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6.1 Residential Handler Exposure .................................................................................... 29

6.2 Post-Application Exposure .......................................................................................... 30

6.3 Residential Risk Estimates for Use in Aggregate Assessment.................................. 31

6.4 Residential Bystander Post-application Inhalation Exposure ................................. 31

6.5 Spray Drift.................................................................................................................... 32

7.0 Aggregate Exposure/Risk Characterization.................................................................. 32

7.1 Acute Aggregate Risk................................................................................................... 32

7.2 Short-Term Aggregate Risk ........................................................................................ 33

7.3 Intermediate-Term Aggregate Risk ........................................................................... 33

7.4 Chronic Aggregate Risk .............................................................................................. 33

7.5 Cancer Aggregate Risk ................................................................................................ 33

8.0 Cumulative Exposure/Risk Characterization ............................................................... 34

9.0 Occupational Exposure/Risk Characterization ............................................................ 34

10.0 References......................................................................................................................... 35

Attachment A. Toxicology Profile and Executive Summaries............................................... 36

A.1 Toxicology Data Requirements................................................................................... 36

A.2 Toxicity Profiles............................................................................................................ 37

A.3 Hazard Identification and Endpoint Selection .......................................................... 43

Attachment B: International Residue Limits.......................................................................... 49
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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 

Committee). 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 use of new formulations and higher maximum 

seasonal use rates for thiamethoxam on imported coffee. In conjunction with the proposed new 

formulations and higher seasonal application rates, Syngenta has requested an increased 

tolerance for residues of thiamethoxam and its metabolite, CGA-322704 (clothianidin), in or on 

coffee. In addition, condition-of-registration data for registration were submitted for the use of 

the Cruiser 70 WS formulation as a seed treatment for leafy vegetables at a seasonal application 

rate of 0.266 lbs ai/A. HED had requested the condition-of-registration data to reflect the higher 

proposed application rate. The submitted residue data for leaf lettuce indicate that the current 

tolerance of 4.0 ppm for Crop Group 4 is appropriate. Residue chemistry condition-ofregistration data are no longer required for carrots and Brassica leafy greens because the seed 

treatment use rate is being limited by the thiamethoxam labels to no more than 0.22 lbs. ai/A, and 

the pre-harvest intervals (PHIs) for seed treatment use are much longer than the 3 days specified

for current foliar uses.

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

for the purpose of this 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), has recently been received and was reviewed. The results of 

that study do not alter the endpoints or points of departure from those used in previous risk 

assessments. The scientific quality of the available toxicology studies is relatively high and the 

toxicity profile of thiamethoxam can be characterized for most effects, including potential 

carcinogenicity, mutagenicity, developmental toxicity, neurotoxicity, and immunotoxicity

In mammals, toxicological effects are primarily in the liver, kidney, testes, and hematopoietic 

system (blood cellular system). In addition, developmental neurological effects were observed in 

rats. These developmental effects are 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. Thiamethoxam is classified as “not likely to be carcinogenic to humans.” 

The endpoints and points of departure selected for risk assessment from the available data are 

protective of all toxicological effects, including potential developmental/reproductive, 

neurological, and immunotoxic effects, observed in the database for all population groups. In 

addition, the dietary and residential exposures are not likely to be underestimated. Therefore, the 

Health Effects Division (HED) has reduced the Food Quality Protection Act (FQPA) Safety 

Factor to account for sensitivity of infants and children from 10X to 1X.
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Based on the use pattern and the toxicological profile of thiamethoxam, HED selected endpoints 

and doses for acute and chronic dietary risk assessment and non-occupational exposures (i.e., 

incidental oral, dermal, or inhalation). For occupational handlers and workers re-entering treated 

areas, HED selected endpoints and doses for dermal and inhalation exposure and risk 

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

in Tables 4.5.4.1 and 4.5.4.2. 

HED has examined the residue chemistry database for thiamethoxam. There are no residue 

chemistry issues that would preclude increasing the existing coffee tolerance from 0.05 to 0.2 

ppm for the combined residues of thiamethoxam and CGA-322704, as specified below.

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

exposures to thiamethoxam. The resulting risk estimates are all well below HED’s level of 

concern for all population subgroups and durations of exposure.

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.

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

human health risk assessment.

This risk assessment is based, in part, on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. 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.

2.0 HED Recommendations

HED recommends for increasing the existing tolerance for thiamethoxam in/on coffee to 0.20

ppm to allow the use of new thiamethoxam formulations and higher application rates on foreigngrown coffee. The specific tolerance recommendations are discussed in 2.2, and label 

modifications are discussed in section 2.3.

2.1 Data Deficiencies

None.
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2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate method, HPLC Method AG-675, is available to enforce the established tolerances. 

The FDA multiresidue methods in PAM Vol. I are not adequate for tolerance enforcement as 

thiamethoxam residues of concern are not adequately recovered by any of the tested multiresidue 

method protocols.

2.2.2 Recommended Tolerances

The current tolerance for thiamethoxam in or on coffee is 0.05 ppm; this submission proposes to 

amend the tolerance by increasing it to 0.2 ppm. HED concurs with the increased tolerance 

level; however, we recommend increasing the precision of the expression to 0.20 ppm for 

compliance with enforcement policies.

Table 2.2.3. Tolerance Summary for Thiamethoxam.

Commodity

Proposed 

Tolerance 

(ppm)

Recommended 

Tolerance

(ppm)

Comments; Correct Commodity Definition

Coffee 0.2 0.20

Coffee, bean, green1

Existing tolerance level is 0.05 ppm

1- There are no US registrations as of (insert FR Notice data).

2.2.3 Revisions to Petitioned-For Tolerances

The registrant needs to submit a revised Section F in which the tolerance recommended in Table 

2.2.3 is proposed, i.e., changing the tolerance from 0.2 to 0.20. This change is to reflect the 

necessary level of precision for enforcement purposes.

2.2.4 International Harmonization

Codex maximum residue limits (MRLs) are established for residues of thiamethoxam in coffee at 

0.2 ppm. Canada has established an MRL of 0.05 mg/kg for residues of thiamethoxam and 

CGA-322704 in coffee. HED is recommending increasing the tolerance to 0.20 ppm which will 

harmonize with the Codex MRL of 0.2 ppm. (Note: the MRL expressions continue to remain 

different, as the Codex MRL is for the parent compound only.)

2.3 Label Recommendations

None.

3.0 Introduction

Thiamethoxam is a broad-spectrum nitroguanidine insecticide which belongs to class of 

compounds known as the neonicotinoids (Group 4A). It has activity against sucking and 
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chewing insects, such as leafhoppers and potato beetles, as well as other insect pests, on a wide 

variety of crops. It also is effective against a wide variety of interior and exterior pests, 

including termites, ants, beetles, and cockroaches. 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, nor does it interfere with sodium channels, and 

thus has a different mode of action than the organophosphate, carbamate and pyrethroid 

insecticides.

3.1 Chemical Identity

The nomenclature for thiamethoxam is presented in Table 3.1, and the physicochemical 

properties are summarized in Table 3.2.

Table 3.1. Thiamethoxam Nomenclature.

Chemical structure

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) Tolerance without US registration.

Chemical Class Neonicotinoid, Group 4A

Known Impurities of Concern None

Chemical structure of 

CGA-322704 metabolite

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

Common Name Clothianidin

N

O

N

N

H C3

N

S

Cl

O2N

N

H

N

H

N

H C3

N

S

Cl

O2N
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3.2 Physical/Chemical Characteristics

Table 3.2. 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.

3.3 Pesticide Use Pattern

Proposed labels for Brazil were provided for these new formulations. The proposed use 

directions are summarized in Table 3.3.

Table 3.3. Summary of Directions for Use of Thiamethoxam in Brazil, Columbia and Costa Rica*.

Applic. Timing, 

Type, and Equip. Formulation 

Applic. 

Rate 

(lb ai/A)=

Max. No. 

Applic. 

per Season

Max. Seasonal 

Applic. Rate (lb 

ai/A)

PHI 

(days)

Use Directions and 

Limitations

Apply with fertilizer 

in furrow.

Verdadero 20 GR

(1% 

thiamethoxam

ai)

0.178 – 0.268

lbs ai/A

(0.2 – 0.3 kg 

ai/ha)

1* 0.535 lbs. ai/A

(0.6 kg ai/ha) 90 Applied once a year, Oct to Nov.

Soil drench around the 

plant, or application 

via drip irrigation. 

Actara 10 GR

0.223 - 0.446 

lbs ai/A

(0.25 - 0.50 

kg ai/ha)

1-2

0.535 lbs. ai/A

(0.6 kg ai/ha) 90

Apply 25 kg/ha after the main 

flowering + 25 kg/ha in the 

beginning of the fruit 

development (initial growth), 

as per the regional conditions 

of pest occurrence.

Soil drench around the

plant.

