Thiamethoxam Human Health Risk Assessment DP No. 402441

Page 3 of 49 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

................................ ................................ .......... 49Thiamethoxam Human Health Risk Assessment DP No. 402441

Page 4 of 49 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 organophosp hate, carbamate, and pyrethroid insecticides.

This risk assessment addresses the requested use of new formulations and higher maximum

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

formulation s and higher sea sonal application rates , Syngenta has requested a n 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

- of

registration 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 us e are much longer than the 3 days specified

for current foliar use s

.

Da tabases 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 reg istration 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 availa ble 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, toxicologica l effects are primarily in the liver, kidney, testes, and hematopoietic system (blood cellular system). In addition, developmental neurological effects were observed in

rats. The se developmental effect s are being used to assess risks associated with acut e 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 assess ment 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 e xposures 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.Thiamethoxam Human Health Risk Assessment DP No. 402441

Page 5 of 49 Based on the use pattern and the toxicological profile of thiamethoxam , HED selected endpoints

and doses for acute and ch ronic 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 exam ined the residue chemistry database for thiamethoxam. T here 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.

HE D 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 th e 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 standar d 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 sub jects 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 Huma n Subjects of Research (40 CFR Part 26) have been

satisfied.

2.0 HED Recommendations

HED recommend s for increasing the existing tolerance for thiamethoxam in/ on coffee to 0.2 0

ppm to allow the use of new thiamethoxam formulations and higher application rate s on foreign

grown coffee . The specific tolerance recommendations are discussed in 2.2, and label

modifications are discussed in section 2.3

.

2.1 Data Deficiencies

None.Thiamethoxam Human Health Risk Assessment DP No. 402441

Page 6 of 49 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 th e 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 toleranc e 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 0.2 0 Coffee, bean, green 1
Existing tolerance level is 0.05 ppm

1

- There are no US registration s 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 In ternational 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 incre asing the tolerance to 0.2 0 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 In troduction

Thiamethoxam is a broad

- spectrum nitroguanidine insecticide which belongs to class of compounds known as the neonicotinoids (Group 4A). It has activity against sucking andThiamethoxam Human Health Risk Assessment DP No. 402441

Page 7 of 49 chewing insects, such as leafhoppers and potato beetles, as well as other insect pe sts, 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 sy stem, 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 Che mical Identity

The nomenclature f

o r 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 C 8 H 10 ClN 5 O 3 S

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

- oxadiazin

4

- 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 ClothianidinThiamethoxam Human Health Risk Assessment DP No. 402441

Page 8 of 49 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/cm 3

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, pK

a No dissociation within the pH range 2

– 12
Octanol/water partition coefficient, Log(K OW ) 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 Thi amethoxam 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.Thiamethoxam Human Health Risk Assessment DP No. 402441

Page 9 of 49 Table 3.3 . Summary of Directions for Use of Thi amethoxam 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. Ver d adero 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 a i/A) of thiamethoixam can be appli ed 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 i n this s ummary d ocument

.

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. Ther e are no new residential uses of thiamethoxam, but there are existing e xposure s 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

occu pational 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 f ields.

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 Conside ration 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 Justi ce 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 var iety 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 allThiamethoxam Human Health Risk Assessment DP No. 402441

Page 10 of 49 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 subgroup s 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 fa rm 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 o f 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 wer e 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 S cience 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 i nhalation

risk s for thiamethoxam w ere 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

- ex amine 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 differencesThiamethoxam Human Health Risk Assessment DP No. 402441

Page 11 of 49 observed in absorption, distribution, or e limination between sexe s
, low or high dose s, single or repeated dosing, or the position of the radiolabel in metabolism studies . The highest tissue

concentrations are in skelet al 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, approximate ly 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 nitrogua nidine 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 3 22704; 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 fracti on 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 sk in 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 c arcass 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 Toxicologica l 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 rece ptors 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,Thiamethoxam Human Health Risk Assessment DP No. 402441

Page 12 of 49 thiamethoxam appears to function at a different location 1 . 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 wi th 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 rel ated 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 studi es 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).

