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### UNITED STA**TES ENVIRONMENTA L PROTECTION A** **GENCY**

**WA SHINGTON, D.C. 20460**  **OFFICE OF CHEMICAL SAFETY AND**

**POLLUTION PREVENTION** 

### MEMORANDUM Date: 2 6 September 2012 SUBJECT: Clothianidin

– New Uses on Strawberry, Pistachio, Citrus, and Tea . Evaluation of

Residue Chemistry

Data. PC Code: 044309 DP Barcode: D39 7689 Decision No.: 455249 Registration No. : 59639 - 150, 59639 - 152 Petition No s .: 1E7923 Regulatory Action: Section 3 Risk Assessment T ype: N/A Case No.: 7620 T XR No.: N/A CAS No.: 210880 - 92 - 5 MRID No.: 48600001 - 48600005 40 CFR:180.586 

### FROM: Michael A. Doherty, Ph.D., Chemist Risk Assessment Branch II Health Effects Division (7509P) THROUGH: Dennis McNeill y, Chemist

Risk Assessment Branch II Health Effects Division (7509P) TO: Marianne Lewis/Venus Eagle, RM 01 Insecticide - Rodenticide Branch Registration Division (7505P) Barbara Madden Risk Integration, Minor Use, and Emergency Response Branch Registration Division (7505P) **Background** Interregional Research Project No. 4 (IR- 4) has petitioned the Agency to approve new uses of the insecticide clothianidin on strawberry, pistachio, and the citrus crop group (Crop Group 10 - 10), and to establish tolerances in support of those uses. Additionally , IR- 4 has requested the establishment of a tolerance for residues of clothianidin in/on tea without a domestic registration (i.e., an import tolerance). Insupport of the petition, IR- 4 has submitted field trial data depicting residues of clothianidin in/on strawberry, lemon, grapefruit, orange, and tea , and an orange processing study . IR - 4 has requested that the tolerance for pistachio be translated from the existing tolerance for residues in/on tree nuts.Page 2 of 9



### Regulatory Recommendations There are no residue chemistry considerations that would preclude granting the requested registrations and establishing permanent tolerances at the following levels: Pistachio ................................ ................................ ..... 0.01 ppm Strawberry ................................ ................................ .. 1.50 ppm Fruit, citrus, group 10 - 10 ................................ ........... 0. 6 0 ppm Tea , dried ................................ ................................ ... 70 ppm The se recommended tolerance levels differ from the petitioned- for tolerance level s for strawberry, citrus, and tea , and HED has determined that a separate tolerance is not necessary for citrus, dried pulp . There are no Canadian or Codex MRL s for clothianidin that are relevant to the recommended tolerances. Codex MRL s (see Attachment 1 ) are in place for tea, strawberry, citrus, and fruiting vegetables; however, the MRL s are based on clothianidin derived from treatment with thiamethoxam rather than treatment with clothianidin. Therefore, it is not appropriate to harmonize U.S. tolerances with the Codex MRL s. Prior to registrati on, the petitioner should submit a revised Section F which requests tolerances at the recommended levels and with the commodity definitions listed above. Furthermore, the tolerance expression in the Section F should be revised to reflect the current tolerance definition in 40 CFR 180.586. **Label Revision Recommendations** We note that IR- 4 has included some restrictions against use of adjuvants and aerial application. HED has recentl y recommended that aerial application be allowed for Brassica vegetables, fruiting vegetables, leafy

vegetables, peach, pomegranate, and tree nuts , and that restrictions regarding use of adjuvants be removed . If these requested uses are approved, RD should ensure that the product label reflects all of the recent revisions/recommendations that were made outside of this new -use action. This includes updating the rotational crop restrictions to include strawberry

as a crop suitable for immediate plant back. In addition, HED recommends that the label be revised for all crops to state that the maximum amount of active ingredient applied per season is 0.2 lb a.i./A regardless of the formulation and ty pe of application being made. Finally, HED notes that the maximum seasonal foliar use rate for V - 10170 2.13 SC on strawberry

