Thiamethoxam D373376

Page 1 of 60 o UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

Office of Chemical Safety

a nd Pollution Prevention

Date: Dec. 20, 2010

MEMORANDUM

SUBJECT: Thiamethoxam

– Human H ealth R isk A ssessment for N ew S eed T reatment U se s

o n A lfal fa and P eanuts, and U se in Food Handling Establishments

.

PC Code: 060109 DP Barcode s : D37 3376 , D376092, D380393

Decision No s .: 424517, 430284,

436785 Registration Nos. : 100

- RGAL

, 100

- 94 9, 100

- 1306

Petition No.: 9F7657, 0F7707,

0F7734 Regulatory Action: Amended Section 3

Risk Assessment Type: Single Chemical Aggregate Case No.: 7614

T XR No.: None CAS No.: 153719

- 23

- 4

MRID No.: None 40 CFR: 180.565

FROM: Dennis McNeilly, Chemist/ Risk Assessor

William T. Drew, Chemist

Shih

- Chi Wang , Biologist

R isk Assessment Branch II (RAB2) Health Effects Division (7509P)

THROUGH: Margarita Collantes, Biologist

Risk Assessment Branch II (RAB2) Health Effects Division (7509P)

& Richard Loranger, Ph.D., Senior Chemist Christina Swartz, Branch Chief

Risk Assessment Branch II (RAB2) Health Effects Division (7509P)

TO: Kable Davis /Venus Eagle, Team 01

Insecticide/Rodenticide Branch Registration Division (7505P)Thiamethoxam D373376

Page 2 of 60 Table of Contents

` 1.0 Executive Summary

................................ ................................ ................................ ............... 4 2.0 Ingredient Profile

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

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

2.2 Structure and Nomenclature

................................ ................................ ...................... 10 2.3 Physical and Chemical Properties

................................ ................................ .............. 11

3.0 Hazard Ch aracterization/Assessment

................................ ................................ ................ 11

3.1 Hazard and Dose

- Response Characterization

................................ ............................ 11

3.1.1 Database Summary

................................ ................................ ................... 11

3.1.1.1 Studies available and considered

................................ ............... 12

3.1.1.2 Mode of action, metabolism, toxicokinetic data

........................ 12

3.1.1.3 Sufficiency of studies/data

................................ ......................... 12

3.1.2 Toxicological Effects

................................ ................................ ................ 13

3.1.3 Dose

- response

................................ ................................ ........................... 15

3.2 Absorption, Distribution, Metabolism, Excretion (ADME)

................................ . 16

3.3 FQPA Considerations

................................ ................................ ........................... 16

3.3.1 Adequacy of the Toxicity Database

................................ .......................... 16

3.3.2 Evidence of Neurotoxicity

................................ ................................ ........ 16

3.3.3 Developmental Toxicity Studies

................................ ............................... 17

3.3.4 Reproductive Toxicity Study

................................ ................................ .... 17

3.3.5 Additional Information from Literature Sources

................................ ...... 18

3.3.6 Pre

- and/or Postnatal Toxicity

................................ ................................ ... 18

3.3.6.1 Determination of Susceptibility

................................ ................. 18

3.3.6.2 Degree of Conc ern Analysis and Residual Uncertainties for Pre

and/or Postnatal Susceptibility

................................ ................................ .. 19

3.3.7 Recommendation for a Developmental Neurotoxicity Study

................... 19

3.4 Safety Factor for Infants and Children

................................ ................................ .. 20

3.5 Hazard Identification and Toxicity Endpoint Selection

................................ ........ 20

3 .5.1 Acute Reference Dose (aRfD)

- Females age 13

- 49

................................ . 20

3.5.2 Acute Reference Dose (aRfD)

- General Population

................................ 20

3.5.3 Chronic Reference Dose (cRfD)

................................ ............................... 21

3.5.4 Incidental Oral Exposure (Short

- and Intermediate

- Term)

....................... 22

3.5.5 Dermal Absorption

................................ ................................ .................... 23

3.5.6 Dermal Exposure (Short

- , Intermediate

- and Long

- Term) Adults

........... 23 3.5.7 Dermal Exposure (Short

- , Intermediate

- and Long

- Term) Children.......24

3.5. 8 Inhalation Exposure (Short

- , Intermediate

- and Long

- Term)

................... 24

3.5. 9 Level of Concern for Margin of Exposure

................................ ................ 24

3. 5. 10 Recommendation for Aggregate Exposure Risk Assessments

................. 25

3.5.1 1 Classification of Carcinogenic Potential

................................ ................. 25

3.5.1 2 Summary of Toxicological Doses and Endpoints for Use in Human Risk

Assessments

................................ ................................ ................................ .......... 25

3.6 Endocrine disruption

................................ ................................ ............................. 29

4.0 Public Health and Pe sticide Epidemiology Data

................................ ............................... 29Thiamethoxam D373376

Page 3 of 60 5.0 Dietary Exposure/Risk Characterization

................................ ................................ .......... 29 5.1 Pesticide Metabolism and Environmental Degradat ion

................................ ............. 29 5.2 Analytical Methodology.......................................................................30 5.3 Drinking Water Residue Profile

................................ ................................ ................. 30

5.4 Food Residue Profil e

................................ ................................ ................................ .. 33

5.5 International Residue Limits

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

................................ ................................ ........................ 35 5.6.1 Anticipated Residue and Percent Crop Treated (%CT) Information

.......... 36 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

................................ . 37 7.0 Aggregate Risk Assessments and Risk Characterization

................................ ................. 39 7.1 Acute Aggregate Risk

................................ ................................ ................................ 40

7.2 Short

- Term Aggregate Risk

................................ ................................ ....................... 40

7.3 Intermediate

- Term Aggregate Risk

................................ ................................ ........... 41 7.4 Long

- Term Aggregate Risk

................................ ................................ ....................... 42

7.5 Cancer Risk

................................ ................................ ................................ ................ 42

8.0 Cumulative Risk Characterization/Assessment

................................ ................................ 42 9.0 Occupational Expos ure/Risk Pathway

................................ ................................ ............... 43

9.1 Short

- and Intermediate

- Term Handler Risk

................................ ............................. 43

9.2 Short

- and Intermediate

- Term Postapplication Risk

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

................................ .............................. 49 10.1 Toxicology

................................ ................................ ................................ ............... 50 10.2 Residue Chemistry

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

................................ ................................ .. 51

References

................................ ................................ ................................ ................................ .... 52 Ap pendix A

- Toxicity Profile for Thiamethoxam................................................... 53Thiamethoxam D373376

Page 4 of 60 1.0 Executive Summary

Thiamethoxam is a broad spectrum nitroguanidine insecticide which belongs to the pesticidal class of compounds known as the neonicot inoids (Group 4A; Insecticide Resistance Action Commitee). It has activity against sucking and chewing insects on a wide variety of crops. Thiamethoxam appears to interfere with the nicotinic acetylcholine receptors of the insect’s nervous system, but th e specific receptor site is unknown at this time. It does not inhibit cholinesterase or interfere with sodium channels and, therefore, has a different mode of action than organophosphate, carbamate, and pyrethroid insecticides.

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

and peanut s eeds

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

in food /feed handling establishment s

. It is proposed for indoor spot, void, and crack and cr evice applications a s 0.05 and /or 0.1 % active ingredient ( ai ) solutions , to control a wide variety of insect pests. In conjunction with the proposed new use s , Syngenta has requested the establishment of permanent tolerances for residues of thiamethoxam an d its metabolite, CGA

322704 (clothianidin), in or on the commodities, as listed below.

Alfalfa, forage

................................ ................................ ............. 0.05 ppm Alfalfa, hay

................................ ................................ .................. 0.12 ppm

Peanut

................................ ................................ .......................... 0.05 ppm Peanut, hay

................................ ................................ .................. 0.25 ppm

Food commodities/feed commodities (other than those covered by a higher

toleranc e as a result of use on growing crops) in food/feed handling

establishm ents

................................ ................................ ............. 0.01 ppm

Databases for toxicology, residue chemistry, and occupational/residential exposure are sufficient for purposes of human health risk assessment. An immunotoxicity study

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

non

- food uses)

, is needed to complete the database . An y registrations granted should be made conditional upon receipt and review of those data

. In addition, there are label modifications and tolerance revisions that should be completed prior to registration or establishment of tolerances (see section 10)

.

In mammals, thiamethoxam shows toxicological effects primarily in the liver, kidney, testes, and hematopoietic system (blood cellular system) . In addition, developmental neurological effects

were observed in rats. Th e developmental effect is being used to assess risks associated with acute exposures to thiamethoxam, and the liver and tes ticular effects are the bas is for assessing longer term exposures. It is classified as ―not likely to be carcinogenic to humans.‖ T he select ed endpoints and points of departure for risk assessment from the available data are protective of all toxicologic al effects , including potential immunotoxic effects, observed in the database for allThiamethoxam D373376

Page 5 of 60 population groups . In addition, the dietary and residential exposures are not likely to be

underestimated. T herefore

, t he Health Effects Division (HED) has reduced the FQPA Safety Factor to account for sensitivity of infants and children from 10 X to 1 X

.

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

- and

intermediate

- term inhalation risk s for thiamethoxam w ere assessed using an oral t oxicity study. The Agency is in the process of evaluating a March

, 2010 Federal Insecticide, Fungicide, and

Rodenticide Act S cientific A dvisory P anel (SAP) report and may, as appropriate, re

- examine and develop new policies and procedures for conducting i nhalation 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 inhalati on toxicity risk assessment.

The submitted field trial data for thiamethoxam seed treatment of alfalfa and peanuts are acceptable, and support the proposed use of thiamethoxam as a seed treatment. HED recommends a tolerance of 0.05 ppm in peanut nutmeat, 0.25 ppm in peanut hay

, 0.05 ppm in alfalfa forage, and a tolerance of 0.12 ppm in alfalfa hay. Based on the highest field trial (HAFT) combined residues of 0.05 ppm (0.09 ppm at a 2X rate) in peanut nutmeat, and the

theoretical concentration factor for peanut meal of 2.2X, HED recommends a tolerance of 0.15 ppm in peanut meal. The submitted data for thiamethoxam use in food /feed handling areas are acceptable, and support the proposed use of Optigard Flex Liquid as a spot, void, and crack and

crevice tre atment in food handling establishments

. Based on maximum thiamethoxam and

CGA

- 322704 residues of <0.01 ppm in food commodities exposed to 1X treatment in food handling areas (with the vast majority of samples containing non

- detectable residues), HED

recom mends a combined tolerance of 0.02 ppm in food /feed commodities (other than those covered by a higher tolerance as a result of use on growing crops)

.

HED has assessed dietary (food + drinking water) as well as various non

- dietary ―residential‖

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

- protective assumptions regarding residue levels in food and water as well as the extent to which crops are treated with thiamethoxam. Risk estimates associated with dietary exposure are below HED’s level of concern for all population subgroups, including those of infants and children. Exposures in a residential setting may occur following application of thiamethoxam to turf and/ or indoor

crack and crevice treatment

. Therefore, HED h as assessed dermal and incidental oral (hand

- to

mouth) exposures. Risk estimates for these exposures are below HED’s level of concern for the assessed population subgroups. Similarly, highly conservative estimates of aggregate risk (combined risk from di etary and non

- dietary exposures) are below HED’s level of concern for all population subgroups. Given the existing and proposed use patterns for thiamethoxam as well as

the health

- protective assumptions throughout this risk assessment, it is unlikely that any geographic, ethnic, or socioeconomic population will have increased exposure relative to the standard population subgroups assessed by OPP.

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

5FS t o treat al falfa and peanut seeds and Cruiser® PD to treat peanut seeds were assessed for both open and closed commercial seed treatment systems. No on

- farm uses were assessed. TheThiamethoxam D373376

Page 6 of 60 occupational exposures/risks resulting from the proposed uses of Cruiser ® 5FS and Cr uiser PD for treatment of peanut and alfalfa seed using open and closed systems do not exceed HED’s level of concern (MOEs ≥ 100) with the exception of the following two scenario s

.

(1) The Cruiser® PD is intended for use as a dry application on peanuts. Since the treater (loader/ operator) unit exposure values from the Seed Treatment SOP ( Policy 14 ) are based on liquid formulations, the loader/operator exposure for Cruiser® PD was estimated using surrogate unit exposure values for a wettable powder formul ation in the Pesticide Handlers Exposure Database (PHED). The treater scenario resulted in a MOE of 100 with the use of additional PPE (i.e.

, gloves, coveralls

, and a PF10 respirator). Currently the label only requires a use dust mask (quarter

- or half

- m ask) respirator. HED recommends that the Registration Division ensure that the appropriate respirator is required on the final Cruiser PD label

.

(2 ) In assessing the multiple activity scenario for commercially treating 718,000 lbs of alfalfa seed using an open system, handler exposure resulted in a MOE of 59 at baseline with addition of gloves. The addition of a PF 5 dust mist respirator to current label personal protective equipment (PPE) [ i.e. gloves and coveralls] was required for multiple activity workers scenario to reach an MOE greater than 100 (MOE = 1 7 0)

, the level of concern. However, the Cruiser ® 5FS label contains a restriction for commercial open system seed treatment facilities that limits the amount of product handled per day to no more t han 38 gallons product/worker/8

- hr day which is equivalent to treating 413,043 lbs of seed a day. Therefore, HED also assessed treatment of 413,043 lbs of alfalfa seed at baseline with addition of gloves which resulted in a

MOE of 100 and was not of conce rn.

Risks for all other commercial open and closed system scenarios were not of concern. All MOEs for secondary seed handlers (i.e., those who plant treated seed) are greater than 100 assuming a single layer of clothing plus gloves, with MOEs ranging f rom 760 to 250 0 and were

not of concern.

The assessment also includes exposure estimates resulting from the proposed use of thiamethoxam in food/feed handling establishments. The handler assessment was based on surrogate unit exposure data from the Pes ticide Handlers Exposure Database (PHED) Version 1.1 (HED Science Advisory Council for Exposure, SOP Number 007, January 1999). Commerical handlers applying thiamethoxam as a liquid spray to cracks and crevices, spots, and structural voids using low pressu re handwand, resulted in combined MOEs ranging from 280 to 8, 3 00 and do not exceed HED’s level of concern with use of personal protective equipment (PPE) (i.e., gloves). However, the handler scenario using a foam application resulted in an MOE

of 160 with the use of additional PPE (gloves, coveralls

, and PF5 dust mist respirator). The proposed label does not require use of coveralls and respirators. HED recommends that if this use is to remain on the label, the Registration Division ensure that the corre ct PPE be included in the final registered label.

There are no new residential exposure scenarios associated with this action. Exposures related to already registered indoor residential activities have been combined with chronic dietary exposure

estima tes to assess the worst

- case short

- and intermediate

- term aggregate exposure s . The indoorThiamethoxam D373376

Page 7 of 60 crack and crevice scenario has higher exposure for both adults and children than the exposure

levels in the turf scenario and has been used for the aggregate exposur e assessment

. The short

term aggregate MOEs range from 370 to 490, while intermediate

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

are below HED’s level of concern.

Potential a reas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, ―Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Po pulations‖ http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ). As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to we ll

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intakes by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Whenever appropriate, non

dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and model s that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

This exposure/risk assessment relies in part on data from studies in which adult human subjects were intentionally expo sed to a pesticide to determine their dermal and inhalation exposure. Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as the Pesticide Handlers Exposure Database (PHED). EPA has

revie wed 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 prevai ling when they were conducted. There is no regulatory barrier to continued reliance on these studies, and all applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26)

have been satisfied.

HED is recommendi ng in favor of the establishment of permanent tolerance s as shown in Table 10, and for conditional registration of thiamethoxam for the requested uses, pending receipt and review of the data requested in Section 10. Prior to granting the registration or e stablishing the

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

revised Section F be submitted . These items are also described in Section 10.Thiamethoxam D373376

Page 8 of 60 2.0 Ingredient Profile

Thiame thoxam is a broad spectrum nitroguanidine insecticide which belongs to the pesticidal class of compounds known as the neonicotinoids. It has activity against sucking and chewing insects on a wide variety of crops. It appears to interfere with the nicotin ic acetylcholine receptors of the insect’s nervous system, but the specific receptor site is unknown at this time. It
does not inhibit cholinesterase or interfere with sodium channels and, therefore, has a different mode of action than organophosphate, ca rbamate, and pyrethroid insecticides.

The chemical structure and nomenclature of thiamethoxam and its regulated metabolite, CGA

322704, are presented in Table 2.2. The physicochemical properties of the technical grade of thiamethoxam are presented in Tab le 2.3. The metabolite CGA

- 322704 is the active ingredient clothianidin (PC Code 044309).

