UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

 

MEMORANDUM

Date: 1 February 2012

SUBJECT: Clothianidin – Human Health Risk Assessment for 

Rice, Seed Treatment on Leafy Vegetables, Increased Application Rate for 

Vegetables, and Expanded Uses on Fruiting Vegetables and Pome Fruit

PC Code: 044309

MRID Nos.: 48364801, 48364802, 48438001

Petition No.: 1F7832

Assessment Type: Single Chemical, Aggregate

TXR No.: None

Decision Nos.: 444551, 447268

FROM: Michael A. Doherty, Ph.D., Senior Chemist

Alan Levy, Ph.D., Toxicologist

Suku Oonnithan, Biologist

Shih-Chi Wang, Ph.D., Biologist

Risk Assessment Branch II

Health Effects Division (7509P)

THROUGH: Margarita Collantes, Biologist

Zaida Figueroa, Industrial Hygenist

Elizabeth Holman, Chemist

Karlyn Middleton, Toxicologist

Richard A. Loranger, Senior Scientist

Christina Swartz, Branch Chief

Risk Assessment Branch II

Health Effects Division (7509P)

TO: Marianne Lewis/V

Insecticide-Rodenticide Branch 

Registration Division (7505P)

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND

 POLLUTION PREVENTION

Human Health Risk Assessment for Requested Foliar 

Rice, Seed Treatment on Leafy Vegetables, Increased Application Rate for 

Vegetables, and Expanded Uses on Fruiting Vegetables and Pome Fruit

DP Barcode: D387290, 

MRID Nos.: 48364801, 48364802, 48438001 Registration Nos.: 59639

Petition No.: 1F7832 Regulatory Action: Section 3

Single Chemical, Aggregate Registration Case No.: 7620

CAS No.: 210880-92-5

Decision Nos.: 444551, 447268 40 CFR 180.586

A. Doherty, Ph.D., Senior Chemist

Alan Levy, Ph.D., Toxicologist

Suku Oonnithan, Biologist

Chi Wang, Ph.D., Biologist

Risk Assessment Branch II

Health Effects Division (7509P)

Margarita Collantes, Biologist

Zaida Figueroa, Industrial Hygenist

Elizabeth Holman, Chemist

Karlyn Middleton, Toxicologist

Richard A. Loranger, Senior Scientist

Christina Swartz, Branch Chief

Risk Assessment Branch II

Health Effects Division (7509P)

Marianne Lewis/Venus Eagle, RM 01

Rodenticide Branch 

Registration Division (7505P)

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF CHEMICAL SAFETY AND

POLLUTION PREVENTION

Requested Foliar Uses on 

Rice, Seed Treatment on Leafy Vegetables, Increased Application Rate for 

Vegetables, and Expanded Uses on Fruiting Vegetables and Pome Fruit. 

D387290, D389529

: 59639-150, 59639-151

Regulatory Action: Section 3

Registration Case No.: 7620
Clothianidin Human Health Risk Assessment DP No. D387290, D389529

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1.0 Executive Summary................................................................................................................. 4

2.0 HED Recommendations........................................................................................................... 4

2.1 Data Deficiencies/Conditions of Registration ..................................................................... 4

2.2 Tolerance Considerations..................................................................................................... 5

2.2.1 Enforcement Analytical Method................................................................................... 5

2.2.2 International Harmonization ......................................................................................... 5

2.2.3 Recommended Tolerances............................................................................................ 5

2.2.4 Revisions to Petitioned-For Tolerances........................................................................ 5

2.3 Label Recommendations...................................................................................................... 5

3.0 Introduction.............................................................................................................................. 6

3.1 Chemical Identity................................................................................................................. 6

3.2 Physical/Chemical Characteristics....................................................................................... 6

3.3 Pesticide Use Pattern............................................................................................................ 7

3.4 Anticipated Exposure Pathways ..................................................................................... 7

3.5 Consideration of Environmental Justice ......................................................................... 7

4.0 Hazard Characterization and Dose-Response Assessment.................................................. 8

4.1 Toxicology Studies Available for Analysis.................................................................... 8

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME).................................... 8

4.2.1 Dermal Absorption...................................................................................................... 9

4.3 Toxicological Effects...................................................................................................... 9

4.4 Safety factor for Infants and Children (FQPA Safety Factor)........................................ 9

4.4.1 Completeness of the Toxicology Database............................................................... 10

4.4.2 Evidence of Neurotoxicity ........................................................................................ 10

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ........... 10

4.4.4 Residual Uncertainty in the Exposure Database....................................................... 11

4.5 Toxicity Endpoint and Point of Departure Selections.................................................. 11

4.5.1 Dose-Response Assessment...................................................................................... 11

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment.......... 11

4.5.3 Cancer Classification and Risk Assessment Recommendation................................ 11

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment............................................................................................................................ 11

5.0 Dietary Exposure and Risk Assessment ............................................................................ 13

5.1 Metabolite/Degradate Residue Profile.......................................................................... 13

5.1.2 Residues of Concern Summary and Rationale.......................................................... 13

5.2 Food Residue Profile..................................................................................................... 13

5.3 Water Residue Profile ................................................................................................... 14

5.4 Dietary Risk Assessment .............................................................................................. 15

5.4.1 Description of Residue Data Used in Dietary Assessment....................................... 15

5.4.2 Percent Crop Treated Used in Dietary Assessment .................................................. 15

5.4.3 Dietary Exposure and Risk Estimates....................................................................... 15

6.0 Residential (Non-Occupational) Exposure/Risk Characterization .................................... 16

6.2 Residential Bystander Post-Application Inhalation Exposure...................................... 19

6.3 Spray Drift .................................................................................................................... 19

7.0 Aggregate Exposure/Risk Characterization....................................................................... 20

7.1 Acute Aggregate Risk................................................................................................... 20

7.2 Short- and Intermediate-Term Aggregate Risk......................................................... 20
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7.3 Chronic Aggregate Risk................................................................................................ 21

7.4 Cancer Aggregate Risk ................................................................................................. 21

8.0 Cumulative Exposure/Risk Characterization..................................................................... 21

9.0 Occupational Exposure/Risk Characterization .................................................................. 22

9.1 Short- and Intermediate-Term Handler Risk ................................................................ 22

9.2 Short- and Intermediate-Term Post-Application Risk .................................................. 25

10.0 References.......................................................................................................................... 26

Appendix A. Toxicology Profile.................................................................................................. 27

A.1. Toxicology Data Requirements ....................................................................................... 27

a The subchronic inhalation study is required. HED has recommended that this study be called 

in to support registration review. As discussed in Section 2.1, it is not being required to 

support the requested uses. ....................................................................................................... 27

A.2. Toxicity Profiles............................................................................................................... 28
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1.0 Executive Summary

Valent U.S.A. Corporation, one of the registrants for clothianidin, has submitted two petitions 

regarding expanded uses of the insecticide. The first, PP# 1F7832, requests the following three 

actions: (1) register clothianidin for foliar and seed treatment uses on rice; (2) increase the 

application rate from 4 fl. oz/A/application to 6 fl. oz/A/application for vegetables; and (3) 

modify the crop listing for fruiting vegetables (Crop Group 8) and pome fruits (Crop Group 11) 

to include the most recent definitions for those crop groups (08-10 and 11-10, respectively). The 

second is a request to register a seed treatment for leafy green vegetables (Crop Subgroup 4A).

There is no petition number associated with the second request (i.e., there are no tolerance 

actions associated with the request). The end-use products for these actions are V-10170 5 FS 

(EPA Reg. No. 59639-151) for the seed treatment uses and V-10170 2.13 SC (EPA Reg. No. 

59639-150) for the foliar uses.

HED has evaluated the toxicological and residue chemistry databases associated with 

clothianidin, and has determined that there are no human health risk issues that would preclude 

granting the requests.

2.0 HED Recommendations

Rice. HED recommends granting the requested registrations and establishing a permanent 

tolerance for residues of clothianidin in/on rice, grain at 0.01 ppm. Upon establishment of the 

permanent tolerance, the existing time-limited tolerance can be removed from the CFR.

Label Amendment – Foliar Application Rate to Vegetables. HED recommends amending the 

submitted proposed label for V-10170 2.13 SC to allow applications of up to 6 fl. oz of product 

(0.1 lb a.i.) per acre per application. The maximum allowable application per acre per season 

should not be increased. The rate increase does not require changes to existing tolerance levels.

Expansion of Crops for Groups 8 and 11. No new data have been submitted regarding this 

request. Data requirements for these crop groups have already been met. The revised definitions

of these groups did not result in changes to the representative commodities relative to the 

previous definition. HED recommends expanding the crops listed on the label to those defined 

as Crop Group 8-10 and Crop Group 11-10 in 40 CFR 180.41. 

Seed Treatment of Leafy Green Vegetables (Crop Subgroup 4A). HED recommends amending 

the submitted proposed label for V-10170 5 FS to include crops in Crop Subgroup 4A.

Tolerances for residues of clothianidin in/on these crops are already established and are based on 

foliar applications. No revisions to the current tolerances are necessary to accommodate the 

requested seed-treatment use.

2.1 Data Deficiencies/Conditions of Registration

There are no data deficiencies or conditions of registration associated with the requested actions. 

The toxicological database for clothianidin lacks a subchronic inhalation study. HED has 

recommended that this study be required to support registration review; it is not required at this 
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time. Currently, all inhalation margins of exposure (MOEs) associated with residential scenarios 

are greater than or equal to 170,000 and indicate that a subchronic inhalation study will have no 

significant impact on our conclusions that residential and aggregate risks are not of concern. 

Occupational inhalation MOEs range from 340 to over 170,000. The MOEs at the low end of 

the range are associated with secondary handlers of pelletized lettuce seed or multiple-activity

seed treatment scenarios. HED does not have inhalation unit exposure estimates that are specific 

to either low-acreage crops, such as lettuce, or pelletized seed treatment. The unit exposure 

values used to assess inhalation exposure during secondary handling of pelletized lettuce seed 

are based on information from standard seed treatment of high-acreage crops (e.g., corn, wheat, 

soybeans) and are considered to be extremely conservative when used to assess the lettuce 

scenarios. Similarly, the assumptions used to assess multiple-activity seed treatment scenarios 

result in very conservative estimates of exposure and risk. For these reasons, HED has 

determined that it is not appropriate in this case to apply an additional uncertainty factor to 

account for the lack of the subchronic inhalation study.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

The current tolerance enforcement method, a liquid chromatography tandem mass spectroscopy 

(LC-MS/MS) method, is available to enforce tolerances for residues of clothianidin.

2.2.2 International Harmonization

There are no international harmonization issues associated with these actions.

2.2.3 Recommended Tolerances

Granting the requests regarding the increased application rate to vegetables and the seed 

treatment of leafy green vegetables does not involve any changes to existing tolerances for 

residues of clothianindin. For the requests regarding uses on rice, fruiting vegetables, and pome 

fruit, HED recommends the following changes in the Code of Federal Regulations:

 40 CFR 180.586(a)(1)

o Add “Rice, grain” at 0.01 ppm to the tolerance table,

o Change “Fruit, pome” to “Fruit, pome, group 11-10,” and

o Change “Vegetables, fruiting, group 8” to “Vegetables, fruiting, group 8-10.”

 40 CFR 180.586(a)(2)

o Remove this section completely as it is no longer needed.

2.2.4 Revisions to Petitioned-For Tolerances

None.

2.3 Label Recommendations

None.
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3.0 Introduction

3.1 Chemical Identity

Table 3.1. Clothianidin Nomenclature.

Compound

Common name Clothianidin

Company experimental name TI-435, V-10066

IUPAC name (E)-1-(2-Chloro-1,3-thiazol-5-ylmethyl)-3-methyl-2-nitroguanidine

CAS name (E)-N-[(2-Chloro-5-thiazolyl)methyl]-N’-methyl-N”-nitroguanidine

CAS registry number 210880-92-5 (formerly 205510-53-8)

Chemical class Neonicotinoid

End-use products V-10170 5 FS (EPA Reg. No. 59639-151), 

V-10170 2.13 SC (EPA Reg. No. 59639-150)

Known impurities of concern None

3.2 Physical/Chemical Characteristics

The vapor pressure and octanol/water partition coefficient for clothianidin (Table 3.2) suggest 

that there is low potential for exposure to this chemical in the vapor phase and low potential for 

bioaccumulation. The physicochemical properties of clothianidin do not provide much insight 

regarding the potential for dermal absorption of this compound.

Table 3.2. Physicochemical Properties of Clothianidin.