(0.1 lb a.i./A) differs from the maximum use rate for the Arena product (0.2 lb a.i./A) . HED recommends that RD ensure that these differences are intended by the petitioner . The available residue data support a maximum seasonal application rate of 0.2 lb a.i./A to strawberry . **Submitted Material and Evaluations**Page 3 of 9



### No data were submitted to support the tolerance for residues in/on pistachio. The existing tolerance for residues of clothianidin in/on tree nuts is suitable for translation to pistachio. IR- 4 has submitted an acceptable proposed label and acceptable guideline studies depicting residues of clothianidin in/on strawberry and the representative crops of the citrus crop group (grapefruit, lemon, and orange) as well as an acceptable guideline study showing the behavior of residues upon processing of oranges into processed commodities. An acceptable number of trial s were conducted and demonstrate adequate geographical representation. The residue data are supported by

adequate method validation and storage stability information (summarized below). For tea, IR- 4 has submitted a compilation of reports conducted by Sumitomo Chemical Co., Ltd. and Takeda Pharmaceutical Co., Ltd. as well as data summary report from the Taiwanese Council of Agriculture. These data are also supported by adequate method validation and storage stability

information. Details regarding the u se pattern for tea were not provided. Entries in the table are derived from information about the use patterns used in the field trials. Summary of Proposed Use Patterns for Clothianidin on Pistachio, Straw berry, Citrus, and Tea. Crop Form

ulation Applic ation T ype Number of Applics . ( min . RTI) Maximum

Application Rate , lb a.i./A PHI,

Days Comments per Applic. per Season Pistachio V - 10170 2.13 SC Foliar (ground or air) 2 (10 - 14) 0.1 0.2 21 -- Straw berry Arena 50 WDG Foliar (ground or air) 2 (7) 0.2 0.2 1 -- Soil (pre - or at-plant incorporated, furrow, transplant drench, chemigation into root zone) 1 0.2 0.2 21 --

V - 10170 2.13 SC Foliar (ground or air) NS 0.1 0.1 1 --

Soil (pre - or at-plant incorporated, furrow, transplant drench, chemigation into root zone) 1 0.2 0.2 21 --

Citrus V - 10170 2.13 SC Foliar (ground or air) 2 [implied] (14) 0.1 0.2 1 -- Basal Bark Spray NS 0.2 0.2 1 -- Soil (drench at base of tree, chemigation into root zone, soil surface band) 2 [implied]

(NS) 0.2 0.2 1 -- Tea NS Foliar 1 1.8 1.8 7 Use patterns are im plied from the field trial application parameters NS = Not Specified Summary of Analytical Methods and Storage . Crop Method Description LOQ, ppm Storage StabilityPage 4 of 9 ID Sam ple Duration and Conditions Demonstrated

Stability Straw berry Residue

Analytical Method 00552 Extraction with ACN:H 2 O (2:1, v/v),

Cleanup with partitioning on a ChemElut column , Separation/Quantification via HPLC MS/MS 0.014 (calc.) 0.02 (L owest Limit of Method Validation, LLMV) ≤ 515 days at

- 20°C 482 days

Citrus (including processed commodities) RM - 39C - 1 Extraction with acidified water (0.1% formic acid) , Cleanup on Celite, Separation/Quantification via HPLC MS/MS 0.01 (LLMV) ≤ 338 days at - 15 to - 5°C 374 days

(lemon) Tea Not

Specified Extraction with ACN : 0.1 M HCl,

Cleanup on multiple solid phase columns, Separation/Quantification via HPLC/UV ≤ 1.6 (LLMV) ≤ 0.04 (LOD) ≤ 306 days at

