Document ID: EPA-HQ-OPP-2007-0280-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-04-30T04:00Z

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EPA has received a pesticide petition ([XXXXX]) from [Bayer
CropScience], [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 in or on the raw
agricultural commodities [beet, sugar, roots] at [0.02] parts per
million (ppm), [beet, sugar, tops] at [0.04] ppm, and [beet, sugar,
molasses] at [0.06] ppm.  EPA has determined that the petition contains
data or information regarding the elements set forth in section
408(d)(2) of the FFDCA; 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 

                                      

.  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-[(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.

.  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.

– A total of 12 field trials were conducted to measure the magnitude
of clothianidin residues in sugar beet following the planting of sugar
beet seeds treated with CLOTHIANIDIN + CYFLUTHRIN 600 SE at a target
rate of 60 g clothianidin /100,000 seeds and 16 g cyfluthrin/100,000
seeds. CLOTHIANIDIN + CYFLUTHRIN 600 SE is an emulsifiable concentrate
containing clothianidin and cyfluthrin. Following treatment, the seeds
were planted at seeding rates ranging from 52,870 to 71,320 seeds/A. 
The resulting soil application rates for clothianidin were 0.070 to
0.094 lb ai/A (0.078 to 0.105 kg ai/ha).  In all trials, duplicate
composite samples of sugar beet roots and tops were collected at crop
maturity. 

Residues of clothianidin and the metabolite TMG
(N-[(2-chloro-5-thiazolyl)methyl]-N’-methyl-guanidine were quantified
in sugar beet roots and tops by liquid chromatography-mass
spectrometry/mass spectrometry (lc-ms/ms) using the stable isotopically
labeled analytes as internal standards and the method of external
standard quantitation.  The individual analyte residues, reported in
clothianidin equivalents, were summed to obtain a total clothianidin
residue. The limit of quantification (LOQ) for each analyte was 0.01 ppm
in sugar beet roots and tops.

The highest average total clothianidin residues (clothianidin + TMG)
were 0.018 ppm in sugar beet roots and 0.030 ppm in sugar beet tops at
maturity.  No TMG was found in the sugar beet roots.  Based on the
magnitude of the TMG residues in the sugar beet roots and tops it is
proposed that the residues of concern for the tolerance expression
continue to be parent clothianidin, but that the residues of the
metabolite TMG in sugar beets be included for risk assessment.  A
processing study showed concentration of clothianidin residues in
molasses with only slight concentration of residues in dried pulp.  No
concentration of residues was seen in refined sugar.

B. Toxicological Profile

. The acute oral LD50 was >5,000 milligrams/ kilograms/ body weight
(mg/kg bw) for both male and female rats.  The acute dermal LD50 was
greater than 2,000 mg/kg bw in rats.  The 4-hour inhalation LC50 was
5.538 mg/L for male and female rats.  Clothianidin was not irritating to
rabbit skin and only slightly irritating to the eyes and did not cause
skin sensitization in guinea pigs.

  Extensive mutagenicity studies were conducted with clothianidin. 
Based on the weight of evidence clothianidin was considered negative for
genotoxicity.

.  In a 2-generation reproduction study, rats were administered dietary
levels of 0, 150, 500 and 2500 ppm.  The No Observed Effect Level
(NOAEL) for reproductive parameters was 500 ppm (31.2/36.8 mg.kg/day;
M/F) 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
using dose levels of 0, 10, 50 and 125 mg/kg bw by gavage.  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 treated orally
by gavage at 0, 10, 25, 75 and 100 mg/kg bw.  The NOAEL for maternal
toxicity was 25 mg/kg bw and for developmental toxicity it was 75 mg/kg
bw.

Developmental toxicity studies showed no primary developmental toxicity
and no teratogenic potential was evident.

Ninety-day feeding studies were conducted in rats and dogs.  The rat
study was conducted at dietary levels of 0, 150, 500 and 3,000 ppm and
the dog study was conducted at 0, 325, 650 and 1,500 ppm.  The NOAELs
were established at 500 ppm (27.9/34.0 mg/kg/day; M/F) for rat and 650
ppm (19.3 mg/kg/day) for the female dog and 1,500 ppm (42.1 mg/kg/day)
for the female dog. 

.  A 2- year combined rat chronic/oncogenicity conducted at dietary
levels of 0, 150, 500, 1,500 and 3,000 ppm demonstrated a NOAEL of 500
ppm (27.9/34.0 mg/kg/day) based on reduced weight gains and
non-neoplastic histomorphological changes.  A 78-week mouse oncogenicity
study conducted at dose levels of 0, 100, 350, 1,250 and 2,000, and
1,800 ppm for males and females, respectively, revealed a NOAEL of 350
ppm (47.2/65.1 mg/kg/day; M/F) based on reduced body weight gains and
increased incidence of hypercellular hypertrophy.  No evidence of
oncogenicity was seen in the rat or the mice.  A 52-week chronic
toxicity study in dogs conducted at dietary levels of  0, 325, 650,
1,500 and 2,000 ppm 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. 

.  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.

.  Eight in vivo metabolites of clothianidin identified in the rat were
investigated for acute oral endpoint 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.

.  All guideline studies conducted to characterize toxicological profile
showed no endocrine related toxicity or tumorgenicity.  No effects on
triiodothyronine (T3), throxine (T4) or thyroid stimulating hormone
(TSH) were observed in the subchronic rat study.  In a 2-generation
reproduction study in rat; and rat and rabbit teratology studies,
clothianidin did not show reproductive or teratogenic effects.  The
extensive database shows that clothianidin has no endocrine properties.

