EPA REGISTRATION DIVISION CO MPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER (7/1/2007)

EPA Registration Division contact: Julie Chao, Insecticide-Rodenticide Branch Team 1; (703) 308-8735

Syngenta Crop Protection, Inc., PO Box 18300, Greensboro, NC 27419

Petition Number 0F7707

EPA has received a pesticide petition (petition number 0F7707) from Syngenta Crop Protection, Inc., PO Box 18300, Greensboro, NC 27419 proposing, pursuant to section 408(d) of the Federal Food, Drug, a nd Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180.565 by es tablishing tolerances for residues of thiamethoxam {3-[(2-chl oro-5-thiazolyl)methyl ]tetrahydro-5-methyl- N -nitro-4 H

1,3,5-oxadiazin-4-imine}(CAS Reg. N o. 153719-23-4) and its metabolite [ N -(2- chloro-thiazol-5-ylmethyl)- N ’-methyl- N ’-nitro-guanidine] in or on alfalfa, forage ( 0.05 ppm) and alfalfa, hay (0.12 ppm). EPA has determined that the petition contains data or information regarding the el ements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluate d the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. The primary metabolic pathways of thiamethoxam in plants (corn, rice, pears, and cucumb ers) were similar to those described for animals, with certain extensions of the pathway in plants. Parent compound and CGA-322704 were the major residues in all crops. The metabolism of thiamethoxam in plants and animals is understood for the purposes of the proposed

tolerance. Parent thiamethoxam and th e metabolite, CGA-322704, are the residues of concern for tolerance setting purposes.

2. Analytical method. Syngenta Crop Protection, Inc. has submitted practical analytical methodology for detecting and me asuring levels of thiamethoxam in or on raw agricultural commodities. This me thod is based on crop specific cleanup procedures and determination by liquid chromatography with either UV or MS detections. The limit of detection (LOD) fo r each analyte of this method is 1.25 ng injected for samples analyzed by UV and 0.25 ng injected for samples analyzed by MS, and the limit of quantification (LOQ) is 0.005 ppm for milk and juices, and 0.01 ppm for all other substrates.

3. Magnitude of residues. Syngenta Crop Protection, Inc. has submitted complete residue data for thiamethoxam on alfalfa, forage and alfalfa, hay).2

B. Toxicological Profile

1. Acute toxicity. The acute oral LD50 for thia methoxam in the rat is 1563 mg/kg body weight. The acute dermal LD 50 of thiamethoxam is >2000 mg/kg body weight. Thiamethoxam is non-toxic at a tmospheric concentrations of 3.72 mg/l. Thiamthoxam is minimally irritating to the ey e, non-irritating to skin and is not a

dermal sensitizer.

In an acute neurotoxicity study in rats (OPPTS 870.6200a), the NOAEL was 100 mg/kg/day with a NOAEL of 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 leve ls, mortality, abnormal body tone, ptosis, impaired respiration, tremors, longer latency to first step in the open field, crouched over posture, gait impairment, hypo-arousal, decreased number of rears, uncoordinated landing during the righting re flex test, slight lacrimation (females only) and higher mean average input stimulus value in the auditory startle response test (males only).

2. Genotoxicty. In gene mutation studies with S. typhimurium and E. coli (OPPTS 870.5100 and 870.5265, there was no evidence of gene mutation when tested up to 5000 μ g/plate and there was no evidence of cytoxicity.

In a gene mutation study with chinese hamster V79 cells at HGPRT focus (OPPTS 870.5300) there was no evidence of gene mutati on when tested up to the solubility

limit.

In a CHO cell cytogenetics study (O PPTS 870.5375) there was no evidence of chromosomal aberrations when tested up to cytotoxic or solubility limit

concentrations.

An in vivo mouse bone marrow micronucleus st udy (OPPTS 870.5395) was negative when tested up to levels of toxicity in wh ole animals; however, no evidence of target cell cytoxicity. A UDS assay (OPPTS 870.555 0) was negative when tested up to precipitating concentrations.