Actara 250 WG 0.312 - 0.446 

lbs ai/A 1

0.446 lbs ai/A

(0.5 kg/ha) 90

Applied once a year, after the 

beginning of the rain period 

(Oct/Nov) or during Feb–

March. 
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Table 3.3. Summary of Directions for Use of Thiamethoxam in Brazil, Columbia and Costa Rica*.

Applic. Timing, 

Type, and Equip. Formulation 

Applic. 

Rate 

(lb ai/A)=

Max. No. 

Applic. 

per Season

Max. Seasonal 

Applic. Rate (lb 

ai/A)

PHI 

(days)

Use Directions and 

Limitations

(0.35-0.5 kg 

ai/ha)

Drench application 

made to the leaves.

Verdadero 600 

WG

0.267 lbs 

ai/A

(0.3 kg ai/ha) 

1-2

0.535 lbs. ai/A

(0.6 kg ai/ha) NS 45 day retreatment interval.

* The label specifies only one application at an application rate of 0.268 lba ai/A and also states that 600 grams (0.535 lbs ai/A) 

of thiamethoixam can be applied per season. No labels were provided for Columbia or Costa Rica, although the submission 

indicates the use patterns are similar to those in Brazil, with the exception that a higher use rate is apparently used in 

Columbia/Costa Rica.

Conclusions. The submitted use directions are sufficient to allow for evaluation of the submitted 

residue data relative to the proposed use patterns, which are all outside the US. The available 

field trial data support the proposed use directions for the crops addressed in this summary 

document.

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the 

proposed new use of thiamethoxam on imported coffee. Humans may be exposed to 

thiamethoxam in food and drinking water, since thiamethoxam may be applied directly to 

growing crops and application may result in thiamethoxam reaching surface and ground water 

sources of drinking water. There are no new residential uses of thiamethoxam, but there are 

existing exposures in residential and/or non-occupational settings; exposures via the dermal and 

inhalation routes are expected, and incidental oral exposure is expected for children. In an 

occupational setting, applicators may be exposed via the dermal and inhalation routes while 

handling the pesticide prior to application, as well as during application. There is a potential for 

dermal post-application exposure for workers re-entering treated fields. 

Risk assessments have been previously prepared for the existing uses of thiamethoxam. This 

risk assessment considers the potential increased dietary exposure from thiamethoxam on coffee, 

but also considers the existing uses as well.

3.5 Consideration of Environmental Justice

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

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

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

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

assessment, OPP considers a large variety of consumer subgroups according to well-established 

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

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

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

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

Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all 
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registered food uses of a pesticide. These data are analyzed and categorized by subgroups based 

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

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

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

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

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

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

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

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

subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

The toxicological database for thiamethoxam is complete under the revised 40 CFR Part 158 

guidelines and sufficient for purposes of human health risk assessment. The scientific quality of 

the available studies is relatively high and the toxicity profile of thiamethoxam can be 

characterized for most effects, including potential carcinogenicity, mutagenicity, developmental 

toxicity, neurotoxicity, and immunotoxicity. The doses and endpoints for use in human health 

risk assessments are summarized in Tables 4.5.4.1 and 4.5.4.2. 

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; immunotoxicity in mice, and metabolism. In addition, a number of 

studies were submitted to support the mode of action for carcinogenicity.

A repeated-exposure inhalation study is required according to the revised 40 CFR Part 158 

guidelines. An inhalation toxicity study is not available for thiamethoxam; however, the Hazard 

and Science Policy Council (HASPOC) recommends based on a weight-of-evidence (WOE)

approach that the study is not required at this time (TXR# 0052354). 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 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.

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

The ADME of thiamethoxam is similar between rats and mice. In rats, thiamethoxam is rapidly 

and extensively absorbed, widely distributed, and rapidly eliminated. There were no differences 
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observed in absorption, distribution, or elimination between sexes, low or high doses, single or 

repeated dosing, or the position of the radiolabel in metabolism studies. The highest tissue 

concentrations are in skeletal muscle (10-15% administered dose (AD)); all other tissues 

examined were generally below 2% of the AD. Maximum blood concentrations were achieved 

within 1-4 hours of an oral dose, and the elimination half-lives were ~7 hours from blood and ~4 

hours from tissues. Very low residues in tissue were reported after 7 days. Plasma 

concentrations in the blood were proportional between the low (0.5 mg/kg) and high (100 mg/kg) 

doses, indicating absorption was not saturated within that range. When compared with an 

intravenous dosing study, bioavailability of the oral dose was 70-80%. 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% AD). The major 

biotransformation reaction is cleavage of the oxadiazine ring to form the corresponding 

nitroguanidine compound (CGA-322704). Enterohepatic circulation is negligible.

In a 14-day repeated-dose study in the mouse, approximately 72% of the administered dose was 

excreted in the urine and 19% was excreted in feces. Greater than 90% of the administered dose 

was eliminated within 24 hours of the final dose. Small but measurable amounts were detected 

in expired air (approximately 0.2% of dose). Parent (33-41% AD) and two metabolites, CGA 

322704 (8-12% AD) and CGA 265307 (a demethylation product of CGA 322704; 9-18% AD)

were the only major metabolites identified. These are the same structures that were most 

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

Pretreatment with thiamethoxam did not impact the relative fraction of metabolites observed in 

rats or mice, indicating that species difference are not due to the induction of metabolizing 

enzymes.

4.2.1 Dermal Absorption

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

dermal penetration studies in the rat using formulated products containing thiamethoxam. 

Technical thiamethoxam made up 21.1% or 48.6% of the final formulated products. Following a 

10-hour exposure, significant amounts of test article remained in the skin at the application site 

(i.e., 18 to 28% of the applied dose). However, skin residues did not decline over 336 hours 

indicating that skin-bound residues were not systemically available. The total absorbed dose 

based on residues in urine, feces, and carcass was between 1.3-3.5% of the administered dose, 

depending on dose level and sampling time. The estimate for dermal absorption was rounded up 

to 5% for risk assessment and is applicable to both formulated and technical thiamethoxam.

4.3 Toxicological Effects

Thiamethoxam is a broad spectrum insecticide which belongs to the neonicotinoid class of 

compounds. While laboratory data indicate that thiamethoxam controls sucking and chewing 

insects through interference with the nicotinic acetylcholine 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 known to interfere with nicotinic acetylcholine receptors, 
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thiamethoxam appears to function at a different location1. In an in vitro nicotinic receptor 

binding study, thiamethoxam had essentially no affinity for the mammalian nicotinic 

acetylcholine receptor and was considered inactive.

Thiamethoxam does not inhibit cholinesterase or interfere with sodium channels and, therefore, 

has a different mode of action than organophosphates, carbamates and pyrethroid insecticides. 

Thiamethoxam is a systemic insecticide with movement through the xylem and phloem.

The available database of guideline studies for thiamethoxam indicates that the primary targets 

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. Although the 

insecticidal MOA is based on disruption of the nervous system, clinical signs of neurotoxicity 

were only observed in the acute neurotoxicity study. Decreased motor activity, tremors, 

impaired respiration, and other effects related to neurotoxicity, were observed within 2-3 hours 

after dosing. No adverse effects were observed beyond the day of dosing, consistent with the 

rapid absorption and clearance observed in the metabolism studies. Evidence of neurotoxicity in 

other studies included a decrease in absolute brain weight in females in the 28-day dog study, 

although this effect was not observed in the 90-day or chronic dog studies. Increased relative 

brain weight in male mice and microscopic changes in the male rat brains in chronic studies were 

not considered treatment-related but were determined to be secondary to reduced body weight 

gain (mouse) or pituitary adenomas (rat). 

Liver effects were observed in the rat and mouse across 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 results in an increase in the 

incidence of foci in females. 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, and increased mitotic activity (chronic). Male mice are 

more sensitive to the liver effects than females. Chronic dosing results in the development of 

benign and malignant liver tumors in both sexes and an increase in the number of animals with 

multiple tumors. 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. However, in rats there does not seem to be an increase 

in severity with increased duration. 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.

 

1 R. Nauen, et al. (2003). Pesticide Biochemistry and Physiology, 76(2):55-69
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Testicular effects are observed in the rat and dog. In 2-generation reproduction studies in the 

rat, testicular effects are only observed in the F1 males, not in parental or F2 animals. In the first 

reproduction study, there are sperm abnormalities while in the second study there is an increased 

incidence and severity of testicular tubular atrophy. While the effects observed in the two 

studies differ, the findings are consistent with respect to the testes as a target organ. In the 

subchronic dog study, decreased testicular weights and a reduction in spermatogenesis associated 

with the occurrence of spermatic giant cells in the testes were noted. Atrophy of the 

seminiferous tubules was found in the chronic dog study at minimally to moderately toxic dose 

levels. It is anticipated that testicular effects 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 more pronounced 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 to accumulation of α2u-globulin, 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 were 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 and 

increased 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. 

