Page 1 of 33 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND
POLLUTION PREVENTION

M EMORANDUM

Date : 2/1 6 /11

SUBJECT: Flazasulfuron

. Summary of Analytical Chemistry and Residue Data for Use on Citrus, Grapes and Sugar cane

.

PC Code: 119011 DP Barcode s : D 372901 , D389318
Decision No.: 425252 Registration No. : 71512

- RI
Petition No.: 9F7 666 Regulatory Action: Section 3 Registration Risk Assessment Type: NA Case No.: NA
T XR No.: N A CAS No.: 104040

- 78

- 0
MRID No.: See MRID Summary Table 40 CFR: 180.xxx (pending)

FROM: Nancy Dodd, Chemist Risk Assessment Branch III (RAB3)
Health Eff ects Division (HED) (7509P)

THROUGH: Leung Cheng, Senior Chemist RAB3/HED (7509P)

TO: James Tompkins /Hope Johnson, RM#25 Registration Division (7505P)

Note: This document was original ly prepared under contract by Versar, Inc. (6850 Versar Center, Springfield, VA 22151;
submitted 9/28/10). The document has been reviewed by the Health Effects Division (HED) and revised to reflect current Office of Pesticide Program s (OPP) policies.

MRID Summary Table

MRID No. Study Type Comments

47939901 860. 1380, 860.1 500, 860.1520 New DER; 47939901 .der1 (860.1380, 860.1500) New DER; 47939901 .der2 (860.1520)

47939902 860. 1380, 860.1 500, 860.1520 New DER; 47939902 .der1 (860.138 0, 860.1500) New DER; 47939902 .der2 (860.1520)

47939903 860.1380 New DER; 47939903.der

47939904 860.1 380, 860.1 5 00 , 860.1520 New DER; 47939904 .der1 (860.1380, 860.1500) New DER; 47939904 .der2 (860.1520)

47939905 860.1300 (plant) New DER; 4793990 5.der

4 7939906 860.1300 (plant) New DER; 4793990 6.der

47939907 860.1300 (plant) New DER; 4793990 7.der

47939908 860.1300 (livestock) New DER; 47939908 .der

48092201 860.1340 New DER; 48092201.derPage 2 of 33 MRID Summary Table

MRID No. Study Type Comments

48451001 860.1300 (livestock) No DER; additional sample history information

48451002 860.1300 (plant) No DER; additional sample history information

Executive Summary

Flazasulfuron is a sulfonylurea herbicide for control of certain broad

- leaf weeds and grasses, and acts by inhibiting the acetolactate synthase (ALS) biochemical process. Flazasulfuron has been registered as a reduced risk product for use on turf grasses in non

- residential areas.

ISK Biosciences Corporation , a wholly owned subsidiary of Ishihara Sangyo Kaisha, Ltd., has submitted a petition, PP#9F766 6, for the establishment of permanent tolerances for residues of
the herbicide f lazasulfuron ( N

- [[(4,6

- dimethoxy

- 2

- pyrimidinyl)amino]carbonyl]

- 3

- (trifluoromethyl)

- 2

- pyridinesulfonamide) in/on the following raw agricultural commodities (RACs):

Citrus

................................ ................................ ........ 0.01 ppm Grapes

................................ ................................ ...... 0. 01 ppm Sugarcane

................................ ................................ . 0. 01 ppm

The end

- use product relevant for this petition is ISK Flazasulfuron Herbicide , a water dispersible granular (WDG /WG ) formulation containing 25% active ingredient ( ai )

. The product is proposed for u se on citrus, grap es, and sugar cane at a maximum single application rate of 0.045 lb ai/A or a maximum seasonal application rate of 0.15 lb ai/A. The use of a non

- ionic surfactant is recommended for post

- emergence applications to citrus and grapes. The pre

- harvest interval s (PHI s ) for these crops are 1 day for citrus, 75 days for grapes, and 180 days for sugar cane.

A cceptable metaboli sm studies on grapes, sugar cane , and tomatoes are available

. Residues of the parent (flazasulfuron) were not detected in the tomato study and were only detected as a trace
or minor c omponent in the grape and sugar cane studies. The major metabolites (>10% total radioactive residues [TRR]) which were identified were DTPU in grape leaves and grape fruit, DTPP in grape leaves

, and HTPP (primari ly conjugated) and TPSA in tomato fruit . There were no major metabolites (>10% TRR) in sugarcane but the primary minor metabolites (<10% TRR)

were HTPP, TPSA

, and ADMP. (Refer to Appendix 2 for chemical names and structures). The metabolic pathways for grapes, tomat oes, and sugarcane are similar. The pathways involv e intramolecular rearrangement of the sulfonyl urea bridge to form DTPU , followed by hydrolysis

t o form DTPP and HTPP , and c leavage of the sulfonylurea bridge to form TPSA and ADMP.

The grape , sugarcane, and tomato metabolism studies were evaluated by EPA’s Residues of Concern Knowledgebase Subcommitte e (ROCKS) on 2/15/11

. Based on the available information, the ROCKS determined that the residue of concern for plants for both the tolerance

ex pression and risk assessment is parent. This conclusion is based on the fact that no residues of parent or DTPU were found in any field trials.

A n acceptable goat metabolism study is available . The m ajor metabolites identified in kidney,
liver and/or mu scle included the parent (flazasulfuron), HTPP, and DTPU. DTPP was identifiedPage 3 of 33 as a minor metabolite only. The petitioner indicated that flazasulfuron undergoes not only loss of the sulfonyl moiety and rearrangement to form DTPU, DTPP, and HTPP, but is fu rther metabolized and excreted as HTPU glucuronide, HTPP glucuronide (TPPG), HDTP glucuronide (HDTG), and HTPP + O

- glucu ronide. Chromatographic analysis showed that the radioactivity extracted from a tissue type was consistent regardless of label position and yielded little evidence of cleavage of the parent molecule by the goat, elimination of the sulfonyl moiety and reconnection of the urea bridge notwithstanding.

The goat metabolism study w as evaluated by the ROCKS on 2/15/11 . Based on the available
i nformation, the ROCKS determined for the proposed uses that the residue of concern for ruminants for both the tolerance expression and risk assessment is parent. There is no concern
with metabolites b ecause of the low dietary burden associated with the pr oposed uses

.

An adequate residue analytical method using high performance liquid chromatography/tandem mass spectrometry with multiple reaction monitoring (HPLC/MS

- MS/MRM) ( ADME study
code S09

- 03106 ; MRID 48092201 ) is available for enforcing the proposed tolerance s. The
method underwent a successful independent laboratory validation (ILV) using olives, tomatoes,
and wheat. T he validated limit of quantitation (LOQ) is 0.01 ppm . Radiovalidation is not needed since the extraction solvent is the same (acet onitrile : water, 80 : 20 , v/v ) in the method (MRID 48092201) and in the grape, sugarcane, and tomato metabolism studies (MRIDs 47939905, 47939906, and 47939907, respectively).

In the field trials a nd processing studies submitted , residue s of flazasulfuron an d/or DTPU were determined using an adequate HPLC

- MS/MS method from Central California Research Laboratories, Inc., titled “Analytical Method for Determination of SL

- 160 and Its Metabolite in Soil” (CRL

- MTH

- 045). Residues of parent and D TPU were reported f or citrus and grapes, while residues of parent were reported for sugarcane. The method w as adequately validated both prior to and in conjunction with the analysis of the field trial and processing study samples. The lowest level of method validation (LLM V) was 0.01 ppm in each matrix tested

.

Flazasulfuron and metabolite DTPU are not listed in the FDA PESTDATA database ( Pesticide Analytical Manual , Volume I, Appendix I, 3 rd edition, 1994, revised October 1999) . A multiresidue method study must be submit ted.

S torage stability stud ies with flazasulfuron demonstrated that the residues are stable for 12 months in grapes and 183 days in oranges and sugarcane. Residue s of the metabolite DTPU are also stable for 90 days in grapes and 183 days in oranges. The available storage stability data are adequate to support the storage durations and conditions for the RAC samples in this petition. Storage stability data were not provided for the processed commodities

. A s the orange processed commodity samples (juice, pulp, and oil) and raisin samples were stored for less than 30 days, no supporting storage stability data are required for these commodities. Because the grape juice, grape pomace, sugarcane bagasse, molasses, and refined sugar processed commodities were only stored for 5 to 12 days longer than the one month threshold, and because the stability of flazasulfuron and/or DTPU was demonstrated in the RACs, the availabl e storage stability data
for fl azasulf u ron and/or DTPU are adequate to support the storage i ntervals for the processed
commodities.Page 4 of 33 T here are no poultry or swine feedstuffs associated with the subject petition ; therefore

, data requirements pertaining to poultry and swine are not relevant to this petition.

The ruminant feedstuffs associated w ith the proposed uses of flazasulfuron are dried citrus pulp and sugarcane molasses , each at a maximum of 10% of the diet in beef and dairy cattle. The petitioner did not submit a livestock feeding study. Because of the low transfer factors from the
goat metabolism study and the low predicted residues in cow milk and tissues, HED is waiving the requirement for a cow feeding study. If future uses significantly increase the dietary burden, livestock feeding studies would be required, in which parent and me tabolites HTPP and DTPU
would be determined.

For all livestock, the proposed uses fall under 40 CFR §180.6(a)(3), i.e., there is no reasonable expectation that finite residues will occur in poultry, swine, or ruminant commodities as a result of the propos ed uses. Therefore, no tolerances are needed for livestock commodities.

Adequate field trial data were submitted supporting the use of the flazasulfuron WDG
formulation on the proposed crop/ crop groups. An adequate number of field trials were conducted on the required representative crops in the appropriate geographic regions, with the exception of citrus in which one lemon trial in Region 3 is missing. An additional lemon field trial will not be required because data from the remaining field trials w ill sufficiently represent residues likely to be seen. All trials reflect the proposed use pattern; however, for the sugarcane trials, the maximum seasonal application rate was applied in a single application. Residues of flazasulfuron and DPTU were separ ately determined in the citrus and grape field trials; residues of flazasulfuron were determined in the sugarcane field trials. Data from these trials are
sufficient ; residues of flazasulfuron and residues of DTPU were all <LOQ (<0.01 ppm )

. The
available field trial data will support the proposed tolerance of 0.01 ppm for residues of
flazasulfuron in/on citrus, grapes, and sugarcane. The tolerance spreadsheet in the Agency’s Guidance for Setting Pesticide Tolerances Based on Field Trial Data was not util ized for determining appropriate tolerance level s because all of the treated samples bore residues below the LOQ.

