### Clothianidin Human Health Risk Assessment DP No. D418320

Page 1 of 19 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND

POLLUTION PREVENTION



### MEMORANDUM

Date: April 2, 2014

SUBJECT: Clothianidin

– Aggregate Human Health Risk Assessment for the Section 18 Use

on Immature Citrus Trees in FL (14FL03).

PC Code: 044309 DP Barcode s : D418320

Decision Nos.: 488203 Registration No. : 59639

- 150

Petition No.: 14FL03 Regulatory Action: Section 18

Risk Assessment Type: Single Chemical, Aggregate Case No.: 7620

T XR No.: N A CAS No.: 210880

- 92

- 5

MRID No.: NA 40 CFR 180.586



### FROM: Dennis McNeilly, Chemist Margarita Collantes, Biologist

Risk Assessment Branch II Health Effects Division (7509P)

THROUGH: Michael A. Doherty, Ph.D., Chemist

Christina Swartz, Branch Chief

Risk Assessment Branch II Health Effects Division (7509P)

TO: St acey G r oce/Tawanda Maignan (RM

- 09) Risk Integration, Minor Use, and Emergency Response Branch Registration Division (7505P)

The Registration Division (RD) requested that the Health Effects Division (HED) conduct an exposure and risk assessment for the Section 18 use of the insecticide clothianidin { (E)

- N

- [(2

-

c hloro

- 5

- thiazolyl)methyl]

- N’

- methyl

- N”

- nitroguanidine} on immature citrus trees in FL

. The proposed use involves the application of tree

- size specific doses of clothianidin via soil drench applicat ion to the base of citrus trees as described in Table 1 below

. The requested use is for Belay Insecticide (EPA Reg. No. 59639

- 15 0 ), containing 23.6 % active ingredient (a.i.). Currently, clothianidin is registered for use on non

- bearing citrus.

HED notes that a previous request for the Section 3 use of clothianidin on citrus involv ed f oliar,

soil in

- furrow, band drench, irrigation, and basal bark spray uses for the same product w as reviewed by HED ( D395348, M. Doherty, 27 Sep 2012 )

. That Section 3 petition was reviewed

### Clothianidin Human Health Risk Assessment DP No. D418320

Page 2 of 19 and HED recommended establishing a tolerance for residues in/on citrus at 0.6 ppm, but the use

on citrus has not been registered, and the associated citrus tolerance has not yet been established.

The citrus uses in tha t S ection 3 registration risk assessment include very similar soil application s to that proposed in the current Section 18

, and are shown in Table 2. Th e S ection 3

risk assessment for use on citrus evaluated the available hazard and residue chemistry data to derive risk estimates associated with dietary, residential, and occupational exposure. HED’s aggregate risk assessment was based on screening

- level assumptions and the resulting estimated

exposu re levels likely overestimate actual exposures that may occur. Sentinel aggregate risk indices (ARIs) are 1.21 for children aged 1

- 2 years old and 6.9 for adults, and are not of concern. Similarly, occupational ARIs are not of concern, ranging from 1.1 t o 660. Even with the conservative assumptions used to estimate exposure , aggregate and occupational risk estimates

were below HED’s level of concern for all scenarios and population groups.

As stated above, t he Section 3 use on citrus as well as the othe r Section 3 uses on s trawberry, pistachio, and tea evaluated in the last risk assessment , are still pending . T he tolerances

recommended for those uses are utilized in th e dietary evaluation that supports this Section 18 risk assessment, in order to not un der estimate exposure and risk, if and when those uses are registered. The tolerance required to support the Section 18 use on citrus is 0. 0 4 ppm, i.e., a much lower tolerance than the Section 3 use on citrus (0.6 ppm driven by foliar uses ) . The higher concentration of the Section 3 use is used to evaluate the dietary risk. However, a new acute dietary assessment was needed to support the proposed Section 18 use; t he only difference s in this assessment for citrus are: 1) the revised ( higher ) acute drin king water estimate provided by EFED ; and 2) the d eleti on of the f ood h andling e stablishment (FHE) residues of clothianidin resulting from thiamethoxam use in FHEs from the acute dietary analysis, per HED policy

. The

revised acute dietary risk estimates a re below HED’s level of concern for all population subgroups.

The chronic estimated drinking water concentration (EDWC) and resulting dietary risk estimates

remain the same as they were in the most recent chronic dietary analysis that included proposed

Section 3 use on citrus

. Since the chronic d ietary exposure estimate is used in evaluating the

short

- , intermediate

- , and long

- term aggregate risk s , th ose risk estimates remains unchanged

from the last assessment.

Conclusion s /Recommendation s

There are no human health risk issues that would preclude granting the requested S ection 1 8 use on FL citrus , and establishing a temporary tolerance of 0. 0 4 ppm for Fruit, citrus, Group 10

- 10

. This tolerance should be established to support th e FL Section 18 use until the Section 3

tolerance is established

, or until the Section 18 expires

. HED notes that the Section 18 label

should include a PHI of 1

- Day for citrus , which is reflected in the citrus field trial data

.

The tolerance current tolerance expression i s appropriate and includes the required coverage and compliance statements; therefore, the tolerance expression in 40 CFR §180. 586 should remain as it is currently w ritten: “ Tolerances are established for residues of the insecticide clothianid in, including its metabolites and degradates. Compliance with the tolerance levels specified below is

### Clothianidin Human Health Risk Assessment DP No. D418320

Page 3 of 19 to be determined by measuring only clothianidin, (E)

- N

- [(2

- Chloro

- 5

- thiazolyl)methyl]

- N′

- methyl

- N′′

- nitroguanidine, in or on the following raw agricultur al commodities : ”

An a dequate method, based on solvent extraction and LC

- MS/MS separation, identification, and quantification, is available for plant (Morse Method #Meth

- 164

- modified, RM

- 39C

- 1, or Bayer Method 00552) matrices. The LOQ for clothianidin in plant commodities is 0.01 ppm

. Clothianidin and its major metabolites are not adequately recovered using any of the FDA

multiresidue methods.