Indirect supporting evidence includes 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. While the 

toxicological significance of this observation is unclear, there is no doubt regarding its 

association to treatment with thiamethoxam. 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 (HIARC, 3/14/01; TXR# 0014504).

There was no indication of toxicity to the immunological system in a 28-day immunotoxicity 

study in the rat. In acute lethality studies, technical thiamethoxam is slightly toxic to rats and 
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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.

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

TXR# 0056482. Thiamethoxam. Summary of Hazard and Science Policy Council (HASPOC) Meeting of October 

11, 2012: Recommendation on the need for a 28-day inhalation study.

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

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

includes developmental neurotoxicity, and immunotoxicity studies; (2) HED characterized the 

degree of concern for the quantitative susceptibility observed in the thiamethoxam 2-generation 

reproduction study as low based on the clear NOAELs for the offspring effects and the selection 

of regulatory doses that are protective of those effects; (3) the endpoints selected for risk 

assessment are conservative and protective of neurotoxicity and brain effects observed in the 

neurotoxicity studies; (4) HED is regulating the use of thiamethoxam based upon the most 

sensitive offspring effects observed in the reproduction toxicity study, and therefore the risk 

assessment is protective of these and other effects that occurred at higher doses; (6) the exposure 

databases (dietary food, drinking water, and residential) are complete; and (7) the risk 

assessment for each potential exposure scenario includes all metabolites and/or degradates of 

concern and does not underestimate potential exposure and risk for infants or children. 

No additional factors are required to protect for the lack of an inhalation study. The lung does 

not appear to be a target organ based on acute inhalation and other neonicotinoid insecticides. 

The Hazard and Science Policy Council (HASPOC, TXR# is 0056482) recommends, based on a 

weight-of-evidence (WOE) approach, that a 28-day inhalation toxicity study is not required for 

thiamethoxam at this time. This recommendation is based on: (1) the use of an oral point of 

departure (POD) that results in MOEs > 1,000 for all exposure scenarios, except mixing/loading 

for application to sod farms, mixing/loading/applying for crack and crevice application, and 

primary seed treatment of cotton seeds in a closed system. These MOEs are considered 

conservative based on the inputs of amount treated; (2) the lung is not the target organ of 

thiamethoxam toxicity and no adverse respiratory effects were observed in the acute inhalation 

toxicity study; (3) the current POD for risk assessment is protective of testicular effects observed 

in subchronic oral toxicity studies; and (4) other chemicals similar to thiamethoxam do not 

demonstrate respiratory toxicity.

4.4.1 Completeness of the Toxicology Database

Acceptable guideline studies for developmental, reproductive toxicity and neurotoxicity 

(including DNT) are available for FQPA assessment. An immunotoxicity study in mice has also 

been submitted and reviewed.

4.4.2 Evidence of Neurotoxicity

In the acute neurotoxicity study, there were indications of neurotoxicity at the study LOAEL of 

500 mg/kg including drooped palpebral closure, lower rectal temperature, increased forelimb 
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grip strength (males only) and decreased locomotor activity observed 2-3 hours after dosing. At 

1500 mg/kg, the effects were more severe and included abnormal body tone, ptosis, impaired 

respiration, tremors, longer latency to first step in 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), and the death of 3 females within 1 or 2 days of 

dosing. These effects were no longer evident at the 1 week and 2 week post-dosing 

examinations. 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 neurological 

effects observed at any dose. In addition, no treatment-related histopathological findings were 

noted in the central or peripheral nervous systems. Although the subchronic neurotoxicity study 

was not tested at the limit dose, 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).

Neurotoxicity was also 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.

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

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 equal to or greater than the maternal NOAELs and the effects observed in the 

fetuses are not 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) at the 

same dose. The NOAEL and LOAEL for this study were 34.5 and 298.7 mg/kg/day.
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There is evidence of increased quantitative susceptibility for male pups in 2 two-generation 

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

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

lactation. This contributes to an overall decrease in bodyweight gain during the entire lactation 

period. The reproductive effects in males appear in the F1 generation in the form of increased 

incidence and severity of testicular tubular atrophy. 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). Similar effects were observed in the second twogeneration reproduction study; increased incidence of hyaline change in the renal tubes were 

observed of the F0 and F1 males at 61.25 mg/kg/day (NOAEL 1.84 mg/kg/day) while tubular 

atrophy was found in the F1 males at 1.84 mg/kg/day (NOAEL 0.61 mg/kg/day).

Although there is evidence of increased quantitative and qualitative susceptibility in the 

developmental neurotoxicity and reproduction studies, there are no residual uncertainties with 

regard to pre- and/or postnatal toxicity following in utero exposure to rats or rabbits and pre 

and/or post-natal exposures to rats. Considering the overall toxicity profile and the doses and 

endpoints selected for risk assessment, the degree of concern for the effects observed in the 

studies is low based on the following: the developmental/offspring effects observed in the studies 

are well characterized and clear NOAELs/LOAELs have been identified in the studies for the 

effects of concern. Additionally, the Agency is confident that the endpoints and PODs selected 

for risk assessment are protective of potential developmental/reproductive effects and the most 

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

database.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties with respect to dietary, residential, or occupational exposure. 

The dietary exposure assessments are based on high-end, health protective residue levels and 

processing factors, both of which account for parent and metabolites of concern. Actual risk 

from exposure to thiamethoxam will likely be much lower than HED’s risk estimates conducted 

for the proposed and existing uses. Furthermore, conservative, upper-bound assumptions were 

used to determine exposure through drinking water, such that these exposures have not been 

underestimated.

The residential and occupational exposure estimates are conservative and do not under estimate 

exposure or risk. 

4.5 Toxicity Endpoint and Point of Departure Selections

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

and doses for acute and chronic dietary risk assessment and non-occupational exposures (i.e., 

incidental oral, dermal, or inhalation). For occupational handlers and workers re-entering treated 

areas, HED selected endpoints and doses for dermal and inhalation exposure and risk 

assessment.
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4.5.1 Dose-Response Assessment

Acute Dietary Endpoint (All Populations): The endpoint used for establishing the acute 

population-adjusted dose (aPAD) for the general population was selected from the 

developmental neurotoxicity study in the rat. An aPAD of 0.35 mg/kg/day was derived from a 

NOAEL of 34.5 mg/kg/day and a 100-fold factor that included 10x for inter-species 

extrapolations, 10x for intra-species variations, and a 1x FQPA SF. The LOAEL of 298.7 

mg/kg/day was based on delayed sexual maturation in male pups, and reduced brain 

morphometric measurements. This endpoint is appropriate for the acute dietary exposure 

assessment because the change in brain morphometrics could be the result of a single exposure at 

a critical junction during pregnancy or from multiple exposures throughout pregnancy, it is an 

appropriate route of exposure (oral), and it is protective of developing offspring. Furthermore, 

the selection of the developmental toxicity is protective of effects observed after a single dose in 

the acute neurotoxicity study.

Chronic Dietary (All Populations): The endpoint used for establishing the chronic populationadjusted dose (cPAD) was selected from the 2-generation reproduction study in the rat. A cPAD 

of 0.01 mg/kg/day was derived from a NOAEL of 1.2 mg/kg/day and a 100-fold factor that 

included 10x for inter-species extrapolation, 10x for intra-species variability, and a 1x FQPA SF. 

The LOAEL of 1.8 mg/kg/day was based on testicular effects in the F1 males. The endpoint is 

based on the most sensitive effect observed in offspring and is protective of in utero and 

developmental effects that could be associated with developing children. The endpoint is 

appropriate because effects were observed after subchronic exposure and are thus likely to be 

observed after chronic exposure.

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

selected from the 90-day oral toxicity study in the dog. The NOAEL is 8.2 mg/kg/day, and the 

level of concern (LOC) is an MOE of 100 (10x for inter-species extrapolation, 10x for intraspecies variability, and a 1x FQPA SF). The effects observed at the LOAEL of 33.9 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; 

decreased cholesterol and phospholipid levels, testis weights, spermatogenesis, and spermatic 

giant cells in testes (males). The study, dose and endpoint were selected because of the exposure 

duration and because selection of the offspring effects is protective of the population of concern, 

developing children. Although testicular effects were noted at a lower dose (1.8 mg/kg/day) in 

the rat reproduction study, this endpoint is not appropriate for developing children because the 

effects were only observed in sexually mature animals.

Dermal – Adults (Short- and Intermediate-Term): The endpoint used for assessing dermal 

exposure was selected from the 2-generation reproduction study in the rat. The NOAEL is 1.2 

mg/kg/day, and the LOC is an MOE of 100 (10x for inter-species extrapolation, 10x for intraspecies variability, and a 1x FQPA SF). The effects and LOAEL have been described above (see 

chronic dietary). Although a 28-day dermal toxicity study in rats is available, HED selected a 

reproductive NOAEL to protect for the effects observed in the reproduction study that were not 

evaluated in the dermal toxicity study. Since an oral toxicity study was selected, a 5% dermal 

absorption factor is recommended.
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Dermal – Children Age 1 to 6 years (Short-Term): The endpoint used for assessing dermal 

exposure was selected from the 28-day dermal study in rats. The NOAEL is 60 mg/kg/day, and 

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

and a 1x FQPA SF). The LOAEL of 250 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. 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.