Parameter Value Reference

Melting point, oC 176.8 D335355, W. Drew, 

Molecular wt. 10/16/07 249.68

pH at 23oC 6.24 (1% solution/suspension)

Density, g/cm31.61 (PAI)*, 1.59 (TGAI)

Water solubility, g/L at 20oC 0.327

Solvent solubility, g/L at 25oC Acetone 15.2 Dichloromethane 1.32

Ethyl acetate 2.03 Heptane <0.00104

Methanol 6.26 Octanol 0.938

Xylene 0.0128

Vapor pressure (at 25oC) 1.3 x 10-10 Pa, 9.75 x 10-13 mm Hg

Dissociation constant, pKa at 20oC 11.09

Octanol/water partition 

coefficient, Log(KOW) at 25oC

0.7

UV/visible absorption spectrum 

(Maximum, nm)

265.5 (acidic or neutral)

246.0 (basic)

*PAI = Purified Active Ingredient; TGAI = technical grade active ingredient.

S

N

N

H

N

NH

Cl

H C3

NO2
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3.3 Pesticide Use Pattern

Table 3.3.1. Proposed Use Pattern for Clothianidin as Foliar Treatments for Rice.

Reg. No., Form type, &

AI or AE Crop Applic. Timing, Type, and Equip. 

Max. Applic. 

Rate, 

1

lb ai/A

Max. No. 

Applic. per 

Season 2

Max. Seasonal 

Applic. Rate,

lb ai/A

PHI, 

3

days

EPA Reg. No. 59639-150, 

V-10170 2.13 SC

Insecticide,

23.60% ai, Liquid

Rice Foliar Application: 

Ground + Aerial 0.075 1 0.075 Not Applicable

1

Rate = Maximum application rates as specified on proposed labels.

2 Maximum number of applications allowed on the proposed label.

3

PHI = Pre-harvest Interval. For this use, application may not occur after tillering has initiated (BBCH Growth Stage 21). 

Table 3.3.2. Proposed Application Rate of Clothianidin on Rice and Leafy Green Vegetable Seeds.

Product Vegetable 

Crops 1 Application Method

Max. Appl. 

Rate, mg 

ai/seed

No. of seeds/lb

(representative 

crops) 

lb ai/lb

of seed

EPA Reg. No.

59639-151,

V-10170 5 FS,

Insecticide,

47.8% ai, Liquid

Rice (dry-seeded)

Commercial 

equipment utilizing 

standard liquid or 

slurry treaters

Not 

Applicable

Not 

Applicable 0.00075

Short-season crops (Parsley) Liquid Open-Pour 

Mix/Load System 

0.05 454,000 0.05

Spinach group (Spinach) 0.15 45,360 0.015

Full-season crops (Head lettuce) Pelletized 0.4 480,000 0.42

1.5 1.59

1 Representative crops that have seed weights in ExpoSAC Policy #15 are in parenthesis. 

3.4 Anticipated Exposure Pathways

Clothianidin is registered for use on a number of agricultural row and orchard crops, as well as 

turf and ornamental plants in a residential setting. As a result of these uses, humans may be 

exposed to clothianidin in their diet and from activities on golf courses, lawns, and around home 

exteriors. Application of clothianidin to agricultural crops may result in clothianidin migration 

to surface and/or groundwater sources of drinking water, making drinking water a potential 

pathway of exposure. Persons involved in agricultural occupations may be exposed to 

clothianidin during handling of clothianidin-containing products prior to application, during 

application, and during post-application activities.

This risk assessment addresses these exposure pathways as well as the potential for aggregate 

exposures from multiple pathways. 

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 
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procedures. In line with OPP policy, HED estimates risks from pesticide exposures to 

population subgroups that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the USDA under the Continuing 

Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all 

registered food uses of a pesticide. These data are analyzed and categorized by subgroups based 

on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to 

assess dietary exposure to smaller, specialized subgroups and exposure assessments are 

performed when conditions or circumstances warrant. Whenever appropriate, non-dietary

exposures based on home use of pesticide products and associated risks for adult applicators and 

for toddlers, youths, and adults entering or playing on treated areas after application are 

evaluated. Further considerations are currently in development as OPP has committed resources 

and expertise to the development of specialized software and models that consider exposure to 

bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific 

subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

Clothianidin is a major metabolite of the active ingredient thiamethoxam and is a systemic 

insecticide that belongs to the nitroguanidine sub-class of neonicotinoid compounds, which have 

agonistic activity on nicotinergic acetylcholine receptors (nAChR). It enters through the roots 

and cotyledons of newly germinating seedlings and protects below- and above-ground plant parts 

from insect damage.

4.1 Toxicology Studies Available for Analysis

The toxicological database for clothianidin is complete, with the exception of a subchronic 

inhalation study. The scientific quality of the available studies is relatively high and the toxicity

profile of clothianidin can be characterized for most effects, including potential carcinogenic, 

mutagenic, developmental and reproductive, neurotoxic and immunotoxic effects. The following 

studies were submitted: acute and subchronic neurotoxicity; subchronic in rats, mice and dogs; 

subchronic dermal, chronic/carcinogenicity in rats; carcinogenicity in mice; chronic in dogs; 

developmental in rats and rabbits; developmental neurotoxicity; reproduction; mutagenicity 

battery; metabolism (rats and mice); dermal penetration (monkeys) and immunotoxicity as well 

as developmental immunotoxicity.

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

In rats, clothianidin was readily absorbed and excreted within 96 hours following a single dose or 

repeated low doses, but at a high dose, absorption became biphasic and was saturated. The 

studies suggest that a multiple exposure regimen did not affect the absorption/excretion 

processes. There was rapid absorption and distribution of administered radioactivity to all 

organs and tissues followed by rapid excretion primarily via the urine (>89% of dose) and to a 

lesser extent, the feces, with reduction to background levels in most tissues and organs within 24 

hours. There was a somewhat greater rate of absorption and elimination in females. Excretory

patterns did not exhibit gender-related variability but reflected the delayed absorption in the 
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high-dose group. The metabolites identified (primarily oxidative demethylation products and 

cleavage products of the nitrogen-carbon bond between the nitroimino and thiazolyl moieties) 

were consistent with Phase I processes of oxidation, reduction and hydrolysis.

In mice, clothianidin was readily absorbed and excreted within 168 hours following a single low 

dose. Urine was the major route of excretion. Neither clothianidin nor its metabolites appeared 

to exhibit potential for bioaccumulation. Excretory patterns did not exhibit gender-related 

variability. The major residues in both urine and feces were the parent compound (clothianidin) 

and TZNG [N-(2-chlorothiazol-5-ylmethyl)-N’-nitroguanidine], which resulted from Ndemethylation of clothianidin.

4.2.1 Dermal Absorption

In a dermal absorption study in monkeys, absorption was calculated as 0.24% (±0.11%). This 

value was determined by adding the radioactivity recovered from urinary excretion, fecal 

excretion and from cage/pan/chair wash debris. Adjustment of the direct absorption 

determination was not necessary because recovery from the dermal dose was >90%. A value of 

1% dermal absorption has been recommended as appropriate for use in risk assessment. This 

estimation takes into account any variability that would have likely occurred with testing several

dose levels. The mouse single-dose and rat single- and multiple-dose metabolism studies 

indicated that oral absorption was in the range of 90% or greater. Therefore, any extrapolation 

from the oral to the dermal route using the dermal absorption factor is not likely to underestimate 

anticipated adverse effects.

4.3 Toxicological Effects

Clothianidin and its metabolites have relatively low (Category III or IV) acute toxicity via oral, 

inhalation and dermal routes of exposure in the rat and there is no evidence of dermal 

sensitization or eye irritation with the exception of the clothianidin-triazan intermediate, which is 

a dermal sensitizer. The other exceptions were for technical clothianidin and the TMG 

metabolite via the oral route in the rat, both of which were toxicity Category II.

Clothianidin induces some effects that are similar to other neonicotinoid insecticides, particularly 

on the liver, hematopoietic system and kidneys. For a complete description of toxicological 

effects, see D355373 (M. Doherty et al., 13 August 2009).

The toxicological database lacks a subchronic inhalation study. Based on the use pattern, 

inhalation exposure is anticipated; therefore, a subchronic (21/28-day) inhalation toxicity study

(870.3465) is required and will be called in to support registration review (D391496, M. Doherty 

et al., 8 December 2011). As discussed in Section 2.1, a database-uncertainty factor is not being 

used to account for the lack of the subchronic inhalation study. 

4.4 Safety factor for Infants and Children (FQPA Safety Factor)

HED recommends that the 10X FQPA safety factor for the protection of infants and children be 

reduced to 1X.
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4.4.1 Completeness of the Toxicology Database

The database for evaluating in utero or postnatal susceptibility is adequate for evaluation of the 

FQPA safety factor. The following acceptable studies are available:

Developmental toxicity studies in rats and rabbits,

Two-generation reproduction study in rats,

Developmental neurotoxicity study in rats, and

Developmental immunotoxicity study in rats.

4.4.2 Evidence of Neurotoxicity

Clothianidin was tested in the following rat neurotoxicity studies: acute, 90-day and 

developmental. In addition, a neurotoxicity/pharmacology single dose study was performed in 

mice. 

In the acute neurotoxicity study, decreased arousal, motor activity and locomotor activity were 

observed at the LOAEL; however, in the subchronic study, the LOAEL was based on decreased 

body weights, body weight gains and food consumption with no evidence of neurotoxicity.

In the developmental neurotoxicity study, the maternal effects observed included decreased body

weights, body weight gains and food consumption at the high dose. In offspring decreased body 

weights, body weight gains, motor activity and acoustic startle response were seen at a lower 

dose.

In the single dose mouse study, transient signs of decreased spontaneous motor activity, tremors 

and deep respirations were observed.

No signs of neurotoxicity were observed in the remainder of the toxicity studies.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

While no evidence of increased quantitative or qualitative susceptibility was observed in the 

developmental rat or rabbit studies, increased quantitative susceptibility was seen in both the 

developmental neurotoxicity and rat reproduction studies. In both studies, offspring toxicity was 

seen at doses lower than doses that caused maternal toxicity. However, HED determined that the 

degree of concern for the developmental neurotoxicity and reproduction studies is low and there 

are no residual uncertainties for pre- and/or postnatal toxicity because the observed effects are 

well characterized and there are clear NOAELs/LOAELs determined for toxic effects seen.

Immunotoxicity and developmental immunotoxicity studies were performed and neither showed 

any changes in the immune system parameters examined.
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4.4.4 Residual Uncertainty in the Exposure Database

The assessment for clothianidin is based on high-end assumptions regarding dietary and nondietary exposures. As such, the exposure assessment is unlikely to underestimate actual 

exposures to clothianidin.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

For a complete discussion of the dose-response assessment and the points of departure for use in 

risk assessment, please see D355373, M. Doherty et al., 13 August 2009.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

For all durations, oral, dermal, and inhalation exposures may be aggregated because of the 

selection of a common endpoint for these routes of exposure.

4.5.3 Cancer Classification and Risk Assessment Recommendation

In accordance with the EPA’s Final Guidelines for Carcinogen Risk Assessment (March, 2005), 

clothianidin is classified as “Not Likely to be Carcinogenic to Humans.” 

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

Table 4.5.4.1. 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 

for Risk 

Assessment

Study and Toxicological Effects

Acute Dietary

Females age 

13-49

NOAEL = 

25 mg/kg/day

UFA = 10X

UFH = 10X

SFFQPA =1

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 = 1

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 =1

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 and 

intermediate term)

NOAEL= 

9.8 mg/kg/day

UFA= 10X

UFH= 10X

SFFQPA=1

LOC= 100 2-Generation reproduction study 

LOAEL= 31.2 mg/kg/day based on 

decreased body weight gains and delayed 

sexual maturation, decreased absolute thymus 
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Table 4.5.4.1. 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 

for Risk 

Assessment

Study and Toxicological Effects

weights in F1 pups 

Dermal (all 

durations) 

Oral study 

NOAEL= 

9.8 mg/kg/day

(dermal 

absorption = 1%)

UFA= 10X

UFH= 10X

SFFQPA=1

LOC= 100 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 

considered 

equivalent to oral 

toxicity)

UFA= 10X

UFH= 10X

SFFQPA=1

LOC= 100 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). FQPA SF = FQPA Safety Factor. PAD = 

population adjusted dose (a = acute, c = chronic). RfD = reference dose. LOC = level of concern. N/A = not 

applicable.