Processed food / feed studies for citrus (oil, juice, and dried pulp), grape (juice and raisin )

, and

sugar cane ( molasses and refined sugar ) are available

. Processing factors for parent could not be calculated for any of the processed commodities because no quantifiable residues of parent occurred. Therefore, separate tolerances are not required for the processed commodities of citrus (oil, juic e, and dried pulp )

, grape ( juice and raisin ) , and sugarcane (molasses and refined sugar ).Page 5 of 33 There are no rotational crop data requirements associated with the use on citrus or grapes (OPPTS 860.1850)

. The rotational crop gu ideline s are applicable for sugar cane ; however, rotational crop data have not been submitted. The proposed label for sugarcane requires a 12

- month interval between the last application and the planting of the rotational crop. While HED considers this restriction to be adequate for condi tional registration of flazasulfuron based on the
fact that no detectable residues of flazasulfuron were found in the primary crops, the restriction
will need to be re

- evaluated after submission and review of the confined rotational crop study which is req u ired to support permanent registration of sugarcane

.

No Codex, Canadian, or Mexican maximum residue limits (MRLs) /tolerances have been
established for residues of flazasulfuron

.

Regulatory Recommendations and Residue Chemistry Defi ciencies

HED has examined the residue chemistry database for flazasulfuron. Pending submission of a revised Section B (see requirements under Directions for Use) and a revised Section F (see requirement under Proposed Tolerances)

, there are no residue chemistry issues that would preclude granting permanent tolerances on citrus, grape, and sugarcane and conditional registration for ISK Flazasulfuron Herbicide (EPA Reg. No. 71512

- RI ) on citrus, grape, and sugarcane. Tolerances for r esidues of flazasulfuron are recommended as follow:

Fruit, c itrus, group 10

- 10

................................ ......... 0.01 ppm Grape

................................ ................................ ........ 0.01 ppm Sugarcane

................................ ................................ . 0.01 ppm

As conditions of registration, the remaining deficiencies listed below must be resolved.

A human health risk assessment is forthcom ing.

Note to PM:

The tolerance expression for flazasulfuronl in 40 CFR § 180.xxx should be stated according to HED’s Interim Guidance on Tolerance Expressions (5/27/09, S. Knizner) as follows:

“Tolerances are established for residues of flazasulfuron, including its 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 flazasulfuron ( N

- [[(4,6

- dimethoxy

- 2

- pyrimidinyl)amino]carbonyl]

- 3

- (trifluoro methyl)

- 2

- pyridinesulfonamide)

. ”Page 6 of 33 **•** The Section B/ label should be changed to clarify/revise the minimum retreatment interval (RTI)

. The general label application restrictions state that repeat applications may be
made at 2 to 6 weeks after application. However, the label also states that split applications should be made at 4 to 6 weeks after the first application, and that sequential applications are made on a longer term interval such as spring followed by a fall application. The petitioner should also consider that the label directions regarding the

RTI should reflect the field trials. The re treatment intervals for citrus in the field trials
were 95

- 308 days for citrus and 14

- 118 days for grapes. Based on the residue data, the

re treatment interval should be at least 3 months for citrus and at least 2 weeks for grapes. 860.1200 Directions for Use

**•** The proposed label for sugarcane requires a 12

- month interval between the last application and the planting of the rotational crop. While HED considers this restriction to be adequate for conditional registration of flazasulfuron based on the fact that no
detectable residues of flazasulfuron were found in the primary crops, the restriction will
need to be re

- evaluated after submission and review of the confine d rotational crop study which is required to support permanent registration of sugarcane

.

**•** The petitioner is required to submit multiresidue methods data since tolerances will be
established. 860.1360 Multiresidue Methods

860.1380 Storage Stability Dat a

**•** For MRID 47939903 ( Howald, M., Ullrich

- Mitzel, A. (1997) Storage Stability of SL

- 160 Residues in Grapes. Document Number: 634713), t he petitioner must provide dates of sample spiking and analysis to verify reported storage intervals.

860.1550 Propose d Tolerances

**•** The petitioner must submit a revised Section F to propose tolerances which reflect the correct commodity definitions as specified in Table 1 1

.

**•** A confined rotational crop stud y is required to support permanent registration of

sugarcane . Depending on the results, a study to determine field accumulation in rotational crops may be required. 860.1850/860.1900 Confined/Field Accumulation in Rotational Crops

Background

Flazasulfuron is a herbicide developed by ISK Biosciences Corporation for c ontrol of certain broadleaf weeds and grasses in ci trus, grapes, and sugar cane. Flazasulfuron has also been proposed for use on Christmas trees and industrial vegetation management in nonagricultural
areas. This is the first food/feed use for flazasulfuro n. Flazasulfuron is registered for use on turf. Flazasulfuron acts by inhibiting the acetolactate synthase (ALS) biochemical process.Page 7 of 33 The chemical name and structure of flazasulfuron are listed below in Table 1. The physicochemical properties of flaza sulfuron are listed in Table 2.

Table 1. Flazasulfuron N omenclature. Compound Chemical Structure

Common name Flazasulfuron Company experimental name SL

- 160

IUPAC name 1

- (4,6

- dimethoxypyrimidin

- 2

- yl)

- 3

- (3

- trifluoromethyl

- 2

- pyridylsulfonyl)urea

C AS name N

- [[(4,6

- dimethoxy

- 2

- pyrimidinyl)amino]carbonyl]

- 3

- (trifluoromethyl)

- 2

- pyridinesulfonamide CAS registry number 104040

- 78

- 0

End

- use product (EP) ISK Flazasulfuron Herbicide, a WDG/WG formulation containing 25% active ingredient (ai) (EPA File Symb ol 71512

- RI ) , for use on citrus, grapes, and sugarcane; Flazasulfuron 25WG (EPA Reg. No 71512

- 12), registered on turf

Table 2. Physicochemical Properties of Flazasulfuron.

Parameter Value Reference
Melting point 150 ° C MRID 46220905
pH 4.01 at 25 ° C (1% w/w)
Density 0.66 g/cm 3 at 25 ° C (bulk density)

Water solubility (25 **°** C) pH 5 buffer 0.027 mg/mL pH 7 buffer 2.1 mg/mL pH 9 buffer not stable

Solvent solubility (25 **°** C) Acetone 22.7 mg/mL
Acetonitrile 8.7 mg/mL
Dichloromethane 22.1 mg/mL Ethyl ac etate 6.9 mg/mL

Hexanes * 0.50 μg/mL
Methanol 4.2 mg/mL
Octanol 0.20 mg/mL
Toluene 0.56 mg/mL

Vapor pressure <1 x 10 - 7 torr (<1.33 x 10 - 5 Pa) at 25, 35,
and 45 ° C
Dissociation constant (pK

a ) at 20 ° C 4.37
Octanol/water partition coefficient Log(K OW ) a t 25 ° C K
ow = 20.0 in pH 5 buffer

K
ow = <10 in pH 7 buffer
UV/visible absorption spectrum Not reported

*n

- hexane with various methylpentanesPage 8 of 33 860.1200 Directions for Use

ISK Bioscience Corporation has submitted a copy of the proposed use directions fo r the 25% ai WDG formulation of flazasulfuron (ISK Flazasulfuron Herbicide; EPA File Symbol 71512

- RI ) on citrus, grapes, and sugar cane. The proposed use directions are presented in Table 3 below.

Table 3

. Summary of Directions for Use of Flazasulfuron

.

Applic. Timing, Type, and Equip. Applic ation

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

Rate (lb ai/A) Minimum

RTI (days) PHI (days) Use Directions and Limitations

Citrus

Pre

- emergence and

Post

- emergence; Soil applicatio n using ground spray equipment 0.045 Not reported 0.15 Not reported 1 1 Apply only as a directed spray to the soil
beneath the trees.

Use a non

- ionic surfactant at 0.25% v/v for
post

- emergence applications.

Grapes

Pre

- emergence and

Post

- emergence; Soi l application using ground spray equipment 0.045 Not reported 0.15 Not reported 1 75 Apply only as a directed spray to the soil
beneath the vines.

Use a non

- ionic surfactant at 0.25% v/v.

Sugarcane

Over

- the

- Top or
Post

- directed 0.023 Not reported 0.15 14 180 Apply prior to spiking or on ratoon up to
24 inches tall at a 0.014 lb ai/A rate.

Use a non

- ionic surfactant at 0.25% v/v.

Allow a 12 month interval between the last application and the planting of the rotational crop.

Post

- Directed 0.045 Not rep orted 0.15 14 180 Apply to sugarcane that is 18 inches tall up through layby. Applications should
minimize contact with the whorl of the

sugarcane.

Use a non

- ionic surfactant at 0.25% v/v.

Allow a 12 month interval between the last application and the p lanting of the rotational crop.

1 A re treatment interval specifically for citrus and grapes was not provided. A ge neric re treatment interval was provided.

General application information on the label states that pre

- emergence and post

- emergence applicat ions should be made in 15 to 50 gallons of water per acre. For directed post

- emergence sprays, a spray volume of 20 gallons or more per acre is recommended. Applications should be made using conventional low pressure ground spray equipment. Applications cannot be made aerially or through any irrigation system. The general label application restrictions also state that repeat applications may be made at 2 to 6 weeks after application. However, the label also states that split applications should be made at 4 to 6 weeks after the first application

, and thatPage 9 of 33 sequential applications are made on a longer term interval such as spring followed by a fall application.

HED Conclusions

. The Section B/ label should be changed to clarify/revise the minimum

retrea tment interval. The general label application restrictions state that repeat applications may be made at 2 to 6 weeks after application. However, the label also states that split applications should be made at 4 to 6 weeks after the first application, an d that sequential applications are made on a longer term interval such as spring followed by a fall application. The petitioner
should also consider that the label directions regarding the retreatment interval should reflect the
field trials. The re treat ment intervals for citrus in the field trials were 95

- 308 days for citrus and
14

- 118 days for grapes. Based on the residue data, the re treatment interval should be at least 3 months for citrus and at least 2 weeks for grapes.

The proposed label for sug arcane requires a 12

- month interval between the last application and the planting of the rotational crop. While HED considers this restriction to be adequate for conditional registration of flazasulfuron based on the fact that no detectable residues were found in the primary crops, the restriction will need to be re

- evaluated after submission and review of the confined rotational crop study which is required to support permanent registration.

860.1300 Nature of the Residue

– Plants

DER References: 47939 90 5.der (grapes), 4793990 6.der (sugarcane), 4793990 7.der (tomatoes)

Grapes

47939905.der

ISK Biosciences Corporation has submitted a study investigating the metabolism of [pyridyl

- 14 C]flazasulfuron (P

- label; specific activity 113

- 137 μCi/mg ) and [pyrimid inyl

14 C]flazasulfuron (Pm

- label; 122 μCi/mg ) in grape vines grown in treated soil under field and greenhouse
conditions

. As shown in Table 4 below, the test substances were radiolabeled at the 2

- or 5

- positions , respectively, of the pyridyl or pyrimidiny l rings.