Inhalation (Short- and Intermediate-Term): The endpoint used for assessing inhalation exposure 

for all lifestages was selected from the 2-generation reproduction study in the rat. The NOAEL 

is 1.2 mg/kg/day, and the LOC is an MOE of 100 (10x for inter-species extrapolation, 10x for 

intra-species variability, and a 1x FQPA SF). The effects observed and the LOAEL have been 

described above. The study was selected because of the exposure duration, and because the 

endpoint (testicular effects) is protective of all other effects in the database; while the endpoint is 

considered appropriate for adults, it is considered to be conservative for populations including 

children. [Note: For future exposure and risk assessments, HED will consider using a childspecific dose and endpoint for assessing the inhalation route. This change will not impact 

conclusions related to aggregate risk for children, which is based on exposure to thiamethoxam 

following application to turf.] No route-specific information is available for the inhalation 

toxicity of thiamethoxam. In the absence of a route-specific study, the NOAEL and LOAEL 

from an oral study have been used for risk assessment (i.e., inhalation toxicity is assumed to be 

equivalent to oral toxicity).

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

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. 

For adults, similar endpoints were selected for short- and intermediate-term exposures via the

dermal and inhalation routes, so they have been combined in the risk assessment. 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. For children, similar 

effects were chosen as the basis of the dermal and oral endpoints, and therefore these were 

combined. As noted in the endpoint selection rationale, HED did not choose child-specific 

endpoints for inhalation risk assessment, so inhalation exposure was not added to the combined 

dermal and incidental oral exposures.

4.5.3 Cancer Classification and Risk Assessment Recommendation

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

These findings served as the basis for HED’s initial conclusion that thiamethoxam was likely to 
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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. 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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4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Thiamethoxam for Use in Dietary and 

Non-Occupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/FQP

A Safety Factors

RfD, PAD, 

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

FQPA SF=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

FQPA SF =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 F1 generation 

males.

2-Generation reproduction study 

LOAEL = 3 (males), not determined 

(females) mg/kg/day based on sperm 

abnormalities in F1 males.

Incidental Oral 

(Short-term)

NOAEL= 

8.23 

mg/kg/day

UFA= 10x

UFH= 10x

FQPA SF =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

(Short-term)

(Adults)

Oral study 

NOAEL= 1.2

mg/kg/day

(Dermal 

Absorption = 

5%)

UFA= 10x

UFH= 10x

FQPA SF =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

(Short-term)

(infants/

children 1-6

yrs)

Dermal 

Study

NOAEL=60 

mg/kg/day

UFA= 10x

UFH= 10x

FQPA SF =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. 
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Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Thiamethoxam for Use in Dietary and 

Non-Occupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/FQP

A Safety Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Inhalation 

(Short-term)

Oral study 

NOAEL= 1.2 

mg/kg/day

(inhalation 

toxicity = 

oral toxicity)

UFA= 10x

UFH= 10x

FQPA SF =1x

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.

Cancer (oral, 

dermal, 

inhalation)

“Not Likely to be Carcinogenic to Humans” based on convincing evidence that a nongenotoxic 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). 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 4.5.4.2. 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 

= 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 toxicity = 

oral toxicity

UFA= 10x

UFH= 10x

FQPA SF =1x

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.
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Table 4.5.4.2. Summary of Toxicological Doses and Endpoints for Thiamethoxam for Use in Occupational 

Human Health Risk Assessments.

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). 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.

5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile

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 

for purposes of tolerance enforcement are the combined residues of thiamethoxam and 

clothianidin (CGA-322704). Clothianidin is an active ingredient in its own right and its database 

shows that it has a different toxicological profile than that of thiamethoxam. Therefore, HED 

conducts separate risk assessments for thiamethoxam and clothianidin, taking into account that 

uses of thiamethoxam have the potential to affect the risk assessment for clothianidin.

For a complete discussion of metabolism in crops and livestock, including chemical names and 

structures, see the Residue Chemistry Summary Document (M. Doherty, D281702, March 2007).

5.1.1 Summary of Plant and Animal Metabolism Studies

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)

The metabolism of thiamethoxam in crops generally involves: (i) opening of the oxadiazine ring 

by hydrolysis; (ii) loss of the nitro group; (iii) hydrolysis of the guanidine moiety to urea 

derivatives; (iv) cleavage of the N-C bridge between the two ring systems; and (v) 

N-demethylation of the oxadiazine ring or its derivatives. Initial hydrolysis of the oxadiazine 

ring of thiamethoxam yields CGA-322704, which is a major metabolite in corn, pears, rice and 

wheat. The metabolite CGA-322704 can then either: (i) lose its nitro group to form NOA421275 (a major metabolite in corn); (ii) undergo N-demethylation to yield CGA-265307; or (iii) 

be cleaved at the N-C bridge to form NOA-405217 and the thiazole ring metabolites CGA359683 and CGA-349208. Alternatively, thiamethoxam may initially lose its nitro group to form 

NOA-407475, and then undergo hydrolysis of the oxadiazine ring to form NOA-421275, or 

oxidation of the oxadiazine ring to form CGA-355190.
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The nature of the residue in livestock is adequately understood based on acceptable goat and hen 

metabolism studies. The metabolism of thiamethoxam in ruminants and poultry is similar. The 

major metabolic pathway involves hydrolysis of the oxadiazine ring to form CGA-322704 and 

subsequent demethylation to produce CGA-265307; loss of the nitro group from these two 

metabolites also yields NOA-421275 and NOA-421276. Several major metabolites (MU3, L14, 

and MU12) in both ruminants and poultry also result from the reduction of the nitro group in 

thiamethoxam or CGA-265307 to a hydrazine, and subsequent conjugation with acetic or 2-oxopropionic acids. Separation of the thiazole and oxadiazine rings was only a minor pathway in 

ruminants and poultry.

5.1.2 Summary of Environmental Degradation

Thiamethoxam is expected to be persistent and mobile in terrestrial and aquatic environments. 

Fate studies show that thiamethoxam is generally stable in soils and in water under neutral and 

acidic conditions. At high pHs, which are not likely to be encountered in the natural 

environment, hydrolysis of thiamethoxam is likely to occur. These fate properties suggest that 

thiamethoxam has the potential to move into surface water and shallow ground water.

5.1.3 Comparison of Metabolic Pathways

Metabolism studies with thiamethoxam have been submitted on corn, cucumber, lettuce, pear, 

potato, rice, tobacco, and wheat. The studies on cucumber, lettuce, pear, and rice reflected foliar 

applications, and the studies on corn, potato, and wheat reflected seed treatment and/or soil 

drench applications. The tobacco studies included soil and foliar treatments. The metabolic 

pathways were similar for the different plants.

Thiamethoxam metabolism in rats is similar to that observed in the goat and in poultry. 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.

5.1.4 Residues of Concern Summary and Rationale

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

Residue Chemistry Memo D252021, 3/30/00, G.J. Herndon

Residue Chemistry Memo D265079, 5/8/00, G.J. Herndon

Residue Chemistry Memo D281702, 4/17/07, M. Doherty

HED’s Metabolism Assessment Review Committee (MARC) concluded that the majority of any 

toxicity associated with thiamethoxam and its metabolites was due to the presence of the N-nitro 

group. The MARC concluded that metabolites that did not contain this N-nitro group (including 
Thiamethoxam Human Health Risk Assessment DP No. 402441

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those that contain only the chlorothiazole ring) would exhibit less toxicity and therefore would 

not need to be regulated.

 

In target crops, ruminant muscle and milk the parent and the CGA-322704 metabolite (i.e., 

clothianidin) accounted for a high percentage of the identified radioactivity. Other metabolites 

occurring at significant levels did not contain the N-nitro group. The situations in poultry and 

rotational crops were similar with the exception that the MARC recommended the additional 

metabolite CGA-265307 be analyzed in any laying hen feeding study or field rotational crop 

studies. 

With respect to drinking water, the fate data indicated that the parent molecule is stable in water 

at neutral and acidic pHs, but at elevated pHs was likely to be hydrolyzed. Major metabolites (> 

10% of applied parent compound) included CGA-355190, CGA-353968, and NOA-405217. The 

parent is also quite stable in soil (half lives of about 300 - 350 days). The Committee was not 

concerned with the relative levels of the metabolites CGA-355190 and CGA-353968 due to the 

absence of the N-nitro group. NOA-405217 contained the N-nitro group, but was only a 

significant metabolite under hydrolysis at pH 9. The MARC concluded that the residue of 

concern in drinking water is the parent thiamethoxam considering its stability in water and soil. 