L iver effects were observed in the rat and mouse across sexes and routes of administration. In

th e 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 expos ure results in an increase in the

incidence of foci in females. T here 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 observe d 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 incid ence of foci, and increased mitotic activity (chronic). Male mice are

more sensitive to the liver effects than females. Chronic dosing result s in the development of benign and malignant liver tumors in both sexes and a n increase in the number of animals with multiple tumors . H owever, 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 clea r 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 i ncreased 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

- 69Thiamethoxam Human Health Risk Assessment DP No. 402441

Page 13 of 49 Testicular effects are observed in the rat and dog. In 2

- generation reproduction studies in the

rat , testicular effects are only observed in the F 1 males, not in parental or F 2 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. Wh ile 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 sp ermatic 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 o r 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 (hyalin e changes in the renal tubules) have been attributed to accumulation of α 2u - globulin, a protein that is unique to male rats, in the proximal convoluted tubules. The observed pathology is consistent
with α 2u - globulin mediated kidney toxicity. Collectively , special studies submitted demonstrate
an increase in accumulation of α 2u - 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 r at, 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 a nd 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 mea n 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 t he 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. T he 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 interfere s 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 ac ute lethality studies, technical thiamethoxam is slightly toxic to rats andThiamethoxam Human Health Risk Assessment DP No. 402441

Page 14 of 49 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 I V). It is not irritating to the skin and minimally irritating to the eye, and is not a dermal sensitizer.

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

TXR# 0056482

. Thiamethoxam . S ummary of Hazard and Science Policy Council (HASPOC) Me eting 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 l ow based on the clear NOAEL s for the offspring effect s and the selection

of regulatory doses that are protectiv e of th o se 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 pot ential 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 Haza rd 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 ora l 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 PO D 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 o f 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 N eurotoxicity

In the acute neurotoxic ity study, there were indications of neurotoxicity at the study LOAEL of 500 mg/kg including drooped palpebral closure, lower rectal temperature, increased forelimbThiamethoxam Human Health Risk Assessment DP No. 402441

Page 15 of 49 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, uncoordi nated 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 n o 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 tr eatment

- 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 neur otoxicity 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 obse rved 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/d ay). 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 e ffects 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, r ather, secondary to a pituitary adenoma.

4.4.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r 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 e ffects 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 s evere 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.Thiamethoxam Human Health Risk Assessment DP No. 402441

Page 16 of 49 There is evidence of increased quantitative susceptibility for male pups in 2 two

- genera tion 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 bo dyweight gain during the entire lactation period. The reproductive effects in males appear in the F 1 generation in the form of increased incidence and severity of testicular tubular atrophy. These data are considered to be evidence of increased quantitat ive 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 two

generation reproduction study; increased incidence of hyaline change in the renal tubes were

observed of the F 0 and F 1 males at 61.25 mg/kg/day (NOAEL 1.84 mg/kg/day) while tubular atrophy was found in the F 1 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, t he 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 Datab ase

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

T he dietary exposure assessments are based on high

- end

, health protective residue levels and processing factors , both of which account for parent and metabolite s 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 D eparture Selections

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

and doses for acute and ch ronic 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.Thiamethoxam Human Health Risk Assessment DP No. 402441

Page 17 of 49 4.5.1 Dose

- Response Assessment

Acute Dietary Endpoint ( All Population s ): The endpoint used for establishing the acute population

- adjuste d 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. T his 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 population

adjusted 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 F 1 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 develop ing 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 intr a

species variability, and a 1x FQPA SF). The effects observed at the LOAEL of 33.9 mg/kg/day

based on s lightly prolonged prothrombin times and decreased plasma albumin and A/G ratio (both sexes); decreased calcium levels and ovary weights and delayed ma turation 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

e ffec t s w ere 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 L OC is an MOE of 100 (10x for inter

- species extrapolation, 10x for intra

species 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 selec ted 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.Thiamethoxam Human Health Risk Assessment DP No. 402441

Page 18 of 49 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,

an d 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 sele cted 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 select ed, 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 b ecause 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

childr en

. [Note: For future exposure and risk assessments, HED will consider using a child

specific 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, s imilar endpoints were selected for short

- and inter mediate

- term exposures via the dermal and inhalation routes, so they have be en 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 thiametho xam 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 toThiamethoxam Human Health Risk Assessment DP No. 402441

Page 19 of 49 be carcinogenic to humans; furthermore, HED recommended using a linear low dose extrapolation for assessing cancer risk. The registrant subs equently 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, hepatoto xicity, 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 metab olites, 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 alon g 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 sensiti vity 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 thiamet hoxam 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 amo unts 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.Thiamethoxam Human Health Risk Assessment DP No. 402441

Page 20 of 49 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 UF A = 10x

UF H = 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) UF A = 10x

UF H = 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 F 1 generation

males.

