Imazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 1 of 40 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION

MEMORANDUM

Date: 10/18/2010

SUBJECT: Imazosulfuron. Request for Section 3 Registration for New Uses on Pepper, Rice, and Tomato. Summary of Analytical Chemistry and Residue Data.

PC Code: 118602 DP Barcode: D367019

Decision No.: 406200 Registration No.: 59639-RLL

Petition No.: 9F7535 Regulatory Action: Section 3 Registration Risk Assessment Type: NA Case No.: NA

TXR No.: NA CAS No.: 122548-33-8

MRID No.: See MRID Summary Table 40 CFR: 180.###

FROM: Stephen Funk, Senior Science Advisor

Risk Assessment Branch 3 Health Effects Division (7509P)

THROUGH: Paula Deschamp, Branch Chief

Risk Assessment Branch 3 Health Effects Division (7509P)

TO: James Thompson, RM Team #25

Herbicide Branch Registration Division (7505P)

MRID Summary Table

MRID No. Study Type Comments

47679115 860.1300 Lactating goat New DER; 47679115.der.doc

47679116 860.1300 Laying hen New DER; 47679116.der.doc

47679117 860.1300 Rice New DER; 47679117.der.doc

47679118 860.1300 Tomato New DER; 47679118.der.doc

47679119 860.1300 Potato New DER; 47679119.der.doc

47679120 860.1360 MRM New DER; 47679120.der.doc

47679121 860.1340 ILV plant method New DER; 47679121.der.doc; includes review of

data from MRIDs 47814801 and 48238301Imazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 2 of 40 MRID Summary Table MRID No. Study Type Comments
47814801;

48238301 860.1340 Plant method See 47679121.der.doc

47679122 860.1480 Waiver request (no data submitted) No DER; MRID addressed herein.

47679123 860.1380 Pepper, rice grain, tomato New DER; 47679123.de2.doc; includes review of

data from MRIDs 47679124 and 47679125

47679123 860.1500 Pepper New DER; 47679123.de1.doc 860.1500 Rice grain New DER; 47679124.de1.doc 47679124

860.1520 Rice New DER; 47679124.de2.doc

860.1500 Tomato New DER; 47679125.de1.doc 47679125

860.1520 Tomato New DER; 47679125.de2.doc

47679126 860.1850 Kale, radish & sorghum/wheat New DER; 47679126.der.doc

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

Executive Summary

Imazosulfuron is a new sulfonylurea herbicide bei ng developed by Valent U.S.A Corporation for control of broad-leaf weeds and sedges in pepper, rice, and tomato. Imazosulfuron acts by inhibiting the enzyme acetolactate synthase. This petition (PP#9F7535) is the first food/feed use request for imazosulfuron; Valent has also reque sted registration for use on turf, ornamentals, and bare ground.

Under PP#9F7535, Valent has requested the establishment of tolerances for residues of imazosulfuron (2-chloro- N -[[(4,6-dimethoxy-2-pyrimidi nyl)amino]carbonyl]imidazo[1,2- a]pyridine-3-sulfonamide) in or on the following raw agricultural commodities:

Pepper ........................................................................................................ 0.02 ppm Rice, grain.................................................................................................. 0.02 ppm Tomato ....................................................................................................... 0.02 ppm

In conjunction with this petition, Valent has submitted an application for Section 3 registration of a new end-use product, a 75% water-dispersible granule (WG) formulation (V-10142 Ag Herbicide; EPA File Symbol 59639-RLL) for use on pepper, rice, and tomato. The 75% WG formulation is proposed for preemergence and/or postemergence applications to peppers, rice, and tomato at maximum seasonal application rates up to 0.3 lb ai/A. Use on peppers is restricted to soil-directed application with a 21-day preharvest interval (PHI). Soil and/or foliar applications are proposed for rice and tomato, with a 21-day PHI for tomato; applications to rice may be made until the 2-inch internode growth stage.

The nature of the residue in plants is adequately understood for purposes of this petition based on acceptable metabolism studies with potato, rice, and tomato. The data demonstrate that the metabolism of imazosulfuron is similar in three dissimilar crops, and that hydrolysis of the sulfonylurea linkage is the major metabolic process. Hydrolytic degradation of the sulfonamide moiety yields metabolites IPSN, or 2-chloro-i midazo[1,2-a]pyridine-3-sulfonic acid amide, UDPM, or (4,6-dimethoxy-pyrimidin-2-yl)-urea, and ADPM, or 4,6-dimethoxy-pyrimidin-2-Imazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 3 of 40 ylamine. In addition, O-demethylation of the pyrimidinyl ring yields the only identified doublering metabolite, HMS. See Appendix I for chemical names and structures of metabolites. Imazosulfuron and UDPM were the major residues in rice grain, rice straw, and tomato, but were minor residues in potato tuber, where total radi oactive residues (TRR) were significantly lower overall. HED has determined that the residue of concern in crop commodities for tolerance

enforcement assessment is imazosulfuron. The residue of concern for risk assessment is the sum of imazosulfuron and UDPM, expressed as equivalents of imazosulfuron.

The nature of the residue in livestock is adequately understood based on acceptable metabolism studies with goats and hen. The data demonstrate that metabolism of imazosulfuron is similar in ruminants and poultry, and that hydrolysis of the sulfonylurea linkage is the major metabolic process. Imazosulfuron was a major residue in ruminant milk and tissues, except fat, and in poultry eggs and tissues. IPSN was also a major metabolite in ruminant and poultry tissues, and was present in milk and eggs at up to 10% TRR. UDPM was identified as a minor metabolite in eggs only, and the double-ring metabolite HMS was identified in ruminant milk and kidney and in poultry liver at <10% TRR. HED has determined that the residue of concern in livestock

commodities for tolerance enforcement is imazosulfuron. The residue of concern for risk assessment is the sum of imazosulfuron and IPSN, expressed as equivalents of imazosulfuron.

The petitioner has proposed a high performance liquid chromatography method with tandem mass spectroscopy detection (LC/MS/MS), Method RM-42C-3, for enforcement of tolerances for residues of imazosulfuron in/on crop commodities. The method has been adequately validated and has undergone a successful independent laboratory validation (ILV) with rice grain. HED has evaluated the method against the criteria (SOP AOB-019, 09/15/08) for a tolerance method validation (TMV) and has concluded that the method is acceptable for tolerance enforcement. The method adequately determines residues of imazosulfuron as well as the metabolite UDPM in pepper, rice, and tomato commodities. The validated limit of quantitation (LOQ) is 0.02 ppm for each analyte (imazosulfuron, UDPM) in/on pepper, rice, and

tomato commodities.

The method will be forwarded to FDA for inclusion in the Pesticide Analytical Manual (PAM) Vol. II. The proposed enforcement method was used for data collection in the submitted storage stability, crop field trial, and processing studies. Enforcement methods for livestock commodities are not needed to support the proposed uses. Although additional information is required concerning multiresidue methods testing, the submitted data indicate that the

multiresidue methods are not suitable for determination of imazosulfuron.

Interim storage stability data have been submitted for residues of imazosulfuron and UPDM in/on pepper, rice grain, tomato, and tomato paste. The submitted storage stability data are not adequate to support the storage durations of samples from the crop field trials and processing studies because sample storage durations were greater than the intervals reported in the interim study for all commodities. The final report(s) of the storage stability studies must be submitted.

The petitioner has submitted a waiver request for the requirements for cow and hen feeding studies. The only livestock feed items resulting from the proposed uses are rice grain and rice bran. The request is based on the low residues of imazosulfuron observed in rice grain (<LOQ) and low recommended tolerance; the relatively low dietary burdens of imazosulfuron toImazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 4 of 40 livestock; and the results of the ruminant and poultry metabolism studies. The petitioner also notes that the rice processing study did not show concentration of residue in bran. However, the rice grain processed had no quantifiable residues and therefore the study has little quantitative utility. HED concludes that the proposed uses of imazosulfuron in this petition result in a 40 CFR §180.6(a)(3) situation for livestock commodities; i.e., there is no reasonable expectation of finite residues in ruminant, poultry, or swine commodities. No feeding studies need be submitted to support the proposed uses of imazosulfuron on pepper, rice, and tomato. Feeding studies may be necessary if uses on additional crops with significant animal feed commodities are requested in the future.

Pending submission of the final report(s) of the storage stability studies, adequate field trial data have been submitted for pepper, rice, and tomato. The data indicate that residues of

imazosulfuron are ≤ LOQ in/on pepper, rice grain, and tomato following application of the 75% WG formulation according to the proposed use patterns. The proposed tolerances of 0.02 ppm each for rice grain and tomato are appropriate. The proposed tolerance for pepper of 0.02 ppm must be replaced by proposal for a tolerance of 0.02 ppm for each of bell pepper and non-bell

pepper.

Pending submission of the final report(s) of the storage stability studies, adequate processing

data have been submitted for rice and tomato. The data indicate that residues of imazosulfuron do not concentrate in the processed commodities of rice grain or tomato; therefore, no tolerances are needed for processed commodities. HED notes that the RACs used in the processing studies did not have incurred residues of imazosulfuron (<0.02 ppm) and that the maximum required exaggerated rate treatment of 5X was not used in the trials used to generate the samples for processing. However, use on rice is early season with no residues found in any of the trial samples. Use on tomato is later season (through early bloom), but again no residues were found, and a 3X exaggerated rate was used to generate the processing sample.

A tentatively acceptable confined rotational crop study has been submitted; supporting storage stability data are required for the [pyrimidinyl-5- 14 C]imazosulfuron label (Py) grain. The study results indicate that the metabolism of imazosulfuron proceeds in rotational crops via routes similar to metabolism in primary crops, and suggest, based on the presence of higher levels of HMS and metabolites derived from IPSN, that soil metabolites may contribute significantly to residues in rotated crops. Imazosulfuron was not identified in any rotational crop commodity; however, HMS and UDPM were identified as major metabolites in rotational sorghum and wheat matrices (except grain) at PBIs of 30 – 120 days. In addition, three major metabolites were identified in rotational sorghum and wheat matrices (except grain) that were not identified in primary crops: the IPSA conjugate metabolites I PSA-isoserine, IPSA-acetylisoserine, and IPSAcaffeoylisoserine

No field rotational crop data were submitted in support of this petition; however, Valent is conducting a wheat field rotational crop study to support the rotation of cereal grains.

The petitioner has proposed PBIs based on the results of the confined rotational crop study, in which TRRs were <0.01 ppm in radish roots and tops and kale at a 144-day PBI, and which indicated that no quantifiable residues (>0.01 ppm each) of imazosulfuron or metabolites would be expected in cereal grain crops planted 12 months following treatment at 1x. HED hasImazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 5 of 40 concluded that the following proposed PBIs are appropriate: 0 days for rice; 100 days for transplanted tomato; 8 months for cantaloupe, cucumber, eggplant, lettuce, mustard greens, peppers (bell and nonbell), radish, spinach, turnip, turnip greens, and white potatoes; and 9 months for cabbage and squash. The proposed PBIs of 12 months for field and sweet corn and 24 months for “All crops not listed” are appropriate; however, the 8-month PBI for field corn planted following rice must be removed and the 8-month PBI for soybeans must be removed. A PBI of 12 months must be proposed for soybeans. The 24 months is related to crop safety (phytotoxicity).

The acceptability of the proposed PBIs of 4 months for wheat and 8 months for grain sorghum cannot be assessed pending submission of field ro tational crop data for cereal grains. HED has determined that the IPSN conjugates found at very low levels in livestock feed commodities from rotated grain crops at a 365-day PBI in the confined rotational crop study are most likely not of concern, but will reconsider the issue after review of the rotational grain field trial study. Likewise, a similar situation may exist with soybean forage/silage. Pending submission of this information/data, a 12-month PBI must be proposed for wheat and grain sorghum and for soybean.

Regulatory Recommendations and Residue Chemistry Deficiencies

HED has examined the residue chemistry database for imazosulfuron. A revised Section B (see requirements under Directions for Use) and a revised enforcement method (see requirements under Residue Analytical Methods) are required prior to registration. After resolution of these residue chemistry issues, there are no additional residue chemistry issues that would preclude granting a conditional registration for the requested uses of imazosulfuron or establishment of

tolerances for residues of imazosulfuron as follows:

Tolerances are established for residues of imazosulfuron, including is metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only imazosulfuron, or 2-

chloro- N -[[(4,6-dimethoxy-2-pyrimidi nyl)amino]carbonyl]imidazo-[1,2- α ]pyridine-3- sulfonamide, in or on the commodity. Pepper, bell .................................................................0.02 ppm Pepper, nonbell.......................................... ...0.02 ppm Rice, grain...................................................................0.02 ppm Tomato ........................................................................0.02 ppm

The conditional registration may be upgraded upon resolution of the following issues: additional information for the confined rotational crop study, a small grain field rotational crop study, additional information for the multiresidue methods, and a final storage stability study. These requirements are detailed below.

A human health risk assessment is forthcoming.

860.1200 Directions for UseImazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 6 of 40 • The label must be amended to add the following restriction for application to rice: Do not apply to rice fields if fields are used for the aquaculture of edible fish and/or

crustaceans.

• A 12-month PBI must be proposed for soybeans and for cereal grain crops, and the 8- month rotational interval for field corn planted following rice must be removed. In addition, the petitioner will need to remove the statement concerning the use of shorter rotational intervals “where local experience has shown crop safety.”

