Clothianidin Human Health Risk Assessment

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

 

MEMORANDUM

Date: 27 September 2012

SUBJECT: Clothianidin – Aggregate Human Health Risk Assessment of New Uses on 

Strawberry, Pistachio, and Citrus; New Tolerance for Tea; and Revised PHI and 

Tolerance for Pepper and Eggplant (Crop Subgroup 8

PC Code: 044309

Decision Nos.: 455249, 459388

Petition No.: 2F8008, 1E7923

Risk Assessment Type: 

TXR No.: None

MRID No.: NA

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

Suku Oonnithan, Ph.D., Biologist

Edward Scollon, Ph.D., Toxicologist

Risk Assessment Branch II

Health Effects Division (7509P)

THROUGH: Zaida Figueroa, Industrial Hygenist

Linnea Hansen, Toxicologist

Elizabeth Holman, Chemist

Christina Swartz, Branch Chief

Risk Assessment Branch II

Health Effects Division (7509P)

TO: Marianne Lewis/Venus Eagle 

Insecticide/Rodenticide Branch

Registration Division (7505P)

Barbara Madden

Risk Integration, Minor Use, and Emergency Response Branch

Registration Division (7505P)

Clothianidin Human Health Risk Assessment DP No. D395348

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND

 POLLUTION PREVENTION

September 2012

Aggregate Human Health Risk Assessment of New Uses on 

Strawberry, Pistachio, and Citrus; New Tolerance for Tea; and Revised PHI and 

Tolerance for Pepper and Eggplant (Crop Subgroup 8-10B).

DP Barcodes: D395348, 

455249, 459388 Registration No.: 59639

2F8008, 1E7923 Regulatory Action: Section 3

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

CAS No.: 210880-92

40 CFR 180.586

Michael A. Doherty, Ph.D., Chemist

Suku Oonnithan, Ph.D., Biologist

Edward Scollon, Ph.D., Toxicologist

Risk Assessment Branch II

Health Effects Division (7509P)

roa, Industrial Hygenist

Linnea Hansen, Toxicologist

Elizabeth Holman, Chemist

Christina Swartz, Branch Chief

Risk Assessment Branch II

Health Effects Division (7509P)

Marianne Lewis/Venus Eagle (RM 01)

Insecticide/Rodenticide Branch

Registration Division (7505P)

Risk Integration, Minor Use, and Emergency Response Branch

Registration Division (7505P)

DP No. D395348

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF CHEMICAL SAFETY AND

POLLUTION PREVENTION

Aggregate Human Health Risk Assessment of New Uses on 

Strawberry, Pistachio, and Citrus; New Tolerance for Tea; and Revised PHI and 

D395348, D397647

59639-150, 59639-152

Section 3

92-5
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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................................................................................................ 4

2.2.1 Enforcement Analytical Method................................................................................. 4

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................................................................................................. 6

2.3.1 Recommendations from Residue Reviews ................................................................. 6

2.3.2 Recommendations from Occupational and Residential Assessments ........................ 6

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 ..................................................................................... 8

3.5 Consideration of Environmental Justice ......................................................................... 8

4.0 Hazard Characterization and Dose-Response Assessment.................................................. 9

4.1 Toxicology Studies Available for Analysis.................................................................... 9

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME).................................... 9

4.2.1 Dermal Absorption.................................................................................................... 10

4.3 Toxicological Effects.................................................................................................... 10

4.4 Safety factor for Infants and Children (FQPA Safety Factor)...................................... 12

4.4.1 Completeness of the Toxicology Database............................................................... 13

4.4.2 Evidence of Neurotoxicity ........................................................................................ 13

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ........... 13

4.4.4 Residual Uncertainty in the Exposure Database....................................................... 14

4.5 Toxicity Endpoint and Point of Departure Selections.................................................. 14

4.5.1 Endpoint Selection.................................................................................................... 14

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment.......... 16

4.5.3 Cancer Classification and Risk Assessment Recommendation................................ 16

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

Assessment............................................................................................................................ 17

5.0 Dietary Exposure and Risk Assessment ............................................................................ 18

5.1 Metabolite/Degradate Residue Profile.......................................................................... 18

5.2 Food Residue Profile..................................................................................................... 19

5.3 Water Residue Profile ................................................................................................... 20

5.4 Dietary Risk Assessment .............................................................................................. 20

5.4.1 Description of Residue Data Used in Dietary Assessment....................................... 20

5.4.2 Percent Crop Treated Used in Dietary Assessment .................................................. 21

5.4.3 Acute and Chronic Dietary Risk Estimates .............................................................. 21

5.4.4 Dietary Exposure and Risk Estimate Summary Table.............................................. 22

6.0 Residential (Non-Occupational) Exposure/Risk Characterization .................................... 22

6.1 Residential Handler Exposure....................................................................................... 22

6.2 Post-Application Exposure ........................................................................................... 23

6.3 Combined Exposure...................................................................................................... 24
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6.4 Residential Bystander Post-Application Inhalation Exposure...................................... 25

6.5 Spray Drift .................................................................................................................... 25

7.0 Aggregate Exposure/Risk Characterization....................................................................... 26

7.1 Acute Aggregate Risk................................................................................................... 26

7.2 Short- and Intermediate-Term Aggregate Risk............................................................. 26

7.3 Chronic Aggregate Risk................................................................................................ 27

7.4 Cancer Aggregate Risk ................................................................................................. 27

8.0 Cumulative Exposure/Risk Characterization..................................................................... 27

9.0 Occupational Exposure/Risk Characterization .................................................................. 28

9.1 Short- and Intermediate-Term Handler Risk ................................................................ 28

9.2 Short- and Intermediate-Term Post-Application Risk .................................................. 29

9.2.1 Dermal Post-Application Risk .................................................................................. 29

9.2.2 Inhalation Post-Application Risk.............................................................................. 30

10.0 References.......................................................................................................................... 31

Appendix A. Toxicology Profile and Executive Summaries....................................................... 32

A.1. Toxicology Data Requirements ....................................................................................... 32

A.2. Toxicity Profiles............................................................................................................... 33

A.3. Endpoint Selection ........................................................................................................... 42

Appendix B. Metabolism Summary Table ................................................................................... 45

Appendix C. Physical/Chemical Properties................................................................................. 46

Appendix D. Review of Human Research................................................................................... 47

Appendix E. Occupational Exposure/Risk Summary Tables...................................................... 48

Appendix F. Summary of Relevant International Residue Limits for Clothianidin.................... 52
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1.0 Executive Summary

The Registration Division (RD) requested that the Health Effects Division (HED) conduct an 

exposure and risk assessment for a revision to the pre-harvest interval (PHI) for Crop Subgroup 

8-10B (peppers and eggplant) proposed by Valent BioSciences and for the IR4 (Inter-Regional 

Project #4) proposed new uses on strawberry, pistachio, and citrus (Crop Group 10-10), and use 

on tea without a U.S. registration. This assessment takes into account previously registered uses 

on other crops and in residential use sites.

The toxicological database for clothianidin is largely complete; the only missing study is the 

subchronic (28-day) inhalation toxicity study. HED has determined that the study is required 

and has requested its submission during registration review. Pending the results of the study, a 

10X database uncertainty factor has been retained for residential and occupational inhalation 

exposure assessments. The residue chemistry database for clothianidin is complete.

HED has evaluated the available hazard and residue chemistry data to derive risk estimates 

associated with dietary, residential, and occupational exposure. HED’s aggregate risk 

assessment is based on screening-level assumptions and the resulting estimated exposure levels 

likely overestimate actual exposures that may occur. Sentinel aggregate risk indices (ARIs) are 

1.21 for children aged 1-2 years old and 6.9 for adults, and are not of concern. Similarly, 

occupational ARIs are not of concern, ranging from 1.1 to 660. Even with the conservative, 

health-protective assumptions, aggregate and occupational risk estimates are below HED’s level 

of concern for all scenarios and population groups.

There are no human health risk issues that would preclude granting the requested label 

amendment and new uses, and establishing permanent tolerances as described below.

2.0 HED Recommendations

2.1 Data Deficiencies/Conditions of Registration

A 28-day inhalation toxicity study in rats is required, based on weight of evidence 

considerations, including the available toxicity data and the potential for exposure to clothianidin 

via the inhalation route. The study has been requested under registration review.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate methods, based on solvent extraction and LC-MS/MS separation, identification, and 

quantification, are available for plant (Morse Method #Meth-164 - modified, RM-39C-1, or 

Bayer Method 00552) and livestock (Bayer Method 00624) matrices. The LOQ for clothianidin 

in plant commodities is 0.01 ppm, except for wheat straw (0.02 ppm), and the validated LOQs

are 0.01 ppm in milk and 0.02 ppm in animal tissues. Clothianidin and its major metabolites are 

not adequately recovered using any of the FDA multiresidue methods.
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2.2.2 International Harmonization

There are no Canadian or Codex Maximum Residue Limits (MRLs) for clothianidin that are 

relevant to the recommended tolerances. Codex MRLs (see Appendix F) are in place for tea, 

strawberry, citrus, and fruiting vegetables; however, the MRLs are based on clothianidin derived 

from treatment with thiamethoxam rather than treatment with clothianidin. Therefore, it is not 

appropriate to harmonize U.S. tolerances with the Codex MRLs. 

The Pest Management Regulatory Agency (PMRA) of Health Canada intends to establish an 

MRL for residues in Crop Subgroup 13-07G (low-growing berries) at 1.5 ppm. Strawberry is the 

representative crop for this subgroup; therefore, in terms of strawberry, the residue level will be 

harmonized. HED is not recommending for the entire subgroup because the requested use was 

on strawberry only.

With respect to Crop Subgroup 8-10B, the new tolerance for this subgroup is considerably 

greater than the existing Crop Group 8 tolerance. The new tolerance will result in regulatory

action levels for this subgroup being out of harmonization with PMRA.

2.2.3 Recommended Tolerances

Table 2.2.3. Summary of Requested and Recommended Tolerances for Residues of Clothianidin.

Commodity

Tolerance, ppm

Requested Recommended Comments/Corrections

Vegetable, fruiting, peppers and 

eggplant, Subgroup 8-10B

0.7 0.80 Upon establishment of this tolerance, the existing 

tolerance listing for vegetables, fruiting, Group 8 

should be revised to Vegetable, fruiting, group 8-

10, except pepper/eggplant subgroup 8-10B

Pistachio 0.01 0.01 --

Strawberry 1.4 1.50 --

Tea, dried 50 70 --

Fruit, citrus, Group 10-10 0.5 0.60 --

Citrus, dried pulp 1 -- A tolerance for this processed commodity is not 

necessary.

2.2.4 Revisions to Petitioned-For Tolerances

HED is recommending tolerance levels for Subgroup 8-10B (peppers and eggplant), strawberry, 

tea, and citrus (including dried citrus pulp) that are different from those requested by the 

petitioners. In the case of Subgroup 8-10B, strawberry, and citrus, the difference is likely due to 

the petitioners’ use of the NAFTA MRL calculation procedures rather than the OECD MRL

calculation procedures. The recommended tolerance for residues in/on tea appears to include a 

broader scope of data than was used to derive the petitioned-for tolerance. HED has determined 

that a separate tolerance for the processed commodity dried citrus pulp is not necessary. 

Although residues concentrate in dried citrus pulp, it is anticipated that they would not exceed 

the recommended tolerance level for the whole fruit.
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2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

 RD should ensure that the restrictions listed on the proposed label regarding use of 

adjuvants and restrictions on aerial application reflect all of the recent 

revisions/recommendations that were made by HED outside of these petitions (e.g., see 

M. Doherty, D404897, 13 August 2012; M. Doherty, D405080, 5 September 2012).

 Update the rotational crop restrictions to include strawberry as a crop suitable for 

immediate plant back.