2

- Generation reproduction study LOAEL = 3 (males), not determined (females) mg/kg/day based on sperm

abnormalities in F 1 males.

Incidental Oral ( Short

- term ) NO AEL=

8.23 mg/kg/day UF A = 10x

UF H = 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 ( D ermal

A bsorption = 5%) UF A = 10x

UF H = 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 F 1 generation

males.

2

- Generation reproduction study LOAEL = 3 (males), not determined (females) mg/kg/day based on sperm

abnormalities in F 1 males.

Dermal ( Short

- term ) (infants/

children 1

- 6 yrs) Dermal

Study

NOAEL=60 mg/kg/day UF A = 10x

UF H = 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 f emales.Thiamethoxam Human Health Risk Assessment DP No. 402441

Page 21 of 49 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) UF A = 10x

UF H = 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 F 1 generation

males.

2

- Generation reproduction study LOAEL = 3 (males), not determined (females) mg/kg/day based on sperm

abnormalities in F 1 males. Cancer (oral, dermal, inhalation) “Not Likely to be Carcinogenic to Human s” 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 ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = 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

Intermediate

term (1

- 6 months) Oral study NOAEL=

1.2 mg/kg/day (Dermal Absorption = 5%) UF A = 10x

UF H = 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 F 1 generation males.

2

- Generation reproduction study LOAEL = 3 (males), not determined (females) mg/kg/day based on sperm

abnormalities in F 1 males.

Inhalation

Short

- term (1

- 30 days)

and

Intermediate

term (1

- 6 months) Oral study NOAEL=

1.2 mg/kg/day (inhalation toxicity = oral toxicity UF A = 10x

UF H = 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 F 1 generation males.

2

- Generation r eproduction study LOAEL = 3 (males), not determined (females) mg/kg/day based on sperm

abnormalities in F 1 males.Thiamethoxam Human Health Risk Assessment DP No. 402441

Page 22 of 49 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 = uncertain ty factor. UF A = extrapolation from animal to human (interspecies). UF H = 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 tox icological 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 comp lete 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

Reference s : 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

derivati ves; (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 NOA

421275 (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 CGA

359683 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

.Thiamethoxam Human Health Risk Assessment DP No. 402441

Page 23 of 49 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 b oth 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

- oxo

propionic acids. Separation of the thiazole and oxadiazine rings was only a minor pat hway 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 ne utral 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 s hallow 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

ap plications, and the studies on corn, potato, and wheat reflected seed treatment and/or soil drench applications. The tobacco studies included soil and foliar treatments. T he metabolic pathways were similar for the different plants.

Thiamethoxam metabol ism 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 r anged 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 metabo lites was due to the presence of the N

- nitro group. The MARC concluded that metabolites that did not contain this N

- nitro group (includingThiamethoxam Human Health Risk Assessment DP No. 402441

Page 24 of 49 those that contain only the chlorothiazole ring) would exhibit less toxicity and therefore would not need to be regu lated.

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

- nitr o 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 drinkin g 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, NOA

405217, 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 NOA

405217 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 submittedThiamethoxam Human Health Risk Assessment DP No. 402441

Page 25 of 49 residue chemistry data are adequate to support increasing the tole rance to 0. 2 0 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

t olerances 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 lea f 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 l bs. ai/A

, and the PHIs for the seed treatments are much longer than

the 3

- day minimum s pecified for foliar use

.

For a complete discussion of metabolism in crops and livestock, including chemical names and structures, see the Residue Chemistry Summary Docu ment (M. Doherty, D281702, March 2007).