3. Reproductive and developmental toxicity. A prenatal developmental study in the rat (OPPTS 870.3700a) resulted in Mat ernal and Developmental NOAELs of 30 mg/kg/day and 200 mg/kg/day, respectiv ely. The maternal LOAEL is 200 mg/kg/day based on decreased body weight, body weight gain and food consumption. The developmental LOA EL was 750 mg/kg/day ba sed on decreased fetal body weight and an increased incidence of skeletal anomalies.

A prenatal developmental study in the rabbit (OPPTS 870.3700b) resulted in maternal and developmental NOAELs of 50 mg/kg/day. The maternal and developmental LOAEL is 150 mg/kg/day. The maternal LOAEL is based on maternal deaths, hemorrhagic discharge, d ecreased body weight and food intake3

during the dosing period. The developmen tal LOAEL is based on decreased fetal body weights, increased incidence of post-i mplantation loss and a slight increase in

the incidence of skeletal anomalies/variations.

In a reproduction and fertility effe cts study in rats (OPPTS 870.3800) the Parental/sytemic NOAEL is 1.84 (males) , 202.06 (females) mg/kg/day; the reproductive NOAEL is 0.61 (males), 202.06 (f emales) mg/kg/day and the offspring NOAEL is 61.25 (males), 79.20 (females) mg/k g/day. The parental /sytemic LOAEL is 61.25 (males), not determined (females) mg/kg/day based on inscreased incidence of hyaline change in renal tubules in F0 and F1 males. The reproductive LOAEL is 1.84 (males), not determined (females) mg/kg/day based on increased incidence and severity of tubular atrophy observed in te stes of the F1 generation males. The offspring LOAEL is 158.32 (males), 202.06 (fema les) mg/kg/day based on reduced body weight gain during lactat ion period in all litters.

4. Subchronic toxicity. A 90 day oral toxicity study in rats (OPPTS 870.3100) resulted in a NOAEL of 1.74 (males, 92.5 (fe males) mg/kg/day. The LOAEL is 17.4 (male), 182.1 (female) mg/kg/d ay based on increased incidence of hyaline change or renal tubules epitheliu m (males), fatty change in ad renal gland of females, liver changes in females, all at the LOAEL.

A 90 day oral toxicity in mice (OPP TS 870.3100) resulted in a NOAEL of 1.41 (males, 19.2 (females) mg/kg/day. The LOAEL was 14.3 (male) 231 (female) mg/kg/day based on increased incidence of hepatocellular hypertrophy. At higher dose levels: decrease in body weight and body weight gain, necrosis of individual hepatocytes, pigmentation of Kupffer cells, and lymphocytic infiltration of the liver in both sexes; slight hematologic effects and decreased absolute and relative kidney weights in males; and ovarian atrophy, decreased ovary and spleen weights and increased liver weights in females.

In a 90 day oral toxicity in dogs (OPPTS 870.3150), the NOAEL is 8.23 (males), 9.27 (females) mg/kg/day. The LOAEL is 32.0 (ma le), 33.9 (female) mg/kg/day based on slightly prolonged prothrombin times and decreased plasma albumin and A/G ration (both sexes; decreased calciu m levels and ovary weights and delayed maturation in the ovaries (female); decrea sed cholesterol and phospholipid levels, testis weights, spermatogenesis, and sp ermatic giant cells in testes (male).

In a 28 day dermal study in rats (OPPTS 870.3200) the NOAEL was 250 (male), 60 (female) mg/kg/day. The LO AEL was 1000 (male), 250 (femal e) mg/kg/day based on increased plasma glucose, triglyceride leve ls, and alkaline phosphatase activity and inflammatory cell infilt ration in the liver and necrosis if single hepatocyts in females and hhaline change in renal tubules and a v ery slight reduction in body weight in males. At higher dose levels in females, chronic tubular lesion s in the kidneys and inflammatory cell infilt ration in the adrenal cortex were observed.

In a subchronic neurotoxicity screen ing study in rats (OPPTS 870.6200b) the NOAEL was 95.4 (male), 216.4 (female) mg/kg/day, both at the highest dose tested.4

The LOAEL was not determined. No treatme nt related observations at any dose level. LOAEL was not achieved. May not h ave been tested at sufficient high dose levels; however, a new study is not required because the weight of evidence from other toxicity studies indica tes no evidence of concern.