TABLE 4

. Test Material Characteristics. Field Study

Chemical structure

Radiolabel position [ 14 C

- pyridyl]

- flazasulfuron (P label) [ 14 C

- pyrimidinyl]

- flazasulfuron (Pm label)

The test substances, diluted with water, were applied as a sp ray application to the soil around grape vines grown either outdoors or in a greenhouse at a target rate of 0.045 lb ai/A per application (50 g ai/ha/application). In both the field and greenhouse, there were two sets of plants: one set received a single a pplication and the second set received two applications. ForPage 10 of 33 plants receiving two applications, the first application was made at early bud break or at post bud break when vines were approximately 10 feet in height and the second application was made

seve n or eight weeks after the first. For plants receiving two applications, the total seasonal application rate was 0.089 lb ai/A (100 g ai/ha). Samples of foliage and grapes were collected at maturity (85 days after the second application for the field stu dy and 34 days after the second application for the greenhouse study). T he in

- life phase of the field study was conducted by Plant Sciences, Inc. (PSI; Watsonville, CA), and the in

- life phase of the greenhouse study and the analytical phase of both studie s were conducted by Ricerca, LLC (Painesville, OH).

Total radioactive residues (TRR) for the 0.089 lb ai/A treatment plots (i.e. two applications), as determined by combustion/liquid scintillation counting (LSC) of sample extracts, were <10 ppb in grap e fruit from both the field and greenhouse studies for the Pm

- label. For the P

- label, TRR in grape fruit was <10 ppb in the greenhouse study as well. No grape fruits were obtained from
the P

- label field study. In the grape leaves, TRR was 164.2 ppb for the P

- label and 51.5 ppb for
the Pm

- label from the field study and 18.9 ppb for the P

- label and 47.1 ppb for the Pm

- label from the greenhouse study. The samples from the 0.089 lb ai/A treatment plots were analyzed
for 14 C

- residue distribution.

Total ra dioactive residues (TRR) for the 0.045 lb ai/A treatment plots (i.e. one application), as determined by combustion/LSC of sample extracts, were <10 ppb in the grape fruit from the greenhouse study for both the P

- label and Pm

- label. For the field study, TR R in grape fruit was
not detected for the Pm

- label. No grape fruits were obtained from the P

- label field study . TRR in grape leaves was not reported for either the field or greenhouse single

- application studies. The samples from the single

- application studies were not analyzed for 14 C

- residue distribution.

No storage stability data are required to support the study because all samples were stored frozen and were analyzed within 4.5 months of collection.

The majority of the radioactivity for both label s was released from grape leaves with acetonitrile (ACN) /water solvent extraction (~91

- 92% TRR for field study and ~76

- 83% TRR for greenhouse study). The extracted residues were partitioned into organic (30.4

- 67.9% TRR for
the field study and 52.9

- 56.1% T RR for the greenhouse study) and aqueous (22.7

- 62.0% TRR
for the field study and 23.1

- 27.2% TRR for the greenhouse study) fractions. Nonextractable
residues were 4.8

- 12.4 ppb (7.6

- 9.3% TRR) in field

- grown grape leaves and 3.2

- 11.3 ppb (16.7

- 24.1% TRR) in greenhouse

- grown grape leaves. These procedures adequately extracted the majority of residues from grape leaves. Extraction and partitioning results were normalized by the petitioner, resulting in accountabilities of 100%.

In field

- grown grape plants, t he majority of the radioactivity for the Pm

- label was released from grape fruit with ACN/water solvent extraction (~91% TRR). The extracted residues were partitioned into organic (61.9% TRR) and aqueous (28.6% TRR) fractions. Nonextractable
residues were 0.2 ppb (9.5% TRR) in grape fruit. In greenhouse

- grown grape plants, the majority of the radioactivity for both labels was released from grape fruit with ACN/water solvent extraction (~88

- 91% TRR). The extracted residues were partitioned into organic (4 7.1

- 57.5% TRR) and aqueous (33.4

- 40.6% TRR) fractions. Nonextractable residues were 0.1

- 0.3 ppb in grape fruit (9.1

- 12.3% TRR). Extraction and partitioning results were normalized by thePage 11 of 33 petitioner, resulting in accountabilities of 100%.

The metaboli c p rofiles were similar for both labels in both the field and greenhouse studies. In grape leaves, trace amounts of parent flazasulfuron were detected in the organic fraction for both labels, accounting for 0.22

- 2.04% TRR, 0.3

- 0.5 ppb. The major metabolites found in the organic fraction of leaf extracts for both labels were DTPU (5.78

- 50.90% TRR, 5.4

- 26.2 ppb) and DTPP (1.16

- 10.21% TRR, 0.8

- 5.3 ppb). Trace amounts of HTPP (0.7

- 1.72% TRR, 0.3

- 1.1 ppb) were
also identified. In P

- label grape leaves, Metabolit e ‘H’ was tentatively identified in the organic
fraction at 12.75

- 18.76% TRR (2.4

- 30.8 ppb) along with trace amounts of TPSA at 1.74

- 2.36% TRR (0.4

- 2.9 ppm). In the aqueous fractions of the P

- label grape leaves, Metabolite ‘S’ was tentatively identified a t 14.70

- 16.01% TRR, 3.0

- 24.1 ppb. A 14 C peak with a retention time of 16.7 minutes was isolated from the aqueous extract (P

- label) and did not match any provided standard. The conjugate was further characterized by sequential acid hydrolysis (1 N HCl for ~18 hours at 40 °C) and base hydrolysis (1 N NaOH for ~18 hours at 40 °C). The results show that the isolated sample coeluted with the standard TPSA, accounting for 6.11

- 35.23% TRR, 1.2

- 57.8 ppb. Two unknowns in Pm

- label grape leaf samples, neither pres ent at >8.0 ppb, accounted
for 17.06

- 18.84% TRR.

A few potential discrepancies are noted: 1) For the P

- label greenhouse grown grape leaves and grape fruit, it appears that the petitioner may have reversed the %TRR for the TPSA Conjugate
and Metabolite ‘S ’; 2) Metabolite H was reported in the organic phase of the P

- label greenhouse grown grapes, but this compound was not shown on the HPLC chromatogram; and 3) for the P

label greenhouse grown grape fruit, the %TRR for the identified metabolites may be incor rect as it appears that the petitioner calculated the metabolite %TRRs using the incorrect aqueous phase and organic phase %TRR (i.e. the petitioner reversed the aqueous and organic phase %TRRs).

The major metabolic pathway of flazasulfuron in grapes in volves the rearrangement of sulfonylurea bridge to form DTPU and cleavage between the pyridyl and pyrimidine ring to give
TPSA and TPSA related residues.

Sugarcane

47939906.der

ISK Biosciences Corporation has submitted a study investigating the metabol ism of [pyridyl

- 14 C]flazasulfuron (P

- label; specific activity 137 μCi/mg ) and [pyrimidinyl

14 C]flazasulfuron (Pm

- label; 122 μCi/mg ) in sugar cane grown in treated soil under greenhouse conditions

. As shown in Table 4 above, the test substances were radiola beled at the 2

- or 5

- positions

, respectively, of the pyridyl or pyrimidinyl rings. The radiolabeled test substances were formulated as water dispersible granular (WDG) formulations and applied as two so il applications to potted sugar cane at the two to thr ee leaf stage and again at the five to six leaf stage (re

- treatment interval of 23 to 25 days). Both 1x and 3x treatment plots were established, with the 1x treatment plot receiving two applications at 0.067 lb ai/A (75 g ai/ha) for a total of
0.134 lb ai /A ( 150 g ai/ha) and the 3x treatment plot receiving two applications at 0.20 lb ai/A (225 g ai/ha) for a total of 0.40 lb ai/A (450 g ai/ha). Sugar cane samples were collected following th e second application at nominal intervals of 0 days, 30 days, 100 d ays, and at final maturity (364 to 367 days). The in

- l ife phase of the study was conducted by Plant Sciences, Inc.Page 12 of 33 (PSI; Watsonville, CA).

Total radioactive residues (TRR s ) were determined by liquid scintillation counting (LSC) of the entire plant samp les (entire above ground portion ) for Day s 0 and 30 and of stalk only for Day
100 and at final maturity. For the 0.134 lb ai/A plots, TRR declined from 1.074 to 0.0059 ppm
for the P

- label treatment and from 1.299 to 0.0053 ppm for the Pm

- label treatment. For the 0.40 lb ai/A plots, TRR declined from 2.684 to 0.010 ppm for the P

- label treatment and from 5.509 to 0.0076 ppm for the Pm

- label treatment. Only samples collected at maturity from the 0.40 lb ai/A treatment plot were analyzed for 14 C

- residue dist ribution.

Initial sample analysis was completed in less than 4.3 months. Samples were re

- extracted and analyzed up to 8 months after the initial analysis . The results after 8 months were similar to the initial results and were averaged together by the p etitioner.

Radioa ctivity released from the sugar cane stalks with ACN/water solvent extraction was 59.9%
for the P

- label and 39.5% for the Pm

- label. The extracted residues were partitioned into organic and aqueous fractions using a low polarity solvent (DCM at pH 5). Residues mainly remained in aqueous phases, accounting for 42.5% TRR in the P

- label and 25.4% TRR in the Pm

- label. The organic phase accounted for 8.5% TRR (Pm

- label) to 12.5% TRR (P

- label). Nonextractable residues were 4.0 ppb (40.1% TRR ) for the P

- label and 4.6 ppb (60.5% TRR) for the Pm

- label. Bound residues could not be further characterized due to the low TRR levels. Approximately 5% TRR was lost during the partition due to the formation of unrecovered insolubles.

In sugar cane stal ks, p arent flazasulfuron accounted only for a minor portion of the residue, at
1.02% TRR or 0.08 ppb (Pm

- label) to 1.53% TRR or 0.153 ppb (P

- label). The major metabolites identified were HTPP, TPSA (P

- label metabolite only) and ADMP (Pm

- label
metabolite o nly). HTPP accounted for 2.6% TRR (0.26 ppb; P

- label) to 3.8%TRR (0.29 ppb;

Pm

- label) ; TPSA accounted for 5.91% TRR (0.591 ppb; P

- label) ; and ADMP accounted for 6.68% TRR (0.51 ppb; Pm

- label ). It was noted, however, that TPSA might be an unknown that

ret ained both ring systems, based on the fact that peaks at very close retention times to TPSA were observed in both the organic and aqueous phases of the Pm

- label. DTPU was found in the organic fraction from both labels, though only at a very small level in the P

- labe l (0.72% TRR, 0.072 ppb) and at <LOQ in the Pm

- label. DTPP was also found in the organic fraction from
bot h labels, but was <LOQ. Organo soluble unknowns included four peaks in the P

- label, each
less than 1.92% TRR (0.192 ppb) and four peaks in the Pm

- label, each less than 2.86%TRR (0.22 ppb). Four of the P

- label and Pm

- label organosoluble unknowns had similar retention times. Aqueous unknowns included three peaks in the P

- label, with each representing 2.6% to
16. 8 % TRR (0.261 to 1.68 ppb) and four peaks in the Pm

- label, with each representing 0.26% to
12.2% TRR (<0.038 to 0.929 ppb). Only one P

- label and Pm

- label aqueous unknowns had a similar retention time. It was the most polar component

.