 Revise the labels to ensure that for all crops, the maximum amount of active ingredient 

applied per season is generic for clothianidin and not specific to any one particular enduse product or type of application being made. 

 HED notes that the maximum seasonal foliar use rate for V-10170 2.13 SC on strawberry

(0.1 lb a.i./A) differs from the maximum seasonal use rate for the Arena product (0.2 lb 

a.i./A). HED recommends that RD ensure that these differences are intended by the 

petitioner. The available residue data support a maximum seasonal application rate of 0.2 

lb a.i./A to strawberry, irrespective of formulation types.

2.3.2 Recommendations from Occupational and Residential Assessments

None.

3.0 Introduction

3.1 Chemical Identity

Table 3.1. Clothianidin Nomenclature.

Parent Compound

Common name Clothianidin

Company experimental name TI-435, V-10066

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

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

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

Molecular wt. 249.68

End-use product (EP) 50% WDG (Arena®50 WDG; EPA Reg. No. 59639-152)

2.13 lb/gal FlC (V-10170 2.13 SC; EPA Reg. No. 59639-150)

3.2 Physical/Chemical Characteristics

Appendix C summarizes the physical and chemical properties of clothianidin. Based on the 

available data, clothianidin has a low vapor pressure and exposure to this chemical in the vapor 

S

N

N

H

N

NH

Cl

H C3

NO2
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phase is not expected. The octanol/water partitioning coefficient is also quite low, indicating that 

clothianidin is unlikely to accumulate in fatty tissues.

3.3 Pesticide Use Pattern

Table 3.3. Summary of Directions for Use of Clothianidin. 

Appl. timing,

type, and (equip.)

Formulation

[EPA Reg. No.]

Max. Single 

Appl. rate

(lb ai/A)

Max. No. 

of Appl. / 

Season

Max.

Seasonal 

Appl. Rate 

(lb ai/A)

PHI 

(days)

Use Directions 

and 

Limitations

Strawberry

Foliar, ground or aerial (FWA, 

ground boom and air-blast 

sprayers) Arena®

50 

WDG

[59639-152]

0.05-0.2 40.2 1 RTI=7 days

Soil broadcast, pre- or at 

transplanting, in-furrow, band 

or bed, transplant water 

drench, drip/trickle irrigation 

(back pack and MPHG)

0.15-0.2 1 0.2 21 RTI=Not 

applicable

Foliar, ground or aerial (FWA, 

ground boom and air-blast 

sprayers) V-10170 2.13 

SC

[59639-150]

0.05-0.1 2 0.1 1 RTI=7 days

Soil in-furrow, band, drench, 

drip or trickle irrigation (back 

pack and MPHG)

0.15-0.2 1 0.2 21 RTI=not 

applicable

Citrus fruit

Foliar, ground or aerial

(aircraft, and air-blast sprayer)

V-10170 2.13 

SC

[59639-150]

0.05-0.1 4 0.2 1 RTI=14 days

Soil in-furrow, band, drench, 

drip or trickle irrigation (backpack and MPHG)0.15-0.2 1 0.2 21 RTI=not 

applicable

Basal bark spray

(back-pack)

0.1 for 2-4 

ft. 

and 0.2 for 

4-8 ft. trees

1 0.2 1

RTI=not 

applicable

Nectarine

Foliar, post bloom ground (air 

blast sprayer)

V-10170 2.13 

SC

[59639-150]

0.05-0.1 4 0.2 21 RTI=10 days

Pistachio

Foliar, ground or aerial

(FWA and air blast sprayer)

V-10170 2.13 

SC

[59639-150]

0.05-0.1 4 0.2 21 RTI=10 days

Tea

Foliar NS 1.8 1 NS 7

Use patterns 

are implied 

from the field 

trial 

application 

parameters

Peppers and Eggplant (Crop Subgroup 8-10B)*

Foliar Arena®

50 

WDG

[59639-152]

0.05-0.1 4 0.2 1 RTI=10 days

Soil in-furrow, band, drench, 

drip or trickle irrigation (back0.15-0.2 1 0.2 NS Apply at planting
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Table 3.3. Summary of Directions for Use of Clothianidin. 

Appl. timing,

type, and (equip.)

Formulation

[EPA Reg. No.]

Max. Single 

Appl. rate

(lb ai/A)

Max. No. 

of Appl. / 

Season

Max.

Seasonal 

Appl. Rate 

(lb ai/A)

PHI 

(days)

Use Directions 

and 

Limitations

pack and MPHG)

Foliar

V-10170 2.13 

SC

[59639-150]

0.05-0.067 3 0.2 1 RTI = 7 days

Soil broadcast, pre- or at 

transplanting, in-furrow, band 

or bed, transplant water 

drench, drip/trickle irrigation 

(back pack and MPHG)

0.15-0.2 1 0.2 NS Apply at 

planting

Abbreviations used: MPHG= mechanically pressurized hand gun, PHI = Preharvest interval, RTI= re-treatment 

interval, NS=not specified.

* Uses on peppers and eggplant are already registered, with a PHI of 7 days. This entry reflects the requested label 

amendment to reduce the PHI to 1 day.

The personal protective equipment (PPE) requirements proposed for applicators and other 

handlers include: long-sleeved shirt and long pants, socks plus shoes, and chemical-resistant 

gloves. The Restricted Entry Interval (REI) is 12 hours. The PPE and REI on both labels are 

appropriate based on the acute toxicity and estimated handler exposures and risks for 

clothianidin.

3.4 Anticipated Exposure Pathways

Clothianidin is registered for use on numerous agricultural crops as well as on residential turf, 

and there is also an indoor use to control bed bugs. Exposure to clothianidin may occur from 

ingestion of residues in/on foods and in drinking water, and via the dermal and inhalation routes 

for adults using clothianidin products in occupational and residential settings. Finally, incidental 

oral ingestion can occur for toddlers playing in areas previously treated with clothianidin (e.g., 

turf and indoor surfaces).

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 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures 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 Dept. of Health and Human 

Services under the National Health and Nutrition Examination Surveys 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 
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for adult applicators and for toddlers, youths, and adults entering or playing on treated areas 

post-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

4.1 Toxicology Studies Available for Analysis

Appendix A summarizes the toxicity profile for clothianidin. The toxicity database is largely 

complete, and the following studies are available: acute, subchronic, and developmental 

neurotoxicity; subchronic oral in rats, mice and dogs; subchronic dermal, chronic/carcinogenicity 

in rats; carcinogenicity in mice; chronic in dogs; developmental in rats and rabbits; 2-generation 

reproduction in the rat; mutagenicity battery; metabolism (rats and mice); dermal penetration 

(monkeys); 28-day immunotoxicity as well as developmental immunotoxicity in the rat; and a 

special neurotoxicity and pharmacology study in mice. A complete battery of mutagenicity

studies was also conducted with clothianidin and several metabolites.

The only missing toxicology study is a subchronic (28-day) inhalation study, which HED has 

determined is required, based on weight-of-evidence considerations. 

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

The ADME of clothianidin was examined in single-dose studies in rats (2.5 and 250 mg/kg) and 

mice (5 mg/kg) and a 14-day repeated-dose study in the rat (25 mg/kg/day) using radiolabeled 

chemical. The rate of absorption, route of excretion, and nature of metabolism was similar 

across species and gender. Following an oral dose, greater than 90% of the administered dose is 

excreted in the urine within the first 24 hours. At 250 mg/kg/day, there was a lag in urinary

clearance, taking up to 48 hours to excrete 90% of the administered dose (AD). The lag 

indicates saturation of the absorption mechanism at this high dose. The remaining 5-6% of the 

AD is eliminated via the feces. Females absorbed slightly greater amounts of the administered 

dose in the rat; 90% for males and 95% for females in the 2.5 mg/kg group. However, females 

also had a slightly greater clearance rate so there was not a greater net accumulation in the

females. Females were only tested at the 2.5-mg/kg dose. The time-to-peak plasma 

concentrations in the rat (Tmax) were 1.5 and 2.7 hours for the 2.5 and 25 mg/kg dose groups, 

respectively. 

Following absorption, clothianidin is distributed throughout the body. Although the organs 

associated with the absorption and elimination systems (i.e., bladder, kidney, liver, and nasal 

mucosa) initially demonstrate elevated levels, none of the tissues examined contained residue 

levels >1% of the administered 24 hours after dosing in the rat. Therefore, bioaccumulation is 

not a concern. 

Parent was the most abundant residue indentified in the urine, at 30% AD in the mouse and 55-

74% in the rat. Three metabolites were identified as major (>10% AD), with several additional 
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metabolites identified at <10% AD. The major metabolites were the result of demethylation of 

the parent or cleavage products of the nitrogen-carbon bond between the nitroimino and thiazolyl 

moieties. 

4.2.1 Dermal Absorption

A dermal penetration study was conducted in monkeys, using the undiluted FS 600 formulation

of clothianidin (10% ai). The exposure duration was 8 hours and the subjects were monitored for 

120 hours. Dermal absorption was estimated based on the sum of the administered dose 

measured in fecal and urinary excretions. Dermal penetration was low at 0.24% of the 

administered dose. A value of 1% dermal absorption has been recommended as appropriate for 

use in risk assessment (K. Schumacher, D331226, 28 November 2006).

4.3 Toxicological Effects

The insecticidal mode of action of clothianidin is agonism of the nicotinic acetylcholine receptor, 

leading to overstimulation of the central nervous system and death. In mammals, the toxic 

effects of clothianidin appear to be much less specific and involve multiple organ systems. The 

primary effects as indicated by the toxicity database are on the liver, hematopoietic system and 

kidneys. Liver, body weight changes, thyroid effects and neurotoxicity are all commonly

observed in toxicity studies of other neonicotinoids.

Acute neurotoxicity studies were conducted in rats and mice following exposure by gavage. In 

the acute neurotoxicity rat study, FOB effects, including decreased arousal as well as decreased 

motor and locomotor activity, were seen at the lowest observed adverse effect level (LOAEL) on 

Day 0 in males. Effects at dose levels above the LOAEL in the rat study included tremors, 

slightly uncoordinated gait, effects on pupil response and righting reflex, and decreases in both 

temperature and ataxia. In the acute neurotoxicity study in mice, effects were also observed on 

Day 0 in males (no female mice were tested), but occurred at lower doses than those that 

produced neurotoxic effects in rats. Effects seen at the LOAEL in the mouse study included 

transient signs of decreased spontaneous motor activity, tremors and deep respirations. At higher 

dose levels, decreases in reactivity, grooming and muscle tone, prone position, staggered gait,

mydriasis, and hypothermia were observed. 

In subchronic oral studies in rats and dogs, decreases in body weight and body weight gain were 

observed. In addition, dogs also displayed decreased white blood cells, albumin and total 

protein, as well as some anemia, and they appeared to be more sensitive than rats. Male dogs 

were more sensitive than females. Neurotoxicity was not observed in the subchronic 

neurotoxicity study. No effects were observed up to the limit dose in the 28-day dermal study in 

rats.

