Thiamethoxam D373376

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oUNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

 Office of Chemical Safety

and Pollution Prevention

Date: Dec. 20, 2010

MEMORANDUM

SUBJECT: Thiamethoxam – Human Health Risk Assessment for New Seed Treatment Uses

on Alfalfa and Peanuts, and Use in Food Handling Establishments. 

PC Code: 060109 DP Barcodes: D373376, D376092, D380393

Decision Nos.: 424517, 430284, 

436785

Registration Nos.: 100-RGAL, 100-949, 100-

1306

Petition No.: 9F7657, 0F7707, 

0F7734

Regulatory Action: Amended Section 3

Risk Assessment Type: Single 

Chemical Aggregate

Case No.: 7614

TXR No.: None CAS No.: 153719-23-4

MRID No.: None 40 CFR: 180.565

 FROM: Dennis McNeilly, Chemist/Risk Assessor

William T. Drew, Chemist

Shih-Chi Wang, Biologist

Risk Assessment Branch II (RAB2)

Health Effects Division (7509P)

THROUGH: Margarita Collantes, Biologist 

Risk Assessment Branch II (RAB2)

Health Effects Division (7509P)

&

Richard Loranger, Ph.D., Senior Chemist

Christina Swartz, Branch Chief

Risk Assessment Branch II (RAB2)

Health Effects Division (7509P)

TO: Kable Davis/Venus Eagle, Team 01

Insecticide/Rodenticide Branch

Registration Division (7505P)
Thiamethoxam D373376

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Table of Contents

`

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

2.0 Ingredient Profile................................................................................................................... 8

2.1 Summary of Proposed Uses......................................................................................... 8

2.2 Structure and Nomenclature ...................................................................................... 10

2.3 Physical and Chemical Properties.............................................................................. 11

3.0 Hazard Characterization/Assessment................................................................................ 11

3.1 Hazard and Dose-Response Characterization............................................................ 11

3.1.1 Database Summary ................................................................................... 11

3.1.1.1 Studies available and considered ............................................... 12

3.1.1.2 Mode of action, metabolism, toxicokinetic data........................ 12

3.1.1.3 Sufficiency of studies/data......................................................... 12

3.1.2 Toxicological Effects................................................................................ 13

3.1.3 Dose-response ........................................................................................... 15

3.2 Absorption, Distribution, Metabolism, Excretion (ADME)................................. 16

3.3 FQPA Considerations ........................................................................................... 16

3.3.1 Adequacy of the Toxicity Database.......................................................... 16

3.3.2 Evidence of Neurotoxicity ........................................................................ 16

3.3.3 Developmental Toxicity Studies............................................................... 17

3.3.4 Reproductive Toxicity Study .................................................................... 17

3.3.5 Additional Information from Literature Sources...................................... 18

3.3.6 Pre-and/or Postnatal Toxicity ................................................................... 18

3.3.6.1 Determination of Susceptibility ................................................. 18

3.3.6.2 Degree of Concern Analysis and Residual Uncertainties for Preand/or Postnatal Susceptibility.................................................................. 19

3.3.7 Recommendation for a Developmental Neurotoxicity Study................... 19

3.4 Safety Factor for Infants and Children.................................................................. 20

3.5 Hazard Identification and Toxicity Endpoint Selection........................................ 20

3.5.1 Acute Reference Dose (aRfD) - Females age 13-49................................. 20

3.5.2 Acute Reference Dose (aRfD) - General Population................................ 20

3.5.3 Chronic Reference Dose (cRfD)............................................................... 21

3.5.4 Incidental Oral Exposure (Short- and Intermediate-Term)....................... 22

3.5.5 Dermal Absorption.................................................................................... 23

3.5.6 Dermal Exposure (Short-, Intermediate- and Long-Term) Adults ........... 23

3.5.7 Dermal Exposure (Short-, Intermediate- and Long-Term) Children.......24

3.5.8 Inhalation Exposure (Short-, Intermediate- and Long-Term)................... 24

3.5.9 Level of Concern for Margin of Exposure................................................ 24

3.5.10 Recommendation for Aggregate Exposure Risk Assessments................. 25

3.5.11 Classification of Carcinogenic Potential................................................. 25

3.5.12 Summary of Toxicological Doses and Endpoints for Use in Human Risk 

Assessments.......................................................................................................... 25

3.6 Endocrine disruption............................................................................................. 29

4.0 Public Health and Pesticide Epidemiology Data............................................................... 29
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5.0 Dietary Exposure/Risk Characterization .......................................................................... 29

5.1 Pesticide Metabolism and Environmental Degradation............................................. 29

5.2 Analytical Methodology.......................................................................30

5.3 Drinking Water Residue Profile................................................................................. 30

5.4 Food Residue Profile.................................................................................................. 33

5.5 International Residue Limits...................................................................................... 35

5.6 Dietary Exposure and Risk ........................................................................................ 35

5.6.1 Anticipated Residue and Percent Crop Treated (%CT) Information.......... 36

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ................................. 37

7.0 Aggregate Risk Assessments and Risk Characterization................................................. 39

7.1 Acute Aggregate Risk................................................................................................ 40

7.2 Short-Term Aggregate Risk....................................................................................... 40

7.3 Intermediate-Term Aggregate Risk ........................................................................... 41

7.4 Long-Term Aggregate Risk ....................................................................................... 42

7.5 Cancer Risk................................................................................................................ 42

8.0 Cumulative Risk Characterization/Assessment................................................................ 42

9.0 Occupational Exposure/Risk Pathway............................................................................... 43

9.1 Short- and Intermediate-Term Handler Risk ............................................................. 43

9.2 Short- and Intermediate-Term Postapplication Risk.................................................. 49

10.0 Regulatory Recommendations and Data Needs.............................................................. 49

10.1 Toxicology ............................................................................................................... 50

10.2 Residue Chemistry................................................................................................... 51

10.3 Occupational and Residential Exposure .................................................................. 51

References.................................................................................................................................... 52

Appendix A - Toxicity Profile for Thiamethoxam...................................................53
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1.0 Executive Summary

Thiamethoxam is a broad spectrum nitroguanidine insecticide which belongs to the pesticidal 

class of compounds known as the neonicotinoids (Group 4A; Insecticide Resistance Action 

Commitee). It has activity against sucking and chewing insects on a wide variety of crops. 

Thiamethoxam appears to interfere with the nicotinic acetylcholine receptors of the insect’s 

nervous system, but the specific receptor site is unknown at this time. It does not inhibit 

cholinesterase or interfere with sodium channels and, therefore, has a different mode of action 

than organophosphate, carbamate, and pyrethroid insecticides.

This risk assessment addresses the requested new use of thiamethoxam for treatment of alfalfa 

and peanut seeds. Additionally, Syngenta submitted a petition to register thiamethoxam for use 

in food/feed handling establishments. It is proposed for indoor spot, void, and crack and crevice 

applications as 0.05 and/or 0.1% active ingredient (ai) solutions, to control a wide variety of 

insect pests. In conjunction with the proposed new uses, Syngenta has requested the 

establishment of permanent tolerances for residues of thiamethoxam and its metabolite, CGA322704 (clothianidin), in or on the commodities, as listed below. 

Alfalfa, forage .............................................................................0.05 ppm

Alfalfa, hay..................................................................................0.12 ppm

Peanut..........................................................................................0.05 ppm

Peanut, hay..................................................................................0.25 ppm

Food commodities/feed

commodities (other than

those covered by a higher

tolerance as a result of use

on growing crops) in

food/feed handling

establishments .............................................................................0.01 ppm

Databases for toxicology, residue chemistry, and occupational/residential exposure are sufficient 

for purposes of human health risk assessment. An immunotoxicity study, a new requirement 

under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide (food and 

non-food uses), is needed to complete the database. Any registrations granted should be made 

conditional upon receipt and review of those data. In addition, there are label modifications and 

tolerance revisions that should be completed prior to registration or establishment of tolerances

(see section 10).

In mammals, thiamethoxam shows toxicological effects primarily in the liver, kidney, testes, and 

hematopoietic system (blood cellular system). In addition, developmental neurological effects 

were observed in rats. The developmental effect is being used to assess risks associated with 

acute exposures to thiamethoxam, and the liver and testicular effects are the basis for assessing 

longer term exposures. It is classified as ―not likely to be carcinogenic to humans.‖ The selected 

endpoints and points of departure for risk assessment from the available data are protective of all 

toxicological effects, including potential immunotoxic effects, observed in the database for all 
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population groups. In addition, the dietary and residential exposures are not likely to be 

underestimated. Therefore, the Health Effects Division (HED) has reduced the FQPA Safety 

Factor to account for sensitivity of infants and children from 10X to 1X.

Based on the available toxicity database and the Agency's current practices, short- and 

intermediate-term inhalation risks for thiamethoxam were assessed using an oral toxicity study. 

The Agency is in the process of evaluating a March, 2010 Federal Insecticide, Fungicide, and 

Rodenticide Act Scientific Advisory Panel (SAP) report and may, as appropriate, re-examine and 

develop new policies and procedures for conducting inhalation risk assessments, including routeto-route extrapolation of toxicity data. If any new policies or procedures are developed, the 

Agency may revisit the need for an inhalation toxicity study for thiamethoxam and/or a reexamination of the inhalation toxicity risk assessment.

The submitted field trial data for thiamethoxam seed treatment of alfalfa and peanuts are 

acceptable, and support the proposed use of thiamethoxam as a seed treatment. HED 

recommends a tolerance of 0.05 ppm in peanut nutmeat, 0.25 ppm in peanut hay, 0.05 ppm in 

alfalfa forage, and a tolerance of 0.12 ppm in alfalfa hay. Based on the highest field trial 

(HAFT) combined residues of 0.05 ppm (0.09 ppm at a 2X rate) in peanut nutmeat, and the 

theoretical concentration factor for peanut meal of 2.2X, HED recommends a tolerance of 0.15 

ppm in peanut meal. The submitted data for thiamethoxam use in food/feed handling areas are 

acceptable, and support the proposed use of Optigard Flex Liquid as a spot, void, and crack and 

crevice treatment in food handling establishments. Based on maximum thiamethoxam and 

CGA-322704 residues of <0.01 ppm in food commodities exposed to 1X treatment in food 

handling areas (with the vast majority of samples containing non-detectable residues), HED 

recommends a combined tolerance of 0.02 ppm in food/feed commodities (other than those 

covered by a higher tolerance as a result of use on growing crops).

HED has assessed dietary (food + drinking water) as well as various non-dietary ―residential‖ 

exposures. The dietary exposure estimates are based on highly conservative, health-protective 

assumptions regarding residue levels in food and water as well as the extent to which crops are 

treated with thiamethoxam. Risk estimates associated with dietary exposure are below HED’s

level of concern for all population subgroups, including those of infants and children. Exposures 

in a residential setting may occur following application of thiamethoxam to turf and/or indoor 

crack and crevice treatment. Therefore, HED has assessed dermal and incidental oral (hand-tomouth) exposures. Risk estimates for these exposures are below HED’s level of concern for the 

assessed population subgroups. Similarly, highly conservative estimates of aggregate risk 

(combined risk from dietary and non-dietary exposures) are below HED’s level of concern for all 

population subgroups. Given the existing and proposed use patterns for thiamethoxam as well as 

the health-protective assumptions throughout this risk assessment, it is unlikely that any 

geographic, ethnic, or socioeconomic population will have increased exposure relative to the 

standard population subgroups assessed by OPP.

Primary (treater) and secondary (planter) handler exposure associated with the use of Cruiser® 

5FS to treat alfalfa and peanut seeds and Cruiser® PD to treat peanut seeds were assessed for 

both open and closed commercial seed treatment systems. No on-farm uses were assessed. The 
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occupational exposures/risks resulting from the proposed uses of Cruiser® 5FS and Cruiser PD 

for treatment of peanut and alfalfa seed using open and closed systems do not exceed HED’s 

level of concern (MOEs ≥ 100) with the exception of the following two scenarios.

(1) The Cruiser® PD is intended for use as a dry application on peanuts. Since the treater 

(loader/ operator) unit exposure values from the Seed Treatment SOP (Policy 14) are based on 

liquid formulations, the loader/operator exposure for Cruiser® PD was estimated using surrogate 

unit exposure values for a wettable powder formulation in the Pesticide Handlers Exposure 

Database (PHED). The treater scenario resulted in a MOE of 100 with the use of additional PPE 

(i.e., gloves, coveralls, and a PF10 respirator). Currently the label only requires a use dust mask 

(quarter- or half-mask) respirator. HED recommends that the Registration Division ensure 

that the appropriate respirator is required on the final Cruiser PD label.

(2) In assessing the multiple activity scenario for commercially treating 718,000 lbs of alfalfa 

seed using an open system, handler exposure resulted in a MOE of 59 at baseline with addition 

of gloves. The addition of a PF 5 dust mist respirator to current label personal protective 

equipment (PPE) [i.e. gloves and coveralls] was required for multiple activity workers scenario 

to reach an MOE greater than 100 (MOE = 170), the level of concern. However, the Cruiser® 

5FS label contains a restriction for commercial open system seed treatment facilities that limits 

the amount of product handled per day to no more than 38 gallons product/worker/8-hr day 

which is equivalent to treating 413,043 lbs of seed a day. Therefore, HED also assessed 

treatment of 413,043 lbs of alfalfa seed at baseline with addition of gloves which resulted in a 

MOE of 100 and was not of concern. 

Risks for all other commercial open and closed system scenarios were not of concern.

All MOEs for secondary seed handlers (i.e., those who plant treated seed) are greater than 100 

assuming a single layer of clothing plus gloves, with MOEs ranging from 760 to 2500 and were 

not of concern. 

The assessment also includes exposure estimates resulting from the proposed use of 

thiamethoxam in food/feed handling establishments. The handler assessment was based on 

surrogate unit exposure data from the Pesticide Handlers Exposure Database (PHED) Version 

1.1 (HED Science Advisory Council for Exposure, SOP Number 007, January 1999). 

Commerical handlers applying thiamethoxam as a liquid spray to cracks and crevices, spots, and 

structural voids using low pressure handwand, resulted in combined MOEs ranging from 280 to 

8,300 and do not exceed HED’s level of concern with use of personal protective equipment 

(PPE) (i.e., gloves). However, the handler scenario using a foam application resulted in an MOE 

of 160 with the use of additional PPE (gloves, coveralls, and PF5 dust mist respirator). The 

proposed label does not require use of coveralls and respirators. HED recommends that if this 

use is to remain on the label, the Registration Division ensure that the correct PPE be 

included in the final registered label. 

There are no new residential exposure scenarios associated with this action. Exposures related to 

already registered indoor residential activities have been combined with chronic dietary exposure 

estimates to assess the worst-case short- and intermediate-term aggregate exposures. The indoor 
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crack and crevice scenario has higher exposure for both adults and children than the exposure 

levels in the turf scenario and has been used for the aggregate exposure assessment. The shortterm aggregate MOEs range from 370 to 490, while intermediate-term aggregate MOEs range 

from 370 to 540. Since these are greater than 100, they represent aggregate risk estimates that 

are below HED’s level of concern.

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 USDA under the Continuing 

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

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

on age, season of the year, ethnic group, and region of the country. Whenever appropriate, nondietary exposures based on home use of pesticide products and associated risks for adult 

applicators and for toddlers, youths, and adults entering or playing on treated areas 

postapplication 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.

This exposure/risk assessment relies in part on data from studies in which adult human subjects 

were intentionally exposed to a pesticide to determine their dermal and inhalation exposure. 

Many such studies, involving exposure to many different pesticides, comprise generic pesticide 

exposure databases such as the Pesticide Handlers Exposure Database (PHED). EPA has 

reviewed all the studies in these multi-pesticide generic exposure databases, and on the basis of 

available evidence has found them to have been neither fundamentally unethical nor significantly 

deficient relative to standards of ethical research conduct prevailing when they were conducted. 

There is no regulatory barrier to continued reliance on these studies, and all applicable 

requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) 

have been satisfied.

 

HED is recommending in favor of the establishment of permanent tolerances as shown in Table 

10, and for conditional registration of thiamethoxam for the requested uses, pending receipt and 

review of the data requested in Section 10. Prior to granting the registration or establishing the 

new tolerances, HED recommends that revisions to the proposed label be completed and that a 

revised Section F be submitted. These items are also described in Section 10.
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2.0 Ingredient Profile

Thiamethoxam is a broad spectrum nitroguanidine insecticide which belongs to the pesticidal 

class of compounds known as the neonicotinoids. It has activity against sucking and chewing 

insects on a wide variety of crops. It appears to interfere with the nicotinic acetylcholine 

receptors of the insect’s nervous system, but the specific receptor site is unknown at this time. It 

does not inhibit cholinesterase or interfere with sodium channels and, therefore, has a different 

mode of action than organophosphate, carbamate, and pyrethroid insecticides.

The chemical structure and nomenclature of thiamethoxam and its regulated metabolite, CGA322704, are presented in Table 2.2. The physicochemical properties of the technical grade of 

thiamethoxam are presented in Table 2.3. The metabolite CGA-322704 is the active ingredient 

clothianidin (PC Code 044309).

2.1 Summary of Proposed Uses

Peanuts: The end-use products (EP) proposed for use on peanuts are Cruiser PD (EPA File 

Symbol 100-RGAL), a WS formulation of thiamethoxam containing 70% ai, and Cruiser 5FS 

(EPA Registration #100-941), an FS formulation of thiamethoxam containing 5 lb ai/gal. They 

are proposed for use as seed treatments of peanuts to provide early season protection of seedlings 

against injury from thrips, aphids, wireworms and white grubs, and suppression of threecornered alfalfa hoppers, and plant bugs. In response to questions from HED, Syngenta clarified 

that the maximum use rate for peanuts should be 0.08 lb ai/A (18 Oct 2010 email from 

Syngenta’s Patrick McCain to RD’s Kable Davis). This rate was calculated using assumptions 

which HED considers reasonable (850 seeds/ lb, and planting 142 lbs seed/A). The proposed use 

directions are presented in Table 2.1 (below). 

Alfalfa: The EP proposed for use on alfalfa is Cruiser 5FS (EPA Registration #100-941). It is 

proposed for use as a seed treatment of alfalfa to provide early season protection of seedlings 

against damage caused by aphids and leafhoppers (first cut crop only). The proposed use 

directions on alfalfa, obtained from a draft label dated 3 March 2010 for Cruiser 5FS, are 

presented in Table 2.1 (below). 

Food handling establishments: The EP proposed for use in food handling establishments is 

Optigard Flex Liquid (EPA Registration #100-1306), an SC formulation of thiamethoxam that 

contains 2 lb ai/gal. It is proposed for use as spot, void, and crack and crevice applications in 

food handling and other areas of food handling establishments. The proposed use directions for 

food handling establishments, obtained from a draft label dated 10 June 2010 for Optigard Flex 

Liquid, are presented in Table 2.1. 
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TABLE 2.1 Summary of Proposed Use Directions on Peanuts and Alfalfa, and in Food

Handling Establishments.