860.1360 Multiresidue Methods

• The following additional information must be provided concerning the multiresidue methods testing for imazosulfuron: (1) the petitioner must explain why testing for imazosulfuron under Protocol D through the complete method without cleanup was not conducted or provide the results of testing without cleanup; and (2) the petitioner must explain why imazosulfuron was only tested using one of the two Protocol D Florisil elution procedures.

860.1380 Storage Stability

• The final report(s) of the storage stability studies must be submitted, reflecting storage intervals of up to 12 months for peppers, up to 35 months for rice grain and rice processed commodities, and up to 18 months for tomatoes and tomato processed commodities.. Details concerning the preparation of samples and fortification solutions should be provided with the final report(s).

860.1850 Confined Accumulation in Rotational Crops

• The HPLC profile for the Py-label grain storage stability analysis must be submitted to confirm that the metabolite profile was stable in Py-label grain.

860.1900 Field Accumulation in Rotational Crops

• The petitioner previously indicated that a wheat rotational crop study was being conducted. This study has not been submitted and is required.

Background

The chemical name and structure of imazosulfuron are listed in Table 1. The physicochemical properties of imazosulfuron are listed in Table 2. The chemical names and structures of imazosulfuron and its transformation products are presented in Appendix 1.Imazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 7 of 40 Table 1. Imazosulfuron Nomenclature

. Chemical structure

N N

N N

N H N H S O

O Cl

O CH 3 O CH 3

O

Common name Imazosulfuron

Company experimental name V-10142; TH-913

IUPAC name 1-(2-chloroimidazo[1,2- α ]pyridin-3-ylsulfonyl)-3-(4,6-dimethoxypyrimidin-2- yl)urea

CAS name 2-chloro- N -[[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]imidazo- [1,2- α ]pyridine-3-sulfonamide

CAS registry number 122548-33-8

End-use product (EP) 75% WG (V-10142 Ag Herbicide; EPA File Symbol 59639-RLL)

Table 2. Physicochemical Properties of Imazosulfuron.

Parameter Value Reference 1

Melting point/range 198.0 oC 47305112

pH 4.61 at 25 oC (1% suspension in water) 47305105

Density 1.652 at 20 oC 47305105

Water solubility at 20 oC 429 mg/L at pH 7; 3936 mg/L at pH 9 47305115

Solvent solubility 0.820 mg/L in hexane 174.6 mg/L in n -octanol 597.2 mg/L in toluene 4478.5 mg/L in acetone 144.8 mg/L in methanol 12,744.7 mg/L in dichloromethane 2,220.3 mg/L in ethyl acetate 47305105

Vapor pressure at 25 oC below LOD (<3.5 x 10 -6 Pa) 47305116

Dissociation constant, pK

a at 20 oC 3.94 in methanol/0.01 M citrate buffer at 252 nm

0.30 in methanol/HCl at 268 nm 47305113

Octanol/water partition coefficient, Log(P OW ) at 25 oC 2.43 at n -octanol/pH 4 buffer

-0.07 at n -octanol/pH 7 buffer

-1.56 at n -octanol/pH 9 buffer 47305114

UV/visible absorption spectrum pH Wavelength A ε , x10 4

acidic 238.5 0.8877 3.55

201.0 1.1653 4.66

neutral 238.0 0.8293 3.32

232.0 0.8278 3.31

200.5 1.1497 4.60

basic 244.0 0.7607 3.04

231.0 0.8500 3.40 47305111

1 As referenced in the petition summary document (Report No. 200900084) for PP#9F7573.Imazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 8 of 40 860.1200 Directions for Use

Valent has submitted a draft label dated 2/16/09 for a new end-use product, V-10142 Ag Herbicide, a 75% WG formulation (EPA File Symbol 59639-RLL), for use on pepper, rice, and tomato. The proposed use directions are summarized in Table 3.

Table 3. Summary of Directions for Use of Imazosulfuron.

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

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

Season Max.

Seasonal Applic. Rate

(lb ai/A) PHI (days) Use Directions and

Limitations

Peppers (Bell and Nonbell): Use is restricted to field-grown peppers.

Postemergence, Directed to soil,

Ground 75% WG 0.2-0.3 1 0.3 21 Apply to established pepper plants ≥ 10 inches tall; apply to row middles, avoiding contact with the crop, or under the rows toward the pepper stem

≤ 2 inches above the soil

surface.

Rice

Preemergence/

Delayed Preemergence, Broadcast to soil,

Ground or aerial 0.2-0.3 1 0.3 Drill seeded : Apply to prepared moist seedbed.

Postemergence, Broadcast foliar,

Ground or aerial 0.15-0.2 1 0.2 Dry or water seeded : Apply to moist soil or

flooded fields.

Drill seeded : Apply to

rice in at least the 2-leaf growth stage (second leaf fully expanded),

Preemergence +

Postemergence, Broadcast,

Ground or aerial 75% WG

0.15 2 0.3 Not specified; application may be made

until 2-inch

internode stage of rice

Drill seeded : Apply preemergence to moist seedbed, then postemergence to moist

soil or flooded fields with a minimum 21-day

retreatment interval

Tomato: Use is restricted to field-grown tomatoes

Pre-transplant, Broadcast to soil,

Ground Apply to prepared bed prior to transplant or installation of plastic mulch; transplanting may begin 1 day after application.

Postemergence, Broadcast foliar,

Ground 75% WG 0.2-0.3 1 0.3 21

Direct seeded : Apply “over the top” to

established tomatoes at the 4- to 5-leaf stage through early bloom.Imazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 9 of 40 Table 3. Summary of Directions for Use of Imazosulfuron.

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

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

Season Max.

Seasonal Applic. Rate

(lb ai/A) PHI (days) Use Directions and

Limitations

Postemergence, Broadcast foliar,

Ground Transplanted : Apply “over the top” 3-5 days after transplanting through early bloom stage only if a pre-transplant application was not made.

Postemergence, Directed to soil,

Ground Direct seeded or transplanted : Apply to

established tomatoes at the 4- to 5-leaf stage only if a pre-transplant application was not made. Apply to soil surface from crop row to row middle.

Ground applications are to be made in 20-40 gal/A for peppers and tomatoes, and 15-20 gal/A for rice. Aerial applications are only to be made to rice, in a minimum 10 gal/A. A 12-hour restricted entry interval is specified.

The label includes the following additional use directions for rice: (1) use of an approved surfactant is recommended when application is made to weeds 1-3 inches tall; (2) the maximum application rate is 0.15 lb ai/A for tank mixtures with propanil products, or Bolero® (thiobencarb), Command® (clomazone), Facet® (quinclorac), or Prowl® (pendimethalin); (3) when application is made post-flood, the flood water must be lowered so that at least 70% of the weed surface is above the flood water; the field should be returned to normal flood levels 3-4 days after application; (4) when application is made to non-flooded fields, the fields should be flooded as soon as the rice will tolerate a flood but no sooner than 24 hours after application; (5) do not drain the field for 7 days after application when making a postemergence application to a flooded field; (6) water drained from treated fields must not be used to irrigate other crops; and (7) do not apply to second crop (stubble/ratoon) rice.

The proposed rotational crop restrictions are specified in the table below. The label states that the rotational intervals are recommended for crop safety, and that shorter intervals may be used where local experience has shown crop safety, except that there is a minimum rotational interval of 144 days for non-small grain crops other than transplanted tomato, and 120 days for small grain crops.Imazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 10 of 40 Proposed Rotational

Interval Rotational Crop

Immediately Rice

100 days Tomato (transplanted)

4 months Wheat

8 months Cantaloupe 1 , cucumber 1 , eggplant, grain sorghum, lettuce, mustard greens, peppers (bell and nonbell), radish, spinach, soybean, turnip, turnip greens, white potato

9 months Cabbage 1 , squash 1

12 months Field corn 2 , sweet corn

24 months All crops not listed

1 5 months in FL and GA.

2 8 months following rice.

Conclusions . The submitted use directions are adequate to allow evaluation of the residue data relative to the proposed use. The submitted field trial data for peppers, rice, and tomatoes reflect the maximum proposed use rates and minimum PHIs or designated growth stage. HED notes that, although all trials were conducted at exaggerated total application rates (3x for pepper and tomato and 1.7-2.5x for rice), for peppers and tomatoes, where two applications were made, the second applications were separated from initial applications by relatively lengthy retreatment intervals and would represent the maximum proposed use pattern for each crop at a ~1.3x exaggerated rate based on the final application only. It is also noted that even at the exaggerated rates, residue levels were at or below the LOQ.

The label recommends use of a spray adjuvant for applications to rice and does not prohibit use of spray adjuvants for peppers or tomatoes. None of the submitted field trials reflected use of spray adjuvants. HED has concluded that spra y adjuvant use generally must be prohibited on product labels when the field trials do not incl ude adjuvants (see minutes of 4/16/08 Chemistry Science Advisory Council (ChemSAC) meeting). However, as the use is early season and/or directed to the soil about the plants, the addition of adjuvant is anticipated to have no impact on the commodity residue levels. Therefore, no label change for adjuvants is needed.

In addition, the label must be amended to add the following restriction for application to rice: Do not apply to rice fields if fields are used for the aquaculture of edible fish and/or crustaceans.

• Pending submission of field rotational crop data for small grains (wheat), a 12-month PBI must be proposed for soybeans and for cereal grain crops, and the 8-month rotational interval for field corn planted following rice must be removed. In addition, the petitioner will need to remove the statement concerning the use of shorter rotational intervals “where local experience has shown crop safety.” The remaining rotational crop restrictions appear to be supported by the available data from the confined rotational crop study.Imazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 11 of 40 860.1300 Nature of the Residue - Plants

DER References: 47679119.der.doc (Potato) 47679117.der.doc (Rice) 47679118.der.doc (Tomato)

Potato

Valent has submitted a study investigating the metabolism of [imidazolyl-3- 14 C]imazosulfuron (Im label) and [pyrimidinyl-5- 14 C]imazosulfuron (Py label) in potato; the specific activity was 0.77 GBq/mmol for each radiolabel. The radiolabeled test substances, prepared as WG formulations, were diluted with water and applie d to separate plots of potatoes grown outdoors. Two spray applications were made at ~0.5 lb ai/A/application for a total application rate of ~1.1 lb ai/A (~3.7x the maximum proposed seasonal application rate for other crops). The first application was made preemergence after hilling (42 days after planting), and the second application was made 64 days later to potato pl ants at the BBCH 44 (40% of final tuber mass) growth stage. A third plot was treated with fo rmulation blank only for controls. Mature potatoes were harvested 46 days following the last application; samples of desiccated foliage were collected at this time but were not further analyzed. Samples of fresh foliage were also harvested 21 days after the last application to ai d in metabolite identification. The in-life phase of the study was conducted by Research for Hire (Porterville, CA), and the analytical phase of the study was conducted by Valent Technical Center (Dublin, CA).

TRRs in tubers were determined by summing the radioactivity in surface washes (determined by direct LSC) and radioactivity in the rinsed tubers, as determined either by combustion/LSC or by summing extractable and nonextractable radioactivity. Accountability (sum of extractable and nonextractable radioacitivy compared to radioactivity by combustion/LSC of the tubers) was 92 – 100%. TRR values reflecting summed extractable and nonextractable radioactivity were used for all further calculations. TRR in foliage were determined by combustion/LSC. TRR were 0.026 ppm in Im-label tubers and 0.022 ppm in Py-label tubers harvested 46 days after the last application. TRR in fresh foliage harvested 21 days after the last application were 8.690 and 6.748 ppm in/on Im- and Py-label foliage, respectively.

Samples of fresh foliage were extracted for purposes of metabolite identification only; therefore, quantitative data are not presented herein. Water and acetonitrile (ACN) surface washes removed 7.9-13.4% TRR from tubers. The majority of the radioactivity (26-43% TRR) was extracted from tubers with ACN; extraction with water released an additional 14-19% TRR.

Nonextractable residues in tubers accounted for 35-42% TRR (0.009 ppm). These procedures adequately extracted the majority of the residues from potato tubers. Accountabilities based on

combustion TRR were 92-100%.

Residues were initially identified and quantitated by high performance liquid chromatography (HPLC). Identification of imazosulfuron and metabolites in tubers was confirmed by thin-layer chromatography (TLC) via co-chromatography of fr actions isolated from bulk samples of potato foliage Samples of fresh foliage were also analyzed by high performance liquid chromatography with mass spectrometry detection (LC/MS) fo r further confirmation of imazosulfuron and investigation of an unknown metabolite (Rt 23). Potatoes were stored frozen for a maximum of 4.9 months prior to the completion of chromatographic analyses. The petitioner submittedImazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 12 of 40 storage stability data demonstrating that residues of imazosulfuron were stable in tubers stored frozen for up to ~4 months. No additional storage stability data are required because sample integrity was maintained by appropriate freezer storage, and final analysis was completed within 6 months of sample collection.

Residues were low (<0.03 ppm) in potato tubers following combined preemergence and postemergence applications. No individual components, including unknown fractions, were detected at individual levels >0.003 ppm. Th e parent, imazosulfuron, accounted for 3.6% TRR (0.001 ppm) and 8.4% TRR (0.002 ppm) in Im- and Py-label tubers, respectively, and it was the major identified residue in Py-label tubers. The double-ring metabolite HMS was identified as a minor residue (4.1-5.2% TRR, 0.001 ppm) in both Im- and Py-label tubers. The imidazolyl-ring metabolite IPSN was identified as the major residue in Im-label tubers, accounting for 12.0% TRR (0.003 ppm). In Py-label tubers, the pyrimidine-ring metabolites UDPM, ADPM, and ADNG were minor residues, accounting for 0.7-1.3% TRR (<0.001 ppm) each. Remaining residues in potato tuber were characterized as discrete unknowns based on HPLC retention times, and accounted for ~14-19% TRR ( ≤ 0.005 ppm). The lipophilic unknown eluting at Rt 23 was found to have a molecular weight twice that of imazosulfuron and was tentatively identified as a dimer of imazosulfuron but was not further investigated. An aqueous suspension that

resulted from concentration of the ACN ex tract accounted for 10-12% TRR (0.002-0.003 ppm); this fraction could not be chromatographed because it contained the bulk of the co-extracted matrix components.

