EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

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

EPA Registration Division contact: [insert name and telephone number with area code]

INSTRUCTIONS: Please utilize this outline in preparing the pest icide petition. In cases where the outline element does not apply, ple ase insert “NA-Remove” and maintain the outline. Please do not change the marg ins, font, or format in your pesticide petition. Simply replace the instructions that appear in green , i.e., “ [insert company name] ,” with the information specific to your action.

TEMPLATE:

[Bayer CropScience]

[Insert petition number]

EPA has received a pesticide petition ([insert petition number]) from [Bayer CropScience], [P.O. Box 12014, 2 T.W. Alexander Dri ve, Research Triangle Park, NC 27709] proposing, pursuant to section 408(d) of the Feder al Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 4 0 CFR part 180. by establishing a

tolerance for residues of [ clothianidin, (E)-1-(2-chloro-1,3-thiazol-5-ylmethy l)-3- methyl-2-nitroguanidine ] in or on mustard seed at [0.01] parts per million ( 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 w hether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. [ 1. Plant metabolism

. In plants, the metabolism of clothianidin is adequately understood for the purpo ses of establishing these proposed tolerances. Unchanged parent clothianidin was the predominant residue in all crop matrices (14.4% to 64.5% in corn, 66.1% to 96.6% in tomatoes, 4.3% to 24.4% in sugar beets, and 24.3% to 63.3% in apples), with the exce ption of sugar beet leaves. In sugar beet leaves, the main components were the methylgua nidine and thiazolylmethylguanidine metabolites, accounting fo r 28.6% and 27.7%, respectively. In

the EPA assessment of the clothianidin data for the corn and canola registration the Agency concluded that clothianidin was the residue of concern for corn and canola commodities, but that for root crops and leafy vege tables residues of the metabolite (N-2

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[(2-chloro-5-thiazolyl)methyl]-N’-methylguanidine w ould need to be quantified. All metabolites found in plants were also found in the animal metabolism studies. In animals, parent clothianidin was the major componen t in liver, muscle and fat. Based on the available metabolism data, the Agency concluded that parent clothianidin was the residues of concern for the tolerance expression fo r animal commodities, but that the

metabolites N

-(2-Chlorothiazol-5-ylmethyl)- N’ -nitroguanidine (TZNG), thiazolylguanidine (TZG), thiazolyl-urea (TZU), and aminoth iazolyl methylguanidine-pyridine (ATMG-Pyr) need to be included as residues of conce rn in livestock matrices for risk

assessment.

2. Analytical method

. In plants and plant products, the residue of concer n, parent clothianidin, can be determined using High Performa nce Liquid Chromatography (HPLC) with Electrospray MS/MS detection. In an ex traction efficiency testing, the plant residues method has also demonstrated the abi lity to extract aged clothianidin

residue.

Although the plant residues LC-MS/MS method is high ly suitable for enforcement method, an LC-UV method has also been developed whi ch is suitable for enforcement (monitoring) purposes in all relevant matrices.
]

3. Magnitude of residues. [ Magnitude of residue studies for canola were previously submitted and approved by the Agency. Th ese data can be used to support the expansion of the tolerance to include mustard seed.

The available metabolism and residue data indicate that the residue of concern for the rapeseed subgroup is clothianidin per se

. ]

B. Toxicological Profile

1. Acute toxicity . The acute oral, dermal, and inhalation toxicity f or clothianidin is very low (EPA Toxicity Category IV). Clothianidin was not irritating to the skin and only slightly irritating to the eyes and did not ca use skin sensitization. A special acute neurotoxicity/pharmacology study was conducted in r ats and mice. The resulting NOAEL of 25 mg/kg/day, was established in mice base d on clinical signs of neurotoxicity in the FOB.

2. Genotoxicty. Extensive mutagenicity studies were conducted wit h clothianidin. Based on the weight of evidence clothianidin was co nsidered negative for genotoxicity.