Pesticide Use Pattern

The proposed Section 18 use application rate is based on tree size , and involves mix ing the requi red dose in water and appl ying 8

- 12 fl oz of solution uniformly around the base of each tree,

directed at the root zone. The proposed label states that for optimal uptake and performance, the

soil must be kept moist

, via irr igation or rainfall, f or seven days following application

. To ensure efficacy, the application site around the base of the tree should be as weed

- free as possib le.

Table 1 . Summary of Directions for Section 18 Use of Clothianidin.

Tree Size Formul ation

[EPA Reg.
No.] Max. Single

Appl. rate ( lb ai/A ) Max. N o.

of A ppl. /

Year Max

.

S easonal

A ppl. R ate (lb ai/A) PHI

(days) Use D irections

and L imitations

Citrus fruit

New planting or resets, less

than 3 feet tall

Belay

Insecticide

SC (2.13 lb/gallon) [59639

- 150] 3.0 fl oz/acre

(0.05 lb a /A i) 0.001 lb ai/gal 8 24 fl

oz/acre (0. 4 lb

ai /A ) NS RTI= 6 weeks

One to two year old trees, 3

to 5 feet tall 6.0 fl oz/acre (0.1 lb ai /A ) 0.002 lb ai/gal 4 24 fl

oz/acre (0.4 lb

ai /A ) NS RTI= 6 weeks

Three to five years old trees,

5 to 9 feet tall 12 fl oz/acre (0.2 lb ai /A ) 0.004 lb ai/gal 2 24 fl

oz/acre (0.4 lb

ai /A ) NS RTI= 4 months

Do not apply more

than two applications per tree per twelve month period. Do not apply from Nov 1 through the

end of the following bloom period.

Abbreviations used: PHI = Preharvest interval, RTI= re

- treatment interval, NS=not specified.



### Table 2 below reflects the uses propose d and evaluated in the Section 3 request for use of

clothianidin on citrus , i.e., f oliar, soil in

- furrow, band drench, ir rigation, and basal bark spray

. The same product w as reviewed in this assessment on citrus ( D395348, M. Doherty, 27 Sep

2012 )

.

### Clothianidin Human Health Risk Assessment DP No. D418320

Page 4 of 19 Table 2 . Summary of Directions for Citrus Use s Previously Reviewed by HED for Clothianidin ( D395348, M. Doherty, 27 Sep 2012)

.

Appl. timing, type, and (equip.) Formul ation [EPA Reg. No.] Max. Single

Appl. rate ( lb ai/A ) Max. N o.

of A ppl. /

S eason Max

.

S easonal

A ppl. R ate (lb ai/A) PHI

(days) Use D irections

and

L imitations

Citrus fruit Foliar, ground or aerial (aircraft, and air

- blast sprayer)

V

- 10170 2.13

SC [59639

- 150] 0.05

- 0.1 4 0.2 1 RTI=14 days

Soil in

- furrow, band, drench, drip or trickle irrigation (back

pack and MPHG) 0.15

- 0.2 1 0.2 21 RTI=not applicable

Basal bark spray (back

- pack) 0.1 for 2

- 4

ft.

and 0.2 for

4

- 8 ft. trees 1 0.2 1 RTI=not applicable

Abbreviations used: PHI = Preharvest interval, RTI= re

- treatment interval.



### Endpoints and Doses for Risk Assessment

HED notes that the toxicity database for clothianidin is complete for the purpose of making a safety finding under the Food Quality Protection Act (FQPA). Based on both hazard and exposure considerations, HED has reduced the required 10x FQPA factor to 1x

. Detailed information regarding the available toxicity data and hazard characterization of clothianidin can

be found in HED’s 2012 risk assessment ( D395348, M. Doherty, 27 Sep 2012 )

. D oses and endpoints used in the most recent aggregate risk assessment for clothianidin have not changed,

and are described below :

The acute dietary endpoints and dose selected for risk assessment were based on single dose effects observed in the toxicity database; separate endpoints were selected for females 13

- 49 and the g eneral US population including infants and children. For all other exposure scenarios, including incidental oral, dermal and inhalation, HED relied on the endpoint and dose selected

from the 2

- generation reproduction toxicity study. Because effects seen in the reproduction study can occur as the result of a single exposure at a critical junction during pregnancy or from multiple exposures throughout pregnancy and lactation, the NOAEL for offspring effects observed in the reproduction study was selected as the dose for all durations of exposure. The dose selected for risk assessment is also the most sensitive for repeated exposures, and is protective of all other effects in the database.

Acute Dietary Endpoint for Females 13

- 49: The endpoint used for establishing the aPAD for

females 13

- 49 was selected from the developmental study in the rabbit. An aPAD of 0.25 mg/kg/day was derived f

rom a NOAEL of 25 mg/kg/day and a 100

- fold factor that included 10x

for inter

- species extrapolati ons, 10x for intra

- species variations, and a 1x FQPA SF. The

LOAEL of 75 mg/kg /day was based on increased litter incidence of a missing lobe of the lung. This endpoint is appropriate for the acute dietary exposure assessment because it could be the

resul t of a single exposure at a critical junction during pregnancy or from multiple exposures throughout pregnancy , it is an appropriate route of exposure (oral)

, and it is protective of developing offspring

.

