28 ± 3	8	<0.01	<0.01	<0.01	0.01	0.01	--

Combined

Lettuce, leaf	0.77-0.78	22-54	1	8	<0.023	<0.230	<0.153	0.049	0.071	0.070

29-60	7 ± 1	8	<0.02	<0.055	<0.048	0.021	0.028	0.013

36-67	14 ± 2	8	<0.02	<0.078	<0.050	0.022	0.032	0.020

43-74	21 ± 3	8	<0.02	<0.044	<0.039	0.023	0.028	0.010

50-81	28 ± 3	8	<0.02	<0.057	<0.043	0.024	0.031	0.014

Tomato	0.77-0.80	47-72	1	8	<0.02	<0.02	<0.02	0.02	0.02	--

54-79	7 ± 1	8	<0.02	<0.02	<0.02	0.02	0.02	--

61-86	14 ± 2	8	<0.02	<0.02	<0.02	0.02	0.02	--

68-93	21 ± 3	8	<0.02	<0.02	<0.02	0.02	0.02	--

75-99	28 ± 3	8	<0.02	<0.02	<0.02	0.02	0.02	--

1  HAFT = Highest Average Field Trial.

Conclusions.  IR-4 had originally proposed use of cyazofamid as a single drench application on all transplants, and ChemSAC approved the protocol for the study on leaf lettuce and tomato, (see minutes of 2/2/05 meeting), concluding that if no residues ≥LOQ were found in the 10x study, the use would be considered non-food.  On examination of the leaf lettuce and tomato data presented above, ChemSAC concluded (see minutes of 1/16/08 and 3/18/09) that a non-food use classification for tomato is appropriate; lettuce will not be allowed a nonfood use classification since there were detectable residues in the 10x study.

The submitted data for tomato are adequate to fulfill data requirements in support of the proposed use on tomato seedlings intended for transplant.  The number and location of trials are acceptable, and the submitted data reflect application at 10x the proposed application rate to vegetables to be transplanted.  Samples were analyzed for residues of cyazofamid and CCIM using an acceptable method, and the study is supported by adequate storage stability data.

To support transplant use for the remaining fruiting vegetables, okra, and cucurbit vegetables, the ChemSAC has concluded (see minutes of 3/18/09 meeting) that the petitioner should submit residue data similar to the lettuce and tomato residue data.  Greenhouse trials using a single drench application of cyazofamid at 10x the proposed rate are required for the representative crops:  2 trials each for bell and non-bell pepper and 4 trials each for cucumber and summer squash.  The results for peppers and tomatoes can be translated to okra.  If these data demonstrate that residues are <LOQ following treatment at 10x the proposed rate, then additional data to support the drench use on fruiting vegetables, okra, and cucurbit vegetables will not be needed.

A revised label is needed to state that the use on transplants will be allowed for tomatoes but will not be allowed for any other crops..  The statement on the label “for use on all transplants” must be deleted.

860.1520 Processed Food and Feed

Residue Chemistry Memo; DP# 285680, 2/20/04, A. Acierto (PP#1F06305).

Grape

Grape processing studies were previously submitted in conjunction with PP#1F06305 in support of the use of cyazofamid on imported grape wine.  The available processing data indicate that residues of cyazofamid and CCIM do not concentrate in raisins.    SEQ CHAPTER \h \r 1 Following processing, the average concentration factor in must was 1.2x but was reduced by 0.1-0.3x in wine.  Residues of CCIM were below the LOQ in/on all samples of grapes and grape must (unfermented or fermenting grape juice) but ranged <0.01-0.02 ppm in wine, indicating processing factors of >1x to >2x.

Conclusions.  The available grape processing data are adequate to satisfy data requirements.  The average processing factor for must is 1.2x.  The processing studies on must can be used in place of studies on grape juice.  Since a processing study is not available for juice, the processing factor of 1.2x for grape juice will be used in the dietary exposure assessment.  The proposed tolerance for grapes, 1.5 ppm, is adequate to cover grape juices.  No additional processing study is required.

Tomato

An adequate tomato processing study was previously submitted in conjunction with PP#1F06305.  Following application of the 3.33 lb ai/gal FlC formulation of cyazofamid to tomato plants at 0.567 lb ai/A (1.3x the maximum proposed seasonal application rate), the available processing data indicated that residues of cyazofamid do not concentrate in tomato paste and puree (processing factors of <0.3x) and residues of CCIM do not concentrate in puree but concentrated in paste by a factor of 4x.

HED previously concluded that, based on the available field trial data for tomato reflecting a 7-day PHI, and the respective processing factors for cyazofamid and CCIM, a tolerance for tomato paste was not required.

