EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

(7/1/2007)

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

Syngenta Crop Protection, Inc., P.O. Box 18300, Greensboro, NC 27419

[Petition number 9F7582]

EPA has received a pesticide petition ([petition number 9F7582]) from 

Syngenta Crop Protection, Inc., P.O. Box 18300, Greensboro, NC 27419

proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act 

(FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180.565 by establishing a tolerance 

for residues of thiamethoxam {3-[(2-chloro-5-thiazolyl)methyl]tetrahydro-5-methylN-nitro-4H-1,3,5-oxadiazin-4-imine}(CAS Reg. No. 153719-23-4) and its metabolite 

[N-(2-chloro-thiazol-5-ylmethyl)-N’-methyl-N’-nitro-guanidine] in or on onion, dry 

bulb (0.03 ppm). EPA has determined that the petition contains data or information 

regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not 

fully evaluated 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 cucumbers) 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 the 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 measuring levels of thiamethoxam in or on 

raw agricultural commodities. This method is based on crop specific cleanup 

procedures and determination by liquid chromatography with either UV or MS 

detections. The limit of detection (LOD) for 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.
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3. Magnitude of residues. Syngenta Crop Protection, Inc. has submitted 

complete residue data for thiamethoxam on dry bulb onions.

B. Toxicological Profile

1. Acute toxicity. The acute oral LD50 for thiamethoxam in the rat is 1563 

mg/kg body weight. The acute dermal LD50 of thiamethoxam is >2000 mg/kg body 

weight. Thiamethoxam is non-toxic at atmospheric concentrations of 3.72 mg/l. 

Thiamthoxam is minimally irritating to the eye, 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 

strenght (males only). At higher dose levels, mortality, abnormal body tone, ptosis, 

impaired respiration, tremors, longer latency to first step in the open field, crouched 

over posture, gait impairment, hypo-arousal, decreased number of rears, 

uncoordinated landing during the righting reflex test, slight lacrimation (females 

only) and 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 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 mutation when tested up to the solubility 

limit.

In a CHO cell cytogenetics study (OPPTS 870.5375) there was no evidence of 

chromosomal aberrations when tested up to cytotoxic or solubility limit 

concentrations.

An in vivo mouse bonemarrow micronucleus study (OPPTS 870.5395) was negative 

when tested upto levels of toxicity in whole animals; however, no evidence of target 

cell cytoxicity. A UDS assay (OPPTS 870.5550) 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 Maternal and Developmental NOAELs of 30 

mg/kg/day and 200 mg/kg/day, respectively. The maternal LOAEL is 200 

mg/kg/day based on decreased body weight, body weight gain and food 

consumption. The developmental LOAEL was 750 mg/kg/day based on decreased 

fetal body weight and an increased incidenceof skeletal anomalies.

A prenatal developmental study in the rabbit (OPPTS 870.3700b) resulted in 
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maternal and developmental NOAELs of 50 mg/kg/day. The maternal and 

develomental LOAEL is 150 mg/kg/day. The maternal LOAEL is based on 

maternal deaths, hemorrhagic discharge, decreased body weight and food intake 

during the dosing period. The developmental LOAEL is based on decreased fetal 

body weights, increased incidence of post-implantation loss and a slight increase in 

the incidence of skeletal anomalies/variations.

In a reproduction and fertility effects 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 (females) mg/kg/day and the offspring 

NOAEL is 61.25 (males), 79.20 (females) mg/kg/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 testes of the F1 generation males. The 

offspring LOAEL is 158.32 (males), 202.06 (females) mg/kg/day based on reduced 

body weight gain during lactation 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 (females) mg/kg/day. The LOAEL is 17.4 

(male), 182.1 (female) mg/kg/day based on increased incidence of hyaline change or 

renal tubules epithelium (males), fatty change in adrenal gland of females, liver 

changes in females, all at the LOAEL.

A 90 day oral toxicity in mice (OPPTS 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 hpertrophy. 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 erlative kidney 

weights in males; and ovarion 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 (male), 33.9 (female) mg/kg/day based on 

slightly prolonged prothrombin times and decreased plasma albumin and A/G 

ration (both sexes; decreased calcium levels and ovary weights and delayed 

maturation in the ovaries (female); decreased cholesterol and phospholipid levels, 

testis weights, spermatogenesis, and spermatic 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 LOAEL was 1000 (male), 250 (female) mg/kg/day based on 

increased plasma glucose, triglyceride levels, and alkaline phosphatase activity and 

inflammatory cell infiltration in the liver and necrosis if single hepatocyts in females 

and hhaline change in renal tubules and a very slight reduction in body weight in 

males. At higher dose levels in females, chronic tubular lesions in the kidneys and 

inflammatory cell infiltration in the adrenal cortex were observed.
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In a subchronic neurotoxicity screening study in rats (OPPTS 870.6200b) the 

NOAEL was 95.4 (male), 216.4 (female) mg/kg/day, both at the highest dose tested. 