### Clothianidin Human Health Risk Assessment DP No. D418320

Page 5 of 19 Acute Dietary Endpoint for the General Populatio n: The endpoint used for establishing the aPAD for the general population was selected from the acute neurotoxicity study in rats. An aPAD of 0.25 mg/kg/day was derived from a NOAEL of 25 mg/kg/day and a 100

- fold factor

that included 10x for inter

- speci es extrapolations, 10x for intra

- species variations, and a 1x FQPA SF. The LOAEL of 50 mg/kg was based on transient signs of spontaneous motor activity, tremors, and deep respirations observed on D ay 1. Similar signs of neurotoxicity were observed

in the acute neurotoxicity study in the rat at 100 mg/kg, with a NOAEL of 60 mg/kg. This endpoint is appropriate for the acute dietary exposure assessment because it is the result of a single dose, is an appropriate route of exposure (oral) and is protective of the general population. Although the developmental toxicity study in the rat had a lower maternal NOAEL of 10 mg/kg/day (LOAEL 40 mg/kg/day), this study was not chosen for endpoint selection because the NOAEL is considered to be artificially low due to d ose spacing and because the effects (decreased body weight and food consumption) were not the result of acute exposure.

Chronic Dietary: The endpoint used for establishing the cPAD was selected from the 2

- generation reproduction study in the rat. A cP AD of 0. 098 mg/kg/day was derived from a

NOAEL of 9.8 mg/kg/day and a 100

- fold factor that included 10x for inter

- species extrapolation,

10x for intra

- species variability, and a 1x FQPA SF. The LOAEL of 31.2 mg/kg was based on decreased body weight gains, delayed sexual maturation, decreased thymus weights in F1 pups, and increased stillbirths in both generations. This study had the lowest NOAEL resulting from repeated dose exposure in the database.

Incidental Oral : The endpoint used for assessing short

- term incidental oral exposure w as selected from the 2

- generation reproduction study in the rat. The NOAEL is 9.8 mg/kg/day , and the level of concern (LOC) is an MOE of 100 ( 10x for inter

- species extrapolation, 10x for intra

species variability, and a 1x FQPA SF ) . The effects observed at the LOAEL of 31.2 mg/kg have been described above (see chronic dietary). The study, dose and endpoint were selected because of the exposure duration and because selection of the offspring effects is protective of the population of concern, developing children.

Dermal (All Durations) : The endpoint used for assessing all durations of dermal exposure w as selected from the 2

- generation reproduction study in the rat. The NOAEL is 9.8 mg/kg/day , and

the LOC is an MOE of 1 00 ( 10x for inter

- species extrapolation, 10x for intra

- species variability, and a 1x FQPA SF ) . The effects observed at the LOAEL of 31.2 mg/kg have been described above (see chronic dietary). The study was selected because of the exposure duration, and

b ecause it is protective of the population of the most sensitive population, developing children. Although a dermal (route specific) toxicity study in ra t s was submitted, no effects were seen at the highest dose tested of 1000 mg/kg/day. Use of the route

- specific study for dermal risk assessment would not be protective of the offspring effects observed in both the DNT and the 2

- generation reproduction studies because the dermal study does not evaluate reproduction and developmental parameters . Since the d ermal endpoint was selected from an oral study, a 1% dermal absorption factor (DAF) is used to determine dermal exposure and risk.

Inhalation (All Durations) : The endpoint used for assessing all durations of inhalation exposure

w as selected from the 2

- g eneration reproduction study in the rat. The NOAEL is 9.8 mg/kg/day

,

### Clothianidin Human Health Risk Assessment DP No. D418320

Page 6 of 19 and the LOC is an MOE of 1000 ( 10x for inter

- species extrapolation, 10x for intra

- species variability, a 1 0 x FQPA SF for residential scenarios, and a 10x database uncertainty factor for occupational scenarios) . The effects observed at the LOAEL of 31.2 mg/kg have been described above. The study was selected because of the exposure duration, and because it is protective of the most sensitive population, developing children. No route

- spe cific information is available for the inhalation toxicity of clothianidin . In the absence of a route

- specific study, the NOAEL and LOAEL from an oral study have been used for risk assessment (i.e., inhalation toxicity is assumed to be equivalent to oral toxicity).

Table 3a . Summary of Toxicological Doses and Endpoints for Clothianidin for Use in Dietary and Non

Occupational Human Health Risk Assessments. Exposure/

Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors Level of

Concern (LOC)

for Risk

Assessment Study and Toxicological Effects

Acute Dietary Females age

13

- 49 NOAEL =

25 mg/kg/day UF A = 10X

UF H = 10X

SF FQPA =1 X aRfD=0.25

mg/kg/day

aPAD=0.25 mg/kg/day Rabbit developmental study

LOAEL = 75 mg/kg/day based on increased litter incidence of a missing lobe of the lung

Acute Dietary General population NOAEL =

25 mg/kg/day UF A = 10X

UF H = 10X

SF FQPA = 1 X aRfD = 0.25

mg/kg/day

aPAD 0.25 mg/kg/day Special neurotoxicity/pharmacol ogy

study in mice LOAEL = 50 mg/kg/day based on transient signs of decreased spontaneous motor activity, tremors and deep respirations Chronic Dietary All populations including infants

and children NOAEL=

9.8 mg/kg/day UF A = 10X

UF H = 10X

SF FQPA =1 X cRfD=0.098

mg/kg/day

cPAD=0.098 mg/kg/day 2

- Generation reproduction study

LOAEL = 31.2 mg/kg/day based on decreased body weight gains and delayed sexual maturation, decreased absolute thymus weights in F1 pups and increased stillbirths in both generations

Incidental Oral (short

- term) NOAEL=

9.8 mg/kg/day UF A = 10X

UF H = 10X

SF FQPA =1 X MOE= 100

(residential) 2

- Generation reproduction study

LOAEL= 31.2 mg/kg/day based on decreased body weight gains and delayed sexual maturation, decreased absolute thymus weights in F1 pups Dermal (all durations) Oral study

NOAEL= 9.8 mg/kg/day (dermal absorption = 1%

of oral absorption ) UF A = 10X

UF H = 10X

SF FQPA =1 X MOE= 100

(residential) 2

- Generation reproduction study

LOAEL = 31.2 mg/kg/day based on decreased body weight gains and delayed sexual maturation, decreased absolute thymus weights in F1 pups and increased stillbirths in both generations