5.3 Water Residue Profile

Reference: EFED Memo D3 73378 , 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 D3 73378 , C. Koper, 2 0 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, d irect, all sources” and “water, indirect, all sources.” The estimated drinking water concentrations (EDWCs) in surface water are 0.13 177 ppm and 0.011 31 ppm for acute and chronic scenarios, respectively. Typically, HED uses the higher of the surface or

g roundwater estimates for each duration when assessing dietary risk.

The EDWC s w ere incorporated into the acute and chronic thiamethoxam assessment s

. 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 Ap ril 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 th e 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)

.Thiamethoxam Human Health Risk Assessment DP No. 402441

Page 26 of 49 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 compar ed to 4.14 μg/L reported for grap es 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. Sin ce 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 EDWC s in surface water (0.131 77 and 0.01131 ppm
, respectively ) w ere obtained via exposure modeling which uti lized 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/w ater/

.

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) 131.77 1,2 11.31 1,3 11.31 1,3

Cranberry (0.188 lbs ai/A/year) 54.75 2 4.50 3 4.50 3

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 0.34Thiamethoxam Human Health Risk Assessment DP No. 402441

Page 27 of 49 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 s etting. 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 l evels. The maximum observed residue levels from any monitoring well were 1.0 ppb for thiamethoxam and 0.73 ppb for CGA

322704. These values are well below the modeled estimates summarized above, indicating that the modeled estimates are protective of wha t actual exposures are likely to be.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Reference: D 406562

, D . M cNeilly, 15 Nov 201 2

.

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 ( D 406562 , D. McNeilly, 15 Nov 201 2 ) residues and assumes 100% crop treated for all co mmodities.

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 surf ace water are 0.13 177 ppm and

0.011 31 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.Thiamethoxam Human Health Risk Assessment DP No. 402441

Page 28 of 49 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 level s and anticipated residue s ( calculated from f ield trial data ) for selected commodities (discussed in detail in D 406562 , D. McNeilly, 15 Nov 201 2 ) were used in

the chronic assessment. The chronic assessment a nticipated residues were average residues from

c rop field trial data. F or 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

95 th percentile of exposure.

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

95 th 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 4 4 % 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 PA D; 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.Thiamethoxam Human Health Risk Assessment DP No. 402441

Page 29 of 49 5.4.6 Summary Table

Table 5.4.6. Summary of Dietary (Food + Drinki ng Water) Exposure and Risk Estimate s for Thiamethoxam.

Population Subgroup 2 aPAD, mg/kg/day Acute Estimates (95 th

Percentile) 1 cPAD,

mg/kg/day Chronic Estimates

Exposure, mg/kg/day Risk,

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

cPAD MOE 3

U.S. Population 0.35 0.017192 4.9 0.012 0.002663 22 3100
All infants (< 1 year) 2 0.35 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 99 th and 99.9 th percentile are reported in Attachment 2

. 2

- The population subgroup s 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, D ec 4, 2012

There are no new residential uses associated with this action. F or 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 SOPs 2 along with policy changes for body weight ass umptions. The revision s to the residential exposure

estimate s 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). R esidential handler exposures are expected from these uses and are expected to be short

term (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 th iamethoxam. 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.htmlThiamethoxam Human Health Risk Assessment DP No. 402441

Page 30 of 49 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

- and

crevice) Liquid Manually

- pressurized handwand 0.00021 0.000067 5

, 700 18

, 000 4

, 300

6.2 Post

- Application Exposure

T here is a potential for exposure from entering areas previously treated with thiamethoxam

. Post

- application residential scenario s w ere re assessed 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 us es. 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 Estimat es for Existing Residential Uses of

Thiamethoxam

.