A processing factor for combined residues of cyazofamid and CCIM was not calculated in the original petition review (PP#1F06305).  The data indicate that the processing factors for combined residues of cyazofamid and CCIM are 1x for tomato paste and 0.4x for tomato puree.

Conclusions.  The available processing data for tomato are acceptable.  The data indicate that combined residues of cyazofamid and CCIM are unlikely to concentrate in the processed commodities of tomato; therefore, tolerances are not needed.

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

Analytical standards for   SEQ CHAPTER \h \r 1 cyazofamid (expiration date 2/16/2012) and its metabolite CCIM (expiration date 8/18/2009) are currently available in the EPA National Pesticide Standards Repository (personal communication with Dallas Wright, ACB, 12/18/08).

860.1850 Confined Accumulation in Rotational Crops

Residue Chemistry Memo DP# 285680, 2/20/04, A. Acierto (PP#1F06305)

Residue Chemistry Memo DP# 323339, 2/8/07, A. Acierto (PP#1F06305)

A tentatively acceptable confined rotational crop study was previously submitted in conjunction with PP#1F06305; representative chromatograms must be submitted before the study may be considered to be fully acceptable.  In the study, loamy sand soil was treated separately with cyazofamid radiolabeled in either the phenyl ring ([benzene-14C]cyazofamid) or in the fourth position of the imidazole ring ([imidazole-14C]cyazofamid) at a maximum seasonal rate of 0.445 lb ai/A.  At plantback intervals (PBIs) of 31, 119, and 360 days, the soil was seeded with carrot (a root vegetable), lettuce (a leafy vegetable), and wheat (a cereal grain).  Total radioactive residues (TRR) were ≥0.01 ppm in carrot roots (31- and 119-day PBIs), lettuce leaves (31-day PBI), wheat forage, straw, and chaff (all PBIs), and wheat grain (31- and 119-day PBIs).  TRR were generally highest in samples from the 31-day PBI and decreased thereafter.  Residue characterization in samples with TRR >0.01 ppm from the 31-day PBI identified cyazofamid (0.2-0.6% TRR) as a minor residue component along with the following metabolites:  CCIM (0.2-0.9% TRR), CCIM-AM (4-chloro-5-p-tolylimidazole-2-carboxamide, 0.1-0.9% TRR), and CCBA [4-(4-chloro-2-cyanoimidazole-5-yl)benzoic acid, 0.1-1.3% TRR].  The majority of radioactivity eluted at the solvent front, suggesting that much of the bound residue was due to incorporation of the label into biomolecules.

HED previously concluded that the residue of concern in rotational crop commodities is the parent cyazofamid.

860.1900 Field Accumulation in Rotational Crops

No limited rotational crop data have been submitted.  Based on the results of the confined rotational crop study reviewed in conjunction with PP#1F06305, HED previously concluded that a field accumulation study in rotational crops and tolerances for rotational crop commodities were not needed because cyazofamid and structurally related metabolites are not expected to be present at a level greater than 0.01 ppm in/on the commodities of three representative rotational crops at a 30-day PBI.

860.1550 Proposed Tolerances

Cyazofamid tolerances for plant commodities have been established in 40 CFR §180.601 and are expressed in terms of the combined residues of cyazofamid and its metabolite CCIM.  The tolerance expression proposed by the petitioner is consistent with the 40 CFR §180.601.

Presently, there are no MRLs established by Codex or Mexico for cyazofamid; therefore, harmonization is not an issue.  A Canadian MRL has been established for residues of cyazofamid and CCIM at 0.20 ppm for tomatoes.

The tolerances proposed by IR-4 are listed in Table 7, along with the tolerance levels recommended by RAB3.  For the foliar uses, adequate field trial data reflecting the proposed use pattern are available for grape and for bell and non-bell pepper and tomato, the representative commodities of the fruiting vegetables group.

The available European field trial data are adequate to support the proposed use on grapes grown east of the Rocky Mountains.  No change in the established tolerance level for grapes is necessary; however, the tolerance must be moved to 180.601(c) for tolerances with regional registration.

The Agency’s Guidance for Setting Pesticide Tolerances Based on Field Trial Data was utilized for determining appropriate tolerance levels for the fruiting vegetables crop group; see Appendix I for tolerance calculations.  Based on the submitted/available data for peppers and tomato, the recommended tolerances for the individual crops are 0.20 ppm for tomato, 0.35 ppm for bell pepper, and 0.40 ppm for non-bell pepper.  Because the recommended tolerances differ by less than 5x, a crop group tolerance is appropriate; however, the proposed tolerance of 0.80 ppm is too high.  A revised tolerance of 0.40 ppm must be proposed for the fruiting vegetables crop group.  Concomitant with the establishment of the group tolerance for fruiting vegetables, the established individual tolerance for tomato should be removed.

