Document ID: EPA-HQ-OPP-2008-0772-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-12-03T05:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

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
[imidacloprid,
1-[(6-chloro-3-pyridinyl)methyl]-N-nitro-2-imidazolidinimine] and its
metabolites containing the 6-chloropyridinyl moiety, all expressed as
the parent, in or on the raw agricultural commodity [cereal, grain,
group 15] at [0.05] ppm.  

Bayer CropScience is also proposing use of the currently established
tolerances for residues of [imidacloprid,
1-[(6-chloro-3-pyridinyl)methyl]-N-nitro-2-imidazolidinimine] and its
metabolites containing the 6-chloropyridinyl moiety, all expressed as
the parent, in or on the raw agricultural commodity [vegetable, root,
except sugar beet, subgroup 01B],  [vegetable, tuberous and corm,
subgroup 01C], [vegetable, leafy greens, except Brassica, subgroup 04A],
[vegetable, Brassica, leafy, group 05], [vegetable, fruiting, group 08],
 [vegetable, cucurbit, group 09] to support the use of imidacloprid as a
seed treatment on these crops.  

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 nature of the imidacloprid residue in plants
and livestock is adequately understood. The residues of concern are
combined residues of imidacloprid and it metabolites containing the
6-chloropyridinyl moiety, all calculated as imidacloprid.    

	2. Analytical method. [All required analytical methods have previously
been submitted to the Agency and validated. Therefore, no additional
methods are needed.]

	3. Magnitude of residues. [Imidacloprid grain tolerances (all at 0.05
ppm) currently exist for the cereal grains: barley, corn, popcorn,
millet, oats, rye, sorghum and wheat, all of which are on the current
Gaucho seed treatment label. The residue data used to register these
crops can be used to support a crop group 15 tolerance at 0.05 ppm. 

Studies were previously conducted and submitted to the USEPA that
demonstrate that residues of imidacloprid from seed treatment will be
substantially lower than those resulting from soil or foliar
applications, especially foliar applications.  The lower residues result
from lower seed treatment application rates and significantly longer
pre-harvest intervals. Therefore, residue data generated for the soil
and foliar uses will support the seed treatment uses where specific seed
treatment residue data do not exist.]

B. Toxicological Profile

	1. Acute toxicity.  [Imidacloprid has low acute toxicity via the dermal
and inhalation routes and moderate acute toxicity via the oral route. 
The acute oral LD50 value for imidacloprid technical was found to be 424
mg/kg for male rats and >450 mg/kg for female rats.  The acute dermal
LD50 is >5,000 mg/kg and the 4 hour rat inhalation LC50 is >5.33 mg/L in
the rat.  Imidacloprid is not irritating to rabbit skin or eyes. 
Imidacloprid did not cause skin sensitization in guinea pigs.]

	2. Genotoxicty. [Imidacloprid has been evaluated for genotoxicity using
in vivo and in vitro tests, including mammalian cell gene mutation
tests, chromosomal aberration tests, unscheduled DNA synthesis tests,
bacterial DNA repair tests and other mutagenicity studies.  The weight
of evidence shows that imidacloprid is not mutagenic.]

	3. Reproductive and developmental toxicity. [In a developmental
toxicity study with Sprague Dawley rats, pregnant animals received an
oral administration of imidacloprid at 0, 10, 30, or 100 mg/kg/day
during gestation. The maternal NOAEL was 10 mg/kg/day based on decreased
body weight gain and the fetal NOAEL was 30 mg/kg/day based on a slight
increase in the incidence of wavy ribs in the presence of maternal
toxicity.  

In a developmental toxicity study with rabbits, pregnant animals were
given oral doses of imidacloprid at 0, 8, 24, or 72 mg/kg bwt/day during
gestation. For maternal toxicity, the NOAEL was 24 mg/kg /day and the
LOEL was 72 mg/kg/day based on mortality, decreased body weight gain,
and decreased food consumption. For developmental toxicity, the NOAEL
was 24 mg/kg bwt/day and the LOAEL was 72 mg/kg bwt/day based on
decreased fetal body weight and increased resorptions.

In a 2-generation reproductive toxicity study, imidacloprid was
administered to rats at dietary levels of 0, 100, 250, or 700 ppm. For
parental/systemic toxicity, the NOAEL was 250 ppm (16.5 mg/kg/day) and
the LOAEL was 700 ppm based on decreased body weight in both sexes.  The
reproductive NOAEL was the highest dose tested, 700 ppm.]