Table 4.5.4.2. 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 

for Risk Assessment

Study and Toxicological Effects

Dermal (all 

durations) (Adults)

Oral study 

NOAEL= 

9.8 mg/kg/day

(dermal 

absorption = 

1%)

UFA= 10X

UFH= 10X

SFFQPA=1

LOC= 100 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 

considered 

equivalent to 

oral toxicity)

UFA= 10X

UFH= 10X

SFFQPA=1

LOC= 100 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 
Clothianidin Human Health Risk Assessment DP No. D387290, D389529

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sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = 

population adjusted dose (a = acute, c = chronic). RfD = reference dose. LOC = level of concern. N/A = not 

applicable.

5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile

The metabolism of clothainidin in primary crops, rotational crops, livestock, and rats was 

evaluated by HED in 2003. The clothianidin risk assessment team concurs with the previous 

findings regarding the residues of concern for risk assessment and tolerance enforcement (Table 

5.1.2).

The metabolism of clothianidin is complex, with a few major (> 10% of the total radioactive 

residues) and numerous minor metabolites. The list of terminal residues is fairly consistent 

across plants, goats, hens, and rats, although the designation of major vs. minor metabolites 

varies depending on the test species. 

5.1.2 Residues of Concern Summary and Rationale

Table 5.1.2. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance 

Expression.

Matrix Residues included in Risk Assessment Residues included in 

Tolerance Expression

Plants Primary Crop Crops except Leafy and Root/Tuber Vegetables: Parent 

Leafy and Root/Tuber Vegetables: Parent + TMG

Parent

Rotational Crop Parent, TZNG, MNG Parent

Livestock Ruminant Parent, TZU, TZG, TZNG, ATMG-Pyr Parent

Poultry Parent, TZU, TZG, TZNG, ATG-Ac Parent

Drinking Water Parent Not Applicable

Based on the available metabolism studies, HED concluded that the nature of the residue has 

been adequately delineated, and that parent only is the residue of concern (ROC) to be used for

the tolerance expression for primary crops. HED had previously determined that future new uses 

on root crops and/or leafy vegetables will require analysis for residues of TMG along with parent 

in field trial samples and that TMG should be included as a ROC for risk assessment if 

significant levels of TMG were observed. In a previous submission, residues of TMG were 

shown to occur in leafy vegetables at levels approximately 10-fold below those of clothianidin.

5.2 Food Residue Profile

The petitioner has submitted data, from studies conducted at an exaggerated rate, depicting 

residues of clothianidin in/on rice grain following foliar or seed treatment applications of 

clothianidin. No new data were submitted to support the other requests (increased application 

rate for vegetables, seed treatment of leafy vegetables, and expansion for crop groups 8 and 11 to 

include the 2010 definitions); rather, these requests are supported by previously

submitted/reviewed data. In summary, the uses on rice resulted in no quantifiable residues; the 

requested rate increase for vegetables brings the application rate up to the level used in the field 
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trials (reviewed in 2009); residues resulting from seed treatment of leafy vegetables are expected 

to be significantly less than those resulting from foliar application (a registered use pattern), 

without any increase to the overall field loading of clothianidin; and the expansions from Crop 

Group 8 to Crop Group 8-10 and from Crop Group 11 to Crop Group 11-10 are supported by the 

data submitted to originally register those uses and establish tolerances.

A full discussion of the residue chemistry evaluation can be found in D395799 (M. Doherty, 1 

February 2012).

5.3 Water Residue Profile

Based on available data, clothianidin is persistent under most field and laboratory conditions and 

is mobile to highly mobile based on laboratory adsorption tests. 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. The 

assessment also addresses residues resulting from the seed treatment of leafy vegetables. 

EDWCs from that use are significantly lower than those associated with the use on rice (Table 

5.3).

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.

The concentrations predicted in release water from rice paddies treated with clothianidin were 

compared to two (2) aquatic field dissipation studies - one in California, one in Louisiana - that 

are currently under review by the Agency (MRID 48364804, MRID 48364803). The maximum 

concentration at day zero, pre-irrigation, was 210 ppb in the Louisiana plot cropped with rice. 

Clothianidin residues quickly dissipated to an average of 74.1 ppb three days after application, 

and further dissipated to 0.7 ppb 28 days after application. The California plots show similar 

dissipation results with a maximum clothianidin concentration of 51.9 ppb at day zero, quickly 

dissipating to an average of 1.1 ppb ten days after application in the plots cropped with rice. 

These interim results show that Tier I rice estimate may under estimate the initial exposure in the 

rice paddy soon after application, but it is a conservative estimate of clothianidin concentrations 

in release water shortly after application occurs.

Table 5.3. Tier I EDWCs for drinking water risk assessment based on the proposed clothianidin use on rice and 

leafy vegetables

Use (application rate, lbs a.i./A) Model Acute Chronic

Surface water drinking water sources, downstream 

of rice paddy (0.084 lb a.i./A) Tier I Rice Model (v1.0) 72 ppb <72 ppb

Leafy vegetables (including brassica) (0.05 lb a.i./A) FIRST 4.0 ppb 2.2 ppb

The EDWC of 72 ppb has been used to account for residues of clothianidin in both the acute and 

chronic dietary risk assessments.
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5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

The acute and chronic dietary assessments (D395798, M. Doherty, 1 February 2012) rely on 

tolerance-level residues for all crops with registered and/or requested clothianidin uses. There 

are a number of crops for which uses of both clothianidin and thiamethoxam have been 

registered. The labels for the various end-use products containing these active ingredients 

prohibit the application of both active ingredients to the same crop during a growing cycle. Due 

to that restriction and the assumption of 100% crop treated, a single value reflecting the greatest 

clothianidin residue from either active ingredient has been used for crops listed for use with both 

active ingredients (versus combined estimates from clothianidin and from thiamethoxam). 

Generally, this assessment uses the established or recommended clothianidin tolerance for crops 

having tolerances for both compounds (Subgroup 13G, based on observed clothianidin residues 

in thiamethoxam strawberry field trials, being the exception). For foods with thiamethoxam 

tolerances but without clothianidin tolerances, maximum residues of clothianidin observed in 

thiamethoxam field trials have been used in these assessments.

5.4.2 Percent Crop Treated Used in Dietary Assessment

Both the acute and chronic dietary assessments assumed that all crops with uses of either 

clothianidin or thiamethoxam were treated (i.e., 100% crop treated).

5.4.3 Dietary Exposure and Risk Estimates

The results of the screening-level dietary exposure assessments are summarized in Table 5.4.3. 

For both the acute and chronic analyses, the greatest exposure estimate is for the population 

subgroup Children 1-2 years old. Risk estimates for this subgroup are 24% aPAD and 21% 

cPAD. These estimates are well below HED’s level of concern (typically 100% of the PAD).

Clothianidin has been classified as “Not Likely to be Carcinogenic to Humans;” therefore, there 

are no cancer risks associated with exposure to clothianidin.

Table 5.4.3. Summary of Dietary Exposure and Risk Estimates for Clothianidin.

Population Subgroup Acute (95th Pecentile of Exposure) Chronic

Exposure, mg/day Risk, % aPAD Exposure, mg/day Risk, % cPAD

U.S. Population (total) 0.017373 7 0.006107 6

All infants (< 1 year) 0.054584 22 0.017497 18

Children 1-2 yrs 0.059972 24 0.020868 21

Children 3-5 yrs 0.041530 17 0.014497 15

Children 6-12 yrs 0.020012 8 0.007335 8

Youth 13-19 yrs 0.012230 5 0.004312 4

Adults 20-49 yrs 0.012257 5 0.004636 5

Adults 50+ yrs 0.011920 5 0.004882 5

Females 13-49 yrs 0.012765 5 0.004737 5

The population subgroup(s) with the highest exposure/risk estimates are shown in bold.
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6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no new or proposed residential uses associated with this action. This assessment 

provides the most recent residential exposure assessment which includes revised residential 

handler exposure estimates for use on turf (see assessments by G. Bangs, 12/1997, and M. Dow, 

D296176, 2/24/2004) and tree trunks (S. Wang, D375369, 9/30/2010). No chemical specific unit 

exposure data were available for this assessment; therefore, the Occupational Pesticide Handler 

Unit Exposure Surrogate Reference Table (June 2011) and the Outdoor Residential Exposure 

Task Force (ORETF) study (MRID 44972201) unit exposures were used to estimate handler 

exposures. HED’s level of concern (LOC) is equal to a margin of exposure (MOE) of 100 for 

residential exposure. 

Handler dermal, inhalation and total exposure scenarios resulted in MOEs greater than 100 and 

therefore are not of concern. Although a point of departure from an oral study was used to assess 

the handler inhalation risks, the calculated inhalation MOEs are all >170,000, thus providing a

suitable margin of safety to account for any uncertainties in the route-to-route extrapolation. 

Handler exposure and risk estimates are summarized in Table 6.1. Residential postapplication 

exposure estimates for use of clothianidin on turf resulted in MOEs greater than 100 and,

therefore, are not of concern. HED does not assess postapplication exposure resulting from use 

on ornamental plants as it is not likely that individuals would have continuous contact with such 

sites on a regular basis. Postapplication exposure resulting from treated ornamentals is expected 

to be minimal and protected by the broadcast turf scenario assessment. Postapplication exposure 

and risk estimates are summarized in Table 6.2 
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Table 6.1: Residential Handler Exposure and Risk Estimates for Clothianidin

Scenario

Unit Exposure,

1

mg/lb ai

Application 

Rate 2 Amount 

Treated 3

Dose, mg/kg/day MOE 7

Dermal Inhalation Dermal 4Inhalation 5 Total 6 Dermal Inhalation Total

Granular Push-Type Spreader

Turf

Arena 0.5G 

Reg. No. 59639-156

0.67 0.00088 0.4

lb ai/A 0.5 A 0.00002233 0.00000293 0.0000253 440,000 3,300,000 390,000

Hose-End Sprayer

Fruit trees & ornamentals

Arena 50 WDG

Reg.No. 59639-156

39 0.0015 0.15

lb ai/gal.

5 gals

0.004875 0.00001875 0.004894 2000 520,000 2000

Hand-Held Pump Sprayer 

Fruit trees & ornamentals

Arena 50 WDG

Reg.No. 59639-156

56 0.0038 0.0004

lb ai/gal. 0.0000187 0.000000126 0.000018 520,000 77,000,000 520,000

Hose-End Sprayer

Lawn

Arena 50 WDG

Reg.No. 59639-156

11 0.017 0.4

lb ai/A 0.5 A 0.000367 0.0000566 0.000423 27,000 170,000 23,000

1. All scenarios use Occupational Residential Exposure Task Force (ORETF) Study Data (MRID 449722-01)

2. Label application rate = 0.4 lb ai/acre for turf ; 0.15 lb ai/gal. for tree trunks; and 0.0004 lb ai/gal for ornamentals

3. Policy 12: Recommended Revision to the SOPs for Residential Exposure Assessment

4. Dermal Dose (mg/kg/day) = dermal unit exposure (mg/lb ai) × application rate (lb ai/A or gal.) × amount treated × DAF (.01) ÷ body weight (60 kg).

5. Inhalation dose (mg/kg/day) = inhalation unit exposure (mg/lb ai) × application rate (lb ai./A or gal) × amount treated ÷ body weight (60 kg).

6 Total Dose = Dermal Dose (mg/kg/day) + Inhalation Dose (mg/kg/day)

7. MOE = NOAEL (9.8 mg/kg/day) ÷ Dose (mg/kg/day)

Table 6.2: Residential Postapplication Exposure and Risk Estimates for Clothianidin

Lifestage Postapplication Exposure Scenarios Dose1 MOE1

Adult

Golfer Dermal 0.000075 130,000

Inhalation NA NA

Turf Dermal 0.00108 9,000

Inhalation NA NA

Child Turf

Dermal 0.00155 6,300

Inhalation NA NA

Hand-to-mouth 0.0059 1,700

Soil Ingestion 0.00002 490,000

1. M. Dow, D296176, 2/24/2004
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Combined Residential Exposure Estimates

HED combines risk estimates resulting from separate exposure scenarios when it is likely they

can occur simultaneously based on the use pattern and the behavior associated with the exposed 

population, and when similar toxicological effects occur from different routes of exposure. HED 

reviewed all residential sources of exposure to determine which residential exposure scenarios 

would be appropriate to combine.