Inhalation (all durations) Oral study

NOAEL= 9.8 mg/kg/day (inhalation toxicity = oral toxicity ) UF A = 10X

UF H = 10X

SF FQPA =10X

for lack of

subchronic

inhalation study MOE= 1000

(residential) 2

- Generation reproduction study

LOAEL = 31.2 mg/kg/day based on decreased body weight gains and delayed sexual maturation, decreased absolute thymus weights in F1 pups and increased stillbirths in both generations

Cancer (oral, dermal, inhalation) “Not Likely to be Carcinogenic to Humans ”

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF =

### Clothianidin Human Health Risk Assessment DP No. D418320

Page 7 of 19 uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF DB = to account for the absence of key data

. SF FQPA = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

Table 3b . Summary of Toxicological Doses and Endpoints for Clothianidin for Use in Occupational Human Health

Risk Assessments. Exposure/

Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors Level of

Concern (LOC)

for Risk

Assessment Study and Toxicological Effects

Dermal (all durations) (Adults) Oral study

NOAEL= 9.8 mg/kg/day (dermal absorption = 1%

of oral absorption ) UF A = 10X

UF H = 10X MOE= 100

(occupational) 2

- Generation reproduction study

LOAEL = 31.2 mg/kg/day based on decreased body weight gains and delayed sexual maturation, decreased absolute thymus weights in F1 pups and increased stillbirths in both generations

Inhalation (all durations) Oral study

NOAEL= 9.8 mg/kg/day (inhalation toxicity = oral toxicity ) UF A = 10X

UF H = 10X

UF DB = 10X MOE= 1000

(occupational) 2

- Generation reproduction study

LOAEL = 31.2 mg/kg/day based on decreased body weight gains and delayed sexual maturation, decreased absolute thymus weights in F1 pups and increased stillbirths in both generations

Cancer (oral,

dermal , inhalation) “Not Likely to be Carcinogenic to Humans

. ”

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in

sens itivity among members of the human population (intraspecies). UF DB = to account for the absence of key data

. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.



### Residue Chemistry

Residue data are available from the Section 3 petition to evaluate the proposed Section 18 use on citrus. Those data reflect a seasonal application rate of 0

. 2 lbs ai/A/year, or half the proposed

Section 18 use rate of 0

. 4 lbs ai/A/year for most of the sa mples. HED’s assessment is that the data are adequate to set a Section 18 tolerance and the calculated tolerance is normalized to the higher application rate (i.e., using a 2X factor). Although residue data are available from field trials with oranges, g rapefruit and lemon, only the orange residue data had residues from the drench treatment and were used for the purpose of estimating the tolerance.

Orange. The data show that f ollowing the soil drench treatment of oranges at the approximate rate of 90 gr ams ai/A (ca. 0.2 lbs ai/A) , and a 1

- day PHI, maximum residues of clothianidin in/on orange samples was 0.016 ppm. Residues of clothianidin on oranges from the soil drench treatment declined from 0.014 ppm on day 1 to <0.005 ppm on day 28. Only the resid ue results

from field sites that included soil drench (shown in bold in Table 4 below ) were used for the purpose of calculating the tolerance associated with the prop o sed Section 18 use. The side

- by

-

### Clothianidin Human Health Risk Assessment DP No. D418320

Page 8 of 19 side foliar residue data are shown for comparison; other test sites that involved only foliar application s are not included.

Table 4. Residue Data from Orange Field Trials with Clothianidin ( MRID No. 48600004 )

Trial ID (City,State/Year) Region Crop/Variety Application

method Total Rate

(gram ai/A) PHI (days) Clothianidin (ppm)

V

- 33019

- E

(Volusia Co., FL/2008) 3 Orange Fruit/

Valencia Foliar 90.2

1 0.269

0.168

Soil drench * 89.2 < 0.005

0.009

V

- 33019

- F

(Seminole Co., FL/2008) 3 Orange Fruit/

Hamlin Foliar 90.6 1 0.224

0.184

3 0.230

0.185

7 0.142

0.156

14 0.116

0.117

21 0.165

0.087

28 0.067

0.112

Soil drench 89.0 1 0.012

0.016

7 0.005

0.006

14 0.012

< 0.005

21 0.006

< 0.005

28 <0.005

< 0.005

V

- 33019

- G

(Polk Co., FL/2008) 3 Orange Fruit/

Hamlin Foliar 90.5

1 0.037

0.046

Soil drench 89.0 < 0.005

< 0.005

V

- 33019

- I
(Imperial Co., CA/2008) 10 Orange Fruit/

Valencia Foliar 91.2

1 0.100

0.103

178.4 0.300

0.312

Soil drench 90.1

1 < 0.005

< 0.005

180.1 < 0.005

< 0.005

V

- 33019

- J

(Fresno Co., CA/2008) 10 Orange Fruit/

Navel Foliar 92.2

1 0.054

0.032

Soil drench 90.0 < 0.005

< 0.005

V

- 33019

- M
(Hidalgo Co., TX/2008) 6 Orange fruit/

Marrs Foliar 92.5

1 0.072

0.042

Soil drench 93.1 < 0.005

< 0.005

 Bold = Average of values was used in calculating the required tolerance (N=7), which was multiplied by 2

to obtain the recommended tolerance.



### Grapefruit. Clothianidin residues found in grapefruit samples from plots treated with a single drench application of Belay 2.13 SC at a rate of approximately 0.2 lb ai/A with PHIs of 1 , 7 14,

### Clothianidin Human Health Risk Assessment DP No. D418320

Page 9 of 19 20

- 21, and 27

- 28 days were <0.01 p pm. (MRID No. 48600002)

.