Use Timing; 

Type; and 

Equipment

Product [File 

Symbol or 

Registration 

Number]

Single 

Use Rate

Maximum 

Uses per 

Season

Maximum 

Seasonal 

Use Rate

PHI

(Days)

Use Directions and 

Limitations

Peanuts

Seed 

treatment. 

Cruiser PD

[100-RGAL]

Cruiser 5FS

[100-941]

0.20-0.29

mg ai

/seed 

1 (Implied) 0.08

lb ai/A

NS

1 No soil or foliar application of 

thiamethoxam to peanuts 

grown from seed treated with 

Cruiser PD or Cruiser 5FS. 

Apply Cruiser PD in dry form, 

using equipment intended for 

dry-application seed treatment 

only (not for use in on-farm 

applicators; use in commercial 

seed treatment facilities only). 

Alfalfa

Seed 

treatment. 

Cruiser 5FS

[100-941]

0.001 mg 

ai/seed

1 (Implied) NS 

(0.0130) 2

NS No soil or foliar application of 

thiamethoxam to alfalfa grown 

from seed treated with Cruiser 

5FS. For use in commercial 

seed treatment facilities only.

Food Handling Establishments

Pest pressure; 

coarse lowpressure spot

spray, void

injection, or 

crack and 

crevice spray. 

Optigard Flex 

Liquid

[100-1306]

0.05-

0.10% 

spray

NS NS NA 3Prior to application, remove or 

cover all food items in areas to 

be treated. Do not apply where 

food utensils or food surfaces 

may become contaminated. 

Treatments to be made by 

commercial pesticide 

applicators only. 

1. NS = Not Specified. 

2. The alfalfa field trials utilized single (and seasonal) use rates of 0.0037-0.0130 lb ai/A, based on the respective 

seeding rates (8.00-27.90 lb seeds/A), and an average of 210,000 alfalfa seeds/lb. 

3. NA = Not Applicable. 

Conclusion

The submitted use directions for seed treatment of peanuts and alfalfa, and for applications in 

food handling establishments, are sufficient to allow for evaluation of the submitted residue data 

relative to the proposed use patterns.
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2.2 Structure and Nomenclature

Table 2.2. Nomenclature.

Chemical structure

N

O

N

N

H C3

N

S

Cl

O2N

Empirical Formula C8H10ClN5O3S

Common name Thiamethoxam

Company experimental name CGA 293343

IUPAC name 3-(2-chloro-1,3-thiazol-5-ylmethyl)-5-methyl-1,3,5-oxadiazinan-4-

ylidene(nitro)amine

CAS name 3-[(2-chloro-5-thiazolyl)methyl]tetrahydro-5-methyl-N-nitro-4H-1,3,5-oxadiazin4-imine

CAS registry number 153719-23-4

End-use products (EP) 70% WS formulation in water soluble bags (Cruiser® 70WS; EPA Reg. No. 100-

1294)

25% WG formulation (Actara® Insecticide; EPA Reg. No. 100-938)

2 lb/gal FlC formulation (Platinum® Insecticide; EPA Reg. No. 100-939)

40% WG formulation (Centric® 40WG Insecticide; EPA Reg. No. 100-1147)

2 lb/gal FlC formulation (Actara® 240 SC Insecticide; EPA File Symbol 100-

RELN)

47.6% liquid formulation (Cruiser® Insecticide; EPA Reg. No. 100-941)

0.22% granular formulation (Flagship® Insecticide; EPA File Symbol 100-OAN)

0.33% granular formulation (Meridian® Insecticide; EPA File Symbol 100-OAR)

25% WG formulation (MeridianTM Insecticide; EPA File Symbol 100-OUG)

Chemical Class Neonicotinoid, Group 4A

Known Impurities of Concern None

Chemical structure of 

CGA-322704 metabolite

N

H

N

H

N

H C3

N

S

Cl

O2N

N-[(2-chloro-5-thiazoyl)methyl]-N’-methyl-N‖-nitroguanidine

Common Name Clothianidin
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2.3 Physical and Chemical Properties

Table 2.3. Physicochemical Properties of Thiamethoxam. 

Parameter Value Reference

Melting point/range 139.1°C PMRA Regulatory Note 

(REG2001-03) on 

Thiamethoxam, 2/9/01

pH 4.7 (1% solution in water)

Density 1.57 g/cm3

Water solubility 4.1 g/L (25°C)

Solvent solubility Solvent

acetone

dichloromethane

ethyl acetate

hexane

methanol

octanol

toluene

Solubility (g/L)

48

110

7.0

<1 mg/L

13

0.62

0.68

Vapor pressure 2.7 x 10-9 Pa (20°C)

6.6 x 10-9 Pa (25°C)

Dissociation constant, pKa No dissociation within the pH range 2–12

Octanol/water partition coefficient, 

Log(KOW)

0.13 (25°C)

UV/visible absorption spectrum Not available

Thiamethoxam is a solid under ambient conditions and has a low volatility. The compound has 

relatively low solubility in nonpolar organic solvents and its octanol/water partition coefficient 

suggests that accumulation of thiamethoxam in fatty tissues is unlikely to occur.

3.0 Hazard Characterization/Assessment

3.1 Hazard and Dose-Response Characterization

3.1.1 Database Summary

The toxicological database for thiamethoxam is sufficient for purposes of human health risk 

assessment. The scientific quality is relatively high and the toxicity profile of thiamethoxam can 

be characterized for most effects, including potential carcinogenic, mutagenic, developmental, 

and neurotoxic. The doses and endpoints for use in human health risk assessments are 

summarized in Tables 3.5.12a and 3.5.12b, below. Recent changes to 40 CFR Part 158 make 

immunotoxicity testing (870.7800) required for pesticide registration. The study was required in 

conjunction with a previous risk assessment for proposed uses of thiamethoxam (9/25/2008), and 

remains a datagap and condition of registration. Despite the lack of the immunotoxicity study, 

HED has not retained a database uncertainty factor (UFDB) for the lack of the study, because the 

doses and endpoints for risk assessment are considered to be protective of potential 

immunotoxicity.
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3.1.1.1 Studies available and considered

The following studies were submitted in support of thiamethoxam registration: acute and 

subchronic neurotoxicity; subchronic feeding studies in rats, mice and dogs; a subchronic dermal

study in rats; chronic/carcinogenicity in rats; carcinogenicity in mice; a chronic study in dogs; 

developmental studies in rats and rabbits; developmental neurotoxicity; two reproduction studies 

in rats; mutagenicity battery; and metabolism. In addition, in conjunction with the update of the 

cancer classification in 2005, a number of studies were submitted to support the mode of action 

for carcinogenicity.

3.1.1.2 Mode of action, metabolism, toxicokinetic data

Thiamethoxam has activity against sucking and chewing insects. It is a broad spectrum 

insecticide which belongs to the neonicotinoid class of compounds. While laboratory data 

indicate that thiamethoxam interferes with the nicotinic acetyl choline receptors of the insect’s 

nervous system, the specific binding site/receptor(s) is unknown at this time. Although 

imidacloprid, also a neonicotinoid insecticide, is also known to interfere with nicotinic acetyl 

choline receptors, thiamethoxam appears to function at a different location. Thiamethoxam does 

not inhibit cholinesterase or interfere with sodium channels and, therefore, has a different mode 

of action than organophosphate, carbamate and pyrethroid insecticides. Thiamethoxam is 

reported to have excellent acropetal translocation in the xylem and no basipetal movement in the 

phloem.

In an in vitro nicotinic receptor binding study, thiamethoxam had essentially no affinity for either 

mammalian nicotinic acetyl choline receptor subtype and was considered inactive. This 

thiamethoxam binding affinity study to rat forebrain α4β2 and α7-type nicotinic receptors was 

considered Acceptable/Non-Guideline.

In rats, thiamethoxam is absorbed rapidly and extensively, and is widely distributed, followed by 

very rapid elimination, mostly in the urine (84-95%). The half-life times from tissues ranged 

from 2-6 hours. The major biotransformation reaction is cleavage of the oxadiazine ring to form 

the corresponding nitroguanidine compound (i.e., chlothianidin, the regulated metabolite in 

plants and livestock). In mice, approximately 72% of the administered dose is excreted in the 

urine, while 19% is excreted in the feces. The predominant components are unchanged parent 

(33-41% of administered dose) and two other metabolites (8-12% and 9-18% of administered 

dose). These are the same structures that were most commonly observed in rat excreta; however, 

the proportions are quite different in mouse excreta. 

3.1.1.3 Sufficiency of studies/data

Data are sufficient for FQPA evaluation, toxicity endpoint selection and dose-response 

evaluation. In accordance with the revised part 158 toxicology data requirements, an 

immunotoxicity study should be submitted. To date, this study has not been received. However, 

HED has concluded that a 10X UFDB is not needed to account for the lack of the required 

immunotoxicity study.
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3.1.2 Toxicological Effects

Acutely, technical thiamethoxam is slightly toxic to rats and moderately toxic to mice via the 

oral route (Toxicity Category III); it is of low toxicity to rats via the dermal (Toxicity Category 

III) and inhalation routes (Toxicity Category IV). It is not irritating to the skin and minimally 

irritating to the eye, and is not a dermal sensitizer.

The database on thiamethoxam indicates that the primary targets for this chemical are the liver, 

testes, kidney, and hematopoietic system. In addition, effects on the thyroid (rats and dogs) and 

the adrenal gland (rats) are seen in the short-term studies.

The liver effects occur across species, sexes and routes of administration. In the rat, 

inflammatory cell infiltration and necrosis of single hepatocytes are observed in the 28-day 

dermal study and hepatocellular hypertrophy and lymphohistiocytic infiltration of the liver are 

observed in the subchronic oral studies. Chronic oral exposure induces an increase in the 

incidence of foci of cellular alteration in females. In rats, there was no evidence of liver tumors 

at the dose levels tested. Females appear to be more sensitive than males for liver effects in rats. 

In the mouse, the following effects were observed in oral studies: hepatocellular hypertrophy, 

necrosis of single hepatocytes, lymphocytic infiltration (subchronic and chronic), apoptosis, 

induction of microsomal enzymes, Kupffer cell pigmentation (subchronic), Kupffer cell 

hyperplasia, increased incidence of foci of cellular alteration, and increased mitotic activity 

(chronic). Male mice are more sensitive to the liver pathology than are females. Chronic dosing 

also results in the development of benign and malignant liver tumors in both sexes of mice. An 

increase in the number of animals with multiple tumors is also observed; however, treatment 

does not affect the latency to tumor formation nor lethality resulting from the observed tumors. 

The incidence of non-neoplastic and neoplastic pathology is increased at the same dose level, 

i.e., there is no clear departure point between doses that induce tumors and other systemic toxic 

effects. In both rats and mice, there appears to be increasing severity of effects with increasing 

dose. In rats, the lowest dose at which an effect is observed in the liver does not appear to 

decrease significantly with increasing length of exposure to the test material. Due to dose 

spacing, it is not possible to determine if this is the case in the mouse, which appears to be the 

most sensitive species.

Testicular effects are observed in the rat and dog. They consist of decreased testes weights, 

increased incidence and severity of seminiferous tubular atrophy and sperm abnormalities at low 

dose levels in the rat; decreased testes weights associated with microscopic evidence of reduction 

in spermatogenesis and occurrence of spermatic giant cells in the testes at toxic dose levels in the 

subchronic dog study; and atrophy of the seminiferous tubules at minimally to moderately toxic 

dose levels in the chronic dog study. Testicular effects were noted in both of the 2-generation 

reproduction studies. The effects in the rat are only observed in the F1 males in the twogeneration reproduction study and are not observed at any other time. In both studies, there is 

evidence of increased quantitative susceptibility for male pups. Reproductive effects in males 

appear in the F1 generation in the form of increased incidence and severity of testicular tubular 

atrophy in one study and sperm abnormalities in the other study. While the testicular effects 
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observed in the two studies differ, the findings of the two studies support each other and are 

consistent relative to observed thiamethoxam toxicity. These effects are being used as the basis 

for risk assessment because they are observed at very low dose levels. It is anticipated that they 

may be observed after either intermediate-term or chronic exposure, particularly when exposure 

occurs in utero.

The kidney effects occur in both sexes of the rat but are found primarily in the male. They are 

observed following either oral or dermal exposure. The majority of the kidney effects (hyaline 

changes in the renal tubules) have been attributed by the study authors to accumulation of α2uglobulin, a protein that is unique to male rats, in the proximal convoluted tubules. The observed 

pathology is consistent with α2u-globulin mediated kidney toxicity. Collectively, special studies

submitted demonstrate an increase in accumulation of α2u-globulin in conjunction with the 

observance of hyaline droplets in some dose groups as compared to lower levels observed in 

controls. 

Hematological effects are observed in the rat, dog and mouse with the dog being the most 

sensitive species. Both sexes appear to be affected; although the male appears to be more 

affected in the rodent and the female more affected in the dog. In the rat, increased spleen 

weights, increases in the incidence and severity of hemosiderosis and/or extramedullary 

hematopoiesis are observed in both the subchronic and chronic studies. In the mouse, a slight 

reduction in erythrocytes, hemoglobin and hematocrit, accompanied by increased mean 

corpuscular volume and mean corpuscular hemoglobin are observed in the subchronic feeding 

study at very high dose levels. In the dog, leukopenia and slight microcytic anemia are observed 

in the subchronic oral study.

Thyroid effects in the rat (thyroid follicular cell hypertrophy) and dog (increase in thyroid 

weight) may be due to induction of microsomal enzymes in the liver, which in turn affect the 

hypothalamus-pituitary-thyroid-liver homeostatic process for regulation of thyroid hormones. 

Evidence of this is the presence of hepatocellular hypertrophy in several species. The adrenal 

effects observed in the subchronic rat studies generally consist of fatty change and inflammatory 

cell infiltration of the adrenal cortex.

Alanine aminotransferase (ALT) levels are significantly decreased in the dog and companion 

animal studies. While the toxicological significance of this observation is unclear, there is no 

doubt regarding its association to treatment with thiamethoxam. It has been proposed that the 

decreases in ALT activity may be caused by either interference with or suppression of in vivo

concentrations of pyridoxal phosphate (vitamin B6, a cofactor necessary for ALT activity) or by 

direct suppression of ALT synthesis. If thiamethoxam interferes with vitamin B6, it could have 

significant implications regarding potential adverse developmental effects.

Developmental/Reproductive Effects: In the developmental studies, there is no quantitative or 

qualitative evidence of increased susceptibility of rat or rabbit fetuses to in utero exposure to 

thiamethoxam. The developmental NOAELs are either higher than or equal to the maternal 

NOAELs. The toxicological effects in fetuses do not appear to be any more severe than those in 
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the dams or does. In the rat developmental neurotoxicity study, there was no quantitative 

evidence of increased susceptibility. 

Two reproduction studies are available. In both studies, there is evidence of increased 

quantitative susceptibility for male pups. Reproductive effects in males appear in the F1

generation in the form of increased incidence and severity of testicular tubular atrophy in one 

study and sperm abnormalities in the other study. While the testicular effects observed in the 

two studies differ, the findings of the two studies support each other and are consistent relative to 

observed thiamethoxam toxicity. 

Carcinogenicity and Mutagenicity: Thiamethoxam induces hepatocellular adenomas and 

carcinomas in male and female Tif:MAGf (SPF) mice. The HED Cancer Assessment Review 

Committee (June 13, 2005) concluded that the mouse liver tumors arise through a non-genotoxic 

mode of action characterized by a series of key events that include: perturbation of cholesterol 

biosynthesis, hepatotoxicity, cell death (both as single cell necrosis and apoptosis) and a 

sustained increase in cell replication rates. The mouse appears to be uniquely sensitive to this 

mode of action. Because of the threshold nature of the mode of action and the unique sensitivity 

of the mouse, it is concluded that humans are unlikely to be at risk for developing tumors 

following exposures to thiamethoxam. The CARC classified Thiamethoxam as “Not Likely to 

be Carcinogenic to Humans” based on convincing evidence that a non-genotoxic mode of 

action for liver tumors was established in the mouse and that the carcinogenic effects are a result 

of a mode of action dependent on sufficient amounts of a hepatotoxic metabolite produced

persistently. Quantification of carcinogenic potential is not required. The submitted 

mutagenicity studies are adequate and indicate that thiamethoxam is not mutagenic.

3.1.3 Dose-response

The database on thiamethoxam indicates the primary targets for this chemical are the liver, 

testes, kidney, and hematopoietic system. The testicular effects are considered to be 

toxicologically significant and occur at low doses, and therefore most of the endpoints for risk 

assessment are based on these effects.

In the liver, enzyme induction and hepatocellular hypertrophy in and of themselves are not 

necessarily considered adverse effects. However, other effects were associated with these 

observations that are considered to be toxicologically significant. These include necrosis of 

single hepatocytes, foci of cellular alteration, apoptosis, Kupffer cell infiltration, pigmentation 

and hyperplasia, and benign and malignant liver tumors. The majority of the kidney effects may 

be attributed to accumulation of α2u-globulin, a protein that is unique to male rats, and, therefore,

these kidney effects are not relevant to humans. The hematological effects are observed in three 

species. These include increased spleen weights, increases in the incidence and severity of 

hemosiderosis and/or extramedullary hematopoiesis and a slight reduction in erythrocytes, 

hemoglobin and hematocrit. In the dog, leukopenia and slight microcytic anemia have been 

observed. While these effects could be potential indication of immunotoxicity, HED concluded 

that the leukopenia was associated with an anemic response, as opposed to direct 

immunotoxicity. The decreases in spleen weight occurred at very high doses, and were not 
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statistically significant. These effects are not considered to be as significant as the testicular, 

liver, and kidney effects. They often appear at very high dose levels and the changes are not 

dramatic.

3.2 Absorption, Distribution, Metabolism, Excretion (ADME)

In rats, thiamethoxam is rapidly and extensively absorbed, widely distributed, and very rapidly 

eliminated, mostly in urine. The highest tissue concentrations are in skeletal muscle (10-15% of 

administered dose). The half-life times from tissues ranged from 2-6 hours. Very low tissue 

residues were reported after 7 days. Within 24 hours, approximately 84-95% of the administered 

dose was excreted in urine, while 2.5-6% was excreted in the feces. Most was excreted as 

unchanged parent (70-80% of dose). The major biotransformation reaction is cleavage of the 

oxadiazine ring to form the corresponding nitroguanidine compound (CGA-322704). 

Enterohepatic circulation is negligible.

In mice, approximately 72% of the administered dose was excreted in the urine and 19% was 

excreted in feces. Small but measurable amounts were detected in expired air (approximately 

0.2% of dose). Parent (33-41% of administered dose) and 2 predominant metabolites: 8-12% 

and 9-18% of administered dose were found. These are the same structures that were most 

commonly observed in rat excreta; however, the proportions are quite different in mouse excreta. 