 

HED combined handler exposure resulting from treatment of residential lawns and ornamental 

tree trunks as it is probable that a homeowner would use the same pesticidal product to treat their 

lawn and ornamentals simultaneously on the same day. However, HED did not combine 

exposure resulting from adult handler and postapplication exposure because of the conservative 

assumptions and inputs within each estimated exposure scenario. The likelihood that a 

homeowner would treat their lawn and then repeatedly re-enter the treated site continuously for 

30 days is minimal. Furthermore, it is unlikely that a home owner would treat their lawn and 

then play golf on a course treated with the same pesticide on the same day. HED believes that 

combining co-occurring exposures resulting from handler and postapplication exposure would 

result in an overestimate of adult exposure. Therefore, HED selected the most conservative

combined adult residential scenario, handler exposure (MOE = 1800) as the contributing source 

of adult residential exposure. The adult combined handler exposure resulted in an MOE greater 

than HED's level of concern (LOC = MOE ≥ 100) and was not a risk of concern.

 

There is the potential for postapplication dermal and oral exposure for children resulting from 

use of clothianidin on turf. A child's postapplication exposure assessment was not performed for 

use on ornamental tree trunks as children's contact with ornamentals is typically significantly less 

than turf. Therefore a turf postapplication exposure assessment would be protective of 

postapplication exposure from ornamental uses. The children’s oral exposure is based on 

postapplication hand-to-mouth exposures only. To include exposure from object-to-mouth and 

soil ingestion in addition to hand-to-mouth could result in a very conservative estimation of 

exposure as it would overestimate the potential of oral exposure. Since the toxicological effects 

from the dermal and oral routes of exposure are the same, a total residential exposure assessment 

was conducted for children. The total residential children's postapplication exposure assessment 

result in an MOE significantly greater than HED's LOC (MOE ≥100) and is not a risk of 

concern. 

Table 6.2 summarizes the combined residential exposure scenarios and their risk estimates.
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Table 6.3. Combined Residential Exposure and Risk Estimates for Clothianidin

Combined Exposure Scenario

Life-stage Total Handler

MOE 1

Combined

Handler MOE 2

Total Postapplication 

Exposure,

3 

mg/kg/day

Total Postapplication 

MOE 4

Lawn/Turf

Spreader

Arena 0.5G [Reg. No. 59639-156]

Adult 390,000

1800

0.00108 9,100

Lawn/Turf

Hose-End Sprayer

Arena 50 WDG [Reg.No. 59639-156]

Adult 20,000 0.00108 9,100

Tree Trunk (Bark) Application

Hose-End Sprayer

Arena 50 WDG [Reg.No. 59639-156]

Adult 2000 NA NA

Tree Trunk (Bark) Application

Hand-Held Sprayer

Arena 50 WDG [Reg.No. 59639-156]

Adult 520,000 NA NA

Turf /Lawn Child NA 0.00745 1300

1. From Table 6.1.

2. 1/(1/Total Handler MOE Arena 50 WDGTurf + 1/Total Handler MOE Arena 50 WDGTree Trunk Hose-End Sprayer)

3. From Table 6.2. For child, the total post-application exposure estimate is from dermal and hand-to-mouth 

exposures.

4. Total Postapplication MOE = NOAEL (9.8 mg/kg/day) ÷ Total Postapplication Exposure (mg/kg/day)

6.2 Residential Bystander Post-Application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for clothianidin at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category III and IV), low vapor pressure (1.3 x 10-10 Pa), and the 

low proposed use rate (not to exceed 0.2 lb a.i./A/season). However, volatilization of pesticides 

may be a source of post-application inhalation exposure to individuals nearby pesticide 

applications. The Agency sought expert advice and input on issues related to volatilization of 

pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel 

(SAP) in December 2009, and received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report and may, as appropriate, develop policies and procedures to 

identify the need for and, subsequently, the way to incorporate post-application inhalation 

exposure into the Agency's risk assessments. If new policies or procedures are developed, the 

Agency may revisit the need for a quantitative post-application inhalation exposure assessment 

for clothianidin.

6.3 Spray Drift

Spray drift is always a potential source of exposure to residents nearby spraying operations. This 

is particularly the case with aerial application, but, to a lesser extent, could also be a potential 

source of exposure from the ground application method employed for clothianidin. The Agency

has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead 

Agencies for pesticide regulation and other parties to develop the best spray drift management 

practices (see the Agency’s Spray Drift website for more information at 

http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the 

Agency is now requiring interim mitigation measures for aerial applications that must be placed 
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on product labels/labeling. The Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is 

developing a policy on how to appropriately apply the data and the AgDRIFT computer model to 

its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. 

After the policy is in place, the Agency may impose further refinements in spray drift 

management practices to reduce off-target drift with specific products with significant risks 

associated with drift.

Although a quantitative residential post-application exposure assessment was not performed to 

address pesticide drift from neighboring treated agricultural fields, it is noted that residential 

exposure of children from use on turf and occupational exposure of flaggers during aerial 

application were assessed and were found to be not of concern. Exposures from these scenarios 

are likely to be significantly greater than those associated with spray drift from agricultural 

applications of clothianidin. By extension, therefore, risks associated with spray drift of 

clothianidin are expected to be also not of concern.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and, if appropriate, aggregate (add) pesticide

exposures and risks from three major sources: food, drinking water, and residential activities. In 

an aggregate assessment, exposures from relevant sources are added together and compared to 

quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be 

aggregated. When aggregating exposures and risks from various sources, HED considers both 

the route and duration of exposure.

7.1 Acute Aggregate Risk

Typically, HED does not consider residential exposures when assessing acute aggregate risk 

unless such exposures can be characterized as a series of single-day exposures, which is not the 

case for clothianidin. Therefore, acute aggregate risk estimates for clothianidin are equivalent to 

the acute dietary risk estimates (Section 5.4) and are below HED’s level of concern. There are 

no acute aggregate risk issues that would preclude granting the actions requested by the 

registrant.

7.2 Short- and Intermediate-Term Aggregate Risk

Short-term aggregate assessments address exposures that may occur for durations of one to thirty

days. Intermediate-term assessments address exposures lasting from between thirty days to 6 

months. In the case of clothianidin, the endpoints and doses for risk assessment are the same for 

short- and intermediate-term exposures; therefore, separate assessments are not being conducted 

for these two durations. Oral, dermal, and inhalation endpoints and doses for risk assessment are 

equal and were selected from the same study (two-generation reproduction study). In order to 

assess aggregate risk, exposure estimates from residential sources (Section 6.3) are combined 

with the chronic exposure estimate from food and drinking water, which represents a background 

level of dietary exposure. Aggregate exposures and risks are summarized in Table 7.2. The 

level of concern for each exposure pathway is 100; thus, any MOE that is less than 100 indicates 
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a potential risk of concern. For clothianidin, all aggregate MOEs are greater than 100 and are 

not of concern to HED. There are no short- or intermediate-term aggregate risk issues that 

would preclude granting the actions requested by the registrant.

Table 7.2. Short- and Intermediate-Term Aggregate Exposure and Risk Estimates for Clothianidin.

Population Subgroup Estimated Exposure, mg/kg/day Aggregate 

MOE 4

Combined Residential 1 Dietary 2 Aggregate 3

Adults 0.0054 0.0049 0.0103 950

Children 0.0075 0.0145 0.0220 450

1 The value shown is the short-/intermediate-term NOAEL (9.8 mg/kg/day) divided by the MOE from Table 6.3. 

For adults, the handler exposure estimate is greater than the post-application exposure estimate and is being used to 

assess aggregate exposure.

2 From Table 5.4.3. Adult = Adults 50+ (highest adult exposure estimate). Children = Children 3-5 yrs.

3 Aggregate = Combined Residential + Dietary.

4 Aggregate MOE = short-/intermediate-term NOAEL (9.8 mg.kg.day) divided by the aggregate exposure. Value 

rounded to two significant figures.

7.3 Chronic Aggregate Risk

Chronic aggregate risk assessments address exposures that are likely to occur, continuously, for 

greater than six months. In the case of clothianidin, residential exposures are not expected to 

occur on a chronic basis; therefore, the chronic aggregate risk estimates are equivalent to the 

dietary risk estimates (Section 5.4.3) and are below HED’s level of concern. There are no 

chronic aggregate risk issues that would preclude granting the actions requested by the registrant.

7.4 Cancer Aggregate Risk

Clothianidin has been determined to be “not likely carcinogenic to humans.” Therefore, there is 

no cancer risk associated with exposure to clothianidin.

8.0 Cumulative Exposure/Risk Characterization

Clothianidin is a member of the neonicotinoid class of pesticides and is a major metabolite of 

another neonicotinoid, thiamethoxam. Structural similarities or common effects do not 

constitute a common mechanism of toxicity. Evidence is needed to establish that the chemicals 

operate by the same, or essentially the same, sequence of major biochemical events (EPA, 2002). 

Although clothianidin and thiamethoxam bind selectively to insect nicotinic acetylcholine 

receptors (nAChR), the specific binding site(s)/receptor(s) for clothianidin, thiamethoxam and 

the other neonicotinoids are unknown at this time. Additionally, the commonality of the binding 

activity itself is uncertain, as preliminary evidence suggests that clothianidin operates by direct 

competitive inhibition, while thiamethoxam is a non-competitive inhibitor. Furthermore, even if 

future research shows that neonicotinoids share a common binding activity to a specific site on 

insect nAChRs, there is not necessarily a relationship between this pesticidal action and a 

mechanism of toxicity in mammals. Structural variations between the insect and mammalian 

nAChRs produce quantitative differences in the binding affinity of the neonicotinoids towards 

these receptors which, in turn, confers the notably greater selective toxicity of this class towards 

insects, including aphids and leafhoppers, compared to mammals. While the insecticidal action 

of the neonicotinoids is neurotoxic, the most sensitive regulatory endpoint for clothianidin is 
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based on unrelated effects in mammals, including changes in body and thymus weights, delays in 

sexual maturation, and still births. Additionally, the most sensitive toxicological effect in 

mammals differs across the neonicotinoids (such as testicular tubular atrophy with 

thiamethoxam, and mineralized particles in thyroid colloid with imidacloprid). Thus, there is 

currently no evidence to indicate that neonicotinoids share common mechanisms of toxicity, and 

EPA is not following a cumulative risk approach based on a common mechanism of toxicity for 

the neonicotinoids. For information regarding EPA’s efforts to determine which chemicals have 

a common mechanism of toxicity, and to evaluate the cumulative effects of such chemicals, see 

the policy statements concerning common mechanism determinations, and procedures for 

cumulating effects from substances found to have a common mechanism, released by OPP on 

EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

9.1 Short- and Intermediate-Term Handler Risk

Based on the proposed use patterns, exposures may be of short- to intermediate-term durations. 

Long-term exposure is not expected. Both dermal and inhalation exposures are expected to be 

significant. No chemical-specific data for assessing human exposure during pesticide 

occupational activities were submitted to the Agency in support of the proposed new uses. 

Exposure estimates for foliar treatments were derived using data from the Pesticide Handlers 

Exposure Database Version 1.1 (PHED 1.1), the Agricultural Handler Exposure Task Force 

(AHETF) database, and the Outdoor Residential Exposure Task Force (ORETF) database. For 

seed treatments, exposure estimates were derived using data from the Science Advisory Council 

for Exposure (Exposure SAC) Policy #14: Standard Operating Procedures (SOP) for Seed 

Treatment (May 1, 2003) and the treating/planting data from the Exposure SAC Policy #15 & 

Policy # 14: Amount of Seed Treated or Planted Per Day (March 2, 2004). For these 

assessments, female body weight (60 kg) was used since the doses for risk assessment are based 

on developmental endpoints.

Foliar Treatment on Rice 

Dermal and inhalation risks were combined, since the toxicological effects for the dermal and 

inhalations routes were the same. MOEs for handler activities associated with foliar applications

on rice, assuming PPE of single-layer + gloves, are greater than 100 and are not of concern

(Table 9.1a).

Table 9.1a. Short- and Intermediate-Term Occupational Exposure and Risk Estimates Associated with Foliar 

Application of Clothianidin on Rice.

Exposure Scenario PPE Level 1

Unit Exposure, 2

μg/lb ai

Appl. 

Rate,

lb ai/A

Acres 

Treated

per day 3

Dose,

4,5,6 mg/kg/day Total

MOE 7

Dermal Inhal. Dermal Inhal. Total

Mixer/Loader

Liquids for Aerial 

Application

Baseline

plus gloves 37.6 0.219 0.075 1200 0.00056 0.00033 0.00089 11,000

Liquids for Groundboom Application Baseline

plus gloves 37.6 0.219 0.075 200 9.4E-5 5.5E-5 0.00015 66,000

Applicator
Clothianidin Human Health Risk Assessment DP No. D387290, D389529

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Table 9.1a. Short- and Intermediate-Term Occupational Exposure and Risk Estimates Associated with Foliar 

Application of Clothianidin on Rice.