5. Chronic toxicity. In a chronic toxicity study in dogs (OPPTS 870.4100) the NOAEL was 4.05 (male), 4.49 (female) mg/k g/day. The LOA EL was 21.0 (male), 24.6 (female) mg/kg/day based on increase in creatinine in both sexes, transient decease in food consumption in females, and occasional increase in urea levels, decrease in ALT, and atrophy of seminiferous tubules in males.

In a mouse carcinogenicity study (OPPTS 870.4200) the NOAEL was 2.63 (male), 3.68 (female) mg/kg/day. The LOAEL wa s 63.8 (male), 87.6 (female) mg/kg/day based on hepatocyte hypertrophy, single ce ll necrosis, inflammato ry cell infiltration, pigment deposition, foci of cellular alte ration, hyperplasia of Kupffer cells and increased mitotic activity, also an increa se in the incidence of hepatocellular adenoma (both sexes). At higher doses, th ere was an increase in the incidence of hepatocellular adenocarcinoma (both se xes) and the number of animals with multiple tumors, evidence of carcinogenicity.

In a combined carcinogenicity study in rats (OPPTS 870.4300) the NOAEL was 21.0 (male), 50.3 (female) mg/kg/day. Th e LOAEL was 63.0 (male), 255 (female) mg/kg/day based on the increased incidence of lymphocytic infiltration of the renal pelvis and chronic nephropathy in males and decreased body weight gain, slight increase in the severity of hemosiderosis of the spleen, foci of cellular alteration in

liver and chronic tubular lesions in ki dney in females. No evidence of carcinogenicity.

In a hepatic cell proliferation study in mice, the NOAEL was 16 (male), 20 (female) mg/kg/day. The LOAEL was 72 (male), 87 (female) mg/kg/day based on proliferative activity of hepatocytes. At higher dose levels, increa ses in absolute and relative liver weights, speckled liver, ha ptocellular glycogenisis/fatty change, heptocellular necrosis, apoptosis and pigmentation were observed.

In a 28 day feeding study to assess replic ative DNA synthesis in the amle rat, the NOAEL was 711 mg/kg/day. The LO AEL was not established. Immunohistochemical staining of the liver sections from control and high dose animals for proliferating ce ll nuclear antigen gave no indication for a treatment

related increase in the fraction of DNA synthesizing hepatocytes in S-phase. CGA293343 did not stimulate hepatocyte ce ll proliferation in male rats.

In a special study to assess liver bioche mistry in the mouse, the NOAEL was 17 (male), 20 (female) mg/kg/day. The LOA EL was 74 (male), 92 (female) mg/kg/day based on marginal to slight increases in ab solute and relative liver weights, a slight increase in the microsomal protein content of the livers, modera te increases in the cytochrome P450 content, slight to modera te increases in the activity of several microsomal enzymes, slight to moderate i nduction of cystolic glutathion S-transfer5

activity. Treatment did not affect peroxisomal fatty acid β -oxidation.

6. Animal metabolism. The metabolism of thiamethoxam in rats and livestock animals is adequately understood. The resi dues of concern have been determined to be parent thiamethoxam and its metabolite [ N -(2-chloro-thiazol-5-ylmethyl)- N ’- methyl- N ’-nitro-guanidine] expressed as thiamethoxam.

7. Metabolite toxicology

. For most risk assessment purposes, residues of the metabolite corrected for molecular weight are considered to be toxicologically equivalent to parent thiamethoxam. However, EPA has determined that the

metabolite should not be include d in the cancer risk assessment.

8. Endocrine disruption

. There are no specific studies requested by the Endocrine Disruptor Screening Program (EDS P) at this time because endocrine

effects have been well characterized in an acceptable 2-generation reproduction study with a clear NOAEL and LOAEL, and the chronic reference dose (cRfD)

selected for thiamethoxam risk assessments is considered protective of the observed

endocrine effects.