Use/Target Lifestage Post

- application Exposure Scenario Dose

(mg/kg

- day) MOE 3 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

640 Hand to Mouth 0.0017 4

, 900 X 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 2 5 00

Inhalation 9.1 E

- 0 7 1,300,000 X

Child 1<2 Dermal (playing on

carpet) 3 0.0081 7

, 400 X

3500 Inhalation 3.4 E

- 0 7 360,000

-- 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 granul e 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.Thiamethoxam Human Health Risk Assessment DP No. 402441

Page 31 of 49 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. Th is 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 estimate s 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

- A pplication Exposure (mg/kg/day) 4 Residential Post

application MOE 5 Dermal Inhalation Dermal Inhalation Oral

Short

- /Intermediate

- Term

Adult 0.0018 0.0000039 0.0 018 6 7 0 0.0024 N/A N/A 500

Child 1<2 N/A 0.0 8 2 N/A 0.0 017 640

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

- appl ication 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 M OE) + (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 (han d

- to

mouth) 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

B ased 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 Categor y I V ) 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 i ts Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 3 . The Agency is in the process of evaluating the SAP report and may, as appropriate, develop poli cies 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.htmlThiamethoxam Human Health Risk Assessment DP No. 402441

Page 32 of 49 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 application s , but, to a lesser extent, could also be a potential source of exposure from ground application method s 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 data base 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 airbla st 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 use s, exposures resulting from direct application to lawns/turf are likely protective of an y 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) p esticide 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.htmThiamethoxam Human Health Risk Assessment DP No. 402441

Page 33 of 49 7.2 Short

- Term Aggregate Risk

References: D375247 , D. McNeilly, 3 May 2010

D359207, M. Collantes; 24 July 2009 D406746, M. Crowley , D ec 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 expo sure levels in indoor (crack and crevice) scenario (Table 6.2) and that for adults,
post

- application exposure may be greater than handler exposure (Table s 6. 1 and 6.2 ) . Therefore, exposure estimates resulting from entering turf areas previously treated wi th 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 s hort

- 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. Estim ates of Short

- term Aggregate Risks for Thiamethoxam Population Subgroup Margins of Exposure (MOEs) Dietary Aggregate 1 Residential Combined

MOE 2 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/MOE Dietary ) + (1/MOE Resi dential 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 fr om 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 su bgroups.

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

Page 34 of 49 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

opera te 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 clothianid in, 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 thiameth oxam 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, includ ing 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 mineralize d 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

th e 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

c oming 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 asses sment 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

Page 35 of 49 10.0 References

References:

D 389375

, 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: Recommendat ion on the need for a 28

- day inhalation study.

D 373378, 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 B eets, and Tropical Fruits.

Attachments:

Attachment A : Toxicology Profile and Executive Summaries

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

Page 36 of 49 A ttachment A . Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) fo r 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

Page 37 of 49 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 LD 50 : 1563 mg/kg (♂+♀) III

870.1200 Acute Dermal 44703316 LD 50 > 2000 mg/kg (♂+♀) III

870.1300 Acute Inhalation 44703317 LC 50 > 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) 4 4 703322 (1995 )

p pm =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 hepatocy tes, 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 redu ced brainThiamethoxam Human Health Risk Assessment DP No. 402441

Page 38 of 49 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); decrease d 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 Deve lopmental

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 post

implantation loss and a slight increase in th e 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

F 0 M=0, 1.2, 3.0, 61.7,155.6

F 1 M=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 F 1 males. At higher

doses of 15 5.6 mg/kg/day kidney lesions were

observed in both F 0 and F 1 males, and decreased body weight, body weight gain, food consumption

and food utilization in F 0 males. Females had significantly increased relative liver weights. Reproductive NOAEL = 1.2 (males ), >208.8Thiamethoxam Human Health Risk Assessment DP No. 402441

Page 39 of 49 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Thiamethoxam Type of Study/Guide

line Study Title MRID Results

191.5

F 0 F=0, 1.7, 4.3, 84.4,

208.8

F 1 F=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 F 1 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 F 0 and F 1 males. Reproductive NOAEL = 0.61 (mal es), 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

F 1 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 occasiona l 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 al teration, 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

ga in, slight increase in the severity of hemosiderosis of the spleen, foci of cellular alteration in liver andThiamethoxam Human Health Risk Assessment DP No. 402441

Page 40 of 49 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

Accep table/ 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 non

induced mouse liver, Aroclor 1254 induced mouse liver, or thiamethoxam induced mouse liver, following dietary administration of thiamethoxam for 14 days at concentrations up to 25 00 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 Battery

rat (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

streng th (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 la nding during the righting reflex test, slight lacrimation (females only) andThiamethoxam Human Health Risk Assessment DP No. 402441

Page 41 of 49 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

Neurot oxicity 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 mal es, reduced brain weight and size in males and females, and significant changes in brain morphometric

measurements.

