  SEQ CHAPTER \h \r 1 FILE NAME:   company.wpt   (1/1/2006) (xml)

Template Number P25	

	

COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE

(1/1/2006)

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

TEMPLATE:

 by establishing tolerances for residues of [imidacloprid,
1-[(6-chloro-3-pyridinyl)methyl]-N-nitro-2-imidazolidinimine] in or on
the raw agricultural commodity [soybean, seed] at [1.6] parts per
million (ppm); [soybean, forage] at [8.0] ppm; [soybean, hay] at [30]
ppm and [soybean, aspirated grain fractions] at [240] 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.

                                      

. [ Twenty-one field trials were conducted throughout the USA to support
the requested tolerances on the above soybean commodities by measuring
the magnitude of imidacloprid residues in soybean commodities resulting
from pre-plant seed treatment followed by three foliar applications of 
TRIMAX 4F to the growing soybean plants. In addition, a processing study
was conducted where soybeans were treated at 5X the normal application
rate and the resulting soybean seed was processed into the commodities
of meal, hulls, refined oil, and defatted flour. Aspirated grain
fractions were also collected. The processing study showed no
concentration of imidacloprid residues in the soybean meal, hulls,
refined oil or defatted flour. However, the processing factor for the
aspirated grain fraction was 161X.

	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. [NA]

	8. Endocrine disruption.  [The toxicology database for imidacloprid is
current and complete.  Studies in this database include evaluation of
the potential effects on reproduction and development, and an evaluation
of the pathology of the endocrine organs following short- or long term
exposure.  These studies revealed no primary endocrine effects due to
imidacloprid.]	

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 imidacloprid.  These analyses cover
all registered and pending uses for imidacloprid including the above
soybean commodities.

Novigen Sciences, Inc.'s Dietary Exposure Evaluation Model
(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 inter-species, 10x for
intra-species 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 inter-species and 10x for intra-species. 

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 3 acute and chronic risk assessments were conducted
using PDP data or the results of field trials conducted at maximum label
application rates and the shortest pre-harvest intervals.  No
adjustments were made to account for dissipation of residues during
storage, transportation from the field to the consumer, washing or
peeling.  Therefore, the actual dietary exposure will be less than that
presented here.

For the chronic analysis, mean field trial residues were calculated. 
For the acute Monte Carlo analysis, the entire distribution of residue
field trial data was used for the "non-blended" and "partially blended"
foods as determined by EPA's HED SOP 99.6.  For the foods considered as
"blended" by EPA'S HED SOP 99.6, mean field trial residue data were
used.  As allowed in EPA's draft guidance for submission of
probabilistic human health exposure assessments one half LOD/LOQ values
were used for all non-detected values (values below the sensitivity of
the method).  

The acute Monte Carlo dietary exposure assessment estimated  the percent
of the aPAD and corresponding margins of exposure (MOE) for the overall
U.S. population, (all seasons), and various subpopulations.  In this
analysis, the exposure for the total U.S. population was equal to 9.2%
of the aPAD at the 99.9th percentile.  The most highly exposed
population subgroup, non-nursing infants <1yr, had an exposure equal to
26.1% of the aPAD at the 99.9th percentile.  Therefore, the acute
dietary exposure estimates are below EPA's level of concern for the
overall U.S. population as well as the various subpopulations.

The chronic dietary exposure estimated the percent of the chronic
population adjusted dose (cPAD) for the overall US population (all
seasons) and various subpopulations.  In this analysis, the exposure for
the total U.S. population was equal to 1.8% of the cPAD.  The most
highly exposed population subgroup, children (1-2 yrs), had an exposure
equal to 5.5% of the cPAD.  Therefore, the chronic exposure estimates
are below EPA's level of concern for the overall U.S. population as well
as the various subpopulations.]

	ii. Drinking water. [EPA, as published in the Federal Register (68 FR
35303-35315), calculated EECs for surface water (acute 36.04 ppb and
chronic 17.24 ppb) and ground water (acute and chronic both 2.09 ppb).
Since the maximum application rate (single and seasonal) for the new
uses do not exceed previously established use rates, these EECs are
still valid for the new uses.  The current exposure assessment
calculated acute and chronic DWLOCs at 1,034 ppb and 539 ppb,
respectively, for the most exposed subpopulation (non-nursing infants <1
yr and children 1-2 yrs, respectively). Since the DWLOCs are
significantly larger than the EECs, there is no concern with dietary
exposure to residues of imidacloprid for even the most exposed
subpopulation.]

	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
soybean 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 these tolerance petitions, 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 utilizes 9.2% of the aPAD and 1.8% 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.  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 26.1% of the aPAD at the 99.9th percentile and
5.5% of the cPAD for the most sensitive population subgroup, non-nursing
infants <1 yr 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.]

F. International Tolerances

	[Imidacloprid is a insecticide used throughout the world to control
insect pests in crops, trees, ornamental plants and turf. An evaluation
of the maximum residue limits (MRLs) was conducted. No CODEX Maximum
Residue Levels (MRLs) have been established for residues of imidacloprid
on soybean commodities.]

	Commodity	Proposed USEPA Tolerance, ppm



Soybean, seed	1.6

Soybean, forage	8.0

Soybean, hay	30

Soybean, aspirated grain fractions	240



										

	

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