	4. Subchronic toxicity. [In a dermal toxicity study, groups of 5 male
and 5 female New Zealand White rabbits received repeated dermal
applications of imidacloprid at 1,000 mg/kg body weight/day, 6
hours/day, 5 days/week for 3 weeks. No dermal or systemic toxicity was
seen.  For systemic and dermal toxicity, the no observable adverse
effect level (NOAEL) was >1,000 mg/kg/day.]

	5. Chronic toxicity. [A chronic toxicity/carcinogenicity study was
performed with imidacloprid administered to male and female rats for two
years at dietary levels of 100, 300, 900 or 1,800 ppm.  There was no
evidence of carcinogenicity.  At 300 ppm, there was an increased
incidence of mineralized particles in thyroid colloid of male rats.  The
NOAEL was 100 ppm (5.7 mg/kg/day for males and 7.6 mg/kg/day for
females).  

The oncogenic potential of imidacloprid was investigated in B6C3F1 mice.
 Dietary doses were 0, 100, 330, 1,000 or 2,000 ppm.  Decreased body
weights, decreased food consumption and hepatocellular hypertrophy were
seen at the highest dose level.  There was no evidence of
carcinogenicity.  The NOAEL was 2,000 ppm (208 mg/kg for males and 274
for females). ]

	6. Animal metabolism. [The metabolism of NTN 33893 (imidacloprid) in
rats was reported in seven studies. These data show that imidacloprid
was rapidly absorbed and eliminated in the excreta (90% of the dose
within 24 hours), demonstrating no biologically significant differences
between sexes, dose levels, or route of administration. Elimination was
mainly renal (70 - 80% of the dose) and fecal (17 - 25%). The major part
of the fecal activity originated in the bile. Total body accumulation
after 48 hours consisted of 0.5% of the radioactivity with the liver,
kidney, lung, skin and plasma being the major sites of accumulation.
Therefore, bioaccumulation of imidacloprid is low in rats. Maximum
plasma concentration was reached between 1.1 and 2.5 hours. Two major
routes of biotransformation were proposed for imidacloprid. The first
route included an oxidative cleavage of the parent compound rendering
6-chloronicotinic acid and its glycine conjugate. Dechlorination of this
metabolite formed the 6-hydroxynicotinic acid and its mercapturic acid
derivative. The second route included the hydroxylation followed by
elimination of water of the parent compound rendering NTN 35884. A
comparison between [methylene -14C] imidacloprid and [imidazolidine
4,5-14C] imidacloprid showed that while the rate of excretion was
similar, the renal portion was higher with the imidazolidine labeled
compound. In addition, accumulation in tissues was higher with the
imidazolidine labeled compound (approximately 1% of the recovered
radioactivity).]

	7. Metabolite toxicology. [N/A.]

	8. Endocrine disruption. [EPA is required under the FFDCA, as amended
by FQPA, to develop a screening program to determine whether certain
substances (including all pesticide active and other ingredients) “may
have an effect in humans that is similar to an effect produced by a
naturally occurring estrogen, or other such endocrine effects as the
Administrator may designate.”  Following recommendations of its
Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC),
EPA determined that there was a scientific basis for including, as part
of the program, the androgen and thyroid hormone systems, in addition to
the estrogen hormone system.  EPA also adopted EDSTAC’s recommendation
that the Program include evaluations of potential effects in wildlife. 
For pesticide chemicals, EPA will use FIFRA and, to the extent that
effects in wildlife may help determine whether a substance may have an
effect in humans, FFDCA authority to require the wildlife evaluations. 
As the science develops and resources allow, screening of additional
hormone systems may be added to the Endocrine Disruptor Screening
Program (EDSP).

When additional appropriate screening and/or testing protocols being
considered under the Agency’s EDSP have been developed, imidacloprid
may be subjected to further screening and/or testing to better
characterize effects related to endocrine disruption.]

C. Aggregate Exposure

(DEEM-FCID™), which is licensed to Bayer, was used to estimate the
chronic and acute dietary exposure. This software uses the food
consumption data from the 1994_1998 USDA Continuing Surveys of Food
Intake by Individuals (CSFII 1994_1998).

	

The endpoint for acute dietary risk assessments is based on
neurotoxicity characterized by decreases in motor or locomotor activity
in female rats at 42 mg/kg bwt/day (LOEL) from an acute neurotoxicity
study. Based on an uncertainty factor of 10x for interspecies, 10x for
intraspecies and 3x for use of a LOAEL rather than a NOAEL, EPA has
established an acute reference dose (aRfD) = 0.14 mg/kg bwt/day.  

For chronic dietary analyses, EPA has established the reference dose
(cRfD) for imidacloprid at 0.057 mg/kg/day based on a NOAEL of 5.7 mg/kg
bwt/day from a rat chronic toxicity carcinogenicity study and
uncertainty factors of 10x for interspecies and 10x for intraspecies. 