However, EFED should inform the Committee in the future if additional data show levels of 

other nitro-containing compounds (e.g., CGA-322704, CGA-282149, CGA-265307, NOA405217, NOA-404617) comparable to that of the parent. For example, in areas where soil pH is 

8 or higher, EFED should consult with the Committee if they conclude that levels of NOA405217 in water approach those of parent thiamethoxam.

Based on the above rationale, HED concludes that the residues of concern for thiamethoxam are 

as outlined in table 5.1.4 below. In the case of rotational crops, tolerances are not needed with 

the plant-back intervals on current labels and residues on these crops do not need to be 

considered in dietary risk assessment.

Table 5.1.4. 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 Food Residue Profile

A tolerance for coffee already exists, but new formulations are being proposed for use on coffee 

grown outside the US, and these formulations result in higher residue levels. The submitted 
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residue chemistry data are adequate to support increasing the tolerance to 0.20 ppm. The 

residues on coffee were, in most cases, quantifiable and the residue levels were not especially 

sensitive to the PHI, but did decline with longer PHIs.

Condition-of-registration data were submitted for use of the Cruiser 70 WS formulation as a seed 

treatment for carrots, leafy vegetables, except Brassica (Group 4), and Brassica leafy greens 

(Group 5B) at a seasonal application rate of 0.266 lbs ai/A. In 2007 HED had recommended for 

tolerances based on applications of thiamethoxam that did not exceed 0.172 lbs. ai/A and a 3-day 

PHI (Group 4 and Subgroup 5B). HED had requested the condition-of-registration data to reflect 

the higher application rate. The submitted residue data for leaf lettuce indicate that the current 

tolerance of 4.0 ppm for Crop Group 4 is adequate. Data are no longer required for carrots and 

Brassica leafy greens because the seed treatment use rate is being limited by the thiamethoxam 

labels to no more than 0.22 lbs. ai/A, and the PHIs for the seed treatments are much longer than

the 3-day minimum specified for foliar use.

For a complete discussion of metabolism in crops and livestock, including chemical names and 

structures, see the Residue Chemistry Summary Document (M. Doherty, D281702, March 2007).

5.3 Water Residue Profile

Reference: EFED Memo D373378, C. Koper, 20 May 2010

 EFED Memo D391528, C. Koper, 28 July 2011

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 

(D391528, C. Koper, 28 July 2011; and D373378, C. Koper, 20 May 2010), and incorporated 

directly into the dietary assessments. These modeled drinking water residue results are 

summarized in Table 5.3. 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. 

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

on other crops. 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).
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For groundwater, based on the highest annual use rate for dry bulb onions and the 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 and chronic scenario EDWCs in surface water (0.13177 and 0.01131 ppm, 

respectively) were 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/. 

Table 5.3. 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)

131.771,2 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
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Table 5.3. 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)

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 a percent cropped area (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.

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 protective of what actual exposures are likely to be.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Reference: D406562, D. McNeilly, 15 Nov 2012.

The acute assessment is based on tolerance level residues of thiamethoxam/clothianidin (the 

tolerance is for combined residues). The chronic analysis is based on tolerance level/proposed 

tolerance levels and/or average field trial (D406562, D. McNeilly, 15 Nov 2012) residues and 

assumes 100% crop treated for all commodities.

The drinking water residues discussed above were incorporated directly 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 (rice tail water) having higher values in this case.
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5.4.2 Percent Crop Treated Used in Dietary Assessment

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 D406562, D. McNeilly, 15 Nov 2012) 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.

5.4.3 Acute Dietary Risk Assessment

The DEEM-FCIDTM analyses estimate the dietary exposure of the US population and various 

population subgroups. The results reported in Table 5.4.6 are for the general U.S. population, all 

infants (<1 year old), children 1-2, children 3-5, children 6-12, youth 13-19, females 13-49, 

adults 20-49, and adults 50-99 years. The acute results summarized in Table 5.4.6 are for the 

95th percentile of exposure. 

Based on highly conservative assumptions, acute dietary (food and water) risk estimates at the 

95th percentile of exposure are less than or equal to 9.4% of the acute population-adjusted dose 

(aPAD) for all population subgroups. Generally, HED is concerned when risk estimates exceed 

100% of the PAD; therefore, all acute dietary risk estimates are below HED’s level of concern 

(LOC).

5.4.4 Chronic Dietary Risk Assessment

Chronic dietary (food and water) risk estimates are less than or equal to 44% of the chronic 

population-adjusted dose (cPAD) for all population subgroups (Table 5.4.6). Generally, HED is 

concerned when risk estimates exceed 100% of the PAD; therefore, all acute and chronic dietary 

risk estimates are below HED’s level of concern (LOC).

Generally, HED is concerned when risk estimates exceed 100% of the PAD; therefore, all 

chronic dietary risk estimates are below HED’s level of concern (LOC).

5.4.5 Cancer Dietary Risk Assessment

Thiamethoxam has been classified as “not likely to be carcinogenic to humans.” As such, the 

risk of cancer from thiamethoxam is not of concern.
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5.4.6 Summary Table

Table 5.4.6. Summary of Dietary (Food + Drinking Water) Exposure and Risk Estimates for Thiamethoxam.

Population Subgroup2 aPAD, 

mg/kg/day

Acute Estimates (95th

Percentile)1

cPAD, 

mg/kg/day

Chronic Estimates

Exposure, 

mg/kg/day

Risk,

% aPAD

Exposure, 

mg/kg/day

Risk, % 

cPAD MOE3

U.S. Population 0.35 0.017192 4.9 0.012 0.002663 22 3100

All infants (< 1 year)20.35 0.027915 8.0 0.012 0.002560 21 3200

Children 1-2 yrs 0.35 0.032993 9.4 0.012 0.005286 44 1600

Children 3-5 yrs 0.35 0.027008 7.7 0.012 0.004446 37 1900

Children 6-12 yrs 0.35 0.017406 5.0 0.012 0.002767 23 3000

Youth 13-19 yrs 0.35 0.012830 3.7 0.012 0.002026 17 4100

Adults 20-49 yrs 0.35 0.016102 4.6 0.012 0.002502 21 3300

Adults 50-99 yrs 0.35 0.015572 4.5 0.012 0.002585 22 3200

Females 13-49 yrs 0.35 0.016655 4.8 0.012 0.002585 22 3200

1 - Results for the 99th and 99.9th percentile are reported in Attachment 2. 

2 - The population subgroups used in the aggregate risk assessment are bolded.

3 - MOEs are based on the short-term incidental oral NOAEL of 8.23 mg/kg/day.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

6.1 Residential Handler Exposure

Reference: Thiamethoxam: Occupational and Residential Exposure Assessment for Section 3 Registration,

 M. Collantes; July 24, 2009; D359207

 D406746, M. Crowley, Dec 4, 2012

There are no new residential uses associated with this action. For the purpose of evaluating 

aggregate (dietary and non-dietary) exposure for the current regulatory action, the existing 

residential uses have been reassessed to reflect updates to HED’s 2012 Residential SOPs2along 

with policy changes for body weight assumptions. The revisions to the residential exposure

estimates impact the human health aggregate risk assessment of the tolerance assessment for 

imported coffee.

Thiamethoxam has existing residential uses on turf and indoor environments (crack-and-crevice

uses). Residential handler exposures are expected from these uses and are expected to be shortterm (i.e., up to 30 days) in duration. Based on HED’s revised “Residential SOPs,” no risks of 

concern were identified for the existing residential uses of thiamethoxam. A summary of the

residential handler risk estimates is provided in Table 6.1.

Table 6.1. Residential Handler Non-cancer Exposure and Risk Estimates for Existing Residential Uses of Thiamethoxam.

Scenario Formulation Equipment

Dose

(mg/kg-day) MOE

Dermal Inhalation Dermal Inhalation Combined

Lawns/Turf

WDG Manually-pressurized handwand 0.00033 0.00011 3,600 11,000 2,700

Backpack 0.00033 0.00011 3,600 11,000 2,700

Granule Rotary / push-type spreader 0.000073 0.0000047 16,000 260,000 15,000

Belly grinder 0.0018 0.0000039 670 310,000 670

 

2 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
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Table 6.1. Residential Handler Non-cancer Exposure and Risk Estimates for Existing Residential Uses of Thiamethoxam.

Scenario Formulation Equipment

Dose

(mg/kg-day) MOE

Dermal Inhalation Dermal Inhalation Combined

Indoor 

(crack-andcrevice)Liquid Manually-pressurized handwand 0.00021 0.000067 5,700 18,000 4,300

6.2 Post-Application Exposure

There is a potential for exposure from entering areas previously treated with thiamethoxam. 

Post-application residential scenarios were reassessed using the HED’s 2012 Residential 

Standard Operating Procedures (SOPs)2. The level of concern (LOC) for the margin of exposure 

(MOE) is 100 for all residential uses. All post-application dermal and oral scenarios associated 

with turf and indoor crack and crevice uses resulted in MOEs greater than 100 and are not of 

concern (Table 6.2).