The LOAEL was not determined. No treatment related observations at any dose 

level. LOAEL was not achieved. May not have been tested at sufficient high dose 

levels; however, a new study is not required because the weight of evidence from 

other toxicity studies indicates 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/kg/day. The LOAEL 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 was 63.8 (male), 87.6 (female) mg/kg/day 

based on hepatocyte hypertrophy, single cell necrosis, inflammatory cell infiltration, 

pigment deposition, foci of cellular alteration, hyperplasia of Kupffer cells and 

increased mitotic activity, also an increase in the incidence of hepatocellular 

adenoma (both sexes). At higher doses, there was an increase in the incidence of 

hepatocellular adenocarcinoma (both sexes) and the number of animals with 

multiple tumors, evidence of carcinogenicity.

In a combined carcinogenicity study in rats (OPPTS 870.4300) the NOAEL was 21.0 

(male), 50.3 (female) mg/kg/day. The 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 kidney 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, increases in absolute and 

relative liver weights, speckled liver, haptocellular glycogenisis/fatty change, 

heptocellular necrosis, apoptosis and pigmentation were observed.

In a 28 day feeding study to assess replicative DNA synthesis in the amle rat, the 

NOAEL was 711 mg/kg/day. The LOAEL was not established. 

Immunohistochemical staining of the liver sections from control and high dose 

animals for proliferating cell nuclear antigen gave no indication for a treatment 

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

In a special study to assess liver biochemistry in the mouse, the NOAEL was 17 

(male), 20 (female) mg/kg/day. The LOAEL was 74 (male), 92 (female) mg/kg/day 

based on marginal to slight increases in absolute and relative liver weights, a slight 
5

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 cystolic glutathion S-transfer 

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

6. Animal metabolism. The metabolism of thiamethoxam in rats and livestock 

animals is adequately understood. The residues 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 included in the cancer risk assessment.

8. Endocrine disruption. There are no specific studies requested by the 

Endocrine Disruptor Screening Program (EDSP) 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 thiamethoxam using the Dietary Exposure 

Evaluation Model (DEEM-FCIDTM, 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 established tolerances (40 CFR 180.565) for the 

combined residues of thiamethoxam (CGA293343) and its metabolite (CGA322704) 

in or on a variety of raw agricultural commodities including meat and milk. These 

exposure assessments also included the proposed crop tolerance for seed treatment 

use on onions (0.03 ppm). Percent of crop treated values were conservatively 

estimated to be 100% for all registered and proposed uses. Field trials residue 

values were used in the Tier III chronic assessments where thiamethoxam was 

applied at the maximum intended use rate and samples were harvested at the 

minimum pre-harvest interval (PHI) to obtain the maximum expected residues. 

Calculated percent 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 dietary (food only) risk 

assessment was performed for all population subgroups using an acute reference 

dose of 0.35 mg/kg-bw/day based upon a developmental neurotoxicity study in rats 
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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 intra- and inter-species 

variations. No additional FQPA safety factor was applied. For the purpose of 

aggregate risk assessment, the exposure values were expressed 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 95th percentile, acute (food only) exposure to 

the U.S. population resulted in a MOE of 2,573 (3.83% of the aRfD of 0.35 mg/kgbw/day). The most exposed sub-population was children (1-2 years old) with a 

MOE of 1,349 (7.30% of the aRfD of 0.35 mg/kg-bw/day). Since the Benchmark 

MOE for this assessment was 100 and since the EPA generally has no concern for 

exposures below 100% of the aRfD, Syngenta believes that there is a reasonable 

certainty that no harm will result from dietary (food only) exposure to residues 

arising from all current and proposed uses of thiamethoxam.

Chronic Exposure. The thiamethoxam chronic dietary (food only) 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 

observable adverse effect level (NOAEL) of 1.2 mg/kg/day and an uncertainty factor 

of 100X. The 100X safety factor includes intra- and inter-species variations. No 

additional FQPA safety factor was applied. For the purpose of aggregate risk 

assessment, the exposure values were expressed 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). Chronic (food only) exposure to the U.S. 

population resulted in a MOE of 15,879 (0.6% 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 4,756 

(2.1% of the RfD of 0.012 mg/kg-bw/day). Since the Benchmark MOE for this 

assessment was 100 and since the EPA generally 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 using a cancer endpoint was not performed.

ii. Drinking water. EPA uses the Tier 2 model PRZM/EXAMS to estimate 

potential surface water concentrations and the screening model SCI-GROW to 

estimate potential ground water concentrations. None of these models includes 

consideration of the impact that processing (mixing, dilution, or treatment) would 

have on the removal of pesticides from the water source prior to distribution as 

drinking water. The primary use of these models is to provide a conservative 

approximation of the Estimated Drinking Water Concentrations (EDWCs) of 

specific pesticides in drinking water. These models were used by Syngenta to 

provide EDWCs of thiamethoxam for the registered uses and the proposed use on 

onions as a seed treatment. Based on these assumptions, the highest acute surface 

water EDWC (generated using the standard PRZM crop scenario for Florida 
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peppers) is 12.15 parts per billion (ppb) based on the existing pepper use. The 

highest chronic surface water EDWC, generated using the PRZM crop scenario for 

California lettuce, is 0.764 ppb based on the existing lettuce use. The highest acute 

and chronic EDWC for ground water (based on an application rate of 1 x 0.266 

lb./acre) is 4.12 ppb. The highest of these values was used for the acute and chronic 

aggregate assessments and will be considered to be protective for all drinking water 

concerns.