Based on the results of the potato metabolism study, the petitioner proposes that metabolism of imazosulfuron in potato occurs via initial O-demethylation of the pyrimidinyl ring to form HMS. Hydrolytic degradation of the sulfonamide moie ty yields IPSN, UDPM, and ADPM. IPSN may also be formed by further degradation of HMS, and ADPM may be formed by degradation of UDPM. The petitioner noted that all of these metabolites may have been conjugated with plant endogenous compounds to form bound residues and other minor components in the potato plant as evidenced by trace amounts of the glucose conjugate ADNG.

Rice

Valent has submitted a study investigating the metabolism of [imidazolyl-3- 14 C]imazosulfuron and [pyrimidinyl-5- 14 C]imazosulfuron in rice; the specific activity was 1.17 GBq/mmol for each radiolabel. The radiolabeled test substances, prepared as WG formulations, were diluted with water and applied to separate plots of rice grown outdoors. Two foliar spray applications were made at a target rate of 0.20 lb ai/A/application for a total application rate of 0.40 lb ai/A (~1.3x the maximum proposed seasonal application rate for rice). The first application was made to rice at the 2-leaf stage, and the second application was made 56 days later to plants at the early boot stage. A third plot was untreated to provide controls. Plants were grown in standing water to mimic rice paddy conditions. Mature rice grain and straw were harvested 70 days following the last application. The in-life phase of the study was conducted by Research for Hire (Porterville, CA), and the analytical phase of the study was conducted by PTRL West, Inc. (Hercules, CA).

TRR were determined in rice grain and straw by combustion/LSC and by summing extractable and nonextractable radioactivity; summed TRR were used for all subsequent calculations. TRR were 0.193 and 2.151 ppm in/on Im-label grain and straw, respectively, and 0.201 and 3.070 ppm in/on Py-label grain and straw, respectively.Imazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 13 of 40 The majority of the radioactivity was extracted with ACN from rice grain (~47-57% TRR) and straw (~76-82% TRR), and ~9-15% TRR was rel eased from both matrices with subsequent ACN/water extractions. Sequential extractions with buffers, amylase, protease, EDTA, DMSO, KOH, and/or H 2 SO 4 released 30-34% TRR from grai n and 4-8% TRR from straw. Nonextractable residues remaining after exhaustive extraction accounted for ≤ 6.9% TRR (0.009- 0.013 ppm) in grain and <1% TRR (0.016 ppm) in straw. These procedures adequately extracted the majority of the residues from rice grain and straw. Accountabilities based on combustion TRR were 105-118% for grain and 84-95% for straw.

Residues were initially identified and quantitated by HPLC. Identification of imazosulfuron and its metabolites was confirmed in rice grain and straw by TLC co-chromatography. Rice samples were stored frozen for a maximum of 2.8 months prior to the completion of chromatographic analyses; no storage stability data are required because sample integrity was maintained by appropriate freezer storage, and final analysis was completed within 6 months of sample

collection.

The parent, imazosulfuron, was the major residue identified in rice matrices (both labels), accounting for 17.6-27.9% TRR (0.034-0.056 ppm) in grain and 60.7-64.3% TRR (1.306-1.974 ppm) in straw. The double-ring metabolite HMS was identified in Im-label samples only, at 0.9- 2.6% TRR (0.005-0.020 ppm) in grain and straw; the petitioner noted that an unidentified metabolite with a similar retention time to HMS was present in Py-label grain and straw at 3.5% and 0.1% TRR, respectively. The imidazolyl-ring metabolite IPSN was identified at 5.2% TRR (0.010 ppm) in Im-label grain only. In Py-label grain and straw, the pyrimidine-ring metabolite UDPM was identified as a significant residue at 18.4% TRR (0.037 ppm) in grain and 12.7% TRR (0.389 ppm) in straw. The pyrimidine-ring metabolite ADPM was identified in Py-label grain and straw as a minor residue (3.3-5.5% TRR, 0.011-0.102 ppm).

Polar metabolites accounted for 9.4-9.9% TRR in Im-label grain and straw, and 2.0-6.7% TRR in Py-label grain and straw. TLC analysis of the isolated polar fractions from rice straw and grain indicated that they were comprised of multiple minor components. Other unknowns represented 20.3-23.8% TRR in Im-label grain and straw, a nd 8.6-11.9% TRR in Py-label grain and straw; no individual component was present at >3.5% TRR. Nonextractable residues characterized as pectin, lignin, hemicellulose, cellulose, polysaccharid es, starch and/or proteins on the basis of extraction/hydrolysis procedures accounted individually for ≤ 10.4% TRR in grain and 2.3%

TRR in straw.

Based on the results of the rice metabolism study, the petitioner proposes that metabolism of imazosulfuron in rice occurred via demethylation and/or hydrolysis at the sulfonylurea linkage.

Tomato

Valent has submitted a study investigating the metabolism of [imidazolyl-3- 14 C]imazosulfuron and [pyrimidinyl-5- 14 C]imazosulfuron in tomato; the specific activity was 1.17 GBq/mmol for each radiolabel. The radiolabeled test substances, prepared as WG formulations, were diluted with water and applied to separate outdoor plots. The first spray application was made to bare soil at ~0.5 lb ai/A, 7 days prior to transplanting tomato plants. A second foliar spray application at ~0.3 lb ai/A was made 100 days later to the tomato plants, which bore mature and immatureImazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 14 of 40 fruit. The total application rate was 0.78-0.81 lb ai/A (~2.7x the maximum proposed seasonal application rate for tomato). A third plot was untreated to provide controls. Samples of mature and green tomatoes were harvested 21 and 28 days following the last application; leaves were also harvested to aid in metabolite identification. The in-life phase of the study was conducted by Research for Hire (Porterville, CA), and the analytical phase of the study was conducted by PTRL West, Inc. (Hercules, CA).

TRR were determined initially by combustion/LSC. TRR in fruit were also determined by summing extractable and nonextractable radioactivity; summed TRR were used for all subsequent calculations. TRR were 0.019 and 0.012 ppm in 21- and 28-day Im-label tomato samples, and 6.215 and 4.819 ppm in the corresponding leaf samples. In Py-label samples, TRR were 0.054 and 0.026 ppm in 21- and 28-day tomato samples, and 5.567 and 4.706 ppm in the respective leaf samples.

Although both fruit and leaf samples were subjected to extraction procedures, residues in leaves were not further investigated; therefore, the petitioner presented results for fruit only. The majority of the radioactivity (60-84% TRR) was extracted from tomatoes with ACN. Additional radioactivity was released by subsequent extr action with acidic ACN (4-13% TRR) and basic ACN (3-19% TRR). Nonextractable residues in all samples accounted for 7-12% TRR (0.001- 0.005 ppm). These procedures adequately extracted the majority of the residues from tomatoes.

Accountabilities based on combustion TRR were 95-104%.

Residues were generally low ( ≤ 0.05 ppm) in tomato following combined pretransplant and postemergence applications, and no metabolites, including unknown fractions, were detected at individual levels >0.02 ppm. Residues were initially identified and quantitated by HPLC. Identification of imazosulfuron and the pyrimidine-ring metabolite UDPM was confirmed by TLC co-chromatography. Identification of the pa rent compound, isolated from ACN extracts of Im-label leaf samples, was further confirmed by LC/MS. Identification of remaining metabolites, HMS (double-ring metabolite) and ADPM (pyrimidine-ring metabolite), was limited to the initial HPLC analyses, and is considered tentative. Because neither metabolite was identified at >8.3% TRR, confirmatory analysis is not required. Samples of tomatoes were stored frozen for a maximum of 3.5 months prior to the completion of chromatographic analyses; no storage stability data are required because sample integrity was maintained by appropriate freezer storage, and final analysis was completed within 6 months of sample collection.

The parent, imazosulfuron, accounted for 5.3% TRR (0.001 ppm) and 16.7% TRR (0.009 ppm) in Im- and Py-label tomato, respectively, harvested at the 21-day PHI. At the 28-day PHI, the parent was not found in Im-label tomato, and residues were 3.8% TRR (0.001 ppm) in Py-label tomato. HMS was a minor residue in both Im- and Py-label samples (1.9-8.3% TRR, 0.001 ppm). In Py-label tomato, UDPM was the major residue at both PHIs, accounting for 26.9- 29.6% TRR (0.007-0.016 ppm), while ADPM was a minor residue (3.7-7.7% TRR, 0.002 ppm).

Polar metabolites were the major residue component in Im-label tomato, accounting for ~37- 50% TRR (0.006-0.007 ppm); polar metabolites were significant in Py-label tomato as well, accounting for ~15-23% TRR (0.006-0.008 ppm). To further characterize polar residues, the polar fractions from 21- and 28-day Im-label tomato were isolated and subjected to acid and enzyme hydrolysis. The results indicated that limited conjugation of metabolites occurred in

tomatoes.Imazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 15 of 40 Based on the results of the tomato metabolism study, the petitioner proposes that metabolism of imazosulfuron in tomato occurred via demethylation and/or hydrolysis at the sulfonylurea linkage. Further metabolism to polar products occurred, but conjugation was minimal.

Conclusions . The submitted potato, rice, and tomato metabolism studies are adequate to satisfy data requirements. The data demonstrate that metabolism of imazosulfuron is similar in three dissimilar crops, and that hydrolysis of the sulfonylurea linkage is the major metabolic process. Imazosulfuron was a major residue in rice grain, rice straw, and tomato, accounting for up to ~28%, 64%, and 17% TRR, respectively. A pyrimidinyl-ring metabolite, UDPM, was also a major residue in rice grain, rice straw, and tomato, accounting for up to 18%, 13%, and 30% TRR. In potato tuber, where TRR were significantly lower overall, imazosulfuron was identified at 8% TRR, ISPN was identified at 12% (but 0.003 ppm), and UDPM was present at <1% TRR. The only double-ring metabolite identified in the studies was HMS, which accounted for ≤ 8% TRR in all crops.

Based on the submitted data, HED concludes that the nature of the residue in plants is adequately understood for purposes of this petition. The residue of concern for tolerance enforcement is imazosulfuron. Imazosulfuron was the major component of most matrices and is an acceptable marker for tolerance enforcement. Imazosulfuron was proposed as the residue for tolerance

enforcement. The residue of concern for diet ary risk assessment is the sum of imazosulfuron and the metabolite UDPM, expressed as equivalents of imazosulfuron (E. Scollon, ROCKS, D377141, 05/19/2010). HED notes that the proposed enforcement method and data collection

method determine imazosulfuron and UDPM.

860.1300 Nature of the Residue - Livestock

DER References: 47679115.der.doc (Goat) 47679116.der.doc (Hen)

Ruminant

Valent has submitted a study investigating the metabolism of [imidazolyl-3- 14 C]imazosulfuron and [pyrimidinyl-5- 14 C]imazosulfuron in the lactating goat; the specific activity was 0.859 GBq/mmol for each radiolabel. The test substances were administered orally via gelatin capsule to two goats (one goat per radiolabel) at ~13 ppm (~1600x the dietary burden to cattle) in the diet for 5 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 evening. Tissues, including muscle (composite of loin and hindquarter), fat (composite of omental and renal), liver, and kidney, were collected at sacrifice, 23 hours after the final dose. The in-life phase of the study was conducted by Genesis Midwest LLC (Neillsville, WI), and the analytical phase of the study was conducted by PTRL West, Inc. (Hercules, CA).

TRR were determined initially by LSC (following solubilization for tissues). In Day 5 evening milk and tissues with TRR >0.01 ppm, TRR were also determined by summing extractable and nonextractable radioactivity; summed TRR values were used for all further calculations. TRR inImazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 16 of 40 milk were generally low and consistent during the dosing period; lower levels were observed in morning samples prior to dosing (0.006-0.009 ppm, both labels) and higher levels were observed in evening samples (0.029-0.038 ppm in Im-label milk, and 0.022-0.028 ppm in Py-label milk). TRR were <0.01 ppm in Py-label muscle (0.005 ppm) and Im- and Py-label fat (0.003 and 0.007 ppm, respectively); residues in these samples were not further investigated. In Day 5 evening milk and remaining tissues, TRR were ≥ 0.01 ppm: 0.030, 0.010, 0.159, and 0.222 ppm in Imlabel milk, muscle, kidney, and liver, respectively, and 0.028, 0.154, and 0.442 ppm in Py-label milk, kidney, and liver, respectively. The majority of the applied dose (~80%) was excreted:

22-39% in urine and 41-58% in feces.