The major metabolic pa thway of flazasulfuron in su gar cane involves 1) the intramolecular rearrangement of parent flazasulfuron to form DTPU, and hydrolysis to DTPP and HTPP ; and 2) cleavage at the sulfonylurea bridge to form TPSA and ADMP.Page 13 of 33 Tomatoes

47939907.der

ISK Biosciences Corporation has submitt ed a study investigating the metabolism of [ 14 C

P]flazasulfuron (P

- label; specific activity 113 μCi/mg) and [ 14 C

- Pm]flazasulfuron (Pm

- label; 122 μCi/mg) in tomato plants grown in 10 inch pots under field conditions. As shown in Table 4 above, the test sub stances were radiolabeled at the 2

- or 5

- positions , respectively, of the pyridyl or pyrimidinyl rings. The test substances were formulated as a suspension and applied once as a foliar spray at a target rate of 0.045 lb ai/A/application (50 g ai/ha/applica tion) and at an exaggerated application rate of 0.178 lb ai/A/application (200 g ai/h/application). There were four treatment groups of four plants each and one control group of four plants. The first two treatment groups received either [ 14 C

- P]flazasulf uron or [ 14 C

- Pm]flazasulfuron as a s ingle application at the normal target rate and the second and third treatment groups received either [ 14 C

- P]flazasulfuron or [ 14 C

- Pm]flazasulfuron as a single application at the exaggerated application rate. The applic ations were made 14 days after the tomato plants were transplanted
into the 10 inch pots and moved outdoors. Fourteen days after the application, a plant from each treatment group was harvested. There was no fruit present at this time so only a portion o f the
leaves and vines were collected. Upon maturity (83 days after application) , tomato fruits, stems
and leaves were collected

. The in

- life phase of the field study and the analytical phase of both studies were conducted by Ricerca, LLC (Painesville, OH).

A sample history table was provided which contains the dates of collection, processing, radioassay, extraction, and analysis (MRID 48451002). Leaf/vine samples harvested on 7/11/96 (intermediate harvest) were extracted and analyzed on 8/8/96. The f inal harvest of red fruit, green fruit, and leaf/vine occurred on 9/16/96. The HPLC analys e s of juice, pomace, and
leaf/vine were conducted between 9/25/96 and 10/10/96. Samples were stored under freezer conditions, typically defined as ≤

- 15°C. The data indicate that the tomato metabolism samples were analyzed within 6 months of collection; therefore, the metabolic profile of the samples is
considered to be stable for the duration of the stud y

.

The total radioactive residues ( TRR s) in mature tomato frui ts were determined as a sum of contributions from juice and pomace fractions. The TRR was less than 10 ppb in all samples. For the 0.045 lb ai/A treatment plots, TRR in whole tomatoes was 1.55 ppb for the P

- label and 1.35 ppb for the Pm

- label. For the 0. 178 lb ai/A treatment plot, TRR in whole tomatoes was 7.96 ppb for the P

- label and 3.17 ppb for the Pm

- label.

Only juice and pomace from the 0.045 lb ai/A treatment plots were analyzed for 14 C

- residue distribution. Tomato samples (including fruit, leaf, and stem) from the exaggerated rate
treatment were used for metabolite isolation and identification.

The TRR presented for 14 C

- residue distribution in the juice and pomace fractions is in terms of
whole fruit. The majority of the radioactivity for bot h labels was concentrated in the juice (75% and 77% TRR, respectively). The remaining radioactivity was found in the pomace (25% and 23% TRR, respectively). The pomace was extracted with ACN/water solvent . For the P

- label

pomace , the majority of the rad ioactivity was extracted (18.8% TRR, 0.3 ppb) , with 6.3% (0.1 ppb) left in the post

- extracted solid . For the Pm

- label pomace , the majority of the radioactivityPage 14 of 33 was left in the post

- extracted solid (15.4% TRR, 0.2 ppb), with only 7.7% TRR (0.1 ppb) in the extract. Overall, approximately 85% to 94% TRR was solubilized as juice and pomace extracts.
Due to the low levels of 14 C residues present as unextractable, no further characterization was

necessary of the post

- extracted solid.

The metabolic profiles we re similar for both labels. Residues of the parent flazasulfuron were not detected in any of the samples. HTPP was identified as the major metabolite, the majority of which was present as a conjugate in all of the juice and pomace samples. For the whole tomato (sum of juice and pomace), the HTPP conjugate residue was 18.7% to 33% TRR (0.2 to 0.5 ppb)
and the HTPP metabolite was 2.0% to 4.3% TRR (<0.05 ppb). Minor metabolites included

DTPU (7.8% TRR; both labels) , TPSA (13.6% TRR; P

- label only) and ADMP (3.3% TRR; Pm

label only)

. Also characterized were p olar metabolites (6.9% TRR in P

- label and 37.7% TRR in

Pm

- label) , three unknown metabolites (4.1% TRR to 12.1% TRR) and a small number of minor peaks.

The major metabolic pathway of flazasulfuron in tom ato fruit and vines involves the rearrangement of the sulfonyl urea bridge to form DTPU, followed by hydrolysis to form HTPP,
and cleavage of the sulfonyl urea linkage to form TPSA and ADMP. Primary metabolites are further metabolized to more polar products involving conjugation reactions.

HED Conclusions . The nature of the residue stud ies on grapes

, sugarcane , and tomatoes are adequate. The grape, sugarcane, and tomato metabolism studies were evaluated by EPA’s Residues of Concern Knowledgebase Subcommit te e (ROCKS) on 2/15/11 . Based on the available information, the ROCKS determined that the residue of concern for plants for both the tolerance expression and risk assessment is parent. This conclusion is based on the fact that no residues of parent or DT PU were found in any field trials.

860.1300 Nature of the Residue

- Livestock

DER Reference: 4793990 8.der

Ruminants

47939908.der

Ishihara Sangyo Kaisha, Ltd. has submitted a study investigating the metabolism of [pyridyl

- 14 C]flazasulfuron (P

- label) an d [pyrimidinyl

14 C]flazasulfuron (Pm

- label) in the lactating goat; the specific activity was 4.81 and 4.89 MBq/mg for each radiolabel, respectively. As shown in Table 4 above, the test substances were radiolabeled at the 2

- or 5

- positions , respectively, o f the pyridyl or pyrimidinyl rings. The test substances were administered orally via capsule t o two goats (one goat per radiolabel) at average dosing rates of 11.4 ppm (P

- label) and 14.3 ppm (Pm

label) in the diet for 3 consecutive days. A third goat was treated with capsules containing carrier only, as a control. Milk was collected twice daily throughout the study, in the morning after dose administration and in the afternoon; urine and feces were collected twice daily; and tissues, including muscle (co mposite of loin and hindquarter) , fat ( composite of renal and
omental ), liver, and kidney s , were collected at sacrifice, 2 3

- 24 hours after the final dose. The in

life phase and the analytical phase of the study were conducted by WIL Research Laboratories,Page 15 of 33 LLC (Ashland, OH).

A sample history table was provided which contains the sample history, including dates of collection, tissue processing, radioassay, extraction, and analysis (MRID 48451001) . Storage temperatures were also provided. Samples were coll ected on February 6 , 2009 and stored at

- 20°C. After tissue processing, samples were stored at

- 20°C; extracts were stored at 2

- 8°C. HPLC analys e s of liver, kidney, muscle and milk were conducted on March 17

- 18, 2009

. Additional samples of liver and ki dney were extracted on July 15, 2009 and analyzed by HPLC on July 24, 2009; the results indicated that the radioactive residue profile did not significantly change over the course of the study. The data indicate that the goat metabolism samples were analy zed within 6 months of collection; therefore, the metabolic profile of t he samples is
considered to be stable for the duration of the stud y

.

Total radioactive residues (TRRs) in samples were determined by combustion and liquid scintillation counting (LSC) or by direct LSC. TRR in milk was typically higher in the afternoon samples. Maximum levels were observed in afternoon samples on Day 3 (0.022 ppm) in P

- label milk and Days 2 and 3 (0.010 ppm) in Pm

- label milk. TRR was <0.01 ppm in fat (both labels)

an d Pm

- label milk and muscle; res idues in these samples were not further investigated. In Day 4 morning milk and remaining tissues, TRRs were ≥0.01 ppm: 0.021, 0.049, 0.166, and 0.352 ppm
in P

- label milk, muscle, kidney, and liver, respectively, and 0.026 and 0.055 ppm in Pm

- label
kidne y and liver. Only P

- label liver and kidney contained radioactive residues >0.1 ppm. The majority of the applied dose (90

- 91%) was excreted: 82

- 86% in urine and 5

- 9% in feces. The majority of the radioactivity was solvent extracted with acetone (milk) an d ACN (tissues)
from P

- label milk (~91% TRR), kidney (both labels; ~85

- 87% TRR), and muscle (both labels;
~88

- 90% TRR). Solvent extraction released lower amounts of radioactivity from Pm

- label milk (~57% TRR) and liver (both labels; ~45

- 64% TRR). In P

- La bel milk after partition with hexane

, the majority of the radioactivity (~70% TRR) remained in the aqueous phase. Fractionation of the aqueous phase by C18 solid phase extraction ( SPE ) resulted in ~46% TRR and lesser amounts in subsequent increasingly non

- polar fractions. Unextractable residues remaining after the initial extraction of samples of liver and kidney (both labels) and muscle (P

- label) were further extracted with ACN/MeOH which released an additional 5% TRR from liver, 5

- 9% from kidney, and 7% from muscle. Unextractable residues remaining after the second extraction of samples of liver and kidney (both labels) and muscle (P

- label) were sequentially subjected to mild acid and base hydrolysis which released ~30

- 31% TRR from liver, ~3

- 6% from kid ney, and ~2% from muscle. Unextractable residues in liver samples (both labels) were sequentially subjected to strong acid and base hydrolysis which released an additional ~2

- 8% TRR. Unextractable residues remaining after extraction/hydrolysis were not r eported.

Residues were initially identified and quantitated by HPLC. Identification of flazasulfuron and
its metabolites was confirmed in P

- label liver, kidney, and muscle by thin layer co

chromatography. Samples were stored frozen prior to analysis, bu t no information pertaining to storage intervals was provided. To support storage durations, samples of liver (both labels) and kidney (both labels) were re

- extracted and analyzed b y HPLC following frozen storage; however, no dates were provided.