Acute Exposure from Drinking Water: The acute surface water EDWC of 12.15 

ppb was input directly into the DEEM-FCIDTM software as “water, direct and 

indirect, all sources”. Acute exposure (water only) to the U.S. population resulted in 

a MOE of 132,184 (0.07% of the aRfD of 0.35 mg/kg-bw/day). The most exposed 

sub-population was children (1-2 years old) with a MOE of 42,435 (0.23% of the 

aRfD of 0.35 mg/kg-bw/day). Since the Benchmark MOE for this assessment was 

100 and since the EPA generally has no concern for exposures below 100% of the 

RfD, Syngenta believes that there is a reasonable certainty that no harm will result 

from acute dietary (food and drinking water) exposure to residues arising from all 

current and proposed uses of thiamethoxam.

Chronic Exposure from Drinking Water: The chronic EDWC of 4.12 ppb (ground 

water) was used to calculate the chronic drinking water exposure values for the U.S. 

Population and population subgroups. Chronic drinking water estimates were 

incorporated directly into the DEEM-FCIDTM software as “water, direct and 

indirect, all sources”. Chronic exposure (water only) to the U.S. population resulted 

in a MOE of 13,953 (0.72% of the chronic RfD of 0.012 mg/kg-bw/day). The most 

exposed sub-population was infants (<1 year old) with a MOE of 4,211 (2.38% of the 

chronic RfD of 0.012 mg/kg-bw/day). Since the Benchmark MOE for this 

assessment was 100 and since the EPA generally has no concern for exposures below 

100% of the RfD, Syngenta believes that there is a reasonable certainty that no 

harm will result from chronic drinking water exposure to residues arising from all 

current and proposed uses of thiamethoxam.

2. Non-dietary exposure. A residential exposure and risk assessment was 

performed for thiamethoxam using the recently revised endpoints and uncertainty 

factors established by the EPA. The residential exposure and risk assessment was 

performed for thiamethoxam uses on turf and ornamentals using the Meridian 

0.33G and 25WG labels. Based on these Meridian labels, there is a potential for 

residential handler exposure from consumers making applications to home lawns 

and ornamentals. There is also a potential for post-application residential exposure 

to adults and children re-entering treated lawns and to adults playing golf on 

treated turf. 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 children 1-6, from a 

short-term dermal from a 28-day dermal study in rats). The post-application 

residential MOE for children (1-6 years) from turfgrass use of Meridian 25 WG is 

1,347, which exceeds the residential risk arising from the turfgrass use Meridian 
8

0.33G (MOE = 1,650). The resultant combined short-term MOEs were1,347 (total 

post-application risk) and 2,111 (combined post-application and handler risk) for 

children (1-6 years) and adults (20-49 years), respectively. Both children (1-6 years) 

and adults (20-49 years) MOEs are above the Benchmark MOE of 100 and thus 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 tolerance, the Agency consider “available 

information” concerning the cumulative effects of a particular pesticide’s residues 

and “other substances that have a common 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 produced by other substances. For the 

purposes of this tolerance action, the EPA 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 established and proposed thiamethoxam tolerances 

would result in a MOE of 2,523 (3.91% 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 tolerances resulted in a MOE of 7,389 (1.4% 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 2,040 for adults (20-49 years old), which exceeds the 

Benchmark MOE of 100. Based on the completeness and reliability of the toxicity 

data supporting these petitions, Syngenta believes that there is a reasonable 

certainty that no harm will result from aggregate exposure to residues arising from 

all current and proposed thiamethoxam uses, including anticipated dietary exposure 

from food, water, and all other types of non-occupational exposures.

2. Infants and children. The acute dietary exposure analysis (food plus water) 

showed that exposure from all established and proposed thiamethoxam uses would

result in a MOE of 1,308 (7.54% of the aRfD of 0.35 mg/kg-bw/day) for the most 

sensitive population subgroup, children 1-2 years old, which exceeds the Benchmark 

MOE of 100. The chronic aggregate dietary (food plus water) exposure analysis 

showed that exposure from all established and proposed thiamethoxam uses would 

result in a MOE of 3,015 (3.3% of the chronic RfD of 0.012 mg/kg-bw/day) for the 
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most sensitive population subgroup, children 1-2 years 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 1,281 for the children (1-6 years), which exceeds the Benchmark MOE of 

100. Based on the completeness and reliability of the toxicity data supporting these 

petitions, Syngenta believes that there is a reasonable certainty that no harm will 

result to infants 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 non-occupational exposures.

F. International Tolerances

There are currently no Maximum Residue Limits (MRLs) set for 

thiamethoxam for crops by the Codex Alimentarius 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, Russia, Serbia and Montenegro, Slovak 

Republic, Slovenia, South Africa, Spain, Switzerland, Taiwan, Ukraine, and United 

States.