 

Table 6.2. Residential Post-application Non-cancer Exposure and Risk Estimates for Existing Residential Uses of 

Thiamethoxam.

Use/Target Lifestage Post-application 

Exposure Scenario

Dose

(mg/kg-day) MOE3

Combined Routes

(X indicates included 

in Combined MOE)

Combined 

MOE

Turf

(spray application)1

Adult Dermal

High-contact 

(playing) 0.0024 500 --

NA Mowing 0.000049 25,000 --

Golfing 0.00019 6,400 --

Child 11<16 Dermal Mowing 0.000048 25,000 NA Golfing 0.00019 6,400 --

Child 6<11 Dermal Golfing 0.00022 5,400 -- NA

Child 1<2

Dermal (high-contact 

play) 0.082 740 X

Hand to Mouth 0.0017 4,900 X 640

Object to Mouth 0.00005 160,000 --

Incidental Soil Ingestion 9.0E-06 910,000 --

Indoor

(crack-and-crevice)

Adult

Dermal (playing on 

carpet)2 0.00049 2,500 X

2500

Inhalation 9.1E-07 1,300,000 X

Child 1<2

Dermal (playing on 

carpet)3 0.0081 7,400 X

Inhalation 3.4E-07 360,000 -- 3500

Hand to Mouth (playing 

on carpet)2 0.0012 6,800 X

1 Risk estimates are based on the maximum day-of-application value from a submitted turf transferable residue study (MRID 

46402915) conducted at the maximum application rate. Risks from liquid spray applications are presented and are considered 

health-protective of granule formulation uses as most measured TTR values for granule formulations were < LOD.

2 Risk estimates presented in this table are from contacting treated carpets only; risks from contacting other surfaces are lower.

3 MOEs are for short-term exposures only.
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6.3 Residential Risk Estimates for Use in Aggregate Assessment

In the previous 2007 thiamethoxam residential assessment, a combined residential assessment 

was performed for turf dermal and oral post-application 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 crevice use. This re-assessment indicates that exposures and risks for children are greater for 

the turf use, rather than the indoor (crack and crevice) use. Therefore, the turf exposure

estimates should be used in an aggregate assessment in order to be protective.

Table 6.3. Recommendations for the Residential Exposures for the Thiamethoxam Aggregate Assessment.1

Lifestage

Handler Exposure 

(mg/kg/day)2

Residential 

Handler 

Total 

Exposure 

(mg/kg/day)3

Residential 

Handler 

Total MOE

Post-Application Exposure 

(mg/kg/day)4

Residential Postapplication MOE5

Dermal Inhalation Dermal Inhalation Oral

Short-/Intermediate-Term

Adult 0.0018 0.0000039 0.0018 670 0.0024 N/A N/A 500

Child 1<2 N/A 0.082 N/A 0.0017 640

1 Bolded risk estimates should contribute to the residential exposure portion of the aggregate assessment. 

2 Residential Handler Dose = the highest handler dose for each applicable lifestage of all scenarios assessed from Table 6.1 (i.e., belly grinder). 

Total = dermal + inhalation. 

3 Residential Handler MOE = the MOEs associated with the highest doses identified in Table 6.1 (i.e., belly 

grinder). Total = 1/ (1/Dermal MOE) + (1/Inhalation MOE).

4 Residential Post-application Dose = the highest post-application dose for each applicable lifestage of all scenarios assessed from Table 6.2

(adults: turf post-application; children 1< 2: turf post-application). Total = dermal + inhalation + incidental oral, where applicable.

5 Residential Post-application MOE = the MOEs associated with the highest doses identified in Table 6.2 (adults: turf post-application; children 

1< 2: turf post-application). Total = 1/ (1/Dermal MOE) + (1/Inhalation MOE) + (1/Incidental oral MOE).

HED combined non-dietary sources of post-application exposure to obtain an estimate of 

potential combined exposure which should be used for the aggregate assessment. These 

scenarios consisted of adult and toddler dermal post-application exposure and oral (hand-tomouth) exposures for children 1 to 2 years of age. All post-application scenarios resulted in 

combined MOEs greater than 100 and were not of concern to HED.

6.4 Residential Bystander Post-application Inhalation Exposure

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

assessment was not performed at this time for the agricultural thiamethoxam uses primarily 

because of the low acute inhalation toxicity (Toxicity Category IV) and low vapor pressure (6.6

x 10-9 mmHg). However, volatilization of pesticides may be a source of post-application 

inhalation exposure to individuals nearby pesticide applications. The Agency sought expert 

advice and input on issues related to volatilization of pesticides from its Federal Insecticide, 

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

received the SAP’s final report on March 2, 20103. The Agency is in the process of evaluating 

the SAP report and may, as appropriate, develop policies and procedures to identify the need for 

and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's 

risk assessments. If new policies or procedures are developed, the Agency may revisit the need 

for a quantitative post-application inhalation exposure assessment for the existing uses of 

thiamethoxam.

 

3 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
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Note, however, that inhalation exposure from volatilization of thiamethoxam following indoor 

uses was assessed and no risks of concern were identified.

6.5 Spray Drift

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

This is particularly the case with aerial applications, but, to a lesser extent, could also be a 

potential source of exposure from ground application methods employed for thiamethoxam. The 

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

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

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

4

. On a 

chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial 

applications that must be placed on product labels/labeling. The Agency has completed its 

evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. 

pesticide registrants, and is developing a policy on how to appropriately apply the data and the 

AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast 

and ground hydraulic methods. After the policy is in place, the Agency may impose further 

refinements in spray drift management practices to reduce off-target drift with specific products 

with significant risk estimates associated with drift.

Note that an application rate of 0.266 lb ai/acre was used in the updated assessment of the 

existing lawn/turf registration to estimate post-application residential exposure of children. As 

this rate is equal to or higher than those from other thiamethoxam uses, exposures resulting from 

direct application to lawns/turf are likely protective of any exposure via spray drift from other 

thiamethoxam uses.

7.0 Aggregate Exposure/Risk Characterization

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

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

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

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

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure.

7.1 Acute Aggregate Risk

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 5.4.6. As noted in that section, the acute risk estimates are well 

below HED’s level of concern for all population subgroups.

 

4 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm 
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7.2 Short-Term Aggregate Risk

References: D375247, D. McNeilly, 3 May 2010

 D359207, M. Collantes; 24 July 2009

 D406746, M. Crowley, Dec 4, 2012

Short-term residential exposures (1 to 30 days of continuous exposure) to thiamethoxam may 

occur. Estimates indicate that the turf scenario has higher exposure for both adults and children 

than the exposure levels in indoor (crack and crevice) scenario (Table 6.2) and that for adults, 

post-application exposure may be greater than handler exposure (Tables 6.1 and 6.2). Therefore, 

exposure estimates resulting from entering turf areas previously treated with a thiamethoxam 

product are the focus of the short-term aggregate risk estimates. Exposures related to turf

activities (Table 6.3) have been combined with chronic dietary exposure estimates (as an 

estimate of background dietary exposure, Table 5.4.6) to assess the worst-case short-term 

aggregate exposure. The short-term aggregate MOEs range from 430 to 460 (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

Residential Combined 

MOE2

Total Short-Term

Aggregate 3

Adult 3100 500 430

Children 1<2 years of age 1600 640 460

1 Dietary Aggregate MOE = Incidental Oral NOAEL (8.23 mg/kg/day) ÷ Chronic Dietary (Food + Water) Exposure 

(mg/kg/day; from Table 5.4.6). Values are rounded to 2 significant figures.

2 Turf exposure (which has higher exposure than indoor crack and crevice) from Table 6.2. 

3 Total Aggregate MOE = 1/[(1/MOEDietary) + (1/MOEResidential Combined))]. Values rounded to 2 significant figures.

7.3 Intermediate-Term Aggregate Risk

Intermediate-term exposures (30 to 180 days of continuous exposure) are not expected from the 

turf and/or indoor uses of thiamethoxam.

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 5.4.6. As noted in that section, the chronic risk estimates are 

below HED’s level of concern for all population subgroups.

7.5 Cancer Aggregate 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.
Thiamethoxam Human Health Risk Assessment DP No. 402441

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8.0 Cumulative Exposure/Risk Characterization

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

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

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

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

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

of the neonicotinoids is neurotoxic, the most sensitive regulatory endpoint for clothianidin is 

based on unrelated effects in mammals, including changes in body and thymus weights, delays in 

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

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

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

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

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

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

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

the policy statements concerning common mechanism determinations, and procedures for 

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

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

Note that because clothianidin is a major metabolite of thiamethoxam, EPA has to consider the 

impact of thiamethoxam uses on the clothianidin risk assessment. In this case, clothianidin has a 

registered use on coffee and residues from that direct use are expected to be greater than those 

coming from thiamethoxam; therefore, HED has not conducted a new risk assessment for 

clothianidin. Furthermore, labeling for formulations containing either of these compounds 

specifies that other neonicotinoid insecticides are not to be applied during the growing season 

(i.e., a crop treated with clothianidin will not be treated with thiamethoxam). Given that, in 

combination with the assumption of 100% crop treated for both the acute and chronic dietary 

assessments, obviates the need to do a combined assessment for crops with approved uses of 

both clothianidin and thiamethoxam.