Lemon. S oil drench applications were made using a single application of 90 g ai/A at three trials 1 day before harvest. The test substance was diluted in 2

- 3 gallons of water for each tree and poured around the drip line of eac h tree at approximately 200

- 300 gallons per acre. Following the test substance application, plots were irrigated with approximately 0.25” of water per acre. Lemon samples from the soil drench plots were collected at 1 and 14 days after the last applicati on. Clothianidin residues were not detected (<0.005 ppm) in any of the lemon samples collected from the decline study with a soil drench application. ( MRID No. 4860000 3)

.

Processing. Residues of clothianidin are not expected to concentrate during processing of oranges into oil or juice, but may concentrate by 1.7X, on average, during the production of dried citrus pulp. A dried citrus pulp tolerance is not required for the Section 18.

Enforcement Analytical Method

Adequate methods, based on sol vent 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 commod ities 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.

Drinking Wate r Data

The E stimated Drinking Water Concentration (EDWC) of 72 ppb was used in the last acute and

chronic dietary exposure evaluation (D397690, M. Doherty, 26 September 2012) to account for

residues of clothianidin in water . Th at EDWC is still considered appropriate for chronic dietary

assessment ; however, a new and higher acute EDWC was provided by EFED for the proposed

Section 18 use on immature citrus trees in FL.

A cute (W. Eckel, email 3/18/2014)



### The groundwater E stimated Drinking Water Concentration (E DWC ) was evaluated by the Environmental Fate and Effects Division (EFED) for the Section 18 use on citrus in FL using the

PRZM

- GW model (Version 1.07). At 84 ppb (peak)

, the result is higher than the rice model results used in the previous assessment for clothianidin (see Chronic, below) , although the post

breakthrough estimate (67 ppb) and mean (60 ppb) are lower. Estimated groundwater concentrations and breakthrough times for clothianidin are presented for the acute evaluation in

Table 5 a for the Florida Citrus

- FL Central Ridge, Polk County

- (Tampa). The SCIGROW EDWC for the same application rate (0.2 lb/A, two applications), Koc (160) and soil metabolism

half

- life (744 days) is 3 ppb.

### Clothianidin Human Health Risk Assessment DP No. D418320

Page 10 of 19 Table 5 a. Groundwater Results for clothianidin and the Florida Citrus

- FL Central Ridge, Polk County

- (Tampa). Use (application rate, lbs a.i./A) Model Concentration (ppb)

Section 18 Use on Citrus in FL 0.2 lb/A, two applications PRZM

- GW model Peak 84.5

Post

- Breakthrough Mean 67.3

Entire Simulation Mean 60



### Chronic

The Environmental Fate and Effects Division (EFED) has supplied HED with Tier I estimated drinking water concentrations (EDWC) for clothianidin in surface water resulting from foliar application to rice (R. Baris, 15 September 2011, D393235).

EFED used the Tier I Rice Model (v 1.0) as a screening model to calculate the surface water EDWC resulting from a single foliar application of clothianidin to a flooded field (as proposed on the label). This concentration represents the estimated concentr ation that would be expected in the release water downstream of the treated rice paddy. FIRST (FQPA Index Reservoir Screening Tool, version 1.1, 01/01/07) was used to calculate the surface water EDWC resulting from a single foliar application to leafy veg etables. These concentrations are presented in Table

5 b

.

Table 5 b . Tier I EDWCs for chronic drinking water risk assessment based on the proposed clothianidin use on rice and leafy vegetables Use (application rate, lbs a.i./A) Model Chronic

Surface water drinking water sources, downstream of rice paddy (0.084 lb a.i./A) Tier I Rice Model (v1.0) <72 ppb



### The EDWC of 72 ppb has been used to account for residues of clothianidin in the chronic dietary

risk assessments , and is still considered appropriate

.

Diet a ry Exposure and Risk

D 418668

, D. McNeilly

, April 2, 2014



### The acute and chronic assessments are both based on the screening

- level input assumptions, including tolerance

- level residues, 100% crop treated, and high

- end estimates of residue s in drinking water. These inputs resulted in risk estimates that are, at most, 28% of the population

adjusted dose for all population subgroups for both the acute and chronic assessments; the

maximum risk estimate is for children 1

- 2 years of age. All d ietary risk estimates are below

HED’s level of concern (Table 6)

.

HED notes that a previous request for the Section 3 use of clothianidin on citrus involv ed f oliar,

soil in

- furrow, band drench, irrigation, and basal bark spray uses for the same product an d w ere reviewed in HED’s recent dietary analysis ( D395348, M. Doherty, 27 Sep 2012 ) . That Section 3 petition was reviewed, but the Section 3 use on citrus has not been registered . The citrus uses in that Section 3 dietary risk analysis include soil applications similar to those proposed in the

current Section 18. The Section 3 use on citrus, as well as the other Section 3 uses on

s trawberry, pistachio, and tea , is pending, and the tolerances recommended for those uses are

included in t his dietary evaluation in order not to underestimate exposure and risk, when those

### Clothianidin Human Health Risk Assessment DP No. D418320

Page 11 of 19 uses are registered. The tolerance required to support the Section 18 use on citrus is 0. 0 4 ppm, i.e., much lower than the recommended tolerance associated with the Section 3 use on citrus. The higher concentration from the Section 3 use , which included both soil drench and foliar application, has been used to evaluate dietary risk for the proposed Section 18

.

The only difference in this dietary analysis for citrus is the revised and higher acute drinking water estimate provided by EFED for the Section 18 use on citrus. The chronic analysis drinking water estimate remains the same as it was in the most recent dietary assessment.

Table 6 . Summary of Acute and Chronic Dietary Exposure and Risk Estimates for Clothianidin.