Exposure Scenario PPE Level 1

Unit Exposure, 2

μg/lb ai

Appl. 

Rate,

lb ai/A

Acres 

Treated

per day 3

Dose,

4,5,6 mg/kg/day Total

MOE 7

Dermal Inhal. Dermal Inhal. Total

Sprays with FixWing Aerial 

Equipment 

Enclosed 

cockpit 5.0 0.068 0.075 1200 0.00008 0.0001 0.00018 55,000

Sprays with 

Ground-boom

Equipment 

Baseline

plus gloves 16.1 0.34 0.075 200 0.00004 0.00009 0.00013 78,000

Flagger

Flagging Baseline

plus gloves 12 0.35 0.075 350 0.00005 0.00015 0.00021 48,000

1. PPE consists of long-sleeve shirt, long pants, shoes, and socks plus gloves. 

2. Dermal and inhalation unit exposures are from Occupational Pesticide Handler Unit Exposure Surrogate 

Reference Table.

3. Acres treated values are from EPA estimates of acreage that could be treated in a day based on the appl. Method

and formulation/packaging type.

4. Dermal dose (mg/kg/day) = unit dermal exposure (μg/lb ai) × (1 mg/1000 μg) conversion × application rate (lb 

ai/acre) × acres treated/day × dermal absorption rate (0.01) ÷ body weight (60 kg).

5. Inhalation dose (mg/kg/day) = unit exposure (μg/lb ai) × (1 mg/1000 μg) conversion × application rate (lb 

ai/acre) × acres treated/day ÷ body weight (60 kg).

6. Total dose (mg/kg/day) = Dermal dose/day + inhalation dose/day.

7. Total MOE = NOAEL (9.8 mg/kg/day) ÷ total dose/day. 

Primary Handlers for Seed Treatments on Rice and Leafy Vegetables

The dermal and inhalation exposures were combined to calculate a total MOE because the 

endpoint selected for both exposure routes is the same. For seed-treatment activities on rice and 

leafy green vegetables, MOEs for all primary handler activities (loader/applicator, sewer, bagger, 

and multiple activities seed treatment workers) are greater than 100 at the baseline level (single 

layer + gloves for loader/applicator and multiple activities worker; single layer + no gloves for 

sewer and bagger), and therefore, do not exceed HED’s level of concern. 

Table 9.1b. Occupational Handler Exposures and Risk Estimates Associated with Seed Treatment of Clothianidin: 

Rice and Leafy Green Vegetables.

Seed 

Groups 

Treated 

PPE

Appl. rate

lb ai/lb

of seed 

Lbs. seeds 

treated

per day

unit exposure, 

μg ai/lb ai 1

Dose,

mg/kg/day 2,3,4 Total 

MOE 5

Dermal Inhalation Dermal Inhalation Total

Loader/Treater 

Rice

B + G

0.00075 718,000 23 0.34 0.002061 0.003046 0.005107 1,900

Parsley 0.05 5,500 23 0.34 0.00105 0.00156 0.00261 3,800

Spinach 0.015 5,500 23 0.34 0.00032 0.00047 0.00078 13,000

Lettuce [P] 0.42 500 23 0.34 0.00081 0.00119 0.002 4,900

Lettuce [P] 1.59 500 23 0.34 0.00305 0.00451 0.00755 1,300

Bagger

Rice

B

0.00075 718,000 9.1 0.16 0.000815 0.001434 0.002249 4,400

Parsley 0.05 5,500 9.1 0.16 0.00042 0.00073 0.00115 8,500

Spinach 0.015 5,500 9.1 0.16 0.00013 0.00022 0.00035 28,000

Lettuce [P] 0.42 500 9.1 0.16 0.00032 0.00056 0.00088 11,000
Clothianidin Human Health Risk Assessment DP No. D387290, D389529

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Lettuce [P] 1.59 500 9.1 0.16 0.00121 0.00212 0.00333 2,900

Sewer

Rice

B

0.00075 718,000 6.2 0.23 0.000555 0.002061 0.002616 3,700

Parsley 0.05 5,500 6.2 0.23 0.00028 0.00105 0.00134 7,300

Spinach 0.015 5,500 6.2 0.23 0.00009 0.00032 0.0004 24,000

Lettuce [P] 0.42 500 6.2 0.23 0.00022 0.00081 0.00102 9,600

Lettuce [P] 1.59 500 6.2 0.23 0.00082 0.00305 0.00387 2,500

Multiple Worker

Rice

B + G

0.00075 718,000 42 1.6 0.003763 0.014337 0.01810 540

Parsley 0.05 5,500 42 1.6 0.00193 0.00733 0.00926 1,100

Spinach 0.015 5,500 42 1.6 0.00058 0.0022 0.00278 3,500

Abbreviation used: PPE= personal protective equipment; B = long-sleeved shirt, long pants and shoes with socks;

G=gloves; MOE = margin of exposure; [P] = pelleted seed treatment.

1. Dermal and inhalation unit exposures are from ExpoSAC SOP #14.

2. Dermal dose (mg/kg/day) = [Appl. rate (lb ai/lb of seed) × lbs of seeds treated/day × dermal unit exposure ×

1 mg/1000μg × dermal absorption factor (1%)] ÷ body wt (60 kg). 

3. Inhalation dose (mg/kg/day) = [Appl. rate (lb ai/lb of seed) × lbs of seeds treated/day × inhalation unit exposure

× 1 mg/1000μg × inhalation absorption factor (100%)] ÷ body wt (60 kg).

4. Total dose (mg/kg/day) = dermal exposure + inhalation exposure. 

5. Total MOE = NOAEL (9.8 mg/kg/day) ÷ Total dose (mg/kg/day).

Secondary Handlers for Seed Treatments on Rice and Leafy Vegetables

Exposures to secondary handlers occur when bags of clothianidin treated seeds are transported to 

the field, poured into hoppers, and planted in the field. Both dermal and inhalation exposures 

may result from handling treated seeds. Use of pelletized seeds is expected to further reduce 

exposures to secondary handlers due to the multiple layers of coating of the seeds. MOEs for 

these scenarios are all greater than 100 (Table 9.1c) and are not of concern.

Table 9.1c. Exposures and Risk Estimates to Secondary Handlers From Planting Leafy Green Seeds Treated with 

Clothianidin.

Seed Groups

Treated PPE 

A. R

lb ai/lb

of seed 1

Lbs. seeds 

planted

per day 2

unit exposure, 

μg ai/lb ai 

Dose,

mg/kg/day 3, 4, 5 Total 

MOE 6

Dermal Inhalation Dermal Inhalation Total

Parsley 

Baseline*

0.05 480 250 3.4 0.001 0.00136 0.00236 4,200

Spinach 0.015 1,200 250 3.4 0.00075 0.00102 0.00177 5,500

Lettuce [P] 0.42 320 250 3.4 0.0056 0.00762 0.01322 740

Lettuce [P] 1.59 320 250 3.4 0.0212 0.02883 0.05003 200

Abbreviation used: same as in Table 9.1b. 

* Gloves are required only when loading treated seeds into planter hopper.

[P] Pelleted seed 

1. Application rates from Table 1 

2. Pounds of seeds of leafy greens planted per day are from ExpoSAC’s Policy # 15.

3. Dermal dose (mg/kg/day) = [Appl. rate (lb ai/lb of seed) × lbs of seeds treated/day × dermal unit exposure ×

1 mg/1000 μg × dermal absorption factor (1%)] ÷ body wt (60 kg). 

4. Inhalation dose (mg/kg/day) = [Appl. rate (lb ai/lb of seed) × lbs of seeds treated/day × inhalation unit exposure

× 1 mg/1000 μg × inhalation absorption factor (100%)] ÷ body wt (60 kg).

5. Total dose (mg/kg/day) = dermal exposure + inhalation exposure. 

6. Total MOE = NOAEL (9.8 mg/kg/day) ÷ total dose (mg/kg/day).
Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 25 of 41

9.2 Short- and Intermediate-Term Post-Application Risk

In estimating post-application risk, HED has considered both dermal and inhalation routes of 

exposure. 

Inhalation Post-Application Exposure

For field foliar applications of clothianidin, as per the Agency's current practices, a quantitative 

post-application inhalation exposure assessment was not performed for at this time primarily

because of the low acute inhalation toxicity (Toxicity Category III and IV), low vapor pressure 

(1.3 x 10-10 Pa, 9.75 x 10-13 mm Hg), and the low proposed use rate (0.075 lb ai/A). However, 

there are multiple potential sources of post-application inhalation exposure to individuals 

performing post-application activities in previously treated fields. These potential sources 

include volatilization of pesticides and resuspension of dusts and/or particulates that contain 

pesticides. The Agency sought expert advice and input on issues related to volatilization of 

pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel 

(SAP) in December 2009, and received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate occupational 

post-application inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for clothianidin.

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

higher exposure than post-application exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of most occupational post-application 

inhalation exposure scenarios.

For seed treatments, a post-application inhalation exposure assessment is not required as 

exposure is expected to be negligible. Seed treatment assessments provide quantitative 

inhalation exposure assessments for seed treaters and secondary handlers (i.e., planters). It is 

expected that these exposure estimates would be protective of most post-application inhalation 

exposure scenarios.

Dermal Post-application Exposure

Foliar Treatments

For the foliar application to rice, the post-application activity that involves the highest contact 

with foliage is scouting. The MOE associated with scouting foliarly treated rice fields is 39,000 

(Table 9.2) and is not of concern.

Table 9.2. Summary of Occupational Post-Application Exposure and Risk Estimates Associated with Clothianidin 
Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 26 of 41

Foliar Rice Treatments.

Crop Treatment Type Activity Mitigation Level Daily Dose, 

mg/kg/day a MOE b

Rice Foliar Broadcast Scouting Single Layer, Gloves 0.000246 40,000

Hand Weeding Single Layer, Gloves 0.0000157 620,000

a Daily Dose from D397004, S. Wang, 30 January 2012.

b MOE = NOAEL (9.8 mg/kg/day) ÷ Combined Daily Dose. Level of concern = 100.

The Restricted Entry Interval (REI) is based on the acute toxicity of clothianidin technical 

material, which is classified in acute toxicity category III and IV. Acute toxicity category III or 

IV chemicals require a 12-hour REI. Thus, the 12-hour REI that appears on the labels for foliar 

treatments is adequate.

Seed Treatments

For seed treatments there is a possibility that farm workers may be exposed to residues of 

clothianidin if they enter fields that are planted with treated seeds of leafy greens to do irrigation 

and/or scouting. The registrant has not submitted any chemical-specific postapplication 

exposure data to evaluate such risks. HED’s evaluation indicates that dermal exposure to 

postapplication workers is minimal due to the lack of dermal contact with planted seeds. 

The Worker Protection Standard (WPS) and Restricted Entry Interval (REI) contain 

requirements for protecting postapplication workers from dermal and inhalation exposures after 

application of a pesticide in the field. However, WPS and REI are not required for pesticide 

formulations that are registered for seed treatment uses, because of the low potential for such 

exposures to postapplication workers.

10.0 References

D395799. M. Doherty. 1 February 2012. Clothianidin-Requested Foliar Uses on Rice, Seed 

Treatment on Leafy Vegetables, Increased Application Rate for Vegetables, and 

Expanded Uses on Fruiting Vegetables and Pome Fruit – Evaluation of Residue 

Chemistry Data.

D395798. M. Doherty. 1 February 2012. Clothianidin Acute and Chronic Aggregate Dietary

(Food and Drinking Water) Exposure and Risk Assessments.

D376358. S. Wang. 22 October 2010. Clothianidin: Occupational and Residential Exposure/

Risk Assessment for Proposed Seed Treatment Use of Clothianidin on Rice.

D389737. S. Oonnithan. 30 January 2012. Clothianidin: Occupational and Residential 

Exposure Assessment for the New Use as Seed Treatment of Leafy Greens.

D397004. S. Wang. 30 January 2012. Clothianidin: Occupational and Residential 

Exposure/Risk Assessment for Section 3 Registration of Foliar Use on Rice.
Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 27 of 41

Appendix A. Toxicology Profile

A.1. Toxicology Data Requirements

The requirements (40 CFR 158.340) for food uses for clothianidin are in Table 1. Use of the new 

guideline numbers does not imply that the new (1998) guideline protocols were used.

Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

870.1200 Acute Dermal Toxicity ..................................................

870.1300 Acute Inhalation Toxicity..............................................

870.2400 Primary Eye Irritation....................................................

870.2500 Primary Dermal Irritation ..............................................

870.2600 Dermal Sensitization......................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)...............................................