C. Aggregate Exposure

	1. Dietary Exposure.  Assessments were conducted to evaluate potential
risks due to chronic and acute dietary exposure of the U.S. population
and selected population subgroups to residues of clothianidin.  These
analyses included all registered and pending uses for clothianidin
including the above sugar beet commodities. The acute population
adjusted dose (aPAD) of 0.025 mg/kg bw/day based on an acute NOAEL of 25
with an uncertainty factor of 1000 was used to assess acute dietary
exposure.  The chronic population adjusted dose (cPAD) of 0.0098 mg/kg
bw/day based on a chronic NOAEL of 9.8 with an uncertainty factor of
1000 was used to assess chronic exposure. 

	       i.Food. In the February 16, 2005 Federal Register notice
clothianidin tolerance were established for use on pome fruit.  To
support that tolerance the EPA conducted Tier 1 acute and chronic
dietary assessments for clothianidin.  These assessments included
residues of clothianidin that arise from the uses of thiamethoxam which
has clothianidin as a common metabolite. Additional tolerance petitions
are pending with the Agency for registration of clothianidin as a seed
treatment on sorghum and cotton. Bayer CropScience has submitted a
revised dietary assessment which includes all of the current and
proposed uses of clothianidin as well as clothianidin residues from
thiamethoxam. The US Population utilized 17.4% of the aPAD and 10.8% of
the cPAD.  The most highly exposed sub-population utilized 81.5% of
acute PAD (Infants) and 47.9% of the cPAD (Children 1-2).

US EPA’s Standard Operating Procedure (SOP) for Drinking Water
Exposure and Risk Assessments was used to perform the drinking water
assessment.  This SOP uses a variety of tools to conduct drinking water
assessment.   These tools include water models such as SCI-GROW, FIRST,
PRZMS/EXAMS, and monitoring data.  If monitoring data are not available
then the models are used to predict potential residues in surface and
ground water and the highest is assumed to be the drinking water
residue.  In the case of clothianidin monitoring data do not exist
therefore SCI-GROW and FIRST were used to estimate a water residue.  The
calculated drinking water levels of comparison (DWLOC) for acute chronic
exposure for all adults and children exceed the estimated drinking water
concentrations (EDWC) from the models.  The chronic DWLOC for adults is
306 ppb and the acute DWLOC is 723 ppb.  The chronic DWLOC for children
1-2 is 51 ppb and the acute DWLOC for infants is 46 ppb.  The EDWC for
the worst case chronic scenario is 5.84 ppb (FIRST) and the acute EDWC
(FIRST) is 7.29 ppb.  The drinking water levels of comparison are based
on conservative dietary (food) exposures and are expected to be much
higher in real world situations.

2.  Non-dietary Exposure.  Clothianidin is currently registered for use
on turfgrasses. Exposures and risk resulting from the clothianidin
residues on turfgrasses were included in the EPA risk assessment for
thiamethoxam published in the Federal Register, January 5, 2005 and the
clothianidin risk assessment published in the Federal Register, February
16, 2005.

D. Cumulative Effects

	Clothianidin is a metabolite of thiamethoxam. Therefore, residues of
clothianidin resulting from use of thiamethoxam were included in the
above risk assessment. Currently, EPA has not determined that toxic
effects produced by clothianidin are cumulative with those of any other
compound.

E.  Safety Determination

	1. US Population.  Using the conservative exposure assumptions
described above and based on the completeness of the toxicity data, it
can be concluded that aggregate exposure to residues of clothianidin
present a reasonable certainty of no harm.  Exposure from residues in
crops utilizes 17.4% of the aPAD and 10.8% of the cPAD.  EPA generally
has no concerns for exposures below 100% of the Population Adjusted
Doses.  Drinking water levels of concern are well above the estimated
drinking water concentrations as calculated by conservative models. 
Clothianidin is registered for use on turf.  The aggregate exposure to
the U.S. Population and population subgroups was assessed by EPA and
published in the Federal Register February 16, 2005. The sorghum, cotton
and sugar beet uses do not change the water exposure. The conservative
Tier 1 assessments demonstrate a reasonable certainty of no harm will
result from uses of clothianidin for the US Population.

.  In assessing the potential for additional sensitivity of infants and
children to residues of clothianidin, the data from developmental
toxicity studies in both the rat and rabbit, a 2-generation reproduction
study in rats and a developmental neurotoxicity study in rats have been
considered.

The developmental toxicity studies evaluate potential adverse effects on
the developing animal resulting from pesticide exposure of the mother
during prenatal development.  The reproduction study evaluates effects
from exposure to the pesticide on the reproductive capability of mating
animals through two generations, as well as any observed systemic
toxicity.

The developmental neurotoxicity studies evaluate the neurobehavioral and
neurotoxic effects on the developing animal resulting from the exposure
of the mother. FFDCA Section 408 provides that EPA may apply an
additional uncertainty factor for infants and children based on the
threshold effects to account for prenatal and postnatal effects and the
completeness of the toxicity database.  Based on the current
toxicological data requirements the toxicology database for clothianidin
relative to prenatal and postnatal development is complete, including
the developmental neurotoxicity study.  None of the studies indicated
the offspring to be more sensitive.  All effects were secondary to
severe maternal toxicity.  Therefore, no additional safety or
uncertainty factor is justified.

F. International Tolerances

		

	No CODEX Maximum Residue Levels (MRL’s) have been established for
residues of clothianidin on any crops at this time.



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