2.1 Summary of Proposed Uses

Peanuts: The end

- use products ( EP ) proposed for use on peanuts are Cruiser PD (EPA File Symb ol 100

- RGAL), a WS formulation of thiamethoxam containing 70% ai, and Cruiser 5FS (EPA Registration #100

- 941), a n FS formulation of thiamethoxam containing 5 lb ai/gal . They

ar e proposed for use as seed treatments of peanuts to provide early season protec tion of seedlings against injury from thrips, aphids, wireworms and white grubs, and suppression of three

cornered alfalfa hoppers, and plant bugs

. In response to questions from HED, Syngenta clarified that the maximum use rate for peanuts should be 0.08 lb ai/A ( 18 Oct 2010 email from Syngenta’s Patrick McCain to RD’s Kable Davis). Th is rate was calculated using assumptions which HED considers reasonable (850 seeds/ lb, and planting 142 lbs seed/A). The proposed use

directions are presented in Table 2.1 ( below )

.

Alfalfa: The EP proposed for use on alfalfa is Cruiser 5FS (EPA Registration #100

- 941) . It is proposed for use as a seed treatment of alfalfa to provide early season protection of seedlings against damage caused by aphids and leafhoppers (fi rst cut crop only)

. The proposed use

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

, are presented in Table 2.1 ( below )

.

Food handling establishments: The EP proposed for use in food handling establishment s is Op tigard Flex Liquid (EPA Registration #100

- 1306)

, a n SC formulation of thiamethoxam that contains 2 lb ai/gal . It is proposed for use as spot, void, and crack and crevice applications in food handling and other areas of food handling establishment s. The p roposed use directions for food handling establishment s, obtained from a draft label dated 10 June 2010 for Optigard Flex Liquid

, are presented in Table 2.1

.Thiamethoxam D373376

Page 9 of 60 TABLE 2.1 Summary of Proposed Use Directions on Peanuts and Alfalfa , and in Food Handling Esta blishments. Use Timing; Type; and Equipment Product [File

Symbol or Registration Number] Single

Use Rate Maximum

Uses per

Season Maximum

Seasonal

Use Rate PHI

(Days) Use Directions and

Limitations

Peanuts

S eed

treatment

. Cruiser PD

[100

- RGAL ]

Cruiser 5FS [100

- 94 1 ] 0. 2 0

- 0.2 9

mg ai

/seed 1 (Implied) 0. 08

lb ai/ A N S 1 No soil or foliar application of

thiamethoxam to p eanut s grown from seed treated with

Cruiser PD or Cruiser 5FS

. Apply Cruiser PD in dry form, using equipment intended for dry

- applicatio n seed treatment only (not for use in on

- farm applicators; use in commercial seed treatment facilities only).

Alfalfa

S eed

treatment

. Cruiser 5FS

[100

- 94 1 ] 0.00 1 mg

ai/seed 1 (Implied) NS (0.0130) 2 N S No soil or foliar application of

thiamethoxam to alfalfa grown from seed treated with Cruiser

5FS

. For use in commercial seed treatment facilities only.
Food Handling Establishment s Pest pressure;

coarse low

pressure spot

spray , void injection , or crack and

crevice spray

. Optigard Flex

Liquid [100

- 1306] 0.05

-

0.10%

spray N S NS NA 3 Prior to application, remove or

cover all food items in areas to be treated. Do not apply where

food utensils or food surfaces may become contaminated. Treatments to be made by commercial pesticide applicators only.

1

. NS = Not S pecified

. 2. The alfalfa field trials utilized single (and seasonal ) use rate s of 0.0037

- 0. 0 1 30 lb ai/A

, based on the respective seeding rate s ( 8.00

- 27.90 lb seed s /A) , and an average of 210,000 alfalfa seed s/lb

. 3. NA = Not Applicable.

C onclusion

The submitted use directions for seed treatment of peanuts and alfalfa, and for applications in food handling establishment s, are sufficient to allow for evaluation of the submitted residue data

relative to the proposed use patterns.Thiamethoxam D373376

Page 10 of 60 2.2 Struc ture and Nomenclature

Table 2.2. 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 product s (EP) 70% WS formulation in water soluble bags ( Cruiser® 70WS ; EPA Reg. No. 100

- 1294) 25% WG formulation (Actara® Insecticide; EPA Reg. No. 100

- 938) 2 lb/gal FlC formulation (Platinum® Insecticide; EPA Reg. No. 100

- 939)

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

- 1147) 2 lb/gal FlC formulation (Actara® 240 SC Insecticide; EPA File Symbol 100

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

- 941) 0.22% granular formulation (Flagship® Insec ticide; EPA File Symbol 100

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

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

- OUG)

Chemical Class Neonicotinoid, Group 4A

Know n Impurities of Concern None

Chem ical structure of

CGA

- 322704 metabolite

N

- [(2

- chloro

- 5

- thiazoyl)methyl]

- N’

- methyl

- N‖

- nitroguanidine

Common Name ClothianidinThiamethoxam D373376

Page 11 of 60 2.3 Physical and Chemical Properties

Table 2.3. Physicochemical Propertie s 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

aceton e 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/wa ter 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 oc tanol/water partition coefficient suggests that accumulation of thiamethoxam in fatty tissues is unlikely to occur.

3.0 Hazard Characterization/Assessment

3.1 Hazard and Dose

- Response Characterization

3.1.1 Database Summary

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

assessment

. The scientific quality is relatively high and the toxicity profile of thiamethoxam can be characterized for most effects, including potential carcinogenic, mutagenic, developmental, and neurotoxic. The doses and endpoints for use in human health risk assessments are

summarized in Tables 3. 5 .1 2a and 3. 5

. 12 b, below. Recent changes to 40 CFR Part 158 make immunotoxicity testing (870.7800) required for pesticide registration. The study was required in conjunction with a previous risk assessment for proposed uses of thiamethoxam (9/25/2008), an d remains a datagap and condition of registration. Despite the lack of the immunotoxicity study, HED has not retained a database uncertainty factor (UFDB) for the lack of the study, because the doses and endpoints for risk assessment are considered to be protective of potential immunotoxicity.Thiamethoxam D373376

Page 12 of 60 3.1.1.1 Studies available and considered

The following studies were submitted in support of thiamethoxam registration : acute and subchronic neurotoxicity; subc hronic 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 st udies

in rats ; mutagenicity battery; and metabolism. In addition, in conjunction with the update of the cancer classification in 2005, a number of studies were submitted to support the mode of action for carcinogenicity.

3.1.1.2 Mode of action, metaboli sm, toxicokinetic data

Thiamethoxam has activity against sucking and chewing insects. It is a broad spectrum insecticide which belongs to the neonicotinoid class of compounds. While labora tory data indicate that thiamethoxam interferes with the nicotinic acetyl choline receptors of the insect’s nervous system, the specific binding site/receptor(s) is unknown at this time. Although imidacloprid, also a neonicotinoid insecticide, is also kno wn to interfere with nicotinic acetyl choline receptors, thiamethoxam appears to function at a different location. Thiamethoxam does not inhibit cholinesterase or interfere with sodium channels and, therefore, has a different mode of action than organopho sphate, carbamate and pyrethroid insecticides. Thiamethoxam is reported to have excellent acropetal translocation in the xylem and no basipetal movement in the phloem.

In an in vitro nicotinic receptor binding study, thiamethoxam had essentially no affin ity for either mammalian nicotinic acetyl choline receptor subtype and was considered inactive. This thiamethoxam binding affinity study to rat forebrain α 4 β 2 and α 7 - type nicotinic receptors was considered Acceptable/Non

- Guideline.

In rats, thiamethoxam is absorbed rapidly and extensively, and is widely distributed, followed by very rapid elimination, mostly in the urine (84

- 95%). The half

- life times from tissues ranged

from 2

- 6 hours. The major biotransformation reaction is cleavage of the oxadiazine r ing 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 predomina nt components are unchanged parent (33

- 41% of administered dose) and two other metabolites (8

- 12% and 9

- 18% of administered dose). These are the same structures that were most commonly observed in rat excreta; however, the proportions are quite different in mouse excreta.

3.1.1.3 Sufficiency of studies/data

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

- response evaluation. In accordance with t he revised part 158 toxicology d ata requirements

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

HED has concluded that a 10X UF DB is not needed to account for the lack of the required immunotoxicity study.Thiamethoxam D373376

Page 13 of 60 3.1.2 Toxicological Effects

Acutely, technical thiamethoxam is slightly toxic to rats and moderately toxic to mice via the oral route (Toxicity Category III); it is of low toxicity to rats via the dermal (Toxicity Category III) and inhalation r outes (Toxicity Category IV). It is not irritating to the skin and minimally irritating to the eye , and is not a dermal sensitizer.

The database on thiamethoxam indicates that the primary targets for this chemical are the liver, testes, kidney, and hemat opoietic system. In addition, effects on the thyroid (rats and dogs) and the adrenal gland (rats) are seen in the short

- term studies.

The liver effects occur across species, sexes and routes of administration. In the rat, inflammatory cell infiltration and necrosis of single hepatocytes are observed in the 28

- day dermal study and hepatocellular hypertrophy and lymphohistiocytic infiltration of the liver are observed in the subchronic oral studies. Chronic oral exposure induces an increase in the

inciden ce of foci of cellular alteration in females. In rats, there was no evidence of liver tumors at the dose levels tested. Females appear to be more sensitive than males for liver effects in rats. In the mouse, the following effects were observed in oral s tudies: hepatocellular hypertrophy, necrosis of single hepatocytes, lymphocytic infiltration (subchronic and chronic), apoptosis, induction of microsomal enzymes, Kupffer cell pigmentation (subchronic), Kupffer cell hyperplasia, increased incidence of foc i of cellular alteration, and increased mitotic activity (chronic). Male mice are more sensitive to the liver pathology than are females. Chronic dosing also results in the development of benign and malignant liver tumors in both sexes of mice. An

incre ase in the number of animals with multiple tumors is also observed; however, treatment does not affect the latency to tumor formation nor lethality resulting from the observed tumors.

The incidence of non

- neoplastic and neoplastic pathology is increased a t the same dose level, i.e., there is no clear departure point between doses that induce tumors and other systemic toxic effects. In both rats and mice, there appears to be increasing severity of effects with increasing dose. In rats, the lowest dose at which an effect is observed in the liver does not appear to

decrease significantly with increasing length of exposure to the test material. Due to dose spacing, it is not possible to determine if this is the case in the mouse , which appear s to be the

most sensitive species.

Testicular effects are observed in the rat and dog. They consist of decreased testes weights, increased incidence and severity of seminiferous tubular atrophy and sperm abnormalities at low dose levels in the rat; decreased testes wei ghts associated with microscopic evidence of reduction in spermatogenesis and occurrence of spermatic giant cells in the testes at toxic dose levels in the subchronic dog study; and atrophy of the seminiferous tubules at minimally to moderately toxic

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

- generation reproduction studies. The effects in the rat are only observed in the F 1 males in the two

generation reproduction study and are not observed at any other time. In both studies, there is evidence of increased quantitative susceptibility for male pups. Reproductive effects in males appear in the F 1 generation in the form of increased incidence and severity of testicular tubular atrophy in one study and sperm abnorma lities in the other study. While the testicular effectsThiamethoxam D373376

Page 14 of 60 observed in the two studies differ, the findings of the two studies support each other and are consistent relative to observed thiamethoxam toxicity. These effects are being used as the basis

for ri sk assessment because they are observed at very low dose levels. It is anticipated that they may be observed after either intermediate

- term or chronic exposure, particularly when exposure

occurs in utero

.

The kidney effects occur in both sexes of the rat but are found primarily in the male. They are observed following either oral or dermal exposure. The majority of the kidney effects (hyaline changes in the renal tubules) have b een attributed by the study authors 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 rat, dog and mouse with the dog being the most sensitive species. Both sexes appear to be affected; although the male appears to be more affected in the rodent and the female more affected in the dog. In the rat, increased spleen weights, increases in the incidence and se verity of hemosiderosis and/or extramedullary hematopoiesis are observed in both the subchronic and chronic studies. In the mouse, a slight reduction in erythrocytes, hemoglobin and hematocrit, accompanied by increased mean corpuscular volume and mean cor puscular hemoglobin are observed in the subchronic feeding study at very high dose levels. In the dog, leukopenia and slight microcytic anemia are observed in the subchronic oral study.

Thyroid effects in the rat (thyroid follicular cell hypertrophy) and dog (increase in thyroid weight) may be due to induction of microsomal enzymes in the liver, which in turn affect the hypothalamus

- pituitary

- thyroid

- liver homeostatic process for regulation of thyroid hormones. Evidence of this is the presence of hepatoc ellular 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 decreas ed in the dog and companion animal studies. While the toxicological significance of this observation is unclear, there is no doubt regarding its association to treatment with thiamethoxam. It has been proposed that the decreases in ALT activity may be ca used by either interference with or suppression of in vivo concentrations of pyridoxal phosphate (vitamin B6, a cofactor necessary for ALT activity) or by direct suppression of ALT synthesis. If thiamethoxam interferes with vitamin B6, it could have signi ficant implications regarding potential adverse developmental effects.

Developmental/Reproductive Effects: In the developmental studies, there is no quantitative or qualitative evidence of increased susceptibility of rat or rabbit fetuses to in utero exp osure to thiamethoxam. The developmental NOAELs are either higher than or equal to the maternal NOAELs. The toxicological effects in fetuses do not appear to be any more severe than those inThiamethoxam D373376

Page 15 of 60 the dams or does. In the rat developmental neurotoxicity study , there was no quantitative evidence of increased susceptibility.

Two reproduction studies are available. In both studies, there is evidence of increased quantitative susceptibility for male pups. Reproductive effects in males appear in the F 1 generat ion in the form of increased incidence and severity of testicular tubular atrophy in one study and sperm abnormalities in the other study. While the testicular effects observed in the two studies differ, the findings of the two studies support each other and are consistent relative to observed thiamethoxam toxicity.

Carcinogenicity and Mutagenicity : Thiamethoxam induces hepatocellular adenomas and carcinomas in male and female Tif:MAGf (SPF) mice. The HED Cancer Assessment Review Committee (June 13, 2 005) concluded that the mouse liver tumors arise through a non

- genotoxic mode of action characterized by a series of key events that include: perturbation of cholesterol biosynthesis, hepatotoxicity, cell death (both as single cell necrosis and apoptosis) and a sustained increase in cell replication rates. The mouse appears to be uniquely sensitive to this mode of action. Because of the threshold nature of the mode of action and the unique sensitivity of the mouse, it is concluded that humans are unlikel y to be at risk for developing tumors following exposures to thiamethoxam. The CARC classified Thiamethoxam as “Not Likely to be Carcinogenic to Humans” based on convincing evidence that a non

- genotoxic mode of

action for liver tumors was established in t he mouse and that the carcinogenic effects are a result of a mode of action dependent on sufficient amounts of a hepatotoxic metabolite produced persistently . Quantification of carcinogenic potential is not required. The submitted mutagenicity studies ar e adequate and indicate that thiamethoxam is not mutagenic.

3.1.3 Dose

- response

The database on thiamethoxam indicates the primary targets for this chemical are the liver, testes, kidney, and hematopoietic system. The test icular effects are considered to be toxicologically significant and occur at low doses, and therefore most of the endpoints for risk

assessment are based on these effects.

In the liver, enzyme induction and hepatocellular hypertrophy in and of themselves are not necessarily considered adverse effects. However, other effects were associated with these observations that are considered to be toxicologically significant. These include necrosis of single hepatocytes, foci of cellular alteration, apoptosis, Ku pffer cell infiltration, pigmentation and hyperplasia, and benign and malignant liver tumors. The majority of the kidney effects may

be attributed to accumulation of α 2u - globulin, a protein that is unique to male rats

, and

, therefore

, these kidney effects are not relevant to humans. The hematological effects are observed in three species. These include increased spleen weights, increases in the incidence and severit y of hemosiderosis and/or extramedullary hematopoiesis and a slight reduction in erythrocytes, hemoglobin and hematocrit. In the dog, leukopenia and slight microcytic anemia have been

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

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

immunotoxic i ty. The decreases in spleen weight occurred at very high doses, and were notThiamethoxam D373376

Page 16 of 60 statistically significant. These effects are not considered t o be as significant as the testicular, liver, and kidney effects. They often appear at very high dose levels and the changes are not

dramatic.

3.2 Absorption, Distribution, Metabolism, Excretion (ADME)

In rats, thiamethoxam is rapidly and extensively absorbed, widely distributed, and very rapidly eliminated, mostly in urine. The highest tissue concentrations are in skeletal muscle (10

- 15% of administered dose). The half

- life times fr om tissues ranged from 2

- 6 hours. Very low tissue residues were reported after 7 days. Within 24 hours, approximately 84

- 95% of the administered dose was excreted in urine, while 2.5

- 6% was excreted in the feces. Most was excreted as unchanged parent (70

- 80% of dose). The major biotransformation reaction is cleavage of the oxadiazine ring to form the corresponding nitroguanidine compound (CGA

- 322704). Enterohepatic circulation is negligible.