C. Aggregate Exposure

1. Dietary exposure. Tier I acute, and Tier III chronic aggregate risk assessments were performed for thia methoxam using the Dietary Exposure Evaluation Model (DEEM-FCID TM , version 2.16) from Exponent. All consumption data for these assessments was taken from the USDA’s Continuing Survey of Food Intake by individuals (CSFII) with the 1994-96 consumption database and the Supplemental CSFII children’s survey (1998) consumption database. In the Tier I acute assessment, in addition to estab lished tolerances (40 CFR 180.565) for the combined residues of thiamethoxam (C GA293343) and its metabolite (CGA322704) in or on a variety of raw agricultural co mmodities including meat and milk, these exposure assessments also included the pendi ng seed treatment use on peanuts and the proposed seed treatment use on alfa lfa. Percent of crop treated values were conservatively estimated to be 100% for a ll registered and proposed uses. Field

trials residue values were used in the Tier III chronic assessments where thiamethoxam was applied at the maximu m intended use rate and samples were harvested at the minimum pre-harvest in terval (PHI) to obtain the maximum expected residues. Calculated pe rcent crop treated (%CT) values were incorporated in these chronic Tier III assessments. Drinking water estimates were incorporated directly into the dietary exposure assessments using the highest estimated drinking water concentrations (EDWCs) for surface and ground water.

i. Food. Acute Exposure. The thiamethoxam acute food risk assessment was performed for all population subgroups using an acute reference dose of 0.35 mg/kg-bw/day based upon a developmental ne urotoxicity study in rats with a no observed adverse effect level (NOAEL) of 34.5 mg/kg/day and an uncertainty factor of 100X. The 100X safety factor includes in tra- and inter-species variations. No additional FQPA safety factor was app lied. For the purpose of aggregate risk6

assessment, the exposure values were expre ssed in terms of margin of exposure (MOE), which was calculated by dividing the NOAEL by the exposure for each population subgroup. In addition, exposure was expressed as a percent of the acute reference dose (%aRfD). At the 95 th percentile, acute (food only) exposure to the U.S. population resulted in a MOE of2,466 (4.0% of the aRfD of 0.35 mg/kgbw/day). The most exposed sub-population was children (1-2 years old) with a MOE of 1,256 (7.8% of the aRfD of 0.35 mg/kg-bw/day). Since the Benchmark

MOE for this assessment was 100 and sin ce the EPA generally has no concern for exposures below 100% of the aRfD, Syngen ta believes that there is a reasonable certainty that no harm will result from dietary (food only) exposure to residues arising from all current and pr oposed uses of thiamethoxam.

Chronic Exposure. The thiamethoxam ch ronic dietary food risk assessment was performed for all population subgroups using a chronic reference dose of 0.012 mg/kg-bw/day based upon a two generation reproduction study in rats with a no observed adverse effect level (NOAEL) of 1.2 mg/kg/day and an uncertainty factor of 100X. The 100X safety factor includes in tra- and inter-species variations. No additional FQPA safety factor was app lied. For the purpose of aggregate risk assessment, the exposure values were expre ssed in terms of margin of exposure (MOE), which was calculated by dividing the NOAEL by the exposure for each population subgroup. In addition, exposure was expressed as a percent of the chronic reference dose (%RfD). Chroni c (food only) exposure to the U.S. population resulted in a MOE of 9,538 ( 1.0% of the RfD of 0.012 mg/kg-bw/day). The most exposed sub-population was children (1-2 years old) with a MOE of 4,016 (2.5% of the RfD of 0.012 mg/kg-bw/day). Since the Benchmark MOE for this assessment was 100 and since the EPA genera lly has no concern for exposures below 100% of the RfD, Syngenta believes that there is a reasonable certainty that no harm will result from dietary (food only) exposure to residues arising from the current and proposed uses of thiamethoxam.