Chronic feeding studies were conducted in the dog, rat and mouse. Anemia was the only adverse 

effect observed in the dog, and was only found in females at the highest dose tested. In the rat, 

decreased body weight and food consumption, interstitial gland hyperplasia in the ovary, 

increased lymphohistiocytic infiltrate and altered hepatocellular eosinophilic foci of the liver 

were observed in females; decreased body weight and food consumption, slightly increased 
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incidences of pelvic mineralization, and transitional cell hyperplasia in the kidney, mottled 

livers, and altered hepatocellular eosinophilic foci in the liver were observed in male rats. In the 

mouse, decreases in body weight and body weight gain in females and increases in vocalization 

in both sexes were the only observed effects. 

A comparison of the subchronic and chronic feeding studies in rats showed that a wider spectrum 

of effects was observed in the chronic study, even though the no observed adverse effect levels 

(NOAELs) and LOAELs in these two studies were similar. Thus, it appears that there may be 

more toxicity in rats when exposure is over a longer period of time. In contrast, administration 

to the dog for a longer period of time does not appear to result in any additional effects or effects 

at lower doses.

No increased quantitative or qualitative susceptibility was observed in the developmental rat or 

rabbit studies. In the rat, no developmental toxicity was observed at the highest dose tested, 

although this dose induced decreases in body weight gain and food consumption in the dams. In 

the rabbit, premature deliveries, decreased gravid uterine weights, an increase in litter incidence 

of a missing lobe of the lung and decreased ossification of the sternum were noted at a dose level 

at which maternal death, a decrease in food consumption and clinical signs (scant feces and 

orange urine) were observed. The developmental effects in this study are not considered to be 

quantitatively more severe than the maternal effects because they occurred at the same dose and 

they are not considered to be qualitatively more severe because death occurred in the dams.

There was an increase in quantitative susceptibility in the developmental neurotoxicity and 

reproductive toxicity studies; offspring effects were observed in the absence of maternal toxicity. 

In the DNT, maternal effects observed at the high-dose included decreased body weights, body 

weight gains and food consumption. Effects seen in the offspring observed at the mid-dose

included decreased body weights, body weight gains, motor activity and acoustic startle response 

in females. In the two-generation reproduction study, the LOAEL for offspring toxicity is based 

on decreased body weight gains, delayed sexual maturation (males), decreased absolute thymus 

weights in F1 pups of both sexes, and an increase in stillbirths in both generations at the middose. The parental systemic LOAEL is based on decreased absolute body weights and body

weight gains with decreased absolute and relative thymus weights in both sexes observed at the 

high-dose.

Clothianidin is classified as not likely to be carcinogenic to humans. In the rat chronic 

carcinogenicity study, an apparent increase in thyroid c-cell tumors was observed in females. A 

statistical analysis revealed that the increase in these tumors did not appear to be significant, 

especially when carcinomas and adenomas were combined. Increased incidences of 

hepatocellular carcinomas at the low and high doses were just outside historical control 

incidences for the same testing laboratory (only 2 studies) but were within the historical control 

range for the animal supplier. In addition, there was no dose-response and no continuum (i.e., no 

preneoplastic lesions and no adenomas). There was no evidence of an increase of tumors in 

mice. 

In the mutagenicity studies, none of the intermediates or metabolites appeared to have genotoxic 

potential under the conditions of the studies, but the studies for the technical material gave mixed 
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results. Some of the batches of test material were positive and some were negative. HED had 

requested that the composition of the test materials used in the mutagenicity studies be 

investigated to determine whether or not the differences in composition may have affected the 

results from the studies. To address the request, additional mutagenicity studies were performed 

and it was determined that there was no concern because clothianidin was neither clastogenic nor 

aneugenic in the mouse bone marrow micronucleus assay up to a toxic oral dose (100 mg/kg); 

also, there was no induction of unscheduled DNA synthesis (UDS) in the livers of Wistar male 

mice when administered at the limit dose of 2000 mg/kg.

In some of the toxicity studies, there was evidence of possible effects on the immune system. 

Decreased absolute and relative thymus and spleen weights were observed in multiple studies. 

In addition, juvenile rats in the two-generation reproduction study appeared to be more 

susceptible to these effects. The thymus is involved in the production of T cells, whose function 

is to recognize and respond to foreign antigens. The spleen serves an important function in 

clearing the blood of infectious organisms. A guideline immunotoxicity study showed no 

evidence of clothianidin-mediated immunotoxicity in adult rats, in the form of a T-cell dependent 

anti-Sheep Red Blood Cell (SRBC) forming cell response, at doses lower than those resulting in 

generalized signs of toxicity (e.g., decreases in body weight). However, since effect in the 

offspring occurred at lower doses in the two-generation study, HED concluded that the lack of 

effects on immunotoxicity in adults did not alleviate concerns for immunotoxicity in the 

offspring. A developmental immunotoxicity study was required and demonstrated no increased 

susceptibility with respect to immunotoxicity.

Clothianidin and numerous metabolites were examined for acute toxicity. Acute toxicity via 

oral, inhalation and dermal routes of exposure in the rat is relatively low (Category III or IV). 

Only technical clothianidin in the mouse and the TMG metabolite in the rat via the oral route 

were toxicity Category II. There is no evidence of dermal sensitization or eye irritation with the 

exception of the clothianidin-triazan intermediate, which is a dermal sensitizer.

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

HED recommends that the FQPA SF of 10X be reduced to 1X for dermal and oral exposure 

pathways based on the following considerations: (1) the toxicology data base is complete (with 

the exception of an inhalation study) and includes developmental neurotoxicity, immunotoxicity

and developmental immunotoxicity studies; (2) HED characterized the degree of concern for the 

quantitative susceptibility observed in the clothianidin 2-generation reproduction and DNT 

studies as low based on the clear NOAELs for the offspring effects and the selection of 

regulatory doses that are protective of those effects; (3) the rat is the most sensitive species 

tested, and the NOAEL and LOAEL selected from the 2-generation reproduction study in rats 

are protective of effects observed in other species throughout the toxicology database; (4) there 

are no residual uncertainties for pre- and/or post-natal toxicity, since the submitted 

developmental immunotoxicity study indicated no evidence of susceptibility; (5) HED is 

regulating the use of clothianidin based upon the most sensitive offspring effects observed in the 

reproduction toxicity study, and therefore the risk assessment is protective of these and other 

effects that occurred at higher doses; (6) the exposure databases (dietary food, drinking water, 

and residential) are complete; and (7) the risk assessment for each potential exposure scenario 
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includes all metabolites and/or degradates of concern and does not underestimate potential 

exposure and risk for infants or children. 

In the absence of the required inhalation toxicity study, HED is recommending the 10X FQPA 

factor be retained as a database uncertainty factor for assessing inhalation exposure and risk

only, for both adults and children.

4.4.1 Completeness of the Toxicology Database

Acceptable guideline studies for developmental, reproductive toxicity and neurotoxicity

(including DNT) are available for FQPA assessment. Immunotoxicity studies in rats and mice 

have also been submitted and reviewed. A subchronic inhalation study remains outstanding and 

is considered a data deficiency (TXR 0055320).

4.4.2 Evidence of Neurotoxicity

Neurotoxicity was observed in acute neurotoxicity studies in the rat and mouse. Neurotoxicity

was observed on the day of dosing and was not observed in subsequent evaluations. In the rat, 

decreased arousal and motor activity were observed at the LOAEL of 100 mg/kg (NOAEL 60 

mg/kg). Effects at dose levels above the LOAEL in the rat study included tremors, slightly 

uncoordinated gait, effects on pupil response and righting reflex, and decreases in both 

temperature and ataxia. In the mouse, transient signs of decreased spontaneous motor activity, 

tremors and deep respirations were observed at the LOAEL 50 mg/kg (NOAEL 25 mg/kg). At 

higher dose levels, decreases in reactivity; grooming and muscle tone; prone position; staggered

gait; mydriasis; and hypothermia were observed. In the developmental neurotoxicity study, 

toxicity in the offspring was observed at a lower dose level than the dose that caused toxicity in 

the maternal animals. Maternal effects included decreased body weights, body weight gains, and

food consumption. Effects seen in the offspring included decreased body weights, body weight 

gains, motor activity, and acoustic startle response in the females. Neurotoxicity was not 

observed in the subchronic neurotoxicity study with a high dose of 177/200 mg/kg/day (M/F) or 

any other study in the toxicity database.

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

There is no residual concern for increased qualitative or quantitative susceptibility in the rat or 

rabbit developmental toxicity studies. 

In the two-generation reproduction developmental neurotoxicity studies in the rat, there was 

increased quantitative susceptibility as the offspring NOAELs were below the parental NOAELs. 

However, clear NOAELs were identified for the offspring effects. 

There were indications of potential immunotoxicity in the database. Decreased absolute and 

relative thymus and spleen weights were observed in multiple studies. Juvenile rats in the twogeneration reproduction study appeared to be more susceptible to these effects, indicating a 

concern for qualitative susceptibility. However, a guideline immunotoxicity study showed no 

evidence of clothianidin-mediated immunotoxicity in adult rats, and a developmental 
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immunotoxicity study demonstrated no susceptibility with respect to immunotoxicity. Therefore, 

the residual concern for immunotoxicity in adults and offspring is reduced.

Since there is evidence of increased quantitative susceptibility of the young following exposure 

to clothianidin in the rat reproduction study and the DNT study, HED performed a degree of 

concern analysis to: 1) determine the level of concern for the effects observed when considered 

in the context of all available toxicity data; and, 2) identify any residual uncertainties after 

establishing toxicity endpoints and traditional uncertainty factors to be used in the clothianidin

risk assessment. If residual uncertainties are identified, HED examines whether the residual 

uncertainties can be addressed by a FQPA safety factor, and if so, what factors should be 

retained.

Considering the overall toxicity profile and the endpoints and doses selected for the clothianidin

risk assessment, HED characterized the degree of concern for the effects observed in the 

clothianidin 2-generation reproduction and DNT studies as low, noting that there are clear 

NOAELs for the offspring effects and regulatory doses were selected to be protective of these 

effects. No other residual uncertainties were identified with respect to susceptibility. HED 

believes that the endpoints and doses selected for clothianidin are protective of adverse effects in 

both offspring and adults.

4.4.4 Residual Uncertainty in the Exposure Database

In the absence of the 28-day inhalation study, there is uncertainty about potential portal of entry 

effects occurring via the inhalation route of exposure, and HED is recommending retaining the 

10X FQPA factor as a database uncertainty factor for the inhalation route of exposure only, 

pending submission of the required study (Hazard and Science Policy Council, 23 March 2012, 

TXR# 0055320). 

HED has used conservative assumptions in the dietary exposure assessment, including the use of 

100% crop treated assumptions, tolerance-level residue values, and upper-bound estimates of 

potential exposure through drinking water. In addition, the residential exposure assessment was 

conducted such that residential exposure and risk will not be underestimated. The aggregate 

exposure and risk estimates presented in this assessment are expected to over-estimate actual 

exposure and risk expected based on the current and proposed use patterns, and no risk estimates 

of concern were identified.

4.5 Toxicity Endpoint and Point of Departure Selections

Based on the use pattern and the toxicological profile of clothianidin, HED selected endpoints 

and doses for acute and chronic dietary risk assessment and non-occupational and occupational 

exposures (i.e., incidental oral, dermal, or inhalation). For occupational handlers and workers reentering treated areas, HED selected endpoints and doses for dermal and inhalation exposure and 

risk assessment.

4.5.1 Endpoint Selection
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The acute dietary endpoints and dose selected for risk assessment were based on single dose 

effects observed in the toxicity database; separate endpoints were selected for females 13-49 and 

the general US population including infants and children. For all other exposure scenarios, 

including incidental oral, dermal and inhalation, HED relied on the endpoint and dose selected 

from the 2-generation reproduction toxicity study. Because effects seen in the reproduction 

study can occur as the result of a single exposure at a critical junction during pregnancy or from 

multiple exposures throughout pregnancy and lactation, the NOAEL for offspring effects 

observed in the reproduction study was selected as the dose for all durations of exposure. The 

dose selected for risk assessment is also the most sensitive for repeated exposures, and is 

protective of all other effects in the database.