In go at milk

, the low level of radioactivity in the extract was characterized as polar based on itsPage 16 of 33 hexane partition behavior. The parent, flazasulfuron, was the major residue identified in Pm

label kidney, accounting for 59.7% TRR (0.016 ppm) and a minor resi due in P

- label kidney at 16.6% TRR (0.028 ppm). The parent was not identified in liver and muscle. The metabolite M7 (HTPP) was the major residue identified in P

- label liver at 40.2% TRR (0.142 ppm), P

- label muscle at 89.6% TRR (0.044 ppm), and Pm

- label liver at 31.5% TRR (0.017 ppm). M7 (HTPP)
was also identified as a minor residue in P

- label kidney at 13.4% TRR (0.022 ppm) and not
identified in Pm

- label kidney. Metabolite M8 (DTPU) was the major residue in P

- label kidney at 50.2% TRR (0.083 ppm) and a minor residue in Pm

- label kidney at 17.6% TRR (0.005 ppm). Metabolite M9 (DTPP) was a minor residue in kidney (both labels) accounting for 4.5

- 9.1% TRR (0.002

- 0.007 ppm). Discrete unknowns in P

- label liver samples accounted for up to 23.3% TRR, with non e present at >0.026 ppm. Discrete unknowns in Pm

- label liver samples accounted for up to 13.6% TRR, with none present at >0.004 ppm.

Based on the goat metabolism study, the petitioner indicated that flazasulfuron undergoes not only loss of the sulfonyl m oiety and rearrangement to form DTPU, DTPP, and HTPP, but is further metabolized and excreted as HTPU glucuronide, HTPP glucuronide (TPPG), HDTP glucuronide (HDTG), and HTPP + O

- glucoronide. Chromatographic analysis showed that the radioactivity extracted from a tissue type was consistent regardless of label position and yielded little evidence of cleavage of the parent molecule by the goat, elimination of the sulfonyl moiety and reconnection of the urea bridge notwithstanding.

Poultry

No poultry metabol ism study was submitted but none is required since no poultry feed items are associated with citrus, grapes, and sugarcane.

HED Conclusions

. T he metabolism study using goats is adequate.

The goat metabolism study w as evaluated by the ROCKS on 2/15/11

. Based on the available information, the ROCKS determined for the proposed uses that the residue of concern for ruminants for both the tolerance expression and risk assessment is parent. There is no concern with metabolites because of the low dietary burd en associated with the proposed uses.

Since no poultry feed items are associated with citrus, grapes, and sugarcane, a poultry metabolism study is not needed.Page 17 of 33 860.1340 Residue Analytical Methods

DER References: 48092201.der (grape ILV), 4793990 1.der1 (citrus), 4793990 1.der2 (citrus), 4793990 2.der1 (grape),
4793990 2.der2 (grape), 4793990 4.der1 (sugarcane), 4793990 4.der2 (sugarcane) Plant

Enforcement

48092201.der

An adequate residue analytical method ( ADME study code S09

- 03106 ; MRID 48092201 ) which

us es high performance liquid chromatography/tandem mass spectrometry with multiple reaction monitoring (HPLC/MS

- MS/MRM) to quantitate residues of flazasulfuron in various crops is available for enforcing the proposed tolerance s. The monitored ion transition s are 408 →182 for quantitation and 408 →83 for confirmation.

A successful ILV of the method described in the final report of ADME study code S09

- 03106 was performed. ISK Bioscience Corporation has submitted the results from the indep endent laboratory validation (ILV), which was c onducted by Eurofins Dr. Specht GLP GmbH in Hamburg, Germany. The laboratory reported that the method presented in ADME study code
S09

- 03106 was followed as written with a few minor exceptions. These exception s were: (1) use
of the mass transition 4 08 →83 for confirmation purposes instead of the mass transition
408 →227

, and (2) use of a slightly different column with adapted HPLC conditions

. These changes were not significant and had no impact on the study. Acceptable recoveries were
obtained from o lives (fruit), tomatoes (fruit), and wheat (grain) fortified with flazasulfuron at the method LOQ (0.01 ppm) and 10x the LOQ (0.10 ppm).

Homogenized olives, tomatoes, and wheat samples were fortified at the limit of quantitation (0.01 ppm) and 10x the L OQ (0.10 ppm). R esidues of flazasulfuron were extracted from crop samples each weighing 20 grams with a mixture of acetonitrile/water (80/20, v/v) , filtrated over paper filters and then further purified over an Oasis HLB cartridge and through a solid

- phas e extraction ( SPE) cartridge

. An extra liquid

- liquid parti ti on step was added in between for the
olive high fat content matrix only. Dry matrices (wheat) were immersed into water overnight before the extraction step.

Data

- Collection

In the current fie ld trial and processing studies submitted by Ishihara Sangyo Kaisha, Ltd. , the residue data were collected using an HPLC

- MS/MS method (CCRL

- MTH

- 045) from Central California Research Laboratories, Inc., titled “Analytical Method for Determination of SL

- 160
and Its Metabolite in Soil

. ” Residues of parent and DPTU were reported for citrus and grapes, while residues of parent were reported for sugarcane. Ions monitored were 408.1 →181.7 for parent and 344.0 →301.0 for DTPU.

Briefly, samples of homogenized oran ge RAC, orange pulp, grape R AC, raisin, grape pomace,

sugar cane RAC, and bagasse were extracted with acetonitrile:water (80:20, v:v), centrifuged, filtered, and diluted with 15% acetonitrile:85% HPLC grade water prior to analysis by HPLC

MS/MS. Orange jui ce and grape juice samples were extracted with acetonitrile:water (80:20,Page 18 of 33 v:v), hand

- shaken, centrifuged, and then handled the same as the orange and grape RAC samples. Orange oil samples were vortexed for 30 seconds with methanol , filtered, diluted, and analyzed following the procedure for the orange RAC samples. For molasses and refined sugar samples, aliquot s w ere extracted with water . The mixture was shaken by hand for 5

- 10 seconds
and otherwise handled the sam e as the sugarcane RAC samples.

Method CCRL

- MTH

- 045 was adequately validated both prior to and in conjunction with the analysis of the field trial and processing study samples. For method validation and concurrent recovery analysis, control samples were fortified with flazasulfuron and/or DPTU separately at 0.01 ppm and 0.2 ppm. Average recoveries were generally within 70% to 120%, with standard deviations <20%. The following exceptions occurred: method validation orange juice sample recoveries at the 0.2 ppm level were 122% ± 19.7% for flaza sulfuron and 123% ± 18.4% for

DTPU ; method validation grape RAC sample recoveries at the 0.2 ppm level were 104% ± 21%
for flazasulfuron and 102% ± 21% for DTPU ; method validation raisin sample recoveries at the 0.01 ppm level were 82% ± 22% for flazasulfu ron and 153% ± 35% for DTPU ; method validation raisin sample recoveries at the 0.2 ppm level were 124% ± 19% for flazasulfuron and
132% ± 26% for DT PU ; and method validation sugar cane bagasse sample recovery at the 0.01 ppm level was 122% ± 8.2% for flazas ulfuron

. Apparent residues of flazasulfuron and DTPU were <LOQ in control samples of each matrix tested.

HED Conclusions . Adequate methods are available for both enforcing the proposed tolerance and for collecting data.

An adequate residue analytical method using high performance liquid chromatography/tandem mass spectrometry with multiple reaction monitoring (HPLC/MS

- MS/MRM) ( ADME study
code S09

- 03106 ; MRID 48092201 ) is available for enforcing the proposed tolerance s. The
method underwent a successfu l independent laboratory validation (ILV) using olives, tomatoes,
and wheat. T he validated limit of quantitation (LOQ) is 0.01 ppm . Radiovalidation is not needed since the extraction solvent is the same (acetonitrile:water, 80:20, v/v) in the method

(M RID 48092201) and in the grape, sugarcane, and tomato metabolism studies (MRIDs 47939905, 47939906, and 47939907, respectively).

In the field trials a nd processing studies submitted , residue s of flazasulfuron and/or DTPU were determined using an adequate HPLC

- MS/MS method ( CCRL

- MTH

- 045 ) . The method w as adequately validated both prior to and in conjunction with the analysis of the field trial and processing study samples. The lowest level of method validation (LLMV) was 0.01 ppm in each
matrix tested

.

An imal

The petitioner did not submit residue analytical methods for livestock.

HED Conclusions . HED is waiving the requirement for residue analytical methods for livestock
commodities because tolerances for livestock commodities are not needed.Page 19 of 33 860.1360 Multiresidue Methods

Flazasulf u ron is not listed in the FDA PESTDATA database ( Pesticide Analytical Manual

, Volume I, Appendix I, 3 rd edition, 1994, revised October 1999)

. Additionally, the petitioner did
not submit multiresidue method s data

.

HED Conc lusions . The petitioner is required to submit multiresidue method s data since
tolerances will be established.

860.1380 Storage Stability

DER References: 4793990 1.der1 (citrus), 4793990 2.der1 (grape), 4793990 3.der (grape), 4793990 3.der (sugarcane)

ISK Biosciences Corporation has submitted the results of a storage stability study with flazasulfuron in grapes. Untreated grape samples from four field trials conducted in France were combined to form one homogenous bulk sample and then fortified with flaza sulfuron at nominal fortification levels of 1.0 ppm and 0.05 ppm. Samples were placed in frozen storage at approximately

- 20oC and analyzed at storage intervals of 0 (Day 0), 1.5 (Day 50), 4 (Day 121), 8 (Day 237) and 12 months (Day 363). The storage sta bility data indicate that residues of

flazasulfuron are stable in grapes stored at approximately

- 20 **°** C for at least 12 months

.

In conjunction with field trials and processing studies, Ishihara Sangyo Kaisha, Ltd. generated data demonstrating the frozen st orage stability of flazasulfuron and/or DTPU in citrus, grape, and sugarcane commodities. The stability of flazasulfuron was determined in oranges, grapes, and sugarcane and the stability of DTPU was determined in oranges and grapes. For each commodity, control samples were separately fortified with flazasulfuron or DTPU at approximately 0.2 ppm and stored under the same conditions as the field trial and processing study samples. The fortified stored samples were analyzed along with a control sample and freshly fortified control samples of each commodity at the following storage intervals: 0, 32, 92, and 183 days for oranges and sugarcane and 0 and 90 days for grapes. The storage stability data
indicate that residues of flazasulfuron and DTPU are stable in oranges stored at

- 24 to

- 7 °C for 183 days (6 months) and in grapes stored at

- 23°C to

- 12°C for 90 days. In sugarcane,
flazasulfuron is stable at

- 7 to

- 22°C for 183 days (6 months ).

The storage durations and conditions of samples from the crop fiel d trials and processing studies submitted to support th ese petition s are presented in Table 5.

Table 5. Summary of Storage Conditions and Durations of Samples from Crop Field Trial Studies.

Matrix Storage Temperature (°C) Actual Storage
Duration

( days) Interval of Demonstrated Storage Stability (days)

Citrus (orange, grapefruit, lemon) - 27 to

- 6 3

- 125 days (0.1

- 4.1 months) Storage s tability data indicate that residues of flazasulfuron and
metabolite DTPU are stable in/on oranges stored under froz en conditions (average of

- 18oC) for up to 183 days (6.1 months)

. Orange Juice

- 27 to

- 6 11

- 12 days (<1 month) No storage stability data are required for processed commodities because samples were stored less than 30 days prior to analysis.
Orange Pulp

- 27 to

- 6 10

- 11 days (<1 month)Page 20 of 33 Table 5. Summary of Storage Conditions and Durations of Samples from Crop Field Trial Studies.