- 20°C 306 days

Summary of Clothianidin Residue Data. Commodity Application

Rate, lb a.i./A PHI,

days n Clothianidin, ppm

Min. Max. LAFT HAFT Median Mean Std. Dev. Straw berry 0. 2 1 10 0.096 1.170 0.103 1.120 0.258 0.327 0.301 Grapefruit 0.2 1 5 0.0 22 0. 346 0.0 27 0.2 81 0.0 7 2 0. 113 0. 103 Lemon 0.2 1 6 0.022 0.201 0.034 0.176 0. 102 0.10 7 0.05 5 Orange 0.2 1 1 3 0.005 0. 269 0.00 8 0. 219 0.0 57 0. 083 0.0 66 Tea 0.9

– 1.8 3 - 7 12 2.14 38.0 2.15 37.55 13.95 15.21 11.76 Summary of Residues and Processing Factors from the Orange Processing Study. Commodity Residues (ppm) [Average] P rocessing Factor 1 Fruit 0.223 0.236 [0.242] 0.267 _ Oil < 0.005 < 0.005 [<0.005] < 0.005 <0.02 Juice 0.006 0.007 [0.006] 0.006 0.03X Dried P ulp 0.417 0.406 [0.406] 0.396 1. 6 8 X 1 Processing factor from RAC, calculated from the average residues . 

### Tolerance Derivation Tolerances for residues of clothianidin in/on strawberry , citrus, and tea were derived using the O rganization for E conomic C ooperation and D evelopment Maximum Residue Level (OECD MRL) Calculation Procedures. The data and results are summarized below. For the citrus crop group, the representative crops were analyzed separatel y and the highest recommended MRL of 0. 6 ppm from grapefruit was selected as the appropriate tolerance for the crop group. For citrus pulp, HED used the greatest HAFT from the field trial for citrus (0.281 ppm from grapefruit) andPage 5 of 9



### multiplied it by

the processing factor for dried pulp (1.68X). The resulting value (0.47 ppm) is less than the recommended tolerance f or residues in/on citrus. Therefore, a separate tolerance for dried citrus pulp is not required. For tea, HED performed an anal ys is of variance of the 3 - and 7 - day PHI residue values. That anal ys is indicated that there was no significant difference in residues from these PHI groups (see ANOVA table below); therefore, the data from the 3 - and 7 - day PHItrials were pooled for the tolerance anal ys is. Summary of Inputs and Results from the OECD MRL Calculation Procedures for Straw berry, Citrus, and Tea. C om pound Clothianidin Clothianidin Clothianidin Clothianidin Clothianidin Crop Straw berry Lemon Grapefruit Orange Tea GAP 1 - Day PHI 1 - Day

PHI 1 - Day

PHI 1 - Day

PHI 3 - and 7 - Day PHI Total number of data (n) 10 6 5 13 12 Percentage of censored data 0 0 0.286 0 0 Number of non censored data 10 6 5 13 12 Lo west residue 0.103 0.034 0.0 27 0.008 2.150 Highest residue 1.120 0.176 0.281 0.219 37.550 Median residue 0.258 0. 102 0.0 72 0.057 13.950 Mean 0.327 0.10 7 0. 113 0.083 15.214 Standard deviation (SD) 0.301 0.05 5 0.103 0.066 11.757 Correction factor for censoring (CF) 1.000 1.000 1.000 1.000 1.000 Proposed MRL estimate

- Highest residue 1.120 0.176 0.281 0.219 37.550

- Mean + 4 SD 1.529 0.32 5 0. 526 0.347 62.243

- CF x 3 Mean 0.981 0.3 21 0. 339 0.249 45.641 Unrounded MRL 1.529 0.3 2 5 0. 526 0.347 62.243 **Rounded MRL 1.5**  **0.4 0.**  **6 0.4**  **70** Notes -- High uncertainty of MRL estimate due to small dataset. High uncertainty