One additional significant metabolite (mouse R6) was isolated from feces samples. Between 30-

60% of the administered dose was excreted as metabolites.

3.3 FQPA Considerations

3.3.1 Adequacy of the Toxicity Database

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

current risk assessment, and for evaluating the need for an FQPA safety factor. However, the 

database is not complete because the required immunotoxicity study has not been submitted. 

The following acceptable studies are available:

Developmental toxicity studies in rats and rabbits

Two two-generation reproduction studies in rats

Developmental neurotoxicity study in rats

3.3.2 Evidence of Neurotoxicity

Thiamethoxam was tested in acute, 90-day and developmental neurotoxicity studies. In the acute 

neurotoxicity study, drooped palpebral closure, lower rectal temperature, increased forelimb grip 

strength (males only) and decreased locomotor activity were observed 2-3 hours after dosing. 

Effects at a higher dose included abnormal body tone, ptosis, impaired respiration, tremors, 

longer latency to first step in the open field, crouched-over posture, gait impairment, hypoarousal, decreased number of rears, uncoordinated landing during the righting reflex test, slight 

lacrimation (females only) and higher mean average input stimulus value in the auditory startle 
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response test (males only). These effects were no longer evident at the 1 week and 2 week postdosing examinations. In addition to these findings, 3 females were found dead within the first 2 

days after treatment. There were no treatment-related histopathological findings noted in the 

central or peripheral nervous system at any dose level tested.

In the 90-day neurotoxicity study, there were no treatment-related systemic or neurotoxicological 

effects observed at any dose level tested up to 95 mg/kg bw/day in males and 216.4 mg/kg 

bw/day in females. In addition, no treatment-related histopathological findings were noted in the 

central or peripheral nervous systems. The subchronic mammalian neurotoxicity study was not 

tested at sufficiently high dose levels; however, a new study is not required at this time because 

no neuropathology was observed at the dose levels tested, and the weight of the evidence from 

the other toxicity studies indicates that there is no reason for concern.

In the developmental neurotoxicity study, there was no evidence of neurotoxicity in the dams 

exposed up to 298.7 mg/kg/day; a dose that was associated with decreases in body weight gain 

and food consumption. In pups exposed to 298.7 mg/kg/day, there were significant reductions in 

absolute brain weight and size (i.e., length and width of the cerebellum was less in males on day 

12, and there were significant decreases in Level 3-5 measurements in males and in Level 4-5 

measurements in females on day 63).

The following evidence of neurotoxicity was observed in other oral studies. In the 28-day dog 

study there was a decrease in absolute but not relative brain weight in females at 43 mg/kg/day. 

This does not appear in either the 90-day study (up to 50 mg/kg/day) or the chronic dog study 

(up to 45 mg/kg/day). In the mouse carcinogenicity study, there was an increase in relative brain 

weight in high dose males that was attributed to reduction in body weight gain. In the rat 

chronic/carcinogenicity study, there was a slight increase in incidence of brain effects in high 

dose males. Microscopically, this increase was associated with hydrocephalus and pressure 

atrophy which was secondary to pituitary adenomas. The increased incidence of brain effects is 

not likely due to a neuronal tissue malformation but, rather, secondary to a pituitary adenoma. 

3.3.3 Developmental Toxicity Studies

In the developmental studies, there is no evidence of increased quantitative or qualitative 

susceptibility of rat or rabbit fetuses to in utero exposure to thiamethoxam. The developmental 

NOAELs are either higher than or equal to the maternal NOAELs. The toxicological effects in 

fetuses do not appear to be any more severe than those in the dams or does. In the rat 

developmental neurotoxicity study, there was no quantitative evidence of increased 

susceptibility. An increase in qualitative susceptibility was based upon reduced brain weight and 

size in male and female pups at the highest dose tested; whereas, effects in dams were limited to 

decreased body weight gain and food consumption.

3.3.4 Reproductive Toxicity Study

Two acceptable reproduction studies are available. In both studies, there is evidence of increased 

quantitative susceptibility for male pups. Reproductive effects in males appear in the F1
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generation in the form of increased incidence and severity of testicular tubular atrophy in one 

study and sperm abnormalities in the other study. HED has determined that there is evidence of 

increased quantitative susceptibility for male pups (NOAEL: 0.6 mg/kg/day for increased 

incidence of testicular tubular atrophy at 1.8 mg/kg/day) when compared to the parents 

(NOAEL: 1.8 mg/kg/day for hyaline changes in renal tubules at 61 mg/kg/day).

In another two-generation reproductive study, there was quantitative evidence of increased 

susceptibility. In this study, the NOAEL for reproductive effects is 1.2 mg/kg/day based upon 

sperm abnormalities, and the LOAEL is 3 mg/kg/day. The study is classified as acceptable-nonguideline and is useful for risk assessment, even though additional information pertaining to the 

study has been requested. HED does not believe the outstanding information will impact the 

NOAEL identified for sperm abnormalities in this study.

Histopathology findings from the 1998 study cannot be combined with data from the new 

reproduction study due to differences in histopathology reporting criteria which may affect both 

incidence and severity of reported testicular lesions and may make comparison to the previous 

study or other historical control data (where such criteria were not applied) inappropriate at this 

time. While the testicular effects observed in the two reproductive studies differ, the findings 

support each other and are consistent relative to observed thiamethoxam toxicity. Although 

histopathological effects (tubular atrophy) were not observed in the more recent 2004 study at 

low dose levels, the observation of reduced sperm production would be expected to co-occur 

with the tubular atrophy that was observed in the 1998 study.

3.3.5 Additional Information from Literature Sources

None.

3.3.6 Pre-and/or Postnatal Toxicity

3.3.6.1 Determination of Susceptibility

In the developmental studies, there is no evidence of increased quantitative or qualitative 

susceptibility of rat or rabbit fetuses to in utero exposure to thiamethoxam. The developmental 

NOAELs are either higher than or equal to the maternal NOAELs. The toxicological effects in 

fetuses do not appear to be any more severe than those in the dams or does. In the rat 

developmental neurotoxicity study, there was no quantitative evidence of increased 

susceptibility; however, there was increased qualitative susceptibility because the effects in the 

pups (reduced brain weight and significant changes in brain morphometric measurements) were 

considered to be more severe than findings in the dams (decreased body weight gain and food 

consumption).

There is evidence of increased quantitative susceptibility for male pups in both two-generation 

reproductive studies. In one study, there are no toxicological effects in the dams; whereas, for 

the pups, reduced bodyweights are observed at the highest dose level, starting on day 14 of 

lactation. This contributes to an overall decrease in bodyweight gain during the entire lactation 
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period. The reproductive effects in males appear in the F1 generation in the form of increased 

incidence and severity of testicular tubular atrophy (see developmental/reproductive section). 

These data are considered to be evidence of increased quantitative susceptibility for male pups 

(increased incidence of testicular tubular atrophy at 1.8 mg/kg/day) when compared to the 

parents (hyaline changes in renal tubules at 61 mg/kg/day; NOAEL is 1.8 mg/kg/day).

In a more recent two-generation reproduction study, the most sensitive effect was sperm 

abnormalities at 3 mg/kg/day (the NOAEL is 1.2 mg/kg/day) in the F1 males. This study also 

indicates increased susceptibility for the offspring for this effect.

Although there is evidence of increased quantitative susceptibility for male pups in both 

reproductive studies, NOAELs and LOAELs were established in these studies and the Agency 

selected the NOAEL for testicular effects in F1 pups as the basis for risk assessment. The 

Agency has confidence that the NOAEL selected for risk assessment is protective of the most 

sensitive effect (testicular) for the most sensitive subgroup (pups) observed in the toxicological 

database.

3.3.6.2 Degree of Concern Analysis and Residual Uncertainties for Pre- and/or Postnatal 

Susceptibility

There is low concern for an increase in quantitative susceptibility in the rats or rabbits since 

developmental and offspring toxicity occurred at dose levels equal to or higher than the doses 

where parental toxicity was observed in three studies (rat developmental, rabbit developmental 

and rat developmental neurotoxicity). There is also low concern for the increased qualitative 

susceptibility observed in the DNT study because the doses and endpoints selected for risk 

assessment are protective of the effects in the offspring. As noted previously, the Agency 

selected the NOAEL for testicular effects in F1 pups based on two reproductive toxicity studies 

for risk assessment to be protective of all sensitive subpopulations.

There is evidence of neurotoxicity after acute exposure to thiamethoxam at doses of 500 

mg/kg/day including drooped palpebral closure, decrease in rectal temperature and locomotor 

activity and an increase in forelimb grip strength. However, no evidence of neuropathology was 

observed. These effects occurred at doses at least 14-fold and 416-fold higher than the doses 

used for the acute, and chronic risk assessments, respectively; thus, there is low concern for these 

effects since it is expected that the doses used for regulatory purposes would be protective of the 

effects noted at much higher doses.

3.3.7 Recommendation for a Developmental Neurotoxicity Study

A developmental neurotoxicity study has been requested, received, and reviewed by the Agency 

(see Section 3.3.2).
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3.4 FQPA Safety Factor for Infants and Children

The toxicity database for thiamethoxam is not complete because the required immunotoxicity 

study has not been submitted. The available data for thiamethoxam show the potential for 

immunotoxic effects, including changes in spleen weight and leukopenia. However, HED 

concluded that the leukopenia was associated with an anemic response as opposed to direct 

immunotoxicity. In addition, the reduced spleen weights were observed at high doses, and were 

not statistically significant. Based on these considerations, HED previously concluded that an 

additional database uncertainty factor (UFDB) was not needed to account for the lack of the 

immunotoxicity study.

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

children be reduced to 1X. There is no quantitative or qualitative evidence of increased 

susceptibility of rat or rabbit fetuses to in utero exposure to thiamethoxam in the developmental 

toxicity studies. The developmental NOAELs are either higher than or equal to the maternal 

NOAELs. There was no evidence of increased quantitative susceptibility in the DNT study in

rats.

Although there is evidence of increased quantitative susceptibility for male pups of both twogeneration reproductive studies, NOAELs and LOAELs were established in these studies, and 

HED selected the NOAEL for testicular effects in F1 pups as the basis for risk assessment. HED

has confidence that the NOAEL selected for risk assessment is protective of the most sensitive 

effect (testicular) for the most sensitive subgroup (pups) observed in the toxicological database.

In addition, the NOAELs selected for risk assessment are protective of all toxicological effects 

observed in the database including treatment-related changes in the adrenal gland, thyroid, testes 

and ovaries. Thus, HED believes the FQPA safety factor should be reduced to 1X.

The dietary food exposure assessment is not likely to underestimate exposure/risk. The dietary 

drinking water assessment utilizes water concentration values generated by models and 

associated modeling parameters that are designed to provide conservative, health protective, 

high-end estimates of water concentrations which will not likely be exceeded. The residential 

exposure assessment was conducted using standard, health-protective assumptions.

3.5 Hazard Identification and Toxicity Endpoint Selection

3.5.1 Acute Reference Dose (aRfD) - Females age 13-49

A separate aRFD is not being used for females age 13-49. Females in this age group will be 

assessed using the aRFD for the general population (see 3.5.2).

3.5.2 Acute Reference Dose (aRfD) - General Population

Study Selected: Developmental Neurotoxicity Study—rat (OPPTS 870.6300)
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MRID No.: 46028202, 46028201

Dose and Endpoint for Establishing aRfD: Developmental NOAEL = 34.5 mg/kg/day based on 

delayed sexual maturation in male pups, and reduced brain morphometric measurements LOAEL 

= 298.7 mg/kg/day.

Comments on Study/Endpoint/Uncertainty Factors: The endpoint chosen was presumed to occur 

following a single exposure and could be relevant for all populations, including children. The 

endpoint is based on the most sensitive effect in the most sensitive subpopulation (pups). 

Although the toxicological effects occurred in pups, it is not known if these effects resulted from 

pre- or post-natal dosing, and therefore the endpoint is relevant to all populations, and is 

considered to be protective. An UF of 100 was applied to account for inter-species extrapolation 

(10x) and intra-species variation (10x).

Acute RfD = 34.5 mg/kg/day (NOAEL) = 0.35 mg/kg/day

 100 (UF)

3.5.3 Chronic Reference Dose (cRfD) 

Study Selected: Two 2-Generation Reproduction Toxicity Studies—rat (OPPTS 870.3800)

MRID No.: 44718707; 46402902, 46402904, 46402906

Dose and Endpoint for Establishing the cRfD: The Agency selected both two-generation 

reproductive studies as co-critical. The NOAEL of 1.2 mg/kg/day is based on sperm 

abnormalities in the F1 males observed after in utero and post-natal exposure in the rat 

reproduction study at 3 mg/kg/day. In the other two-generation reproduction study, the NOAEL 

of 0.6 mg/kg/day and LOAEL of 1.8 mg/kg/day are based on testicular atrophy in F1 males. The 

higher NOAEL was selected from these two studies based on the rationale detailed below in 

―Comments on Study/Endpoints/Uncertainty Factors.‖ While the testicular effects observed in 

the two reproductive studies differ, the findings support each other and are consistent relative to 

observed thiamethoxam toxicity. Although histopathological effects (tubular atrophy) were not 

observed in the more recent 2004 study at low dose levels, the observation of reduced sperm 

production would be expected to co-occur with the tubular atrophy that was observed in the 1998 

study.

Uncertainty Factor(s): An UF of 100 was applied to account for inter-species extrapolation (10x) 

and intra-species variation (10x).

Comments on Study/Endpoint/Uncertainty Factors: The endpoint is based on the most sensitive 

effect observed in offspring. The endpoint is appropriate because effects were observed after 

subchronic exposure and are thus likely to be observed after chronic exposure.

Although the NOAEL of 1.2 mg/kg/day is very close to the LOAEL of 1.8 mg/kg/day for 

testicular effects, the Agency has confidence that the NOAEL is protective. The NOAEL of 1.2 
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mg/kg/day is based on the 2004 study for significant reductions in the number of sperm in the 

right testes of F1 males at 3 mg/kg/day. This endpoint is considered conservative and protective 

because there was no dose-response relationship and these findings were not observed in the F0

males. Most of the other sperm parameters were not significantly altered until much higher dose 

levels of 155 mg/kg/day. Although some sperm abnormalities were noted in the 1998 study,

such as decreased sperm motility, even at 0.6 mg/kg/day, there was no dose-response 

relationship, there was high variability among all groups and there were no treatment-related 

effects on sperm count or sperm morphology. Based on a special complementary study 

conducted to evaluate this finding, HED concluded the sperm effects in this study were likely 

due to technical error and not treatment-related. However, based on consideration of both 

reproductive studies, the Agency believes that it is appropriate to select a NOAEL of 1.2 

mg/kg/day for these sperm effects for use in risk assessment.

The LOAEL of 1.8 mg/kg/day is based on testicular atrophy in F1 generation males. In the 2004 

study, testicular lesions were marginal even at much higher dose levels of 155 mg/kg/day where 

there was an increase in incidence but not severity of testicular lesions. The difference in the two 

studies may possibly be due to different grading criteria, and also differences in histopathological 

evaluation protocols. The 1998 study only evaluated one slice per testis. The 2004 study 

evaluated 4 slices per testis, calculated an average numerical grade and reported only marginal 

testicular lesions at 155 mg/kg/day. Therefore, HED believes the LOAEL of 1.8 mg/kg/day for 

testicular atrophy is likely to be conservative and protective because of the findings of the 2004 

study.

Although there are no indications of effects on other reproductive parameters (i.e. mating, 

gestation, fertility and viability), similar effects were observed in a second species (dog) after 

subchronic exposure. Due to the high fecundity of rats, the lack of effects on other reproductive 

parameters is not necessarily an indication that the testicular effects would not be a problem in 

humans. Since no data are available to indicate how the testicular effects occur, whether or not 

they can be considered an endocrine effect, or whether or not they can definitively be considered 

adverse, the testicular effects were selected to provide a conservative approach for assessment of 

risk to humans. In addition, it is not known whether the observed effects are due to exposure to 

either the male or female or both parents in the study. Therefore, the endpoint will be applied to 

the general population.

The Agency recognizes that this endpoint may not be relevant for young children that are 

sexually immature. However, this endpoint was determined to be conservative and healthprotective for use in risk assessment.

Chronic RfD = 1.2 mg/kg/day (NOAEL) = 0.012 mg/kg/day

 100 (UF)

3.5.4 Incidental Oral Exposure (Short- and Intermediate-Term) 

Study Selected: 90-day Oral Toxicity —dog (OPPTS 870.3150)
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MRID No.: 44718702

Dose and Endpoint for Risk Assessment: The incidental oral endpoint (all durations) of 8.23 

mg/kg/day is based on slightly prolonged prothrombin times and decreased plasma albumin and 

A/G ratio (both sexes); decreased calcium levels and ovary weights and delayed maturation in 

the ovaries; decreased cholesterol and phospholipid levels, testis weights, spermatogenesis, and 

spermatic giant cells in testes (males) that occurred at 32 mg/kg/day in males and 33.9 

mg/kg/day in females.

Comments on Study/Endpoint: The Agency recognizes that some of the observed effects in this 

study (i.e., testicular and ovarian effects) may not be relevant for young children that are sexually 

immature. However, these effects occurred along with other more toxicologically relevant 

findings for children, and thus this endpoint was determined to be conservative and healthprotective for use in risk assessment.

The Agency also considered the rat and mouse 90 day toxicity studies for endpoint selection that 

reported LOAELs of 17.64 mg/kg/day and 14.3 mg/kg/day, respectively. The dog NOAEL of 

8.23 mg/kg/day is protective of the effects noted in rats and mice. In addition, the renal effects 

in the rat study are most likely attributed to accumulation of α2u-globulin, and thus are not 

relevant to humans.

3.5.5 Dermal Absorption

Dermal Absorption Factor: 5%.

HED recommends use of a 5% dermal absorption factor based on an evaluation of in vivo dermal 

absorption data for two formulated products containing thiamethoxam and an in vivo dermal 

absorption study in the rat using technical thiamethoxam. The 5% dermal absorption value 

represents the maximum amount absorbed for all dose groups for either formulation tested in the 

most recent study.

3.5.6 Dermal Exposure (Short-, Intermediate- and Long-Term) Adults

Study Selected: Two 2-Generation Reproduction Toxicity Studies—rat (OPPTS 870.3800)

MRID No.: 44718707; 46402902, 46402904, 46402906

Dose and Endpoint for Risk Assessment: The dermal endpoint for adults, all durations (1.2 

mg/kg/day) is based on sperm abnormalities and testicular effects observed after in utero and 

post-natal exposure in the rat reproduction studies (see comments from the chronic dietary 

section above). 