Population Subgroup Acute (95 th Percentile) Chronic
Exposure, mg/kg/day % aPAD Exposure, mg/kg/day % cPAD ARI
Total US Population 0.0213 30 9 0.007458 8 13.1

All Infants 0.052 610 21 0.016683 17 5.87

Children 1

- 2 years old 0.0697 71 28 0.027256 28 3.60

Children 3

- 5 years old 0.049 104 20 0.018444 19 5.31

Children 6

- 12 years old 0.0245 79 10 0.009165 9 10.7

Youth 13

- 19 years old 0.01458 6 6 0.005346 6 18.3

Adults 20

- 49 years old 0.0154 67 6 0.005822 6 16.8

Adults 50

- 99 years old 0.0148 21 6 0.006109 6 16.0

Female 13

- 49 years old 0.0157 59 6 0.005974 6 16.4 The population subgroup(s) with the highest exposure/risk estimates are shown in bold

. A RI = Aggregate Risk Index. ARI values < 1 indicate a potential risk of concern. ARI = NOAEL (9.8 mg/kg/day) ÷ Exposure ÷ LOC (Oral LOC = 100).



### Residential Exposure

There are no new residential exposures as a result of the proposed Section 18 use on citrus in FL. Existing u se s of clothianidin on turf, ornamental plants, and/or indoor surfaces may result in human exposure in a residential setting. Such exposures may occur during application of products containing clothianidin (handler exposure) as well as following application (post

application exposure) and are expected to be of short

- term (1

- 30 days) duration . HED assessed exposure and developed risk estimates for numerous residential handler and post

- application

scenarios using the 2012 residential SOPs ( M. Collantes

, D39772 4, 15 August 2012)

.

For clothianidin, residential handler risk estimates are considered to be of potential concern when the dermal MOE is less than 100, the inhalation MOE is less than 1000, and/or the aggregate risk index (ARI), reflecting combined derma l and inhalation exposure, is less than one. As shown in

Table 7 , the residential handler risk estimates are not of concern (ARIs range from 11 to 990).

### Clothianidin Human Health Risk Assessment DP No. D418320

Page 12 of 19 Table 7 . Summary of Residential Handler Exposure and Risk Estimates for Clothianidin. M. Collante s D397724, 15 August 2012.

Use Site Application Method Formulation Activity Exposure Estimate, mg/kg/day (MOE)

ARI 1 Dermal Inhalation

Turf Push

- Type Spreader Arena 0.5G Mixing/ Loading/ Applying 2.3x10

- 5

(420,000) 7.5x10

- 6

(1,300,000) 990

Turf Belly Grinder Arena 0.5G Loading/ Applying 5.7x10

- 4

(17,000) 6.2x10

- 6

(1,600,000) 160

Tree Trunk Manually Pressurized

Handwand Arena 50 WDG Mixing/ Loading/ Applying 6.8x10

- 3

(1,400) 2.0x10

- 4

(50,000) 11

Lawns Hose

- End Sprayer Arena 50 WDG Mixing/ Loading/ Applying 3.8x10

- 4

(25,000) 6.4x10

- 5

(150,000) 96

Fruit Trees Hose

- End Sprayer Arena 50 WDG Mixing/ Loading/ Applying 1.4 x 10

- 3

(7,100) 3.3 x 10

- 6

(2,900,000) 69

Indoor

Surfaces (Bed Bug) Manually Pressurized

Handwand File Symbol

73049

- UIE Mixing/ Loading/

Applying 1.7x10

- 4

(58,000) 2.7x10

- 4

(36,000) 34

Indoor

Surfaces (Bed Bug) Paintbrush File Symbol

73049

- UIE Applying 1.1x10

- 3
(9,000) 4.9x10

- 5

(200,000) 62

1 ARI is calculated as the NOAEL ÷ Σ (Exposure i × LOC), where Exposure i is each exposure source being included in the ARI calculation and LOC is the product of the applicable safety factors (100 for dermal and oral exposures and 1000 for inhalation exposures).



### Combined Exposure

HED combines risk estimates resulting from separate residential exposure scenarios when it is likely they can occur simultaneously based on the use

- pattern and the behavior associated with the exposed life stage

. Although there is potential for adult exposure resulting from both

ap plying the product and post

- application activities, HED did not combine exposure estimates from adult handler and post

- application activities because of the conservative assumptions and inputs within each exposure scenario.

For purposes of performing an aggregate assessment, HED selected the worst

- case adult and children exposure scenarios. The treatment of tree trunks using a manually

- pressurized hand

wand presents the worst

- case exposure estimate for adults (ARI=11), while the bed bug scenario

presents the worst

- case exposure estimates for children 1 to < 2 yrs old (ARI=1.8). A summary of the residential exposure scenarios for the aggregate assessment is provided in Table 8

.

### Clothianidin Human Health Risk Assessment DP No. D418320

Page 13 of 19 Table 8 . Residential Exposure Scenario and Risk Estimates for Aggregate Asse ssment.

Scenario Life S tage Scenario Scenario

ARI 1 Combined

ARI 2

Handler Scenarios

Tree Trunk Adult Manually Pressurized Handwand 11 11

Lawns Adult Hose

- End Sprayer 96 40 Fruit Trees Adult Hose

- End Sprayer 69

Post

- Application Scenarios

Bed Bug Adult Perimeter (Carpet) 25 21 Mattress 140

Children 1 to < 2 years old Perimeter (Carpet) 1.9 1. 8 Mattress 61

1 Scenario ARIs are from Tables 4 and 5 for handler and post

- application exposures, respectively.

2 Combined ARI = 1 ÷Σ (1 ÷ ARI Scenario ), where ARI Scenario is the ARI for each scenario being included in the combined

ARI.



### Aggregate Risk

The most recent aggregate risk assessment for clothianidin showed no risks of concern for any population subgroup ( D395348, M. Doherty, 27 Sep 2012 ). As this use is restricted to citrus

trees and the use does not result in residues of clothianidin in the chronic drinking water which are greater than those already assessed , there are no concerns regarding chronic dietary exposure

. In addition, HED note s that residues resulting from soil drench applications were significantly (10

- 100 times) lower than residues resulting from foliar uses, which were used in evaluating the

citrus tolerance and f

o r evaluating the dietary exposure and risk

. Acute and chroni c aggregate risk estimates are equivalent to the acute and chronic dietary risk estimates which are not of

concern.