Results from the acute and chronic dietary exposure analyses described
below demonstrate a reasonable certainty of no harm to the overall U.S.
population or any population subgroup will result from the use of
imidacloprid on currently registered and pending uses.]

	i. Food. [Tier 1 acute and Tier 2 chronic assessments were conducted
for all current and proposed uses of imidacloprid. The assessments show
that the total exposure for all registered and proposed uses of
imidacloprid is 28% and 15% of the acute (aRfD) and chronic (cRfD)
reference doses for the general US population and 71% and 42% of the
aRfD and cRfD, respectively for Children 1-2, the most exposed
population subgroup.]

	ii. Drinking water. [EPA assessment of the drinking water exposure
showed the estimated drinking water concentration to be 36 ppb and 17
ppb for acute and chronic exposure, respectively. The calculated
drinking water levels of comparison were 408 and 330 ppb, respectively.
]

	2. Non-dietary exposure. [Imidacloprid is currently registered for use
on the following residential non-dietary sites: Granular products for
application to lawns and ornamental plants; ready-to-use spray for
application to flowers, shrubs and house plants; plant spikes for
application to indoor and outdoor residential potted plants;
ready-to-use potting medium for indoor and outdoor plant containers;
liquid concentrate for application to lawns, trees, shrubs and flowers;
and ready-to-use liquid for directed spot application to cats and dogs.
In addition, there are numerous registered products intended for use by
commercial applicators to residential sites. These include gel baits for
cockroach control; products intended for commercial ornamental, lawn and
turf pest control; products for ant control; and products used as
preservatives for wood products, building materials, textiles and
plastics. The non-dietary exposure assessment is discussed in the Final
Rule on Imidacloprid Pesticide Tolerance published in Unit III.C.3. of
the Federal Register of June 13, 2003 (68 FR 35303). Addition of the
seed treatment use will have no impact on the non-dietary exposure to
imidacloprid.]

D. Cumulative Effects

	[Imidacloprid is a chloronicotinyl insecticide.  At this time, the EPA
has not made a determination that imidacloprid and other substances that
may have a common mechanism of toxicity would have cumulative effects.
Therefore, for this proposal, it is assumed that imidacloprid does not
have a common mechanism of toxicity with other substances and only the
potential risks of imidacloprid in its aggregate exposure are
considered.]

E. Safety Determination

	1. U.S. 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 imidacloprid
present a reasonable certainty of no harm.  Exposure from residues in
crops (based on a Tier 1 assessment) utilizes 28% of the aPAD and 15% 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.  An aggregate assessment for all uses for
imidacloprid demonstrated that there is a reasonable certainty that no
harm will result to the US Population from these uses of imidacloprid.]

	2. Infants and children. [EPA has considered data from developmental
toxicity studies in the rat and rabbit and a 2 generation reproduction
study in the rat. These studies are discussed under Section B
(Toxicology Profile) above.  The developmental toxicity data
demonstrated no increased sensitivity of rats or rabbits to in utero
exposure to imidacloprid. In addition, the multi generation reproductive
toxicity study did not identify any increased sensitivity of rats to in
utero or post natal exposure. Parental NOAELs were lower or equivalent
to developmental or offspring NOAELs. The developmental toxicity studies
are designed to evaluate adverse effects on the developing organism
resulting from maternal pesticide exposure during gestation.
Reproduction studies provide information relating to effects from
exposure to the pesticide on the reproductive capability of mating
animals and data on systemic toxicity.

FFDCA section 408 provides that EPA shall apply an additional tenfold
margin of safety for infants and children in the case of threshold
effects to account for pre and post natal toxicity and the completeness
of the data base unless EPA determines that a different margin of safety
will be safe for infants and children. EPA has determined that the
toxicological database is complete for FQPA purposes and that there are
no residual uncertainties for pre-/post-natal toxicity for imidacloprid.
 Based on the available toxicity data the EPA has recommended that the
Special FQPA Safety Factor be reduced to 1x.  

Based on the exposure assessments described above and on the
completeness and reliability of the toxicity data, it can be concluded
that the dietary exposure from all label and pending uses of
imidacloprid consumes 71% of the aPAD at the 95th percentile and 42% of
the cPAD for the most sensitive population subgroup, all infants and
children 1-2 years, respectively.  Thus, it can be concluded that there
is a reasonable certainty that no harm will result from aggregate
exposure to imidacloprid residues.]

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F. International Tolerances

	[Imidacloprid is an insecticide used throughout the world to control
insect pests in crops, trees, ornamental plants and turf. Codex MRLs
have been established for numerous uses of imidacloprid. 

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