Comments on Study/Endpoint: Although a 28-day dermal toxicity study in rats is available, 

HED selected a reproductive NOAEL because the reproductive parameters are not evaluated in 

the dermal toxicity study and thus the consequences of these effects cannot be ascertained for the 
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dermal route of exposure. Since an oral toxicity study was selected, a 5% dermal absorption 

factor is recommended.

3.5.7 Dermal Exposure (Short-, Intermediate- and Long-Term) Children Age 1 to 6 Years 

Study Selected: 28-Day Dermal Toxicity Study—rat (OPPTS 870.3200)

MRID No.: 44710402

Dose and Endpoint for Risk Assessment: The dermal endpoint (children 1-6, all durations) of 60 

mg/kg/day is based on increased plasma glucose, triglyceride levels, and alkaline phosphatase 

activity as well as inflammatory cell infiltration in the liver and necrosis of single hepatocytes in 

females at 250 mg/kg/day.

Comments on Study/Endpoint: The Agency selected the dermal toxicity study to assess young 

children because the testicular effects observed in the two-generation rat reproduction study are 

not relevant for young children that are sexually immature. Because a route-specific toxicity 

study was selected, a dermal absorption factor is not necessary when assessing dermal exposure 

to children.

3.5.8 Inhalation Exposure (Short-, Intermediate- and Long-Term) 

Based on the available toxicity database and the Agency's current practices, short- and 

intermediate-term inhalation risks for thiamethoxam were assessed using an oral toxicity study. 

The Agency sought expert advice and input on issues related to this route to route extrapolation 

approach (i.e. the use of oral toxicity studies for inhalation risk assessment) from its Federal 

Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. 

The Agency 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, re-examine and develop new 

policies and procedures for conducting inhalation risk assessments, including route to route 

extrapolation of toxicity data. If any new policies or procedures are developed, the Agency may 

revisit the need for an inhalation toxicity study for thiamethoxam and/or a re-examination of the 

inhalation toxicity risk assessment.

Study Selected: Two 2-Generation Reproduction Toxicity Studies—rat (OPPTS 870.3800)

MRID No.: 44718707, 46402902, 46402904, 46402906

Dose and Endpoint for Risk Assessment: NOAEL of 1.2 mg/kg/day is based on sperm 

abnormalities and testicular effects observed after in utero and post-natal exposure in the rat 

reproduction studies (see comments from the chronic dietary endpoint section above).

Comments about the Study/Endpoint: Since no data are available to indicate how much 

exposure will induce the effects, the effects are considered to be appropriate for all exposure 
Thiamethoxam D373376

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durations. Other than acute toxicity, no inhalation studies are available. Therefore, the 

reproductive endpoint is selected for inhalation exposure. Inhalation absorption is assumed to be 

100% of oral absorption. The Agency recognizes that this endpoint may not be relevant for 

young children that are sexually immature. However, based on the use pattern and physicalchemical characteristics, the Agency does not anticipate inhalation exposure to young children.

3.5.9 Level of Concern for Margin of Exposure

Table 3.5.9 Summary of Levels of Concern for Risk Assessment.

Route Short-Term

(1 - 30 Days)

Intermediate-Term

(1 - 6 Months)

Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal 100 100 100

Inhalation 100 100 100

Residential Exposure

Dermal 100 100 100

Inhalation 100 100 100

Incidental Oral 100 100 100

3.5.10 Recommendation for Aggregate Exposure Risk Assessments

According to FQPA (1996), when there are potential residual exposures to a pesticide, an 

aggregate risk assessment must consider exposures from 3 major routes: oral, dermal, and 

inhalation. 

Similar endpoints were selected for short-, intermediate- and long-term exposures via oral, 

dermal and inhalation routes, so they may be aggregated. The endpoints are protective of 

adverse testicular, liver and hematological effects, which appear to be the most sensitive effects 

of thiamethoxam exposure via oral and dermal routes.

3.5.11 Classification of Carcinogenic Potential

Thiamethoxam induces hepatocellular adenomas and carcinomas in male and female mice. 

These findings served as the basis for HED’s conclusion that thiamethoxam was likely to be 

carcinogenic to humans; furthermore, HED recommended using a linear low dose extrapolation 

for assessing cancer risk. The registrant subsequently conducted a number of studies to support a 

mode of action for carcinogenicity in mice. These studies were evaluated, and the Cancer 

Assessment Review Committee (CARC) agreed with the registrant that a plausible mode of 

action has been established for the development of liver tumors in a mouse bioassay with 
Thiamethoxam D373376

Page 26 of 60

thiamethoxam. The liver tumors in the mouse arise through a non-genotoxic mode of action 

characterized by a series of key events that include: perturbation of cholesterol biosynthesis, 

hepatotoxicity, cell death (both as single cell necrosis and apoptosis) and a sustained increase in 

cell replication rates. Neither the key events nor an increase in liver tumors are seen in rats fed 

on diets containing up to 3000 ppm thiamethoxam. The key metabolites, CGA330050 and 

CGA265307, responsible for the key events in the mouse are not formed in sufficient quantities 

in the rat and explain the lack of a carcinogenic response in this species.

A sufficient amount of active metabolite must be produced along with persistent exposure to the 

active metabolite to lead to the hepatotoxic/regenerative proliferative/neoplastic response in the 

mouse. Limited human in vitro metabolism studies suggest that humans are more similar to the 

rat compared to the mouse in producing the active metabolite. The rat does not develop tumors 

following treatment with thiamethoxam. Thus, the mouse appears to be uniquely sensitive to this 

mode of action. Because of the threshold nature of the mode of action and the unique sensitivity 

of the mouse, it is concluded that humans are unlikely to be at risk for developing tumors 

following exposures to thiamethoxam.

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

the CARC re-classified thiamethoxam as “Not Likely to be Carcinogenic to Humans” based 

on convincing evidence that a non-genotoxic mode of action for liver tumors was established in 

the mouse and that the carcinogenic effects are a result of a mode of action dependent on 

sufficient amounts of a hepatotoxic metabolite produced persistently. Although humans are 

qualitatively capable of producing the active metabolite, thiamethoxam is unlikely to pose a 

cancer risk to humans unless sufficient amounts of metabolites are persistently formed to drive a 

carcinogenic response. Lastly, the non-cancer assessment is sufficiently protective of the key 

events (perturbation of liver metabolism, hepatotoxicity/regenerative proliferation) in the animal 

mode of action and, thus, cancer is not an issue. Thus, quantification of carcinogenic potential is 

not required.
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3.5.12 Summary of Toxicological Doses and Endpoints for Thiamethoxam for Use in 

Human Health Risk Assessments.

Table 3.5.12a. Toxicological Doses and Endpoints for Thiamethoxam for Use in Dietary and Residential 

Human Health Risk Assessments.

Exposure/

Scenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors

Level of Concern 

for Risk Assessment

Study and Toxicological Effects

Acute Dietary

All populations

including infants 

and children 

NOAEL = 34.5 

mg/kg/day

UFA= 10x

UFH= 10x

SFFQPA=1

aRfD=0.35 

mg/kg/day

aPAD=0.35 

mg/kg/day

Rat Developmental Neurotoxicity 

study 

LOAEL = 298.7 mg/kg/day based on 

delayed sexual maturation in male 

pups, and reduced brain morphometric 

measurements.

Chronic Dietary

All populations

including infants 

and children

NOAEL= 1.2 

mg/kg/day 

(MRID 

46402904)

UFA= 10x

UFH= 10x

SFFQPA=1

cRfD=0.012 

mg/kg/day

cPAD=0.012 

mg/kg/day

2-Generation reproduction study 

LOAEL = 1.8 mg/kg/day based on 

increased incidence and severity of 

tubular atrophy in testes of F 1

11

generation males.

2-Generation reproduction study 

LOAEL = 3 (males), not determined 

(females) mg/kg/day based on sperm 

abnormalities in F1 males.

Incidental Oral (all 

durations)

NOAEL= 8.23 

mg/kg/day

UFA= 10x

UFH= 10x

SFFQPA=1

MOE= 100 

(residential)

90-day Dog study 

LOAEL= 32 (males) 33.9 (females) 

mg/kg/day based on slightly prolonged 

prothrombin times and decreased 

plasma albumin and A/G ratio (both 

sexes); decreased calcium levels and 

ovary weights and delayed maturation 

in the ovaries (females); decreased 

cholesterol and phospholipid levels, 

testis weights, spermatogenesis, and 

spermatic giant cells in testes (males).

Dermal (all 

durations) (Adults)

Oral study 

NOAEL= 1.2

mg/kg/day

(dermal 

absorption rate 

= 5%)

UFA= 10x

UFH= 10x

SFFQPA=1

MOE= 100 

(residential)

2-Generation reproduction study 

LOAEL = 1.8 mg/kg/day based on 

increased incidence and severity of 

tubular atrophy in testes of F1

generation males.

2-Generation reproduction study 

LOAEL = 3 (males), not determined 

(females) mg/kg/day based on sperm 

abnormalities in F1 males.

Dermal (all 

durations) (infants/

children 1-6 yrs)

Dermal Study

NOAEL=60 

mg/kg/day

UFA= 10x

UFH= 10x

SFFQPA=1

MOE= 100 

(residential)

Rat 28-Day Dermal Toxicity Study

LOAEL = 250 (females) mg/kg/day 

based on increased plasma glucose, 

triglyceride levels, and alkaline 

phosphatase activity and inflammatory 

cell infiltration in the liver and 

necrosis of single hepatocytes in 

females. 

Inhalation (all 

durations)

Oral study 

NOAEL= 1.2 

mg/kg/day

UFA= 10x

UFH= 10x

SFFQPA=1

MOE= 100 

(residential)

2-Generation reproduction study

LOAEL = 1.8 mg/kg/day based on 

increased incidence and severity of 
Thiamethoxam D373376

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Table 3.5.12a. Toxicological Doses and Endpoints for Thiamethoxam for Use in Dietary and Residential 

Human Health Risk Assessments.

Exposure/

Scenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors

Level of Concern 

for Risk Assessment

Study and Toxicological Effects

(inhalation 

absorption rate 

= 100% of oral 

absorption)

tubular atrophy in testes of F1

generation males.

2-Generation reproduction study 

LOAEL = 3 (males), not determined 

(females) mg/kg/day based on sperm 

abnormalities in F1 males.

Cancer (oral, 

dermal, inhalation)

“Not Likely to be Carcinogenic to Humans” based on convincing evidence that a non-genotoxic 

mode of action for liver tumors was established in the mouse. Quantification of cancer risk is not

required. 

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). UFL = use of a LOAEL to extrapolate a NOAEL. UFS = use of a short-term study for long-term risk 

assessment. UFDB = to account for the absence of key date (i.e., lack of a critical study). FQPA SF = 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 3.5.12b. Summary of Toxicological Doses and Endpoints for Thiamethoxam for Use in Occupational 

Human Health Risk Assessments.

Exposure/

Scenario

Point of Departure Uncertainty 

Factors

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Dermal

Short-term

(1-30 days) 

and 

Intermediateterm (1-6 

months)

Oral study NOAEL= 

1.2

mg/kg/day

(dermal absorption 

rate = 5%)

UFA= 10x

UFH= 10x

MOE= 100 

(occupational)

2-Generation reproduction study 

LOAEL = 1.8 mg/kg/day based on 

increased incidence and severity of 

tubular atrophy in testes of F1

generation males.

2-Generation reproduction study 

LOAEL = 3 (males), not determined 

(females) mg/kg/day based on sperm 

abnormalities in F1 males.

Inhalation

Short-term

(1-30 days) 

and 

Intermediateterm (1-6 

months)

Oral study NOAEL= 

1.2

mg/kg/day

(inhalation 

absorption factor = 

100%)

UFA= 10x

UFH= 10x

MOE= 100 

(occupational)

2-Generation reproduction study 

LOAEL = 1.8 mg/kg/day based on 

increased incidence and severity of 

tubular atrophy in testes of F1

generation males.

2-Generation reproduction study 

LOAEL = 3 (males), not determined 

(females) mg/kg/day based on sperm 

abnormalities in F1 males.

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). UFL = use of a LOAEL to extrapolate a NOAEL. UFS = use of a short-term study for long-term risk 

assessment. UFDB = to account for the absence of key data (i.e., lack of a critical study). FQPA SF = 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.
Thiamethoxam D373376

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3.6 Endocrine disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor 

Screening Program (EDSP) to determine whether certain substances (including pesticide active 

and other ingredients) may have an effect in humans or wildlife similar to an effect produced by 

a ―naturally occurring estrogen, or other such endocrine effects as the Administrator may 

designate.‖ The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first 

group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. 

This list of chemicals was selected based on the potential for human exposure through pathways 

such as food and water, residential activity, and certain post-application agricultural scenarios. 

This list should not be construed as a list of known or likely endocrine disruptors.

Thiamethoxam is not among the group of 58 pesticide active ingredients on the initial list to be 

screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide 

chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all 

pesticide active ingredients. 

For further information on the status of the EDSP, the policies and procedures, the list of 67 

chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: 

http://www.epa.gov/endo/.

4.0 Public Health and Pesticide Epidemiology Data

None.

5.0 Dietary Exposure/Risk Characterization

5.1 Pesticide Metabolism and Environmental Degradation

References: 44939802.der.doc (Cucumber)

45093709.der.doc (Tobacco)

45093711.der.doc (Tobacco)

45093713.der.doc (Potato)

45093714.der.doc (Lettuce)

MARC Decision Memo: D258614, 8/31/99, G.J. Herndon

Residue Chemistry Memo D252021, 3/30/00, G.J. Herndon (PP#9F5046)

Residue Chemistry Memo D265079, 5/8/00, G.J. Herndon (PP#9F5051)
Thiamethoxam D373376

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Data have been submitted and reviewed depicting the metabolism of thiamethoxam in numerous 

crops and the environment. HED has determined that the plant and livestock residues of concern 

(ROC) for purposes of tolerance enforcement and risk assessment are the combined residues of 

thiamethoxam and clothianidin (CGA-322704) (see Table 5.1). For a complete discussion of 

metabolism in crops and livestock, including chemical names and structures, see the Residue 

Chemistry Summary Document (D281702, M. Doherty, March 2007).

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 for Compliance 

Monitoring

Plants Primary Crop Thiamethoxam + clothianidin Thiamethoxam + clothianidin

Rotational Crop Not Applicable Not Applicable

Livestock Ruminant Thiamethoxam + clothianidin Thiamethoxam + clothianidin

Poultry Thiamethoxam + clothianidin Thiamethoxam + clothianidin

Drinking Water Thiamethoxam Not Applicable

5.2 Analytical Methodology

References: Residue Chemistry Memo D252021; G.J. Herndon; 30 March 2000

 Residue Chemistry Memo D265079; G.J. Herndon; 8 May 2000

 Residue Chemistry Memo D271516; M. Doherty; 29 May 2001

 Residue Chemistry Memo D281702; M. Doherty; 17 April 2007

 Residue Chemistry Memo D367065; W. Drew; 3 May 2010

The HPLC Method AG-675 with UV or MS detection was previously submitted in conjunction 

with thiamethoxam petitions. Method AG-675 has been determined to be adequate for enforcing 

tolerances for residues of thiamethoxam and CGA-322704 in crop and livestock commodities. 

Syngenta has submitted a revised Method AG-675, i.e., Method GRM.009.04A. The full 

extraction steps for plant and livestock commodities, including the microwave extraction step for 

liver, have been incorporated. The limits of quantitation (LOQs) of Method GRM.009.04A have 

been established at 0.01 ppm each for residues of thiamethoxam, CGA-322704 and CGA265307. Method validation data are available for Method GRM.009.04A.

The various data-collection methods, used for analysis of samples taken from the magnitude of 

the residue studies discussed in this action, are based on either Methods AG-675 or 

GRM.009.04A. Method recoveries from concurrent analysis of samples were within the 

generally recognized acceptable range of 70-120%.

5.3 Drinking Water Residue Profile

Reference: EFED Memo D373378, C. Koper, 20 May 2010
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Thiamethoxam is expected to be persistent and mobile in terrestrial and aquatic environments. 

These fate properties suggest that thiamethoxam has a potential to move into surface water and 

shallow groundwater.

The drinking water residues used in these dietary risk assessments were provided by EFED 

(D373378, C. Koper, 20 May 2010), and incorporated directly into the dietary assessments. 

Water residues were incorporated in DEEM-FCID via entry into the food categories ―water, 

direct, all sources‖ and ―water, indirect, all sources.‖ The estimated drinking water 

concentrations (EDWCs) in surface water are 0.13177 ppm and 0.01131 ppm for acute and 

chronic scenarios, respectively. Typically, HED uses the higher of the surface or groundwater 

estimates for each duration when assessing dietary risk. 

The EDWCs were incorporated into the acute and chronic thiamethoxam assessments. 

Clothianidin, a major metabolite of thiamethoxam in plants and livestock, is not a significant 

degradate of thiamethoxam in surface or groundwater sources of drinking water. 

A Tier II screening-level drinking water assessment was conducted for the proposed seed 

treatment of alfalfa and peanut seed. EFED also evaluated leafy vegetables, dry bulb onions and 

corn because previous assessments on these commodities were conducted at a lower application 

rate.

For surface water, the EDWCs for the crops modeled in this assessment did not exceed the 

previous EDWCs for rice reported in the previous drinking water assessment (D363202) dated 

07 April 2009. The reported acute concentration of 131.77 μg/L, annual mean (chronic) 

concentration of 11.31 μg/L and the highest 30 year annual average concentration of 11.31 μg/L 

from the rice model are higher than the calculated EDWCs (see Table 5.3) for the various uses. 

Therefore, the current EDWCs for surface water do not supersede the drinking water 

concentrations previously estimated for this chemical (D363202, F. Khan, 7 April 2009).

For groundwater, based on the proposed highest annual use rate for dry bulb onions and the 

proposed use rates for peanut and alfalfa seed treatment, the SCI-GROW model concentration of 

thiamethoxam was 4.66 μg/L, 1.24 μg/L and 0.34 μg/L, respectively. This value was compared 

to 4.14 μg/L reported for grapes in the previous drinking water assessment (D329467) dated 10 

January 2007. The predicted value for grapes is a corrected value described in detail in a 

previous drinking water assessment (D368072) dated 2 Feb 2010. Since 4.66 μg/L is greater 

than 4.14 μg/L, the current EDWC supersedes the previously recommended EDWC for 

groundwater.

The acute scenario EDWC in surface water (0.13177 ppm) was obtained via exposure modeling 

which utilized a modified Tier I Rice Model and the Provisional Cranberry Model. This model 

and its description are available at the EPA internet website via the web link, 

http://www.epa.gov/oppefed1/models/water/. 
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Table 5.3. Tier II Estimated Drinking Water Concentrations (EDWCs) resulting from applications of 

Thiamethoxam.