3. Reproductive and developmental toxicity . In a 2-generation reproduction study, the resulting No Observed Effect Level (NOAEL) for reproductive parameters was 500 ppm (31.2 mg./kg/day), while the NOAEL for developm ental effects was 150 ppm (9.8/11.5 mg/kg/day; M/F). The parental systemic NO AEL was 500 ppm (31.2/36.8 mg/kg/day; M/F).

A developmental toxicity study was conducted in rat s with clothianidin, the NOAEL for3

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maternal toxicity was established at 10 mg/kg bw an d for developmental effects it was >125 mg/kg bw. Additionally, a developmental toxic ity study was conducted with rabbits with a resulting NOAEL for maternal and dev elopmental toxicity of 25 mg/kg bw. These studies showed no primary developmental toxic ity and no teratogenic potential

was evident.

A developmental neurotoxicity in the rat resulted i n a maternal NOAEL of 42.9 mg/kg/day, and an offspring NOAEL of 12.9 mg/kg/day . While there is a quantitative difference between the maternal and offspring NOAEL s, the degree of concern is low, as

the observed effects are well characterized and the re are clear NOAELs/LOAELs.

4. Subchronic toxicity

. Ninety-day feeding studies were conducted in rats a nd dogs. The rat systemic NOAEL was established at 50 0 ppm (27.9/34.0 mg/kg/day; M/F) for rat, and the dog NOAEL was 650 ppm (19.3 mg/kg/ day) for males and 1,500 ppm (42.1 mg/kg/day) for the females. A ninety-day neu rotoxicity in the rat showed no indication of neurotoxicity at any dose.

5. Chronic toxicity

. A 2- year combined rat chronic/oncogenicity demonst rated a NOAEL of 500 ppm (32.5 mg/kg/day) based on reduced weight gains and non-neoplastic morphological changes. A 78-week mouse oncogenicit y revealed a NOAEL of 350 ppm (65.1 mg/kg/day) based on reduced body weight and b ody weight gains. No evidence of oncogenicity was seen in the rat or the mice. A 52 -week chronic toxicity study in dogs revealed a NOAEL of 2,000 ppm (46.4 mg/kg/day) for the male dog and 1,500 ppm (40.1 mg/kg/day) for the female dog.

6. Animal metabolism . The nature of the clothianidin residue in livest ock is adequately understood. In animals, parent clothian idin was the major component in liver,

muscle and fat. Based on the available metabolism data, parent clothianidin, TZG, TZU, and ATMG-Pyr are proposed to be considered as the r esidues of concern in livestock

matrices.

7. Metabolite toxicology

. Eight in vivo metabolites of clothianidin identified in the rat were investigated for acute oral endpoints and mutagenic activity. None of the metabolites were mutagenic either with or without a ctivation and the LD 50 values range from <500 to >2,000 mg/kg, showing low to moderate toxicity.

8. Endocrine disruption

. EPA is required to develop a screening program to determine whether certain substances (including all pesticides and inerts) may have an effect in humans that is similar to an effect produ ced by a naturally occurring estrogen, or such other effect. The Agency is currently working with interested stakeholders, including other government agencies, public interes t groups, industry and research scientists in developing a screening and testing pr ogram and a priority setting scheme to implement this program. EPA may require further tes ting of this active ingredient and end use products for endocrine disrupter effects. B ased on the toxicological findings for clothianidin relating to endocrine disruption effec ts, clothianidin may be considered as a candidate for evaluation as an endocrine disrupter when the exact criteria are established.4

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C. Aggregate Exposure

1. Dietary exposure. [ EPA’s most recent aggregate assessment, conducted A ugust 9, 2009, was based upon an acute reference dose (aR fD) of 0.25 mg/kg bw/day which was established based on an acute NOAEL of 25 mg/kg /day with a 100-fold uncertainty

factor. The assessment included residues of clothia nidin arising from all current and proposed clothianidin uses as well as clothianidin residues from all the thiamethoxam

uses.