In mice, approximately 72% of the administered dose was excre ted in the urine and 19% was excreted in feces. Small but measurable amounts were detected in expired air (approximately 0.2% of dose). P arent (33

- 4 1% of administered dose) and 2 predominant metabolites: 8

- 12%

and 9

- 18% of administered dose were found

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

, the proportions are quite different in mouse excreta. One additional significant metabolite (mouse R6) was isolated from feces samples. Between 30

- 60% of the administ ered dose was excreted as metabolites.

3.3 FQPA Considerations

3.3.1 Adequacy of the Toxicity Database

The database for evaluating in utero or postnatal susceptibility is adequate for the purpose of the current risk assessment, and for evaluating the need for an FQPA safety factor. However, the database is not complete because the required immunotoxicity study has not been submitted. The following acceptable studies a re available:

Developmental toxicity studies in rats and rabbits

Two two

- generation reproduction studies in rats Developmental neurotoxicity study in rats

3.3.2 Evidence of Neurotoxicity

Thiamethoxam was tes ted in acute, 90

- day and developmental neurotoxicity studies . In the acute neurotoxicity study

, drooped palpebral closure, lower rectal temperature, increased forelimb grip strength (males only) and decreased locomotor activity were observed 2

- 3 hours aft er dosing. Effects at a higher dose included abnormal body tone, ptosis, impaired respiration, tremors, longer latency to first step in the open field, crouched

- over posture, gait impairment, hypo

arousal, decreased number of rears, uncoordinated landing during the righting reflex test, slight lacrimation (females only) and higher mean average input stimulus value in the auditory startleThiamethoxam D373376

Page 17 of 60 response test (males only). These effects were no longer evident at the 1 week and 2 week post

dosing examinations. In addition to these findings, 3 females were found dead within the first 2 days after treatment. There were no treatment

- related histopathological findings noted in the central or peripheral nervous system at any dose level tested.

In the 90

- day neurotoxic ity study, there were no treatment

- related systemic or neurotoxicological effects observed at any dose level tested up to 95 mg/kg bw/day in males and 216.4 mg/kg bw/day in females. In addition, no treatment

- related histopathological findings were noted i n the central or peripheral nervous systems. The subchronic mammalian neurotoxicity study was not tested at sufficiently high dose levels; however, a new study is not required at this time because no neuropathology was observed at the dose levels tested, and the weight of the evidence from the other toxicity studies indicates that there is no reason for concern.

In the developmental neurotoxicity study, there was no evidence of neurotoxicity in the dams exposed up to 298.7 mg/kg/day; a dose that was assoc iated 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 si gnificant decreases in Level 3

- 5 measurements in males and in Level 4

- 5 measurements in females on day 63).

The following evidence of neurotoxicity was observed in other oral studies . I n the 28

- day dog study there was a decrease in absolute but not relat ive brain weight in females at 43 mg/kg/day. This does not appear in either the 90

- day study (up to 50 mg/kg/day) or the chronic dog study (up to 45 mg/kg/day). In the mouse carcinogenicity study

, there was an increase in relative brain weight in high do se males that was attributed to reduction in body weight gain. In the rat chronic/carcinogenicity study, there was a slight increase in incidence of brain effects in high

dose males. Microscopically, this increase was associated with hydrocephalus and pr essure atrophy which was secondary to pituitary adenomas. The increased incidence of brain effects is not likely due to a neuronal tissue malformation but

, rather

, secondary to a pituitary adenoma.

3.3.3 Developmental Toxicity Studies

In the developmental studies, there is no evidence of increased quantitative or qualitative susceptibility of rat or rabbit fetuses to in utero exposure to thiamethoxam. The developmental NOAELs are either higher than or equ al to the maternal NOAELs. The toxicological effects in fetuses do not appear to be any more severe than those in the dams or does. In the rat developmental neurotoxicity study, there was no quantitative evidence of increased susceptibility. An increase in qualitative susceptibility was based upon reduced brain weight and

size in male and female pups at the highest dose tested ; whereas

, effects in dams were limited to decreased body weight gain and food consumption.

3.3.4 Reproductive Toxicity Study

Two acceptable reproduction studies are available. In both studies, there is evidence of increased quantitative susceptibility for male pups. Reproductive effects in males appear in the F 1Thiamethoxam D373376

Page 18 of 60 generation in the form of increased incidence and severity of testicular tubular atrophy in one study and sperm abnormalities in the other study. HED has determined that there is evidence of increased quantitative susceptibility for male pups (NOAEL: 0.6 mg/kg/day for increase d incidence of testicular tubular atrophy at 1.8 mg/kg/day) when compared to the parents (NOAEL: 1.8 mg/kg/day for hyaline changes in renal tubules at 61 mg/kg/day).

In another two

- generation reproductive study, there was quantitative evidence of increase d susceptibility. In this study, the NOAEL for reproductive effects is 1.2 mg/kg/day based upon sperm abnormalities, and the LOAEL is 3 mg/kg/day. T h e study is classified as acceptable

- non

guideline and is useful for risk assessment , even though addition al information pertaining to the study has been requested

. HED does not believe the outstanding information will impact the NOAEL identified for sperm abnormalities in this study.

Histopathology findings from the 1998 study cannot be combined with data f rom the new reproduction study due to differences in histopathology reporting criteria which may affect both incidence and severity of reported testicular lesions and may make comparison to the previous study or other historical control data (where such cr iteria were not applied) inappropriate at this

time

. While the testicular effects observed in the two reproductive studies differ, the findings support each other and are consistent relative to observed thiamethoxam toxicity. Although histopathological e ffects (tubular atrophy) were not observed in the more recent 2004 study at low dose levels, the observation of reduced sperm production would be expected to co

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

3.3.5 Additional Informat ion from Literature Sources

None.

3.3.6 Pre

- and/or Postnatal Toxicity

3.3.6.1 Determination of Susceptibility

In the developmental studies, there is no evidence of increased quantitative or qualitative susceptibility of rat or rabbit fetuses to in utero exposure to thiamethoxam. The developmental NOAELs are either higher than or equal to the ma ternal NOAELs. The toxicological effects in fetuses do not appear to be any more severe than those in the dams or does. In the rat developmental neurotoxicity study, there was no quantitative evidence of increased susceptibility ; however, there was incre ased qualitative susceptibility because the effects in the pups (reduced brain weight and significant changes in brain morphometric measurements) were considered to be more severe than findings in the dams (decreased body weight gain and food consumption).

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

- generation reproductive studies. In one study, there are no toxicological effects in the dams; whereas, for the pups, reduced bodyweights are observed at the highest do se level, starting on day 14 of lactation. This contributes to an overall decrease in bodyweight gain during the entire lactationThiamethoxam D373376

Page 19 of 60 period. The reproductive effects in males appear in the F 1 generation in the form of increased incidence and severity of tes ticular tubular atrophy (see developmental/reproductive section). These data are considered to be evidence of increased quantitative susceptibility for male pups (increased incidence of testicular tubular atrophy at 1.8 mg/kg/day) when compared to the

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

In a more recent two

- generation reproduction study, the most sensitive effect was sperm abnormalities at 3 mg/kg/day (the NOAEL is 1.2 mg/kg/day) in the F 1 males. This study also indicates increased susceptibility for the offspring for this effect.

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

selected the NOAEL for testicular effects in F 1 pups as the basis for risk assessment. The Agency has confidence that the NOAEL selected for risk assessment is protective of the most sensitive effect (testicular) for the most sensitive subgroup (pups) obs erved in the toxicological

database.

3.3.6.2 Degree of Concern Analysis and Residual Uncertainties for Pre

- and/or Postnatal Susceptibility

There is low concern for an increase in quantitative susceptibility in the rats or rabbits since developmental and offspring toxicity occurred at dose levels equal to or higher than the doses where parental toxicity was observed in three studies (rat devel opmental, rabbit developmental and rat developmental neurotoxicity). There is also low concern for the increased qualitative susceptibility observed in the DNT study because the doses and endpoints selected for risk assessment are protective of the effect s in the offspring. As noted previously, the Agency

selected the NOAEL for testicular effects in F 1 pups based on two reproductive toxicity studies for risk assessment to be protective of all sensitive subpopulations.

There is evidence of neurotoxicity a fter acute exposure to thiamethoxam at doses of 500 mg/kg/day including drooped palpebral closure, decrease in rectal temperature and locomotor activity and an increase in forelimb grip strength. However, no evidence of neuropathology was

observed. These effects occurred at doses at least 14

- fold and 416

- fold higher than the doses used for the acute, and chronic risk assessments, respectively; thus, there is low concern for these effects since it is expected that the doses used for regulatory purposes wou ld be protective of the effects noted at much higher doses.

3.3.7 Recommendation for a Developmental Neurotoxicity Study

A developmental neurotoxicity study has been requested, recei ved, and reviewed by the Agency (see Section 3.3.2).Thiamethoxam D373376

Page 20 of 60 3.4 FQPA Safety Factor for Infants and Children

The toxicity database for thiamethoxam is not complete because the required immunotoxicity study ha s not been submitted. The available data for thiamethoxam show the potential for immunotoxic effects, including changes in spleen weight and leukopenia. However, HED

concluded that the leukopenia was associated with an anemic response as opposed to direc t immunotoxicity. In addition, the reduced spleen weights were observed at high doses, and were not statistically significant. Based on these considerations, HED previously concluded that an additional database uncertainty factor (UFDB) was not needed to account for the lack of the immunotoxicity study.

HED further recommend s that the 10X FQPA safety factor for the protection of infants and children be reduced to 1X. There is no quantitative or qualitative evidence of increased susceptibility of rat or rabbit fetuses to in utero exposure to thiamethoxam in the developmental toxicity studies. The developmental NOAELs are either higher than or equal to the maternal

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

rats.

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

generation reproductive studies, NOAELs and LOAELs were established in these studies, and

HED selected the NOAEL for testicular effects in F 1 pups as th e basis for risk assessment. HED has confidence that the NOAEL selected for risk assessment is protective of the most sensitive effect (testicular) for the most sensitive subgroup (pups) observed in the toxicological database.

In addition, the NOAELs se lected for risk assessment are protective of all toxicological effects observed in the database including treatment

- related changes in the adrenal gland, thyroid, testes and ovaries. Thus, HED believes the FQPA safety factor should be reduced to 1X.

The dietary food exposure assessment is not likely to underestimate exposure/risk. The dietary drinking water assessment utilizes water concentration values generated by models and associated modeling parameters that are designed to provide conservative, heal th protective, high

- end estimates of water concentrations which will not likely be exceeded. The residential exposure assessment was conducted using standard, health

- protective assumptions.

3.5 Hazard Identification and Toxicity Endpoint Selection

3.5.1 Acute Reference Dose (aRfD)

- Females age 13

- 49

A separate aRFD is not being used for females age 13

- 49. Females in t his age group will be assessed using the aRFD for the general population (see 3.5.2).

3.5.2 Acute Reference Dose (aRfD)

- General Population

Study Selected : Developmental Neurotoxicity St udy

— rat (OPPTS 870.6300)Thiamethoxam D373376

Page 21 of 60 MRID No .: 46028202, 46028201

Dose and Endpoint for Establishing aRfD : Developmental NOAEL = 34.5 mg/kg/day based on delayed sexual maturation in male pups, and reduced brain morphometric measurements LOAEL = 298.7 mg/kg/day.

Comments on Study/Endpoint/Uncertainty Factors : The endpoint chosen was presumed to occur following a single exposure and could be relevant for all populations, including children. The endpoint is based on the most sensitive effect in the most sensitive subpopulation (pups). Although the toxicological effects occurred in pups, it is not known if these effects resulted from

pre

- or post

- natal dosing, and therefore the endpoint is relevant to all populations, and is considered to be protective. An UF of 100 was applied to account for inter

- species extrapolation (10x) and intra

- species variation (10x).

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

100 (UF)

3.5.3 Chronic Reference Dose (cRfD)

Study Selected : Two 2

- Generation Reproduction Toxicity Studies

— rat (OPPTS 870.3800)

MRID No .: 44718707; 46402902, 46402904, 46402906

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

- generation reproductive studi es 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 m g/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 these two studies based on the rationale detailed below in

― Comments on Study/Endpoints/Uncertainty Factors.‖ While the testicular effects observed in the two reproductive studies differ, the findings support each other and are consistent relative to observed thiamethoxam toxicity. Although histopathological effects (tubular atrophy) were not observed in the more recent 2004 study at low do se 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 1.2Thiamethoxam D373376

Page 22 of 60 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 considered conservative and protective

because there was no dose

- response relationship and these findings were not observed in the F 0 males. M ost of the other sperm parameters were not significantly altered until much higher dose levels of 155 mg/kg/day. Although some sperm abnormalities were noted in the 1998 study

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

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

- related effects on sperm count or sperm morphology. Based on a special complementary study conducted to evaluate this finding, HED concluded the sperm effects in t his study were likely

due to technical error and not treatment

- related. However, based on consideration of both reproductive studies, the Agency believes that it is appropriate to select a NOAEL of 1.2 mg/kg/day for these sperm effects for use in risk ass essment.

The LOAEL of 1.8 mg/kg/day is based on testicular atrophy in F 1 generation males

. In the 2004 study, testicular lesions were marginal even at much higher dose levels of 155 mg/kg/day where there was an increase in incidence but not severity of t esticular lesions. The difference in the two studies may possibly be due to different grading criteria, and also differences in histopathological evaluation protocols. The 1998 study only evaluated one slice per testis. The 2004 study

evaluated 4 slices per testis, calculated an average numerical grade and reported only marginal testicular lesions at 155 mg/kg/day. Therefore, HED believes the LOAEL of 1.8 mg/kg/day for testicular atrophy is likely to be conservative and protective because of the finding s 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 fecun dity of rats, the lack of effects on other reproductive parameters is not necessarily an indication that the testicular effects would not be a problem in humans. Since no data are available to indicate how the testicular effects occur, whether or not they can be considered an endocrine effect, or whether or not they can definitively be considered adverse, the testicular effects were selected to provide a conservative approach for assessment of risk to humans. In addition, it is not known whether the obser ved effects are due to exposure to either the male or female or both parents in the study. Therefore, the endpoint will be applied to the general population.

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

sexuall y immature. However, this endpoint was determined to be conservative and health

protective for use in risk assessment.

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

100 (UF)

3.5.4 Incidental Oral Exposure (Short

- and Inte rmediate

- Term)

Study Selected : 90

- day Oral Toxicity

— dog (OPPTS 870.3 150 )Thiamethoxam D373376

Page 23 of 60 MRID No .: 44718702

Dose and Endpoint for Risk Assessment : The incidental oral endpoint (all durations ) of 8.23 mg/kg/day is based on slightly prolonged prothrombin times and decreased plasma albumin and A/G ratio (both sexes); decreased calcium levels and ovary weights and delayed maturation in the ovaries; decreased cholesterol and phospholipid levels, testis weights, spermatogenesis, and spermatic giant cells in testes (males) that occurred at 32 mg/kg/day in males and 33.9 mg/kg/day in females.

Comments on Study/Endpoint : The Agency recognizes that some of the observed effects in this study (i.e., t esticular 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 conservativ e and health

protective for use in risk assessment.

The Agency also considered the rat and mouse 90 day toxicity studies for endpoint selection that reported LOAELs of 17.64 mg/kg/day and 14.3 mg/kg/day, respectively. The dog NOAEL of 8.23 mg/kg/day is p rotective 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.

3.5.5 Dermal Absorption

Dermal Absorption Factor : 5%.

HED recommend s use of a 5% dermal absorption factor based on an evaluation of in vivo dermal absorption data for two formulated products containing thiamethoxam and an in vivo dermal absorption study in the rat using technic al thiamethoxam. The 5% dermal absorption value represents the maximum amount absorbed for all dose groups for either formulation tested in the most recent study.

3.5.6 Dermal Exposure (Short

- , Intermediate

- and Long

- Term) Adults

Study Selected : Two 2

- Generation Reproduction Toxicity Studies

— rat (OPPTS 870.3800)

MRID No .: 44718707; 46402902, 46402904, 46402906

Dose and Endpoint for Risk Assessment : The dermal endpoint for adults, all durations (1.2 mg/kg/day) is based on sperm abnormalities and testicular effects observed after in utero and

post

- natal exposure in the rat reproduction studies (see comments from the chronic dietary section above).

Comments on Study/Endpoint : Alt hough a 28

- day dermal toxicity study in rats is available, HED selected a reproductive NOAEL because the reproductive parameters are not evaluated in the dermal toxicity study and thus the consequences of these effects cannot be ascertained for theThiamethoxam D373376

Page 24 of 60 dermal route of exposure. Since an oral toxicity study was selected, a 5% dermal absorption

factor is recommended.