Acute Dietary Endpoint for Females 13-49: The endpoint used for establishing the aPAD for 

females 13-49 was selected from the developmental study in the rabbit. An aPAD of 0.25 

mg/kg/day was derived from a NOAEL of 25 mg/kg/day and a 100-fold factor that included 10x 

for inter-species extrapolations, 10x for intra-species variations, and a 1x FQPA SF. The 

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

This endpoint is appropriate for the acute dietary exposure assessment because it could be the 

result of a single exposure at a critical junction during pregnancy or from multiple exposures 

throughout pregnancy, it is an appropriate route of exposure (oral), and it is protective of 

developing offspring. 

Acute Dietary Endpoint for the General Population: The endpoint used for establishing the 

aPAD for the general population was selected from the acute neurotoxicity study in rats. An 

aPAD of 0.25 mg/kg/day was derived from a NOAEL of 25 mg/kg/day and a 100-fold factor 

that included 10x for inter-species extrapolations, 10x for intra-species variations, and a 1x 

FQPA SF. The LOAEL of 50 mg/kg was based on transient signs of spontaneous motor activity, 

tremors, and deep respirations observed on Day 1. Similar signs of neurotoxicity were observed 

in the acute neurotoxicity study in the rat at 100 mg/kg, with a NOAEL of 60 mg/kg. This 

endpoint is appropriate for the acute dietary exposure assessment because it is the result of a 

single dose, is an appropriate route of exposure (oral) and is protective of the general population. 

Although the developmental toxicity study in the rat had a lower maternal NOAEL of 10 

mg/kg/day (LOAEL 40 mg/kg/day), this study was not chosen for endpoint selection because the 

NOAEL is considered to be artificially low due to dose spacing and because the effects 

(decreased body weight and food consumption) were not the result of acute exposure. 

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

generation reproduction study in the rat. A cPAD of 0.01 mg/kg/day was derived from a 

NOAEL of 9.8 mg/kg/day and a 100-fold factor that included 10x for inter-species extrapolation, 

10x for intra-species variability, and a 1x FQPA SF. The LOAEL of 31.2 mg/kg was based on 

decreased body weight gains, delayed sexual maturation, decreased thymus weights in F1 pups, 

and increased stillbirths in both generations. This study had the lowest NOAEL resulting from 

repeated dose exposure in the database.

Incidental Oral: The endpoint used for assessing short-term incidental oral exposure was 

selected from the 2-generation reproduction study in the rat. The NOAEL is 9.8 mg/kg/day, and 

the level of concern (LOC) is an MOE of 100 (10x for inter-species extrapolation, 10x for intra-
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species variability, and a 1x FQPA SF). The effects observed at the LOAEL of 31.2 mg/kg have 

been described above (see chronic dietary). The study, dose and endpoint were selected because 

of the exposure duration and because selection of the offspring effects is protective of the 

population of concern, developing children.

Dermal (All Durations): The endpoint used for assessing all durations of dermal exposure was 

selected from the 2-generation reproduction study in the rat. The NOAEL is 9.8 mg/kg/day, and 

the LOC is an MOE of 100 (10x for inter-species extrapolation, 10x for intra-species variability, 

and a 1x FQPA SF). The effects observed at the LOAEL of 31.2 mg/kg have been described 

above (see chronic dietary). The study was selected because of the exposure duration, and 

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

Although a dermal (route specific) toxicity study in rats was submitted, no effects were seen at 

the highest dose tested of 1000 mg/kg/day. Use of the route-specific study for dermal risk 

assessment would not be protective of the offspring effects observed in both the DNT and the 2-

generation reproduction studies because the dermal study does not evaluate reproduction and 

developmental parameters. Since the dermal endpoint was selected from an oral study, a 1% 

dermal absorption factor (DAF) is used to determine dermal exposure and risk. 

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

was selected from the 2-generation reproduction study in the rat. The NOAEL is 9.8 mg/kg/day, 

and the LOC is an MOE of 1000 (10x for inter-species extrapolation, 10x for intra-species 

variability, a 10x FQPA SF for residential scenarios, and a 10x database uncertainty factor for 

occupational scenarios). The effects observed at the LOAEL of 31.2 mg/kg have been described 

above. The study was selected because of the exposure duration, and because it is protective of 

the most sensitive population, developing children. No route-specific information is available 

for the inhalation toxicity of clothianidin. In the absence of a route-specific study, the NOAEL 

and LOAEL from an oral study have been used for risk assessment (i.e., inhalation toxicity is 

assumed to be equivalent to oral toxicity).

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

HED has chosen a single endpoint and dose from the 2-generation reproduction study for

assessing exposure via incidental oral, dermal and inhalation routes. Therefore, these routes of 

exposure can be combined in the risk assessment.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Clothianidin is classified as “not likely to be carcinogenic to humans.” There was no treatmentrelated increase in tumor incidences in treated mice when compared to controls. In the rat, there 

was an increase in thyroid c-cell tumors in female that did not appear to be significant, especially

when carcinomas and adenomas are combined. There was an increase incidence of 

hepatocellular carcinomas in male rats at the low and high doses just outside historical control 

incidences for the same testing laboratory (only 2 studies) but within the historical control range 

for the animal supplier. In addition, there was no dose-response. Finally, there was no 

continuum (i.e. no preneoplastic lesions and no adenomas). Clothianidin was positive for the 
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gene mutation bacterial reverse mutation assay at the highest dose tested. However, clothianidin 

and several metabolites were negative in the remaining mutagenicity studies. 

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

Assessment

Table 4.5.4a. Summary of Toxicological Doses and Endpoints for Clothianidin for Use in Dietary and NonOccupational Human Health Risk Assessments.

Exposure/

Scenario

Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

Level of 

Concern (LOC)

for Risk 

Assessment

Study and Toxicological Effects

Acute Dietary

Females age 

13-49

NOAEL = 

25 mg/kg/day

UFA = 10X

UFH = 10X

SFFQPA =1X

aRfD=0.25 

mg/kg/day

aPAD=0.25 

mg/kg/day

Rabbit developmental study 

LOAEL = 75 mg/kg/day based on increased 

litter incidence of a missing lobe of the lung

Acute Dietary

General population

NOAEL = 

25 mg/kg/day

UFA = 10X

UFH = 10X

SFFQPA = 1X

aRfD = 0.25

mg/kg/day

aPAD 0.25

mg/kg/day

Special neurotoxicity/pharmacology

study in mice 

LOAEL = 50 mg/kg/day based on transient 

signs of decreased spontaneous motor 

activity, tremors and deep respirations

Chronic Dietary

All populations

including infants 

and children

NOAEL= 

9.8 mg/kg/day 

UFA = 10X

UFH = 10X

SFFQPA =1X

cRfD=0.098 

mg/kg/day

cPAD=0.098 

mg/kg/day

2-Generation reproduction study 

LOAEL = 31.2 mg/kg/day based on 

decreased body weight gains and delayed 

sexual maturation, decreased absolute 

thymus weights in F1 pups and increased 

stillbirths in both generations

Incidental Oral 

(short-term)

NOAEL= 

9.8 mg/kg/day

UFA= 10X

UFH= 10X

SFFQPA=1X

MOE= 100 

(residential)

2-Generation reproduction study 

LOAEL= 31.2 mg/kg/day based on 

decreased body weight gains and delayed 

sexual maturation, decreased absolute 

thymus weights in F1 pups 

Dermal (all 

durations) 

Oral study 

NOAEL= 

9.8 mg/kg/day

(dermal 

absorption = 1%

of oral 

absorption)

UFA= 10X

UFH= 10X

SFFQPA=1X

MOE= 100 

(residential)

2-Generation reproduction study 

LOAEL = 31.2 mg/kg/day based on 

decreased body weight gains and delayed 

sexual maturation, decreased absolute 

thymus weights in F1 pups and increased 

stillbirths in both generations

Inhalation (all 

durations)

Oral study 

NOAEL= 

9.8 mg/kg/day

(inhalation

toxicity = oral 

toxicity)

UFA= 10X

UFH= 10X

SFFQPA=10X

for lack of 

subchronic 

inhalation 

study

MOE= 1000 

(residential)

2-Generation reproduction study

LOAEL = 31.2 mg/kg/day based on 

decreased body weight gains and delayed 

sexual maturation, decreased absolute 

thymus weights in F1 pups and increased 

stillbirths in both generations

Cancer (oral, 

dermal, inhalation)

“Not Likely to be Carcinogenic to Humans” 

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

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

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

sensitivity among members of the human population (intraspecies). UF DB = to account for the absence of key data. 
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SFFQPA = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. 

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

Table 4.5.4b. Summary of Toxicological Doses and Endpoints for Clothianidin for Use in Occupational Human 

Health Risk Assessments.

Exposure/

Scenario

Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

Level of 

Concern (LOC) 

for Risk 

Assessment

Study and Toxicological Effects

Dermal (all 

durations) (Adults)

Oral study 

NOAEL= 

9.8 mg/kg/day

(dermal 

absorption = 1%

of oral 

absorption)

UFA= 10X

UFH= 10X

MOE= 100 

(occupational)

2-Generation reproduction study 

LOAEL = 31.2 mg/kg/day based on 

decreased body weight gains and delayed 

sexual maturation, decreased absolute 

thymus weights in F1 pups and increased 

stillbirths in both generations

Inhalation (all 

durations)

Oral study 

NOAEL= 

9.8 mg/kg/day

(inhalation

toxicity = oral 

toxicity)

UFA= 10X

UFH= 10X

UFDB = 10X

MOE= 1000 

(occupational)

2-Generation reproduction study

LOAEL = 31.2 mg/kg/day based on 

decreased body weight gains and delayed 

sexual maturation, decreased absolute 

thymus weights in F1 pups and increased 

stillbirths in both generations

Cancer (oral, 

dermal, inhalation)

“Not Likely to be Carcinogenic to Humans.” 

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

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

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

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

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

5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile

D262541, Y. Donovan, 2 February 2000

Previous risk assessments have described the available metabolism data to support use of 

clothianidin on a number of agricultural crops. Appendix B summarizes the results of the 

available metabolism studies. Based on these results, 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 and livestock commodities. HED had 

previously determined that future new uses on root crops and/or leafy vegetables will require 

analysis for residues of the metabolite 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.

Table 5.1. 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
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Table 5.1. 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 Leafy and Root/Tuber Vegetables: Parent + TMG

Other crops: Parent

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

5.2 Food Residue Profile

D397689, M. Doherty, 26 September 2012

D399953, M. Doherty, 26 September 2012

Adequate field trial data have been submitted to support the requested uses on strawberry, citrus, 

and tea, as well as the requested PHI reduction and tolerance increase for peppers and eggplant 

(Crop Subgroup 8-10B). In addition, HED has adequate data to determine the potential for 

concentration of residues in citrus processed commodities; the data indicate concentration occurs 

only in dried citrus pulp. Adequate data are available from representative tree nut commodities 

to translate the existing tolerance for residues in/on tree nuts to pistachio. The data are 

summarized in the tables below.

Table 5.2.1. Summary of Residue Data for Clothianidin in/on Bell and Non-Bell Peppers Following a 1-Day PHI.