The chronic reference dose (cRfD) of 0.098 mg/kg bw /day (chronic NOAEL of 9.8 mg/kg/day with a 100-fold uncertainty factor), as e stablished by EPA, was used to assess chronic dietary exposure (food and drinking water) for all of the above uses. All the above uses resulted in exposure for the U.S. Popula tion being 5% (0.004582 mg/kg/day) of the chronic RfD and for the most exposed subpopu lation, Children 1-2, being 19% (0.018429 mg/kg/day) of the chronic RfD.

Results from the acute and chronic dietary exposure assessment described below demonstrate a reasonable certainty that no harm to the overall U.S. population or any population subgroup will result from the use of clo thianidin on the above crops. ]

i. Food. [ For all of the clothianidin and thiamethoxam uses t he Agency’s acute assessment (including food and drinking water) show ed that the U.S. Population utilized 6% (0.015019 mg/kg/day at the 95 th percentile) of the acute RfD and the most exposed subpopulation, Children 1-2, utilized 23% (0.057317 mg/kg/day, 95 th percentile) of the

acute RfD.

All the above uses resulted in chronic exposure for the U.S. Population being 5% (0.004582 mg/kg/day) of the chronic RfD and for the most exposed subpopulation, Children 1-2, being 19% (0.018429 mg/kg/day) of the chronic RfD.]

ii. Drinking water. [ No monitoring data are available for residues of cl othianidin in drinking water, and EPA has established no healt h advisory levels or maximum

contaminant levels for residues of clothianidin in drinking water. In order to address drinking water, potential water residues were inclu ded in the dietary analyses for food given above. Potential clothianidin residues in wat er contribute little to the overall dietary exposure to clothianidin for the general US populat ion or any population subgroup

. ]

2. Non-dietary exposure

. [ Residential (non-occupational) exposure to clothian idin results solely from the currently registered use of this compound on turfgrass. EPA has

conducted an assessment for this use. Based on the registered use patterns on turfgrasses, a number of residential or recreational post-applic ation exposures are possible. In a residential setting, a “homeowner” may be exposed d uring application of the material to his or her lawn and as a result of post-application dermal exposure. Toddlers may be exposed via “hand-to-mouth” oral exposures and/or d ermal exposures.5

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The MOEs for the residential post-application expos ures/risks ranged from 1,300 to 490,000. EPA considers MOE values greater than 100 adequate to protect adults and children from residential post-application exposure s to clothianidin. The estimated MOEs are based upon conservative assumptions and ar e >100; therefore, the estimated risks from residential post-application exposures d o not exceed HED’s level of concern. ]

D. Cumulative Effects

[ Clothianidin is a member of the neonicotinoid famil y of insecticides and is a

metabolite of the insecticide thiamethoxam. Therefo re, all dietary (food and water)

assessments for clothianidin consider residues of c lothianidin resulting from application

of thiamethoxam and clothianidin .]

E. Safety Determination

1. U.S. population. [ Based on the conservative exposure assumptions desc ribed above and on the completeness of the toxicity data, it can be concluded that total food and drinking water exposure to clothianidin from al l proposed uses will utilize 6% of the

acute RfD/PAD and 5% of the chronic RfD/PAD for the general US population. EPA generally has no concerns for exposures below 100% of the RfD, because the RfD represents the level at or below which daily aggreg ate exposure over a lifetime will not pose appreciable risks to human health. ]

2. Infants and children

. [ Based on the conservative exposure assumptions described above and on the completeness of the toxi city data, it can be concluded that total food and drinking water exposure to clothiani din from all proposed uses will utilize

23% of the acute RfD/PAD and 19% of the chronic RfD /PAD for the Children 1-2, the most exposed population subgroup. EPA generally has no concerns for exposures below 100% of the RfD, because the RfD represents the lev el at or below which daily aggregate exposure over a lifetime will not pose appreciable risks to human health. ]

F. International Tolerances

[ Although no Codex MRLs are currently established fo r clothianidin there are clothianidin MRLs for numerous crops in many countr ies around the world. ]