3.5.7 Dermal Exposure (Short

- , Intermediate

- and Long

- Term) Children Age 1 to 6 Years

Study Selected : 28

- Day Dermal Toxicity Study

— rat (OPPTS 870.3200)

MRID No .: 44710402

Dose and Endpoint for Risk Assessment : The dermal endpoint ( children 1

- 6, all durations) of 60 mg/kg/day is based on increased plasma glucose, trigly ceride 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 yo ung 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 neces sary when assessing dermal exposure

to children

.

3.5.8 Inhalation Exposure (Short

- , Intermediate

- and Long

- Term)

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

- and

intermediate

- term inhalation risk s for thiamethoxam w ere assessed using an oral toxicity study. The Agency sought expert advice and input on issues related to this route to route extrapolation approach (i.e. the use of oral toxicity studies for inhal ation 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, includi ng route to route extrapolation of toxicity data. If any new policies or procedures are developed, the Agency may revisit the need for an inhalation toxicity study for thiamethoxam and/or a re

- examination of the inhalation toxicity risk assessment.

Study Selected : Two 2

- Generation Reproduction Toxicity Studies

— rat (OPPTS 870.3800)

MRID No .: 44718707

, 46402902, 46402904, 46402906

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

abnormalities and testicular effects obser ved 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 effect s, the effects are considered to be appropriate for all exposureThiamethoxam D373376

Page 25 of 60 durations. Other than acute toxicity, no inhalation studies are available. Therefore, the reproductive endpoint is selected for inhalation exposure. Inhalation absorption is assumed to be 100% of oral absorption. The Agency recognizes that this endpoint may not be relevant for young children that are sexually immature. However, based on the use pattern and physical

chemical characteristics, the Agency does not anticipate inhalation exposu re to young children.

3.5.9 Level of Concern for Margin of Exposure

Table 3.5.9 Summary of Levels of Concern for Risk Assessment.

Route Short

- Term (1

- 30 Days) Intermediate

- Term (1

- 6 Months) Long

- Term (> 6 Months)

Occupational (Worker) Exposure

Dermal 100 100 100

Inhalation 100 100 100

Residential Exposure

Dermal 100 100 100

Inhalation 100 100 100

Incidental Oral 100 100 100

3.5.10 Recommendation for Aggregate Exposur e Risk Assessments

According to FQPA (1996), when there are potential residual exposures to a pesticide, an aggregate risk assessment must consider exposures from 3 major routes: oral, dermal, and

inhalation.

Similar endpoints were selected for short

- , intermediate

- and long

- term exposures via oral, dermal and inhalation routes, so they may be aggregated. The endpoints are protective of adverse testicular, liver and hematological effects, which a ppear to be the most sensitive effects of thiamethoxam exposure via oral and dermal routes

.

3.5.11 Classification of Carcinogenic Potential

Thiamethoxam indu ces hepatocellular adenomas and carcinomas in male and female mice. These findings served as the basis for HED’s conclusion that thiamethoxam was likely to be carcinogenic to humans; furthermore, HED recommended using a linear low dose extrapolation

for a ssessing cancer risk. The registrant subsequently conducted a number of studies to support a mode of action for carcinogenicity in mice. These studies were evaluated, and the Cancer Assessment Review Committee ( CARC ) agreed with the registrant that a pla usible mode of action has been established for the development of liver tumors in a mouse bioassay withThiamethoxam D373376

Page 26 of 60 thiamethoxam. T he liver tumors in the mouse arise through a non

- genotoxic mode of action characterized by a series of key events that include: perturba tion of cholesterol biosynthesis, hepatotoxicity, cell death (both as single cell necrosis and apoptosis) and a sustained increase in cell replication rates. Neither the key events nor an increase in liver tumors are seen in rats fed on diets containing u p to 3000 ppm thiamethoxam. The key metabolites, CGA330050 and CGA265307, responsible for the key events in the mouse are not formed in sufficient quantities in the rat and explain the lack of a carcinogenic response in this species.

A sufficient amount of active metabolite must be produced along with persistent exposure to the active metabolite to lead to the hepatotoxic/regenerative proliferative/neoplastic response in the

mouse. Limited human in vitro metabolism studies suggest that humans are more si milar to the rat compared to the mouse in producing the active metabolite. The rat does not develop tumors following treatment with thiamethoxam. Thus, the mouse appears to be uniquely sensitive to this

mode of action. Because of the threshold nature of the mode of action and the unique sensitivity of the mouse, it is concluded that humans are unlikely to be at risk for developing tumors following exposures to thiamethoxam.

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

the CARC re

- classified t hiamethoxam as “Not Likely to be Carcinogenic to Humans” based on convincing evidence that a non

- genotoxic mode of action for liver tumors was established in the mouse and that the carcinogenic effects are a result of a mode of action dependent on sufficient amounts of a hepatotoxic metabolite produced persistently. Although humans are qualitatively capable of producing the active metabolite, thiamethoxam is unlikely to pose a

cancer risk to humans unless sufficient amou nts 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 D373376

Page 27 of 60 3.5.12 Summary of Toxicological Doses and Endpoints for Thiamethoxam for Use in

Human Health Risk Assessments

.

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

Human Health Risk Assessments. Exposure/

Scenario Point of

Departure Uncertainty/FQPA

Safety Factors Level of Concern

for Risk Assessment Study and Toxicological Effects

Acute Dietary All populations including infants

and children NOAEL = 34.5

mg/kg/day UF A = 10x

UF H = 10x

SF FQPA =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

SF FQPA =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 1 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 (al l durations) NOAEL= 8.23

mg/kg/day UF A = 10x

UF H = 10x

SF FQPA =1 MOE= 100

(residential) 90

- day Dog s tudy

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); decreas ed calcium levels and ovary weights and delayed maturation in the ovaries (females); decreased cholesterol and phospholipid levels, testis weights, spermatogenesis, and spermatic giant cells in testes (males).

Dermal (all durations) (Adults) Oral study

NOAEL= 1.2 mg/kg/day (dermal absorption rate = 5%) UF A = 10x

UF H = 10x

SF FQPA =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

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

abnormalities in F 1 males.
Dermal (all durations) (infants/

children 1

- 6 yrs) Dermal Study

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

UF H = 10x

SF FQPA =1 MOE= 100

(residentia l) Rat 28

- Day Dermal Toxicity Study

LOAEL = 250 (females) mg/kg/day based on increased plasma glucose, triglyceride levels, and alkaline phosphatase activity and inflammatory

cell infiltration in the liver and necrosis of single hepatocytes in

females.

I nhalation (all durations) Oral study

NOAEL= 1.2 mg/kg/day UF A = 10x

UF H = 10x

SF FQPA =1 MOE= 100

(residential) 2

- Generation reproduction study

LOAEL = 1.8 mg/kg/day based on

increased incidence and sev erity ofThiamethoxam D373376

Page 28 of 60 Table 3.5.12a. Toxicological Do ses and Endpoints for Thiamethoxam for Use in Dietary and Residential

Human Health Risk Assessments. Exposure/

Scenario Point of

Departure Uncertainty/FQPA

Safety Factors Level of Concern

for Risk Assessment Study and Toxicological Effects

(inhalation absorption rate

= 100% of oral absorption) tubular atrophy in testes of 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 Humans” based on convincing evidence that a non

- genotoxic

mode of action for liver tumors was established in the mouse

. Quantification of cancer risk is not required.
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL

= no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short

- term study for long

- term risk

assessment. UF DB = to account for the absence of key date (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = l evel of concern. N/A = not applicable.

Table 3.5.12b. Summary of Toxicological Doses and Endpoints for Thiamethoxam for Use in Occupational

Human Health Risk Assessments. Exposure/

Scenario Point of Departure Uncertainty

Factors Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Dermal

Short

- term (1

- 30 days)

and

Intermediate

term (1

- 6 months) Oral study NOAEL=

1.2 mg/kg/day (dermal absorption rate = 5%) UF A = 10x

UF H = 10x MOE= 100

(occupational) 2

- Generation reproduction study

LOAE L = 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

Sh ort

- term (1

- 30 days)

and

Intermediate

term (1

- 6 months) Oral study NOAEL=

1.2 mg/kg/day (inhalation absorption factor = 100%) UF A = 10x

UF H = 10x MOE= 100

(occupational) 2

- Generation reproduction study

LOAEL = 1.8 mg/kg/day based on

increased incidence an d 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.
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL

= no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short

- term study for long

- term risk

assessment. UF DB = to account for the absence of key data (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin o f exposure. LOC = level of concern. N/A = not applicable.Thiamethoxam D373376

Page 29 of 60 3.6 Endocrine disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether cert ain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a ―naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.‖ The EDSP empl oys a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal

sys tems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine related effects caused by the substance, and

establish a dose

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

Between October 2009 and February 2010, EPA i ssued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. This list of chemicals was selected based on the potential for human exposure through pathways

such as food and wa ter, residential activity, and certain post

- application agricultural scenarios. This list should not be construed as a list of known or likely endocrine disruptors.

Thiamethoxam is not among the group of 58 pesticide active ingredients on the initial lis t to be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call

- ins for all pesticide active ingredients

.

For further information on the sta tus of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/.

4.0 Public Health and Pesticide Epidemiology Data

None.

5.0 Dietary Exposure/Risk Characterization

5.1 Pesticide Metabolism and Environmental Degradation

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 Chemist ry Memo D252021, 3/30/00, G.J. Herndon (PP#9F5046) Residue Chemistry Memo D265079, 5/8/00, G.J. Herndon (PP#9F5051)Thiamethoxam D373376

Page 30 of 60 Data have been submitted and reviewed depicting the metabolism of thiamethoxam in numerous

cr ops and the environment. HED has determined that the plant and livestock residues of concern (ROC) for purposes of tolerance enforcement and risk assessment are the combined residues of

thiamethoxam and clothianidin ( CGA

- 322704 ) ( see Table 5.1). For a co mplete discussion of metabolism in crops and livestock, including chemical names and structures, see the Residue Chemistry Summary Document (D281702, M. Doherty, March 2007).

Table 5.1. Summary of Metabolites and Degradates to be included in the Risk Ass essment and Tolerance Expression

Matrix Residues included in Risk

Assessment Residues included in Tolerance Expression for Compliance Monitoring

Plants Primary Crop Thiamethoxam + clothianidin Thiamethoxam + clothianidin

Rotational Crop Not Applicable Not Applicable

Livestock Ruminant Thiamethoxam + clothianidin Thiamethoxam + clothianidin

Poultry Thiamethoxam + clothianidin Thiamethoxam + clothianidin

Drinking Water Thiamethoxam Not Applicable

5.2 Analytical Methodology

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

Residue Chemistry Memo D265079; G.J. Herndon; 8 May 2000 Residue Chemistry Memo D271516 ; M. Doherty; 29 May 2001 Residue Chemistry Memo D28 1702; M. Doherty; 17 April 2007 Residue Chemistry Memo D 367065 ; W. Drew ; 3 May 2010

The HPLC Method AG

- 675 with UV or MS detection w as previously submitted in conjunction with thiamethoxam petitions. Me thod AG

- 675 has been determined to be adequate for enforcing

tolerances for residues of thiamethoxam and CGA

- 322704 in crop and livestock commodities. Syngenta has submitted a re vised Method AG

- 675, i.e., Method GRM.009.04A. The full extraction steps for plant and livestock commodities, including the microwave e xtraction step for liver, have been incorporated. The limits of quantitation ( LOQs ) of Method GRM.009.04A have been established at 0.01 ppm each for residues of thiamethoxam, CGA

- 322704 and CGA

26 5307

. Met hod validation data are available for Method GRM.009.04A

.

The various data

- collection methods, used for analysis of samples taken from the magnitude of the residue studies discussed in this action, are based on either Methods AG

- 675 or

GRM.009.0 4A. Method recoveries from concurrent analysis of samples were within the generally recognized acceptable range of 70

- 120%

.

5.3 Drinking Water Residue Profile

Reference: EFED Memo D3 73378 , C. Koper, 20 May 2010Thiamethoxam D373376

Page 31 of 60 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 (D3 73378 , C. Koper, 2 0 May 2010), and incorporated directly into the dietary assessments. Water residues were incorporated in DEEM

- FCID via entry into the food categories ―water, direct, all sources‖ and ―wa ter, 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 groundwater

estimates for ea ch 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.

A Tier I I screening

- level drinking water assessment was conducted for the proposed seed

treatment of alfalfa and peanut seed

. EFED also evaluated leafy vegetables, dry bulb onions and

corn because previous asses sments on these commodities were conducte d at a lower application

rate.

For surface water, the EDWCs for the crops modeled in this assessment did not exceed the previous EDWCs for rice reported in the previous drinking water assessment (D363202) dated

07 A pril 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 t he various uses. Therefore, the current EDWCs for surface water do not supersede the drinking water concentrations previously estimated for this chemical (D363202, F. Khan, 7 April 2009)

.

For groundwater, based on the proposed highest annual use rate for dry bulb onions and the proposed use rates for peanu t an d alfalfa seed treatment , the SCI

- GROW model concentration of

thiamethoxam was 4 .66 μg/L , 1.24 μg/L and 0.34 μg/L , respectively . This value was compared

to 4.14 μg/L reported for grap es in the previo us drinking water assessment (D329467) dated 10 January 2007. The predicted value for grapes is a corrected value described in detail in a previous drinking water assessment (D368072) dated 2 Feb 2010. Since 4.66 μg/L is greater than 4.14 μg/L, the curre nt EDWC supersede s the previously recommended EDWC for groundwater.

The acute scenario EDWC in surface water (0.131 77 ppm) was obtained via exposure modeling

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

. This model

and i ts description are available at the EPA internet website via the web link, http://www.epa.gov/oppefed1/models/water/

.Thiamethoxam D373376

Page 32 of 60 Table 5.3. Tier II Estimated Drinking Water Concentrations (EDWCs) resultin g 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) 131.7 7 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 0.34

Dry bulb onions: (1 app. X 0.30 lbs. ai/acre) 4.66 4.66 4.66

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

1 Recommended EDWCs for surface water.

2 EDWCs based on day 1.

3 EWDCs based on average of 365 days.

Monitoring Data

Only very limited monitoring d ata are available for thiamethoxam and these data are discussed below; due to this limitation HED used modeling data for the drinking water residue estimate for both the acute and chronic dietary risk assessments.Thiamethoxam D373376

Page 33 of 60 The registrant has conducted small

- scale prospective groundwater studies in several locations in the US to investigate the mobility of thiamethoxam in a vulnerable hydrogeological setting. A review of those data (Amer Al

- Mudallal, D339099, 4/18/06) shows that generally residues of thiamethoxam ( as well as CGA

- 322704) are below the limit of quantitation (0.05 ppb). When quantifiable residues are found, they are sporadic and at low levels. The maximum observed residue levels from any monitoring well were 1.0 ppb for thiamethoxam and 0.73 ppb for CGA

322704. These values are well below the modeled estimates summarized above, indicating that

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

5.4 Food Residue Profile

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

DER for MRID #45093704 (Crop field trials with peanuts) DER for MRID #48020201 (Crop field trials with alfalfa) DER for MRID #48110202 (Food handling establishment

, var ious food items)

Peanuts: The submitted peanut field trial data are adequate, and reflect the planting of peanut
seeds treated with either the 70% ai WS formulation, or the 5 lb ai/gal FS formulation of

thiamethoxam at 200 g ai/ 100 kg seed s

. Based on the amounts of seeds planted per acre, the

rates were 0.126

- 0.24 lb ai/A (1.5

- 3 X the proposed maximum per

- acre use rate). An acceptable method was used for the quantitation of thiamethoxam residues in peanut nutmeat and hay , and adequ ate storage stability data are available to support sample storage durations and conditions.

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

Peanut

Matrix Use Rate (g

ai/ 100 kg S eed s ) EP Combined Residue Levels ( ppm Th iamethoxam E quivalents) 1

n Min. Max. 2 HAFT 3 Mean Std. Dev.
Hay 2 00 5FS 18 <0.02 0.06 0.05 0.026 0.011

70WS 36 <0.02 0.23 0.20 0.032 0.043

Nutmeat 5FS 18 <0.02 0.05 0.05 0.026 0.011

70WS 36 <0.02 0.04 0.03 0.021 0.004 Hay 600 70WS 4 <0.02 0 .79 0.64 0.33 0.38

Nutmeat 4 <0.02 0.02 0.02 0.02 0

1. For calculation of the mean, HAFT, and standard deviation, the LOQ was used for residues reported as below the LOQ. 2. The table does not include the residue level in nutmeat used for the pr ocessing study. A RAC residue of 0.09 ppm was found in nutmeat following application at 200g ai/100 kg seeds (equivalent to 0.16 lb ai/A).

3

. HAFT = Highest Average Field Trial.