The available field trial data for the fruiting vegetables crop group may be translated to support use on okra.  The data support a revised tolerance of 0.40 ppm for okra.

Adequate processing data are available for tomato.  The data indicate that combined residues of cyazofamid and CCIM are not likely to concentrate in tomato paste or puree.  The available processing data for grape are adequate, and indicate processing factors of 1.2x for juice (based on must) and no concentration in raisins.  The tolerance for grapes will cover grape juice.

The proposed tolerances should be revised to reflect the recommended tolerance levels and correct commodity definitions as specified in Table 7.

Table 7. 	Tolerance Summary for Cyazofamid

Commodity	Established Tolerance (ppm)

	Proposed Tolerance (ppm)

	Recommended Tolerance (ppm)	Comments; Correct Commodity Definition

Tolerances established or to be listed under 40 CFR §180.601(a)

Vegetable, fruiting, group 8	--	0.80	0.40

	Okra	--	0.80	0.40

	Grape (import)	1.5	1.5	Move to 180.601(c)	Delete here

Tomato	0.20	--	Remove	Covered by tolerance for fruiting vegetable group.

Tolerance to be listed under 40 CFR §180.601(c)

Grape	[1.5]	1.5	1.5	Because use is to be restricted to areas east of the Rocky Mountains, the tolerance must be established with regional registration.

References

DP#	285680

Subject:	PP#1F06305;   SEQ CHAPTER \h \r 1 Petition for the Establishment of Permanent Tolerances for Use on Cucurbits, Potatoes, Tomatoes, and Imported Wine Grapes.  Summary of Analytical Chemistry and Residue Data.

From:	A. Acierto

To:	J. Whitehurst/C. Giles-Parker

Dated:	2/20/04

MRIDs:	  SEQ CHAPTER \h \r 1 45638502-45638505, 45638506-45638510, 45409014-20, 45409022, 45409023-45409025, 45409026-45409035, 45409036

DP#	285680

Subject:	PP#1F06305. Cyazofamid.    SEQ CHAPTER \h \r 1 Petition for the Establishment of Permanent Tolerances for Use on Cucurbits, Potatoes, Tomatoes, and Imported Wine Grapes.  Summary of Analytical Chemistry and Residue Data.  PC Code:  085601.

From:	A. Acierto

To:	J. Whitehurst/C. Giles-Parker

Dated:	10/1/04

MRIDs:	  SEQ CHAPTER \h \r 1 None

DP#	323339

Subject:	PP#1F06305.  Cyazofamid.  Data Submitted to Satisfy Conditional Registration Requirements for Use on Cucurbits, Potatoes, Tomatoes, and Imported Wine Grapes.  Summary of Analytical Chemistry and Residue Data.

From:	A. Acierto

To:	J. Whitehurst/C. Giles-Parker

Dated:	2/8/07

MRIDs:	  SEQ CHAPTER \h \r 1 46537726, 46537727, 46537728

  SEQ CHAPTER \h \r 1 Attachments:

International Residue Limit Status sheet

Appendix I - Tolerance Assessment Calculations

Template Version September 2005

INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name:  4-Chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-1H-imidazole-1-sulfonam ide 	Common Name:

Cyazofamid	X Proposed tolerance

( Reevaluated tolerance

( Other	Date: 12/2/08

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

X No Codex proposal step 6 or above

( No Codex proposal step 6 or above for the crops requested	Petition Number:  PP#8E7427

DP#:  357042

Other Identifier:

Residue definition (step 8/CXL): N/A	Reviewer/Branch:  A.Acierto/RAB3

	Residue definition:  Combined residues of cyazofamid, 4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-1H-imidazole-1-sulfonam ide and its metabolite, CCIM,  4-chloro-5-(4-methylphenyl)-1H-imidazole-2-carbonitrile, expressed as cyazofamid

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

Vegetable, fruiting, group 8	0.80

Okra	0.80

Grape – East of the Rocky Mountains	1.5

Limits for Canada	Limits for Mexico

( No Limits

( No Limits for the crops requested	X No Limits

( No Limits for the crops requested

Residue definition:  4-chloro-2-cyano-N,N-dimethyl-5-(4-methylphenyl)-1H-imidazole-1-sulfonam ide, including the metabolite 4-chloro-5-(4-methylphenyl)-1H-imidazole-2-carbonitrile 	Residue definition:  N/A

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

Tomatoes	0.2

Notes/Special Instructions:

S. Funk, 11/04/2008.

Appendix I.  Tolerance Assessment Calculations.