9.0 Occupational Exposure/Risk Characterization

Not applicable for an import tolerance on coffee.
Thiamethoxam Human Health Risk Assessment DP No. 402441

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10.0 References

References:

D389375, Dennis McNeilly, 15 Nov 2012. Thiamethoxam. Petitions for an Increased Tolerance, 

Use of New Formulations and a Higher Seasonal Application Rate on Imported Coffee, and 

Conditional Data for Leafy Vegetables (Group 4). Summary of Analytical Chemistry and 

Residue Data.

D406562, D. McNeilly, 15 Nov 2012. Thiamethoxam. Acute, and Chronic Aggregate Dietary 

(Food and Drinking Water) Exposure and Risk Assessments for the Use of Thiamethoxam on 

Imported Coffee Beans and Conditional Residue Data for Leaf Lettuce.

D406746. M. Crowley, Dec 4, 2012. Thiamethoxam: Revised Residential Exposure Assessment 

to Support an Amended Import Tolerance for Coffee.

TXR#: 0056482. Thiamethoxam, Summary of Hazard and Science Policy Council (HASPOC) 

Meeting of October 11, 2012: Recommendation on the need for a 28-day inhalation study.

D373378, Christopher M. Koper, 20 May 2010. Tier II Drinking Water Exposure Assessment to 

Establish a Tolerance of Thiamethoxam on Peanut and Alfalfa Seeds. 

D363202, Faruque Khan, April 7, 2009. Tier I Drinking Water Exposure Assessment to 

Establish Thiamethoxam Tolerances for Cranberry and Proposed New Use on Rice Seed 

Treatment

D382248, Shih-Chi Wang, 7 Dec 2010. Thiamethoxam: Occupational and Residential 

Exposure/Risk Assessment for Proposed Section 3 Registration for Use in Food/Feed Handling 

Establishments.

D329466, Michael Doherty, 22 May 2007. 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. 

D364256, Dennis McNeilly, June 30, 2009. 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. 

Attachments:

Attachment A: Toxicology Profile and Executive Summaries

Attachment B: International Residue Limit Status sheet
Thiamethoxam Human Health Risk Assessment DP No. 402441

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Attachment A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food and non-food uses for thiamethoxam are listed below. Use of the new 

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

Test Technical

Required Satisfied

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

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

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

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

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

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

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

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

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

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

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

870.3465 90-Day Inhalation..........................................................

Yes

Yes

Yes

No

No

Yes

Yes

Yes

No

*

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

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

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

Yes

Yes

Yes

Yes

Yes

Yes

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

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

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

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

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

Yes

No

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

Yes

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

Yes

*A 28-day repeated dose inhalation study is not required for the currently proposed use patterns. See HASPOC 

memo (TXR# 0052354) for details.
Thiamethoxam Human Health Risk Assessment DP No. 402441

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A.2 Toxicity Profiles

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 28-day Oral 

Toxicity –

Supplementary 

Range-finding 

Study rat (diet)

44703322 (1995)

ppm=0, 100, 1000, 

2500, 10000

(0/0, 8.04/8.69, 

81.7/89.3, 199/211, 

711/763 mg/kg/day 

(M/F))

NOAEL = 8.04/8.69 mg/kg/day

LOAEL = 81.7/89.3 mg/kg/day based on increased 

incidence of microscopic lesions of the kidney.

870.3100 90-Day Oral 

Toxicity - rat (diet) 

Acceptable/

guideline

44718703 (1996)

ppm=0, 25, 250, 1250, 

2500 & 5000

(0/0, 1.74/1.88, 

17.64/19.2, 85/93, 

168/182, 329/359 

mg/kg/day (M/F))

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 

Toxicity- mouse 

(diet) 

Acceptable/

guideline

44703323 (1996)

ppm=0, 10, 100, 1250, 

3500 & 7000

(0/0, 1.41/2.01, 

14.3/19.2, 176/231, 

543/626, 1335/1163 

mg/kg/day (M/F))

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 28-day Oral 

Toxicity – dog 

(diet)

Supplementary 

Range-finding 

Study

44703324 (1996)

ppm=0, 300, 1000, & 

3000

(0/0, 10.0/10/7, 

31.6/32.6, 47.7/43.0 

mg/kg/day (M/F))

NOAEL = 31.6/32.6 (M/F) mg/kg/day

LOAEL = 47.7/43.0 (m/F) mg/kg/day based on 

body weight loss; leukopenia and increased 

hematocrit, hemoglobin and erythrocyte count; 

increased plasma urea and creatinine; reduced 

thymus weight in males and females, increased 

thyroid weight in males and reduced brain
Thiamethoxam Human Health Risk Assessment DP No. 402441

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

Type of 

Study/Guide 

line

Study Title MRID Results

weight in females; and, histopathological 

changes in liver, thymus and spleen.

870.3150 13-Week Oral 

Toxicity- dog (diet)

Acceptable/

guideline

44718702 (1998)

ppm=0, 50, 250, 1000 

& 2500/2000 (after 

week 2 reduced to 

2000)

(0/0, 1.58/1.80, 

8.23/9.27, 32.0/33.9, 

54.8/50.5 mg/kg/day 

(M/F))

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).

870.3200 28-Day Dermal 

Toxicity - rat 

Acceptable/

guideline

44710402 (1996)

0, 20, 60, 250 & 1000 

mg/kg/day

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 

Toxicity- rat 

(gavage) 

Acceptable/

guideline

44718706 (1998)

44703329 (1995)

44703330 (1995)

0, 5, 30, 200 & 750 

mg/kg/day

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 

Toxicity- rabbit 

(gavage)

Acceptable/

guideline

44718705 (1998)

44703327 (1995)

44703328 (1995)

0, 5, 15, 50 & 150 

mg/kg/day

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) 

Acceptable/

guideline

46402904 (2004)

46402906 (2000)

(range-finding)

ppm=0, 20, 50, 1000 & 

2500

(mg/kg/day

F0 M=0, 1.2, 3.0, 

61.7,155.6

F1M=0, 1.5, 3.7, 74.8, 

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

Type of 

Study/Guide 

line

Study Title MRID Results

191.5

F0F=0, 1.7, 4.3, 84.4, 

208.8

F1F=0, 2.1, 5.6, 110.1, 

276.6)

(females) mg/kg/day

LOAEL = 3 (males), not determined (females) 

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) 

Acceptable/

guideline

44718707 (1998)

44703401 (1995)

(range-finding)

44703402 (1998)

46402902 (2006)

(PWG report)

ppm=0, 10, 30, 1000 & 

2500

(0/0, 0.61/0.80, 

1.84/2.37, 61.25/79.20, 

158.32/202.06 

mg/kg/day (M/F))

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) 

Acceptable/

guideline

44718704 (1998)

ppm=0, 25, 150, 750 & 

1250

(0/0, 0.70/0.79, 

4.05/4.49, 21.0/24.6, 

42.0/45.1 mg/kg/day 

(M/F))

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) 

Acceptable/

guideline

44703326 (1998)

ppm=0, 5, 20, 500, 

1250 & 2500

(0/0, 0.65/0.89, 

2.63/3.68, 63.8/87.6, 

162/215, 354/479 

mg/kg/day (M/F))

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

870.4300 Chronic/Carcinoge

nicity, 2-Year-rat 

(diet) 

Acceptable/

guideline

44718708 (1998)

ppm (M/F)=0/0, 10/10, 

30/30, 500/1000 

&1500/3000

(0/0, 0.41/0.48, 

1.29/1.56, 21.0/50.3, 

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 
Thiamethoxam Human Health Risk Assessment DP No. 402441

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

Type of 

Study/Guide 

line

Study Title MRID Results

63.0/155 mg/kg/day 

(M/F)

chronic tubular lesions in kidney in females.

no evidence of carcinogenicity

870.5100

870.5265

Gene Mutation in 

S. typhimurium and 

E. coli

Acceptable/

guideline

44710404 (1995) 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

Acceptable/

non-guideline 

(supplementary)

44968301 (1999) 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

Acceptable/

guideline

44710405

(1996)

No evidence of gene mutation when tested up to 

solubility limit.

870.5375 CHO Cell 

Cytogenetics

Acceptable/

guideline

44710403

(1996)

No evidence of chromosomal aberrations when 

tested up to cytotoxic or solubility limit 

concentrations.