In estimating aggregate risk, HED has considered the combined residential ARIs (Table 8 ) and the dietary exposure ARIs ( Table 6 ) . The aggregate ARIs (Table 9 ) are the worst

- case risk estimates for each life stage. The aggregate ARIs are all greater than 1 and indicate that aggregate risks are not of concern ( D395348, M. Doherty, 27 Sep 2012 ).

Table 9

. Aggregate Risk Estimates f or Clothianidin

. Life S tage Residential Combined ARI 1 Dietary ARI 1 Aggregate ARI 2

Adult 11 16.0 6.5 Children 1 to < 2 years old 1.8 3.60 1.2

1 Residential Combined ARIs are the minimum ARI for each life stage from Table 6.3; Dietary ARIs are from Table 5.4.4. The adult dietary ARI is from the population subgroup Adults 50

- 99 years old and is the most conservative ARI from any of the adult

- only subgroups.

2 Aggregate ARI = 1 ÷ (1 ÷ ARI Residential + 1 ÷ ARI Dietary )



### Occupational Risk

The previously evaluated o ccupational exposure and risk associated with soil application uses on citrus ( D397691, S. Oonnithan, 27 September 2012)

, are similar to the proposed section 18 use

. All occupational handler scenarios resulted in risk estimates equal to MOEs ranging from 5.4 (resulting from mechanically pressurized handgun) to 660 (resulting from mixing/loading for

### Clothianidin Human Health Risk Assessment DP No. D418320

Page 14 of 19 airblast) and are not of concern. A summary of the occupational exposu re risk estimates is provided in Table 10 below.

### Clothianidin Human Health Risk Assessment DP No. D418320

Page 15 of 19 Table 10 . Occupational Exposures and Risks Resulting from Use of Clothianidin on Citrus

.

Scenario 1 Crop & Appl.

rate (lb ai/A or lb ai/gal) 2 Area treated

or gal//day 3 Source of

Unit exp.

& PPE # 3 Dermal

UE 3 μg/lb ai Inhal.

UE 3 μg/lb ai Dermal

dose 4 mg/kg/day Inhal.

dose 4 mg/kg/day Short

- term

Dermal

MOE 5 Short

- term

Inhal.

MOE 5 Short

- term

ARI 6

MIXER / LOADER

V

- 10170 2.13 SC, Aerial Strawberry (0.1) Citrus (0.1) Pistachio (0.1) 350 AHETF

B+G 37.6 0.219 0.00019 0.00011 51,383 88,219 75

V

- 10170 2.13 SC, Air

blast Citrus (0.1) Nectarine (0.1) Pistachio (0.1) 40 AHETF

B+G 37.6 0.219 0.00002 0.00001 449,601 77,918 660

APPLICATOR

V

- 10170 2.13 SC, Aerial Strawberry (0.1) Citrus (0.1) Pistachio (0.1) 350 AHETF Closed cockpit 5.0 0.068 0.00003 0.00003 386,400 284,118 260

V

- 10170 2.13 SC, Air

blast Citrus (0.1) Nectarine (0.1) Pistachio (0.1) 350 AHETF

B+G+ open cab 1,590

4.71 0.00092 0.00027 10,632 35,382 27

FLAGGER

V

- 10170 2.1 SC

& Arena WDG All crops (0.2) 350 PHED

B+G 12 0.35 0.00012 0.00036 80,500 27,600 27

MIXER / LOADER / APPLICATOR

Arena WDG and

V

- 10170 2.1 SC

Soil broadcast Backpack Strawberry (0.2), Citrus (0.2)

dilution = 0.02 lb ai/gal 40

gal/day B+G 8,260 2.58 0.00096 0.00003 10,223 327,616 78

Arena WDG and

V

- 10170 2.1 SC

Soil drench

MPHG Strawberry (0.2), Citrus (0.2) ,

dilution = 0.004 lb ai/gal 1000

gal/day B+G 390 3.9 0.000226 0.000226 43,000 43,000 39

V

- 10170 2.13 SC Soil drench in greenhouse

MPHG Citrus

– 0.001 lb ai/gal Baseline 3500 120 0.000507 0.00174 19,000 5,600 5.4

Abbreviations used: AHETF = agricultural handler exposure task force database, ARI = aggregate risk index, B = baseline PPE ( long

- sleeved shirt, long pants, shoes and socks, and no respirator), G = chemical resistant gloves, MOE = margin of exposure, MPHG = mechanically pressurized handgun, PHED = pesticide handler exposure database, PPE = personal protective equipment, and UE = unit exposure.

### Clothianidin Human Health Risk Assessment DP No. D418320

Page 16 of 19 1

. Exposure scenarios are from Table 6 in D397691

. The soil drench in greenhouse use was added to reflect a use pattern very close to the Section 18 use pattern (Note: the Section 18 use is not restricted to greenhouse use). 2. For soil broadcast and drench applications and citrus trunk treatments an application rate of 0.2 lb ai/A was proposed. T he diluent volum e used for back

- pack sprayer was 10 gal/A and at an application rate of 0.2 lb ai/A, the conc. of clothianidin in the spray mix amounted to 0.02 l b ai/gal. The corresponding numbers for MPHG used for soil drench was 50 gal/A at 0.004 lb ai/gal.

3. From http://www.epa.gov/pesticides/science/handler

- exposure

- data.html 

### . F or backpack sprayer, the same unit dermal and inhalation unit exposures were

used for both WDG and SC formul ations.