870.3150 Oral Subchronic (nonrodent).........................................

870.3200 21-Day Dermal ..............................................................

870.3250 90-Day Dermal ..............................................................

870.3465 21- or 28-Day Inhalation .............................................

yes

yes

yes

no

yesa

yes

yes

yes

-

no

870.3700a Developmental Toxicity (rodent)...................................

870.3700b Developmental Toxicity (nonrodent).............................

870.3800 Reproduction .................................................................

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)..............................................

870.4100b Chronic Toxicity (nonrodent)........................................

870.4200a Oncogenicity (rat)..........................................................

870.4200b Oncogenicity (mouse)....................................................

870.4300 Chronic/Oncogenicity....................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial.....................

870.5300 Mutagenicity—Gene Mutation - mammalian................

870.5xxx Mutagenicity—Structural Chromosomal Aberrations...

870.5xxx Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotox. (hen).....................................

870.6100b 90-Day Neurotoxicity (hen)...........................................

870.6200a Acute Neurotox. Screening Battery (rat) .......................

870.6200b 90-Day Neuro. Screening Battery (rat)..........................

870.6300 Develop. Neuro..............................................................

no

no

yes

yes

yes

-

-

yes

yes

yes

870.7485 General Metabolism ......................................................

870.7600 Dermal Penetration........................................................

870.7800 Immunotoxicity..............................................................

yes

yes

yes

yes

yes

yes

Special Studies

Developmental Immunotoxicity.................................. yes yes

a The subchronic inhalation study is required. HED has recommended that this study be called in to support 

registration review. As discussed in Section 2.1, it is not being required to support the requested uses.
Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 28 of 41

A.2. Toxicity Profiles

Table A.2.1 Acute Toxicity Profile - Clothianidin Technical, Intermediates, and Metabolites

Test Material Guideline 

No. Study Type MRID(s) Results Toxicity Category

Technical 870.1100 Acute oral - rat 45422621 LD50 > 5000 mg/kg IV

BN0230M 

Metabolite

870.1100 Acute oral - rat 45422628 LD50 > 2000 mg/kg (♂+♀) III

BN0335E2 

Metabolite

870.1100 Acute oral - rat 45422623 LD50 > 2000 mg/kg (♂+♀) III

MAI 

Metabolite

870.1100 Acute oral - rat 45422629 LD50 = 758 mg/kg (♀)

Males not more susceptible

III

Clothianidin-CCMTAdduct Intermediate870.1100 Acute oral - rat 45422630 LD50 > 2000 mg/kg (♂+♀) III

ClothianidinHexahydropyrimidine 

Intermediate

870.1100 Acute oral - rat 45422631 LD50 > 2000 mg/kg (♂+♀) III

Clothianidin-Triazan 

Intermediate

870.1100 Acute oral - rat 45422632 LD50 > 2000 mg/kg (♂+♀) III

TMG Metabolite 870.1100 Acute oral - rat 45422625 LD50 < 550 mg/kg (♂)

LD50 = 567 mg/kg (♀)

II

TZMU Metabolite 870.1100 Acute oral - rat 45422624 LD50 = 1424 mg/kg (♂)

LD50 = 1282 mg/kg (♀)

III

TZNG Metabolite 870.1100 Acute oral - rat 45422626 LD50 > 1450 mg/kg (♂)

LD50 = 1481mg/kg (♀)

III

Technical 870.1100 Acute oral - mouse 45422622 LD50 = 389 mg/kg (♂; 

95% C.I. = 380-475)

LD50 = 465 mg/kg (♀;

95% C.I. = 384-561)

LD50 = 425 mg/kg (♂+♀;

95% C.I. = 380-475)

II

Technical 870.1200 Acute dermal - rat 45422634 LD50 > 2000 mg/kg III

Technical 870.1300 Acute inhalation 45422636 LC50 > 5.538 mg/L (♂+♀) IV

Technical 870.2400 Acute eye irritation 45422701 Slightly irritating to the eye IV

Clothianidin-CCMTAdduct Intermediate870.2400 Acute eye irritation 45422814 Not irritating to the eye IV

Clothianidin-Triazan 

Intermediate

870.2400 Acute eye irritation 45422819 Not irritating to the eye IV

Technical 870.2500 Acute dermal 

irritation

45422703 Not irritating to the skin IV

Clothianidin-CCMTAdduct Intermediate870.2500 Acute dermal 

irritation

45422813 Not irritating to the skin IV

Clothianidin-Triazan 

Intermediate

870.2500 Acute dermal 

irritation

45422820 Not irritating to the skin IV

Technical 870.2600 Skin sensitization 45422705 Is not a sensitizer under 

conditions of study

N/A

Clothianidin-CCMTAdduct Intermediate870.2600 Skin sensitization 45422815 Is not a sensitizer under 

conditions of study

N/A

Clothianidin-Triazan 

Intermediate

870.2600 Skin sensitization 45422821 Is a sensitizer under 

conditions of study

N/A
Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 29 of 41

Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Clothianidin

Guide line Study Title MRID Results

870.3100 90-Day Oral 

Toxicity - rat

(diet)

45422809

(2000)

45422708

(4-week)

Acceptable/

guideline

ppm=0, 150, 500 & 3000

mg/kg/day (M/F)=0/0, 9.0/10.9, 

27.9/34.0, 202.0/254.2

NOAEL = 27.9/34.0 mg/kg/day (M/F) 

LOAEL = 202.0/254.2 mg/kg/day (M/F) 

based on decreased BW and BW gain.

870.3150 13-Week Oral 

Toxicity- dog 

(diet)

45422810

2000

45422808

2000

4-week

45422811

1998

palatability

Acceptable/

guideline

ppm=0, 325, 650, 1500 & 2250

mg/kg/day

(M/F)=0/0, 9.2/9.6, 19.3/21.2, 

40.9/42.1, 58.2/61.8 

NOAEL = 19.3/42.1 mg/kg/day (M/F)

LOAEL = 40.9/61.8 mg/kg/day (M/F) based 

on thinness, decreased body weight, body 

weight gain and anemia (1 M); and on 

decreased white blood cells, albumin, and 

total protein (F).

870.3200 28-Day Dermal

Toxicity - rat

45422707 (2000)

Acceptable/

guideline

mg/kg/day= 0, 100, 300 & 1000

NOAEL = 1000 mg/kg/day (HDT)

LOAEL = Not established

870.3700a Developmental 

Toxicity- rat 

(gavage)

45422711 (1998)

45422710 (1998)

range-finding

Acceptable/

guideline

mg/kg/day=0, 10, 40 & 125

Maternal NOAEL = 10 mg/kg/day

Maternal LOAEL = 40 mg/kg/day based on 

decreased body weight gain and food 

consumption.

Developmental NOAEL = 125 mg/kg/day 

(HDT)

Developmental LOAEL = Not established

870.3700b Developmental 

Toxicity- rabbit 

(gavage)

45422713 (1998)

45422712 (1998)

range-finding

Acceptable/

guideline

mg/kg/day=0, 10, 25, 75 & 100

Maternal NOAEL = 25 mg/kg/day

Maternal LOAEL = 75 mg/kg/day based on 

increased incidences of clinical signs (scant 

feces and orange urine), mortalities, 

decreased food consumption, early delivery, 

abortion, and decreased body weight gain.

Developmental NOAEL = 25 mg/kg/day

Developmental LOAEL = 75 mg/kg/day 

based on premature deliveries, decreased 

gravid uterine weights, an increased litter 

incidence of a missing lobe of the lung, and 

decreased litter average for ossified sternal 

centra per fetus.

870.3800 Reproduction 

(2- Generation)-

rat (diet)

45422715 (2000)

45422714 (2000)

pilot

45422716

(2001)

Parental/Systemic NOAEL = 31.2/36.8 

mg/kg/day (M/F)

Parental/Systemic LOAEL = 163.4/188.8 

mg/kg/day (M/F) based on decreased body 

weight, body weight gain, and absolute and 
Clothianidin Human Health Risk Assessment DP No. D387290, D389529

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Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Clothianidin

Guide line Study Title MRID Results

supplemental

45422825 (1999)

rat feed

45422826

(1999)

rat feed

Acceptable/

guideline

ppm=0, 150, 500 & 2500

mg/kg/day

(M/F)=0/0, 9.8/10.7, 

31.2/34.3,163.4/188.8

relative thymus weights.

Reproductive NOAEL = 31.2/188.8 

mg/kg/day (M/F)

Reproductive LOAEL = 163.4/not 

established mg/kg/day (M/F) based on 

decreased sperm motility and increased 

number of sperm with detached heads in 

both generations.

Offspring NOAEL = 9.8/11.5 mg/kg/day 

(M/F)

Offspring LOAEL = 31.2/36.8 mg/kg/day 

(M/F) based on decreased body weight gains 

and delayed sexual maturation (M),

decreased absolute thymus weights in F1 

pups of both sexes, and an increase in 

stillbirths in both generations.

870.4100 Chronic (1 year) 

- dog (diet)

45422717 (2000)

45422718

Acceptable/

guideline

ppm=0, 325, 650, 1500 & 2000

mg/kg/day (M/F)=0/0, 4.8/8.5, 

16.6/15.0, 36.3/40.1, 46.4/52.9

NOAEL = 46.4/40.1 mg/kg/day (M/F)

LOAEL = not established/52.9 mg/kg/day

(M/F) based on clinical evidence of anemia 

in females.

Note: dose-related decreases in ALT 

activity observed in mid- and high-dose 

males and females.

870.4200 Carcinogenicity, 

18-Month -

mouse (diet)

45422721 (2000)

45422709

(1997)

4-week

45422722

(2001)

supplementary

Acceptable/

guideline

ppm=0,100, 350 or 1250

mg/kg/day

(M/F)=0/0, 13.5/17.0, 47.2/65.1, 

171.4/215.9

In addition: 50/sex - 700 ppm (wk 

1-4), 2000 (5-10), 2500 (11-34), 

2000/1800 (M/F) 35-79 

[254,1/322,3] 

NOAEL = 171.4/65.1 mg/kg/day (M/F)

LOAEL = 254.1/215.9 mg/kg/day (M/F) 

based on decreased body weight and body 

weight gain; decreased food consumption 

and food efficiency in males at the LOAEL. 

No evidence of carcinogenicity.

870.4300 Chronic/

Carcinogenicity, 

2-Year-rat (diet)

45422719 (2000)

45422720

(2001)

supplementary

Acceptable/

guideline

ppm (M/F)=0, 150, 500, 1500 & 

3000

mg/kg/day

(M/F)=0/0, 8.1/9.7, 27.4/32.5, 

82.0/97.8, 156.5/193.4

NOAEL = 82.0/32.5 mg/kg/day (M/F)

LOAEL = 156.5/97.8 mg/kg/day (M/F) 

based on decreased body weight and food 

consumption and altered hepatocellular 

eosinophilic focus of the liver in both sexes; 

ovary interstitial gland hyperplasia and 

increased lymphohistiocytic infiltrate in 

females; and slightly increased incidences of 

pelvic mineralization and transitional cell 

hyperplasia in the kidney, mottled livers of 

males.

No evidence of carcinogenicity.
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Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Clothianidin

Guide line Study Title MRID Results

870.5100 Gene Mutation 

bacterial reverse 

mutation assay

Parent

45422731 (2000)

Acceptable/

guideline

Small, but significant increase in frequency 

of histidine revertants in TA 1535 strain 

treated at 1500 and 5000 μg/plate +/- S9; 

still present but weaker in its absence. The 

positive response was only reproducible at 

5000 μg/plate +/-S9. Clothianidin 

considered mutagenic under conditions of 

this test.

870.5100 Gene Mutation 

bacterial reverse 

mutation assay

Parent

45422732

(1990)

Acceptable/

guideline

No mutagenic activity in bacteria (S. 

typhimurium and E. coli) under conditions of 

this assay.

870.5100 Gene Mutation 

bacterial reverse 

mutation assay

Parent

45422733

(1999)

Acceptable/

guideline

No mutagenic activity in bacteria (S. 

typhimurium) under conditions of this assay.

870.5100 Gene Mutation 

bacterial reverse 

mutation assay

Parent

45422734

(1999)

Acceptable/

non-guideline

(only TA 1535 assayed)

Only TA 1535 tested. No mutagenic activity 

in bacteria (S. typhimurium) under condtions 

of this assay. 

870.5100 Gene Mutation 

bacterial reverse 

mutation assay

BN0335E2 

metabolite

45422724

(2000)

Acceptable/

guideline

No mutagenic activity in bacteria (S. 

typhimurium) under conditions of this assay.

