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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND

 POLLUTION PREVENTION

MEMORANDUM

Date: 26 September 2012

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

Residue Chemistry Data. 

PC Code: 044309 DP Barcode: D397689

Decision No.: 455249 Registration No.: 59639-150, 59639-152

Petition Nos.: 1E7923 Regulatory Action: Section 3

Risk Assessment Type: N/A Case No.: 7620

TXR 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 McNeilly, 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). In support of the petition, IR-4 has submitted field trial data depicting 

residues of clothianidin in/on strawberry, lemon, grapefruit, orange, and tea, and an orangeprocessing study. IR-4 has requested that the tolerance for pistachio be translated from the 

existing tolerance for residues in/on tree nuts.
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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 ...........................................0.60 ppm

Tea, dried ...................................................................70 ppm

These recommended tolerance levels differ from the petitioned-for tolerance levels 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 MRLs for clothianidin that are relevant to the recommended 

tolerances. Codex MRLs (see Attachment 1) are in place for tea, strawberry, citrus, and fruiting 

vegetables; however, the MRLs 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 MRLs.

Prior to registration, 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 recently 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 

type 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
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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 trials 

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 use 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, Strawberry, Citrus, and Tea.

Crop Formulation Application Type 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 --

Strawberry 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 

implied from the field 

trial application 

parameters

NS = Not Specified

Summary of Analytical Methods and Storage.

Crop Method Description LOQ, ppm Storage Stability
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ID Sample Duration

and Conditions

Demonstrated 

Stability

Strawberry Residue 

Analytical 

Method 

00552

Extraction with ACN:H2O (2:1, v/v),

Cleanup with partitioning on a 

ChemElut column,

Separation/Quantification via HPLCMS/MS

0.014 (calc.)

0.02 (Lowest 

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 HPLCMS/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.

Strawberry 0.2 1 10 0.096 1.170 0.103 1.120 0.258 0.327 0.301

Grapefruit 0.2 1 5 0.022 0.346 0.027 0.281 0.072 0.113 0.103

Lemon 0.2 1 6 0.022 0.201 0.034 0.176 0.102 0.107 0.055

Orange 0.2 1 13 0.005 0.269 0.008 0.219 0.057 0.083 0.066

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] Processing Factor1

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 Pulp

0.417

0.406 [0.406]

0.396

1.68X

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 

Organization for Economic Cooperation and Development Maximum Residue Level (OECD

MRL) Calculation Procedures. The data and results are summarized below. For the citrus crop 

group, the representative crops were analyzed separately 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) and 
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multiplied it by the processing factor for dried pulp (1.68X). The resulting value (0.47 ppm) is 

less than the recommended tolerance for residues in/on citrus. Therefore, a separate tolerance for 

dried citrus pulp is not required.

For tea, HED performed an analysis of variance of the 3- and 7-day PHI residue values. That 

analysis 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 PHI trials were pooled for the 

tolerance analysis.

Summary of Inputs and Results from the OECD MRL Calculation Procedures for Strawberry, Citrus, and Tea.

Compound Clothianidin Clothianidin Clothianidin Clothianidin Clothianidin

Crop Strawberry 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 noncensored data 10 6 5 13 12

Lowest residue 0.103 0.034 0.027 0.008 2.150

Highest residue 1.120 0.176 0.281 0.219 37.550

Median residue 0.258 0.102 0.072 0.057 13.950

Mean 0.327 0.107 0.113 0.083 15.214

Standard deviation 

(SD) 0.301 0.055 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 0.325 0.526 0.347 62.243

- CF x 3 Mean 0.981 0.321 0.339 0.249 45.641

Unrounded MRL 1.529 0.325 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 17.15
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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 Compound

Common name Clothianidin

Company 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

Company 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

H C3

NO2

S

N

N

H

NH

NH

Cl

H C3
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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 adequately 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 ATMGPyruvate. 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 separation, 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 adequately 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.
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Estimation of Dietary Burdens for Clothianidin Residues to Livestock.

Feedstuff Dietary 

Component

% 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 40.001

TOTAL 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

TOTAL BURDEN 100 0.289

Poultry

Field corn grain CC 75 0.01 0.008

Cottonseed meal PC 20 0.02 40.004

Soybean seed PC 5 0.02 0.001

TOTAL BURDEN 100 0.013

Swine

Field corn grain CC 85 0.01 0.009

Cottonseed meal PC 15 0.02 40.003

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.
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Attachment 1. International Harmonization

Clothianidin (044309; 11 September 2012)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex3,4

40 CFR 180.586:

Plant/Livestock: clothianidin, ( E )- N -[(2-

Chloro-5-thiazolyl)methyl]- N' -methyl- N" 

-nitroguanidine

[C(E)]-N-[(2-chloro5-thiazolyl)methyl]-

N'-methylN"-nitroguanidine

clothianidin.

The residue is not 

fat-soluble.

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex3,4

Tea (import only) 70 0.7 Tea, green, 

black (black, 

fermented and 

dried) (T)

Strawberry 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

Completed: 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