Alfalfa: The submitted alfalfa field trial data are adequate, and re flect the planting of alfalfa seeds treated with the 5 lb ai/gal FS formulation of thiamethoxam at 0.001 mg ai/seed , with harvest occurring at 45 days after planting ( DAP )

. An acceptable method was used for the quantitation of thiamethoxam residues in alf alfa forage and hay , and adequate storage stability data are available to support sample sto rage durations and conditions.Thiamethoxam D373376

Page 34 of 60 TABLE 5.4.2 Summary of Residue Data from Alfalfa Field Trials with Thiamethoxam.

Alfalfa Commodity Maximum

Use Rate 1 (lb ai/A) EP 2 Residue Levels (ppm)

Minimum Maximum HAFT 3

Thiamethoxam Forage 1st cutting 0.0130 Cruiser 5FS <0.01 0.03 0.03 Forage 2nd cutting <0.01 <0.01 <0.01 Forage 3rd cutting <0.01 <0.01 <0.01 Hay 1st cutting <0.01 0.09 0.08 Hay 2nd cutti ng <0.01 0.01 0.01 Hay 3rd cutting <0.01 <0.01 <0.01

CGA

- 322704 Forage 1st cutting 0.0130 Cruiser 5FS <0.01 <0.01 <0.01 Forage 2nd cutting <0.01 <0.01 <0.01 Forage 3rd cutting <0.01 <0.01 <0.01 Hay 1st cutting <0.01 <0.01 <0.01 Hay 2 nd cutting <0.01 <0.01 <0.01 Hay 3rd cutting <0.01 <0.01 <0.01
1. The alfalfa field trials utilized single (and seasonal) use rates of 0.0037

- 0.0130 lb ai/A, based on the respective seeding rates (8.00

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

2. EP = End

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

Food handling establishments: The submitted data on thiamethoxam residues in food commodities following indoor spot, and crack and crevice treatments in food handling establishments are adequate. An adequate variety of food commodities were exposed to thiamethoxam, in two different types of food handling establishments, at 1X the maximum proposed rate. An acceptable method was u sed for the quantitation of thiamethoxam residues in the various food commodities, and adequate storage stability data are available to support the sample storage durations and conditions. In addition, there were no thiamethoxam or clothianidin residues f

ound at quantifiable levels in any of the wide variety of uncovered food types which were exposed for up to 8 hours to an exaggerated use pattern (1X rate, followed by 2X rate within 48 hours).

Processing Studies

There are no processed commodities assoc iated wi th the proposed use on alfalfa. Reduction of

thiamethoxam residues in peanut oil after processing was at least 0.22

- 0.40 X

. Residues were

observed in the nutmeat and meal of peanuts ( grown from peanut seeds treated at roughly 2X the proposed use r ate ) from both field trial s

. The empirical concentration factors for thiamethoxam in meal range d from 2.0

- 3.1 X

, with an average of 2.6 X

.

Conclusions

A large percentage of the residue values in peanuts were below the combined LOQ of 0.02 ppm; therefore, the tolerance harmonization spreadsheet was not used to determine an appropriate tolerance. Based on the maximum combined thiamethoxam ROCs of 0.05 and 0.23 ppm in 1X

-Thiamethoxam D373376

Page 35 of 60 treated nutmeat and hay samples, respectively, HED recommends a tolerance of 0.05 ppm in peanut nutmeat, and a tolerance of 0.25 ppm in peanut hay

.

A large percentage of the residue values in alfalfa were below the combined LOQ of 0.02 ppm; therefore, the tolerance harmonization spreadsheet was not used to determine an appropriate

tolerance. Based on the maximum combined thiamethoxam ROCs of 0.04 and 0.10 ppm in 1X

treated forage and hay samples, respectively, HED recommends a tolerance of 0.05 ppm in alfalfa forage, and a tolerance of 0.12 ppm in alfalfa hay.

Based on maximum thiamethoxa m and CGA

- 322704 residues of <0.01 ppm in food commodities exposed to 1X treatment in food handling areas (with the vast majority of samples containing non

- detectable residues), HED recommends a tolerance of 0.02 ppm, the combined LOQ, in food /feed commodi ties (other than those covered by a higher tolerance as a result of use on growing crops)

.

A tolerance is not required in peanut oil. With HAFT combined residues of 0.05 ppm in peanut

nutmeat (based on residues of 0.09 ppm at a 2X rate) , and the theore tical concentration factor for peanut meal of 2.2X, HED recommends a tolerance of 0.15 ppm in peanut meal

.

5.5 International Residue Limits

There are no international residue limits that affect HED’s recommen dations at this time. There are no CODEX or Mexican maximum residue limits (MRLs) for thiamethoxam for the crops requested

. Canada has established an MRL of 0.02 mg/kg for residues of thiamethoxam and

CGA

- 322704 in all food crops (including alfalfa and p eanut) , and is transitioning to specific commodity MRLs ( all at 0.02 mg/kg) on a variety of crops including various cereal grains, peas and beans, soybean s , sweet corn, and sunflower.

5.6 Dietary Exposure and Risk

Reference: D376368 , D. McNeilly, 23 Nov 2010

Acute and chronic dietary risk assessments were conducted using the Dietary Exposure Evaluation Model (DEEM

- FCIDTM, Version 2.03) which uses food consumption data from the U.S. Department of Agriculture’s Continuing Surveys of Food Intakes by Individuals (CSFII)

from 1994

- 1996 and 1998. The analyses were performed to evaluate Sect ion 3 requests for new

seed treatment uses on alfalfa and peanuts and for use in food handling establishments

.

A new chlothianidin dietary assessment (D 384145 , M. Dohert y , in progress) and risk assessment is being conducted ( D 377956

, M. Dohert y , in progre ss) to update clothianidin residues on peanuts and other food commodities in support of the thiamethoxam food handling establishment

use

.

There is available information indicating that thiamethoxam and clothianidin have different toxicological effects in mammals and should be assessed separately; however, in conducting these assessments, residues of clothianidin coming from thiamethoxam were combined withThiamethoxam D373376

Page 36 of 60 residues of thiamethoxam. The total residue was then used to estimate dietary exposure and risk.

Clo thianidin, a major metabolite of thiamethoxam in plants and livestock, is not a significant degradate of thiamethoxam in surface or groundwater sources of drinking water.

T he acute dietary assessment i s based on tolerance level r esidues of thiamethoxam a nd

clothianidin and assumes 100% crop treated for all commodities (registered and requested uses)

. The chronic dietary assessment is based on tolerance level residues and anticipated residues from

thiamethoxam field trials . The chronic assessment assume s that 100% of crops with registered or requested uses of thiamethoxam are treated.

The drinking water residues were provided by EFED (D3 73378 , C. Koper, 2 0 May 2010), and incorporated directly into the acute and chronic dietary assessments. Water residue s were incorporated in DEEM

- FCID via entry into the food categories ―water, direct, all sources‖ and ―water, indirect, all sources.‖ The estimated drinking water concentrations (EDWCs) in surface

water are 0.13 177 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 having higher values in this case.

T hese assumptions result in conservative, health

- pro tective estimates of exposure (Table 5.6). Risk estimates for acute and chronic dietary exposure for all assessed population subgroups are

below HED’s level of concern , which is generally 100% of the acute or chronic adjusted dose ( aPAD or cPAD ).

Table 5.6. Summary of Estimated Dietary (Food + Drinking Water) Exposures and Risk for

Thiamethoxam.

Population Subgroup aPAD, mg/kg Acute Estimates (95 th Percentile) cPAD, mg/kg/day Chronic Estimates
Exposure, mg/kg Risk, % aPAD Exposure, mg/kg/day Ris k, % cPAD

U.S. Population 0.35 0.018094 5. 2 0.012 0.002825 24
All infants (< 1 year) 1 0.35 0.033165 9.5 0.012 0.003052 25

Children 1

- 2 yrs 0.35 0.032947 9.4 0.012 0.005150 43

Children 3

- 5 yrs 0.35 0.026627 7.6 0.012 0.004520 38

Children 6

- 12 yrs 0.35 0.018819 5.4 0.012 0.003241 27

Youth 13

- 19 yrs 0.35 0.014311 4.1 0.012 0.002333 19

Adults 20

- 49 yrs 0.35 0.016277 4.7 0.012 0.002591 22
Adults 50+ yrs 0.35 0.016617 4.8 0.012 0.002648 22

Females 13

- 49 yrs 0.35 0. 0 16123 4.6 0.012 0.002617 22

1

- The population subgroup with the highest estimated exposure/risk is bolded.

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

Reference: D376368 , D. McNeilly

, 23 Nov 2010Thiamethoxam D373376

Page 37 of 60 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 field trial data ) for

selected commodities ( discussed in detail in D376 368

, D. McNeilly, 23 Nov 20 10 ) 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

.

6.0 Residential (N on

- Occupational) Exposure/Risk Characterization

Reference: Thiamethoxam: Occupational and Residential Exposure Assessment for Section 3 Registration, M. Collantes; July 24 , 2009 ; D3 59207

A residential (non

- occupational) exposure/risk assessment was not performed at this time in conjunction with the proposed uses. The proposed seed treatment uses are limited to occupational/ commercial seed treaters (handlers and secondary handle rs). Since the Optigard Flex label stipulates that treatment areas are away from eating areas and other areas where children may come in contact with treated surfaces (i.e., not in or around room where children are playing or eating), a quantitative reside ntial exposure assessment is not required for this action. Furthermore, the registered label also indicates that product is to be applied under the supervision of commercial applicators. HED previously performed a crack and crevice residential exposure a ssessment for this same exact product, previously known as OptigardTM ZT (Registration number 100

- 1170) containing 21.6% of the active ingredient thiamethoxam (M. Collantes, July 2009, D359207). A r esidential exposure assessment for the use of thiamethox am on turf was also previously performed (M. Collantes; March 2007; D332064). 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. A summary of the postapplication exposure is provided below.

Postapplication Exposure

T here is a potential for exposure from entering areas previously treated with thiamethoxam that could lead to exposures for adults and children. Postapplication residential scenario s w ere assessed using the HED Draft Standard Operating Procedures (SOPs) for Residential Exposure Assessments (12/18/97), and the Revisions to the Standard Operating Procedures (SOPs) for Residential Exposure Assessment (Science Advisory Council for Exposur e Policy 12, Revised February 22, 2001). The level of concern (LOC) for the margin of exposure (MOE) is 100 for all

residential uses. All postapplication dermal scenarios for adults and children ranging in age from 3 to 6 years resulted in MOEs greater t han 100 and are not of concern to HED. A summary of the dermal postapplication exposure and risks are included in Table 6.a

.Thiamethoxam D373376

Page 38 of 60 Table 6.a.: Postapplication Dermal Exposure for Children and Adults for 0.1% and 0.05% Sprays for Crack and

Crevice

Surface Po pulation

Subgroup ISR 1

(μg/cm 2 ) CF TC 2

(cm 2 /hr) ED 3

(hrs) Dermal Absorption (mg/kg/day) BW

(kg) Dermal

Dose 4
(mg/kg/day) NOAEL

(mg/kg/day) MOE 5

Carpet adult 0.025 0.001 16,700 8 0.05 60 0.00278 1.2 430

child 6,000 1 15 0.08 60 750 Vinyl adult 0.05 16,700 4 0.05 60 0.00278 1.2 430

child 6,000 1 15 0.08 60 750

1. IS R = indoor surface transferable residues = deposition residue (0.5 ug/cm 2 ) x fraction of residue available for transfer from carpet vs. hard surface (0.05/0.1)

2. Tc = transfer co e fficient based on HED Residential SOPs

3. E D =exposure duration based on HED Residential SOPs

4. Dose = ISR (ug/cm 2 ) x 0.001 (mg/ug) x Tc (cm 2 /hr) x E D (hrs/day) x dermal absorp tion for adults only (mg/kg/day)

BW (kg)

5. Adult MOE = NOAE L (1.2 mg/kg/day) Child MOE = NOAEL (60 mg/kg/day)

D ermal Dose D ermal Dose

O ral non

- dietary ingestion exposures also were assessed for children (i.e. hand

- to

- mouth ) for

indoor crack and crevice use . The hand

- to

- mouth transfer postapplication exposure assessment
resulted in oral MOE s greater than 100 for all scenarios, and therefore oral postapplication risks

are not of concern to HED

. Table 6.b summarizes the MOEs for hand

- to

- mouth transfer of pesticide residues from indoor crack and crevice use.

Table 6.b.: Postapplication Oral Exposure for Children for 0.1% and 0.05% Sprays for Crack and Crevice

Surface ISR 1

(μg/cm 2 ) SA 2

(cm 2 ) FQ 3
(event/hr) ED 4

(hrs) SE 5 CF 6 Oral Dose 7

(mg/kg/day) MOE 8

Short

– term

carpet 0.025 20 20 8 0.5 0.001 0.0026 3100 vinyl 0.05 4

Intermediate

- term

carpet 0.025 20 9.5 8 0.5 0.001 0.00126 6500 vinyl 0.05 4

1. ISR = indoor surface transferable residues = deposition residue (0.5 ug/cm 2 ) x fraction of residue available for

transfer fro m carpet vs. hard surface (0.05/0.1) 2. Surface area. 3. Frequency of hand

- to

- mouth events. 4. Exposure duration.

5. Saliva extraction factor

. 6. Conversion factor (mg/μg) . 7. Oral Dose = ( ISR x SA x FQ x ED x SE x CF1 )/(BW 15 kg)

8. Oral MOE = NOAEL (8.23 mg/kg/day)/Oral dose.

Based on the Agency's current practices, a quantitative residential postapplication inhalation exposure assessment was not performed for thiamethoxam at this time primarily because it has a very low vapor pressure (6 .6 x 10 - 9 Pa @ 25 o C), inhalation exposure is expected to be negligible

as a result of indoor crack and crevice use.

Combined Residential Risk Estimates

In the previous 2007 thiamethoxam residential assessment, a combined residential assessment was perf ormed for turf dermal and oral postapplication exposure of toddlers only

. A more recent 2009 assessment (D365272, D. McNeilly, 6 August 2009) evaluated a n indoor crack and crevice product and provided a revised combined residential assessment based on ind oor crack andThiamethoxam D373376

Page 39 of 60 crevice use. These exposures and risks were greater than exposure/risk from the use on lawns. Therefore, the indoor exposures should be used in an aggregate assessment in order to be protective.

HED combined all non

- dietary sources of po stapplication exposure to obtain an estimate of potential combined exposure which could be used for the aggregate assessment. These scenarios consisted of adult and toddler dermal postapplication exposure and oral (hand

- to

- mouth)

exposures for children 3 to 6 years of age

. All postapplication scenarios resulted in combined MOEs greater than 100 and were not of concern to HED. Table 6. c provides a summary of the combined residential indoor crack and crevice exposures and risks.

Table 6.c . Combined Resi dential Exposure and Risk Estimates from Indoor Crack and

Crevice Use Postapplication

Scenarios Daily Dose (mg/kg/day) 1 MOE 2 Combined

MOE 3

Short

- term

Adult Dermal

– indoor surface 0 .0027 8 430 430

Toddler Dermal

- indoor

surface 0.08 750

610

Hand

- t o

- Mouth 0.0026 7 3100

Intermediate

- term

Adult Dermal

- indoor surface 0.027 8 430 430

Toddler Dermal

- indoor

surface 0.08 750

680

Hand

- to

- Mouth 0.001267 6500

1 Daily Dose = see Tables 6.a. and 6.b. 2 Adult Dermal MOE = NOAEL (1.2 mg/kg/day)

Dermal Dose

Child Dermal MOE = NOAEL (60 mg/kg/day)

Dermal Dose

Child Oral MOE = NOAEL (8.23 mg/kg/day)

Oral Dose

3 Toddler Combined MOE = 1/ [(1/MOE Dermal ) + (1/MOE Hand

- to

- Mouth )]

7.0 Aggregate Risk Assessments and Risk Characterization

Potential areas of en vironmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, ―Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations, ‖ http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- establ ished procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intakes by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These da ta 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 subgroupsThiamethoxam D373376

Page 40 of 60 and exposure assessments are performed when cond itions or circumstances warrant. W henever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are e valuated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional die tary patterns among specific subgroups. Given the existing and proposed use patterns for

thiamethoxam as well as the health

- protective assumptions throughout this risk assessment, it is unlikely that any geographic, ethnic, or socioeconomic population wil l have increased exposure relative to the standard population subgroups assessed by OPP.

7.1 Acute Aggregate Risk

In examining acute aggregate risk, HED has assumed that the only pathway of exposure relevant

to that ti me frame is dietary exposure. Therefore, the acute aggregate risk is composed of exposures to thiamethoxam residues in food and drinking water and is equivalent to the acute dietary risk discussed in Section 5. 6 . As noted in that section, the acute risk estimates are well below HED’s level of concern for all population subgroups.