Drinking Water 

Source (model)

Use

Scenario 

(modeled rate)

1-in-10 year acute 

(μg/L)

1-in-10 year chronic 

(μg/L)

30- year average 

(μg/L)

Surface Water 

(PRZM/EXAMS)

NC Peanuts:

(1 app.1 X 0.08 lbs ai/acre)

1.51 0.16 0.05

CA Alfalfa

(January 9)

MN Alfalfa

(May 25)

NC Alfalfa

(March 25)

PA Alfalfa

(March 9)

TX Alfalfa

(August 25)

IL Alfalfa

(May 25)

(all were 1 app. X 0.022 

lbs. ai/acre)

0.37

0.27

0.55

0.37

0.89

0.58

0.07

0.03

0.08

0.05

0.10

0.06

0.03

0.02

0.03

0.03

0.05

0.03

Dry Bulb Onions:

CA Onion

GA Onion

(1 app. X 0.3 lbs ai/acre)

1.57

20.45

0.25

1.54

0.06

0.44

Leafy Vegetables:

CA Lettuce (1 run)

(1 app. X 0.266 lbs. ai/acre)

23.78 3.68 1.29

Tail water Rice

(0.173 lbs ai/A/year)

131.77

1,2 11.311,3 11.311,3

Cranberry

(0.188 lbs ai/A/year)

54.7524.5034.503

Groundwater 

(SCI-GROW)

Peanuts:

(1 app. X 0.08 lbs ai/acre)

1.24 1.24 1.24

Alfalfa:

(1 app. X 0.022 lbs. ai/acre)

0.34 0.34 0.34

Dry bulb onions:

(1 app. X 0.30 lbs. ai/acre)

4.66 4.66 4.66

Bold text denotes maximum estimated EDWC values. All values adjusted with PCA factor of 0.87.

1 Recommended EDWCs for surface water.

2 EDWCs based on day 1.

3 EWDCs based on average of 365 days.

Monitoring Data

Only very limited monitoring data are available for thiamethoxam and these data are discussed 

below; due to this limitation HED used modeling data for the drinking water residue estimate for 

both the acute and chronic dietary risk assessments.
Thiamethoxam D373376

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The registrant has conducted small-scale prospective groundwater studies in several locations in 

the US to investigate the mobility of thiamethoxam in a vulnerable hydrogeological setting. A 

review of those data (Amer Al-Mudallal, D339099, 4/18/06) shows that generally residues of 

thiamethoxam (as well as CGA-322704) are below the limit of quantitation (0.05 ppb). When 

quantifiable residues are found, they are sporadic and at low levels. The maximum observed 

residue levels from any monitoring well were 1.0 ppb for thiamethoxam and 0.73 ppb for CGA322704. These values are well below the modeled estimates summarized above, indicating that 

the modeled estimates are, in fact, protective of what actual exposures are likely to be.

5.4 Food Residue Profile

Reference: Residue Chemistry Memo D376367; W. Drew; 2 Nov 2010

 DER for MRID #45093704 (Crop field trials with peanuts)

 DER for MRID #48020201 (Crop field trials with alfalfa)

 DER for MRID #48110202 (Food handling establishment, various food items)

Peanuts: The submitted peanut field trial data are adequate, and reflect the planting of peanut 

seeds treated with either the 70% ai WS formulation, or the 5 lb ai/gal FS formulation of 

thiamethoxam at 200 g ai/100 kg seeds. Based on the amounts of seeds planted per acre, the 

rates were 0.126-0.24 lb ai/A (1.5-3X the proposed maximum per-acre use rate). An acceptable 

method was used for the quantitation of thiamethoxam residues in peanut nutmeat and hay, and 

adequate storage stability data are available to support sample storage durations and conditions. 

TABLE 5.4.1 Summary of Residue Data from Peanut Field Trials with Thiamethoxam. 

Peanut 

Matrix

Use Rate (g 

ai/100 kg Seeds)

EP Combined Residue Levels (ppm Thiamethoxam Equivalents) 1

n Min. Max. 2 HAFT 3 Mean Std. Dev.

Hay 200 5FS 18 <0.02 0.06 0.05 0.026 0.011

70WS 36 <0.02 0.23 0.20 0.032 0.043

Nutmeat 5FS 18 <0.02 0.05 0.05 0.026 0.011

70WS 36 <0.02 0.04 0.03 0.021 0.004

Hay 600 70WS 4 <0.02 0.79 0.64 0.33 0.38

Nutmeat 4 <0.02 0.02 0.02 0.02 0

1. For calculation of the mean, HAFT, and standard deviation, the LOQ was used for residues reported as below the

 LOQ. 

2. The table does not include the residue level in nutmeat used for the processing study. A RAC residue of 0.09

 ppm was found in nutmeat following application at 200g ai/100 kg seeds (equivalent to 0.16 lb ai/A).

3. HAFT = Highest Average Field Trial. 

Alfalfa: The submitted alfalfa field trial data are adequate, and reflect the planting of alfalfa 

seeds treated with the 5 lb ai/gal FS formulation of thiamethoxam at 0.001 mg ai/seed, with 

harvest occurring at 45 days after planting (DAP). An acceptable method was used for the 

quantitation of thiamethoxam residues in alfalfa forage and hay, and adequate storage stability 

data are available to support sample storage durations and conditions. 
Thiamethoxam D373376

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TABLE 5.4.2 Summary of Residue Data from Alfalfa Field Trials with Thiamethoxam. 

Alfalfa

Commodity

Maximum

Use Rate 1(lb ai/A)

EP 2 Residue Levels (ppm)

Minimum Maximum HAFT 3

Thiamethoxam

Forage 1st cutting 0.0130 Cruiser 5FS <0.01 0.03 0.03

Forage 2nd cutting <0.01 <0.01 <0.01

Forage 3rd cutting <0.01 <0.01 <0.01

Hay 1st cutting <0.01 0.09 0.08

Hay 2nd cutting <0.01 0.01 0.01

Hay 3rd cutting <0.01 <0.01 <0.01

CGA-322704

Forage 1st cutting 0.0130 Cruiser 5FS <0.01 <0.01 <0.01

Forage 2nd cutting <0.01 <0.01 <0.01

Forage 3rd cutting <0.01 <0.01 <0.01

Hay 1st cutting <0.01 <0.01 <0.01

Hay 2nd cutting <0.01 <0.01 <0.01

Hay 3rd cutting <0.01 <0.01 <0.01

1. The alfalfa field trials utilized single (and seasonal) use rates of 0.0037-0.0130 lb ai/A, based on the respective 

 seeding rates (8.00-27.90 lb seeds/A), and an average of 210,000 alfalfa seeds/lb. 

2. EP = End-use Product.

3. HAFT = Highest Average Field Trial (average of duplicate measurements). 

Food handling establishments: The submitted data on thiamethoxam residues in food 

commodities following indoor spot, and crack and crevice treatments in food handling 

establishments are adequate. An adequate variety of food commodities were exposed to 

thiamethoxam, in two different types of food handling establishments, at 1X the maximum 

proposed rate. An acceptable method was used for the quantitation of thiamethoxam residues in 

the various food commodities, and adequate storage stability data are available to support the 

sample storage durations and conditions. In addition, there were no thiamethoxam or 

clothianidin residues found at quantifiable levels in any of the wide variety of uncovered food 

types which were exposed for up to 8 hours to an exaggerated use pattern (1X rate, followed by 

2X rate within 48 hours).

Processing Studies

There are no processed commodities associated with the proposed use on alfalfa. Reduction of

thiamethoxam residues in peanut oil after processing was at least 0.22-0.40X. Residues were 

observed in the nutmeat and meal of peanuts (grown from peanut seeds treated at roughly 2X the 

proposed use rate) from both field trials. The empirical concentration factors for thiamethoxam 

in meal ranged from 2.0-3.1X, with an average of 2.6X.

Conclusions

A large percentage of the residue values in peanuts were below the combined LOQ of 0.02 ppm; 

therefore, the tolerance harmonization spreadsheet was not used to determine an appropriate 

tolerance. Based on the maximum combined thiamethoxam ROCs of 0.05 and 0.23 ppm in 1X-
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treated nutmeat and hay samples, respectively, HED recommends a tolerance of 0.05 ppm in

peanut nutmeat, and a tolerance of 0.25 ppm in peanut hay.

A large percentage of the residue values in alfalfa were below the combined LOQ of 0.02 ppm; 

therefore, the tolerance harmonization spreadsheet was not used to determine an appropriate 

tolerance. Based on the maximum combined thiamethoxam ROCs of 0.04 and 0.10 ppm in 1Xtreated forage and hay samples, respectively, HED recommends a tolerance of 0.05 ppm in 

alfalfa forage, and a tolerance of 0.12 ppm in alfalfa hay. 

Based on maximum thiamethoxam and CGA-322704 residues of <0.01 ppm in food 

commodities exposed to 1X treatment in food handling areas (with the vast majority of samples 

containing non-detectable residues), HED recommends a tolerance of 0.02 ppm, the combined 

LOQ, in food/feed commodities (other than those covered by a higher tolerance as a result of use

on growing crops). 

A tolerance is not required in peanut oil. With HAFT combined residues of 0.05 ppm in peanut 

nutmeat (based on residues of 0.09 ppm at a 2X rate), and the theoretical concentration factor for 

peanut meal of 2.2X, HED recommends a tolerance of 0.15 ppm in peanut meal. 

5.5 International Residue Limits

There are no international residue limits that affect HED’s recommendations at this time. There 

are no CODEX or Mexican maximum residue limits (MRLs) for thiamethoxam for the crops 

requested. Canada has established an MRL of 0.02 mg/kg for residues of thiamethoxam and 

CGA-322704 in all food crops (including alfalfa and peanut), and is transitioning to specific 

commodity MRLs (all at 0.02 mg/kg) on a variety of crops including various cereal grains, peas 

and beans, soybeans, sweet corn, and sunflower.

5.6 Dietary Exposure and Risk

Reference: D376368, D. McNeilly, 23 Nov 2010

Acute and chronic dietary risk assessments were conducted using the Dietary Exposure 

Evaluation Model (DEEM-FCIDTM, Version 2.03) which uses food consumption data from the 

U.S. Department of Agriculture’s Continuing Surveys of Food Intakes by Individuals (CSFII) 

from 1994-1996 and 1998. The analyses were performed to evaluate Section 3 requests for new 

seed treatment uses on alfalfa and peanuts and for use in food handling establishments.

A new chlothianidin dietary assessment (D384145, M. Doherty, in progress) and risk assessment 

is being conducted (D377956, M. Doherty, in progress) to update clothianidin residues on 

peanuts and other food commodities in support of the thiamethoxam food handling establishment

use.

There is available information indicating that thiamethoxam and clothianidin have different 

toxicological effects in mammals and should be assessed separately; however, in conducting 

these assessments, residues of clothianidin coming from thiamethoxam were combined with 
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residues of thiamethoxam. The total residue was then used to estimate dietary exposure and risk. 

Clothianidin, a major metabolite of thiamethoxam in plants and livestock, is not a significant 

degradate of thiamethoxam in surface or groundwater sources of drinking water. 

The acute dietary assessment is based on tolerance level residues of thiamethoxam and 

clothianidin and assumes 100% crop treated for all commodities (registered and requested uses). 

The chronic dietary assessment is based on tolerance level residues and anticipated residues from 

thiamethoxam field trials. The chronic assessment assumes that 100% of crops with registered 

or requested uses of thiamethoxam are treated.

The drinking water residues were provided by EFED (D373378, C. Koper, 20 May 2010), and 

incorporated directly into the acute and chronic dietary assessments. Water residues were 

incorporated in DEEM-FCID via entry into the food categories ―water, direct, all sources‖ and 

―water, indirect, all sources.‖ The estimated drinking water concentrations (EDWCs) in surface 

water are 0.13177 ppm and 0.01131 ppm for acute and chronic scenarios, respectively. 

Typically, HED uses the higher of the surface or groundwater estimates for each duration when 

assessing dietary risk, with the surface water having higher values in this case.

These assumptions result in conservative, health-protective estimates of exposure (Table 5.6). 

Risk estimates for acute and chronic dietary exposure for all assessed population subgroups are 

below HED’s level of concern, which is generally 100% of the acute or chronic adjusted dose 

(aPAD or cPAD).

Table 5.6. Summary of Estimated Dietary (Food + Drinking Water) Exposures and Risk for 

Thiamethoxam.

Population Subgroup aPAD, 

mg/kg

Acute Estimates (95th Percentile) cPAD, 

mg/kg/day

Chronic Estimates

Exposure, 

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

U.S. Population 0.35 0.018094 5.2 0.012 0.002825 24

All infants (< 1 year)10.35 0.033165 9.5 0.012 0.003052 25

Children 1-2 yrs 0.35 0.032947 9.4 0.012 0.005150 43

Children 3-5 yrs 0.35 0.026627 7.6 0.012 0.004520 38

Children 6-12 yrs 0.35 0.018819 5.4 0.012 0.003241 27

Youth 13-19 yrs 0.35 0.014311 4.1 0.012 0.002333 19

Adults 20-49 yrs 0.35 0.016277 4.7 0.012 0.002591 22

Adults 50+ yrs 0.35 0.016617 4.8 0.012 0.002648 22

Females 13-49 yrs 0.35 0.016123 4.6 0.012 0.002617 22

1 - The population subgroup with the highest estimated exposure/risk is bolded.

5.6.1 Anticipated Residue and Percent Crop Treated (%CT) Information

Reference: D376368, D. McNeilly, 23 Nov 2010
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The dietary assessment is a screening-level assessment using tolerance level residues for the 

acute analysis. Tolerance levels and anticipated residues (calculated from field trial data) for 

selected commodities (discussed in detail in D376368, D. McNeilly, 23 Nov 2010) were used in 

the chronic assessment. The chronic assessment anticipated residues were average residues from 

crop field trial data. For both the acute and chronic analyses, 100% crop treated was 

assumed.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

Reference: Thiamethoxam: Occupational and Residential Exposure Assessment for Section 3 Registration, M. 

Collantes; July 24, 2009; D359207

A residential (non-occupational) exposure/risk assessment was not performed at this time in 

conjunction with the proposed uses. The proposed seed treatment uses are limited to 

occupational/ commercial seed treaters (handlers and secondary handlers). Since the Optigard 

Flex label stipulates that treatment areas are away from eating areas and other areas where 

children may come in contact with treated surfaces (i.e., not in or around room where children 

are playing or eating), a quantitative residential exposure assessment is not required for this 

action. Furthermore, the registered label also indicates that product is to be applied under the 

supervision of commercial applicators. HED previously performed a crack and crevice 

residential exposure assessment for this same exact product, previously known as OptigardTM ZT 

(Registration number 100-1170) containing 21.6% of the active ingredient thiamethoxam (M. 

Collantes, July 2009, D359207). A residential exposure assessment for the use of thiamethoxam 

on turf was also previously performed (M. Collantes; March 2007; D332064). All postapplication dermal and oral scenarios associated with turf and indoor crack and crevice uses 

resulted in MOEs greater than 100 and are not of concern. A summary of the postapplication 

exposure is provided below.

Postapplication Exposure

There is a potential for exposure from entering areas previously treated with thiamethoxam that 

could lead to exposures for adults and children. Postapplication residential scenarios were

assessed using the HED Draft Standard Operating Procedures (SOPs) for Residential Exposure 

Assessments (12/18/97), and the Revisions to the Standard Operating Procedures (SOPs) for 

Residential Exposure Assessment (Science Advisory Council for Exposure Policy 12, Revised 

February 22, 2001). The level of concern (LOC) for the margin of exposure (MOE) is 100 for all 

residential uses. All postapplication dermal scenarios for adults and children ranging in age from 

3 to 6 years resulted in MOEs greater than 100 and are not of concern to HED. A summary of 

the dermal postapplication exposure and risks are included in Table 6.a.
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Table 6.a.: Postapplication Dermal Exposure for Children and Adults for 0.1% and 0.05% Sprays for Crack and 

Crevice

Surface Population

Subgroup

ISR 1

(μg/cm2)

CF TC 2

(cm2/hr)

ED 3

(hrs)

Dermal 

Absorption 

(mg/kg/day)

BW 

(kg)

Dermal 

Dose 4

(mg/kg/day)

NOAEL 

(mg/kg/day)

MOE5

Carpet adult 0.025 0.001 16,700 8 0.05 60 0.00278 1.2 430

child 6,000 1 15 0.08 60 750

Vinyl adult 0.05 16,700 4 0.05 60 0.00278 1.2 430

child 6,000 1 15 0.08 60 750

1. ISR = indoor surface transferable residues = deposition residue (0.5 ug/cm2) x fraction of residue available for transfer from

 carpet vs. hard surface (0.05/0.1) 

2. Tc = transfer coefficient based on HED Residential SOPs

3. ED =exposure duration based on HED Residential SOPs

4. Dose = ISR (ug/cm2) x 0.001 (mg/ug) x Tc (cm2/hr) x ED (hrs/day) x dermal absorption for adults only (mg/kg/day) 

BW (kg)

5. Adult MOE = NOAEL (1.2 mg/kg/day) Child MOE = NOAEL (60 mg/kg/day)

 Dermal Dose Dermal Dose

Oral non-dietary ingestion exposures also were assessed for children (i.e. hand-to-mouth) for

indoor crack and crevice use. The hand-to-mouth transfer postapplication exposure assessment 

resulted in oral MOEs greater than 100 for all scenarios, and therefore oral postapplication risks 

are not of concern to HED. Table 6.b summarizes the MOEs for hand-to-mouth transfer of 

pesticide residues from indoor crack and crevice use.

Table 6.b.: Postapplication Oral Exposure for Children for 0.1% and 0.05% 

Sprays for Crack and Crevice

Surface ISR 1

(μg/cm2)

SA2

(cm2)

FQ3 

(event/hr)

ED4  

(hrs)

SE5 CF6 Oral Dose7 

(mg/kg/day)

MOE8

Short –term

carpet 0.025 20 20 8 0.5 0.001 0.0026 3100

vinyl 0.05 4

Intermediate-term

carpet 0.025 20 9.5 8 0.5 0.001 0.00126 6500 

vinyl 0.05 4

 1. ISR = indoor surface transferable residues = deposition residue (0.5 ug/cm2) x fraction of residue available for

 transfer from carpet vs. hard surface (0.05/0.1) 2. Surface area. 3. Frequency of hand-to-mouth events. 4. Exposure duration.

 5. Saliva extraction factor. 6. Conversion factor (mg/μg). 7. Oral Dose = (ISR x SA x FQ x ED x SE x CF1)/(BW 15 kg) 

 8. Oral MOE = NOAEL (8.23 mg/kg/day)/Oral dose. 

Based on the Agency's current practices, a quantitative residential postapplication inhalation 

exposure assessment was not performed for thiamethoxam at this time primarily because it has a 

very low vapor pressure (6.6 x 10-9Pa @ 25oC), inhalation exposure is expected to be negligible 

as a result of indoor crack and crevice use. 

