                 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 orange-processing study.  IR-4 has requested that the tolerance for pistachio be translated from the existing tolerance for residues in/on tree nuts.

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

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
ID
Description
LOQ, ppm
                               Storage Stability




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 HPLC-MS/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 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.
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 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 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 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 non-censored 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




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[(R)] 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

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/cm[3])
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 ATMG-Pyruvate.  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.

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 [4]
                                     0.001
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 [4]
                                     0.004
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 [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.

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/Livestock:  clothianidin, ( E )- N -[(2-Chloro-5-thiazolyl)methyl]- N' -methyl- 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)
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