Matrix Storage Temperature (°C) Actual Storage
Duration

( days) Interval of Demonstrated Storage Stability (days)

Orange Oil

- 27 to

- 6 10

- 11 days (<1 month)
Grape

- 22 to

- 11 3

- 85 days (0.1

- 2.8 months) Flazasulfuron: 12 months in/on grapes at approximately

- 20 **°** C

.

DTPU: 90 days (3 months) in/on grapes at an average temperature of

- 19oC.

Raisins

- 22 to

- 11 21 days (<1 month) No storage stability data are required for raisins because samples were stored less than 30 days prior to analysis.
Grape Juice

- 22 to

- 11 36

- 38 days ( 1.3 months) Storage stability data were not provided fo r grape processed commodities. Because the juice and pomace processed commodities were only stored for 6 to 8 days longer than the one
month trigger and because the stability of flazasulfuron was
demonstrated in the grape RAC, as well as in other RACs
inc luding sugarcane and citrus, the availabl e storage stability
data for fl azasulf u ron are adequate to support the storage intervals for the processed commodities. Grape Pomace

- 22 to

- 11 36

- 38 days ( 1.3 months)
Sugarc ane

- 6 to

- 24 7

- 111 days (0.23

– 3. 7 months) Storage stability data collected as part of this study indicate that
residues of flazasulfuron are stable under f rozen storage conditions in/on fortified samples of sugarcane for up to 183 days (6 months) at an average temperature of

- 18oC.

Sugarc ane Bagasse

- 6 to

- 24 42 days (1.4 months) Storage stability data were not provided for sugar cane processed commodities. Because the processed commodities were only stored for 5 to 12 days longer than the one month threshold and because the stability of f lazasulfuron was demonstrated in the sugarcane RAC, as well as in other RACs including grapes and citrus, the available storag e stability data for fl azasulf ur on are adequate to support the storage intervals for the processed
commodities. Sugarc ane Molasse s - 6 to

- 24 41 days (1.3 months)

Sugarc ane Refined Sugar - 6 to

- 24 35 days (1.1 months)

HED Conclusions

. The available storage stability data are adequate to support the storage durations and conditions of citrus, grape, and sugarcane RAC samples. S torage stability data were not provided for the processed commodities. A s the orange processed commodity samples (juice, pulp, and oil) and raisin samples were stored for less than 30 days, no supporting storage stability data are required for these commo dities. Because the grape juice, grape pomace , sugarcane bagasse, molasses, and refined sugar processed commodities were only stored for 5 to
12 days longer than the one month threshold

, and because the stability of flazasulfuron was
demonstrated in the R AC s , the availabl e storage stability data for fl azasulf u ron are adequate to support the storage intervals for the processed commodities.

860.1400 Water, Fish, and Irrigated Crops

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

860. 1460 Food Handling

There are no proposed uses that are relevant to this guideline topic.Page 21 of 33 860.1480 Meat, Milk, Poultry, and Eggs

There are no poultry or swine feedstuffs associated with the subject petition ; therefore

, data requirements pertaining to pou ltry and swine are not relevant to this petition. The proposed uses fall under 40 CFR §180.6(a)(3), i.e., there is no reasonable expectation that finite residues will occur in poultry or swine commodities as a result of the proposed uses.

The ruminant feedstuffs associated with the proposed use of flazasulfuron are dried citrus pulp and sugarcane molasses

. The maximum reasonabl y balanced dietary burdens (MRBDB) of
flazasulfuron to ruminants are presented in Table 6. The calculated dietary burdens of flazasulfuron are 0.0024 ppm for both beef and dairy cattle.

Table 6. Livestock Dietary B urdens for Flazasulfuron 1

Feedstuff Type Tolerance,

ppm 2 % Dry
Matter % Diet Dietary Contributions (ppm) 3

Beef Dairy Poultry Swine Beef Diary Poultry Swine

Dried Citrus Pulp R 0.01 91 10 10 0.0011 0.0011

Untreated R NA NA 5 35 0 0

Sugarcane Molasses CC 0.01 75 10 10 0.0013 0.0013

Untreated CC NA NA 70 35 0 0

Untreated PC NA NA 5 10 0 0

Total Bur den 100 100 0.0024 0.0024

1 Potential dietary burdens for livestock were determined using recent Agency guidance on calculating the
maximum reasonably balanced diets for livestock ( Table 1 Feedstuffs , June 2008).

2 The tolerance level for the RAC was used for any associated processed fractions.

3 Contribution = ([tolerance /% DM] x % diet) for beef and dairy cattle; contribution = ([tolerance] x % diet) for poultry and swine.

T he petitioner did not submit a livestock feeding study. Anticipated se condary residues in beef and dairy cattle matrices were estimated using transfer coefficient factors calculated from the
maximum residues of flazasulfuron observed at the dose level closest to the MRBDB in the goat metabolism study. The transfer coefficie nts (calculated as residue level to feed level ratios) are presented in Table 7. The transfer coefficient for each matrix was then used to calculate the expected secondary residues by multiplying the transfer coefficient by the calculated MR B DB

. The expe cted residues of flazasulfuron are presented in Table 8.

Table 7. Transfer Coefficients in Beef and Dairy Cattle Matrices Based on Flazasulfuron Residues in the Goat Metabolism Study.

Matrix Maximum Total Residue
of Flazasulfuron (ppm) Feeding Level (pp m) Transfer
Coefficient 1

Milk, whole 0.022 11.4 0.00193

Liver 0.352 11.4 0.03088Page 22 of 33 Table 7. Transfer Coefficients in Beef and Dairy Cattle Matrices Based on Flazasulfuron Residues in the Goat Metabolism Study.

Matrix Maximum Total Residue
of Flazasulfuron (ppm) Feeding Level (pp m) Transfer
Coefficient 1

Kidney 0.166 11.4 0.01456

Muscle 0.049 11.4 0.00430

Fat 0.008 11.4 0.00070

1 Calculated from the maximum residues observed at the dose level closest to the M RBDB divid ed by the dose
level.

Table 8. Expected Secondary Residues of Flazasulfuron in Meat and Milk.

Matrix Dietary Burden (ppm) Secondary Residues 1
(ppm) Recommended Tolerance (Current Tolerance) (ppm)

Beef and Dairy Cattle

Milk, whole 0.0024 4.6E

- 06 N o ne

Liver 0.0024 7.4E

- 05 N one
Kidney 0.0024 3.5E

- 05 N one Muscle 0.0024 1.0E

- 05 N one

Fat 0.0024 1.7E

- 06 N one

1 Calculated from the dietary burden from Table 6 x the transfer coefficient from Table 7.

HED Conclusions

. There are no poultry or swine feedst uffs associated with the subject petition ; therefore

, data requirements pertaining to poultry and swine are not relevant to this petition.

The ruminant feedstuffs associated with the proposed use s of flazasulfuron are dried citrus pulp and sugarcane mo lasses. The petitioner did not submit a livestock feeding study. Because of the low transfer factors from the goat metabolism study and the low predicted residues in cow milk and tissues, HED is waiving the requirement for a cow feeding study

. The waive r applies to this petition only ; if additional uses with associated livestock feed items are proposed in the future, then this requirement will need to be re

- evaluated.

For all livestock, the proposed uses fall under 40 CFR §180.6(a)(3), i.e., there is no reasonable expectation that finite residues will occur in poultry, swine, or ruminant commodities as a result of the proposed uses. Therefore, no tolerances are needed for livestock commodities.

860.1500 Crop Field Trials

DER References:
47939901.der1 (citrus) 47939902.der1 (grapes) 47939904.der1 (sugar cane)

Ishihara Sangyo Kaisha, Ltd. has submitted field trial data on citrus (orange, grapefruit and lemons), grapes, and sugarcane supporting the proposed uses of flazasulfuron (25% WDG). ThePage 23 of 33 results from these field trials are discussed below and the residue data are summarized in Table
9

.

Table 9 . Summary of Residue Data from Crop Field Trials with Flazasulfuron

Commodity Analyte Total Applic.

Rate (lb ai/A) PHI (days) Residue Levels (ppm) 1

n Min. Max. HAFT 1 Median Mean Std.

Dev. Citrus (proposed use = 0.15 lb ai/A total application rate, 1

- day PHI)

Orange, fruit Flazasulfuron (parent) 0.154

– 0.159 1 24 <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) --

29

- 30 24 < LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) --

DTPU 0.154

– 0.159 1 24 <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) --

29

- 30 24 <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) --

Grapefruit,
fruit Flazasulfuron (parent) 0.153

– 0.161 1 1 2 <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) --

28

- 30 12 <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) --

DTPU 0.153

– 0.161 1 12 <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) --

28

- 30 12 <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) <LO Q (ND) --

Lemon, fruit Flazasulfuron (parent) 0.154

– 0.156 1 8 <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) --

30 8 <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) --

DTPU 0.154

– 0.156 1 8 <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) - -

30 8 <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) -- Grapes (proposed use = 0.15 lb ai/A total application rate, 75

- day PHI)

Grapes, fruit Flazasulfuron (parent) 0.149

- 0.158 74

- 77 24 <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) -

DTPU 0 .149

- 0.158 74

- 77 24 <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) Sugarc ane (proposed use = 0.15 lb ai/A total application rate, 180

- day PHI)

Sugarcane Flazasulfuron (parent) 0.152

- 0.164 179

- 180 16 <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) <LOQ (ND) - -

1 The LOQ is 0.010 ppm. The calculated LOD for fl azasulfuron i s 0.003 ppm.

Citrus

4793990 1.der1

Ishihara Sangyo Kaisha, Ltd. has submitted crop field trial data for flazasulfuron in/on orange, grapefruit, and lemon, the representative commodities of the citrus fruit group 10. Twenty

- three citrus crop field trials were conducted in the U.S. Twelve orange field trials in Zones 3 (FL; 8 trials), 6 (TX; 1 trial), and 10 (CA; 3 trials), six grapefruit field trials in Zones 3 (FL; 3 trials), 6 (TX; 1 tri al), and 10 (CA; 2 trials), and five lemon field trials in Zones 3 (FL; 1 trial) and 10 (CA; 4 trials) were conducted during the 2008 growing season. The lemon field trial in Zone 3 (Fort Pierce, FL) was terminated due to the presence of citrus canker.Page 24 of 33 Each citrus fruit field site included one untreated plot and one treated plot. At each plot, two soil applications of a 25% water dispersible granular (WDG; Flazasulfuron 25 WG) form ulation of
flazasulfuron were m ade to the ground at the base of the test crops at 0.075

- 0.083 lb ai/A per application

, with 95

- to 308

- day retreatment intervals , for a total seasonal rate of 0.153

- 0.161 lb
ai/A (approximately 1x the proposed seasonal rate)

. Applications were made using ground equipment with spray volumes of 20 to 30 gal water /A . A n adjuvant was included in the spray mixture at all test locations. Samples of commercially mature citrus fruits (oranges, grapefruit, and lemons) were collected for each trial at preharvest intervals (PHI s ) of 1 day and 30 days

. Additional samples (oranges, grapefruit, and lemons) were collected from three CA sites at PHIs
of 10 and 20 days to evaluate residue decline.