Combined Residential Risk Estimates

In the previous 2007 thiamethoxam residential assessment, a combined residential assessment 

was performed for turf dermal and oral postapplication exposure of toddlers only. A more recent 

2009 assessment (D365272, D. McNeilly, 6 August 2009) evaluated an indoor crack and crevice 

product and provided a revised combined residential assessment based on indoor crack and 
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crevice use. These exposures and risks were greater than exposure/risk from the use on lawns. 

Therefore, the indoor exposures should be used in an aggregate assessment in order to be 

protective.

HED combined all non-dietary sources of postapplication exposure to obtain an estimate of 

potential combined exposure which could be used for the aggregate assessment. These scenarios 

consisted of adult and toddler dermal postapplication exposure and oral (hand-to-mouth)

exposures for children 3 to 6 years of age. All postapplication scenarios resulted in combined 

MOEs greater than 100 and were not of concern to HED. Table 6.c provides a summary of the 

combined residential indoor crack and crevice exposures and risks.

Table 6.c. Combined Residential Exposure and Risk Estimates from Indoor Crack and 

Crevice Use

Postapplication

Scenarios

Daily Dose

(mg/kg/day) 1

MOE 2 Combined

MOE 3

Short-term

Adult Dermal – indoor surface 0.00278 430 430

Toddler Dermal - indoor 

surface

0.08 750

610

Hand-to-Mouth 0.00267 3100

Intermediate-term

Adult Dermal - indoor surface 0.0278 430 430

Toddler Dermal - indoor 

surface

0.08 750

680

Hand-to-Mouth 0.001267 6500

1 Daily Dose = see Tables 6.a. and 6.b. 2 Adult Dermal MOE = NOAEL (1.2 mg/kg/day)

 Dermal Dose

 Child Dermal MOE = NOAEL (60 mg/kg/day)

 Dermal Dose

 Child Oral MOE = NOAEL (8.23 mg/kg/day)

 Oral Dose 

3 Toddler Combined MOE = 1/ [(1/MOEDermal) + (1/MOEHand-to-Mouth)]

7.0 Aggregate Risk Assessments and Risk Characterization

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 USDA under the Continuing Survey of Food Intakes by Individuals (CSFII) and are used 

in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed 

and categorized by subgroups based on age, season of the year, ethnic group, and region of the 

country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups 
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and exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, non-dietary exposures based on home use of pesticide products and associated risks 

for adult applicators and for toddlers, youths, and adults entering or playing on treated areas 

postapplication 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. Given the existing and proposed use patterns for 

thiamethoxam as well as the health-protective assumptions throughout this risk assessment, it is 

unlikely that any geographic, ethnic, or socioeconomic population will have increased exposure 

relative to the standard population subgroups assessed by OPP.

7.1 Acute Aggregate Risk

In examining acute aggregate risk, HED has assumed that the only pathway of exposure relevant 

to that time frame is dietary exposure. Therefore, the acute aggregate risk is composed of 

exposures to thiamethoxam residues in food and drinking water and is equivalent to the acute 

dietary risk discussed in Section 5.6. As noted in that section, the acute risk estimates are well 

below HED’s level of concern for all population subgroups.

7.2 Short-Term Aggregate Risk

References: D375247, D. McNeilly, 3 May 2010

 D359207, M. Collantes; 24 July 2009

Short-term exposures (1 to 30 days of continuous exposure) may occur as a result of entering 

indoor areas previously treated with a thiamethoxam indoor crack and crevice product. 

Exposures related to indoor activities (Table 6.c) have been combined with chronic dietary 

exposure estimates (as an estimate of background dietary exposure; Table 5.6.b) to assess the 

worst-case short-term aggregate exposure. The indoor crack and crevice scenario has higher 

exposure for both adults and children than the exposure levels in the turf scenario. The shortterm aggregate MOEs range from 370 to 490 (Table 7.2). Since these are greater than 100, they 

represent aggregate risk estimates that are below HED’s level of concern.

Table 7.2. Estimates of Short-term Aggregate Risks for Thiamethoxam

Population Subgroup Margins of Exposure (MOEs)

Dietary 

Aggregate1

Dermal 

2

Hand-to-Mouth 2 Total Short-Term

Aggregate 3

General U.S., 

population 2,900 430 ------- 370

All infants 2,700 750 3,100 490

Children 1-2 yrs 1,600 750 3,100 440

Children 3-5 yrs 1,800 750 3,100 450

Children 6-12 yrs 2,500 430 ------ 370

Youth 13-19 yrs 3,500 430 ------ 380

Adults 20-49 yrs 3,200 430 ------ 380

Adults 50+ yrs 3,100 430 ------ 380
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Table 7.2. Estimates of Short-term Aggregate Risks for Thiamethoxam

Population Subgroup Margins of Exposure (MOEs)

Dietary 

Aggregate1

Dermal 

2

Hand-to-Mouth 2 Total Short-Term

Aggregate 3

Females 13-49 yrs 3,100 430 ------ 380

1 Dietary Aggregate MOE = Incidental Oral NOAEL (8.23 mg/kg/day) ÷ Chronic Dietary (Food + Water) Exposure

(mg/kg/day; from Table 5.6.b). Values are rounded to 2 significant figures.

2 Indoor crack and crevice exposure (which has higher exposure than residential turf) from Table 6c. Hand-tomouth is appropriate for infant and children population subgroups only. 

3 Total Aggregate MOE = 1/[(1/MOEDietary) + (1/MOEDermal) + (1/MOEHtM)]. Values rounded to 2 significant

figures.

7.3 Intermediate-Term Aggregate Risk

Intermediate-term exposures (30 to 180 days of continuous exposure) may occur as a result of 

entering indoor areas previously treated with a thiamethoxam indoor crack and crevice product. 

Exposures related to indoor activities (Table 6.c) have been combined with chronic dietary 

exposure estimates (as an estimate of background dietary exposure; Table 5.6.b) to assess the 

worst-case intermediate-term aggregate exposure. The indoor crack and crevice scenario has 

higher exposure for both adults and children than the exposure levels in the turf scenario. The 

intermediate-term aggregate MOEs range from 370 to 540 (Table 7.3). Since these are greater 

than 100, they represent intermediate-term aggregate risk estimates that are below HED’s level 

of concern.

The difference between short- and intermediate-term aggregate risks is the frequency of hand-tomouth events for children. For short-term exposure there are 20 events per hour and for 

intermediate-term exposure there are 9.5 events per hour (see Table 6.b). The doses and endpoints for short- and intermediate-term aggregate risk are the same. 

Table 7.3. Estimates of Intermediate-term Aggregate Risks for Thiamethoxam

Population Subgroup Margins of Exposure (MOEs)

Dietary 

Aggregate1

Dermal 2 Hand-to-Mouth 2 Total Intermediate-Term

Aggregate 3

General U.S. population 2,900 430 ------- 370

All infants 2,700 750 6,500 540

Children 1-2 yrs 1,600 750 6,500 470

Children 3-5 yrs 1,800 750 6,500 490

Children 6-12 yrs 2,500 430 ------- 370

Youth 13-19 yrs 3,500 430 ------- 380

Adults 20-49 yrs 3,200 430 ------- 380

Adults 50+ yrs 3,100 430 ------- 380

Females 13-49 yrs 3,100 430 ------- 380

1 Dietary Aggregate MOE = Incidental Oral NOAEL (8.23 mg/kg/day) ÷ Chronic Dietary (Food + Water) Exposure

 (mg/kg/day; from Table 5.6.b). Values are rounded to 2 significant figures. 

2 Indoor crack and crevice exposure (which has

higher exposure than residential turf) from Table 6c. Hand-to-mouth is appropriate for infant and children population subgroups

 only. 

3 Total Aggregate MOE = 1/[(1/MOEDietary) + (1/MOEDermal) + (1/MOEHtM)]. Values rounded to 2 significant figures.
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7.4 Chronic Aggregate Risk

In examining chronic aggregate risk, HED has assumed that the only pathway of exposure 

relevant to that time frame is dietary exposure. Therefore, chronic aggregate risk is composed of 

exposures to thiamethoxam residues in food and drinking water and is equivalent to the chronic 

dietary risk discussed in Section 5.6. As noted in that section, the chronic risk estimates are 

below HED’s level of concern for all population subgroups.

7.5 Cancer Risk

Thiamethoxam has been classified as ―not likely to be carcinogenic to humans.‖ As such, the 

risk of cancer from thiamethoxam is not of concern. The chronic risk assessment would be 

protective for any potential cancer effects. 

8.0 Cumulative Risk Characterization/Assessment

Thiamethoxam is a member of the neonicotinoid class of pesticides and produces, as a 

metabolite, another neonicotinoid, clothianidin. 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 nicotinic acetylcholine receptors, 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 thiamethoxam is based on unrelated effects in mammals, including effects on the 

liver, kidney, testes, and hematopoietic system. Additionally, the most sensitive toxicological 

effect in mammals differs across the neonicotinoids (e.g., testicular tubular atrophy with 

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

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

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

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

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

the policy statements concerning common mechanism determinations and procedures for 

cumulating effects from substances found to have a common mechanism released by EPA’s 

Office of Pesticide Programs on EPA’s website at http://www.epa.gov/pesticides/cumulative/.
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9.0 Occupational Exposure/Risk Pathway

Reference: Shih-Chi Wang, D373377, 3 Dec 2010

Reference: Shih-Chi Wang, D382248, 7 Dec 2010

Seed Treatment (Alfalfa, Peanuts)

The Cruiser® 5FS Insecticide (liquid) and Cruiser® PD Insecticide (wettable powder) are 

proposed for use in open and closed commercial seed treatment facilities. Cruiser® 5FS 

Insecticide is proposed for use on alfalfa and peanuts, while Cruiser® PD Insecticide is proposed 

for use on peanuts only. Neither product is to be used for on-farm treatment of seeds. Based on 

the proposed label information, occupational exposure is expected to occur for short- and 

intermediate-term durations.

Food/feed Handling Establishments 

Optigard®Flex Liquid Insecticide is proposed for use in food/feed handling establishments. The 

proposed use is for application of a 0.05% and/or a 0.1% spray solution to cracks & crevice, 

spots, surface, and structural voids using low pressure handwand, backpack and other hand-held 

equipment.

9.1 Short- and Intermediate-Term Handler Risk

Based on application rate and label information for the proposed seed treatment uses of alfalfa 

and peanuts and the use in food handling establishments, exposure is expected to occur for shortand intermediate-term durations. HED considers MOEs of less than 100 to indicate a risk of 

concern for occupational exposure to thiamethoxam. In addition, doses and endpoints for 

assessing occupational risk are based on the same studies for all durations for both dermal and 

inhalation exposures; therefore, the short-term and intermediate-term risk assessments are 

equivalent.

Seed Treatment 

This assessment covers commercial handlers operating open and closed seed treatment systems 

for use on alfalfa and peanuts. The following scenarios were assessed:

The proposed label states that Cruiser® PD is a wettable powder formulation developed for dry 

application to peanut seeds. Since the treater (loader/ operator) unit exposure values from Policy 

14 are based on liquid formulations, the loader/operator exposure for Cruiser® PD was estimated 

using surrogate unit exposure values for a wettable powder formulation in the Pesticide Handlers 

Exposure Database (PHED). 

Loading/Applying Wettable Powder for Seed Treatment (Scenario 1- Cruiser® PD 

peanuts only)
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Handler exposure resulting from treatment of peanut and alfalfa seeds using Cruiser® 5FS and 

Cruiser PD in open systems is based on the following exposure scenarios in accordance with 

HED’s Seed Treatment Standard Operating Procedure (SOP) #14:

Loading/Applying Liquid for Commercial Seed Treatment (Scenario 2) 

Sewing Bags after Seed Treatment (Scenario 3)

Bagging Seeds after Seed Treatment (Scenario 4)

Multiple Activities for Commercial Seed Treatment (Scenario 5)

Handler exposure resulting from treatment of peanut and alfalfa seeds using Cruiser® 5FS and 

Cruiser PD in closed systems is based on the following exposure scenarios in accordance with 

Syngenta’s proprietary seed treatment study, Helix® 289 FS (Novartis Crop Protection Canada 

Inc, J. Purdy. and D. Houghton; August 22, 2000; MRID 452000-02; DP 273566):

Loading/Applying Liquid for Closed-System Seed Treatment (Scenario 6) 

Bagging/Sewing/Stacking Bags (Tyvek) after Seed Treatment (Scenario 7)

Bagging/Sewing/Stacking Bags (Cotton) after Seed Treatment (Scenario 8)

Forklift Operators (Scenario 9)

Cleaner (Scenario 10)

The exposures and risks for seed handlers are summarized in Tables 9.1.a and 9.1.b. The 

potential occupational exposures/risks resulting from the proposed seed uses do not exceed 

HED’s level of concern (MOEs range from 100 to 13,000) with the exception of the following 

scenarios: 

(1) The Cruiser® PD is intended for use as a dry application on peanuts. Since the treater 

(loader/operator) unit exposure values from Policy 14 are based on liquid formulations, the 

loader/operator exposure for Cruiser® PD was estimated using surrogate unit exposure values 

for a wettable powder formulation in the Pesticide Handlers Exposure Database (PHED). The 

treater scenario resulted in a MOE of 100 with the use of additional PPE (i.e. gloves, coveralls 

and a PF10 respirator). Currently the label only requires use of a dust mask (quarter or half 

mask) respirator. HED recommends that the Registration Division ensure that the 

appropriate respirator is required on the final Cruiser PD label.

(2) The multiple activity scenario for commercially treating 718,000 lbs of alfalfa seed, using an 

open system, resulted in a MOE of 59 at baseline with addition of gloves. With the addition of a 

PF 5 dust mist respirator to current label personal protective equipment (PPE) [i.e., gloves and 

coveralls] the multiple activity workers scenario resulted in an MOE greater than 100 (MOE = 

170), which is not of concern. However, the Cruiser® 5FS label contains a restriction for 

commercial open system seed treatment facilities that limits the amount of product handled per 

day to no more than 38 gallons product/worker/8-hr day which results in 413,043 lbs of seed a 

day. Therefore, HED also assessed treatment of 413,043 lbs of alfalfa seed at baseline with

addition of gloves which resulted in a MOE of 100 and was not of concern.
Thiamethoxam D373376

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The exposures/risks resulting from the use of Cruiser® Insecticide in commercial closed peanut 

seed treatment facility were not calculated because they are no greater than those resulting from 

the use of Cruiser® Insecticide on alfalfa because exposures/risks resulting from the peanut use 

are approximately 20% of those resulting from the alfalfa use.

Secondary Seed Handlers 

The exposure associated with handling treated seeds was calculated using unit exposures given 

in the HED Exposure Science Advisory Council (ExpoSAC) SOP #14 (May 1, 2003). All 

MOEs for secondary seed handlers are greater than 100 and do not exceed HED’s level of 

concern at the single layer plus gloves level of mitigation (760 – 2,500). A summary of the 

exposure/risk values is presented in Table 9.1.c.

 

Food Handling Establishments

For the Optigard®Flex Liquid Insecticide use in food/feed handling establishments the following 

four scenarios are expected to result in the highest exposure for the proposed use and were 

evaluated:

Mixing/Loading/Applying Liquid Spray Using Low-Pressure Equipment for Surface 

Treatment

Mixing/Loading/Applying Foam Spray Using Low-Pressure Equipment for Surface 

Treatment

Mixing/Loading/Applying Wettable Powder Formulation (as surrogate for liquid 

formulation) Using Low-Pressure Equipment for Crack and Crevice Treatment

Mixing/Loading/Applying Wettable Powder Formulation (as surrogate for foam 

formulation) Using Low-Pressure Equipment for Crack and Crevice Treatment 

According to the proposed label, applicators and other handlers must wear: (1) long-sleeved shirt 

& long pants, (2) chemical-resistant gloves, and (3) shoes plus socks. Commercial applicators 

are not expected to immediately return to treatment sites; therefore, a quantitative postapplication assessment of handler exposure was not performed.

The handler assessment for the proposed use was based on surrogate unit exposure data from the 

Pesticide Handlers Exposure Database (PHED) Version 1.1 (HED Science Advisory Council for 

Exposure, SOP Number .007, January 1999). Exposure scenarios resulting in MOEs greater than 

100 are not of concern to HED. All but one exposure scenario resulted in a combined MOE 

ranging from 280 to 8,300 for occupational handlers with use of personal protective equipment 

(PPE) mitigation (baseline attire plus chemical-resistant gloves), which are already required on 

the label. The handler scenario using a foam application resulted in an MOE of 160 with the use 

of additional PPE (gloves, coveralls and PF5 dust mist respirator). Current label does not require 

use of coverall and respirators. Without such PPE, the MOE is only 56. HED recommends 

that if this use is to remain on the label, that the Registration Division ensure that the 

correct PPE be included in the final registered label. Exposures/risks for occupational 

handlers are presented in Table 9.1.d. 
Thiamethoxam D373376

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Table 9.1.a. Thiamethoxam Non-Cancer Risk for Commercial Seed-Treatment Handlers-Open System.

Exposure 

Scenario 

(Scenario #)

Mitigation 

Level

Dermal 

Unit 

Exposure 

(mg/lb ai)

Inhalation 

Unit 

Exposure 

(mg/lb ai)

Seed 

Species

Application Rate

(lb ai per lb seed)

Amount Treateda

(lb seed trt per day)

Daily

Dermal

Dose b(mg/kg/day)

Daily

Inhalation

Dosec(mg/kg/day)

Combined 

Daily Dosed 

(mg/kg/day)

MOEe 

Loader/Applicator

Loading/Applying

Wettable Powder 

(PHED) (1)

Double Layer, 

Gloves & PF 

10 Respirator

0.13 0.0043 Peanut 0.00054 120,000 0.00702 0.00464 0.0116 100

Loading/Applying

Liquids for Seed 

Treatment (2)

Single Layer, 

Gloves 0.023 0.00034

Peanut 0.00054 120,000 0.001242 0.0003672 0.001609 750

Alfalfa 0.00046 718,000 0.006325 0.00187 0.008195 150

Sewer

Sewing Bags after 

Seed treatment (3)

Single Layer, 

No Gloves 0.0062 0.00023

Peanut 0.00054 120,000 0.000335 0.000248 0.000583 2,100

Alfalfa 0.00046 718,000 0.001705 0.001265 0.00297 400

Bagger

Bagging Seeds 

after Seed 

treatment (4)

Single Layer, 

No Gloves 0.0091 0.00016

Peanut 0.00054 120,000 0.000491 0.000173 0.000664 1,800

Alfalfa 0.00046 718,000 0.002503 0.00088 0.003383 360

Multiple Activities Worker

Multiple 

Activities for 

Seed treatment (5)

Single Layer, 

Gloves 0.042 0.0016 Peanut 0.00054 120,000 0.002268 0.001728 0.003996 300

Alfalfa 0.00046

718,000

0.01155 0.0088 0.02035 59

Double layer, 

Gloves

0.019

0.0016

0.005229

0.0088 0.0140 85

Double layer, 

Gloves, & 

Dust Mist 

Respirator

0.00032 0.00176 0.00699 170

Single Layer, 

Gloves 0.042 0.0016 413043 * 0.00665 0.0050 0.01171 100

a Daily amounts treated values are based on exposure SAC Policy #15 or the information provided by the Registrant through Registration Division (384,000 lb seed treated per day is the daily seed treated value 

suggested by Syngenta). 

b Daily Dermal Dose (mg/kg/d) = [Unit Dermal Exposure (mg/lb ai) * Dermal Absorption Factor (0.05) * Application Rate (lb ai/lb seed) * Daily Amounts Treated] / Body Weight (60 kg).

c Daily Inhalation Dose (mg/kg/d) = [Unit Exposure (mg/lb ai) * Application Rate (lb ai/lb seed) * Daily Amounts Treated] / Body Weight (60 kg).

d Combined Daily Dose (mg/kg/d) = Daily Dermal Dose (mg/kg/day) + Daily Inhalation Dose (mg/kg/day).

e MOE = NOAEL (1.2 mg/kg/d) / Combined Daily Dose. UF = 100.
Thiamethoxam D373376

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Table 9.1.b. Thiamethoxam Non-Cancer Risk for Commercial Seed-Treatment Handlers-Closed System.