870.5100 Gene Mutation 

bacterial reverse 

mutation assay

TZMU 

metabolite

45422725

(1999)

Acceptable/

guideline

No mutagenic activity in bacteria (S. 

typhimurium) under conditions of this assay.

870.5100 Gene Mutation 

bacterial reverse 

mutation assay

methyl 

guanidine 

intermediate

45422726

(1999)

Acceptable/

guideline

No mutagenic activity in bacteria (S. 

typhimurium) under conditions of this assay.

870.5100 Gene Mutation 

bacterial reverse 

mutation assay

TZNG

metabolite

45422727

(1999)

Acceptable/

guideline

No mutagenic activity in bacteria (S. 

typhimurium) under conditions of this assay.

870.5100 Gene Mutation 

bacterial reverse 

mutation assay

TMG 

metabolite

45422728

(1999)

Acceptable/

guideline

No mutagenic activity in bacteria (S. 

typhimurium) under conditions of this assay.

870.5100 Gene Mutation 

bacterial reverse 

mutation assay

BN0230M 

metabolite

45422729

(2000)

Acceptable/

guideline

No mutagenic activity in bacteria (S. 

typhimurium) under conditions of this assay.

870.5100 Gene Mutation 45422730 No mutagenic activity in bacteria (S. 
Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 32 of 41

Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Clothianidin

Guide line Study Title MRID Results

bacterial reverse 

mutation assay

MAI 

metabolite

(1999)

Acceptable/

guideline

typhimurium) under conditions of this assay.

870.5100 Gene Mutation 

bacterial

reverse mutation 

assay

N=Methylnitro

guanidin 

intermediate

45422812

(2001)

Acceptable/

guideline

No mutagenic activity in bacteria (S. 

typhimurium) under conditions of this assay.

870.5100 Gene Mutation 

bacterial reverse 

mutation assay

TI 435-Triazan 

intermediate

45422822

(2000)

Acceptable/

guideline

No mutagenic activity in bacteria (S. 

typhimurium) under conditions of this assay.

870.5100 Gene Mutation 

bacterial reverse 

mutation assay

TI 435-CCMTAdduct

45422816

(2000)

Acceptable/

guideline

No mutagenic activity in bacteria (S. 

typhimurium) under conditions of this assay.

870.5300 Gene Mutation -

in vitro

mammalian cell 

gene mutation 

test (L5178Y 

TK +/- mouse 

lymphoma cells)

45422737 (2000)

Acceptable/

guideline

Increases in mutant frequency with and 

without S9 at dose levels that were 

cytotoxic. The observed response was 

primarily due to small colony formation, 

indicating clastogenic activity.

870.5300 Gene Mutation -

in vitro

mammalian cell 

gene mutation 

test (V79-HPRT 

Assay)

45422738

(1999)

Acceptable/

guideline

No increase in mutant frequency under the 

conditions of the study.

870.5300 Gene Mutation 

– in vitro

mammalian cell 

gene mutation 

test (V79 -

HPRT Assay)

46339001

(2003)

Acceptable/

guideline

There was no evidence of induced mutant 

colonies over background.

870.5375 Cytogenetics -

in vitro

mammalian 

chromosome 

aberration test 

(CHL Cells)

Parent

45422736

(2000)

Acceptable/

guideline

Significant increases in frequency of cells 

with structural aberrations. Predominant 

types were chromatid breaks and exchanges. 

There was, however, no clear indication of a 

dose-related response in either the presence 

or absence of S9 activation.

870.5375 Cytogenetics –

in vitro

mammalian 

chromosome 

aberration test 

(CHL Cells)

46339002

(2003)

Acceptable/

guideline

Clothianidin was clastogenic in the absence 

of S9 activation but only at precipitating 

concentrations. Some doubt regarding the 

relevance of this finding since clastogenicity 

was abolished when exogenous metabolic 

activation was incorporated into the test
Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 33 of 41

Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Clothianidin

Guide line Study Title MRID Results

Parent system and was confined to precipitating 

concentrations.

870.5395 Cytogenitics -

mammalian 

erythrocyte 

micronucleus 

test

Parent

45422740

(2000)

Acceptable/

guideline

Clothianidin is considered to be neither 

clastogenic nor aneugenic under these test 

conditions.

870.5395 Cytogenetics -

mammalian 

erythrocyte 

micronucleus 

test

Parent

46339003

(2003)

Acceptable/

guideline

No significant increase in the frequency of 

MPCEs in bone marrow after any harvest in 

the test groups up to an overtly toxic dose for 

this test system.

870.5550 Other Effects -

DNA Repair 

Test in B. 

subtilis

Parent

45722735

(1990)

Unacceptable/

non-guideline (only single plates 

used)

No potential for DNA damage under these 

conditions.

870.5500 Other Effects -

(UDS) in 

Mammalian 

Cells in Culture

Parent

45422739

(1999)

Acceptable/

non-guideline

(only males used)

No evidence (or a dose related positive 

response) that UDS was induced.

870.6200a Acute 

Neurotoxicity 

Screening

Battery-rat

(gavage)

45422801

(2000)

45422802

(2000)

to establish NOEL

Acceptable/

guideline

mg/kg=0,100, 200 & 400

NOEL=0, 20, 40 & 60

NOAEL = 60 mg/kg

LOAEL = 100 mg/kg based on FOB 

findings (decreased arousal, motor activity, 

and locomotor activity).

870.6200b Subchronic 

Neurotoxicity 

Study-rat (diet)

45422803 (2000)

45422825

(1999)

supplementary

Acceptable/

guideline

ppm (M/F)=0, 150, 1000 & 3000

mg/kg/day

(M/F)=0/0,9.2/10.6, 60.0/71.0, 

177.0/200.1

NOAEL = 60.0/71.0 mg/kg/day (M/F)

LOAEL = 177.0/200.1 mg/kg/day (M/F) 

based on slightly decreased food 

consumption, body weights, and body 

weight gains.

No evidence of neurotoxicity.

870.6300 Developmental 

Neurotoxicity

Study-rat

(diet)

445422804

(2000)

Acceptable/

non-guideline

(upgradable with FOB 

information)

ppm=0, 150, 500 & 1750

mg/kg/day

gestation=0, 12.9, 42.9, 142

lactation=0, 27.3, 90.0, 299.0

Maternal NOAEL = 42.9 mg/kg/day

Maternal LOAEL = 142 mg/kg/day based 

on decreased body weights, body weight 

gains, and food consumption.

Offspring NOAEL = 12.9 mg/kg/day

Offspring LOAEL = 42.9 mg/kg/day based 

on decreased body weights, body weight 

gains, motor activity, and acoustic startle 

response in females.
Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 34 of 41

Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Clothianidin

Guide line Study Title MRID Results

870.7485 Metabolism

Study- rat

45422805 (2000)

45422806

(2000)

Acceptable/

guideline

single dose=2.5 or 250mg/kg;

14-day repeated dose =25 

mg/kg/day

Overall recovery: 95-100%. Readily 

absorbed and excreted within 96 hours 

following a single 2.5 mg/kg bw or repeated 

oral dose of 25 mg/kg bw, but at a dose of 

250 mg/kg, absorption became biphasic and 

was saturated. Following single or multiple 

oral low doses (2.5 and 25mg/kg bw, 

respectively) of clothianidin, urinary 

excretion accounted for 89.2-94.6% of the 

administered radioactivity suggesting that a 

multiple exposure regimen did not affect the 

absorption/excretion processes. Urinary 

excretion unaffected following single 250 

mg/kg dose. Excretion via the feces 

accounted for the remainder of the 

administered radioactivity in all treatment 

groups (3.8-8.6%). Rapid absorption and 

distribution of administered radioactivity to 

all organs and tissues followed by rapid 

excretion with reduction to background 

levels in most tissues and organs within 24 

hours. Somewhat greater rate of absorption 

and elimination in females. Excretory 

patterns did not exhibit gender-related 

variability but reflected the delayed 

absorption in the high-dose group. Neither 

clothianidin nor metabolites appear to 

undergo significant sequestration. 

The metabolites identified (primarily 

oxidative demethylation products and 

cleavage products of the nitrogen-carbon 

bond between the nitroimino and thiazolyl 

moieties) were consistent with Phase I 

processes. Extraction efficiencies appeared 

to be excellent and most components in all 

of the matrices examined (urine, feces, and 

tissues) were adequately quantified and 

characterized. The available data, based 

upon studies using both the nitroimino- and 

the thiazolyl-2-labeled clothianidin, affirmed 

the metabolism pathway proposed by the 

investigators.

870.7485 Metabolism 

Study – mice

45422807

(2000)

Acceptable/

non-guideline

single gavage dose of 5 mg/kg

Of the administered radioactivity, 98.7-

99.2% was recovered. Readily absorbed and 

excreted within 168 hours following a single 

oral dose of 5 mg/kg body weight. Urine 

was the major route of excretion, accounting 

for 92.4-93.7% of the administered 

radioactivity. Feces accounted for 5.0-6.8% 

of the administered radioactivity. Within 24 

hours, 89.0-91.7 % of the administered 

radioactivity was excreted in the urine and 

4.9-6.2% was excreted in the feces. 
Clothianidin Human Health Risk Assessment DP No. D387290, D389529

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Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Clothianidin

Guide line Study Title MRID Results

Residual radioactivity in any given tissue at 

168 hours post-dose was considerably less 

than 1% of the administered dose. 

Therefore, neither clothianidin nor its 

metabolites appeared to exhibit potential for 

bioaccumulation. Excretory patterns did not 

exhibit gender-related variability.

Both urinary and fecal metabolites were 

identified using TLC and radioautography in 

conjunction with known standards and were 

quantified by TLC/LSC . The major 

metabolites in both urine and feces were the 

parent compound (clothianidin) and TZNG 

[N-(2-chlorothiazol-5-ylmethyl)-N-

nitroguanidine] which resulted from Ndemethylation of clothianidin. Extraction 

efficiencies were excellent and most 

components in the urine and feces were 

adequately quantified and characterized. 

Based on the data from the oral 

administration of [nitroimino-14C]-

clothianidin the metabolism pathway 

proposed by the investigators was supported.

870.7600 Dermal 

Penetration –

monkey

45868001 (2003)

Acceptable/

non-guideline

6.13 μg/cm2

8 hour exposure

Dermal absorption as the sum of urinary and 

fecal excretion and Cage/Pan/Chair Wash, 

Debris was 0.24 (+ 0.11) as percent of dose. 

Adjustment of the direct absorption 

determination was not necessary because 

recovery from the dermal dose was >90%. 

A value of 1% dermal absorption was 

considered appropriate for use in risk 

assessment. This estimation takes into 

account any variability that would have 

likely occurred with testing several dose 

levels.

870.7800 Immunotoxicity

–rat (adult) 

(diet)

46536502

(2004)

Acceptable/

guideline

ppm=0, 150, 500 & 3000

mg/kg/day

(M/F)=0/0, 13.8/14.0, 45.8/46.2, 

252.8/253

Immunotoxicity NOAEL = 253 mg/kg/day 

(M&F)

Immunotoxicity LOAEL = not established

At the highest dose tested, 253 mg/kg/day, a 

decrease in body weights, body weight gains 

and food consumption were noted in adult 

males and females.

Non-guideline Developmental 

Immunotoxicity 

study - rat

(diet)

47526501 (2008)

Acceptable/

non-guideline

ppm=0, 150, 500 & 2000

mg/kg/day

gestation=0, 10, 35, 121

lactation=0, 22, 68, 250

after weaning:

Assay 1=0/0, 28/26, 

No immunotoxicological adverse effects at 

any of the doses tested.
Clothianidin Human Health Risk Assessment DP No. D387290, D389529

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Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Clothianidin

Guide line Study Title MRID Results

98/93,404/404

Assay 2=0/0, 28/27, 89/93, 

338/398

Non-guideline Other 

Genotoxicity –

Unscheduled 

DNA synthesis 

in primary rat 

hepatocytes

46339004

(2003)

Acceptable/

non-guideline

No evidence of DNA damage and repair in 

this test system, as determined by radioactive 

tracer procedures (nuclear silver grain 

counts).

Non-guideline Special Study:

Neurotoxicity 

and 

pharmacology -

mouse

445422823

(2000)

Acceptable/

non-guideline

mg/kg=0, 12.5, 25, 50, 100, 200, 

400 (single gavage dose)

NOAEL = 25 mg/kg/day (M/F)

LOAEL = 50 mg/kg (M/F) based on 

transient signs of decreased spontaneous 

motor activity, tremors and deep 

respirations.
Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 37 of 41

Appendix B. Detailed Occupational Exposure and Risk Estimates.