7 .2 Short

- Term Aggregate Risk

References : D375247 , D. McNeilly, 3 May 2010

D359207, M. Collantes; 24 July 2009

S hort

- term exposures (1 to 30 days of continuous exposure) may occur as a result of entering indoor areas previously treated with a thiamethoxam indoor crack and crevice product

. Exposures related to indoor activities (Table 6 .c ) have been combined with ch ronic dietary exposure estimates (as an estimate of background dietary exposure; Table 5.6. b ) to assess the

worst

- case short

- term aggregate exposure. The indoor crack and crevice scenario has higher exposure for both adults and children than the exposure levels in the turf scenario. The s hort

term aggregate MOEs range from 3 7 0 to 490 (Table 7.2). Since these are greater than 100, they

represent aggregate risk estimates that ar e below HED’s level of concern.

Table 7.2. Estimates of Short

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

2 Hand

- to

- Mouth 2 Total S hort

- T erm Aggregate 3

General U.S.

, p opulation 2

, 900 430

------- 3 7 0

All infants 2, 7 00 750 3,100 490

Children 1

- 2 yrs 1,600 750 3,100 4 4 0

Children 3

- 5 yrs 1,800 750 3,100 4 5 0

Children 6

- 12 yrs 2, 5 00 430

------ 370

Youth 13

- 19 yrs 3, 5 00 430

------ 380

Adults 20

- 49 yrs 3,200 430

------ 380 Adults 50+ yrs 3, 1 00 430

------ 380Thiamethoxam D373376

Page 41 of 60 Table 7.2. Estimates of Short

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

2 Hand

- to

- Mouth 2 Total S hort

- T erm Aggregate 3

Females 13

- 49 yrs 3, 1 00 430

------ 380

1 Dietar y Aggregate MOE = Incidental Oral NOAEL (8.23 mg/kg/day) ÷ Chronic Dietary (Food + Water) Exposure (mg/kg/day; from Table 5.6. b ). Values are rounded to 2 significant figures.

2 I ndoor crack and crevice exposure (which has higher exposure than residential turf) from Table 6 c

. Hand

- to

mouth is appropriate for infant and children population subgroups only.

3 Total Aggregate MOE = 1/[(1/MOE Dietary ) + (1/MOE Dermal ) + (1/MOE HtM )]. Values rounded to 2 significant figures.

7.3 Intermediate

- Term Aggregate Ri sk

Intermediate

- term exposures (30 to 180 days of continuous exposure) may occur as a result of entering indoor areas previously treated with a thiamethoxam indoor crack and crevice product. Exposures relate d to indoor activities (Table 6.c) have been combined with chronic dietary exposure estimates (as an estimate of background dietary exposure; Table 5.6. b ) to assess the

worst

- case intermediate

- term aggregate exposure. The indoor crack and crevice scenario has higher exposure for both adults and children than the exposure levels in the turf scenario. The

i ntermediate

- term aggregate MOEs range from 3 7 0 to 5 4 0 (Table 7. 3 ). Since these are greater than 100, they represent intermediate

- term aggregate risk est imates that are below HED’s level

of concern.

The difference between short

- and intermediate

- term aggregate risk s i s the frequency of hand

- to

mouth events for children. For short

- term exposure there are 20 events per hour and for

intermediate

- term exposu re there are 9.5 events per hour (see Table 6.b) . The doses and end

points for short

- and intermediate

- term aggregate risk are the same.

Table 7.3. Estimates of Intermediate

- term Aggregate Risks for Thiamethoxam Population Subgroup Margins of Exposu re (MOEs) Dietary Aggregate 1 Dermal 2 Hand

- to

- Mouth 2 Total I ntermediate

- T erm Aggregate 3

General U.S. population 2,900 430

------- 3 7 0

All infants 2,700 750 6,500 540

Children 1

- 2 yrs 1,600 750 6,500 4 7 0

Children 3

- 5 yrs 1,800 750 6,500 490

Childre n 6

- 12 yrs 2,500 430

------- 370

Youth 13

- 19 yrs 3,500 430

------- 380

Adults 20

- 49 yrs 3,200 430

------- 380 Adults 50+ yrs 3,100 430

------- 380

Females 13

- 49 yrs 3,100 430

------- 380

1 Dietary Aggregate MOE = Incidental Oral NOAEL (8.23 mg/kg/day ) ÷ Chronic Dietary (Food + Water) Exposure (mg/kg/day; from Table 5.6. b ). Values are rounded to 2 significant figures. 2 Indoor crack and crevice exposure (which has higher exposure than residential turf) from Table 6 c . Hand

- to

- mouth is appropriat e for infant and child ren population subgroups only. 3 Total Aggregate MOE = 1/[(1/MOE Dietary ) + (1/MOE Dermal ) + (1/MOE HtM )]. Values rounded to 2 significant figures.Thiamethoxam D373376

Page 42 of 60 7.4 Chronic Aggregate Risk

In examining chronic aggregate risk, HED has assumed that the only pathway of exposure relevant to that time frame is dietary exposure. Therefore, chronic aggregate risk is composed of exposures to thiamethoxam residues in food and drinking water and is equivalent to the chronic dietary risk discussed in Section 5. 6 . As noted in that section, the chronic risk estimates are below HED’s level of concern for all population subgroups.

7.5 Cancer Risk

Thiamethoxam has been classified as ―not li kely to be carcinogenic to humans.‖ As such, the

risk of cancer from thiamethoxam is not of concern. The chronic risk assessment would be protective for any potential cancer effects.

8.0 Cumulative Risk Characterization/Assessment

Thiamethoxam is a member of the neonicotinoid class of pesticides and produces, as a metabolite, another neonicotinoid, clothianidin. Structural similarities or common effects do not

constitute a common mechanism of toxicity. Evidence is needed to establish that the chemicals operate by the same, or essentially the same, sequence of major biochemical events (EPA, 2002). Although clothianidin and thiamethoxam bind selectively to insect nicotinic acetylcholine

recept ors (nAChR), the specific binding site(s)/receptor(s) for clothianidin, thiamethoxam, and the other neonicotinoids are unknown at this time. Additionally, the commonality of the binding activity itself is uncertain, as preliminary evidence suggests that c lothianidin operates by direct competitive inhibition, while thiamethoxam is a non

- competitive inhibitor. Furthermore, even if future research shows that neonicotinoids share a common binding activity to a specific site on insect nicotinic acetylcholine r eceptors, 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

neonicot inoids 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 mos t sensitive regulatory endpoint for thiamethoxam is based on unrelated effects in mammals, including effects on the liver, kidney, testes, and hematopoietic system. Additionally, the most sensitive toxicological

effect in mammals differs across the neonic otinoids ( e.g., testicular tubular atrophy with thiamethoxam; mineralized particles in thyroid colloid with imidaclop r id). Thus, there is currently no evidence to indicate that neonicotinoids share common mechanisms of toxicity, and EPA is not following a cumulative risk approach based on a common mechanism of toxicity for the neonicotinoids. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, se e the policy statements concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism released by EPA’s Office of Pesticide Programs on EPA’s website at http://www.epa.gov/pesticides/cumulative/

.Thiamethoxam D373376

Page 43 of 60 9.0 Occupational Exposure/Risk Pathway

Reference: Shih

- Chi Wang , D 37 3377

, 3 Dec 2010

Reference: Shih

- Chi Wang , D382248, 7 Dec 2010

Se ed Treatment (Alfalfa, Peanuts)

The Cruiser® 5FS Insecticide (liquid) and Cruiser® PD Insecticide (w ettable powder ) are proposed for use in open and closed commercial seed treatment facilities. Cruiser® 5FS Insecticide is proposed for use on alfalfa and peanuts, while Cruiser ® PD Insecticide is proposed

for use on peanuts only

. Neither product is to be used for on

- farm treatment of seeds. Based on the proposed label information, occupational exposure is expected to occur for short

- and

intermediate

- term durations.

Food/feed Handling Establishments

Optigard ® Flex Liquid Insecticide is proposed for use in food/feed handling establishments. The proposed use is for application of a 0.05% and/or a 0.1% spray solution to cracks & crevice, spots, surface, an d structural voids using low pressure handwand, backpack and other hand

- held equipment.

9.1 Short

- and Intermediate

- Term Handler Risk

Based on application rate and label information for the propos ed seed treatment uses of alfalfa and peanuts and the use in food handling establishments , exposure is expected to occur for short

and intermediate

- term durations. HED considers MOEs of less than 100 to indicate a risk of concern for occupational exposur e to thiamethoxam. In addition, doses and endpoints for assessing occupational risk are based on the same studies for all durations for both dermal and inhalation exposures; therefore, the short

- term and intermediate

- term risk assessments are equivalent.

Seed Treatment

This assessment covers commercial handlers operating open and closed seed treatment systems for use on alfalfa and peanuts. The following scenarios were assessed:

The proposed label states that Cruiser® PD is a wettable powder formulati on developed for dry application to peanut seeds. Since the treater (loader/ operator) unit exposure values from Policy 14 are based on liquid formulations, the loader/operator exposure for Cruiser® PD was estimated using surrogate unit exposure values fo r a wettable powder formulation in the Pesticide Handlers Exposure Database (PHED).

Loading/Applying Wettable Powder for Seed Treatment (Scenario 1

- Cruiser® PD peanuts only)Thiamethoxam D373376

Page 44 of 60 Handler exposure resulting from treatment of peanut and alfalfa seeds using C ruiser® 5FS and

Cruiser PD in open systems is based on the following exposure scenarios in accordance with HED’s Seed Treatment Standard Operatin g Procedure (SOP) #14:

Loading/Applying Liquid for Commercial Seed Treatment (Scenario 2) Sewing Bags after S eed Treatment (Scenario 3) Bagging Seeds after Seed Treatment (Scenario 4) Multiple Activities for Commercial Seed Treatment (Scenario 5)

Handler exposure resulting from treatment of peanut and alfalfa seeds using Cruiser® 5FS and

Cruiser PD in closed sys tems is based on the following exposure scenarios in accordance with Syngenta’s proprietary seed treatment study, Helix® 289 FS (Novartis Crop Protection Canada Inc, J. Purdy. and D. Houghton; August 22, 2000; MRID 452000

- 02; DP 273566) :

Loading/Applying Liquid for Close d

- System Seed Treatment (Scenario 6 ) Bagging/Sewing/Stacking Bags (Tyvek) after Seed Treatment ( Scenario 7 ) Bagging/Sewing/Stacking Bags (Cotton) after Seed Treatment ( Scenario 8 ) Forklift Operators (Scenario 9 ) Cleaner (Scenario 1 0 )

The exposures and risks for seed handlers are summarized in Tables 9.1.a and 9.1.b. The potential occupational exposures/risks resulting from the proposed seed uses do not exceed HED’s level of concern (MOEs range from 1 0 0 to 13,000) with the exception of the following

scenario s :

(1) The Cruiser® PD is intended for use as a dry application on peanuts. Since the treater (loader/operator) unit exposure values from Policy 14 are based on liquid formulations, the loader/operator exposure for Cruiser® PD was est imated using surrogate unit exposure values for a wettable powder formulation in the Pesticide Handlers Exposure Database (PHED). The treater scenario resulted in a MOE of 100 with the use of additional PPE (i.e. gloves, coveralls and a PF10 respirator). Currently the label only requires use of a dust mask (quarter or half mask) respirator. HED recommends that the Registration Division ensure that the appropriate respirator is required on the final Cruiser PD label

.

(2) The multiple activity scenario fo r commercially treating 718,000 lbs of alfalfa seed

, using an

open system

, resulted in a MOE of 59 at baseline with addition of gloves. With t he addition of a

PF 5 dust m ist respirator to current label personal protective equipment (PPE) [i

. e.
, gloves an d coveralls] the multiple activity workers scenario resulted in a n MOE greater than 100 (MOE =

1 7 0)

, which is not of concern

. However, the Cruiser ® 5FS label contains a restriction for commercial open system seed treatment facilities that limits the amoun t of product handled per day to no more than 38 gallons product/worker/8

- hr day which results in 413,043 lbs of seed a day. Therefore, HED also assessed treatment of 413,043 lbs of alfalfa seed at baseline with addition of gloves which resulted in a MOE o f 100 and was not of concern.Thiamethoxam D373376

Page 45 of 60 The exposures/risks resulting from the use of Cruiser® Insecticide in commercial closed peanut seed treatment facility were not calculated because they are no greater than those resulting from

the use of Cruiser® Insecticide on alfalfa because exposures/risks resulting from the peanut use are approximately 20% of those resulting from the alfalfa use

.

Secondary Seed Handlers

The exposure associated with handling treated seeds was calculated using unit exposures given in the HED Exposure Science Advisory Council (ExpoSAC) SOP #14 (May 1, 2003). All MOEs for secondary seed handlers are greater than 100 and do not exceed HED’s level of concern at the single layer plus gloves level of mitigation (760

– 2,500). A summary of the exposure/risk values is presented in Table 9.1. c

.

Food Handling Establishments

For the Optigard ® Flex Liquid Insecticide use in food/feed handling establishments the f ollowing four scenarios are expected to result in the highest exposure for the proposed use and were

evaluated:

Mixing/Loading/Applying Liquid Spray Using Low

- Pressure Equipment for Surface

Treatment Mixing/Loading/Applying Foam Spray Using Low

- Pressure Equipment for Surface

Treatment Mixing/Loading/App lying Wettable Powder Formulation (as surrogate for liquid formulation) Using Low

- Pressure Equipment for Crack and Crevice Treatment Mixing/Loading/Applying Wettable Powder Formulation (as surrogate for foam formulation) Using Low

- Pressure Equipment for Cr ack and Crevice Treatment

According to the proposed label, a pplicators and other handlers must wear: (1) long

- sleeved shirt & long pants, (2) chemical

- resistant gloves, and (3) shoes plus socks. Commercial applicators are not expected to immediately ret urn to treatment sites; therefore, a quantitative post

application assessment of handler exposure was not performed.

The handler assessment for the proposed use was based on surrogate unit exposure data from the Pesticide Handlers Exposure Database (PHED) Version 1.1 (HED Science Advisory Council for Exposure, SOP Number .007, January 1999 ) . Exposure scenarios resulting in MOEs greater than 100 are not of concern to HED. All but one exposure scenario resulted in a combined MOE ranging from 280 to 8, 3 00 fo r occupational handlers with use of personal protective equipment (PPE) mitigation (baseline attire plus chemical

- resistant gloves), which are already required on the label. The handler scenario using a foam application resulted in an MOE of 160 with the use of additional PPE (gloves, coveralls and PF5 dust mist respirator). Current label does not require use of coverall and respirators. Without such PPE, the MOE is only 56. HED recommends that if this use is to remain on the label, that the Registratio n Division ensure that the correct PPE be included in the final registered label. Exposures/risks for occupational handlers are presented in Table 9.1. d

.Thiamethoxam D373376

Page 46 of 60 Table 9.1.a . Thiamethoxam Non

- Cancer Risk for Commercial Seed

- Treatment Handlers

- Open System.

Exposure

Scenario (Scenario #) Mitigation

Level Dermal

Unit Exposure (mg/lb ai) Inhalation

Unit Exposure (mg/lb ai) Seed

Species Application Rate

(lb ai per lb seed) Amount Treated a

(lb seed trt per day) Daily

Dermal

Dose b (mg/kg/day) Daily

Inh alation

Dose c (mg/kg/day) Combined Daily Dose d
(mg/kg/day) MOE e

Loader/Applicator

Loading/Applying

Wettable Powder (PHED) (1) Double Layer,

Gloves & PF 10 Respirator 0.13 0.0043 Peanut 0.00054 120,000 0.00702 0.00464 0.0116 100

Loading/Applying Liq uids for Seed Treatment (2) Single Layer,

Gloves 0.023 0.00034 Peanut 0.00054 120,000 0.001242 0.0003672 0.001609 750

Alfalfa 0.00046 718,000 0.006325 0.00187 0.008195 150

Sewer

Sewing Bags after Seed treatment (3) Single Layer,

No Gloves 0.0062 0. 00023 Peanut 0.00054 120,000 0.000335 0.000248 0.000583 2,100

Alfalfa 0.00046 718,000 0.001705 0.001265 0.00297 400

Bagger

Bagging Seeds

after Seed treatment (4) Single Layer,

No Gloves 0.0091 0.00016 Peanut 0.00054 120,000 0.000491 0.000173 0.0006 64 1,800

Alfalfa 0.00046 718,000 0.002503 0.00088 0.003383 360

Multiple Activities Worker

Multiple

Activities for Seed treatment (5) Single Layer,

Gloves 0.042 0.0016 Peanut 0.00054 120,000 0.002268 0.001728 0.003996 300

Alfalfa 0.00046 718,000 0.01155 0.0088 0.02035 59 Double layer,

Gloves

0.019 0.0016

0.005229 0.0088 0.0140 85

Double layer, Gloves, &

Dust Mist Respirator 0.00032 0.00176 0.00699 170

Single Layer,

Gloves 0.042 0.0016 413043 * 0.00665 0.0050 0.01171 100

a Daily amounts treated values are based on ex posure SAC Policy #15 or the information provided by the Registrant through Registration Division (384,000 lb seed treated per day is the daily seed treated value

suggested by Syngenta )

. b Daily D ermal D ose (mg/kg/ d) = [ U nit D ermal E xposure (mg/lb ai) * D ermal A bsorption Factor (0.0 5 ) * A pplication R ate (lb ai/lb seed) * D aily A mounts T reated ] / B ody W eight ( 6 0 kg).

c Daily I

nhalation D ose (mg/kg/d) = [U nit E xposure (mg/lb ai) * A pplication R ate (lb ai/lb seed) * D aily A mounts T reated ] / B ody W eight ( 6 0 kg).

d Combined D aily D ose (mg/kg/d) = Daily D ermal D ose (mg/kg/d ay ) + Daily I nhalation D ose (mg/kg/d ay )

.

e MOE = NOAEL ( 1

. 2 mg/kg/d) / C ombined D aily D ose. UF = 100.Thiamethoxam D373376

Page 47 of 60 Table 9.1.b . Thiamethoxam Non

- Cancer Risk for Commercial Seed

- Treatment Handlers

- Closed System.