Exposure Scenario 

(Scenario #)

Mitigation 

Level

Dermal 

Unit 

Exposure 

(mg/lb ai)

Inhalation 

Unit 

Exposure 

(mg/lb ai)

Seed Species Application 

Rate

(lb ai per lb 

seed)

Amount 

Treateda

(lb seed trt 

per day)

Daily

Dermal

Dose b

(mg/kg/day)

Daily

Inhalation

Dosec

(mg/kg/day)

Combined 

Daily Dosed 

(mg/kg/day)

MOEe 

Loader/Applicator

TreaterLoader/Applicator (6)

Coveralls, 

Gloves 0.0011 0.00011 Alfalfa 0.00046 718,000 0.0003027 0.0006055 0.0009082 1,300

Bagger/Sewer/Stacker

Bagger/Sewer/Stacker 

(7) + (8)

Coveralls, 

Gloves

0.00027 0.000064 Alfalfa 0.00046 718,000 0.0000743 0.0003552 0.0004295 2,800

0.00037 0.000064 Alfalfa 0.00046 718,000 0.0001018 0.0003552 0.000457 2,600

Forklift Operator

Forklift Operator (9)

Coveralls, 

Gloves 0.000145 0.00001 Alfalfa 0.00046 718,000 0.0000399 0.000055 0.0000949 13,000

Cleaner

Cleaner (10)

Coveralls, 

Gloves 0.00921 0.00115 Alfalfa 0.00046 718,000 0.002535 0.00633 0.008865 140

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

b. Daily Dermal Dose (mg/kg/d) = [Unit Dermal Exposure (mg/lb ai) * Dermal Absorption Factor (0.05) * Application Rate (lb ai/lb seed) * Daily Amounts Treated] / Body Weight (60 kg).

c. Daily Inhalation Dose (mg/kg/d) = [Unit Exposure (mg/lb ai) * Application Rate (lb ai/lb seed) * Daily Amounts Treated] / Body Weight (60 kg).

d. Combined Daily Dose (mg/kg/d) = Daily Dermal Dose (mg/kg/day) + Daily Inhalation Dose (mg/kg/day). e. MOE = NOAEL (1.2 mg/kg/d) / Combined Daily Dose. UF = 100.

Table 9.1.c. Thiamethoxam Non-Cancer Risk for Secondary Seed Handlers.

Exposure Scenario Mitigation 

Level

Dermal 

Unit 

Exposure 

(mg/lb ai)

Inhalation 

Unit 

Exposure 

(mg/lb ai)

Seed Species Application 

Rate

(lb ai per lb 

seed)

Amount 

Planteda

(lb seed 

planted/

day)

Daily

Dermal

Dose b

(mg/kg/day)

Daily

Inhalation

Dosec

(mg/kg/day)

Combined 

Daily Dosed

(mg/kg/day)

MOEe 

Secondary Seed Handlers

Secondary Seed 

Handlers: planting 

seeds in the field

Single 

Layer, 

Gloves

0.25 0.00342

Peanut 0.00054 11,000 0.001238 0.000337 0.001575 760

Alfalfa 0.00046 4,000 0.0003833 0.0001042 0.0004875 2,500

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

b. Daily Dermal Dose (mg/kg/d) = [Unit Dermal Exposure (mg/lb ai) * Dermal Absorption Factor (0.05) * Application Rate (lb ai/lb seed) * Daily Amounts Treated] / Body Weight (60 kg).

c. Daily Inhalation Dose (mg/kg/d) = [Unit Exposure (mg/lb ai) * Application. Rate (lb ai/lb seed) * Daily Amounts Treated] / Body Weight (60 kg).

d. Combined Daily Dose (mg/kg/d) = Daily Dermal Dose (mg/kg/day) + Daily Inhalation Dose (mg/kg/day). e. MOE = NOAEL (1.2 mg/kg/d) / Combined Daily Dose. UF = 100.
Thiamethoxam D373376

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Table 9.1.d. Handler Exposure and Risk for Thiamethoxam Use in Food/Feed Handling Establishments.

Product & 

Formulation

Method of 

Application

Mitigation Dermal Unit 

Exposurea

(mg/lb ai)

Inhalation 

Unit 

Exposurea

(μg/lb ai)

Application 

Rate b

(lb ai/Gal)

Amount

Treated c

(Gal/day)

Dermal Dose

d

(mg/kg/day)

Inhalation 

Dose e

(mg/kg/day)

Combined

Daily Dose f

(mg/kg/day)

Total MOE g

Mixer/Loader/ Applicator

Optigard ® 

Flex 

Insecticide 

(21.6% a.i.

LowPressure 

Spray –

liquid/foam

Baseline + 

gloves

0.43

(liquid surface 

spray)

30

(liquid surface 

spray)

0.0084 

(liquid) 20

0.00006 0.000084 0.000144 8300

0.0423 

(foam)

0.00030 0.000423 0.000726 1700

LowPressure 

Spray –

Wettable 

Powder/foam

Baseline + 

gloves, 

8.6 

(WP crack 

and crevice)

1,100

(WP crack and 

crevice)

0.0084 

(liquid)

0.0012 0.0030 0.00428 280

Baseline + 

gloves, 

8.6 

(WP crack 

and crevice)

1,100

(WP crack and 

crevice)

0.0423 

(foam)

0.006 0.015 0.0215 56

Baseline + 

gloves, 

coveralls and 

PF5 Dust 

Mist Resp.

6.22 

(WP crack 

and crevice)

220

(WP crack and 

crevice)

0.004385 0.0031 0.00748 160

a. Unit Exposures based on PHED Version 1.1. 

b. Application Rate is based on proposed label for Thiamethoxam product--- Optigard® Flex Liquid Insecticide

c. Science Advisory Council for Exposure (11/18/10)

d. Dermal Dose (mg/kg/day) = [ Rate (lb ai/Gal) x UE (mg /lb ai ) x 5% DAF x Amount Treated (Gal/day)/ BW (60 kg)]

e. Inhalation Dose (mg/kg/day) = [ Rate (lb ai/Gal) x UE (mg /lb ai ) x Amount Treated (Gal/day)] / BW (60 kg)

f. Combined Daily Dose (mg/kg/day) = Dermal Dose (mg/kg/day) + Inhalation Dose (mg/kg/day)

g. Total MOE = [NOAEL (1.2 mg/kg/day)]/ Combined Daily Dose (mg/kg/day)
Thiamethoxam D373376

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9.2 Short- and Intermediate-Term Postapplication Risk

Since no quantitative postapplication assessment was completed for treated seeds, the restricted 

entry interval (REI) is based on the acute toxicity of thiamethoxam technical material which is 

classified as Category III for acute oral and dermal toxicity and Category IV for skin and eye 

irritation potential. The default restricted-entry interval is 12 hours for active ingredients 

classified as acute toxicity categories III or IV for these routes of exposure. In accordance with 

the Worker Protection Standard (WPS), for purposes of seed treatment, once the seeds are 

planted, workers can enter during the REI, provided they do not contact the soil/media 

subsurface that contains the treated seeds. Certain tasks may involve contact with the soil 

subsurface (e.g. repair of certain irrigation equipment) and they are covered by the REI. 

Therefore, HED concurs with the 12-hour REI on the proposed label for seed treatment. HED 

recommends that the Registration Division ensure that appropriate language is placed on the 

product label to require the label on treated seed to include the restricted-entry interval following 

the planting of treated seed. (Note: HED does not have transfer coefficients to assess 

postapplication dermal exposures to pesticides in the soil.)

Commercial applicators treating food handling establishments are not expected to immediately 

return to treatment sites; therefore, a quantitative postapplication assessment of handler exposure 

was not performed. 

10.0 Regulatory Recommendations and Data Needs

The submitted field trial data for thiamethoxam on peanuts are acceptable, and support the 

proposed use of Cruiser PD and Cruiser 5FS as pre-plant seed treatments. An adequate number 

of trials were conducted in the appropriate geographic regions at roughly 1.5-3X the maximum 

proposed rate. Based on the maximum combined thiamethoxam ROCs of 0.05 and 0.23 ppm in 

1X-treated nutmeat and hay samples, respectively, HED recommends a tolerance of 0.05 ppm in 

peanut nutmeat, and a tolerance of 0.25 ppm in peanut hay. 

The submitted field trial data for thiamethoxam on alfalfa are acceptable, and support the 

proposed use of Cruiser 5FS as a pre-plant seed treatment. An adequate number of trials were 

conducted in the appropriate geographic regions at 1X the maximum proposed rate. Based on 

the maximum combined thiamethoxam ROCs of 0.04 and 0.10 ppm in 1X-treated forage and hay 

samples, respectively, HED recommends a tolerance of 0.05 ppm in alfalfa forage, and a 

tolerance of 0.12 ppm in alfalfa hay. 

The submitted data for thiamethoxam use in food handling areas are acceptable, and support the 

proposed use of Optigard Flex Liquid as a spot, void, and crack and crevice treatment in food 

handling establishments. An adequate variety of food commodities were exposed to 

thiamethoxam, in two different types of food handling establishments, at 1X the maximum 

proposed rate. Maximum thiamethoxam and CGA-322704 residues were each <0.01 ppm in 

food commodities exposed to 1X treatment in food handling areas (with the vast majority of 

samples containing non-detectable residues). Based on the presence of detectable residues of 
Thiamethoxam D373376

Page 50 of 60

thiamethoxam or CGA-322704 in various samples, HED recommends a tolerance of 0.02 ppm in 

food/feed commodities (other than those covered by a higher tolerance as a result of use on 

growing crops). 

There are no processed commodities associated with the proposed use on alfalfa. The processed 

commodities associated with the proposed use on peanuts are peanut meal and refined oil. The 

theoretical concentration factor for peanut meal (OPPTS Residue Chemistry Test Guideline 

860.1520, Table 3) is 2.2X. The empirical concentration factors for thiamethoxam in meal 

(range 2.0-3.1X, average 2.6X) conform well to the theoretical value. A tolerance is not required 

in peanut oil. Based on the HAFT combined residues of 0.05 ppm in peanut nutmeat, and the 

theoretical concentration factor for peanut meal of 2.2X, HED recommends a tolerance of 0.15 

ppm in peanut meal.

There are no Codex or Mexican MRLs established for residues of thiamethoxam in crops 

associated with this review. Canada has established an MRL of 0.02 mg/kg for residues of 

thiamethoxam and CGA-322704 in all food crops, and is transitioning to specific commodity 

MRLs (all at 0.02 mg/kg) on a variety of crops including various cereal grains, peas and beans, 

soybeans, sweet corn, and sunflower. 

TABLE 10 Tolerance Summary for Thiamethoxam. 

Commodity Proposed/Established 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity 

Definition

Peanut 0.05 0.05

Peanut, hay 0.25 0.25

Peanut, meal None 0.15

Alfalfa, forage 0.05 0.05

Alfalfa, hay 0.12 0.12

Food/feed commodities (other 

than those covered by a higher 

tolerance as a result of use on 

growing crops)

0.01 0.02

HED notes that the tolerance expression for thiamethoxam in 40 CFR 180.565 has already been 

revised to conform to the current policy (i.e., include phrase ―its metabolites and degradates‖ and 

specify compliance by measuring only parent and the CGA-322704 metabolite).

10.1 Toxicology

870-7800 Immunotoxicity Study

The petitioner should submit, as a condition of registration, an immunotoxicity study. This study 

is now required under the new 40 CFR Part 158 data requirements, and was required in 

conjunction with the previous risk assessment. The study remains a data gap for thiamethoxam.

Route to Route Extrapolation Approach
Thiamethoxam D373376

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Based on the available toxicity database and the Agency's current practices, short- and 

intermediate-term inhalation risks for thiamethoxam were assessed using an oral toxicity study. 

The Agency sought expert advice and input on issues related to this route to route extrapolation 

approach (i.e. the use of oral toxicity studies for inhalation risk assessment) from its Federal 

Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. 

The Agency 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, re-examine and develop new 

policies and procedures for conducting inhalation risk assessments, including route to route 

extrapolation of toxicity data. If any new policies or procedures are developed, the Agency may 

revisit the need for an inhalation toxicity study for thiamethoxam and/or a re-examination of the 

inhalation toxicity risk assessment.

10.2 Residue Chemistry

A revised Section F should also reflect the higher tolerance in FHE commodities (0.02 instead of 

0.01 ppm) and the additional tolerance for peanut meal.

10.3 Occupational and Residential Exposure

860.1200 Directions for Use -- Use Limitation

HED recommends that the all labels specifically prohibit on-farm seed treatment for alfalfa and

peanuts.

The Cruiser® 5FS label should contain a restriction for commercial open system seed treatment 

facilities that limits the amount of product handled per day to no more than 38 gallons 

product/worker/8-hr day for peanuts and alfalfa.

The Cruiser® PD is intended for use as a dry application on peanuts. Since the treater (loader/ 

operator) unit exposure values from Policy 14 are based on liquid formulations, the 

loader/operator exposure for Cruiser® PD was estimated using surrogate unit exposure values 

for a wettable powder formulation in the Pesticide Handlers Exposure Database (PHED). The 

treater scenario resulted in a MOE of 100 with the use of additional PPE (i.e., gloves, coveralls,

and a PF10 respirator). Currently the label only requires use of a dust mask (quarter- or halfmask) respirator. HED recommends that the Registration Division ensure that the 

appropriate respirator is required on the final Cruiser PD label.

Commerical handlers applying thiamethoxam as a liquid spray to cracks and crevices, spots, and 

structural voids using a foam application resulted in an MOE of 160 with the use of additional 

PPE (gloves, coveralls, and PF5 dust mist respirator). The proposed label does not require use of 

coveralls and respirators. HED recommends that if this use is to remain on the label, the 

Registration Division ensure that the correct PPE be included in the final registered label. 
Thiamethoxam D373376

Page 52 of 60

References:

D376367. Thiamethoxam. Petition to Establish Permanent Tolerances for Residues of the 

Insecticide Resulting from Food/Feed Use as a Seed Treatment on Peanuts and Alfalfa, and from 

Applications in Food-Handling Establishments. Summary of Analytical Chemistry and Residue 

Data. William Drew, 2 Nov 2010.

D376368. Thiamethoxam. Acute and Chronic Aggregate Dietary (Food and Drinking Water) 

Exposure and Risk Assessments for the Section 3 Registration as a Seed Treatment for Alfalfa 

and Peanuts, and for Use in Food Handling Establishments. Dennis McNeilly, 23 Nov 2010.

D373378. Tier II Drinking Water Exposure Assessment to Establish a Tolerance of 

Thiamethoxam on Peanut and Alfalfa Seeds. Christopher M. Koper, 20 May 2010. 

D373377. Thiamethoxam: Occupational and Residential Exposure/Risk Assessment for 

Proposed Section 3 Registration for Seed Treatment Uses on Peanut and Alfalfa. Shih-Chi 

Wang, 3 Dec 2010.

D382248. Thiamethoxam: Occupational and Residential Exposure/Risk Assessment for 

Proposed Section 3 Registration for Use in Food/Feed Handling Establishments. Shih-Chi 

Wang, 7 Dec 2010.

D329466. Thiamethoxam Human Health Risk Assessment for Proposed New Uses or Revised 

Uses on Artichoke, Barley, Brassica Vegetables, Bushberry, Caneberry, Cotton, Cranberry, 

Cucurbit Vegetables, Fruiting Vegetables, Hops, Juneberry, Leafy Vegetables, Legume 

Vegetables, Lingonberry, Mint, Oilseed Crops, Pecan, Pome Fruit, Potato Seed Pieces, Root 

Vegetables (Except Sugarbeet), Salal, Stone Fruit, Strawberry, Tobacco, Tuberous and Corm 

Vegetables, and Turf. Michael Doherty, 22 May 2007.

D364256. Thiamethoxam. Acute and Chronic Aggregate Dietary (Food and Drinking Water) 

Exposure and Risk Assessments for the Section 3 Registration of Thiamethoxam on Rice, Sugar 

Beets, and Tropical Fruits. Dennis McNeilly, June 30, 2009.

ExpoSAC Policy 14: Standard Operating Procedures (SOPs) for Seed Treatment, May 1, 2003.

ExpoSAC Policy 15: Amount of Seed Treated or Planted per Day, March 2, 2004.

HED Draft Standard Operating Procedures (SOP’s) for Residential Exposure Assessments 

(12/18/97), and the Revisions to the Standard Operating Procedures (SOP’s) for Residential 

Exposure Assessment (Science Advisory Council for Exposure Policy 12, Revised February 22, 

2001).
Thiamethoxam D373376

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Appendix A – Toxicity Profile for Thiamethoxam.

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

numbers does not imply that the new 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 90-Day Inhalation..........................................................

Yes

Yes

Yes

No

No

Yes

Yes

Yes

No

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................

870.5385 Mutagenicity—Mammalian Bone Marrow 

 Chromosome Aberration Aberrations.....

870.5550 Mutagenicity—Unscheduled DNA Synthesis ...............

Yes

Yes

Yes

No

Yes

Yes

Yes

Yes

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

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

870.6300 Developmental Neurotoxicity........................................

Yes

Yes

No

Yes

Yes

Yes

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

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

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

Yes

No

Yes

Yes

Yes

No

Special Studies for Ocular Effects

Acute Oral (rat)...........................................................