The majority of the radioactivity was extracted with ACN and ACN/water from milk (~97-100% TRR), Im-label muscle (~90% TRR) and Im-label kidney (~77% TRR). Solvent extractionreleased lower amounts of radioactivity from Py-label kidney (~34% TRR), and Im- and Pylabel liver (~12-28% TRR). Samples of liver a nd kidney (both labels) were subjected to acid hydrolysis with 6 N HCl which released an additional 20-58% TRR from kidney and 49-50% TRR from liver. Liver samples (both labels) we re also further extracted with 1 N NaOH and pepsin, which released 5-11% and 2-3% TRR, re spectively. Nonextractable residues remaining after extraction/hydrolysis accounted for ≤ 3.3% TRR ( ≤ 0.001 ppm) in milk, 10.0% TRR (0.001 ppm) in Im-label muscle, ~3-8% TRR (0.005-0.013 ppm) in kidney, and ~15-25% TRR (0.033- 0.111 ppm) in liver Accountabilities based on combustion TRR were 90-111% for goat matrices.

Residues were initially identified and quantitated by HPLC. Identification of imazosulfuron and its metabolites was confirmed in milk, muscle, kidney, and liver by TLC co-chromatography. Milk and tissues were stored frozen for a maximum of 2.7 months prior to initial analysis. The petitioner has demonstrated that the metabolic profile in milk and tissues is relatively stable for ~11-12 months. No additional storage stability data are required because sample integrity was maintained by appropriate freezer storage, and initial HPLC analyses were completed within 6 months of sample collection.

The parent, imazosulfuron, was the major residue identified in goat milk, accounting for 46.4- 66.7% TRR (0.013-0.020 ppm). Imazosulfuron was also identified as a significant residue in Im-label muscle at 20.0% TRR (0.002 ppm) and kidney at 23.4-28.3% TRR (0.036-0.045 ppm), and was a minor residue in liver, accounting for 3.4-9.9% TRR (0.015-0.022 ppm). In Im-label samples, the imidazolyl-ring metabolite IPSN was the major residue identified in muscle at 70.0% TRR (0.007 ppm), kidney at 32.7% TRR (0.052 ppm), and liver at 31.1% TRR (0.069ppm). IPSN was identified as a minor residue in milk at 6.7% TRR (0.002 ppm). The doublering metabolite HMS was a minor residue in Im-label milk at 3.3% TRR (0.001 ppm) and kidney at 1.9% TRR (0.003 ppm). No additional metabolites were identified in Py-label samples. Discrete unknowns, none present at >0.010 ppm in Im-label samples accounted for up to 20.0% TRR in milk, 13.8% TRR in kidney, and 6.3% TRR in liver. In Py-label samples, discrete unknowns, none present at >0.018 ppm, accounted for up to 53.6% TRR in milk, 10.4% TRR in kidney, and 8.6% TRR in liver.

Significant amounts of radioactivity in kidney and liver were bound. The largest amount of bound radioactivity was released with 6 N HCl hydrolysis: 20-58% TRR in kidney and 49-50% TRR in liver. The acid hydrolysate was partitioned with dichloromethane (DCM) and/or ethyl acetate for Im-label liver and Py-label kidney and liver. Partitioning with organic solvents extracted <2% TRR for Im-label liver; however, in Py-label samples, the ethyl acetate phaseImazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 17 of 40 contained 15.6% TRR (0.024 ppm) for kidney and 8.1% TRR (0.036 ppm) for liver. HPLC analysis of the ethyl acetate phase of Py-label liver indicated a very polar component (5.2% TRR, 0.023 ppm) that did not match any of the available reference standards. The remaining acidic aqueous phase following acid hydrolysis (41-46% TRR for liver and kidney) was subjected to C18 solid phase extraction (SPE) frac tionation; selected fractions were analyzed by HPLC. IPSN was identified in the Im-label liver fraction; remaining residues in liver and kidney were characterized as diverse radioactivity or multiple components, none of which accounted for >0.05 ppm or co-eluted with any reference standard.

Based on the goat metabolism study, the petitioner proposes that metabolism of imazosulfuron in goats occurred via demethylation and/or by hydrolysis at the sulfonylurea bridge.

Poultry

Valent has submitted a study investigating the metabolism of [imidazolyl-3- 14 C]imazosulfuron and [pyrimidinyl-5- 14 C]imazosulfuron in laying hens; the specific activity was 0.859 GBq/mmol for each radiolabel. The test substances were administered orally via gelatin capsule to two groups of 10 hens (one group per radiolabel ) at ~12-13 ppm (~2000x the dietary burden to poultry) in the diet for 7 consecutive days. A third group of six hens was treated with capsules containing carrier only, for controls. Eggs we re collected twice daily throughout the study, in the evening and in the morning prior to dosing; tissues, including muscle (composite of breast and thigh), abdominal fat, and liver, were collected at sacrifice, 22-23 hours after the final dose. The in-life phase of the study was conducted by Genesis Midwest LLC (Neillsville, WI), and the analytical phase of the study was conducted by PTRL West, Inc. (Hercules, CA).

TRR in egg and tissue samples were determined initially by solubilization prior to radioassay by LSC. In Day 7 evening eggs and all tissue samples, TRR were also determined by summing extractable and nonextractable radioactivity; these values were used for all subsequentcalculations. Following oral dosing for 7 consecutive days, TRR were 0.055-0.122 ppm in Imlabel eggs and 0.045-0.149 ppm in Py-label eggs. Radioactivity in eggs generally increased with each subsequent dosing; maximum evels were observed in eggs following final dosing, in the Day 7 evening samples. In Day 7 evening eggs and tissues, TRR were 0.120, 0.020, 0.007, and 0.253 ppm in Im-label eggs, muscle, fat, and liver, respectively, and 0.148, 0.013, 0.011, and 0.172 ppm in Py-label eggs, muscle, fat, and liver, respectively. The majority of the applied dose (83-87%) was excreted.

The majority of the radioactivity was extracted with ACN and ACN/water from eggs (~91-96% TRR) and muscle (~77-90% TRR); extraction with ACN/water released lower amounts of radioactivity from liver (~29-40% TRR). For fat, extraction with acetone/hexane released the majority of the radioactivity (~71-73% TRR). Acid hydrolysis with 6 N HCl released an additional 43-44% TRR from liver. Liver sample s were also further extracted with 1 N NaOH and pepsin, which released 9-12% TRR and 3-5% TRR, respectively. Nonextractable residues remaining after extraction/hydrolysis accounted for 4.2-9.5% TRR (0.005-0.014 ppm) in eggs, 10.0-23.1% TRR (0.002-0.003 ppm) in muscle, 27.3-28.6% TRR (0.002-0.003 ppm) in fat, and ~2-14% TRR (0.005-0.024 ppm) in liver. The procedures adequately extracted the majority of the residues from eggs and tissues. Accountabilities based on combustion TRR were 70-100%

for hen matrices.Imazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 18 of 40 Residues were initially identified and quantitated by HPLC. Identification of imazosulfuron and its metabolites was confirmed in eggs, muscle, fat, and liver by TLC co-chromatography. Eggs and tissues were stored frozen for a maximum of 2.6 months prior to initial analysis. The petitioner has demonstrated that the metabolic profile in eggs and liver is relatively stable for ~10-11 months. No additional storage stability data are required because sample integrity was maintained by appropriate freezer storage, and initial HPLC analyses were completed within 6 months of sample collection.

The parent, imazosulfuron, was the major residue identified in eggs (both labels) accounting for 70.8-79.7% TRR (0.085-0.118 ppm), and in Py-label muscle at 61.5% TRR (0.008 ppm), fat at 54.5% TRR (0.006 ppm), and liver at 16.9% TRR (0.029 ppm). Imazosulfuron was identified as a significant residue in Im-label muscle and fat, at 15.0% TRR (0.003 ppm) and 14.3% TRR (0.001 ppm), respectively, and was a minor residue in Im-label liver at 4.7% TRR (0.012 ppm). In Im-label samples, the imidazolyl-ring metabolite IPSN was the major residue identified in muscle at 25.0% TRR (0.005 ppm), fat at 28.6% TRR (0.002 ppm), and liver at 43.0% TRR (0.109 ppm). IPSN was also identified in Im-label eggs at 10.0% TRR (0.012 ppm). In Py-label samples, the pyrimidinyl-ring metabolite UDPM was detected only in eggs and at low levels (4.1% TRR, 0.006 ppm). The double-ring metabolite HMS was identified in Py-label fat at 9.1% TRR (0.001 ppm); this metabolite was tentatively identified but was not confirmed and/or quantitated in Py-label egg and Im- and Py-label liver at trace levels.

Significant amounts of radioactivity in liver were bound. The largest amount of bound radioactivity (43.1-43.6% TRR) was released w ith 6 N HCl hydrolysis. The acid hydrolysate was partitioned with DCM and ethyl acetate wh ich released 0.8-1.7% TRR and 1.2-2.9% TRR, respectively. The remaining acidic aqueous phase following acid hydrolysis was subjected to C18 SPE fractionation, and selected fractions were analyzed by HPLC. IPSN was identified in the Im-label liver fraction; residues in Pm-label liver were characterized as heterogeneous in nature and were not further analyzed.

Based on the hen metabolism study, the petitioner proposes that metabolism of imazosulfuron in hens occurred via demethylation and/or by hydrolysis at the sulfonylurea bridge

Conclusions . The submitted ruminant and poultry metabolism studies are adequate to satisfy data requirements. The data demonstrate that metabolism of imazosulfuron is similar in ruminants and poultry, and that hydrolysis of the sulfonylurea linkage is the major metabolic process. Imazosulfuron was a major residue in ruminant milk and tissues, except fat, and in poultry eggs and tissues, accounting for up to ~10-67% TRR in ruminant matrices and up to 17- 80% TRR in poultry matrices. Although nonextract able residues in Py-label ruminant liver exceeded trigger levels (>10% TRR/0.05 ppm), HED concludes that sufficient attempts were made to release bound residues in tissues; the procedures adequately extracted the majority of the residues from goat milk and tissues. An imidazolyl-ring metabolite, IPSN, was also a major metabolite in ruminant and poultry tissues, at 25-70% TRR, and was present in milk and eggs at ~7-10% TRR. The pyrimidinyl-ring metabolite UDPM was identified only in eggs, as a minor metabolite (~4% TRR). The double-ring metabolite HMS was identified in ruminant milk and kidney at <3.3% TRR and in poultry liver at ~9% TRR.

Based on the submitted data HED concludes that the nature of the residue in livestock is adequately understood. The residue of concern for tolerance enforcement is imazosulfuron .Imazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 19 of 40 The residue of concern for dietary risk assessment is the sum of imazosulfuron and the metabolite IPSN, expressed as equivalents of imazosulfuron (E. Scollon, ROCKS, D377141, 05/19/2010).

.

860.1340 Residue Analytical Methods

DER Reference: 47679121.der.doc (includes review of MRIDs 47814801 and 48238301)

Plant Commodities

Enforcement method : Valent has submitted LC/MS/MS Method RM-42C-3 and modification Method RM-42C-3a, for the determination of residues of imazosulfuron and its metabolite UDPM in/on rice, pepper, and tomato. Valent is proposing the method as an enforcement method and has submitted a complete method description, method validation data, and the results

of an ILV of the method.

Briefly, samples are hydrated (rice straw and grain only), extracted with ACN, and filtered. The filtrate is partitioned with hexane, and the ACN phase is collected and evaporated to dryness. The residue is redissolved in methanol for cleanup through either an Oasis HLB ® SPE (pepper, rice straw, and tomato) or C18 SPE (rice grain) cartridge. Residues are eluted with methanol or methanol/water and diluted with water for analysis by LC/MS/MS. The validated LOQ is 0.02 ppm for each analyte, and the limit of detection (LOD) is 0.01 ppm for each analyte.

The method was adequately validated using samples of rice grain and straw fortified with imazosulfuron and UDPM, each at 0.02 and 0.10 ppm. Overall recoveries were 77-96% (average of 86% and standard deviation of 6 %) for imazosulfuron and 75-119% (average of 93% and standard deviation of 13%) for UDPM. The method was further validated in conjunction with the field trial and processing studies. Adequate concurrent recoveries were obtained for pepper, rice bran, rice hulls, polished rice, tomato, tomato paste, and tomato puree fortified with each analyte at 0.02 and 0.10 ppm; and rice grain fortified with each analyte at 0.02-0.30 ppm. The fortification levels used in method validation and concurrent recovery were adequate to bracket expected residues in treated samples.

A confirmatory procedure was added in an addendum, Method RM-42C-3a. Two MS/MS ion transitions are monitored to provide a qualitative confirmation of the identity of imazosulfron. These are in addition to the primary transition used to quantitate imazosulfuron.

A successful ILV was conducted reflecting acceptable recoveries of imazosulfuron and UDPM from samples of untreated rice grain fortifie d with each analyte at 0.02, 0.10, and 3.0 ppm. The ILV laboratory recommended minor modifications to the method, and these modifications were incorporated into Method RM-42C-3a.

No radiovalidation data were included in the submission; however, no data are required because the extraction procedures of the analytical method are similar to those used in the submitted potato, rice, and tomato metabolism studies which showed satisfactory recovery of incurred

residues.Imazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 20 of 40 Data collection method : The proposed enforcement method, LC/MS/MS Method RM-42C-3, was used for data collection in the storage stability, crop field trial, and processing studies for imazosulfuron reviewed under DP# 367019. The method was followed as written except as

noted below.

For data collection in the rice processing study, bran and hulls were analyzed according to the method as written for rice grain. For analysis of polished rice, samples were extracted with ACN/water followed by ACN and filtered. The filtrates were combined and reduced to an aqueous remainder by rotary evaporation. The aqueous fraction was mixed with water and sodium chloride and then partitioned with dichloromethane (2x). Dichloromethane was removed by rotary evaporation, and the remaining aqueous residue was applied to a C18 SPE cartridge for cleanup; residues were eluted with methanol/water. The eluate was diluted with water for analysis by LC/MS/MS.