For each of the crops listed below, the Guidance for Setting Pesticide Tolerances Based on Field Trial Data (SOP), along with the tolerance spreadsheet (January 2008 version), was used for calculating recommended tolerances.  As specified in the SOP, the minimum of the 95% upper confidence limit (UCL) on the 95th percentile and the point estimate of the 99th percentile was selected as the tolerance value in cases when the dataset was large (greater than 15 samples) and reasonably lognormal.  For datasets that were small (≤15 samples) and reasonably lognormal, the upper bound estimate of the 95th percentile based on the median residue value was compared to the minimum of the 95% UCL on the 95th percentile and the point estimate of the 99th percentile, and the minimum value was selected as the tolerance value.  The rounding procedures specified in the SOP were also used.

Vegetables, Fruiting, Crop Group 8

The dataset used to establish a tolerance for cyazofamid on fruiting vegetables consisted of field trial data for tomato, bell pepper, and non-bell pepper (the representative crops of the fruiting vegetable crop group), representing an application rate of 0.413-0.434 lb ai/A (6 applications at 0.067-0.075 lb ai/A per application) with a 0-day PHI.  The field trial application rate and PHI are within 25% of the maximum label application rate and minimum label PHI, respectively.  The residue values that were entered into the tolerance spreadsheet are provided in Table I-1.

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4 pepper datasets were small (12 and 6 samples, respectively).  The tomato dataset was not small (32 samples).  For all three crops, visual inspection of the lognormal probability plots (Figures I-1, I-3, and I-5) and the results from the approximate Shapiro-Francia test statistic (Figures I-2, I-4, and I-6) indicated that the datasets were reasonably lognormal.

Using the tolerance spreadsheet, the recommended tolerances are 0.20 ppm for tomato, 0.35 ppm for bell pepper, and 0.40 ppm for non-bell pepper.  Because the minimum and maximum recommended tolerances differ by less than 5x, a crop group tolerance is appropriate for fruiting vegetables.  The recommended value is 0.40 ppm, the maximum of the recommended individual tolerances.

Table I-1.	Residue data used to calculate tolerance for cyazofamid on fruiting vegetables.

Regulator:	EPA	EPA	EPA

Chemical:	Cyazofamid	Cyazofamid	Cyazofamid

Crop:	Tomato	Pepper, bell	Pepper, non-bell

PHI:	0 Days	0 Days	0 Days

App. Rate:	0.413-0.434 lb ai/A	0.418-0.429 lb ai/A	0.419-0.426 lb ai/A

Submitter:	ISK Biosciences Corporation	IR-4	IR-4

MRID Citation:	MRIDs 45409031, 45638507, 45638508	MRID 47528401	MRID 47528401

	Combined Residues of Cyazofamid and CCIM (ppm)

	<0.06	<0.047	<0.221

	<0.07	<0.048	0.294

	<0.03	<0.065	0.311

	<0.04	<0.070	0.331

	0.05	<0.075	0.260

	0.07	<0.089	<0.258

	<0.06	<0.081

<0.10	<0.134

<0.07	<0.058

<0.08	<0.072

<0.02	<0.174

<0.02	0.297

<0.04

	<0.04

	<0.06

	<0.06

	<0.14

	<0.17

	<0.04

	<0.06

	0.09

	0.15

	<0.06

	<0.06

	0.04

	<0.05

	<0.03

	0.05

	<0.03

	<0.06

	<0.04

	<0.06

Figure I-1.  Lognormal probability plot of cyazofamid field trial data for tomato.

Figure I-2.  Tolerance spreadsheet summary of cyazofamid field trial data for tomato.

Figure I-3.  Lognormal probability plot of cyazofamid field trial data for bell pepper.

Figure I-4.  Tolerance spreadsheet summary of cyazofamid field trial data for bell pepper.

Figure I-5.  Lognormal probability plot of cyazofamid field trial data for non-bell pepper.

Figure I-6.  Tolerance spreadsheet summary of cyazofamid field trial data for non-bell pepper.

Cyazofamid	Summary of Analytical Chemistry and Residue Data	DP#:  357042

Page   PAGE  30  of   NUMPAGES  30

Lognormal Probability Plot

99.9

99

98

95

90

80

70

50

30

20

10

5

2

1

0.1

1.0000

0.5000

0.2500

0.1250

0.0625

0.0313

0.0156

0.0156

0.0156

0.0156

0.0156

0.0156

0.0156

0.0156

0.0156

0.0156

y = 0.5071x - 2.9004

R

2

 = 0.9548

Percentiles

Concentrations

EPA Cyazofamid Tomato 0 days 0.413-0.434 lb ai/A ISK Biosciences Corporation