Subchronic Oral (rat) ..................................................

Six-month Oral (dog)..................................................

No

No

No

No

No

No
Thiamethoxam D373376

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Table A.2.1. Acute Toxicity of Technical Thiamethoxam.

GDLN Study Type MRID Results

Tox

Category

870.1100 Acute Oral - rat 44703314 LD50: 1563 mg/kg (♂+♀) III

870.1200 Acute Dermal 44703316 LD50 > 2000 mg/kg (♂+♀) III

870.1300 Acute Inhalation 44703317 LC50 > 3.72 mg/L (♂+♀) IV

870.2400 Primary Eye Irritation 44703318 Minimally irritating IV

870.2500 Primary Skin Irritation 44703319 Not irritating IV

870.2600 Dermal Sensitization 44710401 Is not a sensitizer using method of 

Magnusson and Kligman

N/A

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

Type of 

Study/Guide 

line

Study Title MRID Results

870.3100 90-Day Oral Toxicity - rat 

(diet)

44718703

(1996)

Acceptable/

guideline

ppm=0, 25, 250, 

1250, 2500 & 

5000

mg/kg/day 

(M/F)=0/0, 

1.74/1.88, 

17.64/19.2, 

85/93, 168/182, 

329/359

NOAEL = 1.74 (males), 92.5 (females) mg/kg/day

LOAEL = 17.64 (males), 182.1 (females) 

mg/kg/day based on increased incidence of hyaline 

change of renal tubular epithelium (males), fatty 

change in adrenal gland of females, liver changes in 

females.

870.3100 90-Day Oral Toxicitymouse (diet)44703323 

(1996)

Acceptable/

guideline

ppm=0, 10, 100, 

1250, 3500 & 

7000

mg/kg/day 

(M/F)=0/0, 

1.41/2.01, 

14.3/19.2, 

176/231, 

543/626, 

1335/1163

NOAEL = 1.41 (males), 19.2 (females) mg/kg/day

LOAEL = 14.3 (males), 231 (females) mg/kg/day 

based on increased incidence of hepatocellular 

hypertrophy in both sexes. At higher dose levels: 

decrease in bodyweight and bodyweight gain, 

necrosis of individual hepatocytes, pigmentation of 

Kupffer cells, and lymphocytic infiltration of the 

liver in both sexes; slight hematologic effects and 

decreased absolute and relative kidney weights in 

males; and ovarian atrophy, decreased ovary and 

spleen weights and increased liver weights in 

females.

870.3150 13-Week Oral Toxicitydog (diet)44718702 

(1998)

Acceptable/

guideline

ppm=0, 50, 250, 

1000 & 

2500/2000 (after 

week 2 reduced 

to 2000)

NOAEL = 8.23 (males), 9.27 (females) mg/kg/day

LOAEL = 32.0 (males), 33.9 (females) mg/kg/day 

based on slightly prolonged prothrombin times and 

decreased plasma albumin and A/G ratio (both 

sexes); decreased calcium levels and ovary weights 

and delayed maturation in the ovaries (females); 

decreased cholesterol and phospholipid levels, testis 

weights, spermatogenesis, and spermatic giant cells 

in testes (males).
Thiamethoxam D373376

Page 55 of 60

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

Type of 

Study/Guide 

line

Study Title MRID Results

(M/F)=0/0, 

1.58/1.80, 

8.23/9.27, 

32.0/33.9, 

54.8/50.5 

870.3200 28-Day Dermal Toxicity -

rat

44710402 

(1996)

Acceptable/

guideline

mg/kg/day= 0, 

20, 60, 250 & 

1000

NOAEL = 250 (males), 60 (females) mg/kg/day

LOAEL = 1000 (males), 250 (females) mg/kg/day 

based on increased plasma glucose, triglyceride 

levels, and alkaline phosphatase activity and 

inflammatory cell infiltration in the liver and 

necrosis of single hepatocytes in females and 

hyaline change in renal tubules and a very slight 

reduction in body weight in males. At higher dose 

levels in females, chronic tubular lesions in the 

kidneys and inflammatory cell infiltration in the 

adrenal cortex were observed.

870.3700a Developmental Toxicityrat (gavage)44718706 

(1998)

44703329 

(1995)

44703330 

(1995)

Acceptable/

guideline

mg/kg/day=0, 5, 

30, 200 & 750

Maternal NOAEL = 30 mg/kg/day

LOAEL = 200 mg/kg/day based on decreased body 

weight, body weight gain, and food consumption.

Developmental NOAEL = 200 mg/kg/day

LOAEL = 750 mg/kg/day based on decreased fetal 

body weight and an increased incidence of skeletal 

anomalies.

870.3700b Developmental Toxicityrabbit (gavage)44718705 

(1998)

44703327 

(1995)

44703328 

(1995)

Acceptable/

guideline

mg/kg/day=0, 5, 

15, 50 & 150

Maternal NOAEL = 50 mg/kg/day

LOAEL = 150 mg/kg/day based on maternal deaths, 

hemorrhagic uterine contents and hemorrhagic 

discharge, decreased body weight and food intake 

during the dosing period.

Developmental NOAEL = 50 mg/kg/day

LOAEL = 150 mg/kg/day based on decreased fetal 

body weights, increased incidence of postimplantation loss and a slight increase in the 

incidence of a few skeletal anomalies/variations.

870.3800 Reproduction (2-

Generation)- rat (diet)

46402904 

(2004)

46402906 

(2000)

(range-finding)

Acceptable/

guideline

ppm=0, 20, 50, 

1000 & 2500

mg/kg/day

F0 M=0, 1.2, 

3.0, 61.7,155.6

Parental/Systemic NOAEL = 3 (males), 84.4 

(females) mg/kg/day

LOAEL =61.7 (males), 208.8 (females) mg/kg/day 

based on kidney lesions in F1 males. At higher 

doses of 155.6 mg/kg/day kidney lesions were 

observed in both F0 and F1 males, and decreased 

body weight, body weight gain, food consumption 

and food utilization in F0 males. Females had 

significantly increased relative liver weights.

Reproductive NOAEL = 1.2 (males), >208.8 

(females) mg/kg/day

LOAEL = 3 (males), not determined (females) 
Thiamethoxam D373376

Page 56 of 60

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

Type of 

Study/Guide 

line

Study Title MRID Results

F1M=0, 1.5, 3.7, 

74.8, 191.5

F0F=0, 1.7, 4.3, 

84.4, 208.8

F1F=0, 2.1, 5.6, 

110.1, 276.6

mg/kg/day based on sperm abnormalities in F1

males.

Offspring NOAEL = 84.4 mg/kg/day

LOAEL = 208.8 mg/kg/day based on significantly 

decreased total litter weights of the F1 pups.

870.3800 Reproduction (2-

Generation)- rat (diet)

44718707 

(1998)

44703401 

(1995)

(range-finding)

44703402 

(1998)

46402902

2006

(PWG report)

Acceptable/

guideline

ppm=0, 10, 30, 

1000 & 2500

mg/kg/day 

(M/F)=0/0, 

0.61/0.80, 

1.84/2.37, 

61.25/79.20, 

158.32/202.06

Parental/Systemic NOAEL = 1.84 (males), 202.06 

(females) mg/kg/day

LOAEL = 61.25 (males), not determined (females) 

mg/kg/day based on increased incidence of hyaline 

change in renal tubules in F0 and F1 males.

Reproductive NOAEL = 0.61 (males), 202.06 

(females) mg/kg/day

LOAEL = 1.84 (males), not determined (females) 

mg/kg/day based on increased incidence and 

severity of tubular atrophy observed in testes of the 

F1 generation males.

Offspring NOAEL = 61.25 (males), 79.20 

(females) mg/kg/day

LOAEL = 158.32 (males), 202.06 (females) 

mg/kg/day based on reduced body weight gain 

during the lactation period in all litters.

870.4100 Chronic (1 year) –dog 

(diet)

44718704 

(1998)

Acceptable/

guideline

ppm=0, 25, 150, 

750 & 1250

mg/kg/day 

(M/F)=0/0, 

0.70/0.79, 

4.05/4.49, 

21.0/24.6, 

42.0/45.1

NOAEL = 4.05 (males), 4.49 (females) mg/kg/day

LOAEL = 21.0 (males), 24.6 (females) mg/kg/day 

based on increase in creatinine in both sexes, 

transient decrease in food consumption in females, 

and occasional increase in urea levels, decrease in 

ALT, and atrophy of seminiferous tubules in males.

870.4200 Carcinogenicity, 18-

Month - mouse (diet)

44703326 

(1998)

Acceptable/

guideline

ppm=0, 5, 20, 

500, 1250 & 

2500

mg/kg/day

(M/F)=0/0, 

0.65/0.89, 

2.63/3.68, 

63.8/87.6, 

NOAEL = 2.63 (males), 3.68 (females) mg/kg/day

LOAEL = 63.8 (males), 87.6 (females) mg/kg/day 

based on hepatocyte hypertrophy, single cell 

necrosis, inflammatory cell infiltration, pigment 

deposition, foci of cellular alteration, hyperplasia of 

Kupffer cells and increased mitotic activity; also, an 

increase in the incidence of hepatocellular adenoma 

(both sexes). At higher doses, there was an increase 

in the incidence of hepatocellular adenocarcinoma 

(both sexes) and the number of animals with 

multiple tumors.

evidence of carcinogenicity
Thiamethoxam D373376

Page 57 of 60

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

Type of 

Study/Guide 

line

Study Title MRID Results

162/215, 

354/479

870.4300 Chronic/Carcinogenicity, 

2-Year-rat (diet) 

44718708 

(1998)

Acceptable/

guideline

ppm (M/F)=0/0, 

10/10, 30/30, 

500/1000 

&1500/3000

mg/kg/day

(M/F)=0/0, 

0.41/0.48, 

1.29/1.56, 

21.0/50.3, 

63.0/155

NOAEL = 21.0 (males), 50.3 (females) mg/kg/day

LOAEL = 63.0 (males), 155 (females) mg/kg/day 

based on increased incidence of lymphocytic 

infiltration of the renal pelvis and chronic 

nephropathy in males and decreased body weight 

gain, slight increase in the severity of hemosiderosis 

of the spleen, foci of cellular alteration in liver and 

chronic tubular lesions in kidney in females.

no evidence of carcinogenicity

870.5100

870.5265

Gene Mutation in S. 

typhimurium and E. coli

44710404 

(1995)

Acceptable/

guideline

No evidence of gene mutation when tested up to 

5000 μg/plate. There was no evidence of 

cytotoxicity.

870.5265 Gene Mutation in S. 

typhimurium

44968301 

(1999)

Acceptable/

non-guideline 

(supplementary)

No evidence of gene mutation when tested up to 

5000 μg/plate. The S9 fraction was from noninduced mouse liver, Aroclor 1254 induced mouse 

liver, or thiamethoxam induced mouse liver, 

following dietary administration of thiamethoxam 

for 14 days at concentrations up to 2500 ppm.

870.5300 Gene Mutation in Chinese 

Hamster V79 Cells at 

HGPRT Locus

44710405

(1996)

Acceptable/

guideline

No evidence of gene mutation when tested up to 

solubility limit.

870.5375 CHO Cell Cytogenetics 44710403

(1996)

Acceptable/

guideline

No evidence of chromosomal aberrations when 

tested up to cytotoxic or solubility limit 

concentrations.

870.5395 In vivo Mouse Bone 

Marrow Micronucleus

44710406 

(1995)

Acceptable/

guideline

Negative when tested up to levels of toxicity in 

whole animals; however no evidence of target cell 

cytotoxicity.

870.5550 Unscheduled DNA 

Synthesis in Primary Rat 

Hepatocytes

44710407

(1996)

Acceptable/

guideline

Negative when tested up to precipitating 

concentrations.

870.6200a Acute Neurotoxicity 

Screening Battery-rat 

(gavage)

44703320 

(1997)

Acceptable/

guideline

mg/kg=0,100, 

500 & 1500

NOAEL = 100 mg/kg/day

LOAEL = 500 mg/kg/day based on drooped 

palpebral closure, decrease in rectal temperature and 

locomotor activity and increase in forelimb grip 

strength (males only). At higher dose levels, 

mortality, abnormal body tone, ptosis, impaired 

respiration, tremors, longer latency to first step in 
Thiamethoxam D373376

Page 58 of 60

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

Type of 

Study/Guide 

line

Study Title MRID Results

the open field, crouched-over posture, gait 

impairment, hypo-arousal, decreased number of 

rears, uncoordinated landing during the righting 

reflex test, slight lacrimation (females only) and 

higher mean average input stimulus value in the 

auditory startle response test (males only).

870.6200b Subchronic Neurotoxicity 

Study-rat (diet)

44703325 

(1998)

Acceptable/

guideline

ppm 

(M/F)=0/0,10/1

0, 30/30, 

500/1000 & 

1500/3000

mg/kg/day

(M/F)=0/0,0.7/0

.7, 1.9/2.1, 

31.8/73.2, 

95.4/216.4

NOAEL = 95.4 (males), 216.4 (females) mg/kg/day, 

both highest dose tested.

LOAEL = not determined. No treatment-related 

observations at any dose level. May not have been 

tested at sufficiently high dose levels; however, new 

study not required because the weight of the 

evidence from the other toxicity studies indicates no 

evidence of concern.

870.6300 Developmental 

Neurotoxicity Study-rat

(diet)

46028202

(2003)

46028201

(2003)

(preliminary)

Acceptable/

non-guideline

(needs positive

control data): 

may be used for 

regulatory 

purposes

ppm= 0, 550, 

400, 4000

mg/kg/day

(gestation/

lactation)

0/0, 4.3/8.0, 

34.5/64.0, 

298.7/593.5

Maternal NOAEL = 34.5 mg/kg/day

LOAEL = 298.7 mg/kg/day based on decreases in 

body weight gain and food consumption. 

Developmental NOAEL = 34.5 mg/kg/day

LOAEL = 298.7 mg/kg/day based on decreased 

fetal body weights and weight gain in males and 

females, delayed sexual maturation in males, 

reduced brain weight and size in males and females, 

and significant changes in brain morphometric 

measurements.

870.7485 Metabolism Study- rat

(gavage)

44703532 

(1996)

44703533 

(1998)

Acceptable/

guideline

low dose=0.5 

mg/kg

high dose=100 

Absorbed rapidly & extensively, widely distributed, 

followed by very rapid elimination, mostly in urine. 

Highest tissue concentrations in skeletal muscle: 10-

15% of administered dose. Half-life times from 

tissues ranged from 2-6 hours. Tissue residues after 

7 days extremely low. Approximately 84-95% of 

administered dose excreted in urine & 2.5-6% 

excreted in feces within 24 hours. < 0.2% detected 

in expired air. Most excreted as unchanged parent: 
Thiamethoxam D373376

Page 59 of 60

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

Type of 

Study/Guide 

line

Study Title MRID Results

mg/kg

Also: I.V., 0.5 

mg/kg

70-80% of dose. The major biotransformation 

reaction is cleavage of oxadiazine ring to 

corresponding nitroguanidine compound. Minor 

pathways: (1) cleavage of nitroguanidine group 

yielding guanidine derivative, (2) hydrolysis of 

guanidine group to corresponding urea, (3) 

demethylation of guanidine group, and (4) 

substitution of the chlorine of the thiazole ring by 

glutathione. Cleavage between thiazole- and 

oxadiazine ring occurs to a small extent. 

Glutathione derivatives prone to further degradation 

of the glutathione moiety resulting in various sulfurcontaining metabolites (e.g. mercapturates, sulfides, 

and sulfoxides). Both the thiazole and oxadiazine 

moiety susceptible to oxidative attack. Small but 

measurable amounts exhaled, most probably as CO2. 

Metabolites eliminated very rapidly. Enterohepatic 

circulation negligible.

870.7485 Metabolism Study – mice

(gavage)

44710408

(1998)

46161502 

(2003)

46161505

(2002)

46161512 

(2000)

Supplementary/

non-guideline

(44710408)

males only: 118 

mg/kg/day, 14 

days

Approximately 72% of administered dose excreted

in the urine; 19% excreted in feces. Small but 

measurable amount detected in expired air 

(approximately 0.2% of dose). Predominant 

metabolites: unchanged parent (33-41% of 

administered dose); 2 other metabolites: 8-12% and 

9-18% of administered dose. These are the same 

structures that were most commonly observed in rat 

excreta; however the proportions are quite different 

in mouse excreta. One additional significant 

metabolite (mouse R6) was isolated from feces 

samples. Between 30-60% of the administered dose 

was excreted as metabolites.

870.7600 Dermal Absorption - rats 44703403 

(1998)

EPA=unaccept./

not upgradable; 

conducted by 

draft OECD 

guideline

Estimates of dermal absorption were based on the 

sum of radioactivity in skin test site, urine, feces, 

blood, and carcass. Dermal absorption is 5%, 

which is the maximum observed for all dose groups.

Non-guideline Hepatic Cell Proliferation 

-mouse (diet)

44703406 

(1998)

Acceptable/

non-guideline

ppm=100, 500 

& 2500

mg/kg/day

(M/F)=16/20, 

72/87, 386/483

NOAEL = 16 (males), 20 (females) mg/kg/day

LOAEL = 72 (males), 87 (females) mg/kg/day 

based on proliferative activity of hepatocytes. At 

higher dose levels, increases in absolute and relative 

liver wts, speckled liver, hepatocellular 

glycogenesis/fatty change, hepatocellular necrosis, 

apoptosis and pigmentation were observed.

Non-guideline Replicative DNA 

Synthesis in 28-Day 

44703405 

(1995)

NOAEL = 711 mg/kg/day (highest dose tested)

LOAEL = not established. Immunohistochemical 
Thiamethoxam D373376

Page 60 of 60

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

Type of 

Study/Guide 

line

Study Title MRID Results

Study-rat, male only (diet) Acceptable/

non-guideline

ppm=0, 100, 

1000, 2500 & 

10000

mg/kg/day=0, 8, 

82, 199, 711

staining of liver sections from control and high-dose 

animals for proliferating cell nuclear antigen gave 

no indication for a treatment-related increase in the 

fraction of DNA synthesizing hepatocytes in Sphase. CGA 293343 did not stimulate hepatocyte 

cell proliferation in male rats.

Non-guideline Special study to assess 

liver biochemistry-mouse

44703407

(1998)

Acceptable/

non-guideline

NOAEL = 17 (males), 20 (females) mg/kg/day

LOAEL = 74 (males), 92 (females) mg/kg/day 

based on marginal to slight increases in absolute and 

relative liver weights, a slight increase in the 

microsomal protein content of the livers, moderate 

increases in the cytochrome P450 content, slight to 

moderate increases in the activity of several 

microsomal enzymes, slight to moderate induction 

of cytosolic glutathione S-transferase activity. 

Treatment did not affect peroxisomal fatty acid ßoxidation.