For data collection in the tomato processing study, the method was modified for analysis of all commodities. For tomatoes and tomato paste, the extraction solvent (ACN/water instead of ACN) and clean-up procedures (partitioning with DCM instead of hexane and use of a C-18 SPE cartridge instead of Oasis HLB cartridge) were modified; for puree, cleanup steps including partitioning with hexane and SPE were eliminated.

Briefly, samples of tomatoes and tomato paste were extracted with ACN/water and filtered; paste samples were initially hydrated with water for 30 minutes. The filtrate was reduced to an aqueous remainder by rotary evaporation. The aqueous fraction was mixed with water and sodium chloride then partitioned with dichloromethane (2x). Dichloromethane was removed by rotary evaporation, and the remaining aqueous residue was applied to a C18 SPE cartridge for cleanup; residues were eluted with methanol/water. The eluate was diluted with water for analysis by LC/MS/MS.

Samples of puree were extracted with acetonitr ile (ACN) and filtered. The ACN filtrate was reduced by rotary evaporation, then dissolved in methanol and diluted with water for analysis by

LC/MS/MS.

Conclusions. The submitted data are adequate to satisfy residue analytical methods data requirements for tolerance enforcement purposes.

HED reviewed the method under the TMV criteria (SOP AOB-019, 09/15/08) and determined that it is acceptable for tolerance enforcement purposes. The method was adequately validated by the developing laboratory, the ILV laboratory, and in conjunction with the pepper, rice, and tomato crop field trials and the rice processing study. The method will be forwarded to FDA for

inclusion in the PAM Vol. II.

Method RM-42C-3 is acceptable for data collection for residues of imazosulfuron and UDPM in/on samples of pepper, rice grain and rice processed commodities, and tomato and tomato processed commodities from the submitted crop field trial and processing study.

Analytical methods for analysis of livestock commodities are not required at this time.Imazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 21 of 40 860.1360 Multiresidue Methods

DER Reference: 47679120.der.doc

Valent has submitted multiresidue method (MRM) testing data for imazosulfuron and its metabolite UDPM following testing and analysis according to FDA Multiresidue Method Test

Guidelines in the PAM Vol. I (1/94). The decision tree for MRM Testing ( PAM Vol. I, Appendix II) was followed in determining the response patterns. Imazosulfuron and UDPM were tested through Protocols A, C, D, E, F, and G; testing under Protocol B was not conducted because neither analyte is an acid or phenol. The study was conducted by EN-CAS Analytical Laboratories (Winston-Salem, NC).

Imazosulfuron and UDPM are not N-methylcar bamates. Under Protocol A testing, imazosulfuron was found to have some fluorescent response; however, recovery was <50% through charcoal/silanized Celite column cleanup; UDPM was not found to be fluorescent. Testing under Protocol A was discontinued.

Both imazosulfuron and UDPM were found to be chromatographable under Protocol C testing using GC/ECD (system DG1) and GC/NPD (sys tem DG17); therefore, further testing was

conducted under Protocol D. Under Protocol D testing, neither imazosulfuron nor UDPM was recovered through the Florisil elution procedure (c leanup system C1 only). The petitioner stated that, based on the Florisil cleanup results, testing under Protocol D was terminated for imazosulfuron. UDPM was successfully recovered through the complete method without cleanup (system DG17), using whole tomato as a representative nonfatty food and yielding partial recoveries (50-80%) at fortifications of 0.05 and 0.25 ppm.

Neither imazosulfuron nor UDPM was further tested under Protocols E and F. The petitioner

stated that imazosulfuron was not further tested because it was not shown to be recovered in Protocol D testing through Section 302 extraction, and that UDPM was not further tested because it was not recovered through Florisil cleanup in Protocol D testing

Both imazosulfuron and UDPM are substituted ureas and were tested under Protocol G. Sensitivity was low for imazosulfuron (2800 ng required to achieve 50% full-scale deflection, FSD) and 50% FSD was not achieved for UDPM even at concentrations up to 40,000 ng.

The petitioner concluded that the multiresidue methods are not suitable for determination of imazosulfuron, and that Protocol D may be suitable for determination of UDPM in nonfatty foods that do not require Florisil cleanup at levels ~10x tolerance (i.e., 0.25 ppm).

Conclusions . The submitted multiresidue methods test data for imazosulfuron and UDPM are considered to be tentatively adequate pending submission of the following additional information: (1) the petitioner must explain why testing for imazosulfuron under Protocol D through the complete method without cleanup was not conducted or provide the results of testing without cleanup; and (2) the petitioner must explain why imazosulfuron and UDPM were only tested using one of the two Protocol D Florisil elution procedures. Because imazosulfuron was recovered by two detectors in Protocol C tes ting, the petitioner must explain why testing for imazosulfuron under Protocol D through the complete method without cleanup was not conducted or provide the results of testing without cleanup. In addition, the petitioner shouldImazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 22 of 40 explain why imazosulfuron and UDPM were only test ed using one of the two Protocol D Florisil elution procedures. PAM I specifies (Appendix II-4) that Florisil elution should be tested by both ethyl ether/petroleum ether and dichloromethane systems (corresponding to systems C5 and C1, respectively, of Protocol D). Provided the petitioner satisfactorily addresses the question of why the compounds were not tested through both Fl orisil elution systems in Protocol D, HED concurs that no further testing under Protocols E and F would be required.

The data indicate that the multiresidue methods are not suitable for determination of imazosulfuron or UDPM. Although UDPM was recovered in Protocol D testing, the concentration at which recovery was achieved far exceeds expected residues in peppers, rice grain, or tomatoes.

Pending submission of the required information concerning testing under Protocol D, the

submitted data will be forwarded to U.S. FDA for further evaluation.

860.1380 Storage Stability

DER Reference: 47679123.de2.doc (includes review of data from MRIDs 47679124 and 47679125)

In conjunction with the associated field trials, Valent has submitted the interim results of storage stability studies with imazosulfuron and its metabolite UDPM in/on bell pepper, rice grain, tomato, and tomato paste. Untreated samples of bell pepper, rice grain, tomato, and tomato paste were fortified with imazosulfuron or UDPM at 0.100 ppm and stored frozen (-20 to -10 °C). Stored fortified and unfortified samples were analyzed at storage intervals of 0, 34, 60, 90, 125 and 194 days for bell peppers; 1, 31, and 113 days for rice grain; 0, 33, 58, 98, 195, and 224 days for tomatoes; and 0 and 44 days for tomato paste. Fresh fortification samples were also analyzed at each interval. HED notes that no details were provided concerning the preparation of samples or fortification solutions for the study. The petitioner has indicated that the final results of the storage stability study will be submitted at a later date.

Samples were analyzed for residues of imazosulfuron and its metabolite UDPM using LC/MS/MS Method RM-42C-3. The method was adequate for data collection based on acceptable concurrent recovery data. The reported LOQ was 0.02 ppm for each analyte.

The interim results indicate that under frozen storage conditions, residues of imazosulfuron and UDPM are relatively stable in/on bell peppers for up to 194 days (6.4 months), rice grain for up to 113 days (3.7 months), tomatoes for up to 224 days (7.4 months), and tomato paste for up to

1.4 months.

Sample storage intervals and conditions

The storage durations and conditions of samples from the crop field trials and processing study submitted to support this petition are presented in Table 4.Imazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 23 of 40 Table 4. Summary of Storage Conditions and Dura tions of Samples from Crop Field Trial and Processing Studies.

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

Pepper -20 to -10 185-359 days (6.1-11.8 months) Imazosulfuron and UDPM are stable in/on bell peppers stored frozen for up to 194 days (6.4 months)

Rice grain (field trials) 185-1049 days (6.1-34.5 months)

Rice grain (processing study) 200 days (6.6 months)

Polished rice 303 days (10 months)

Rice hulls 191 days (6.3 months)

Rice bran -20 to -10

184 days (6.0 months) Imazosulfuron and UDPM are stable in/on rice grain stored frozen for up to for 113 days (3.7 months).

Tomato (field trials) 229-526 days (7.5-17.3 months)

Tomato (processing study) 413 days (13.6 months) Imazosulfuron and UDPM are

stable in/on tomatoes stored frozen for up to 224 days (7.4 months).

Tomato paste 383 days (12.6 months)

Tomato puree -20 to -10

337 days (11.1 months) Imazosulfuron and UDPM are stable in tomato paste stored frozen for up to 44 days (1.4 months).

Conclusions . The storage stability data submitted for pepper, rice grain, tomato, and tomato paste are not adequate to support the storage intervals of crop field trial samples. Although no storage stability data were submitted for rice processed commodities, in consideration of the nature of the processing procedures for rice (i.e., fractions are not heated or chemically treated during processing and are generally physically similar to whole grain), the available data for rice grain may be translated to the processed rice commodities.

The submitted interim storage data are not adequate to support the storage durations of samples of peppers, rice grain, and tomato and tomato processed commodities from the submitted crop field trial and processing studies. The petitione r has indicated that data for longer storage intervals will be reported at a later date. The final report(s) of the storage stability studies must be submitted, reflecting storage intervals of up to 12 months for peppers, up to 35 months for rice grain, up to 18 months for tomatoes, and up to 13 months for processed tomato commodities. Details concerning the preparation of samples and fortification solutions should be provided with the final report(s).

860.1400 Water, Fish, and Irrigated Crops

The proposed use of imazosulfuron on rice may lead to residues in fish and shellfish. Because the use directions prohibit use of water drained from rice fields to irrigate other crops, residues in irrigation water and irrigated crops are not a concern.

No data have been submitted pertaining to residues of imazosulfuron in fish or shellfish. In the absence of such data, the petitioner must include label restrictions prohibiting application to rice if fields are used for fish production, es pecially catfish or crayfish farming.Imazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 24 of 40 If the petitioner wishes to remove these label restrictions, additional data may be required, including metabolism and feeding studies on crayfish and/or freshwater fish.

860.1460 Food Handling

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

860.1480 Meat, Milk, Poultry, and Eggs

No DER; MRID 47679122 (data waiver request) is addressed herein

There are livestock feedstuffs associated with the proposed use on rice: rice grain and bran. The maximum reasonable dietary burdens (MRDBs) are 0.008 ppm for cattle and 0.006 ppm for poultry and swine (Table 5).

Table 5. Calculation of Dietary Burdens of Imazosulfuron Residues to Livestock.

Feedstuff Type 1 % Dry

Matter 2 % Diet 2 Recommended Tolerance (ppm) Dietary Contribution (ppm) 3

Beef Cattle

R not registered R
-- 15

-- -- Rice grain CC 88 20 0.02 0.005

Rice bran CC 90 15 0.02 0.003

CC not registered CC

-- 45

-- -- PC not registered PC

-- 5
-- --
TOTAL BURDEN

-- -- 100

-- 0.008

Dairy Cattle

R not registered R
-- 45

-- -- Rice grain CC 88 20 0.02 0.005

Rice bran CC 90 15 0.02 0.003

CC not registered CC

-- 10

-- -- PC not registered PC

-- 10

-- --
TOTAL BURDEN

-- -- 100

-- 0.008

Poultry

Rice grain CC 88 20 0.02 0.004

Rice bran CC 90 10 0.02 0.002

CC not registered CC

-- 45

-- -- PC not registered PC

-- 25

-- --
TOTAL BURDEN

-- -- 100

-- 0.006Imazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 25 of 40 Table 5. Calculation of Dietary Burdens of Imazosulfuron Residues to Livestock.

Feedstuff Type 1 % Dry

Matter 2 % Diet 2 Recommended Tolerance (ppm) Dietary Contribution (ppm) 3

Swine

Rice grain CC 88 20 0.02 0.004

Rice bran CC 90 10 0.02 0.002

CC not registered CC

-- 55
-- -- PC not registered PC

-- 15

-- --
TOTAL BURDEN

-- -- 100

-- 0.006

1 R: Roughage; CC: Carbohydrate con centrate; PC: Protein concentrate.

2 OPPTS 860.1000 Table 1 Feedstuffs (June 2008).

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

Valent has submitted a waiver request for the requirements for cow and hen feeding studies based on the low residues of imazosulfuron observed in rice grain ( ≤ 0.02 ppm) and low recommended tolerance (0.02 ppm); the results of the rice processing study, which indicate that residues do not concentrate in rice bran; the relatively low dietary burdens of imazosulfuron to livestock; and the results of the ruminant and poultry metabolism studies.

In support of the waiver request, the petitioner used the results of the goat and hen metabolism studies to calculate anticipated residues of imazosulfuron and the major metabolite observed in livestock, IPSN, based on the highest observed TRR in milk, eggs, and ruminant and poultry tissues. Results were compared to the proposed tolerance for rice grain and the enforcement method LOQ of 0.02 ppm. Because of differences in how the metabolism study data were summarized by the petitioner and in the DERs associated with DP# 367019, the petitioner’s calculations are reproduced below with modifications as needed to be consistent with the 860.1300 DERs for MRIDs 47679115 (goat study) and 47679116 (hen study). The calculations have also been adjusted to reflect extrapolation to a 10x dosing level, which is consistent with HED’s policy in assessing the need for feeding study data.

Table 6. Extrapolation of Residues found in th e Livestock Metabolism Studies to Anticipated Residues at a 10x Dosing Level.

