Clothianidin Human Health Risk Assessment DP No. D418320

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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 Barcodes: D418320

Decision Nos.: 488203 Registration No.: 59639-150

Petition No.: 14FL03 Regulatory Action: Section 18

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

TXR No.: NA 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: Stacey Groce/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-

chloro-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 

application to the base of citrus trees as described in Table 1 below. The requested use is for 

Belay Insecticide (EPA Reg. No. 59639-150), 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 involved foliar, 

soil in-furrow, band drench, irrigation, and basal bark spray uses for the same product was

reviewed by HED (D395348, M. Doherty, 27 Sep 2012). That Section 3 petition was reviewed 
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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 that Section 3 registration risk assessment include very similar soil 

applications to that proposed in the current Section 18, and are shown in Table 2. The Section 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 

exposure 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 to 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, the Section 3 use on citrus as well as the other Section 3 uses on strawberry, 

pistachio, and tea evaluated in the last risk assessment, are still pending. The tolerances 

recommended for those uses are utilized in the dietary evaluation that supports this Section 18 

risk assessment, in order to not under estimate exposure and risk, if and when those uses are 

registered. The tolerance required to support the Section 18 use on citrus is 0.04 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; the only differences

in this assessment for citrus are: 1) the revised (higher) acute drinking water estimate provided 

by EFED; and 2) the deletion of the food handling establishment (FHE) residues of clothianidin 

resulting from thiamethoxam use in FHEs from the acute dietary analysis, per HED policy. The

revised acute dietary risk estimates are 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 dietary exposure estimate is used in evaluating the

short-, intermediate-, and long-term aggregate risks, those risk estimates remains unchanged 

from the last assessment.

Conclusions/Recommendations

There are no human health risk issues that would preclude granting the requested Section 18 use

on FL citrus, and establishing a temporary tolerance of 0.04 ppm for Fruit, citrus, Group 10-10. 

This tolerance should be established to support the 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 is appropriate and includes the required coverage and 

compliance statements; therefore, the tolerance expression in 40 CFR §180.586 should remain as 

it is currently written: “Tolerances are established for residues of the insecticide clothianidin, 

including its metabolites and degradates. Compliance with the tolerance levels specified below is 
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to be determined by measuring only clothianidin, (E)-N-[(2-Chloro-5-thiazolyl)methyl]-N′ -

methyl-N′′ -nitroguanidine, in or on the following raw agricultural commodities:”

An adequate 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 mixing the 

required dose in water and applying 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 irrigation or rainfall, for seven days following application. To 

ensure efficacy, the application site around the base of the tree should be as weed-free as 

possible.

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

Tree Size

Formulation

[EPA Reg. 

No.]

Max. Single 

Appl. rate

(lb ai/A)

Max. No. 

of Appl. / 

Year

Max.

Seasonal 

Appl. Rate 

(lb ai/A)

PHI 

(days)

Use Directions 

and Limitations

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/Ai)

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 proposed and evaluated in the Section 3 request for use of 

clothianidin on citrus, i.e., foliar, soil in-furrow, band drench, irrigation, and basal bark spray. 

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

2012).
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Table 2. Summary of Directions for Citrus Uses Previously Reviewed by HED for Clothianidin (D395348, M. 

Doherty, 27 Sep 2012).

Appl. timing,

type, and (equip.)

Formulation

[EPA Reg. No.]

Max. Single 

Appl. rate

(lb ai/A)

Max. No. 

of Appl. / 

Season

Max.

Seasonal 

Appl. Rate 

(lb ai/A)

PHI 

(days)

Use Directions 

and 

Limitations

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 (backpack 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). Doses 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 general 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 from a NOAEL of 25 mg/kg/day and a 100-fold factor that included 10x 

for inter-species extrapolations, 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 

result 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. 
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Acute Dietary Endpoint for the General Population: 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-species 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 Day 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 dose 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 cPAD 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 was 

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 intraspecies 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 was 

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 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 was selected because of the exposure duration, and 

because it is protective of the population of the most sensitive population, developing children. 

Although a dermal (route specific) toxicity study in rats 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 dermal 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 

was selected from the 2-generation reproduction study in the rat. The NOAEL is 9.8 mg/kg/day, 
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and the LOC is an MOE of 1000 (10x for inter-species extrapolation, 10x for intra-species 

variability, a 10x 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-specific 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 NonOccupational 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

UFA = 10X

UFH = 10X

SFFQPA =1X

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

UFA = 10X

UFH = 10X

SFFQPA = 1X

aRfD = 0.25

mg/kg/day

aPAD 0.25

mg/kg/day

Special neurotoxicity/pharmacology

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 

UFA = 10X

UFH = 10X

SFFQPA =1X

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

UFA= 10X

UFH= 10X

SFFQPA=1X

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)

UFA= 10X

UFH= 10X

SFFQPA=1X

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)

UFA= 10X

UFH= 10X

SFFQPA=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 observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 
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uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

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

SFFQPA = 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)

UFA= 10X

UFH= 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)

UFA= 10X

UFH= 10X

UFDB = 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. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity 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 samples. 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, grapefruit 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 following the soil drench treatment of oranges at the approximate 

rate of 90 grams 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 residue 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 proposed Section 18 use. The side-by-
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side foliar residue data are shown for comparison; other test sites that involved only foliar 

applications 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, 
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20-21, and 27-28 days were <0.01 ppm. (MRID No. 48600002).