Table B1. Non-Cancer Occupational Exposure and Risk for Handlers Applying Clothianidin on Rice: Foliar Treatment. D397004, S. Wang, 30 January 

2012.

Exposure

Scenario 

(Scenario #)

PPE

Level a

unit exp. (μg/lb ai) b

Appl. Rate

(lb ai/A)

Acres 

Treated c

/ day

Dermal

Dose d

(mg/kg/day)

Inhal.

Dose e

(mg/kg/day)

Total 

Dose/

day f

Sh. and 

Interm. term 

Total

MOE g

Dermal Inhal. 

MIXER/LOADER

Liquids for Aerial 

Application (1)

Baseline

plus

gloves

37.6 0.219 0.075 1200 0.00056 0.00033 0.00089 11,000

Liquids for 

Ground-boom

Application (2)

Baseline

plus

gloves

37.6 0.219 0.075 200 9.4E-5 5.5E-5 0.00015 66,000

APPLICATOR

Sprays with FixWing Aerial 

Equipment (3)

Enclosed 

cockpit 5.0 0.068 0.075 1200 0.00008 0.0001 0.00018 55,000

Sprays with 

Ground-boom

Equipment (4)

Baseline

plus

gloves

16.1 0.34 0.075 200 0.00004 0.00009 0.00013 78,000

FLAGGER

Flagging (5)

Baseline

plus

gloves

12 0.35 0.075 350 0.00005 0.00015 0.00021 48,000

a. PPE consists of long-sleeve shirt, long pants, shoes, and socks plus gloves. 

b. Dermal and inhalation unit exposures are from Occupational Pesticide Handler Unit Exposure Surrogate Reference Table.

c. Acres treated values are from EPA estimates of acreage that could be treated in a day based on the appl. method and formulation/packaging type.

d. Dermal dose (mg/kg/day) = unit dermal exposure (μg/lb ai) * (1 mg/1000 μg) conversion * application rate (lb ai/acre) * acres treated/day * dermal

 absorption rate (0.01) / body weight (60 kg).

e. Inhalation dose (mg/kg/day) = unit exposure (μg/lb ai) * (1 mg/1000 μg) conversion * application rate (lb ai/acre) * acres treated/day / body weight (60 kg).

f. Total dose (mg/kg/day) = Dermal dose/day + inhalation dose/day.

g. Total MOE = NOAEL (9.8 mg/kg/day) / total dose/day. Since the dermal and inhalation NOAEL are the same for both short and intermediate-term exposure 

 durations, the corresponding risks are also the same and therefore. 
Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 38 of 41

Table B2. Occupational Exposure and Risk Estimates for Primary Handlers Applying Clothianidin on Rice: Seed Treatment. D376358, S. Wang, 22 October 

2010.

Exposure 

Scenario

Mitigatio

n Level

Dermal 

Unit 

Exposur

e (mg/lb 

ai)

Inhalatio

n Unit 

Exposur

e (μg/lb 

ai)

Seed Species Applicati

on Rate

(lb ai per 

lb seed)

Amount 

Treateda

(lb seed 

trt per 

day)

Daily

Dermal

Dose b

(mg/kg/day)

Daily

Inhalation

Dosec

(mg/kg/day)

Combined 

Daily Dosed 

(mg/kg/day)

MOEe 

Loader/Applicator

Loading/Applyin

g

Liquid for 

Seed Treatment

Single 

Layer, 

Gloves

0.023 0.34 Rice 0.00075 718,000 0.002061 0.003046 0.005107 1,900

Sewer

Sewing Seeds 

after Seed 

treatment

Single 

Layer, 

No 

Gloves

0.0062 0.23 Rice 0.00075 718,000 0.000555 0.002061 0.002616 3,700

Bagger

Bagging Seeds 

after Seed 

treatment

Single 

Layer, 

No 

Gloves

0.0091 0.16 Rice 0.00075 718,000 0.0008152 0.0014336 0.0022488 4,400

Multiple Activities Worker

Multiple 

Activities for 

Seed treatment

Single 

Layer, 

Gloves

0.042 1.6 Rice 0.00075 718,000 0.0037633 0.014337 0.01810 540

a Daily amounts treated values are based on exposure SAC Policy #15.

b Daily dermal dose (mg/kg/d) = unit dermal exposure (mg/lb ai) * dermal absorption (0.01) * application rate (lb ai/lb seed) * daily amounts treated / body weight (70 kg).

c Daily inhalation dose (mg/kg/d) = unit exposure (μg/lb ai) * 0.001 * application. rate (lb ai/lb seed) * daily amounts treated / body weight (60 kg).

d Combined daily dose (mg/kg/d) = Daily dermal dose (mg/kg/d) + Daily inhalation dose (mg/kg/d).

e MOE = NOAEL (9.8 mg/kg/d) / combined daily dose. UF = 100.
Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 39 of 41

Table B3. Occupational Exposures and Risk Estimates for Primary Handlers Applying Clothianidin to Leafy Green Vegetable Seeds. D389737, S. Oonnithan, 

30 January 2012.

Seed Groups Treated PPE

Appl. rate

lb ai/lb

of seed 

Lbs. seeds 

treated

per day

Dermal

unit exp., 

μg ai/lb ai 1

Inhal.

unit exp.,

μg ai/lb ai 1

Dermal

dose/day

mg/kg 2

Inhal.

dose/day

mg/kg 3

Total

dose/day

mg/kg 4

Short-term

Total 

MOE 5

Loader/Treater 

Parsley 

Baseline

+ G

0.05 5,500 23 0.34 0.00105 0.00156 0.00261 3,800

Spinach 0.015 5,500 23 0.34 0.00032 0.00047 0.00078 13,000

Lettuce ** 0.42 500 23 0.34 0.00081 0.00119 0.002 4,900

Lettuce ** 1.59 500 23 0.34 0.00305 0.00451 0.00755 1,300

Bagger

Parsley 

Baseline

0.05 5,500 9.1 0.16 0.00042 0.00073 0.00115 8,500

Spinach 0.015 5,500 9.1 0.16 0.00013 0.00022 0.00035 28,000

Lettuce ** 0.42 500 9.1 0.16 0.00032 0.00056 0.00088 11,000

Lettuce ** 1.59 500 9.1 0.16 0.00121 0.00212 0.00333 2,900

Sewer

Parsley 

Baseline

0.05 5,500 6.2 0.23 0.00028 0.00105 0.00134 7,300

Spinach 0.015 5,500 6.2 0.23 0.00009 0.00032 0.0004 24,000

Lettuce ** 0.42 500 6.2 0.23 0.00022 0.00081 0.00102 9,600

Lettuce ** 1.59 500 6.2 0.23 0.00082 0.00305 0.00387 2,500

Multiple Worker

Parsley Baseline

+ G

0.05 5,500 42 1.6 0.00193 0.00733 0.00926 1,100

Spinach 0.015 5,500 42 1.6 0.00058 0.0022 0.00278 3,500

Abbreviation used: Baseline PPE= long-sleeved shirt, long pants and shoes with socks, G=gloves, MOE = margin of exposure, PPE= personal protective 

equipment. 

** Lettuce seeds are pelleted.

1. Dermal and inhalation unit exposures are from ExpoSAC SOP #14.

2. Dermal dose (mg/kg/day) = [Appl. rate (lb ai/lb of seed) * lbs of seeds treated/day * dermal unit exposure * dermal absorption factor (1%)] / body wt (60 kg). 

3. Inhalation dose (mg/kg/day) = [Appl. rate (lb ai/lb of seed) * lbs of seeds treated/day * inhalation unit exposure * inhalation absorption factor (100%)] / body 

wt (60 kg).

4. Total dose (mg/kg/day) = dermal exposure + inhalation exposure. 

5. Total MOE = NOAEL (9.8 mg/kg/day) / Total dose (mg/kg/day).
Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 40 of 41

Table B4. Post-application Exposure and Risk to Workers Scouting Clothianidin Treated Rice Fields: Foliar 

Treament. D397004, S. Wang, 30 January 2012.

Transfer Coefficients (cm2/hr) DAT 1 DFR 2 (ug/cm2) Dose (mg/kg/day) 3 MOE 4

75 0 0.168 0.00025 40,000

1100 0 0.168 0.0000157 620,000

1. DAT = Days after treatment.

2. DFR = Dislodgeable Foliar Residue = application rate (lb ai/A) x (1- daily dissipation rate) tx 4.54E+8 ug/lb x 2.47E-8 A/cm2 x 20% DFR after initial 

treatment.

3. Daily Dose = [DFR (ug/cm2) x TC (cm2/hr) x 0.001 mg/μg x 1% dermal absorption x 8 hrs/day]  body weight (60 kg).

4. MOE = NOAEL/Daily Dose ( Dermal NOAEL = 9.8 mg/kg/day). 

Table B5. Exposures and Risk Estimates to Secondary Handlers From Planting Rice Seeds Treated with Clothianidin. D376358, S. Wang, 22 October 2010.

Exposure 

Scenario

Mitigation 

Level

Dermal 

Unit 

Exposure 

(mg/lb ai)

Inhalation 

Unit 

Exposure 

(μg/lb ai)

Seed 

Category--

Representative

Seed Species

Applicatio

n Rate

(lb ai per 

lb seed)

Amount 

Planteda

(lb seed 

planted/day)

Daily

Dermal

Dose b

(mg/kg/day)

Daily

Inhalation

Dosec

(mg/kg/day)

Combined 

Daily Dosed

(mg/kg/day) 

MOEe 

Secondary Seed Handlers

Secondary Seed 

Handlers: 

planting seeds in 

the field

Single 

Layer, 

Gloves

0.25 3.4 Rice 0.00075 30,000 0.000936 0.0012729 0.0022089 4,400

a Daily amounts planted values are based on exposure SAC Policy #15 or the information provided by the Registrant through Registration Division.

b Daily dermal dose (mg/kg/d) = unit dermal exposure (mg/lb ai) * dermal absorption (0.01) * application rate (lb ai/lb seed) * daily amounts treated / body weight (70 kg).

c Daily inhalation dose (mg/kg/d) = unit exposure (μg/lb ai) * 0.001* application. rate (lb ai/lb seed) * daily amounts treated / body weight (70 kg).

d Combined daily dose (mg/kg/d) = Daily dermal dose (mg/kg/d) + Daily inhalation dose (mg/kg/d).

e MOE = NOAEL (9.8 mg/kg/d) / combined daily dose. UF = 100.
Clothianidin Human Health Risk Assessment DP No. D387290, D389529

Page 41 of 41

Table B6. Exposures and Risk Estimates to Secondary Handlers From Planting Leafy Green Seeds Treated with Clothianidin. D389737, S. Oonnithan, 30

January 2012.

Seed Groups

Treated PPE 

A. R

lb ai/lb

of seed 1

Lbs. seeds 

planted

per day 2

Dermal

unit exp., 

μg ai/lb ai 

Inhal.

unit exp.,

μg ai/lb ai 

Derm.

dose/day

mg/kg 3

Inhal.

dose/day

mg/kg 4

Total

dose/day

mg/kg 5

Total 

MOE 6

Parsley 

Baseline*

0.05 480 250 3.4 0.001 0.00136 0.00236 4,200

Spinach 0.015 1,200 250 3.4 0.00075 0.00102 0.00177 5,500

Lettuce** 0.42 320 250 3.4 0.0056 0.00762 0.01322 740

Lettuce** 1.59 320 250 3.4 0.0212 0.02883 0.05003 200

Abbreviation used: same as in Table 7. 

*. Gloves are required only when loading treated seeds into planter hopper.

**. Pelleted seed.

1. Application rates from Table 1. 

2. Pounds of seeds of leafy greens planted per day are from ExpoSAC’s Policy # 15.

3. Dermal dose (mg/kg/day) = [Appl. rate (lb ai/lb of seed) * lbs of seeds treated/day * dermal unit exposure * dermal absorption factor (1%)] / body wt (60 kg). 

4. Inhalation dose (mg/kg/day) = [Appl. rate (lb ai/lb of seed) * lbs of seeds treated/day * inhalation unit exposure * inhalation absorption factor (100%)] / body 

wt (60 kg).

5. Total dose (mg/kg/day) = dermal exposure + inhalation exposure. 

6. Total MOE = NOAEL (9.8 mg/kg/day) / total dose (mg/kg/day).

Appendix C. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or 

other chemical. These data, which include studies from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the 

Agricultural Handler Exposure Task Force (AHETF) database; and the Outdoor Residential Exposure Task Force (ORETF) database; 

are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements. 

For certain studies that review may have included review by the Human Studies Review Board. Descriptions of data sources as well 

as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html.