of MRL estimate due to small dataset. -- -- Residues (mg/kg) Residues

(mg/kg) Residues

(mg/kg) Residues

(mg/kg) Residues (mg/kg) 1.12 0.128 0.14 0.032 21.15 0.23 0.074 0.281 0.029 10.75 0.405 0.1755 0.04675 0.044 18.45 0.405 0.155 0.0265 0.131 10.05 0.3 0.034 0.0715 0.2185 18.15 0.285 0.075 0.204 5.34 0.205 0.0415 34.6 0.11 0.0755 2.15 0.1085 0.1015 37.55 0.103 0.043 2.23 0.0925 17.15Page 6 of 9 0.0075 4.995 0.057 * Values are less than the limit of quantitation. Single - Factor Analysis of Variance of Clothianidin Residues in Tea Comparing 3 - and 7 - Day PHI. SUMMARY Groups Count Sum Average Variance 3 - day 4 60.4 15.1 30.75 7 - day 8 122.165 15.27063 204.0332 ANOVA Source of Variation SS df MS F P -value F crit Between Groups 0.077634 1 0.077634 0.000511 0.982417 4.964603 Within Groups 1520.483 10 152.0483 Total 1520.56 11 

### Summary of Clothianidin Residue Chemistry Database Nomenclature and Physicochemical Properties **Clothianidin Nomenclature.** Parent Com

pound

Common name Clothianidin Com pany experimental name TI - 435, V - 10066 IUPAC name (E) - 1 - (2 - Chloro - 1,3 - thiazol - 5 - ylmethyl) - 3 - methyl - 2 - nitroguanidine CAS name (E) -N - [(2 - Chloro - 5 - thiazolyl)methyl] -N’- methyl -N” - nitroguanidine CAS registry number 210880 - 92 - 5 (formerly 205510 - 53 - 8) Molecular wt. 249.68 End - use product (EP) 50% WDG (Arena® 50 WDG; EPA Reg. No. 59639 - 152) 2.13 lb/gal FlC (V - 10170 2.13 SC; EPA Reg. No. 59639 - 150) 5 lb/gal FlC (V - 10170 5 FS; EPA Reg. No. 59639 - 151) Metabolite

Common name Thiazolylmethylguanidine Com pany experimental name TMG IUPAC name N - (2 - chlorothiazol - 5 - yl) -N ́ - methylguanidine CAS Name N - (2 - chlorothiazol - 5 - yl) -N ́ - methylguanidine CAS registry number 635283 - 91 - 9 Molecular wt. 204.68 S N N

H N NH Cl C

H 3 N O 2

S N N

H NH NH Cl C

H 3Page 7 of 9

**Physicochemical Properties of Clothianidin.** Parameter Value Reference Melting point (oC) 176.8 D335355, W. Drew , 10/16/07 pH at 23oC 6.24 (1% solution/suspension) Density (g/cm3 ) 1.61 (PAI), 1.59 (TGAI) Water solubility (g/L at 20oC) 0.327 Solvent solubility (g/L at 25oC) Acetone 15.2 Dichloromethane 1.32 Ethyl acetate 2.03 Heptane <0.00104 Methanol 6.26 Octanol 0.938 Xylene 0.0128 Vapor pressure (Pa at 20oC) 1.3 x 10 - 10 Dissociation constant, pKa at 20oC 11.09 Octanol/water partition coefficient, Log(KOW) at 25oC 0.7 UV/visible absorption spectrum (Maximum, nm) 265.5 (acidic or neutral) 246.0 (basic) PAI = Purified Active Ingredient; TGAI = technical grade active ingredient. 

### Nature of the Residue

– Plants Based on the available metabolism studies, HED has concluded that the nature of the residue has been adequatel y delineated, and that parent only is the residue of concern to be used in risk assessment and the tolerance expression for most primary crops. However, for root crops and leafy vegetables TMG is also a residue of concern for risk assessment. Nature of the Residue