At one orange test site, an additional plot received two applications at an exaggerated rate of
0.771

- 0.772 lb a i/A per application for a total rate of 1.543 lb ai/A ( 10x the proposed seasonal rate) to generate samples for processing. Refer to the processing DER for MRID 47939901 (47939901.der2).

S amples of citrus fruit were analyzed for total residues of fl azasul furon and DTPU us ing Central California Research Laboratories, Inc., “Analytical Method for Determination of SL

- 160 and Its Metabolite in Soil” (CCRL

- MTH

- 045), using HPLC

- MS/MS. T his method is acceptable for data collection based on adequate concurrent me thod recovery data. The limit of quantitation (LOQ), defined as the lowest level of method validation (LLMV) at which acceptable recovery
can be achieved , was 0.01 ppm for each analyte. The calculated limit of detection (LOD) for
flazasulfuron and DTPU i n all products was 0.003 ppm based on the lowest standard of the
calibration curve.

Samples were stored frozen for up to 125 days (4.1 months) prior to analysis. To support this storage interval, a concurrent storage stability study was cond ucted in conj unction with the analysis of field trial samples. Samples of orange fruit were fortified with flazasulfuron and

DTPU

, each at 0.2 ppm. Residues were stable in frozen orange fruit for 183 days.

After t wo applications of Flazasulfuron 25 WG were made to the ground/weeds below the base
of citrus trees at total rate of 0.1 53

- 0. 1 6 1 lb ai/A , t here were no detectable residues of
flazasulfuron or DTPU in/on any citrus samples. A decline curve could not be established
because no residues were detected in the r esidue decline samples.

Grapes

47939902.der1

Ishihara Sangyo Kaisha, Ltd. has submitted crop field trial data for flazasulfuron in/on grapes. Twelve field trials were conducted in the U.S. in the 2008 growing season, encompassing Zones 1 (NY, 1 trial; PA; 1 trial), 10 (CA, 8 trials), and 11 (OR, 1 trial; ID, 1 trial). Each trial included one untreated plot and one treated plot. At each treated plot, two soil applications of a 25%

water

- dispersible granular ( WDG/ WG) formulation of flazasulfuron (F lazas ulfuron 25 WG) were made to the ground at the base of the test crops at 0.085 to 0.091 lb ai/A for the first application and 0.064 to 0.068 lb ai/A for the second application, with 14

- to 118

- day retreatment
intervals . The total seasonal rate was 0.149

- 0. 158 lb ai/A (approximately 1x the proposedPage 25 of 33 seasonal rate). Applications were made using ground equipment with spray volumes of 20 to 3 8 gal water /A . A n adjuvant was included in the spray mixture at all test locations. Samples of grapes were collected fo r each trial at a preharvest interval (PHI) of 74 to 77 days. Additional samples were collected from one CA site (Site 09) at PHIs of 55, 65, 75, and 85 days to evaluate
residue decline.

At one CA test site, an additional plot received two applications a t an exaggerated rate of 0.662

- 0.888 lb ai/A per application for a total rate of 1.55 lb ai/A (10x the proposed seasonal rate) to generate samples for processing. Refer to the processing DER for MRID 47939902 (4793990 2 .der2).

S amples of grapes were analy zed for residues of fl azasulfuron and DTPU us ing Central California Research Laboratories, Inc., “Analytical Method for Determination of SL

- 160 and Its Metabolite in Soil” (CCRL

- MTH

- 045), using HPLC

- MS/MS. T his method is acceptable for
data collection bas ed on adequate concurrent method recovery data. The limit of quantitation (LOQ), defined as the lowest level of method validation (LLMV) at which acceptable recovery
can be achieved , was 0.01 ppm for each analyte. The calculated limit of detection (LOD) for flazasulfuron and DTPU in all products was 0.003 ppm based on the lowest standard of the
calibration curve.

Samples were stored frozen for up to 85 days (2.8 months) prior to extraction. Samples were analyzed within one day of extraction. To support this storage interval, a concurrent storage stability study with DTPU was conducted in conjunction with the analysis of field trial samples. Samples of grapes were fortified with DTPU at 0.2 ppm. DTPU residues were stable in frozen grapes for 90 day s. The storage stability of fla zasulfuron in grapes was investigated in a separate study (MRID 47939903; refer to 47939903.der) in which samples were fortified with flazasulfuron at nominal fortification levels of 1.0 ppm and 0.05 ppm. The storage stability data indicate that residues of flazasulfuron are stable at approximately

- 20 **°** C for at least 12 months in

grapes. A dequate storage stability data for flazasulfuron and DTPU are available to support the storage conditions and durations for grapes in the fie ld study.

After t wo applications of Flazasulfuron 25 WG were made to the ground at the base of the grape
vines at a total rate of 0.149

- 0.158 lb ai/ A , t here were no detectable residues of flazasulfuron or DTPU in/on any grape samples. A decline curve co uld not be established because no residues
were detected in the residue decline samples.

Sugarc ane

47939904 .der1

Ishihara Sangyo Kaisha, Ltd. has submitted field trial data for f lazasulfuron in/on sugarcane.

E ight field trials were conducted in the U

. S

. during the 2008 growing season, encompassing Zones 3 (FL, 3 trials), 4 (LA, 3 trials), 6 (TX, 1 trial), and 13 (HI, 1 trial). One treated plot and one untreated control plot were established at each trial site. For each trial , one application of
Flazas ulfuron (SL

- 160) 25 WG (a 25.85% w/w, water

- dispersible granule) was made to the ground at the base of the sugarcane plants using CO 2 backpack sprayers at a target rate of 0.15 lb ai/A. Actual treatment rates ranged from 0.152 to 0.164 lb ai/A (approximat ely 1x the proposedPage 26 of 33 seasonal rate) . Spray volumes ranged from 20 to 31 gal /A (GPA). Sugarcane samples were collected at pre

- harvest intervals (PHIs) of 179

- 180 days. Additional samples were collected at

o ne site ( T rial 02) at PHIs of 160, 170, 180, and 190 day s to establish a decline curve.

At one site (Trial 03), an additional plot was treated at an exaggerated rate of 1.514 lb ai/A (10x
the proposed seasonal rate) to generate samples for processing. Refer to the processing DER for

MRID 47939904.

S ugarcane samples were analyzed for residues of flazasulfuron using Central California Research Laboratories, Inc., “Analytical Method for Determination of SL

- 160 and Its Metabolite in Soil” (CCRL

- MTH

- 045), using HPLC

- MS/MS. This method is acceptable for d ata collection based on adequate concurrent method recovery data. The limit of quantitation (LOQ), defined as the lowest level of method validation (LLMV) at which acceptable recovery can be achieved, was 0.01 ppm and the calculated limit of detection (LO D) was 0.003 ppm based on the lowest
standard of the calibration curve.

Sugarcane samples were stored frozen for up to 91 days (3 months). All sample extracts were analyzed within 1 day of extraction. To support this storage interval, c oncurrent storage stability data were submitted with this study. Samples of sugarcane were fortified with flazasulfuron at 0.2 ppm. The storage stability data indicate that residues of flazasulfuron in sugarcane are stable for up to 183 days (6 mont hs) of freezer storage at

- 7 to

- 22°C (average of

- 18°C).

Following a single application of Flazasulfuron 25 WG at a target applic ation rate of 0.15 lb ai/A, there were no detectable residues of flazasulfuron in/on any sugarcane samples. A decline

cur ve could not be established because no residues were detected in the decline study samples.

HED Conclusions : The number and locations of crop field trials are in accordance with OPPTS
Guideline 860.1500 for grapes and sugarcane. For citrus, one lemon f ield trial is lacking because a lemon field trial in Florida (Region 3) was terminated due to the presence of citrus canker. An additional lemon field trial will not be required because data from the remaining field trials will sufficiently represent resi dues likely to be seen. All trials reflect the proposed use pattern; however, for the sugarcane trials, the maximum seasonal application rate was applied in a single application. The maximum single application rate on the label for sugar cane is approxima tely 3.3x less than the maximum seasonal application rate. The RTI on the label is only 14 days. Data from these trials are sufficient ; f lazasulfuron residues were all <LOQ (<0.01 ppm)

.

Pending the requested revisions to the Section B/label, t he availab le field trial data will support the proposed tolerance of 0.01 ppm for residues of flazasulfuron in/on citrus, grapes, and

sugarcane. The tolerance spreadsheet in the Agency’s Guidance for Setting Pesticide Tolerances
Based on Field Trial Data was not ut ilized for determining appropriate tolerance level s because
all of the treated samples bore residues below the LOQ.Page 27 of 33 860.1520 Processed Food and Feed

DER References: 4793990 1.der2 (citrus), 4793990 2.der2 (grapes), 4793990 4.der2 (sugar cane)

Ishihara Sang yo Kaisha, Ltd. has submitted processed food and feed data on citrus (orange s ), grapes, and sugarcane supporting the proposed uses of flazasulfuron ( 25% WDG). The results
from these field trials are discussed below and the residue da ta are summarized in Table 10

.

Table 10

. Residue Data from Processing Studies with Flazasulfuron.

RAC Processed Commodity Total Rate (lb a.i./A) PHI (days) Residues (ppm) 1 Processing Factor 2 ,3

Flazasulfuron DTPU Flazasulfuron DTPU Orange,
fruit Fruit (RAC) 1.54 1 ND, ND, ND ND, ND, ND

-- -- Juice ND, ND ND, ND NC NC Dried pulp ND, ND ND, ND NC NC

Oil ND, ND ND, ND NC NC Grape RAC

1.55 1 ND, ND, ND ND, ND, ND

-- --

Raisin ND, ND 0.0109, 0.0102 Avg. 0.0106 NC 1.1x 4

Juice ND, ND ND, ND NC NC

Pomace ND, ND <0.01, <0.01 Avg. <0.01 NC NC

Sugarcane RAC 1.51 180 ND, ND Not Analyzed

-- Not Analyzed Bagasse ND, ND Not Analyzed NC Not Analyzed

Molasses ND, ND Not Analyzed NC Not Analyzed Refined Sugar ND, ND Not Analyze d NC Not Analyzed

1 ND = Not detected. The LOD for each analyte was <0.003 ppm. The LOQ was 0.01 ppm.

2 Processing Factor = [ M easured residue for analyte in the processed fraction] / [ M easured residue for analyte in RAC collected

for processing]. The LOQ was used when residues were <LOQ in calculations.

3 Processing factors could not be calculated (NC) because residues were below the LOQ in both the RAC and processed
commodities.

4 This value is not statistically significant to two significant figures. A lso, this value is based on the LOQ of 0.01 ppm. If based on the LOD of 0.003 ppm, it would be 3.5x.