870.5395 In vivo Mouse 

Bone Marrow 

Micronucleus 

Acceptable/

guideline

44710406 (1995) 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

Acceptable/

guideline

44710407

(1996)

Negative when tested up to precipitating 

concentrations.

870.6200a Acute 

Neurotoxicity 

Screening Batteryrat (gavage)

Acceptable/

guideline

44703320 (1997)

0,100, 500 & 1500 

mg/kg

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 

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 
Thiamethoxam Human Health Risk Assessment DP No. 402441

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

Type of 

Study/Guide 

line

Study Title MRID Results

higher mean average input stimulus value in the 

auditory startle response test (males only).

870.6200b Subchronic 

Neurotoxicity 

Study-rat (diet)

Acceptable/

guideline

44703325 (1998)

ppm (M/F)=0/0,10/10, 

30/30, 500/1000 & 

1500/3000

(0/0,0.7/0.7, 1.9/2.1, 

31.8/73.2, 95.4/216.4 

mg/kg/day

(M/F))

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)

Acceptable/

non-guideline

46028202 (2003)

46028201 (2003)

ppm= 0, 50, 400, 4000

(0/0, 4.3/8.0, 

34.5/64.0, 298.7/593.5 

mg/kg/day 

(gestation/lactation))

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 Studyrat

(gavage)

Acceptable/

guideline

44703532 (1996)

44703533 (1998)

low dose=0.5 mg/kg

high dose=100 mg/kg

Also: I.V., 0.5 mg/kg

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: 

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

44710408 (1998)

46161502 (2003)

Approximately 72% of administered dose excreted 

in the urine; 19% excreted in feces. Small but 
Thiamethoxam Human Health Risk Assessment DP No. 402441

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

Type of 

Study/Guide 

line

Study Title MRID Results

(gavage)

Supplementary/

non-guideline

46161505 (2002)

46161512 (2000)

(44710408)

males only: 118 

mg/kg/day, 14 days

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; 

In vivo; 

WG Formulation 

25% a.i.

unacceptable/

not upgradable

44703403 (1998)

Exposure duration

Estimates of dermal absorption were based on the 

sum of radioactivity in skin test site, urine, feces, 

blood, and carcass. After 24 hour exposure, dermal 

absorption estimate is 27%, which is the maximum 

observed for all dose groups.

870.7600 Dermal Absorption 

– rats;

2 in vivo studies 

using 21.1 or 

48.6% a.i.

Formulations; 

Acceptable/

Guideline

45200001 (2000)

3.64, 36.4 μg/cm3

Exposure duration?

Estimates of dermal absorption were based on the 

sum of radioactivity in skin test site, urine, feces, 

blood, and carcass. After 10 hour exposure, dermal 

absorption estimate is 5%, which is the maximum 

observed for all dose groups.

870.7800 Immunotoxicity -

mice

Acceptable/

Guideline

48547101 (2011)

ppm=0, 100, 1250, 

5000 

(0/0,37.7/36.7, 

461.6/433.9, 

2026/2024 mg/kg/day 

(M/F))

Systemic:

LOAEL = 2025 mg/kg/day based on decreased body 

weights and body weight gains in females.

NOAEL = 1250 ppm (461.6 mg/kg/day)

Immunotoxicity:

LOAEL = Not Determined

NOAEL = 5000 ppm (2025 mg/kg/day)

Non-guideline Hepatic Cell 

Proliferation -

mouse (diet)

Acceptable/

non-guideline

44703406 (1998)

ppm=100, 500 & 2500

(16/20, 72/87, 386/483 

mg/kg/day(M/F))

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 Study-rat, 

male only (diet)

Acceptable/

non-guideline

44703405 (1995)

ppm=0, 100, 1000, 

2500 & 10000

(0, 8, 82, 199, 711 

mg/kg/day)

NOAEL = 711 mg/kg/day (highest dose tested)

LOAEL = not established. Immunohistochemical 

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 
Thiamethoxam Human Health Risk Assessment DP No. 402441

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

Type of 

Study/Guide 

line

Study Title MRID Results

cell proliferation in male rats.

Non-guideline Special study to 

assess liver 

biochemistrymouse

Acceptable/

non-guideline

44703407 (1998)

doses

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.

Non-guideline Receptor binding 

study with 

thiamethoxam, 

imidacloprid, and 

nicotine: 

Interaction with 

mammalian 

nicotinic 

acetylcholine 

receptors

What is test 

system?

Acceptable/

non-guideline

46402911 (2004) 

doses

Thiamethoxam had low affinity and was essentially 

inactive in the binding assay

A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD) - - All Populations

Study Selected: Developmental Neurotoxicity Study—rat (OPPTS 870.6300)

MRID No.: 46028202, 46028201

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

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

 100 (UF)

A.3.3 Chronic Reference Dose (cRfD) All Populations

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 

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.
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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 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, female or both parents in the study, or to 

direct effects on the offspring. 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 the chronic dietary risk assessment.

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

 100 (UF)

A.3.4 Incidental Oral Exposure (Short- and Intermediate-Term)

Study Selected: 90-day Oral Toxicity — dog (OPPTS 870.3150)

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.
Thiamethoxam Human Health Risk Assessment DP No. 402441

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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.

A.3.5 Dermal Exposure Adults (Short- and Intermediate-Term)

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 

dermal route of exposure. Since an oral toxicity study was selected, a 5% dermal absorption 

factor is recommended. Protective of potential effects to females seen at higher doses in other 

studies

A.3.5 Dermal Exposure Children Age 1 to 6 Years (Short-Term)

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, short-term) 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.

A.3.6 Inhalation Exposure (Short- and Intermediate-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 
Thiamethoxam Human Health Risk Assessment DP No. 402441

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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 

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 significant post-application inhalation 

exposure to young children.

A.4.9 Immunotoxicity

870.7800 Immunotoxicity

In an immunotoxicity study (MRID 48547101), Thiamethoxam (99.0% a.i., Lot No. 

SGO7K699E) was administered in the diet to female B6C3F1 mice (10/dose) in two groups 

[antibody- forming cell (AFC) and natural killer cell (NKC)] at concentrations of 0, 100, 1250, 

or 5000 ppm for 28 consecutive days. The dose equivalents were 0, 37.7, 461.6, or 2026.6 

mg/kg/day for the AFC groups, and 0, 36.7, 433.9, or 2024.9 mg/kg/day for the NKC groups, 

respectively. For the AFC positive control group, animals received intraperitoneal injections of 

cyclophosphamide (50 mg/kg/day, 10 mL/kg) on Days 24-27. On Day 24, animals in the AFC 

groups were immunized with a suspension of sheep red blood cells (SRBC) by intravenous 

injection (7.5x107 SRBC/animal, 0.2 mL/animal dose volume). Humoral immunotoxicity was 

assessed for the AFC groups by an anti-SRBC antibody plaque-forming cell (AFC) assay. 

Animals in the NKC positive control group received a single intravenous injection of anti-asialo 

GM1 formulation (0.2 mL/animal) on Day 27. The NK cells activity was evaluated with a 51Cr 

release assay. All animals were evaluated for mortality, clinical signs, body weight changes, food 

consumption, and gross pathology. Liver and spleen weights for all animals were measured at 

necropsy; thymus weights were measured for animals in the NKC groups. 
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There were no test substance-related effects on mortality, clinical signs, food consumption, and 

gross pathology. Statistically significant decreases in mean body weight and body weight gain 

were seen in the 5000 ppm AFC and NKC groups. Decreased mean absolute spleen weights were 

observed in the 5000 ppm AFC and NKC groups while decreased relative spleen weights were 

observed in the 5000 ppm NKC group. Significantly decreased mean absolute thymus weight 

was observed in the 5000 ppm NKC group. The thymus weight was not reported in the AFC 

group. Significantly increased absolute liver weights were observed in the 1250 ppm AFC group 

and the 5000 ppm AFC and NKC groups. 
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Attachment B: International Residue Limits

Thiamethoxam (060109; 08/02/2012)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex3

40 CFR 180.565:

Plant/Livestock: (3-[(2-chloro-5-

thiazolyl)methyl]tetrahydro-5-methylN -nitro-4 H -1,3,5-oxadiazin-4-imine) 

and its metabolite CGA-322704 [ N -

(2-chloro-thiazol-5-ylmethyl)- N '-

methyl- N '-nitro-guanidine], 

calculated as the stoichiometric 

equivalent of thiamethoxam

3-[(2-chloro-5-

thiazolyl)methyl]tetrahy

dro-5-methyl-N-nitro4H-1,3,5-oxadiazin-4-

imine, including the 

metabolite ( E )-N-[(2-

chloro-5-

thiazolyl)methyl]-N'-

methyl-N"-

nitroguanidine

thiamethoxam

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

US Canada Mexico2 Codex3

Coffee beans 0.20 0.05 0.2

Completed: M. Negussie; 08/03/2012

1

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

not those proposed by the applicant.2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.3 * = 

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

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

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