Pepper Type Variety Trial Location Application 

Rates, g a.i./A

Clothianidin Residues, 

ppm

Average Residue 

± Std. Dev., ppm

Bell Hunter Tift, GA 44.54 + 45.16 0.085, 0.123 0.104 ± 0.027

Heritage Barnwell, SC 45.42 + 45.30 0.068, 0.049 0.059 ± 0.013

Green Bell Seminole, FL 45.05 + 44.75 0.094, 0.083 0.089 ± 0.008

Revolution Martin County, FL 46.34 + 46.49 0.048, 0.034 0.041 ± 0.010

McCabi Yuma, AZ 46.38 + 45.89 0.122, 0.127 0.125 ± 0.004

Cal Wonder Tulare County, CA 45.21 + 46.30 0.198, 0.225 0.212 ± 0.019

Non-Bell Mesilla Seminole, FL 44.4 + 45.2 0.312, 0.282, 0.311 0.302 ± 0.017

Dulce Yuma, AZ 46.9 + 47.3 0.069, 0.082, 0.114 0.088 ± 0.023

Conch Tift, GA 45.4 + 45.1 0.019, 0.015, 0.021 0.018 ± 0.003

Summary of Clothianidin Residue Data for Strawberry, Citrus, and Tea.

Commodity

Application 

Rate, lb a.i./A

PHI, 

days n

Clothianidin, ppm

Min. Max. LAFT HAFT Median Mean

Std. 

Dev.

Strawberry 0.2 1 10 0.096 1.170 0.103 1.120 0.258 0.327 0.301

Grapefruit 0.2 1 7 0.010 0.346 0.010 0.281 0.047 0.084 0.098

Lemon 0.2 1 7 0.022 0.201 0.034 0.176 0.094 0.105 0.050

Orange 0.2 1 13 0.005 0.269 0.008 0.219 0.057 0.083 0.066

Tea 0.9 – 1.8 3-7 12 2.14 38.0 2.15 37.55 13.95 15.21 11.76

Summary of Residues and Processing Factors from the Orange Processing Study.

Commodity Residues (ppm) [Average] Processing Factor1
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Fruit

0.223

0.236 [0.242]

0.267

_

Oil

< 0.005 

< 0.005 [<0.005]

< 0.005

<0.02

Juice

0.006

0.007 [0.006]

0.006

0.03X

Dried Pulp

0.417

0.406 [0.406]

0.396

1.68X

1

Processing factor from RAC, calculated from the average residues.

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 (R. Baris, 15 

September 2011, D393235). EFED has confirmed that it is the appropriate value to use in this 

assessment (e-mail from R. Baris; 16 July 2012, 3:12:46 pm).

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. For the previous risk assessment in 

which HED also evaluated the use of clothianidin on leafy vegetables, the 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, as shown in the table below. 

Potential residues in drinking water associated with the currently proposed uses would likely be 

much lower than those predicted using the Tier I Rice Model.

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.

5.4 Dietary Risk Assessment

D397690, M. Doherty, 26 September 2012

5.4.1 Description of Residue Data Used in Dietary Assessment
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The acute and chronic assessments rely on tolerance-level residues (40 CFR 180.586) for all 

crops with registered and/or requested clothianidin uses. For crops except leafy vegetables, the

residue of concern for risk assessment purposes is the parent compound. For root crops and 

leafy vegetables, the residues of concern are the parent compound and the TMG metabolite. 

Field trial data show no detectable residues of TMG in root crops and that TMG does not exceed 

10% of the parent compound residue level in leafy vegetables. A factor of 1.1 (entered into the 

model as Adjustment Factor 1) has been incorporated into the assessment for leafy vegetables to 

account for the presence of TMG. For livestock commodities, the residues of concern are the 

parent compound as well as the metabolites TZU, TZG, TZNG, ATMG-pyruvate, and ATGacetate. Milk is currently the only livestock-derived commodity with a tolerance for 

clothianidin. A factor of 1.5, which is based on metabolism data, has been incorporated into the 

assessment to account for the residues of concern in milk.

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. For foods with thiamethoxam tolerances but without 

clothianidin tolerances, maximum residues of clothianidin observed in thiamethoxam residue 

trials have been used in these assessments. These include meats, meat by-products, artichoke, 

tropical fruits, coffee, hop, and mint (the estimate for residue in coffee was updated from 0.01 

ppm to 0.04 ppm to reflect new data from recently submitted thiamethoxam field trials).

Orange processing study data show that clothianidin does not concentrate in citrus oil or juice. 

Relative to the whole fruit, there is a modest increase in residues in pulp (1.8X). These empirical 

processing factors, as well as those derived previously, have been included in these analyses. 

Complete listings of the residue estimates, metabolite factors, and processing factors used in 

these analyses may be found in Attachment 1.

5.4.2 Percent Crop Treated Used in Dietary Assessment

HED assumed 100% crop treated for all food items in the dietary assessment for both acute and 

chronic exposure durations.

5.4.3 Acute and Chronic Dietary Risk Estimates

The acute and chronic assessments are based on highly conservative, health-protective 

assumptions regarding residue levels in food and percentage of crops treated. Likewise, the

estimated concentration in drinking water is highly conservative, especially given that it 

represents residues in rice paddy tail water and no adjustment was made to take into account the 

portion of the watershed that would be cropped to rice. The analyses resulting from these 

assumptions should be considered screening-level analyses that likely overestimate actual dietary
Clothianidin Human Health Risk Assessment DP No. D395348

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exposure to clothianidin. All risk estimates (Table 5.4.4) are below HED’s level of concern

(<100% of the aPAD and cPAD).

There are no dietary exposure or risk considerations that would preclude making the label 

amendment shortening the PHI for Crop Subgroup 8-10B, registering the clothianidin end-use 

products as requested, and establishing tolerances commensurate with those registration actions.

5.4.4 Dietary Exposure and Risk Estimate Summary Table

Table 5.4.4. Summary of Acute and Chronic Dietary Exposure and Risk Estimates for Clothianidin.

Population Subgroup Acute (95th Percentile) Chronic

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

Total US Population 0.020913 8 0.007458 8 13.1

All Infants 0.051461 21 0.016683 17 5.87

Children 1-2 years old 0.069586 28 0.027256 28 3.60

Children 3-5 years old 0.048260 19 0.018444 19 5.31

Children 6-12 years old 0.024264 10 0.009165 9 10.7

Youth 13-19 years old 0.014341 6 0.005346 6 18.3

Adults 20-49 years old 0.015090 6 0.005822 6 16.8

Adults 50-99 years old 0.014403 6 0.006109 6 16.0

Female 13-49 years old 0.015390 6 0.005974 6 16.4

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

1ARI = Aggregate Risk Index. ARI values <1 indicate a potential risk of concern. 

ARI = NOAEL (9.8 mg/kg/day) ÷ Exposure ÷ LOC (Oral LOC = 100).

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

D397691, S. Oonnithan, 27 September 2012

The use of clothianidin on turf, ornamental plants, and/or indoor surfaces may result in human 

exposure in a residential setting. Such exposures may occur during application of products 

containing clothianidin (handler exposure) as well as following application (post-application 

exposure) and are expected to be of short-term (1-30 days) duration. HED assessed exposure 

and developed risk estimates for numerous residential handler and post-application scenarios

using the 2012 residential SOPs (M. Collantes, D397724, 15 August 2012). Those assessments 

are based on conservative estimates of exposure and the results are summarized in Tables 4 and 

5.

6.1 Residential Handler Exposure

For clothianidin, residential handler risk estimates are considered to be of potential concern when 

the dermal MOE is less than 100, the inhalation MOE is less than 1000, and/or the aggregate risk 

index (ARI), reflecting combined dermal and inhalation exposure, is less than one. As shown in 

Table 6.1, the residential handler risk estimates are not of concern (ARIs range from 11 to 990).
Clothianidin Human Health Risk Assessment DP No. D395348

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Table 6.1. Summary of Residential Handler Exposure and Risk Estimates for Clothianidin. M. Collantes D397724, 

15 August 2012.

Use Site Application Method Formulation Activity

Exposure Estimate,

mg/kg/day

(MOE)

ARI1 Dermal Inhalation

Turf Push-Type Spreader Arena 0.5G Mixing/ Loading/ 

Applying

2.3x10-5

(420,000)

7.5x10-6

(1,300,000) 990

Turf Belly Grinder Arena 0.5G Loading/ 

Applying

5.7x10-4

(17,000)

6.2x10-6

(1,600,000) 160

Tree Trunk Manually Pressurized 

Handwand Arena 50 WDG Mixing/ Loading/ Applying

6.8x10-3

(1,400)

2.0x10-4

(50,000) 11

Lawns Hose-End Sprayer Arena 50 WDG Mixing/ Loading/ 

Applying

3.8x10-4

(25,000)

6.4x10-5

(150,000) 96

Fruit Trees Hose-End Sprayer Arena 50 WDG Mixing/ Loading/ 

Applying

1.4 x 10-3

(7,100)

3.3 x 10-6

(2,900,000) 69

Indoor 

Surfaces 

(Bed Bug)

Manually Pressurized 

Handwand

File Symbol

73049-UIE

Mixing/ Loading/ 

Applying

1.7x10-4

(58,000)

2.7x10-4

(36,000) 34

Indoor 

Surfaces 

(Bed Bug)

Paintbrush File Symbol

73049-UIE Applying 1.1x10-3(9,000)

4.9x10-5

(200,000) 62

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

is each exposure source being included 

in the ARI calculation and LOC is the product of the applicable safety factors (100 for dermal and oral exposures 

and 1000 for inhalation exposures).

6.2 Post-Application Exposure

There is potential for post-application dermal and inhalation exposure for adults and children 

resulting from use of clothianidin on residential turf, ornamentals (i.e., trees), and indoor 

surfaces. There is also potential for incidental oral post-application exposure for children. Table 

6.2 provides a summary of the post-application exposure estimates and calculated ARIs. As 

shown in Table 6.2, the residential post-application risk estimates are not of concern (ARIs range 

from 1.9 to 490).
Clothianidin Human Health Risk Assessment DP No. D395348

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Table 6.2. Summary of Residential Post-Application Exposure and Risk Estimates for Clothianidin. M. Collantes 

D397724, 15 August 2012.

Use Site

Life Stage

Exposure Estimate, mg/kg/day (MOE)

ARI1

Hand-toMouthObject-toMouthSoil 

Ingestion Dermal Inhalation

Turf - WDG

Adult NA NA NA 1.7x10-3

(5,600) NA 56

Child 1-2 years old 6.2x10-3

(1,600)

1.9x10-4

(52,000)

1.4x10-5

(720,000)

2.9x10-3

(3,300) 11

Pick-Your-Own 

Tree Crop –

Apples and Pears

Adult

NA NA NA

22,000

NA

220

Child 6<11 yrs 49,000 490

Child 1-2 years old NA NA

Bed Bug – Carpet

Adult NA NA NA 3.9x10-3

(2,500)

7.1x10-10

(1.4x1010)

25

Child 1-2 years old 4.9x10-2

(200)

7.0x10-3

(1,500) NA 3.3x10-3(3,000)

2.5x10-9

(3.9X109)

1.9

Bed Bug – Hard 

Surface

Adult NA NA NA 1.3x10-3

(7,500)

7.1x10-10

(1.4x1010)

75

Child 1-2 years old 1.6x10-2

(600)

4.0x10-3

(2,200) NA 2.2x10-3(4,500)

2.5x10-9

(3.9X109)

5.4

Bed Bug –

Mattress

Adult NA NA NA 6.9x10-4

(14,000)

7.1x10-10

(1.4x1010)

140

Child 1-2 years old NC NC NA 1.6x10-3

(6,200)

2.5x10-9

(3.9X109)

61

1ARI values reflect combined oral, dermal, and inhalation exposure estimates identified by bold text; object-tomouth and soil ingestion are not included due to the conservatism in the hand-to-mouth estimate. ARI is calculated 

as the NOAEL ÷ Σ(Exposurei × LOC), where Exposureiis each exposure source being included in the ARI 

calculation and LOC is the product of the applicable safety factors (100 for dermal and oral exposures and 1000 for 

inhalation exposures).

