 

<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 increasing the tolerance for residues of
[clothianidin,
(E)-1-(2-chloro-1,3-thiazol-5-ylmethyl)-3-methyl-2-nitroguanidine and
its metabolite, TMG,
N-(2-chloro-5-thiazolylmethyl)-N’-methylguanidine] in or on the raw
agricultural commodity [potato] from [0.05] to [0.6] 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 TMG,
(N-[(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),
thiazolyl-guanidine (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 and its metabolite, TMG,
N-(2-chloro-5-thiazolylmethyl)-N’-methylguanidine], 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 were conducted
to support the increased rate and tolerance on potatoes.  A total of 16
field trials were conducted in USA to measure the magnitude of
clothianidin residues in/on potatoes following the planting of potato
seed pieces treated with PONCHO 600 FS at a rate of 18.75 g ai/100 kg
seed pieces (14.2 mL formulated product/45 kg seed pieces) immediately
prior to planting. Following treatment, the seed pieces were planted at
rates ranging from 1637 to 2234 lb seed pieces/A (1835 to 2508 kg seed
pieces/ha). The resulting soil application rates ranged from 0.335 to
0.425 lb ai/A (0.376 to 0.477 kg ai/ha).  Additional five field trials
were conducted in Canada at a target seed treatment rate of 12.5 g
ai/100 kg seed pieces.  In all trials, single control samples and
duplicate treated samples of potato tubers were collected from each plot
at earliest commercial harvest (ECH).

The highest average field trial (HAFT) total clothianidin (clothianidin
+ TMG) residue was 0.23 ppm with a maximum residue of 0.24 ppm in potato
at ECH.

4.  Magnitude of the residues in Potato Processed Commodities - A potato
processing trial was conducted to measure the magnitude of clothianidin
residue on potatoes and potato processed commodities.   Application of
PONCHO 600 FS was made to potato seed pieces at a rate of 0.948 g ai/kg
seed pieces. The treatment rate was equivalent to 48.7 fl oz formulated
product/acre which represents a five-fold (5X) exaggeration of the
maximum recommended label use rate.  Following treatment, the seed
pieces were planted at a rate of 2012 lb seed pieces/A (2255 kg seed
pieces/ha).  The resulting soil application rate was 1.91 lb ai/A (2.138
kg ai/ha).   

A single control and treated bulk sample of potatoes were collected at
commercial.  Prior to processing, random sub-samples of the control and
treated bulk potato samples were collected for analysis, and the
remainder of the potato samples were used to generate the processed
commodities of washed potato, wet peel, chips, cooked potato and
granules. Potato processing was performed using procedures which
simulated commercial processing practices. The resultant potato samples
and processed commodities were analyzed to determine total clothianidin
residue. 

Concentration of the total clothianidin residue was observed in the
processed commodities of potato flakes (6.4X), potato chips (2.6X) and
washed potatoes (2.1X). A slight concentration was observed in potato
wet peel (1.3X), and no concentration was observed in cooked potato
(1X).  An evaluation of the potential residues in processed commodities
indicates that no processed commodity tolerances are required.

The available metabolism and residue data indicate that the residues of
concern for leafy and root vegetables include the parent clothianidin
plus the metabolite TMG while the residue of concern for other crops is
only 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 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. 

<C. Aggregate Exposure>

<	1. Dietary exposure. [An aggregate risk assessment was conducted for
all registered and proposed uses of clothianidin following EPA
methodology (July 8, 2008 Dietary Risk Assessment) and starting with the
EPA residue file. The new uses mentioned above were added to the
existing uses in the EPA residue file to develop the new residue file
for risk assessment. The assessment assumed (based on an evaluation of
existing and proposed uses of clothianidin) that the secondary residues
remain the same. 

The acute assessment is based on an acute reference dose (aRfD) and
population adjusted dose, PAD) of 0.025 mg/kg/day for females 13-50
years of age based on a NOAEL of 25 mg/kg/day from the rabbit
developmental study and an uncertainty factor of 1000 (10X for
interspecies uncertainty, 10X for intraspecies variability and 10X
database uncertainty factor for lack of a developmental immunotoxicity
(DIT) study). The RfD/PAD for the general population and all other
population subgroups was also 0.025 mg/kg/day but was based on a NOAEL
of 25 mg/kg/day from the acute neurotoxicity study and an uncertainty
factor of 1000.

The chronic assessment was conducted using a chronic reference dose
(cRfD) of 0.0098 mg/kg/day based on the two-generation reproduction
study and an uncertainty factor of 1000.

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. [An acute, Tier 2 dietary (food and drinking water) risk
assessment was conducted. The most exposed population subgroup was
Children 1-2 with an exposure equivalent to 52% of the aPAD (food only)
and 54% of the aPAD (food and water). The chronic exposure for Children
1-2 (the most exposed population) was equivalent to 20% of the cPAD
(food only) and 22% of the cPAD (food and water).

For the general US population the acute exposure was equivalent to 14%
of the aPAD (food only) and 17% of the aPAD (food and water).  The
chronic exposure for the general US population was equivalent to 5% of
the cPAD (food only) and 6% of the cPAD (food and water).]>

<	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
and are given above. As can be seen from the above results, 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.  

The MOEs for the residential post-application exposures/risks ranged
from 1,300 to 490,000.  EPA considers MOE values greater than 1000
adequate to protect adults and children from residential
post-application exposures to clothianidin.  The estimated MOEs are
based upon conservative assumptions and are >1000; 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 17% of the acute RfD/PAD and 6% 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 54% of the acute
RfD/PAD and 22% 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 various crops in many countries around
the world. The current petition has also been submitted to the Canadian
PMRA requesting the same MRLs in Canada and the USA.]>

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