870.7485 Metabolism Study

rat (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 hou rs. 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 biotran sformation 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 i n various sulfur

containing 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 CO 2

. Metabolites eliminated very rapi dly. 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 butThiamethoxam Human Health Risk Assessment DP No. 402441

Page 42 of 49 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 metabo lites: 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 f eces samples. Between 30

- 60% of the administered dose

was excreted as metabolites.

870.7600 Dermal Absorption

– rats;

In vi vo ; WG Formulation

25 % a.i.

unaccept able / 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 vi vo studies using 21.1 or

48.6% a.i. Formulations;

Acceptable/

Guideline 45200001 (2000)

3.64, 36.4 μg/cm 3
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 a nd high

- dose animals for proliferating cell nuclear antigen gave

no indication for a treatment

- related increase in the fraction of DNA synthesizing hepatocytes in S

phase. CGA 293343 did not stimulate hepatocyteThiamethoxam Human Health Risk Assessment DP No. 402441

Page 43 of 49 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

- guide line Special study to

assess liver biochemistry

mouse

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 gluta thione S

- transferase activity. Treatment did not affect peroxisomal fatty acid ß

oxidation.

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 1 00 was applied to account for inter

- species extrapolation (10x) and intra

- species variation (10x).Thiamethoxam Human Health Risk Assessment DP No. 402441

Page 44 of 49 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 : T wo 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 F 1 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 F 1 males. The higher NOAEL was selected from t hese 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

obser ved 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 F 1 males at 3 mg/kg/day. This endpoint is consi dered conservative and protective

because there was no dose

- response relationship and these findings were not observed in the F 0 males. Most of the other sperm parameters were not significantly altered until much higher dose levels of 155 mg/kg/day. Alth ough 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 c ount 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

repro ductive 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.Thiamethoxam Human Health Risk Assessment DP No. 402441

Page 45 of 49 The LOAEL of 1.8 mg/kg/day is based on testicular atrophy in F 1 generation males. In the 2004 study, testic ular 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 diff erences 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. Th erefore, 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 testi cular 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 th e 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 health

protective for use in the chronic dietary risk assessmen t.

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 maturati on 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 r ecognizes 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 health

protective for use in risk assessment.Thiamethoxam Human Health Risk Assessment DP No. 402441

Page 46 of 49 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 1 4.3 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 α 2u - 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 can not 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 gl ucose, 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 risk s for thiamet hoxam w ere assessed using an oral toxicity study. The Agency sought expert advice and input on issues related to this route to route extrapolationThiamethoxam Human Health Risk Assessment DP No. 402441

Page 47 of 49 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 Toxic ity 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 end point 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 physical

chemical 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 B 6 C 3 F 1 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 (7.5x10 7 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 51 Cr release assay. All animals were evaluated for mortality, clinical signs, body weight c hanges, 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.Thiamethoxam Human Health Risk Assessment DP No. 402441

Page 48 of 49 There were no test substance

- related effects on mortality, clinical signs, f ood 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 liv er weights were observed in the 1250 ppm AFC group and the 5000 ppm AFC and NKC groups.Thiamethoxam Human Health Risk Assessment DP No. 402441

Page 49 of 49 A ttachment B : International Residue Limits



### Thiamethoxam (060109; 08/02/2012)

Summary of US and International Tolerances and Maximum Residue Limits

Residue Definition :
US Canada Mexico 2 Codex 3

40 CFR 180.565:

Plant/Livestock: (3

- [(2

- chloro

- 5

- thiazolyl)methyl]tetrahydro

- 5

- methyl

N

- 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

- nitro

4 H

- 1,3,5

- oxadiazin

- 4

- imine, including the metabolite ( E )

- N

- [(2

- chloro

- 5

- thiazolyl)methyl]

- N '

- methyl

- N "

- nitroguanid ine thiamethoxam

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 2 Codex 3

Coffee beans 0.2 0 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 ha ve not been finalized by the CCPR and the CAC.