Exposure Scenario (Scenario #) Mitigation

Level Dermal

Unit Exposure (mg/lb ai) Inhalation

Unit Exposure (mg/lb ai) Seed Species Application

Rate (lb ai per lb seed) Amount

Treated a (lb seed trt per day) Daily

Dermal

Dose b
(mg/kg/day) Daily

Inhalation

Dose c (mg/kg/day) Combined

Daily Dose d
(mg/kg/day) MOE e

Loader/Applicator

Treater

Loader/Applicator ( 6 ) Coveralls,

Gloves 0.0011 0.00011 Alfalfa 0.00046 718,000 0.0003027 0.0006055 0.0 009082 1,300

Bagger/Sewer/Stacker

Bagger/Sewer/Stacker ( 7 ) + ( 8 ) Coveralls,

Gloves 0.00027 0.000064 Alfalfa 0.00046 718,000 0.0000743 0.0003552 0.0004295 2,800

0.00037 0.000064 Alfalfa 0.00046 718,000 0.0001018 0.0003552 0.000457 2,600

Forklift Opera tor

Forklift Operator ( 9 ) Coveralls,

Gloves 0.000145 0.00001 Alfalfa 0.00046 718,000 0.0000399 0.000055 0.0000949 13,000

Cleaner

Cleaner (1 0 ) Coveralls,

Gloves 0.00921 0.00115 Alfalfa 0.00046 718,000 0.002535 0.00633 0.008865 140

a

. Daily amounts tre ated values are based on ex posure SAC Policy #15 or the information provided by the Registrant through Registration Division.

b. Daily D ermal D ose (mg/kg/d) = [ U nit D ermal E xposure (mg/lb ai) * D ermal A bsorption Factor (0.0 5 ) * A pplication R ate (lb ai /lb seed) * D aily A mounts T reated ] / B ody W eight ( 6 0 kg).

c

. Daily I nhalation D ose (mg/kg/d) = [U nit E xposure (mg/lb ai) * A pplication R ate (lb ai/lb seed) * D aily A mounts T reated ] / B ody W eight ( 6 0 kg).

d

. Combined D aily D ose (mg/kg/d) = Daily D ermal D ose (mg/kg/d ay ) + Daily I nhalation D ose (mg/kg/d ay )

. e. MOE = NOAEL ( 1

. 2 mg/kg/d) / C ombined D aily D ose. UF = 100.

Table 9.1.c . Thiamethoxam Non

- Cancer Risk for Secondary Seed Handlers.

Exposure Scenario Mitigation

Level Dermal

Uni t Exposure (mg/lb ai) Inhalation

Unit Exposure (mg/lb ai) Seed Species Application

Rate (lb ai per lb seed) Amount

Planted a (lb seed

p lanted /

day) Daily

Dermal

Dose b
(mg/kg/day) Daily

Inhalation

Dose c (mg/kg/day) Combined

Daily Dose d
(mg/kg/day) MOE e

Secondary Seed Handlers

Secondary Seed Handlers: planting

seeds in the field Single Layer,

Gloves 0.25 0.00342 Peanut 0.00054 11,000 0.001238 0.000337 0.001575 760

Alfalfa 0.00046 4,000 0.0003833 0.0001042 0.0004875 2,500

a

. Daily amoun ts planted values are based on ex posure SAC Policy #15 or the information provided by the Registrant through Registration Division.

b

. Daily Dermal Dose (mg/kg/d) = [Unit Dermal Exposure (mg/lb ai) * Dermal Absorption Factor (0.05) * Application Rate (l b ai/lb seed) * Daily Amounts Treated] / Body Weight (60 kg).

c

. Daily Inhalation Dose (mg/kg/d) = [Unit Exposure (mg/lb ai) * Application. Rate (lb ai/lb seed) * Daily Amounts Treated] / Body Weight (60 kg).

d

. Combined Daily Dose (mg/kg/d) = Daily De rmal Dose (mg/kg/day) + Daily Inhalation Dose (mg/kg/day)

. e

. MOE = NOAEL (1.2 mg/kg/d) / Combined Daily Dose. UF = 100.Thiamethoxam D373376

Page 48 of 60 Table 9.1.d. Handler Exposure and Risk for Thiamethoxam Use in Food/Feed Handling Establishments.

Product &

Formulat ion Method of

Application Mitigation Dermal Unit

Exposure a

(mg/lb ai) Inhalation

Unit

Exposure a

(μg/lb ai) Application

Rate b

(lb ai/Gal) Amount

Treated c

(Gal/day) Dermal Dose

d (mg/kg/day) Inhalation

Dose e

(mg/kg/day) Combined

Daily Dose f

(mg/kg/da y) Total MOE g

Mixer/Loader/ Applicator

Optigard ®

Flex

Insecticide (21.6% a.i. Low

Pressure Spray

– liquid/foam Baseline +

gloves 0.43

(liquid surface spray) 30

(liquid surface spray) 0.0084

(liquid) 20 0.00006 0.000084 0.000144 8300

0.0423 (fo am) 0.00030 0.000423 0.000726 1700

Low

Pressure Spray

– Wettable

Powder/foam Baseline +

gloves, 8.6

(WP crack and crevice) 1,100

(WP crack and crevice) 0.0084

(liquid) 0.0012 0.0030 0.00428 280

Baseline + gloves, 8.6

(WP crack and crevice) 1,100

(WP crack and crevice) 0.0423

(foam) 0.006 0.015 0.0215 56

Baseline + gloves,

coveralls and

PF5 Dust Mist Resp. 6.22

(WP crack and crevice) 220

(WP crack and crevice) 0.004385 0.0031 0.00748 160

a. Unit Exposures based on PHED Version 1.1

. b. A pplication Rate is based on proposed label for Thiamethoxam product

--- Optigard® Flex Liquid Insecticide c. Science Advisory Council for Exposure (11/18/10) d. Dermal Dose (mg/kg/day) = [ Rate (lb ai/ Gal ) x UE (mg /lb ai ) x 5% DA F x Amount Treated ( Ga l /day)/ BW (60 kg)] e. Inhalation Dose (mg/kg/day) = [ Rate (lb ai/ Gal ) x UE (mg /lb ai ) x Amount Treated ( Gal /day)] / BW (60 kg) f. Combined Daily Dose (mg/kg/day) = Dermal Dose (mg/kg/day) + Inhalation Dose (mg/kg/day) g. Total MOE = [NOAEL (1.2 m g/kg/day)]/ Combined Daily Dose (mg/kg/day)Thiamethoxam D373376

Page 49 of 60 9.2 Short

- and Intermediate

- Term Postapplication Risk

Since no quantitative postapplication assessment was completed for treated seeds, t he restricted entry inte rval (REI) is based on the acute toxicity of thiamethoxam technical material which is

classified as Category I II for acute oral and dermal toxicity and Category IV for skin and eye irritation potential. The default restricted

- entry interval is 12 hours fo r active ingredients classified as acute toxicity categories III or IV for these routes of exposure. In accordance with

t he Worker Protection Standard (WPS), for purposes of seed treatment, once the seeds are planted, workers can enter during the REI, pro vided they do not contact the soil/media

subsurface that contains the treated seeds. Certain tasks may involve contact with the soil subsurface (e.g. repair of certain irrigation equipment) and they are covered by the REI.

Therefore

, HED concurs with the 12

- hour REI on the proposed label for seed treatment. HED recommends that the Registration Division ensure that appropriate language is placed on the product label to require the label on treated seed to include the restricted

- entry interval following

th e planting of treated seed. (Note: HED does not have transfer coefficients to assess postapplication dermal exposures to pesticides in the soil. )

Commercial applicators treating food handling establishments ar e not expected to immediately

return to treat ment sites; therefore, a quantitative postapplication assessment of handler exposure was not performed.

10.0 Regulatory Recommendations and Data Needs

The submitted field trial data for thiamet hoxam on peanuts are acceptable, and support the proposed use of Cruiser PD and Cruiser 5F S as pre

- plant seed treatments . An adequate number of trials were conducted in the appropriate geographic regions at roughly 1 .5

- 3 X the maximum proposed rate. Based on the maximum combined thiamethoxam ROCs of 0.05 and 0.23 ppm in

1X

- treated nutmeat and hay samples, respectively, HED recommends a tolerance of 0.05 ppm in peanut nutmeat, and a tolerance of 0.25 ppm in peanut hay.

The submitted field trial data for thiamethoxam on alfalfa are acceptable, and support the proposed use of Cruiser 5F S as a pre

- plant seed treatment . An adequate number of trials were conducted in the appropriate geographic regions at 1X the maximum proposed rate. Based on

the maximum com bined thiamethoxam ROCs of 0.04 and 0.10 ppm in 1X

- treated forage and hay samples, respectively, HED recommends a tolerance of 0.05 ppm in alfalfa forage, and a tolerance of 0.12 ppm in alfalfa hay.

The submitted data for thiamethoxam use in food handli ng areas are acceptable, and support the proposed use of Optigard Flex Liquid as a spot, void, and crack and crevice treatment in food handling establishments . An adequate variety of food commodities were exposed to thiamethoxam, in two different types of food handling establishments, at 1X the maximum proposed rate. M aximum thiamethoxam and CGA

- 322704 residues were each <0.01 ppm in food commodities exposed to 1X treatment in food handling areas (with the vast majority of samples containing non

- detectabl e residues) . Based on the presence of detectable residues ofThiamethoxam D373376

Page 50 of 60 thiamethoxam or CGA

- 322704 in various samples, HED recommends a tolerance of 0.0 2 ppm in

food /feed commodities (other than those covered by a higher tolerance as a result of use on growing crops )

.

There are no processed commodities associated with the proposed use on alfalfa. The processed commodities associated with the proposed use on peanut s are peanut meal and refined oil. The theoretical concentration factor for peanut meal ( OPPTS Resid ue Chemistry Test Guideline

860. 1520, Table 3) is 2.2 X

. The empirical concentration factors for thiamethoxam in meal (range 2.0

- 3.1 X

, average 2.6 X ) conform well to the theoretical value

. A tolerance is not required in peanut oil. Based on the HAFT combi ned residues of 0.05 ppm in peanut nutmeat, and the

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

.

There are no Codex or Mexican MRLs established for residues of thiamethoxam in crops

assoc iated with this review. Canada has established an MRL of 0.02 mg/kg for residues of

thiamethoxam and CGA

- 322704 in all food crops, and is transitioning to specific commodity

MRLs ( all at 0.02 mg/kg) on a variety of crops including various cereal grains, p eas and beans, soybean s , sweet corn, and sunflower.

TABLE 1 0 Tolerance Summary for Thiamethoxam. Commodity Proposed/Established Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity Definition

Peanut 0.05 0.05 Peanut, hay 0.25 0. 25
Peanut, meal None 0.15

Alfalfa

, forage 0.05 0.05

Alfalfa

, hay 0.12 0.12
Food/feed commodities (other than those covered by a higher

tolerance as a result of use on growing crops) 0.01 0.0 2

HED notes that the tolerance expression for thiametho xam in 40 CFR 180.565 has already been

revised to conform to the current policy (i.e., include phrase ―its metabolites and degradates‖ and specify compliance by measuring only parent and the CGA

- 322704 metabolite).

10.1 Toxicology

870

- 7800 Immunotoxicity Study

The petitioner should submit, as a condition of registration, an immunotoxicity study. This study is now required under the new 40 CFR Part 158 data requirement s, and was required in conjunction with the previous risk a ssessment. The study remains a data gap for thiamethoxam.

Route to Route Extrapolation ApproachThiamethoxam D373376

Page 51 of 60 Based on the available toxicity database and the Agency's current practices, short

- and

intermediate

- term inhalation risk s for thiamethoxam w ere assessed usi ng an oral toxicity study. The Agency sought expert advice and input on issues related to this route to route extrapolation approach (i.e. the use of oral toxicity studies for inhalation risk assessment) from its Federal Insecticide, Fungicide, and Rodent icide 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 p rocedures are developed, the Agency may revisit the need for an inhalation toxicity study for thiamethoxam and/or a re

- examination of the inhalation toxicity risk assessment.

10.2 Residue Chemistry

A revised Section F s hould also reflect the higher tolerance in FHE commodities (0.02 instead of 0.01 ppm) and the additional tolerance for peanut meal.

10.3 Occupational and Residential Exposure

860.1200 Directions for Use

-- Use Limitation

HED recommends that the all label s specifically p rohibit on

- farm seed treatment for alfalfa and

peanuts.

The Cruiser ® 5FS label should contain a restriction for commercial open system seed treatment

facilities that limits the amou nt of product handled per day to no more than 38 gallons product/worker/8

- hr day for peanuts and alfalfa.

The Cruiser® PD is intended for use as a dry application on peanuts. Since the treater (loader/ operator) unit exposure values from Policy 14 are ba sed on liquid formulations, the loader/operator exposure for Cruiser® PD was estimated using surrogate unit exposure values for a wettable powder formulation in the Pesticide Handlers Exposure Database (PHED). The

treater scenario resulted in a MOE of 100 with the use of additional PPE (i.e.

, gloves, coveralls

, and a PF10 respirator). Currently the label only requires use of a dust mask (quarter

- or half

mask) respirator. HED recommends that the Registration Division ensure that the appropriate respirato r is required on the final Cruiser PD label

.

Commerical handlers applying thiamethoxam as a liquid spray to cracks and crevices, spots, and structural voids using a foam application resulted in an MOE of 160 with the use of additional PPE (gloves, coveral ls

, and PF5 dust mist respirator). The proposed label does not require use of coveralls and respirators. HED recommends that if this use is to remain on the label, the Registration Division ensure that the correct PPE be included in the final registered label.Thiamethoxam D373376

Page 52 of 60 References:

D376367

. Thiamethoxam. Petition to Establish Permanent Tolerances for Residues of the

Insecticide Resulting from Food/Feed Use as a Seed Treatment on Peanuts and Alfalfa, and from Applications in Food

- Handli ng Establishments

. Summary of Analytical Chemistry and Residue Data. William Drew, 2 Nov 2010.

D 376368. Thiamethoxam

. Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 Registration as a Seed Treatment for Alfalfa and Peanuts, and for Use in Food Handling Establishments. Dennis McNeilly, 23 Nov 2010.

D 373378. Tier II Drinking Water Exposure Assessment to Establish a Tolerance of Thiamethoxam on Peanut and Alfalfa Seeds. Christopher M. Koper , 20 May 2010.

D373377

. Thiamethoxam : Occupational and Residential Exposure/Risk Assessment for Proposed Section 3 Registration for Seed Treatment Uses on Peanut and Alfalfa. Shih

- Chi Wang, 3 Dec 2010.

D382248. Thiamethoxam : Occupational and Reside ntial Exposure/Risk Assessment for Proposed Section 3 Registration for Use in Food/Feed Handling Establishments. Shih

- Chi Wang, 7 Dec 2010

.

D329466. Thiamethoxam Human Health Risk Assessment for Proposed New Uses or Revised

Uses on Artichoke, Barley, Br assica 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 Sug arbeet), Salal, Stone Fruit, Strawberry, Tobacco, Tuberous and Corm Vegetables, and Turf . Michael Doherty, 22 May 2007.

D364256. Thiamethoxam

. Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 Registration of Thiamethoxam on Rice, Sugar Beets, and Tropical Fruits. Dennis McNeilly, June 30 , 2009.

ExpoSAC Policy 14: Standard Operating Procedures (SOPs) for Seed Treatment , May 1, 2003

.

ExpoSAC Policy 15: Amount of Seed Tre ated or Planted per Day

, March 2, 2004

.

HED Draft Standard Operating Procedures (SOP’s) for Residential Exposure Assessments (12/18/97), and the Revisions to the Standard Operating Procedures (SOP’s) for Residential Exposure Assessment (Science Advisory C ouncil for Exposure Policy 1 2, Revised February 22, 2001).Thiamethoxam D373376

Page 53 of 60 Appendix A

– Toxicity Profile for Thiamethoxam.