Lemon. Soil 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 each 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 

application. 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. 48600003).

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 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.

Drinking Water Data

The Estimated 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. That 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.

Acute

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

The groundwater Estimated Drinking Water Concentration (EDWC) 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 postbreakthrough 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 5a 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. 
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Table 5a. 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 concentration 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 vegetables. These concentrations are presented in Table 

5b.

Table 5b. 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.

Dietary Exposure and Risk

D418668, 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 residues in 

drinking water. These inputs resulted in risk estimates that are, at most, 28% of the populationadjusted 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 dietary 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 involved foliar, 

soil in-furrow, band drench, irrigation, and basal bark spray uses for the same product and were

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 

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

included in this dietary evaluation in order not to underestimate exposure and risk, when those 
Clothianidin Human Health Risk Assessment DP No. D418320

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uses are registered. The tolerance required to support the Section 18 use on citrus is 0.04 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 (95th Percentile) Chronic

Exposure, mg/kg/day % aPAD Exposure, mg/kg/day % cPAD ARI

Total US Population 0.021330 9 0.007458 8 13.1

All Infants 0.052610 21 0.016683 17 5.87

Children 1-2 years old 0.069771 28 0.027256 28 3.60

Children 3-5 years old 0.049104 20 0.018444 19 5.31

Children 6-12 years old 0.024579 10 0.009165 9 10.7

Youth 13-19 years old 0.014586 6 0.005346 6 18.3

Adults 20-49 years old 0.015467 6 0.005822 6 16.8

Adults 50-99 years old 0.014821 6 0.006109 6 16.0

Female 13-49 years old 0.015759 6 0.005974 6 16.4

The population subgroup(s) with the highest exposure/risk estimates are shown in bold.

ARI = 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 uses 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 (postapplication 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, D397724, 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 dermal 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

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Table 7. Summary of Residential Handler Exposure and Risk Estimates for Clothianidin. M. Collantes D397724, 

15 August 2012.

Use Site Application Method Formulation Activity

Exposure Estimate,

mg/kg/day

(MOE)

ARI Dermal 1Inhalation

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

1ARI is calculated as the NOAEL ÷ Σ(Exposurei × LOC), where Exposurei 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 

applying 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 handwand 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.
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Table 8. Residential Exposure Scenario and Risk Estimates for Aggregate Assessment.

Scenario Life Stage Scenario Scenario 

ARI1

Combined 

ARI2

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

1Scenario ARIs are from Tables 4 and 5 for handler and post-application exposures, respectively.

2Combined ARI = 1÷Σ(1÷ARIScenario), where ARIScenario 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 notes 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 for evaluating the dietary exposure and risk. Acute and chronic 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 for Clothianidin.

Life Stage Residential Combined ARI1 Dietary ARI1 Aggregate ARI2

Adult 11 16.0 6.5

Children 1 to < 2 years old 1.8 3.60 1.2

1Residential 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.

2Aggregate ARI = 1÷(1÷ARIResidential + 1÷ARIDietary)

Occupational Risk

The previously evaluated occupational 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

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airblast) and are not of concern. A summary of the occupational exposure risk estimates is 

provided in Table 10 below.
Clothianidin Human Health Risk Assessment DP No. D418320

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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 PHEDB+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

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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. The diluent volume 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 lb 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. For backpack sprayer, the same unit dermal and inhalation unit exposures were 

used for both WDG and SC formulations. 

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/day). 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.
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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 11. 

The short-term post-application dermal MOE was 22,000, which is significantly greater than 

HED’s level of concern (LOC) of 100, and is not of concern. The post-application dermal 

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 postapplication exposure for workers from the use of soil drench treatments are expected to be much 

lower than those associated with post-application exposure resulting from foliar uses. Postapplication exposure from fruit harvesting is considered protective of potential exposure 

following soil drench treatment, and is not of concern.

Table 11. 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/cm2) 1

Transfer

Coefficient 

(cm2/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) = Application rate (lb ai/A) * (1- Daily dissipation rate)t * Conv. factor, 

4.54E+8 μg/lb * Conv. factor, 2.47E-8 A/cm2 * Residue transfer rate (20% default) after treatment.

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

3. Dermal dose (mg/kg/day) = [DFR * TC * Conv. factor, 0.001 mg/μg * Dermal absorption factor (1%) * 8 

hrs/day] / Body weight (69 kg). 

4: Margin of Exposure, short-term= Short-term dermal NOAEL (9.8 mg/kg/day) / Dermal dose (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, Pistachio, 

Citrus, and Tea. Evaluation of Residue Chemistry Data.

D418668 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).

D397690. 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 Application.
Clothianidin Human Health Risk Assessment DP No. D418320

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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

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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 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

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. MRLs 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.