EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

(7/1/2007) 

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

code] 

INSTRUCTIONS: Please utilize this outline in preparing the pesticide petition. In 

cases where the outline element does not apply, please insert “NA-Remove” and 

maintain the outline. Please do not change the margins, 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 Drive, Research Triangle Park, 

NC 27709] 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. by establishing a 

tolerance for residues of [clothianidin, (E)-1-(2-chloro-1,3-thiazol-5-ylmethyl)-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 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. [1. Plant metabolism. In plants, the metabolism of 

clothianidin is adequately understood for the purposes 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 exception of sugar beet leaves. In sugar 

beet leaves, the main components were the methylguanidine and 

thiazolylmethylguanidine metabolites, accounting for 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 vegetables residues of the metabolite (N-
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[(2-chloro-5-thiazolyl)methyl]-N’-methylguanidine would need to be quantified. 

All metabolites found in plants were also found in the animal metabolism studies. In 

animals, parent clothianidin was the major component 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 for animal commodities, but that the 

metabolites N-(2-Chlorothiazol-5-ylmethyl)-N’-nitroguanidine (TZNG), thiazolylguanidine (TZG), thiazolyl-urea (TZU), and aminothiazolyl methylguanidine-pyridine 

(ATMG-Pyr) need to be included as residues of concern in livestock matrices for risk 

assessment. 

 2. Analytical method. In plants and plant products, the residue of concern, parent 

clothianidin, can be determined using High Performance Liquid Chromatography 

(HPLC) with Electrospray MS/MS detection. In an extraction efficiency testing, the 

plant residues method has also demonstrated the ability to extract aged clothianidin 

residue. 

Although the plant residues LC-MS/MS method is highly suitable for enforcement 

method, an LC-UV method has also been developed which 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. These 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 for 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 cause skin sensitization. A special acute 

neurotoxicity/pharmacology study was conducted in rats and mice. The resulting 

NOAEL of 25 mg/kg/day, was established in mice based on clinical signs of 

neurotoxicity in the FOB. 

 2. Genotoxicty. Extensive mutagenicity studies were conducted with clothianidin. 

Based on the weight of evidence clothianidin was considered 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 developmental effects was 150 ppm 

(9.8/11.5 mg/kg/day; M/F). The parental systemic NOAEL was 500 ppm (31.2/36.8 

mg/kg/day; M/F). 

A developmental toxicity study was conducted in rats with clothianidin, the NOAEL for 
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maternal toxicity was established at 10 mg/kg bw and for developmental effects it was 

>125 mg/kg bw. Additionally, a developmental toxicity study was conducted with 

rabbits with a resulting NOAEL for maternal and developmental toxicity of 25 mg/kg bw. 

These studies showed no primary developmental toxicity and no teratogenic potential 

was evident. 

A developmental neurotoxicity in the rat resulted in 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 NOAELs, the degree of concern is low, as 

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

 4. Subchronic toxicity. Ninety-day feeding studies were conducted in rats and 

dogs. The rat systemic NOAEL was established at 500 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 neurotoxicity in the rat showed no 

indication of neurotoxicity at any dose. 

 5. Chronic toxicity. A 2- year combined rat chronic/oncogenicity demonstrated a 

NOAEL of 500 ppm (32.5 mg/kg/day) based on reduced weight gains and non-neoplastic 

morphological changes. A 78-week mouse oncogenicity revealed a NOAEL of 350 ppm 

(65.1 mg/kg/day) based on reduced body weight and body 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 livestock is 

adequately understood. In animals, parent clothianidin 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 residues 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 activation and the LD50 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 produced by a naturally occurring estrogen, or 

such other effect. The Agency is currently working with interested stakeholders, 

including other government agencies, public interest groups, industry and research 

scientists in developing a screening and testing program and a priority setting scheme to 

implement this program. EPA may require further testing of this active ingredient and 

end use products for endocrine disrupter effects. Based on the toxicological findings for 

clothianidin relating to endocrine disruption effects, clothianidin may be considered as a 

candidate for evaluation as an endocrine disrupter when the exact criteria are established. 
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C. Aggregate Exposure

 1. Dietary exposure. [EPA’s most recent aggregate assessment, conducted August 

9, 2009, was based upon an acute reference dose (aRfD) 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 clothianidin 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 established 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. 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. 

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 clothianidin on the above crops.]

 i. Food. [For all of the clothianidin and thiamethoxam uses the Agency’s acute 

assessment (including food and drinking water) showed that the U.S. Population utilized 

6% (0.015019 mg/kg/day at the 95th percentile) of the acute RfD and the most exposed 

subpopulation, Children 1-2, utilized 23% (0.057317 mg/kg/day, 95th 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 clothianidin 

in drinking water, and EPA has established no health advisory levels or maximum 

contaminant levels for residues of clothianidin in drinking water. In order to address 

drinking water, potential water residues were included in the dietary analyses for food 

given above. Potential clothianidin residues in water contribute little to the overall dietary 

exposure to clothianidin for the general US population or any population subgroup.]

 2. Non-dietary exposure. [Residential (non-occupational) exposure to clothianidin 

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-application exposures are possible. In a 

residential setting, a “homeowner” may be exposed during 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 dermal exposures. 
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The MOEs for the residential post-application exposures/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 exposures to clothianidin. The estimated 

MOEs are based upon conservative assumptions and are >100; therefore, the estimated 

risks from residential post-application exposures do not exceed HED’s level of concern.]

D. Cumulative Effects

 [Clothianidin is a member of the neonicotinoid family of insecticides and is a 

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

assessments for clothianidin consider residues of clothianidin resulting from application 

of thiamethoxam and clothianidin.]

E. Safety Determination

 1. U.S. population. [Based on the conservative exposure assumptions described 

above and on the completeness of the toxicity data, it can be concluded that total food 

and drinking water exposure to clothianidin from all 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 aggregate 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 toxicity data, it can be concluded that 

total food and drinking water exposure to clothianidin 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 level 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 for clothianidin there are 

clothianidin MRLs for numerous crops in many countries around the world.]