Cancer

. A quantitative risk assessment usin g a cancer endpoint was not performed.

ii. Drinking water. The Estimated Drinking Water Concentrations (EDWCs) of thiamethoxam were determined using Ti er l screening models, SCI-GROW which estimates pesticide concentration in gro und water, FIRST which estimates pesticide concentration in surface water (for proposed alfalfa seed treatment use and pending peanut seed treatment use), and for aquatic uses, a modified Tier I Rice Model and Provisional Cranberry Model which estimate s pesticide concentr ation in tail water from rice paddies and cranberry bogs, respe ctively. EDWCs of thiamethoxam from the currently registered uses plus the proposed seed treatment use on alfalfa and the pending seed treatment use on peanuts w ere determined. The highest ground water EDWC resulting from SCI-GROW modeling was 4.12 ppb (acute and chronic) based on the currently registered use on gr apes. The highest surface water EDWCs resulted from the currently registered ri ce use. The modified Tier I Rice model provided a surface water acute EDWC of 147.72 ppb and a chronic EDWC of 12.62 ppb (adjusted for a 0.87 Percent Cropped Area (PCA) factor). Since the surface7

water EDWCs exceed the ground water EDWC , the surface water values were used for risk assessment purposes and will be considered protective for any ground water

concentration concerns.

Acute Exposure from Drinking Water

. The acute surface water EDWC of 147.72 ppb was input directly into the DEEM-FCIDTM software as “water, direct and indirect, all sources” to model the acute drinking water exposures. Exposure contributions at the 95%-ile of exposures were determined by taking the difference between the aggregate (food + drinking wa ter) exposures and the food (alone) exposures for each population subgroup. Acute drinking water exposure U.S. population resulted in a MOE of 7,058 (1.4% of the acut e RfD of 0.35 mg/kgbw/day). The most exposed sub-population was all infants (<1 year old) with a MOE of 1,596 (6.2% of the aRfD of 0.35 mg/kg/day). Since the benchmark MOE

for this assessment was 100 and since EPA generally has no concern for exposures below 100% of the acute RfD, Syngenta be lieves that there is a reasonable certainty that no harm will result from acute drinking water exposure to residues arising from the current and propos ed uses for thiamethoxam.

Chronic Exposure from Drinking Water

. The chronic surface water EDWC of 12.62 ppb was input directly into the DEEM-F CIDTM software as “water, direct and indirect, all sources” to model the chro nic drinking water exposures. Chronic drinking water exposure to the U.S. population resulted in a MOE of 4,511 (2.2% of the chronic RfD of 0.012 mg/kg-bw/day). Ch ronic drinking water exposure to the most exposed sub-population (infants, <1 year old) resulted in a MOE of 1,376 (7.3% of the chronic RfD of 0.012 mg/kg- bw/day). Since the Benchmark MOE for this assessment was 100 and since EPA ge nerally has no concern for exposures below 100% of the chronic RfD, Syngenta believes that there is a reasonable certainty that no harm will result from chro nic drinking water exposure to residues arising from the current and proposed use for thiamethoxam.

2. Non-dietary exposure

. A residential exposure and risk assessment was performed for thiamethoxam using the endpoints and uncertainty factors established by the EPA. Residential ex posure and risk assessments were performed

for thiamethoxam uses on turf and ornamentals (Meridian® 25WG) and for

thiamethoxam indoor crack and crevice uses (Optigard® ZT). These product labels

indicate that thiamethoxam is to be applied by commercial applicators only;

therefore residential assessments were limited to post-application exposure risks for adults and children. The following endpoints were used for these residential risk assessments: NOAEL = 1.2 mg/kg/day (for adults, from a two generation oral reproduction study in rats) and NOAEL = 60 mg/kg/day (for ch ildren 1-6, from a

short-term dermal from a 28-d ay dermal study in rats). Post application dermal exposure risks from thiamethoxam are a cceptable (MOE = 4,070) for adults reentering lawn turf grass following treatment with Meridian® 25WG. Post application dermal plus non-dietary or al exposure risks from thiamethoxam are also acceptable (aggregate MOE = 1,339) for children re-entering lawn turf grass8

following treatment with Meridian® 25WG. Post application dermal exposure risks from thiamethoxam are acceptable (MOE = 900) for adults re-entering indoor carpeted or hard floor areas following crack and crevice treatment with Optigard® ZT. Post application dermal plus non-dietary oral exposure risks from thiamethoxam are also acceptabl e (short-term aggregate MOE = 1,260, intermediate-term aggregate MOE = 1,404) for children re-entering indoor carpeted or hard floor areas following crack a nd crevice treatment with Optigard® ZT. Since the children (1-6 years) and adul t (20-49 years) MOEs are above the Benchmark MOE of 100 the residential exposure risks do not exceed the EPA’s level

of concern.