NA = Not Applicable.

NC = Not Calculated. These exposure pathways are considered to be not relevant. In the case of bed bug mattress 

treatments, the activities are expected to be much less frequent for sleeping children. Exposures via these activities 

are addressed by hard surface and carpet scenarios.

6.3 Combined Exposure

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

likely they can occur simultaneously based on the use-pattern and the behavior associated with 

the exposed life stage. Although there is potential for adult exposure resulting from both 

applying the product and post-application activities, HED did not combine exposure estimates

from adult handler and post-application activities because of the conservative assumptions and 

inputs within each exposure scenario.

Although Table 6.2 provides the estimates MOEs for object-to-mouth and soil ingestion, the 

combined children’s exposure includes only the hand-to-mouth exposure for the incidental oral 

exposure component. To include exposure from object-to-mouth and soil ingestion in addition to 

hand-to-mouth would overestimate incidental oral exposures for purposes of estimating 

combined residential exposure.

For purposes of performing an aggregate assessment, HED selected the worst-case adult and 

children exposure scenarios. The treatment of tree trunks using a manually-pressurized 
Clothianidin Human Health Risk Assessment DP No. D395348

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

scenario presents the worst-case exposure estimates for children 1 to < 2 yrs old (ARI=1.8). A 

summary of the residential exposure scenarios for the aggregate assessment is provided in Table 

6.3.

Table 6.3. Residential Exposure Scenario and Risk Estimates for Aggregate Assessment.

Scenario Life Stage Scenario Scenario 

ARI1

Combined 

ARI2

Handler Scenarios

Tree Trunk Adult Manually Pressurized Handwand 11 11

Lawns Adult Hose-End Sprayer 96 40 Fruit Trees Adult Hose-End Sprayer 69

Post-Application Scenarios

Bed Bug

Adult Perimeter (Carpet) 25 21 Mattress 140

Children 1 to < 2 years old Perimeter (Carpet) 1.9 1.8 Mattress 61

1

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

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

ARI.

6.4 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 IV), low vapor pressure (1.3x10-10Pa, 9.75x10-13 mmHg), 

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 postapplication 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.

Although a quantitative bystander risk assessment was not conducted, post-application inhalation 

assessments were conducted to evaluate uses of clothianidin within a residential dwelling and 

risk estimates were not of concern. It is anticipated that these exposures are greater than those 

that would occur for residential bystanders and are, therefore, protective of bystander exposures 

that may occur.

6.5 Spray Drift

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

This is particularly the case with aerial application, but, to a lesser extent, could also be a 
Clothianidin Human Health Risk Assessment DP No. D395348

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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 

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 inhalation exposure assessment was not 

performed as a result of pesticide drift from neighboring treated agricultural fields, an assessment 

for clothianidin was performed for inhalation exposure to flaggers and the risk was not of 

concern (ARI = 27, Table 9.1). This exposure scenario is representative of a worse case 

inhalation (drift) exposure and may be considered protective of most outdoor agricultural and 

commercial post-application inhalation exposure scenarios.

7.0 Aggregate Exposure/Risk Characterization

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

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

In estimating aggregate risk, HED has considered the combined residential ARIs (Table 6.3) and 

the dietary exposure ARIs in Table 5.4.4. The aggregate ARIs (Table 7.2) are the worst-case risk 

estimates for each life stage. The aggregate ARIs are all greater than 1 and indicate that 

aggregate risks are not of concern.
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Table 7.2. Aggregate Risk Estimates for Clothianidin.

Life Stage Residential Combined ARI1 Dietary ARI1 Aggregate ARI2

Adult 11 16.0 6.5

Children 1 to < 2 years old 1.8 3.60 1.2

1Residential Combined ARIs are the minimum ARI for each life stage from Table 6.3; Dietary ARIs are from Table 

5.4.4. The adult dietary ARI is from the population subgroup Adults 50-99 years old and is the most conservative 

ARI from any of the adult-only subgroups.

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

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 is classified as “Not Likely to be Carcinogenic to Humans;” therefore, cancer risk is

not a concern.

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 

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 
Clothianidin Human Health Risk Assessment DP No. D395348

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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

D397691, S. Oonnithan, 27 September 2012

9.1 Short- and Intermediate-Term Handler Risk

HED has assumed that both short- and intermediate-term occupational exposures may occur. 

Short-term exposures (1-30 days) are likely to occur for many occupational exposure scenarios. 

Certain application scenarios (e.g., aerial application) are likely to be conducted by contract 

applicators whose exposure may extend into an intermediate-term (1-6 months) duration.

Chemical-specific data for estimating occupational exposure to clothianidin were not submitted. 

It is the policy of HED to use the best available data to assess handler exposure. Sources of

generic handler data, used as surrogate data in the absence of chemical-specific data, include the 

Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the Agricultural Handler 

Exposure Task Force (AHETF) database, or other registrant-submitted occupational exposure 

studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data 

protection provisions of FIFRA. The standard values recommended for use in predicting handler 

exposure that are used in this assessment, known as “unit exposures”, are outlined in the 

“Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” 

(http://www.epa.gov/opp00001/science/handler-exposure-table.pdf), which, along with 

additional information on HED policy on use of surrogate data, including descriptions of the 

various sources, can be found at http://www.epa.gov/pesticides/science/handler-exposuredata.html.

Dermal and inhalation exposures were calculated for various levels of personal protective 

equipment (PPE). Results are presented for “baseline,” defined as a single layer of clothing 

consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no 

respirator, as well as baseline with various levels of PPE as necessary (e.g., gloves, respirator, 

etc). The product labels for Arena®50 WDG and V-10170 2.13 SC recommend applicators and 

other handlers must wear long-sleeved shirt and long pants, shoes plus socks and chemicalresistant gloves made of any waterproof material.

Occupational handler exposure and risk estimates are summarized in Table 9.1. Since the shortand intermediate-term endpoints and PODs are the same for each route of exposure, only shortterm exposures were estimated, and are considered protective of intermediate-term exposure and 

risk. Estimated exposure and risk associated with the new foliar and/or soil treatments on citrus 

fruit trees, pistachio, and strawberry resulted in ARIs of 1.1 to 660 for mixers/loaders, 

applicators, and flaggers, assuming baseline PPE plus gloves, engineering controls such as 

enclosed cockpit, and open cabs. These estimated risks are not of concern. For aerial uses of 

Arena®50 WDG and V-10170 2.13 C formulations, the estimated ARIs for mixers/loaders, 

applicators, and flaggers ranged from 1.1 to 260, assuming use of baseline clothing plus gloves 

and an enclosed cockpit (engineering controls) for aerial applications. 
Clothianidin Human Health Risk Assessment DP No. D395348

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Table 9.1. Summary of Occupational Handler Exposure and Risk Estimates for Clothianidin.

Scenario Crop

Dermal 

Dose, 

mg/kg/day

Inhalation 

Dose, 

mg/kg/day

Dermal 

MOE 1

Inhalation 

MOE 2

Combined 

ARI 3

Mixer/Loader

Arena WDG, Aerial Strawberry 0.00052 0.00909 18721 1078 1.1

Arena WDG, 

Groundboom

Strawberry 0.00012 0.00208 81904 4717 5

V-10170 2.13 SC, Aerial Strawberry, 

Citrus, 

Pistachio

0.00019 0.00011 51383 88219 75

V-10170 2.13 SC, 

Ground boom 

Strawberry 0.00004 0.00003 224801 385959 330

V-10170 2.13 SC, Air 

blast

Citrus 0.00002 0.00001 449601 77918 660

Applicator

Arena WDG, Aerial Strawberry 0.00005 0.00007 193200 142059 130

Arena WDG, 

Groundboom

Strawberry 0.00004 0.00008 262500 124301 110

V-10170 2.13 SC, Aerial Strawberry, 

Citrus, 

Pistachio

0.00003 0.00003 386400 284118 260

V-10170 2.13 SC, 

Ground boom 

Strawberry 0.00002 0.00004 525000 248603 240

V-10170 2.13 SC, Air 

blast

Citrus, 

Nectarine, 

Pistachio

0.00092 0.00027 10632 35382 27

Flagger

V-10170 2.1 SC & 

Arena WDG 

All crops 0.00012 0.00036 80500 27600 27

Mixer/Loader/Applicator

V-10170 2.1 SC & 

Arena WDG , Soil 

broadcast, Backpack

Strawberry, 

Citrus; 

dilution 

=0.02 lb 

a.i./gal

0.00096 0.00003 10223 327616 78

V-10170 2.1 SC & 

Arena WDG , Soil 

drench, MPHG

Strawberry, 

Citrus; 

dilution = 

0.004 lb 

a.i./gal

0.000226 0.000226 43000 43000 39

1 Dermal MOE = NOAEL (9.8 mg/kg/day) ÷ Dermal Exposure.

2 Inhalation MOE = NOAEL (9.8 mg/kg./day) ÷ Inhalation Exposure.

3 ARI (Aggregate Risk Index) = 1 ÷ [(1÷ Dermal MOE) + (1÷ Inhalation MOE)]

9.2 Short- and Intermediate-Term Post-Application Risk

9.2.1 Dermal Post-Application Risk

Chemical-specific dislodgeable foliar residue data have not been submitted for clothianidin. 

Therefore, this assessment uses HED’s default assumption that 25% of the application is 
Clothianidin Human Health Risk Assessment DP No. D395348

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available for transfer on day 0 following the application and the residues dissipate at a rate of 

10% each following day.

It is the policy of HED to use the best available data to assess post-application exposure. 

Sources of generic post-application data, used as surrogate data in the absence of chemicalspecific data, are derived from ARTF exposure monitoring studies, and, as proprietary data, are 

subject to the data protection provisions of FIFRA. The standard values recommended for use in 

predicting post-application exposure that are used in this assessment, known as “transfer 

coefficients”, are presented in the ExpoSAC Policy 3 which, along with additional information 

about the ARTF data, can be found at the Agency website.

The post-application dermal exposures and risks resulting from foliar applications of clothianidin

on citrus fruit, nectarine, pistachio, and strawberry are summarized in Table 9.2.1. The shortand intermediate-term post-application dermal MOEs ranged from 8,400 to 22,000 are not of 

concern at the LOC of ≥100. The post-application dermal exposures resulting from soil-directed 

applications of clothianidin on citrus and strawberry and trunk treatment on citrus were not 

assessed as there are no surrogate transfer coefficients available for broadcast, band, in-furrow, 

soil drench, or tree trunk applications. However, dermal post-application exposures for workers 

from such treatments are expected to be minimal because workers do not come in contact with 

the treated surfaces. Therefore, post-application risks for these uses are not of concern. 

Table 9.2.1. Post-application Dermal Exposures and Risks Resulting from Foliar Use of Clothianidin on Citrus, 

Nectarine, Pistachio, and Strawberry. 