Commodity with highest observed

residues Metabolism study dosing level (ppm) TRR (ppm) Transfer

coefficient 1 Maximum anticipated

residues at 10x (ppm) 2 %TRR

imazosulfuron

+ IPSN 3 Maximum anticipated

residues of

concern, ppm

Ruminant

Im-label Day 5 milk 12.8 0.030 0.0023 0.0002 73.4 0.0001

Pm-label liver 12.7 0.442 0.0348 0.0028 41.0 0.0011

Poultry

Pm-label egg 12.4 0.148 0.0119 0.0007 89.7 0.0006

Im-label liver 12.8 0.253 0.0198 0.0012 59.9 0.0007

1 TRR ÷ dosing level.

2 Transfer coefficient * RDB * 10

3 Using highest observed %TRR for imazosulfuron from either label.

Extrapolation of the livestock metabolism study results suggest that anticipated residues of imazosulfuron and the major livestock metabolite IPSN in livestock at a 10x dosing level wouldImazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 26 of 40 be ≤ 0.001 ppm. HED concludes that the proposed uses of imazosulfuron in this petition result in a 40 CFR §180.6(a)(3) situation for livestock commodities; i.e., there is no reasonable expectation of finite residues in ruminant, poultry, or swine commodities.

Conclusions . In consideration of the low anticipated dietary burdens of imazosulfuron to livestock, HED recommends that the requirements for ruminant and poultry feeding studies be waived for this petition. No feeding studies need be submitted to support the proposed uses of imazosulfuron on pepper, rice, and tomato. HED notes that if additional uses of imazosulfuron with livestock feed items are proposed in the fu ture, feeding studies and a tolerance enforcement method for livestock may be required.

860.1500 Crop Field Trials

DER References: 47679123.de1.doc (Pepper) 47679124.de1.doc (Rice) 47679125.de1.doc (Tomato)

Table 7. Summary of Residue Data from Crop Field Trials with Imazosulfuron.

Imazosulfuron Residue Levels (ppm) Crop matrix Total Applic.

Rate (lb ai/A) PHI (days) n Min. Max. HAFT 1 Median Mean Std.

Dev.

PEPPERS (bell and nonbell): (proposed use = 0.3 lb ai/A total application rate, 21-day PHI)

Pepper, bell 0.886-0.914 20-22 16 <0.02 <0.02 0.02 0.02 0.02 NA

Pepper, nonbell 0.873-0.919 20-21 6 <0.02 <0.02 0.02 0.02 0.02 NA

RICE: (proposed use = 0.3 lb ai/A total application rate, up to 2-inch internod e growth stage ( about BBCH 34)

Rice, grain 0.491-0.557; 0.753 (one trial) 52-83 32 <0.02 0.02 0.02 0.02 0.02 NA

TOMATO (proposed use = 0.3 lb ai/A total application rate, 21-day PHI)

Tomato (bedded) 0.875-0.917 20-21 32 <0.02 <0.02 0.02 0.02 0.02 NA

Tomato (staked) 0.871-0.919 6-7 12 <0.02 <0.02 0.02 0.02 0.02 NA

1 HAFT = Highest average field trial result. For purpos es of calculating the HAFT, median, mean, and standard deviation, values reported as <0.02 ppm are assumed to be equal to 0.02 ppm.

Pepper

Valent has submitted field trial data for imazosulfuron on bell and nonbell peppers. Eleven trials were conducted in the United States during the 2007 growing season. Eight bell pepper field trials were conducted in Zones 2 (GA, SC; 2 trials), 3 (FL; 2 trials), 5 (MI; 1 trial), 6 (TX; 1 trial), and 10 (CA; 2 trials), and three nonbell pepper field trials were conducted in Zones 8 (TX; 1 trial) and 10 (AZ, CA; 2 trials).

At each trial site, an untreated and a treated plot were established. The treated plots received two directed spray applications of a 75% WG formulation of imazosulfuron. The first application was made 3-4 days after transplanting at a target rate of ~0.5 lb ai/A, followed 41-94 days later by a second application at a target rate of ~0.4 lb ai/A, for a total seasonal rate of ~0.9 lb ai/A (3x the maximum proposed seasonal application rate). The first application was directed within the row (at the base of the plants) and in the row middles, and the second application was directed in the row middles only. Applications were made using ground equipment in ~12- toImazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 27 of 40 15-gal/A spray volumes without an adjuvant. Samples of mature peppers were collected 20-22 days after the last application.

Samples were analyzed for residues of imazosulfuron and its metabolite UDPM using an adequate method, LC/MS/MS Method RM-42C-3. The validated LOQ was 0.02 ppm for each analyte in/on peppers. Sample storage conditions and durations are reported in Table 4. The final results of the storage stability study, reflecting storage of pepper samples for up to 12 months, are required to support the sample storage durations.

The results of the pepper field trials are summarized in Table 7. Residues of imazosulfuron and UDPM were each nonquantifiable (<0.02 ppm) in/on bell and nonbell peppers harvested 20-22 days following two directed spray applications of the 75% WG formulation made 3-4 days after transplanting and during fruit development, for a total rate of 0.873-0.919 lb ai/A.

Rice

Valent has submitted field trial data for imazosulfuron on rice. Sixteen field trials were conducted in the United States in Zones 4 (AR, LA, MS; 11 trials), 5 (MO; 1 trial), 6 (TX; 2 trials), and 10 (CA; 2 trials) during the 2005, 2006, and 2007 growing seasons.

At each trial site, an untreated plot and one or more treated plots were established. One treated plot at each site received a single broadcast fo liar application of a 75% WG formulation of imazosulfuron made at the 2-inch internode growth stage at a target rate of ~0.5 lb ai/A, with two exceptions: at the MO site (V-28783-06-H) application was made at ~0.75 lb ai/A, and at one MS site (V-28783-07-L) application was made at th e mid-boot growth stage. At one AR site (V28783-05-E), a second treated plot received a single application of the 75% WG formulation at ~0.75 lb ai/A for a side-by-side trial. The target application rate corresponded to ~1.7-2.5x the maximum proposed seasonal application rate for rice. Applications were made using ground equipment in ~10 to 15 gal/A spray volumes without an adjuvant. Samples of mature rice grain were collected 52-83 days after application; samp les of rice straw were collected but were not analyzed. HED notes that rice straw is no longer considered a significant livestock feed item (Table 1 feedstuffs, June 2008); therefore, analysis of rice straw samples is not required to support the submitted field trials.

In two trials intended as residue decline trials, three additional treated plots at each site received a single foliar broadcast application of the 75% WG formulation at ~0.5 lb ai/A made 14 and 7 days before the target growth stage (at growth stages of late tillering/panicle initiation and panicle initiation/elongation) and 7 days after the ta rget growth stage (at growth stages of early booting/boot). Samples were collected from all of the treated plots at each site on the same day, at PHIs of 70, 63, 56 (target), and 49 days at one site, and 80, 73, 66 (target), and 59 days at the other site; samples from the second treatment site harvested at an 80-day PHI were not analyzed.

Samples were analyzed for residues of imazosulfuron and its metabolite UDPM using an adequate method, LC/MS/MS Method RM-42C-3. The validated LOQ was 0.02 ppm for each analyte in/on rice grain. Sample storage conditi ons and durations are reported in Table 4. The final results of the storage stability study, reflecting storage of rice grain samples for up to 35 months, are required to support the sample storage durations.Imazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 28 of 40 The results of the rice field trials are summarized in Table 7. Maximum residues of imazosulfuron and UDPM were <0.02 ppm, each, in/on rice grain harvested 52-83 days following a single broadcast application of a 75% WG formulation of imazosulfuron, at 0.491- 0.557 lb ai/A and 0.753 lb ai/A (one trial). HED c oncludes that data from the trial conducted at 0.753 lb ai/A may be included with data from the other trials because residues were at or below the LOQ in/on samples from all trials. In addition, in side-by-side trials conducted at 0.504 and 0.752 lb ai/A at the AR site (V-28783-05-E), re sidues were <0.02 ppm in/on samples from both plots.

In the trials intended for residue decline, residues of imazosulfuron and UDPM were <LOQ in/on all samples, including earlier, later, and target growth stages, from the first trial. In the second trial (V-28783-05-D), as would be expected, residues were <LOQ in/on samples treated at an earlier growth stage and harvested at a longer PHI than the target; in samples treated at boot stage and harvested at a shorter PHI (59 days), residues of imazosulfuron and UDPM were higher (0.16-0.19 and 0.06 ppm, respectively) than those observed in any samples treated at the target growth stage. This trial result was not included in Table 7 because it does not correspond to the proposed label, i.e., application at or before the 2-inch internode growth stage. The petitioner also speculated that sample contamination may have occurred. Because the target growth stage, 2-inch internode, is a late vegetative growth stage for rice, no residue decline data are needed to support use on rice.

Tomato

Valent has submitted field trial data for imazosulfuron on tomatoes. Seventeen trials were conducted in the United States during the 2006 and 2007 growing seasons in Zones 1 (PA; 1 trial), 2 (SC; 1 trial), 3 (FL; 2 trials), 5 (MI; 1 trial), and 10 (AZ and CA; 12 trials). The tomatoes used in the trials included small, medium, and large varieties.

At each trial site, an untreated and one or two treat ed plots were established. At one treated plot at each of 16 sites (Treatment 2), row or bedded tomatoes received two broadcast foliar applications of a 75% WG formulation of imazosulfuron. The first application was made 2 days post-transplant to tomato plants in the vegetative stage at a target rate of ~0.5 lb ai/A; the second application was made 21-92 days later to plants bearing immature to mature fruit at a target rate of ~0.4 lb ai/A, for a total seasonal rate of ~0.9 lb ai/A (~3x the maximum proposed seasonal application rate). At 5 of the 16 trials and one additional CA trial added for this treatment only, a second treated plot (Treatment 3) was established at which staked tomatoes received one broadcast foliar application of the 75% WG formulation made post-transplant as described above, and a second directed (banded) application between the rows to row middles made 21- 107 days later to plants bearing immature to mature fruit at a target rate of ~0.4 lb ai/A, for a total seasonal rate of ~0.9 lb ai/A. At one FL site, the first application for Treatment 2 was made 1 day pre-transplant to bare soil rather than post-transplant, and the first application for Treatment 3 was made 13 days post-transplant, rather than 2 days post-transplant. In addition, at one CA site, the first application for Treatment 2 was made 9 days post-transplant. Applications were made using ground equipment in ~12-16 ga l/A spray volumes without an adjuvant.Imazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 29 of 40 Samples of mature tomatoes were collected 20-21 and 6-7 days after the last application for Treatments 2 and 3, respectively. Additional samples of tomatoes were collected from one CA trial at 16-, 26-, and 31-day PHIs to evaluate residue decline.

Samples were analyzed for residues of imazosulfuron and its metabolite UDPM using an adequate method, LC/MS/MS Method RM-42C-3. The validated LOQ was 0.02 ppm for each analyte in/on tomatoes. Sample storage conditions and durations are reported in Table 4. The final results of the storage stability study, reflecting storage of tomato samples for up to18 months are required to support the sample storage durations.

The results of the tomato field trials are summarized in Table 7. Residues of imazosulfuron and UDPM were each nonquantifiable (<0.02 ppm) in/on bedded tomatoes harvested 20-22 days following two broadcast foliar applications of the 75% WG formulation made at transplant and during fruit development, for a total rate of 0.875-0.917 lb ai/A. Additionally, residues of imazosulfuron and UDPM were each nonquantifiable (<0.02 ppm) in/on staked tomatoes harvested 6-7 days following one broadcast foliar and one directed spray application of the 75% WG formulation made at transplant and during fruit development, for a total rate of 0.871-0.919

lb ai/A.

In the residue decline study, residues of imazosulfuron and UDPM were less than the LOQ (<0.02 ppm) in/on all samples at all PHIs; therefore, residue decline could not be assessed.

Conclusions . The submitted residue data for pepper, rice, and tomato are tentatively considered to be adequate, pending submission of supporting storage stability data for each crop. The studies reflected the proposed use patterns for peppers, rice, and tomatoes, and the number and location of field trials are in accordance with OPPTS Guideline 860.1500 for each crop. Samples were analyzed for residues of imazosulfuron and UDPM using an acceptable method.

All trials reflected exaggerated-rate application (3x for pepper and tomato and 1.7-2.5x for rice); however, for peppers and tomatoes, where two applications were made, the second applications were separated from initial applications by relatively lengthy retreatment intervals and would represent the maximum proposed use pattern for each crop at a ~1.3x exaggerated rate. Because

residues of imazosulfuron were ≤ LOQ in/on all samples, the exaggerated rates will not affect determination of appropriate tolerances for pepper, rice grain, and tomato.

The available data will support the proposed tolerances of 0.02 ppm each for pepper, rice grain, and tomato. HED notes in addition that the submitted crop field trial data for pepper and tomato would support a crop group tolerance of 0.02 ppm for fruiting vegetables, group 8.

860.1520 Processed Food and Feed

DER References: 47679124.de2.doc (Rice) 47679125.de2.doc (Tomato)

Rice

Valent has submitted a processing study for imazosulfuron on rice. In one field trial conducted in 2007, a single broadcast foliar application of a 75% WG formulation of imazosulfuron wasImazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 30 of 40 made at the 2-inch internode growth stage at 0.495 lb ai/A (1.7x the maximum proposed seasonal application rate). The study was conducted in conjunction with the submitted rice field trials. Bulk samples of rice grain were harvested 71 days after application and were processed into rice hulls, bran, and polished rice using simulated commercial processing procedures.