4 . Dermal dose (mg/kg/day) = [Appl. rate (lb ai/A or lb ai/gal) * Area treated (acres or spray vol. /day) * Dermal unit exp. (μg/lb ai*0.001) * Dermal absorption rate (1.0%)] / Body wt. (69 kg). Inhalation dose (mg/kg/day) = [Appl. rate (lb ai/A or lb ai/gal) * Area treated (acres or spray vol. /day) * Inhal. unit exp. (μg/lb ai *0.001) * Inhalation absorption rate (100%)] / Body wt. (69 kg).

5 . Short

- term dermal MOE = Short

- term dermal NOAEL (9.8 mg/kg/day) / Dermal dose (mg/kg/da y). Short

- term inhalation MOE = Short

- term inhalation NOAEL (9.8 mg/kg/day) / Inhalation dose (mg/kg/day).

6 . Short

- term ARI = 1/[(1/(short

- term dermal MOE/100) + (1/(short

- term inhalation MOE/1000)]. The intermediate

- term ARI is the same as the short

- term,
due to having the same endpoints and doses for both exposure durations.

### Clothianidin Human Health Risk Assessment DP No. D418320

Page 17 of 19 Post

- application Dermal Exposure

The post

- application dermal exposure and risk resulting from foliar applications of clothianidin

on citrus fruit , which are considered to be a worst

- case scenario, are summarized in Table 1 1

. The short

- term post

- application dermal MOE was 22,0 00 , which is significantly greater than HED’s level of concern (LOC) of 100, and is not of concern . The post

- application de rmal exposures resulting from soil

- directed applications of clothianidin on citrus were not assessed quantitatively due to the lack of representative unit exposure values . However, dermal post

application exposure for workers from the use of soil drench t reatments are expected to be much lower than those associated with post

- application exposure resulting from foliar uses

. Post

application exposure from fruit harvesting is considered protective of potential exposure following soil drench treatment, and is not of concern.

Table 1 1 . Post

- application Dermal Exposures and Risks Resulting from Foliar Use of Clothianidin on Citrus, Nectarine, Pistachio, and Strawberry.

Crop Activities Appl. Rate

(lb ai/A) Estimated

DFR (ug/cm 2 ) 1 Transfer

Coefficient (cm 2 / hr) 2 Dermal

Dose 3 (mg/kg/day) Short

- term

Dermal MOE

4

Citrus fruits Fruit harvesting 0.1 0.280 1,400 0.000454 22,000

1 . Dislodgeable Foliar Residue (DFR) = Appl ication r ate (lb ai/A) * (1

- Daily d issipation r ate) t * Conv

. f actor

, 4.54E+8 μg/lb * Conv

. f

actor

, 2.47E

- 8 A/cm 2 * Residue t ransfer r ate (20% default) after treatment.

2 . Transfer coefficient (TC) from ExpoSAC Policy #3, June 3, 2011.

3. D ermal d ose (mg/kg/day) = [DFR * T C * Conv . f actor

, 0.001 mg/μg * Dermal a bsorption factor (1%) * 8

hrs/d ay] / Body w eight (6 9 kg).

4: Margin of Exposure

, s hort

- term= S hort

- term d ermal NOAEL ( 9.8 mg/kg/day) / D ermal d ose (mg/kg/day).



### Conclusion

There are no human health concerns that would preclude granting the requested section 18 use of

clothianidin on immature citrus trees in FL

, and concurrently establishing a Section 18 temporary
tolerance of 0. 04 ppm for citrus to support that use

.

References:

D397689

. M. Doherty

. 26 September 2012. Clothianidin

– New Uses on Strawberry, Pistach io,

Citrus, and Tea. Evaluation of Residue Chemistry Data.

D 418668 D. McNeilly. April 2, 2014

. Clothianidin

– Acute and Chronic Dietary Exposure and

Risk Estimates for Section 18 Use of Clothianidin on Immature Citrus Trees in Florida to Control Asian Citrus Psyllid (14FL03)

. D 397690. M. Doherty. 26 September 2012. Clothianidin

– Acute and Chronic Dietary Exposure

and Risk Estimates for Requested Amended Registration on Peppers and New Uses on Strawberry, Citrus, Pistachio, and Tea.

D397691

. S. Oonnithan

. 27 September 2012. Clothianidin. Occupational Exposure Assessment

for New Uses on Citrus, Nectarine, Pistachio, and Strawberry; and Label Amendments to Add Aerial Appl ication.

### Clothianidin Human Health Risk Assessment DP No. D418320

Page 18 of 19 Attachment 1. Tolerance Calculation

Compound Clothianidin
Crop Citrus Region / Country Florida

GAP 0.2 lbs ai/A soil drench

Total number of data (n) 7

Percentage of censored data 71%

Number of non

- censored data 2

Lowest residue 0.005 Highest residue 0.014

Median residue 0.005

Mean 0.007
Standard deviation (SD) 0.003

Correction factor for censoring (CF) 0.524

Proposed MRL estimate

- Highest residue 0.014

- Mean + 4 SD 0.020

- CF x 3 Mean 0.010

Unrounded MRL 0.020

Rounded MRL 0.02 *

 Since the use rate is 0.4 lbs ai/A and not 0.2 lbs ai/A, the tolerance
must be normalized to the higher application rate of 0.4 lb ai/A
rate of 0.04 ppm. High uncertainty of MRL

estimate due to small dataset and high level of censoring.

Residues (mg/kg)

0.007

0.014

0.005 *

0.005 *

0.005 *

0.005 *

0.005 *

### Clothianidin Human Health Risk Assessment DP No. D418320

Page 19 of 19 Attachment 2 . International Harmonization



## Clothianidin (044309; 11 September 2012 ) (prepared for the Section 3 use on citrus )

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'

- 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

Fruit, Citrus, Group 10

- 10 0.6 * 0.07 citrus fruits (T)

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. MR Ls indicated as proposed have not been finalized by the CCPR and the CAC.

4 The source of the residue; T

- thiamethoxam; C

- clothianidin

* HED recommended tolerance for the Section 3 use on citrus.