Crop Activities 

Appl. Rate

(lb ai/A)

Estimated 

DFR

(ug/cm2) 1

Transfer

Coefficient 

(cm2/hr) 2

Dermal

Dose 3 

(mg/kg/day)

Short-term

Dermal MOE 4

Citrus fruits Fruit harvesting

0.1 0.280

1,400 0.000454 22,000

Nectarine Thinning of fruits 3,600 0.00117 8,400

Pistachio Harvesting 1,400 0.000454 22,000

Strawberry Harvesting, training 0.2 0.561 1,100 0.000715 14,000

1. Dislodgeable Foliar Residue (DFR) = Application Rate (lb ai/A) * (1- Daily Dissipation Rate)t* Conv.

Factor(4.54E+8 μg/lb) * Conv. Factor (2.47E-8 A/cm2)* Residue Transfer Rate (20% default) after treatment.

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

3. Dermal Dose (mg/kg/day) = [DFR * TC * Conv. Factor (0.001 mg/μg) * Dermal Absorption Factor (1%) * 8 

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

4. MOE= Short-term Dermal NOAEL (9.8 mg/kg/day) / Dermal Dose (mg/kg/day).

9.2.2 Inhalation Post-Application Risk

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 IV), low vapor pressure (1.3x10-10 Pa, 9.75x10-13 mm Hg)

and low application rates (0.2 lb ai/A). However, there are multiple potential sources of postapplication inhalation exposure to individuals performing post-application activities in 

previously treated fields. These 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 FIFRA Scientific Advisory Panel (SAP) in 

December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/ 
Clothianidin Human Health Risk Assessment DP No. D395348

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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 

ARTF 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 post-application inhalation exposure assessment was not performed for 

clothianidin, HED has assessed inhalation exposure and risk for occupational flaggers resulting 

from aerial applications and the risk was not of concern (ARI = 27, Table 9.1). Inhalation 

exposure for flaggers is likely to result in higher exposure than that from post-application 

activities performed in the treated field. Therefore, it is expected that the flagger inhalation 

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

exposure scenarios.

10.0 References

D397689. M. Doherty. 26 September 2012. Clothianidin – New Uses on Strawberry, Pistachio, 

Citrus, and Tea. Evaluation of Residue Chemistry Data.

D397690. M. Doherty. 26 September 2012. Clothianidin – Acute and Chronic Dietary Exposure 

and Risk Estimates for Requested Amended Registration on Peppers and New Uses 

on Strawberry, Citrus, Pistachio, and Tea.

D397691. S. Oonnithan. 27 September 2012. Clothianidin. Occupational Exposure Assessment 

for New Uses on Citrus, Nectarine, Pistachio, and Strawberry; and Label 

Amendments to Add Aerial Application.

D399953. M. Doherty. 26 September 2012. Clothianidin – Proposed Label Amendments: 

Reduction in PHI for Crop Subgroup 8-10B (Peppers and Eggplant) and Change in 

Tolerance.

D397724. M. Collantes. 15 August 2012. Clothianidin: Occupational and Residential 

Exposure and Risk Assessment to Support the Proposed Bed Bug Treatment.

TXR# 0055320. J. Van Alstine. 23 March 2012. Clothianidin: Summary of Hazard and 

Science Policy Council (HASPOC) Meeting of March 8, 2012: Recommendation on 

the need for a 28-day inhalation study.
Clothianidin Human Health Risk Assessment DP No. D395348

Page 32 of 52

Appendix A. Toxicology Profile and Executive Summaries

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. 
Clothianidin Human Health Risk Assessment DP No. D395348

Page 33 of 52

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. D395348

Page 34 of 52

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. D395348

Page 35 of 52

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.
Clothianidin Human Health Risk Assessment DP No. D395348

Page 36 of 52

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 

conditions 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. D395348

Page 37 of 52

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. D395348

Page 38 of 52

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. D395348

Page 39 of 52

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. D395348

Page 40 of 52

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

Undiluted FS 600 formulation of 

clothianidin (10% ai)

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.
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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

45422823

(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.
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A.3. Endpoint Selection

Acute Reference Dose (aRfD) - General Population

Studies Selected: Special Neurotoxicity/Pharmacology study in Mice (MRID 45422823)

 

Dose and Endpoint for Risk Assessment: NOAEL = 25 mg/kg/day (both studies) based on 

transient signs of spontaneous motor activity, tremors, and deep respirations observed on Day 1

at 50 mg/kg/day. 

Acute RfD   0.25 mg/kg

100 (UF)

25 mg/kg

Comments about Study/Endpoint/Uncertainty Factors: These endpoints and dose were selected 

because the oral route of exposure is relevant to dietary risk assessment and the duration of 

exposure is relevant to acute dietary risk. Similar signs of neurotoxicity were observed in the 

acute neurotoxicity study in the rat at 100 mg/kg, with a NOAEL of 60 mg/kg. Although the 

developmental toxicity study in the rat had a lower maternal NOAEL of 10 mg/kg/day (LOAEL 

40 mg/kg/day), this study was not chosen for endpoint selection because the NOAEL is 

considered to be artificially low due to dose spacing. The standard uncertainty factors (100x) 

were applied to all dietary exposure scenarios (10x for intraspecies variability and 10x for 

interspecies extrapolation).

Acute Reference Dose (aRfD) – Females 13-49

Studies Selected: Developmental Study in the Rabbit (MRID 45422713, 45422712)

 

Dose and Endpoint for Risk Assessment: NOAEL = 25 mg/kg/day (both studies) based on 

increased litter incidences of a missing lobe of the lung observed on Day 1 at 75 mg/kg/day. 

Acute RfD   0.25 mg/kg

100 (UF)

25 mg/kg

Comments about Study/Endpoint/Uncertainty Factors: The endpoint and dose were selected 

because: 1) the oral route of exposure is relevant to dietary risk assessment, 2) the duration of 

exposure is relevant to acute dietary risk and 3) they are protective of potential offspring effects. 

Based on the available data, HED determined that changes in organ development can occur as 

the result of a single exposure at a critical junction during pregnancy or from multiple exposures 

throughout pregnancy and lactation. The standard uncertainty factors (100x) were applied to all 

dietary exposure scenarios (10x for intraspecies variability and 10x for interspecies 

extrapolation).
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Chronic Reference Dose (cRfD)

Studies Selected: 2-Generation Reproduction Study in the Rat (MRID 45422715, 45422714)

Dose and Endpoint for Risk Assessment: NOAEL = 9.8 mg/kg/day based on decreased body

weights gains, delayed sexual maturation, decreased thymus weights in F1 pups, and increased 

stillbirths in both generations at the LOAEL of 31.2 mg/kg/day. 

Chronic RfD   0.01 mg/kg/day

100 (UF)

9.8 mg/kg/day

Comments about Study/Endpoint/Uncertainty Factors: This endpoint and dose was selected 

because: 1) the oral route of exposure is relevant to dietary risk assessment, 2) the duration of 

exposure is relevant to chronic risk scenarios, and 3) it is the lowest endpoint in the toxicology

database and is therefore protective of both chronic effects and potential qualitative sensitivity of 

offspring. The standard uncertainty factors were applied to all dietary exposure scenarios (10x 

for intraspecies variability and 10x for interspecies extrapolation).

Incidental Oral Exposure 

Short- and Intermediate-Term Incidental Exposure (1-30 days and 1-6 months)

Studies Selected: 2-Generation Reproduction Study in the Rat (MRID 45422715, 45422714)

Dose and Endpoint for Risk Assessment: NOAEL = 9.8 mg/kg/day based on decreased body

weights gains,, delayed sexual maturation, decreased thymus weights in F1 pups, and increased 

stillbirths in both generations at the LOAEL of 31.2 mg/kg/day. 

Comments about Study/Endpoint/Uncertainty Factors: The NOAEL and LOAEL from the 2-

generation reproduction study were selected for the short- and intermediate-term incidental oral

risk assessment because they are protective of developmental effects present in rat pups observed 

in the presence of less severe maternal effects at similar doses. The standard uncertainty factors 

(100x) were applied (10x for intraspecies variability and 10x for interspecies extrapolation).

Dermal Exposure

All Durations

Studies Selected: 2-Generation Reproduction Study in the Rat (MRID 45422715, 45422714)

Dose and Endpoint for Risk Assessment: NOAEL = 9.8 mg/kg/day based on decreased body

weights gains, delayed sexual maturation, decreased thymus weights in F1 pups, and increased 

stillbirths in both generations at the LOAEL of 31.2 mg/kg/day. 
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Comments about Study/Endpoint/Uncertainty Factors: Although a dermal (route specific) 

toxicity study in rats was submitted, no effects were seen at the highest dose tested of 1000 

mg/kg/day. Use of the route-specific study for dermal risk assessment would not be protective of 

the offspring effects observed in both the DNT and the 2-generation reproduction studies 

because reproduction and developmental parameters were not evaluated. Since the dermal 

endpoint is based on an oral study, a 1% dermal absorption factor (DAF) is used to determine 

dermal exposure and risk. The standard uncertainty factors (100x) were applied (10x for 

intraspecies variability and 10x for interspecies extrapolation).

Inhalation Exposure

Short- and Intermediate-Term Inhalation Exposures (1-30 days and 1-6 months)

Studies Selected: 2-Generation Reproduction Study in the Rat (MRID 45422715, 45422714)

Dose and Endpoint for Risk Assessment: NOAEL = 9.8 mg/kg/day based on decreased body

weights gains,, delayed sexual maturation, decreased thymus weights in F1 pups, and increased 

stillbirths in both generations at the LOAEL of 31.2 mg/kg/day. 

Comments about Study/Endpoint/Uncertainty Factors: The study was selected because it is of an 

appropriate exposure length and it is protective of the most sensitive population, developing 

children. No route-specific information is available for the inhalation toxicity of clothianidin. In 

the absence of a route-specific study, the NOAEL and LOAEL from an oral study are used to 

estimate inhalation exposure and the associated risk (i.e., inhalation toxicity is assumed to be 

equivalent to oral toxicity). In this case, the NOAEL and LOAEL from the 2-generation 

reproduction study were selected because the duration is appropriate for short- and intermediateterm exposures and it is protective of potential effects in offspring. Because effects seen in the 

reproduction study can occur as the result of a single exposure at a critical junction during 

pregnancy or from multiple exposures throughout pregnancy and lactation, the NOAEL for 

offspring effects observed in the reproduction study was selected as the dose for all durations of 

exposure scenarios. The standard uncertainty factors were applied to all exposure scenarios (10x 

for intraspecies variability and 10x for interspecies extrapolation). In the absence of the required 

inhalation toxicity study, HED is recommending the 10X FQPA factor be retained as a database 

uncertainty factor for assessing inhalation exposure and risk under the FQPA. Similarly, a 10X 

database uncertainty factor should be applied to non-FQPA assessments (e.g., occupational 

assessments).
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Appendix B. Metabolism Summary Table

Table B1. Overview of clothianidin metabolic profile in plant and animal matrices.

Residue Rat Hen Goat Corn Sugar 

Beet

Rotational

Crops Apple Tomato

Clothianidin        

ACT** 

ATG-Ac *

ATG-Pyr 

ATMG-Pyr *

ATMT 

CTCA**  

MG      

MNG      *  

MTCA** 

NTG       

THMN  

THMN-Glc 

TMG     * (tops)  

TMHG 

TMT 

TZG  * *

TZMU      

TZNG  * *   *  

TZU  * *    

UREA   

* major metabolites

** ACT, MTCA, CTCA did not show up in hen and goat because only the nitroimino label 

was used. There are also no acute studies with these metabolites.
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Appendix C. Physical/Chemical Properties

Physicochemical Properties of Clothianidin.