Samples of rice grain and rice processed commodities were analyzed for residues ofimazosulfuron and its metabolite UDPM using an adequate method, LC/MS/MS Method RM42C-3. The validated LOQ was 0.02 ppm for each analyte in/on rice and rice processed commodities. Sample storage conditions and durations are reported in Table 4. The final results of the storage stability study, reflecting storage of rice grain samples (for processing) for up to 10 months, are required to support the sample storage durations for rice grain and processed rice

fractions.

Residues of imazosulfuron and UDPM were each nonquantifiable (<0.02 ppm) in/on rice grain and the processed commodities rice hulls, bran, and polished rice; therefore, concentration

factors could not be calculated.

The maximum theoretical concentration factors for rice hulls and bran are 5.0x and 7.7x based on separation into components (OPPTS 860.1520, Table 3).

Tomato

Valent has submitted a processing study for imazosulfuron on tomato. In one field trial conducted in 2007, bedded tomato plants received two broadcast foliar applications of a 75% WG formulation of imazosulfuron. The first application was made 2 days post-transplant to tomato plants in the vegetative stage at a target rate of ~0.5 lb ai/A; the second application was made 76 days later to plants bearing immature and mature fruit at a target rate of ~0.4 lb ai/A, for a total seasonal rate of ~0.9 lb ai/A (3x the maximum proposed seasonal application rate). The study was conducted in conjunction with the submitted tomato field trials. Bulk tomato samples were harvested 21 days after the second application and processed into tomato puree and paste using simulated commercial processing procedures.

Samples of tomato and tomato processed commodities were analyzed for residues ofimazosulfuron and its metabolite UDPM using an adequate method, LC/MS/MS Method RM42C-3. The validated LOQ was 0.02 ppm for each analyte in/on tomato and tomato processed commodities. Sample storage conditions and durations are reported in Table 4. The final results of the storage stability study, reflecting storage of tomato RAC and processed commodities for up to 14 months are required to support the storage durations of tomatoes and tomato processed

commodities.

Residues of imazosulfuron and UDPM were each nonquantifiable (<0.02 ppm) in/on whole tomatoes and tomato puree and paste; therefore, concentration factors could not be calculated.

The maximum theoretical concentration factors for tomato puree and paste are 1.4x and 5.5x based on loss of water (OPPTS 860.1520, Table 2).

Conclusions . The submitted processing data for rice and tomato are tentatively considered to be adequate, pending submission of supporting storage stability data for rice and tomato raw andImazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 31 of 40 processed commodities. The processing study field trials reflect the same degree of exaggeration as the corresponding crop field trials: 1.7x for rice and 3x for tomato. OPPTS 860.1520 recommends use of exaggerated application rates (up to 5x) in cases when residues near or below the LOQ are expected in the raw agricultural commodity (RAC) from the maximum proposed rate. No additional data are required because residues were nondetectable in/on all RAC and processed commodity samples, and were at or below LOQ in/on all samples from the

associated field trials which reflected the same degree of exaggeration. Furthermore, for rice, where application is restricted to a late vegetative stage, it is anticipated that residues would be unlikely to occur in rice grain. Samples were analyzed for residues of imazosulfuron and UDPM using an acceptable method.

The processing data indicate that residues of imazosulfuron and UDPM do not concentrate in rice hulls, bran, or polished rice or in tomato puree or paste; therefore, tolerances are not required for the processed commodities of rice or tomato.

860.1650 Submittal of Analytical Reference Standards

An analytical standard for imazosulfuron is currently available (expiration 12/8/10) in the EPA National Pesticide Standards Repository (personal communication with Dallas Wright, ACB, 12/10/09).

860.1850 Confined Accumulation in Rotational Crops

DER Reference: 47679126.der.doc

Valent has submitted a confined rotational crop study with [imidazolyl-3- 14 C]imazosulfuron and [pyrimidinyl-5- 14 C]imazosulfuron. The radiolabeled test substances were isotopically diluted with nonlabeled imazosulfuron in DCM to specific activities of 0.527 GBq/mmol (Im label) and 0.568 GBq/mmol (Pm label) and formulated as WG formulations, then applied to bare soil in outdoor plots at 0.88-0.89 lb ai/A (~3x the maximum proposed seasonal application rate). Rotational crops of Daikon radish (root vegetable) and Chinese kale (leafy vegetable) were planted at a 144-day PBI, sorghum (small grain) was planted at 30- and 365-day PBIs, and wheat (small grain) was planted at a 120-day PBI. The petitioner stated that radish and soybean were initially planted at the 30-day PBI; however, both the radish and soybean failed to grow in the 30-day plots and in the same plots replanted at an 85-day PBI. The in-life phase of the study was conducted by Research for Hire, Inc. (Porterville, CA), and the analytical phase of the study was conducted by Valent Technical Center (Dublin, CA).

TRR accumulated at ≥ 0.01 ppm in all rotational sorghum and wheat matrices planted 30, 120, or 365 days following application. TRR in radish and kale planted at a 144-day PBI were <0.01 ppm: 0.004-0.009 ppm in radish tops, 0.003-0.004 ppm in radish root, and 0.006 ppm in kale.

Residues in radish and kale were not further investigated. In sorghum and wheat, TRR, determined by summing extractable and nonextractable radioactivity, were generally highest in 30-day samples and decreased with increasing PBI; exceptions may be attributed to different grain crops having been planted at the 30/365- and 120-day PBIs. TRR were 0.227-0.267, 0.555-0.581, and 0.027-0.037 ppm in 30-day sorghum forage, stover, and grain respectively; 0.013-0.077, 0.283-0.446, 0.493-0.891, and 0.023-0.089 ppm in 120-day wheat forage, hay,Imazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 32 of 40 straw, and grain, respectively; a nd 0.031-0.061, 0.089-0.110, and 0.014-0.024 ppm in 365-day sorghum forage, stover, and grain, respectively.

The majority of the radioactivity (50.7-93.1% TRR) was extracted with ACN and water from sorghum and wheat forage (both labels; all PBIs), Im-label sorghum and wheat stover, hay, and straw (all PBIs), Pm-label sorghum stover (30- and 365-day PBIs), and Im-label 120-day wheat grain. ACN/water extraction released lower le vels from Pm-label 120-day hay and straw and grain from all PBIs (20.2-45.5% TRR), and Im -label 30- and 365-day sorghum grain (32.6- 40.4% TRR). In general, extraction with ACN a nd water released more residues from Im-label

matrices than from Pm-label matrices. None xtractable residues in 30-day sorghum stover and 120-day wheat straw (both labels) and 30-day sorghum grain (Im label) and 120-day wheat grain (Pm label) were subjected to additional enzyme, acid, and/or base hydrolysis procedures to release and characterize bound residues. These procedures released additional residues accounting for up to ~10-12% TRR in Im-label so rghum stover and wheat straw, 39-46% TRR in Pm-label sorghum stover and wheat straw, ~48% TRR in Im-label sorghum grain, and 66% TRR in Pm-label wheat grain.

Nonextractable residues following extraction a nd hydrolysis procedures accounted for <10% TRR (<0.05 ppm) in all rotational crop matrices except 30-day Pm-label sorghum forage (39.6% TRR, 0.090 ppm), 120-day Im- and Pm-label wheat hay (13.3% TRR, 0.059 ppm, and 54.4% TRR, 0.154 ppm, respectively), 120-day Pm-label wheat straw (18.8% TRR, 0.093 ppm; characterized as unhydrolyzed cellulose), and 365-day Pm-label sorghum stover (48.7% TRR, 0.053 ppm). Although further characterization of nonextractable residues was not conducted on all matrices, HED believes that the results of the characterization procedures conducted on 30- day sorghum stover and 120-day wheat straw (both la bels) are suitable for translation to sorghum forage, and wheat hay and straw; therefore, no fu rther investigation of nonextractable residues is required. The extraction/hydrolysis procedures adequately extracted the majority of residues from rotational crop matrices. Accountabilities were 65-117%.

Residues were identified and quantitated primarily by HPLC with confirmatory analysis by TLC.

Additional confirmation and structure elucida tion was achieved using LC/MS, LC/MS/MS, and

1 H-NMR analyses. Total identified residues were higher in Im-label matrices (68.2-84.0% in forage, 51.6-82.3% TRR in stover, hay, and straw, and 6.6-10.7% TRR in grain) and lower in Pm-label matrices (34.7-37.7% TRR in forage, 10.1-41.3% TRR in stover, hay, and straw, and 2.3-5.1% TRR in grain). Imazosulfuron was not identified in any rotational crop commodity; the only double-ring metabolite identified in commodities from both labels was metabolite HMS. In Pm-label commodities, two additional metabolites, UDPM and ADPM were identified by HPLC and/or TLC co-chromatography with standards. In Im-label commodities three additional metabolites, IPSA-isoserine, IPSA-acetylisoserine, and IPSA-caffeoylisoserine, were identified by LC/MS, LC/MS/MS, and/or 1 H-NMR following purification and isolation by preparative

HPLC. Identification of IPSA-isoserine was confirmed by comparison of MS and 1 H-NMR spectra and HPLC co-chromatography with a synthesized standard.

In Im-label sorghum and wheat, HMS accounted for 32.9% TRR in 30-day forage and declined to 5.0% and 8.0% TRR at the 120- and 365-day PB Is. IPSA-isoserine was identified at 8.5% TRR in 30-day forage, increased to 60.6% TRR in 120-day wheat forage, and declined to 15.9% TRR in 365-day forage. IPSA-acetylisoserine wa s identified in sorghum forage at 34.8% and 40.1% TRR at the 30- and 365-day PBIs but was not identified in 120-day wheat forage, whileImazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 33 of 40 IPSA-caffeoylisoserine accounted for 4.2-7.8% TRR (all PBIs). In 30- and 365-day Im-label sorghum stover, respectively, HMS was identified at 31.8% and 9.8% TRR, IPSA-isoserine was identified at 18.6% and 30.5% TRR, IPSA-acetylisoserine was identified at 25.4% and 32.6% TRR, and IPSA-caffeoylisoserine was identifie d at 6.5% and 4.4% TRR. Neither HMS norIPSA-acetylisoserine was identified in 120-day wheat hay or straw. In these commodities IPSAisoserine and IPSA-caffeoylisoserine accounted for 39.6-48.0% and 12.0-16.8% TRR, respectively. All four metabolites were identified at low levels in grain: HMS at 0.4% TRR (365-day PBI only), IPSA-isoserine at 2.5-3.2% TRR (all PBIs), IPSA-acetylisoserine at 1.0% TRR (all PBIs), and IPSA-caffeoylisoserine at 6.5% TRR declining to 2.7% TRR (over all PBIs).

TRR in Pm-label 120-day wheat forage were not further investigated because extractable residues accounted for 0.006 ppm; in 30- and 365-day sorghum forage, respectively, HMS accounted for 28.8% and 10.8% TRR, UDPM accounted for 5.7% and 13.5% TRR, and ADPM

accounted for 3.2% and 10.4% TRR. HMS accounted for 33.5% and 6.7% TRR in 30- and 365- day sorghum stover, but was not identified in 120-day wheat hay or straw. UDPM was not identified in 30-day sorghum stover, but accounted for 23.2%, 7.9%, and 15.2% TRR in 120-day wheat hay, 120-day wheat straw, and 365-day sorghum stover, respectively, and ADPM was identified at all PBIs at 7.8%, 1.4%, 2.2%, a nd 10.6% TRR in 30-day stover, 120-day hay, 120- day straw, and 365-day stover, respectively. In Pm-label grain, HMS was identified at 0.7% TRR (30-day PBI only), UDPM was identified at 1.9-2.5% TRR (all PBIs), and ADPM was identified at 0.3-2.5% TRR (all PBIs).

Residues were investigated in both the ACN and aqueous extracts of all rotational crop matrices except for Pm-label 120-day wheat forage (both extracts, see above) and the aqueous extracts of Im-label 120-day wheat forage (16.1% TRR, 0.012 ppm), Im-label sorghum or wheat grain (all PBIs; 20.7-39.1% TRR, 0.003-0.009 ppm), and Pm-label sorghum or wheat grain (all PBIs; 11.5-25.2% TRR, 0.004-0.022 ppm). Because TRR were generally low in these extracts and analysis of the aqueous extracts for all other matrices yielded a metabolic profile similar to that for ACN extracts, no further investigation is required.

Discrete unknowns (up to four in forage, up to seve n in stover, hay, and straw, and up to five in grain) characterized by HPLC retention times accounted for up to ~21% TRR in forage, 34% TRR in stover, hay, and straw, and 8% TRR in grain. Of these unknowns, only polar unknowns (Rts 1.8-2.5) were present in any matrix at ≥ 10%. Polar unknowns (Rt 2.1-2.2) accounted for 16% TRR (0.036 ppm) and 13.4% TRR (0.008 ppm) in Pm-label 30- and 365-day sorghum forage, respectively; in Pm-label stover, ha y, and straw, polar unknowns (Rts 1.8-2.3) accounted for 12.3% TRR (0.072 ppm), 9.9% TRR (0.028 ppm), 16.0% TRR (0.079 ppm), and 12.1% TRR (0.013 ppm), respectively, in 30-day sorghum st over, 120-day wheat hay, 120-day wheat straw, and 365-day sorghum stover. Further characteri zation of the polar unknown in 30-day Pm-label sorghum stover indicated that it was multicom ponent and contained HMS and ADPM at low

levels.