– Livestock The nature of clothianidin residues in livestock is understood based on the adequate goat and hen metabolism studies. The residue definition for tolerance enforcement is clothianidin. For risk assessment, the residue definition for ruminants is clothianidin, TZU, TZG, TZNG, and ATMG Py ruvate. For poultry, the residue definition for risk assessment is clothianidin, TZU, TZG, TZNG and ATG - Acetate. Analytical Method Adequate methods, based on solvent extraction and LC - MS/MS separatio n, identification, and quantification, are available for plant (Morse Method #Meth - 164 - modified , RM - 39C - 1, or Bayer Method 00552) and livestock (Bayer Method 00624 ) matrices. The LOQ for clothianidin in plant commodities is 0.01 ppm, except for wheat straw (0.02 ppm), and the validated LOQs are 0.01 ppm in milk and 0.02 ppm in animal tissues. Clothianidin and its major metabolites are not adequatel y recovered using any of the FDA multiresidue methods. Meat, Milk, Poultry, and Eggs Dried citrus pulp is considered to be a significant feed item for beef and dairy cattle. Given the feedstuff makeup of the current livestock dietary burden (below) , residues of clothianidin in dried citrus pulp do not impact the dietary burden or current tolerances for residues of clothianidin in livestock commodities.Page 8 of 9

**Estimation of**  **Dietary Burdens**  **for Clothianidin**  **Residues to Livestock.** Feedstuff Dietary Com ponent % Dry

Matter 1 % Diet 1 Residues (ppm) 2 Dietary Contribution (ppm) 3 **Beef Cattle** Field corn forage R 40 10 0.10 0.025 Cotton gin byproducts R 90 5 4.5 0.250 Sugar beet molasses CC 75 10 0.05 0.007 Field corn grain CC 88 70 0.01 0.008 Cottonseed meal PC 89 5 0.02 4 0.001 TO TAL BURDEN **100 0.291**  **Dairy Cattle** Field corn forage R 40 35 0.1 0.088 Almond, hulls R 90 10 1.5 0.167 Sugar beet molasses CC 75 10 0.05 0.007 Field corn grain CC 88 35 0.01 0.004 Cottonseed PC 88 10 0.20 0.023 TO TAL BURDEN **100 0.289**  **Poultry** Field corn grain CC 75 0.01 0.008 Cottonseed meal PC 20 0.02 4 0.004 Soybean seed PC 5 0.02 0.001 **TOTAL BURDEN 100**  **0.013 Sw**  **ine** Field corn grain CC 85 0.01 0.009 Cottonseed meal PC 15 0.02 4 0.003 **TOTAL BURDEN 100**  **0.012** 1 Potential dietary burdens for livestock were determined using recent Agency guidance on calculating the maximum reasonably balanced diets for livestock (memo, 6/30/2008). 2 The tolerance level for the RAC was used for any associated processed fractions unless otherwise indicated . 3 Contribution = ([tolerance /% DM] X % diet) for beef and dairy cattle; contribution = ([tolerance] X % diet) for poultry and swine. 4 A residue level of 0.02 ppm was used for cottonseed meal, as the cotton processing study indicated that residues are reduced in meal by 0.1x.Page 9 of 9



### Attachment 1. International Harmonization



## Clothianidin (044309; 11 September 2012) Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 2 Codex 3,4 40 CFR 180.586: Plant/Livesto c k: clothianidin, ( E ) - N - [(2 - Chloro - 5 - thiazolyl)methyl] - N' - me thyl - N"

-nitroguanidine [C(E)] -N - [(2 - chloro 5 - thiazolyl)methyl] - N' - methyl N"-nitroguanidine clothianidin. The residue is not fat - soluble. Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 Codex 3,4 Tea (import only) 70 0.7 Tea, green, black (black, fermented and dried) (T) Straw berry 1.5 0.07 berries and other small fruits (except grapes) (c, T) Fruit, Citrus, Group 10 - 10 0.6 0.07 citrus fruits (T) Pistachio 0.01 Pepper and Eggplant (Crop Subgroup 8 - 10B) 0.8 0.05 fruiting vegetables other than cucurbits (T) 0.5 peppers chili, dried Com pleted: M. Negussie; 09/13/2012 1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant. 2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes. 3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC. 4 The source of the residue; T - thiamethoxam; C - clothianidin