Parameter Value Reference

Melting point (oC) 176.8 D335355, W. Drew, 

10/16/07 pH at 23oC 6.24 (1% solution/suspension)

Density (g/cm3) 1.61 (PAI), 1.59 (TGAI)

Water solubility (g/L at 20oC) 0.327

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

Ethyl acetate 2.03 Heptane <0.00104

Methanol 6.26 Octanol 0.938

Xylene 0.0128

Vapor pressure (Pa at 20oC) 1.3 x 10 -10

Dissociation constant, pKa at 20oC 11.09

Octanol/water partition 

coefficient, Log(KOW) at 25oC

0.7

UV/visible absorption spectrum 

(Maximum, nm)

265.5 (acidic or neutral)

246.0 (basic)

PAI = Purified Active Ingredient; TGAI = technical grade active ingredient.
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Appendix D. 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 (HED, version 1.1), 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 HSRB. 

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.
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Appendix E. Occupational Exposure/Risk Summary Tables

Table E1. Occupational Exposures and Risks Resulting from Use of Clothianidin on Proposed New Crops. 

Scen.

#

Scenario 1

Crop & Appl. 

rate (lb ai/A or 

lb ai/gal) 2

Area treated

or gal//day 3

Source of 

Unit exp.

& PPE 4

Dermal

UE 5

μg/lb ai

Inhal.

UE 5

μg/lb ai

Dermal

Dose 6

mg/kg/day

Inhal. 

Dose 6

mg/kg/day

Short-term

Dermal 

MOE 7

Short-term

Inhal.

MOE 7

Combined 

Short-term

ARI 8

MIXER/LOADER

1

Arena WDG

Aerial 

Strawberry

(0.2) 350 AHETFB+G 51.6 8.96 0.00052 0.00909 18,721 1,078 1.1

2

Arena WDG,

Ground boom

Strawberry

(0.2) 80 AHETFB+G 51.6 8.96 0.00012 0.00208 81,904 4,717 5

8, 

14,

23

V-10170 2.13 SC, 

Aerial

Strawberry (0.1)

Citrus (0.1)

Pistachio (0.1)

350

AHETF

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

9

V-10170 2.13 SC, 

Ground boom 

Strawberry

(0.1) 80 AHETFB+G 37.6 0.219 0.00004 0.00003 224,801 385,959 330

15,

21,

24

V-10170 2.13 SC, 

Air blast

Citrus (0.1)

Nectarine (0.1)

Pistachio (0.1)

40 AHETF

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

APPLICATOR

3

Arena WDG

Aerial 

Strawberry

(0.2) 350 AHETFClosed cockpit 5.0 0.068 0.00005 0.00007 193,200 142,059 130

4

Arena WDG,

Ground boom

Strawberry

(0.2) 80

AHETF

B+G+

open cab

16.1 0.34 0.00004 0.00008 262,500 124,301 110

10,

16,

25

V-10170 2.13 SC, 

Aerial

Strawberry (0.1)

Citrus (0.1)

Pistachio (0.1)

350 AHETF

Closed cockpit 5.0 0.068 0.00003 0.00003 386,400 284,118 260

11 V-10170 2.13 SC,

Gr. boom

Strawberry

(0.1) 80

AHETF

B+G+

open cab

16.1 0.34 0.00002 0.00004 525,000 248,603 240

17,

22,

26

V-10170 2.13 SC, 

Air blast

Citrus (0.1)

Nectarine (0.1)

Pistachio (0.1)

350

AHETF

B+G+

open cab

1,590

4.71

0.00092 0.00027 10,632 35,382 27

FLAGGER

7, 

27

V-10170 2.1 SC

& Arena WDG 

All crops

(0.2) 350 PHEDB+G 12 0.35 0.00012 0.00036 80,500 27,600

27
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Table E1. Occupational Exposures and Risks Resulting from Use of Clothianidin on Proposed New Crops. 

Scen.

#

Scenario 1

Crop & Appl. 

rate (lb ai/A or 

lb ai/gal) 2

Area treated

or gal//day 3

Source of 

Unit exp.

& PPE 4

Dermal

UE 5

μg/lb ai

Inhal.

UE 5

μg/lb ai

Dermal

Dose 6

mg/kg/day

Inhal. 

Dose 6

mg/kg/day

Short-term

Dermal 

MOE 7

Short-term

Inhal.

MOE 7

Combined 

Short-term

ARI 8

MIXER / LOADER / APPLICATOR

5,

12,

18,

19

Arena WDG and

V-10170 2.1 SC

Soil broadcast

Backpack

Strawberry (0.2), 

Citrus (0.2) 

dilution =

0.02 lb ai/gal 

40

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

6,

13,

20

Arena WDG and

V-10170 2.1 SC

Soil drench

MPHG

Strawberry (0.2), 

Citrus (0.2) ,

dilution =

0.004 lb ai/gal

1000

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

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

shoes and socks, and no respirator), G = chemical resistant gloves, MOE = margin of exposure, MPHG = mechanically pressurized handgun, PHED = 

pesticide handler exposure database, PPE = personal protective equipment, and UE = unit exposure. 

1. Exposure scenarios are from Table 6. 

2. For soil broadcast and drench applications and citrus trunk treatments an application rate of 0.2 lb ai/A was proposed. The diluent volume used for back-pack 

sprayer was 10 gal/A and at an application rate of 0.2 lb ai/A, the conc. of clothianidin in the spray mix amounted to 0.02 lb ai/gal. The corresponding 

numbers for MPHG used for soil drench was 50 gal/A at 0.004 lb ai/gal. 

3. Area treated per day assumptions are from ExpoSAC (SOP No. 9.1). The spray volumes used per day for backpack and mechanically pressurized handgun 

were assumed to be 40 and 1000 gal/day, respectively.

4. # Source of unit exposures may be proprietary. 

5. From http://www.epa.gov/pesticides/science/handler-exposure-data.html. For backpack sprayer, same unit dermal and inhalation unit exposures were used 

for both WDG and SC formulations. 

6. Dermal dose (mg/kg/day) = [Appl. Rate (lb ai/A or lb ai/gal) * Area Treated (acres or spray vol. /day) * Dermal Unit Exp. * Conversion Factor (μg/lb 

ai*0.001) * Dermal Absorption Factor (1.0%)] / Body wt. (69 kg). Inhalation Dose (mg/kg/day) = [Appl. Rate (lb ai/A or lb ai/gal) * Area Treated (acres or 

amount treated/day) * Inhal. Unit Exp. * Conversion Factor (μg/lb ai *0.001) * Inhalation Absorption Factor (100%)] / Body wt. (69 kg). 

7. Short-term Dermal MOE = Short-term Dermal NOAEL (9.8 mg/kg/day) / Dermal Dose (mg/kg/day). Short-term Inhalation MOE = Short-term Inhalation 

NOAEL (9.8 mg/kg/day) / Inhalation Dose (mg/kg/day). 

8. Short-term ARI = 1/[(1/(Short-term Dermal MOE/100) + (1/(Short-term Inhalation MOE/1000)]. The intermediate-term ARI is the same as the short-term, 

because of the same endpoints and doses for both exposure durations.
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Table E2. Occupational Exposures and Risks Resulting from Aerial Applications of Arena® WDG and V-10170 2.13 SC Formulations of Clothianidin on 

Selected Crops. 

Scen.

# 

Scenario

Used 1 Crops

2

(Appl. 

Rate

lb ai/A) 3

Area

treated/

day (A)

PPE & UE 

Database 4

Dermal

UE 5

μg/lb ai

Inhal.

UE 5

μg/lb ai

Dermal

dose 6

mg/kg/day

Inhal. 

dose 6

mg/kg/day

Short-term

Dermal 

MOE7

Short-term

Inhal.

MOE7

Combined 

Short-term

ARI 8

MIXER & LOADER

1

Aerial 

Arena 

WDG

All crops 0.1 350 AHETF

B+G 51.6 8.96 0.00026 0.00454 37,442 2,156 2.1

2

Aerial

V-10170

2.13 SC 

Brassica

leafy - and 

leafy veg.

0.067 350 AHETF

B+G 37.6 0.219 0.00013 0.00007 76,691 131,670 110

3

Fruiting veg., 

peach, 

pomegranate, 

and tree nuts

0.1 350 AHETF

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

APPLICATOR & FLAGGER

4

Applying 

by aerial All crops 0.1 350

AHETF

closed cockpit 5.0 0.068 0.00003 0.00003 386,400 284,118 260

5 Flagging PHED, B+G 12.0 0.35 0.000061 0.00018 161,000 55,200 53

1. Exposure scenarios are from Table 6.

2. The crops include Brassica leafy -, fruiting - and leafy vegetables, peach, pomegranate, and tree nuts. 

3. The proposed application rate for Brassica- and leafy vegetables is only 0.067 lb ai/A. Since all other crops have the rate at 0.1 lb ai/A, the exposures for 

applicator and flagger were estimated at the higher rate.

4, 5, 6, 7, and 8 are the same as in Table 7.
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Table E3. Post-application Dermal Exposures and Risks Resulting from Foliar Use of Clothianidin on 

Citrus, Nectarine, Pistachio, and Strawberry. 

Crop Activities 

Appl. Rate

(lb ai/A)

Estimated 

DFR

(ug/cm2)

1

Transfer

Coefficient 

(cm2/hr) 2

Dermal

Dose 3 

(mg/kg/day)

Short-term

Dermal 

MOE 4

Citrus fruits Fruit harvesting

0.1 0.280

1,400 0.000454 22,000

Nectarine Thinning of fruits 3,600 0.00117 8,400

Pistachio Harvesting 1,400 0.000454 22,000

Strawberry Harvesting, training 0.2 0.561 1,100 0.000715 14,000

1. Dislodgeable Foliar Residue (DFR) = Application Rate (lb ai/A) * (1- Daily Dissipation Rate)t* Conv. Factor (4.54E+8 μg/lb) * Conv. Factor (2.47E-8 

A/cm2)* Residue Transfer Rate (20% default) after treatment.

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

3. Dermal dose (mg/kg/day) = [DFR * TC * Conv. Factor (0.001 mg/μg) * Dermal Absorption Factor (1%) * 8 hrs/day] / Body Weight (69 kg). 

4: MOE= Short-term Dermal NOAEL (9.8 mg/kg/day) / Dermal Dose (mg/kg/day).
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Appendix F. Summary of Relevant International Residue Limits for Clothianidin.

Clothianidin (044309; 11 September 2012)

Summary of US and International Tolerances and Maximum Residue Limits.

Residue Definition:

US Canada Mexico2 Codex3,4

40 CFR 180.586:

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

[(2-Chloro-5-thiazolyl)methyl]- N' -

methyl- N" -nitroguanidine

[C(E)]-N-[(2-

chloro-5-

thiazolyl)methyl]-

N'-methylN"-nitroguanidine

clothianidin.

The residue is not 

fat-soluble.

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

US Canada Mexico2 Codex3,4

Tea (import only) 70 0.7 Tea, green, 

black (black, 

fermented and 

dried) (T)

Strawberry 1.50 0.07 berries and 

other small fruits 

(except grapes) (c, 

T)

Fruit, Citrus, Group 10-10 0.60 0.07 citrus fruits 

(T)

Pistachio 0.01

Pepper and Eggplant (Crop 

Subgroup 8-10B)

0.80 0.05 fruiting 

vegetables other 

than cucurbits (T)

0.5 peppers chili, 

dried

Completed: M. Negussie; 09/13/2012

1

Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and 

not those proposed by the applicant.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = 

processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the 

fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.

4 The source of the residue; T-thiamethoxam; C-clothianidin