Citrus

4793990 1.der2

Ishihara Sangyo Kaisha, Ltd. has submitted a processing study for flazasulfuron on orange. In
one field trial conducted in CA dur ing the 2008 growing season, two applications of the 25%

water

- dispersible granular (W D G /WG ) formulation of flazasulfuron were applied to the soil at the base of orange trees at 0.077 lb ai/A per application, for a total rate of 1.54 lb ai/A (10x the

propo sed seasonal rate). The first application was made at bud swell and the second application was made at maturity . Ground equipment was used with spray volumes of 29 gal water /A . A n adjuvant was included in the spray mixtures. Mature orange fruits were h arvested one day after the second application.

Samples of orange fruit and processed commodities (juice, dried pulp, and oil) were analyzed for
residues of the parent compound, flazasulfuron

, and metabolite DTPU following Central
California Research Labor atories, Inc., “Analytical Method for Determination of SL

- 160 and Its Metabolite in Soil” (CCRL

- MTH

- 045), included in the study report as part of Appendix 25, Protocol and Amendments. The validated limit of quantitation (LOQ) for flazasulfuron andPage 28 of 33 DTPU w a s 0.01 ppm for each analyte. The limit of detection (LOD) for flazasulfuron and DTPU in all products was 0.003 ppm based on the lowest standard of the calibration curve. The method was adequate based on acceptable concurrent recoveries.

Residues of flaz asulfuron and DTPU were each nondetectable (<0.003 ppm) in/on all orange RAC samples. Following processing, residues of flazasulfuron and DTPU were also

non detectable in orange juice, dried pulp, and oil. Because residues were non detectable in the
RAC an d all processed fractions, no processing factors could be calculated.

The theoretical concentration factors based on separation into components are 3.3x for citrus peel, 1000x for citrus oil, and 2x for juice and dehydrated pulp (OPPTS 860.1520, Table 3).

Grapes

4793990 2.der2

Ishihara Sangyo Kaisha, Ltd. has submitted a processing study for flazasulfuron on grapes. In one field trial conducted in CA during the 2008 growing season, two applications of the 25%

water

- dispersible granular ( WDG/WG ) formulat ion of flazasulfuron were applied to the soil at the base of the grape vines at 0. 888 lb ai/A for the first application and 0. 662 lb ai/A for the second application, for a total rate of 1.55 lb ai/A (10x the proposed seasonal rate). Applications
were made using ground equipment at a spray volume of 25 gal/A of water ; an adjuvant was included in the spray mixture for the second application. Grape samples were harvested 65 days after the second application.

Samples of grape and processed commodities (raisi n, juice, and pomace) were analyzed for
residues of the parent compound, flazasulfuron

, and metabolite DTPU following Central California Research Laboratories, Inc., “Analytical Method for Determination of SL

- 160 and Its Metabolite in Soil” (CCRL

- MTH

- 045), using HPLC

- MS/MS. The validated limit of quantitation (LOQ) for flazasulfuron and DTPU w as 0.01 ppm for each analyte. The limit of detection (LOD) for flazasulfuron and DTPU in all matrices was 0.003 ppm based on the lowest standard
of the calibration cu rve. The method was adequate based on acceptable concurrent recoveries.

Residues of flazasulfuron and DTPU were nondetectable (<0.003 ppm) in/on all grape RAC samples. Following processing, residues of flazasulfuron were also non detectable in grape juic e, pomace and raisins; therefore, no processing factors could be calculated for flazasulfuron. Residues of DTPU were nonquantifiable in grape juice and pomace, but were slightly above the LOQ in raisins (average of 0.0106 ppm). P rocessing factors could not be calculated for DTPU in grape juice or pomace. In raisins, th e estimated concentration factor for DTPU is 1.1x. The theoretical concentration factor based on separation into components is 1.2x for grape juice (OPPTS 860.1520, Table 3). For raisins , the theoretical concentration factor based on loss of water is 4.7x (OPPTS 860.1520, Table 2).Page 29 of 33 Sugarcane

4793990 4.der2

Ishihara Sangyo Kaisha , Ltd. has submitted a sugarcane processing study for flazasulfuron

. In
one trial cond ucted in Cheneyville, Louisiana during the 2008 growing season

, a single application of Flazasulfuron (SL

- 160) 25 WG ( a 25.85% w/w , water

- dispersible granule) was made to the ground at the base of sugarcane plants at a rate of 1.51 lb ai/A/application (10x the proposed seasonal rate). The application was made using a CO 2 backpack sprayer at a spray volume of 22.6 gallons per acre. An adjuvant was added to the spray mixture

. Bulk sugarcane samples were harvested at a pre

- harvest interval (PHI) of 180 days and processed into bagasse, molasses, and refined sugar using procedures that simulated commercial processing.

Sugarcane RAC, bagasse, molasses, and refined sugar were anal yzed for residues of
flazasulfuron using Central California Research Laboratorie s, Inc., “Analytical Method for
Determination of SL

- 160 and Its Metabolite in Soil” (CCRL

- MTH

- 045), using HPLC

- MS/MS. This method is acceptable for data collection based on adequate concurrent method recovery data. The limit of quantitation (LOQ), define d as the lowest level of method validation (LLMV) at which acceptable recovery can be achieved, was 0.01 ppm in each matrix . The calculated limit of detection (LOD) for flazasulfuron was 0.003 ppm based on the lowest standard of the
calibration curve.

Af ter one application of flazasulfuron at an exaggerated rate of 1.51 lb ai/A/application

, flazasulfuron (parent) residues in/on treated RAC (sugarcane) used for processing were
nondetectable ( < 0.0 03 ppm). Following processing, residues of f lazasulfuron (pa rent) were also
nondetectable in bagasse, molasses, and refined sugar. Because residues were non detectable in the RAC and all processed commodities, no processing factors could be calculated.

HED Conclusions: Under the conditions and parameters used in the study, the data are classified as scientifically acceptable

. Processing factors for parent could not be calculated for any of the processed commodities because no quantifiable residues of fl azasulfuron (parent) occurred. Therefore, separate tolerance s are not required for orange dried pulp, orange juice, orange oil, grape juice, raisins, su gar cane refined sugar, or molasses

.

860.1650 Submittal of Analytical Reference Standards

An analytical standard for flazasulf u ron, with an e xpiration date of February 2012

, is currently available in the EPA National Pesticide Standards Repository (personal communication with
Theresa Cole , ACB, 9/27/10).

860.1850 / 860.1900 Confined / Field Accumulation in Rotational Crops

There are no rotational crop data requirements associated with the use on citrus or grapes (OPPTS 860.1850). The rotational crop guidelines are applicable for sugarcane; however, rotational crop data have not been submitted. The proposed label for sugarcane requires a 12

- month interval between the last application and the planting of the rotational crop.Page 30 of 33 HED Conclusions: While HED considers the 12

- month plantback restriction for sugarcane on the proposed label to be adequate for conditional registration of flazasulfuron bas ed on the fact that no detectable residues were found in the primary crops, a confined rotational crop study is required to support permanent registration of sugarcane

. Depending on the results of the confined rotational crop study , a study to determine f ield accumulation in rotational crops may be required.

860.1550 Proposed Tolerances

The ROCKS determined on 2/15/11 that the residue of concern for plants for the tolerance expression is parent.

No tolerances are needed for rotational crops , ruminant s, or poultry.

Adequate field trial data are available for the RACs of citrus, grapes , and sugarcane.

The tolerance spreadsheet in the Agency’s Guidance for Setting Pesticide Tolerances Based on
Field Trial Data was not utilized for determining an appr opriate tolerance level for the RACs of citrus, grapes , and sugarcane because all of the treated samples bore residues below the LOQ.

Tolerances for the processed commodities of citrus (orange juice, pulp and oil), sugarcane (molasses and refined sugar) o r grape (grape juice and raisin) are not needed for the purpose of this petition based on the results of processed food and feed trials which showed that residues of
flazasulfuron (parent) were bel ow the LOQ (<0.01 ppm)

.

A tolerance summary for flazasul furon is presented in Table 11

.

Table 11

. Tolerance Summary for Flazasulfuron

. Commodity Proposed Tolerance (ppm) Recommended Tolerance (ppm) Comments ; Correct Commodity Definition

Citrus 0.01 0.01 Fruit, c itrus, group 10

- 10
Grapes 0.01 0.01 Grape
Sugarcane 0.01 0.01

There are no Codex, Canadian, or Mexican MRLs /tolerances established for residues of flazasulfuron in crop or livestock commodities. Therefore, there are no issues regarding international harmonization raised by this action. An Int ernational Residue Limit (IRL) status sheet is appended to this document

.

HED Conclusion . The petitioner must submit a revised Section F to propose tolerances which reflect the correct commodity definitions as specified in Table 11

.Page 31 of 33 References

DP#: D3 02103 Subject: FEE. Secondary Product Chemistry Review on Flazasulfuron Technical

From: S. Mathur

To: C. T

- Sen/J. Tompkins

Date: 2/26/07

MRID#: 46220905

DP#: None Subject: Flazasulfuron; Report of the Residues of Concern Knowledgebase Subcommittee (ROC KS)

From: Edward J. Scollon

To: Jack Arthur

Date: 5/12/08

MRID#: None

Attachments:

Appendix 1 : International Residue Limits Status Sheet Appendix 2: Chemical Names and Structures TablePage 32 of 33 APPENDIX 1 

### International Residue Limits

Flazasulfuron (PC Code 11 9011)
Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 2 Codex 3

40 CFR 180. xxx : Plant / Livestock : N

- [[(4,6

- dimethoxy

- 2

- pyrimidinyl)amino]carbonyl]

- 3

- (trifluoromethyl)

- 2

- pyridinesulfonamide None None

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

US Canada Mexico 2 Codex
Fruit, citrus, group 10

- 10 0.01 Grape 0.01 Sugarcane 0.01

Com pleted: M. Negussie; 1/12/2010

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.Page 33 of 33 APPENDIX 2

Chemical Names and Structures f or Flazasulfuron and its Metabolites

Common name/code Chemical name Chemical structure

Flazasulfuron /SL

- 160 N

- [[(4,6

- dimethoxy

- 2

- p yrimidinyl)amino]carbonyl]

- 3

- (trifluoromethyl)

- 2

- pyridinesulfonamide

ADMP 2

- amino

- 4,6

- dimethoxypyrimidine

DTPU N

- (4,6

- dimethoxy

- 2

- pyrimidin yl)

- N

- [ 3

- ( trifluoromethyl )

- 2

- pyrid in yl] urea

DTPP 4,6

- dimethoxy

- N

- [ 3

- ( trifluoromet hyl )

- 2

- pyrid inyl]

- 2

- p yrimidin amin e

HTPP 6

- methoxy

- 2

- [[ 3

- ( trifluoromethyl )

- 2

- pyrid in yl ] amino ]

- 4

- pyrimidin ol

TPSA 3

- ( trifluoromethyl )

- 2

- pyridinesul f onamide