D. Cumulative Effects

Cumulative Exposure to Substances with a Common Mechanism of Toxicity. Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tole rance, the Agency consider “available information” concerning the cumulative effe cts of a particular pesticide’s residues

and “other substances that have a commo n mechanism of toxicity”. Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to thiamethoxam and any other substances and thiamethoxam does not appear to produce a toxic metabolite pr oduced by other substances. For the purposes of this tolerance action, the EP A has not assumed that thiamethoxam has a common mechanism of toxicity with other substances.

E. Safety Determination

1. U.S. population. The acute dietary exposure analysis (food plus water) showed that exposure from all establis hed, pending and proposed thiamethoxam tolerances would result in a MOE of 1,827 (5.4% of the aRfD of 0.35 mg/kg-bw/day) for the general U.S. population, which exceeds the Benchmark MOE of 100. The chronic dietary exposure analysis (food plus water) showed that exposure from all registered and proposed thiamethoxam tole rances resulted in a MOE of 3,063 (3.3% of the chronic RfD of 0.012 mg/kg-bw/day) for the general U.S. population, which

also exceeds the Benchmark MOE of 100. For the short-term aggregate exposure analysis the corresponding food, water and residential MOEs were aggregated using the inverse MOE approach. The short-term aggregate (food, drinking water, and residential) MOE was 867 for adults (20-49 years old), which exceeds the Benchmark MOE of 100. Based on the comp leteness and reliability of the toxicity data supporting these petitions, Syngen ta believes that there is a reasonable certainty that no harm will result from agg regate exposure to residues arising from all current and proposed th iamethoxam uses, including an ticipated dietary exposure from food, water, and all other ty pes of non-occupational exposures.

2. Infants and children

. The acute dietary exposure analysis (food plus water) showed that exposure from all es tablished and proposed thiamethoxam uses would result in a MOE of 943 (10.4% of the aRfD of 0.35 mg/kg-bw/day) for the9

most sensitive population subgroup, infa nts <1 year old, which exceeds the Benchmark MOE of 100. The chronic aggregat e dietary (food plus water) exposure analysis showed that exposure from a ll established and proposed thiamethoxam uses would result in a MOE of 1,157 ( 8.6% of the chronic RfD of 0.012 mg/kgbw/day) for the most sensitive population subgroup, infants <1 year old, which exceeds the Benchmark MOE of 100. For the short-term aggregate exposure analysis the corresponding food, water and residential MOEs were aggregated using the inverse MOE approach. The short-term aggregate (food, drinking water, and residential) MOE was 1,214 for the child ren (1-6 years), which exceeds the Benchmark MOE of 100. Based on the comp leteness and reliability of the toxicity data supporting these petitions, Syngen ta believes that there is a reasonable certainty that no harm will result to infa nts and children from aggregate exposure to residues arising from all current and proposed thiamethoxam tolerances, including anticipated dietary exposure from food, water, and all other types of nonoccupational exposures.

F. International Tolerances

There are currently no Maximum Re sidue Limits (MRLs) set for thiamethoxam for crops by the Codex Alim entarius Commission. International

MRLs for the insecticide thiamethoxam have been established for various agricultural commodities in a number of countries including Argentina, Australia, Belarus, Brazil, Canada, Czech Republic, Denmark, Denmark, Estonia, Georgia, Great Britain (UK), Greece, Hungary, India, Israel, Italy, Korea (South), Latvia, Moldova, Netherlands, New Zealand, Ru ssia, Serbia and Montenegro, Slovak Republic, Slovenia, South Africa, Spain, Swit zerland, Taiwan, Ukraine, and United

States.