Characterization of nonextractable residues in Im-label 30-day sorghum stover and 120-day wheat straw indicated that residues released by sonication with water, cellulase and protease hydrolysis, and acid hydrolysis (possible starch co mponent) were comparable for all procedures, ~2-4% TRR. In Pm-label 30-day sorghum stover and 120-day wheat straw, residues characterized as acid-hydrolyzed starch accounted for 5.8-6.6% TRR, as base-hydrolyzed proteinImazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 34 of 40 accounted for 4.0-10.3% TRR, and as base-hydr olyzed lignin accounted for 10.7-27.8% TRR; remaining unextractable residues (2.0-18.8% TRR) were characterized as unhydrolyzed cellulose. In Im-label 30-day sorghum grain and Pm-label 120-day wheat grain, acid-hydrolyzed starch accounted for 24.3-26.8% TRR, and protease hydr olysis released the next most significant proportion of the residue in grain (16.9-17.6% TRR).

All rotational crop samples except grain were initially analyzed within 6 months of harvest; samples of grain were analyzed within 6.4-9.3 months of harvest. Characterization of nonextractable residues in 30-day sorghum stover and grain and 120-day wheat straw and grain was conducted 20.7 and 12.2 months after harvest. To confirm the storage stability of residues of imazosulfuron in rotational crops, stored samp les of 30-day sorghum forage and grain (both labels) were extracted and analyzed by HPLC following completion of characterization/identification analyses, 23.0 and 21.4 months, respectively, after harvest. Comparison of the TRR, extraction profiles, and metabolic profiles suggests that residues were generally stable during frozen storage for 30-day forage for both labels and 30-day grain for the Im label; a metabolite profile was not submitted for stored Pm-label grain. Because the metabolic profiles were similar in 30-, 120-, and 365-day grain, the storage stability data for 30- day grain may be translated to support the storage durations and conditions for all grain samples. Although the petitioner did not address the lengthy storage intervals for grain extracts (62-194 days), HED believes that the storage stability analyses, reflecting analysis on the day of extraction, may be sufficient to demonstrate that residues were equally stable in extracts andstored samples, provided the petitioner can confirm that the metabolic profile was stable in Pylabel grain as well as in Im-label grain. The HPLC profile for the Py-label grain storage stability analysis should be submitted. No additional storage stability data are required for forage, hay, stover, or straw because, except for characterization of nonextractable residues, final analysis was completed within 6 months of sample collection.

Based on the results of the confined rotational crop study, the petitioner proposed that metabolism of imazosulfuron in rotational crops occurs via the initial O-demethylation of the pyrimidinyl ring to form HMS. Hydrolytic degr adation of the sulfonamide moiety yields UDPM and ADPM. In addition, hydrolysis of imazosulfuron or HMS may yield IPSN as an intermediate which may then undergo enzyme-catalyzed conjugation with either 3- phosphoglyceric acid or lactic acid to form IPSA-isoserine. IPSA-isoserine may then undergoesterification with acetic or caffeic acid to form IPSA-acetylisoserine and IPSAcaffeoylisoserine. It is noted that HMS, UDPM, ADPM, and IPSN are all soil degradates of imazosulfuron and may have been taken up directly by the plants.

Conclusions . The submitted confined rotational crop study is tentatively considered to beadequate pending submission of supporting storage stability data. The HPLC profile for the Pylabel grain storage stability analysis must be submitted to confirm that the metabolic profile was stable in Py-label grain.

Imazosulfuron was not identified in any rotational crop commodity; however, the Odemethylated double-ring metabolite, HMS, which was a minor metabolite in primary crops, was identified in 30-day sorghum forage and stover at significant levels, up to 33.5% TRR (0.177 ppm); it was identified in 120-day wheat forage and 365-day sorghum forage and stover at much lower levels. UDPM, the major metabolite in primary crops, was identified in rotational cropImazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 35 of 40 commodities at all PBIs at up to 23.2% TRR (0.066 ppm). If the study results are extrapolated to a 1x application rate, neither metabolite would be present at >0.01 ppm at the 365-day PBI.

In addition, three metabolites were identified in rotational sorghum and wheat matrices that werenot identified in primary crops: the IPSA conjugate metabolites, IPSA-isoserine, IPSAacetylisoserine, and IPSA-caffeoylisoserine. According to the proposed metabolic pathway for rotational crops, these metabolites would arise from the primary crop (and soil) metabolite, IPSN. In the administrative materials accompanying the petition, the petitioner stated that these metabolites are not of toxicological concern because of the small quantities present and their likely lack of bioavailability based on their high molecular weights and high polarity. The petitioner further noted that these metabolites are not expected to be further metabolized because there was essentially no degradation during characterization attempts made using acid, base, and enzyme (sulfatase) hydrolysis (refer to 47679126.der.doc for further details). If the study results are extrapolated to a 1x application rate, none of these metabolites would be present at >0.01 ppm at the 365-day PBI. However, they are present at significant levels through the 120-dayPBI: IPSA-isoserine at up to 60.6% TRR (0.353 ppm) in forage, hay, straw, and stover, IPSAacetylisoserine at up to 40.1% TRR (0.141 ppm) in forage and stover, and IPSAcaffeoylisoserine at up to 16.8% TRR (0.107 ppm) in forage, hay, straw, and stover.

The study results indicate that the metabolism of imazosulfuron proceeds in rotational crops via routes similar to metabolism in primary crops, and suggest, based on the presence of higher levels of HMS and metabolites derived from IPSN and on the absence of parent imazosulfuron in crop commodities, that soil metabolites may contribute significantly to residues in rotated crops. HED concludes that the nature of the residue in rotational crops is adequately understood.

Because TRR were <0.01 ppm in radish and kale at the 144-day PBI, the results of the confined rotational crop study are sufficient to support a 4-month PBI for root and tuber and leafy vegetables. In consideration of the confined rotational crop study results for radish and kale (reflecting application at 3x the maximum proposed seasonal rate), and the proposed use patterns for pepper, rice, and tomato, which resulted in negligible residues in primary crops in field trials conducted at exaggerated rates, HED concludes that the following proposed PBIs are appropriate: 0 days for rice; 100 days for transplanted tomato; 8 months for cantaloupe, cucumber, eggplant, lettuce, mustard greens, peppers (bell and nonbell), radish, spinach, soybean, turnip, turnip greens, and white potatoes; and 9 months for cabbage and squash. The proposed 8-month PBI for grain sorghum is not supported by these data, and is addressed below.

The TRR exceeded the 0.01-ppm trigger value in all rotational sorghum and wheat commodities at all PBIs at 3X in the subject study. Even when residues are adjusted for the 3x exaggerated application rate, this remains true for forage, hay, straw, and stover; residues in grain would be at or near the trigger value at the 30- and 120-day PBIs, but below the trigger value at the 365-day

PHI.

The acceptability of the proposed PBIs of 4 months for wheat and 8 months for grain sorghum cannot be assessed pending submission of field rotational crop data for small grains. The acceptability of the proposed PBI of 8 months for soybeans also cannot be assessed. The likelihood of residues on soybean forage will be considered from the results of the small grain field rotational crop study. Pending submission of this information/data, a 12-month PBI must be proposed for cereal grains and soybean. The proposed PBIs of 12 months for field and sweetImazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 36 of 40 corn, and 24 months for “All crops not listed” are appropriate; however, the 8-month PBI for field corn planted following rice must be removed.

860.1900 Field Accumulation in Rotational Crops

No field rotational crop data were submitted in support of this petition; however, Valent previously submitted a protocol for a reduced wheat field rotational crop study to support the rotation of wheat following application of imazosulfuron to pepper and tomato.

The study protocol was reviewed by ChemSAC (see minutes of the 3/26/08 meeting) which concluded that eight field rotational crop trials would be required to support rotation of wheat following application to pepper and tomato. Th e ChemSAC noted that additional wheat field rotational crop data may be required to support rotation following application to other crops and that the possible rotation of crops to rice fields should be considered in establishing future PBIs.

Conclusions . The petitioner previously indicated that a wheat rotational crop study was planned. This study has not been submitted. The need for additional field rotational crop studies will be addressed after evaluation of the wheat rotational crop study. HED does not consider the low levels of IPSA-conjugates at the 365 day PBI toxicologically significant, but will reassess the situation at the various plantback intervals based on the wheat rotational crop study.

860.1550 Proposed Tolerances

Valent has proposed that tolerances for imazosulfuron residues of concern in crop commodities be expressed in terms of imazosulfuron. HED has concluded that the proposed tolerance expression for plant commodities is appropriate. The tolerance expression (for plant commodities) should be stated as follows:

Tolerances are established for residues of the herbicide imazosulfuron, 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 imazosulfuron, or [2-chloro-N-[[(4,6-dimethoxy-2- pyrimidinyl)amino]carbonyl]imidazo[1,2- α ]pyridine-3-sulfonamide].

There are no Codex, Canadian, or Mexican MRLs established for residues of imazosulfuron in any commodities.

Adequate field trial data reflecting the proposed use patterns are available for purposes of establishing tolerances on pepper, rice grain, and tomato, pending submission of supporting storage stability data for each crop. The data indicate that residues of imazosulfuron do not accumulate above the LOQ (0.02 ppm) in/on any commodity. Because residues were ≤ LOQ in/on all crop commodities, the tolerance spreadsheet in the Agency’s Guidance for Setting

Pesticide Tolerances Based on Field Trial Data was not utilized in determining tolerance levels. The data indicate that the proposed tolerances of 0.02 ppm each for bell pepper, non-bell pepper, rice grain, and tomato are appropriate. HED notes that the submitted crop field trial data for pepper and tomato would support a crop group tolerance of 0.02 ppm for fruiting vegetables, group 8.Imazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 37 of 40 Adequate processing data were submitted for rice grain and tomato, pending submission of supporting storage stability data. The data indicate that residues of imazosulfuron do not concentrate in the processed commodities of rice grain or tomato; therefore, no tolerances are needed for processed commodities.

HED has determined that the proposed uses of imazosulfuron on pepper, rice, and tomato constitute a 40 CFR §180.6(a)(3) situation for livestock commodities; i.e., there is no reasonable expectation of finite residues in ruminant, poultry, or swine commodities. Therefore, no

tolerances are needed for livestock commodities at this time.

The need for rotational crop tolerances will be addressed upon evaluation of the field rotational crop study.

A summary of the proposed and recommended tolerances for the petition is presented in Table 8.

Table 8. Tolerance Summary for Imazosulfuron

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

Pepper, bell 0.02 1 0.02

Pepper, nonbell 0.02 1 0.02

Rice, grain 0.02 0.02

Tomato 0.02 0.02

1 Proposed for “pepper.”

References

None

Attachments:

International Residue Limit Status sheet Appendix I - Chemical Name and Structure Table

Template Version September 2005Imazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 38 of 40 

## INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name: 2-chloroN-[[(4,6-dimethoxy-2- pyrimidinyl)amino]carbonyl]imidazo[1,2-a]pyridine3-sulfonamide Common Name:

Imazosulfuron X Proposed tolerance

9 Reevaluated tolerance

9 Other Date: 12/10/09

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#9F7535

DP#: 367019

Other Identifier:

Reviewer/Branch: S. Funk, P. Deschamp/RAB3 Residue definition (step 8/CXL): N/A

Residue definition: Imazosulfuron per se

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

Pepper 0.02

Rice, grain 0.02

Tomato 0.02

Limits for Canada Limits for Mexico

X No Limits

□ No Limits for the crops requested X No Limits

□ No Limits for the crops requested

Residue definition: N/A Residue definition: N/A

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

Notes/Special Instructions: S.Funk, 12/14/2009Imazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 39 of 40 APPENDIX I. Chemical Names and Structures of Imazosulfuron and Metabolites.

Common name; Company code Chemical name Chemical structure

Imazosulfuron 2-chloro- N -[[(4,6-dimethoxy-2- pyrimidinyl)amino]carbonyl]imidazo- [1,2- α ]pyridine-3-sulfonamide CH 3 O

N N

N N Cl O
O

N H N H S CH 3 O

O

HMS; O-demethylated

imazosulfuron 2-chloro- N -[[(4-hydroxy-6-methoxy-2- pyrimidinyl)amino]carbonyl]imidazo- [1,2- α ]pyridine-3-sulfonamide OH

N N

N N Cl O
O

N H N H S CH 3 O

O

IPSN 2-chloro-imidazo[1,2-a]pyridine-3-

sulfonic acid amide

N N

S O

O Cl

NH 2

UDPM (4,6-dimethoxy-pyrimidin-2-yl)-urea

N N

N H NH

2 O CH 3 O CH 3

O

ADPM 4,6-dimethoxy-pyrimidin-2-ylamine

N N

NH

2 O CH 3 O CH 3

ADNG glucose conjugate of 4,6-dimethoxypyrimidin-2-ylamineImazosulfuron Summary of Analytical Chemistry and Residue Data DP#: 367019

Page 40 of 40 APPENDIX I. Chemical Names and Structures of Imazosulfuron and Metabolites.

Common name; Company code Chemical name Chemical structure

IPSA-isoserine 3-(2-chloro-imidazo[1,2-a]pyridine-3- sulfonylamino)-2-hydroxy-propionic

acid

N N

N H S O

O Cl

OH O OH

IPSA-acetylisoserine 2-acetoxy-3-(2-chloro-imidazo- [1,2-a]pyridine-3-sulfonylamino)- propionic acid

N N

N H S O

O Cl

O O OH

O CH 3

IPSA-caffeoylisoserine 3-(3,4-dihydroxy-phenyl)-acrylic acid 1- carboxy-2-(2-chloro-imidazo- [1,2-a]pyridine-3-sulfonylamino)-ethyl

ester Cl OH

N N

N H S O

O O O OH

O OH

1 Chemical names for metabolites except HMS were generated in ISIS/Draw using AutoNom.