The requirements (40 CFR 158.340) for food uses of thiamethoxam are in Table 1. Use of t he new guideline numbers does not imply that the new guideline protocols were used.

Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity

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

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

................................ .............. 870.2400 Primary Eye I rritation

................................ .................... 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

- D ay Dermal

................................ .............................. 870.3465 90

- Day Inhalation

................................ .......................... Yes

Yes

Yes

No

No Yes

Yes

Yes

No

No

870.3700a Developmental Toxicity (rodent)

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

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

................................ ................................ . Yes

Yes

Yes Yes

Yes

Yes

870.4100a Chronic Toxicity (rodent )

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

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

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

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

................................ .................... Yes

Yes

Yes

Yes

Yes Yes

Yes

Yes

Yes

Yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

..................... 870.5300 Mutagenic ity

— Gene Mutation

- mammalian

................ 870.5385 Mutagenicity

— Mammalian Bone Marrow

Chromosome Aberration Aberrations

..... 870.5550 Mutagenicity

— Unscheduled DNA Synthesis

............... Yes

Yes

Yes

No Yes

Yes

Yes

Yes

870.6200a Acu te Neurotoxicity Screening Battery (rat)

................. 870.6200b 90

- Day Neurotoxicity Screening Battery (rat)

............... 870.6300 Developmental Neurotoxicity

................................ ........ Yes

Yes

No Yes

Yes

Yes

870.7485 General Metabolism

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

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

................................ ............................. Yes

No

Yes Yes

Yes

No

Special Studies for Ocular Effects

Acute Oral (rat)

................................ ........................... Subchronic Oral (rat)

................................ .................. Six

- month Oral (dog)

................................ .................. No

No

No No

No

NoThiamethoxam D373376

Page 54 of 60 Table A.2.1. Acute Toxicity of Technical Thiamethoxam.

GDLN Study Type MRID Results Tox Category

870.110 0 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 Pri mary 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

li ne Study Title MRID Results

870.3100 90

- Day Oral Toxicity

- rat

(diet) 44718703 (1996) Acceptable/ guideline ppm=0, 25, 250, 1250, 2500 &

5000 mg/kg/day (M/F)=0/0, 1.74/1.88, 17.64/19.2, 85/93, 168/182,

329/359 NOAEL = 1.74 (males), 92.5 (females) mg/kg /day

LOAEL = 17.64 (males), 182.1 (females) mg/kg/day based on increased incidence of hyaline change of renal tubular epithelium (males), fatty change in adrenal gland of females, liver changes in

females.

870.3100 90

- Day Oral Toxicity

mouse (diet) 4470 3323 (1996) Acceptable/ guideline ppm=0, 10, 100, 1250, 3500 &

7000 mg/kg/day (M/F)=0/0, 1.41/2.01, 14.3/19.2, 176/231, 543/626,

1335/1163 NOAEL = 1.41 (males), 19.2 (females) mg/kg/day

LOAEL = 14.3 (males), 231 (females) mg/kg/day

based on increased inc idence of hepatocellular hypertrophy in both sexes. At higher dose levels: decrease in bodyweight and bodyweight gain, necrosis of individual hepatocytes, pigmentation of Kupffer cells, and lymphocytic infiltration of the liver in both sexes; slight hemat ologic effects and decreased absolute and relative kidney weights in males; and ovarian atrophy, decreased ovary and spleen weights and increased liver weights in

females.

870.3150 13

- Week Oral Toxicity

dog (diet) 44718702 (1998) Acceptable/ guideline

pp m=0, 50, 250,

1000 & 2500/2000 (after

week 2 reduced to 2000) NOAEL = 8.23 (males), 9.27 (females) mg/kg/day

LOAEL = 32.0 (males), 33.9 (females) mg/kg/day based on slightly prolonged prothrombin ti mes 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 cel ls in testes (males).Thiamethoxam D373376

Page 55 of 60 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Thiamethoxam Type of Study/Guide

li ne Study Title MRID Results

(M/F)=0/0, 1.58/1.80, 8.23/9.27, 32.0/33.9,

54.8/50.5

870.3200 28

- Day Dermal Toxicity

-

rat 44710402 (1996) Acceptable/ guideline mg/kg/day= 0,
20, 60, 250 &

1000 NOAEL = 250 (males), 60 (females) mg/kg/day

LOAEL = 1000 (males), 250 (females) mg/kg/day based on increased plasma glucose , triglyceride levels, and alkaline phosphatase activity and inflammatory cell infiltration in the liver and necrosis of single hepatocytes in females and hyaline change in renal tubules and a very slight reduction in body weight in males. At higher dose

l evels in females, chronic tubular lesions in the kidneys and inflammatory cell infiltration in the

adrenal cortex were observed.

870.3700a Developmental Toxicity

rat (gavage) 44718706 (1998)

44703329 (1995)

44703330 (1995) Acceptable/ guideline mg/kg/day =0, 5, 30, 200 & 750 Maternal NOAEL = 30 mg/kg/day

LOAEL = 200 mg/kg/day based on decreased body weight, body weight gain, and food consumption. Developmental NOAEL = 200 mg/kg/day LOAEL = 750 mg/kg/day based on decreased fetal body weight and an incr eased incidence of skeletal

anomalies.

870.3700b Developmental Toxicity

rabbit (gavage) 44718705 (1998)

44703327 (1995)

44703328 (1995) Acceptable/ guideline mg/kg/day=0, 5, 15, 50 & 150 Maternal NOAEL = 50 mg/kg/day

LOAEL = 150 mg/kg/day based on matern al 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

i mplantation loss and a slight increase in the

incidence of a few skeletal anomalies/variations.

870.3800 Reproduction (2

-

Generation)

- rat (diet) 46402904 (2004)

46402906 (2000) (range

- finding) Acceptable/ guideline ppm=0, 20, 50,

1000 & 2500 mg/kg/day

F 0 M=0, 1.2, 3.0, 61.7,155.6 Parental/Systemic NOAEL = 3 (males), 84.4

(females) mg/kg/day LOAEL =61.7 (males), 208.8 (females) mg/kg/day based on kidney lesions in F 1 ma les. At higher doses of 155.6 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. Repr oductive NOAEL = 1.2 (males), >208.8 (females) mg/kg/day LOAEL = 3 (males), not determined (females)Thiamethoxam D373376

Page 56 of 60 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Thiamethoxam Type of Study/Guide

li ne Study Title MRID Results

F 1 M=0, 1.5, 3.7, 74.8, 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 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 litte r weights of the F1 pups.

870.3800 Reproduction (2

-

Generation)

- rat (diet) 44718707 (1998)

44703401 (1995) (range

- finding)

44703402 (1998)

46402902

2006 (PWG report) Acceptable/ guideline ppm=0, 10, 30,

1000 & 2500 mg/kg/day (M/F)=0/0, 0.61/0.80,

1.84/2. 37, 61.25/79.20,

158.32/202.06 Parental/Systemic NOAEL = 1.84 (males), 202.06

(females) mg/kg/day LOAEL = 61.25 (males), not determined (females) mg/kg/day based on increased incidence of hyaline change in renal tubules in F 0 and F 1 males. Reproductive NOA EL = 0.61 (males), 202.06 (females) mg/kg/day LOAEL = 1.84 (males), not determined (females) mg/kg/day based on increased incidence and severity of tubular atrophy observed in testes of the

F 1 generation males. Offspring NOAEL = 61.25 (males), 79.20 (fema les) mg/kg/day LOAEL = 158.32 (males), 202.06 (females) mg/kg/day based on reduced body weight gain during the lactation period in all litters.

870.4100 Chronic (1 year)

– dog

(diet) 44718704 (1998) Acceptable/ guideline ppm=0, 25, 150,

750 & 1250 mg/kg/d ay (M/F)=0/0, 0.70/0.79, 4.05/4.49, 21.0/24.6,

42.0/45.1 NOAEL = 4.05 (males), 4.49 (females) mg/kg/day

LOAEL = 21.0 (males), 24.6 (females) mg/kg/day based on increase in creatinine in both sexes, transient decrease in food consumption in females,

and o ccasional increase in urea levels, decrease in ALT, and atrophy of seminiferous tubules in males.

870.4200 Carcinogenicity, 18

-

Month

- mouse (diet) 44703326 (1998) Acceptable/ guideline ppm=0, 5, 20, 500, 1250 &

2500 mg/kg/day (M/F)=0/0, 0.65/0.89,

2.63/3 .68, 63.8/87.6, NOAEL = 2.63 (males), 3.68 (females) mg/kg/day

LOAEL = 63.8 (males), 87.6 (females) mg/kg/day based on hepatocyte hypertrophy, single cell necrosis, inflammatory cell infiltration, pigment deposition, foci of cellular alt eration, 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 carcinogenicityThiamethoxam D373376

Page 57 of 60 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Thiamethoxam Type of Study/Guide

li ne Study Title MRID Results

162/215,

354/479

870.4300 Chronic/Carcinogenicity,

2

- Year

- rat (diet) 44718708 (1998) Acceptable/ guideline ppm (M/F)=0/0, 10/10, 30/30,

500/1000

&1500/3000 mg/kg/day (M/F)=0/0, 0.41/0.48, 1.29/1.56,

21.0 /50.3,

63.0/155 NOAEL = 21.0 (males), 50.3 (females) mg/kg/day

LOAEL = 63.0 (males), 155 (females) mg/kg/day based on increased incidence of lymphocytic infiltration of the renal pelvis and chronic nephropathy in males and decreased body weight gain, sligh t increase in the severity of hemosiderosis of the spleen, foci of cellular alteration in liver and chronic tubular lesions in kidney in females. no evidence of carcinogenicity

870.5100

870.5265 Gene Mutation in S.

typhimurium and E. coli 44710404 (1995) Acceptable/ guideline No evidence of gene mutation when tested up to

5000 μg/plate. There was no evidence of cytotoxicity.

870.5265 Gene Mutation in S.

typhimurium 44968301 (1999) Acceptable/

non

- guideline (supplementary) No evidence of gene mutation whe n 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 2500 ppm.

870.5300 Gene Mutation in Chinese

Hamster V79 Cells at

HGPRT Locus 44710405 (1996) Acceptable/ guideline No evidence of gene mutation when tested up to

solubility limit.

870.5375 CHO Cell Cytogenetics 44710403 (1996) Acceptable/ guideline No evidence of chromosom al aberrations when

tested up to cytotoxic or solubility limit

concentrations.

870.5395 In vivo Mouse Bone

Marrow Micronucleus 44710406 (1995) Acceptable/ guideline Negative when tested up to levels of toxicity in

whole animals; however no evidence of tar get cell cytotoxicity.

870.5550 Unscheduled DNA

Synthesis in Primary Rat Hepatocytes 44710407 (1996) Acceptable/ guideline Negative when tested up to precipitating

concentrations.

870.6200a Acute Neurotoxicity

Screening Battery

- rat (gavage) 44703320 (19 97) Acceptable/ guideline mg/kg=0,100,

500 & 1500 NOAEL = 100 mg/kg/day

LOAEL = 500 mg/kg/day based on drooped palpebral closure, decrease in rectal temperature and locomotor activity and increase in forelimb grip strength (males only). At higher dose lev els, mortality, abnormal body tone, ptosis, impaired respiration, tremors, longer latency to first step inThiamethoxam D373376

Page 58 of 60 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Thiamethoxam Type of Study/Guide

li ne Study Title MRID Results

the open field, crouched

- over posture, gait impairment, hypo

- arousal, decreased number of rears, uncoordinated landing during the righting

reflex tes t, slight lacrimation (females only) and higher mean average input stimulus value in the auditory startle response test (males only).

870.6200b Subchronic Neurotoxicity

Study

- rat (diet) 44703325 (1998) Acceptable/ guideline

ppm (M/F)=0/0,10/1 0, 30/30,

50 0/1000 &

1500/3000 mg/kg/day (M/F)=0/0,0.7/0 .7, 1.9/2.1, 31.8/73.2,

95.4/216.4 NOAEL = 95.4 (males), 216.4 (females) mg/kg/day,

both highest dose tested.

LOAEL = not determined. No treatment

- related observations at any dose level. May not have been

teste d at sufficiently high dose levels; however, new study not required because the weight of the evidence from the other toxicity studies indicates no

evidence of concern.

870.6300 Developmental

Neurotoxicity Study

- rat (diet) 46028202 (2003)

46028201 (2003) (preliminary) Acceptable/

non

- guideline (needs positive control data): may be used for regulatory

purposes ppm= 0, 550, 400, 4000 mg/kg/day (gestation/ lactation)
0/0, 4.3/8.0, 34.5/64.0,

298.7/593.5 Maternal NOAEL = 34.5 mg/kg/day

LOAEL = 298.7 mg/kg/da y based on decreases in body weight gain and food consumption. Developmental NOAEL = 34.5 mg/kg/day LOAEL = 298.7 mg/kg/day based on decreased fetal body weights and weight gain in males and females, delayed sexual maturation in males, reduced brain weig ht and size in males and females, and significant changes in brain morphometric

measurements.

870.7485 Metabolism Study

- rat

(gavage) 44703532 (1996)

44703533 (1998) Acceptable/ guideline

low dose=0.5 mg/kg high dose=100 Absorb ed rapidly & extensively, widely distributed,

followed by very rapid elimination, mostly in urine. Highest tissue concentrations in skeletal muscle: 10

- 15% of administered dose. Half

- life times from tissues ranged from 2

- 6 hours. Tissue residues after

7 days extremely low. Approximately 84

- 95% of

administered dose excreted in urine & 2.5

- 6%

excreted in feces within 24 hours. < 0.2% detected in expired air. Most excreted as unchanged parent:Thiamethoxam D373376

Page 59 of 60 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Thiamethoxam Type of Study/Guide

li ne Study Title MRID Results

mg/kg Also: I.V., 0.5 mg/kg 70

- 80% of dose. The major biotransformation

reaction is cleav age 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)

sub stitution of the chlorine of the thiazole ring by glutathione. Cleavage between thiazole

- and oxadiazine ring occurs to a small extent. Glutathione derivatives prone to further degradation of the glutathione moiety resulting in various 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 rapidly. Enterohepatic

circulati on negligible.

870.7485 Metabolism Study

– mice

(gavage) 44710408 (1998)

46161502 (2003)

46161505 (2002)

46161512 (2000) Supplementary/

non

- guideline (44710408) males only: 118 mg/kg/day, 14 days Approximately 72% of administered dose excreted

in the urine; 19% excreted in feces. Small but measurable amount detected in expired air (approximately 0.2% of dose). Predominant metabolites: unchanged parent (33

- 41% of administered dose); 2 other metabolites: 8

- 12% and

9

- 18% of administered dose. T hese are the same structures that were most commonly observed in rat excreta; however the proportions are quite different in mouse excreta. One additional significant metabolite (mouse R6) was isolated from feces samples. Between 30

- 60% of the administer ed dose

was excreted as metabolites.

870.7600 Dermal Absorption

- rats 44703403 (1998) EPA=unaccept./ not upgradable; conducted by

draft OECD guideline Estimates of dermal absorption were based on the

sum of radioactivity in skin test site, urine, feces, blood, and carcass. Dermal absorption is 5%, which is the maximum observed for all dose groups.

Non

- guideline Hepatic Cell Proliferation

- mouse (diet) 44703406 (1998) Acceptable/

non

- guideline ppm=100, 500

& 2500 mg/kg/day (M/F)=16/20, 72/87, 386/483 NO AEL = 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 chan ge, hepatocellular necrosis, apoptosis and pigmentation were observed.

Non

- guideline Replicative DNA

Synthesis in 28

- Day 44703405 (1995) NOAE L = 711 mg/kg/day (highest dose tested)

LOAEL = not established. ImmunohistochemicalThiamethoxam D373376

Page 60 of 60 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Thiamethoxam Type of Study/Guide

li ne Study Title MRID Results

Study

- rat, male only (diet) Acceptable/

non

- guideline ppm=0, 100, 1000, 2500 &

10000 mg/kg/day=0, 8, 82, 199, 711 staining of liver sections from control and high

- dose

animals for proliferating cell nuclear antigen gave

no indication for a treatment

- related increase in the

fraction o f DNA synthesizing hepatocytes in S

phase. CGA 293343 did not stimulate hepatocyte cell proliferation in male rats.

Non

- guideline Special study to assess

liver biochemistry

- mouse 44703407 (1998) Acceptable/

non

- guideline NOAEL = 17 (males), 20 (females) mg/kg/day

LOAEL = 74 (males), 92 (females) mg/kg/day based on marginal to slight increases in absolute and relative liver weights, a slight increase in the microsomal protein content of the livers, moderate increases in the cytochrome P450 content, slight to moderate increases in the activity of several microsomal enzymes, slight to moderate induction of cytosolic glutathione S

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

oxidation.