 

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

<EPA Registration Division contact: [Kathryn MontagueJoanne Miller,
703-305-12436224]>

 

<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:>

<[Dow AgroSciences LLC]>

<[Insert petition number8F7455]>

<	EPA has received a pesticide petition ([8F7455insert petition number])
from [Dow AgroSciences], [9330 Zionsville Road, Indianapolis, IN 46268]
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.>

<(Options (pick one)>

<	1. by establishing a tolerance for residues of>

<	2. to establish an exemption from the requirement of a tolerance for>

<	[combined residues of aminopyralid (XDE-750:
4-amino-3,6-dichloropyridine-2-carboxylic acid) and its glucose
conjugate, expressed as total parent] in or on the raw agricultural
commodity [corn, forage] at [0.30] parts per million (ppm), [corn,
grain] at [0.20] parts per million (ppm), [corn, stover] at [0.20] 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 
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>

<	1. Plant metabolism. [The nature of the residue in plants (grass and
wheat) and in animals is adequately understood for the purpose of this
tolerance. Based on the findings from these metabolism studies, the
residues of concern in corn are the combined residues of aminopyralid
and its glucose conjugates, expressed as the total parent. In animal
commodities, the residue of concern is only the parent, aminopyralid
(free).]

>

<	2. Analytical method. [Adequate analytical methods for enforcement
purposes are available to monitor residues of aminopyralid in corn
commodities, milk, meat and meat by-products. The analytical method uses
liquid chromatography and positive ion electrospray tandem spectrometry
(LC/MS/MS) with limits of quantitation (LOQ) of 0.01 ppm. The methods
had been successfully validated independently by outside laboratories.
Aminopyralid had also been tested through the Food and Drug
Administration (FDA), Multi-residue Methodology, Protocols C, D, and E.]

>

<	3. Magnitude of residues. [Geographically representative field trials
were conducted on corn according to use patterns to support the proposed
tolerances in corn raw agricultural commodities (RAC). In addition, corn
processing and cow feeding studies were conducted to determine transfer
of residues into corn processed products, milk, meat and meat
by-products. The proposed tolerances in corn RAC commodities and in
milk, meat and meat by-products are adequate to cover the highest
residues from the maximum label use of aminopyralid in corn. There was
no appreciable concentration of residue in processed products and
therefore no additional tolerances are requested for these commodities.]

>

<B. Toxicological Profile>

<	1. Acute toxicity.  [Aminopyralid has low acute toxicity. The rat oral
LD50 is >5000 mg/kg and the rat inhalation LC50 is >5.5 mg/L. In
addition, aminopyralid is not a dermal sensitizer in guinea pigs, has no
dermal irritation in rabbits, and shows ocular irritation in rabbits.]>

<	2. Genotoxicty. [Short term assays for genotoxicity consisting of a
bacterial reverse >mutation assay (Ames test), an in vitro assay for
cytogenetic damage using the Chinese hamster ovary cells, an in vitro
chromosomal aberration assay using rat lymphocytes, and an in vivo
cytogenetic assay in the mouse bone marrow (micronucleus test) have been
conducted with aminopyralid. Taken together, these studies show a lack
of genotoxicity.]

<	3. Reproductive and developmental toxicity. [Developmental studies in
rats and rabbits >were conducted with aminopyralid. Studies with
aminopyralid showed maternal NOAELs of 1000 mg/kg/day (rat) and 250
mg/kg/day (rabbit) and fetal NOAELs of 1000 mg/kg/day (rat) and 500
mg/kg/day (rabbit). These studies show that aminopyralid is not
teratogenic nor will it interfere with in utero development. A
multi-generation reproduction study conducted with aminopyralid in
Sprague-Dawley rats showed a NOAEL for reproductive effects of 1000
mg/kg/day for males and 1000 females (highest dose tested). The NOAEL
for neonatal effects was also 1000 mg/kg/day.]

<	4. Subchronic toxicity. [Aminopyralid showed a NOAEL of 100 mg/kg/day
in a 28-day rat dermal study. Ninety day feeding studies with
aminopyralid showed NOAELs of 500 mg/kg/day in Fischer 344 rats, 232
mg/kg/day for females and 282 mg/kg/day for male Beagle dogs, and 1000
mg/kg/day in CD-1 mice.]

>

<	5. Chronic toxicity. [Based on chronic testing with aminopyralid in
the mouse, dog, and rat (two studies), a reference dose (RfD) of 0.5
mg/kg/day is established. The RfD has incorporated a 100-fold safety
factor to the NOAEL found in the rat chronic test. NOAELs found in the
chronic dietary studies are as follows: 96 mg/kg/day (male and female
dogs), 250 mg/kg/day in female mice and 1000 mg/kg/day in male mice, and
50 mg/kg/day in male Fischer 344 rats and 500 mg/kg/day in female
Fischer 344 rats.]

>

<	6. Animal metabolism. [Aminopyralid have been evaluated in a rat
metabolism study. In summary, this study shows that aminopyralid is
efficiently cleared through the urine and feces with an average of 74 -
93% of the administered radioactivity excreted during the first 24-hours
post-dose administration. Aminopyralid is rapidly absorbed and urinary
and fecal elimination totaled 41-59 and 33-43% of the administered dose,
respectively. Analysis of excreted material indicate no evidence of
metabolism. Repeated administration of aminopyralid was not associated
with accumulation in tissues.]

>

<	7. Metabolite toxicology. [No mammalian metabolites of aminopyralid
have been identified in the rat metabolism study. Nature of residue
studies in wheat and grass (3 species) revealed the presence of
unchanged parent aminopyralid and glucose conjugates of aminopyralid.]

>

<	8. Endocrine disruption. [There is no evidence to suggest that
aminopyralid has an effect on any endocrine system.]>

<C. Aggregate Exposure>

<	1. Dietary exposure. [Insert text.]>

 Evaluation Model (DEEM™, Version 2.14, Exponent) software that
evaluated the individual food consumption as reported by respondents in
the USDA 1994-1996, 1998 nationwide Continuing Surveys of Food Intake by
Individuals (CSFII). The dietary exposure assessment was performed using
a conservative approach (Tier I) wherein the estimated theoretical
maximum residue contribution (TMRC) was based on the assumptions that
100% of the crops were treated with aminopyralid and the residues were
present at the proposed tolerance levels.

The chronic population adjusted dose (cPAD) used was 0.50 mg/kg/day
based on a NOEL of 50 mg/kg/day from a 2-year combined chronic
feeding/carcinogenicity rat study and an uncertainty factor of 100 (10
for intraspecies variation X 10 for interspecies variation). No
additional FQPA safety factor is required. For the U.S. general
population, the TMRC was estimated to be 0.00070 mg/kg/day that utilized
less than 1% of the cPAD. The population sub-group with the highest
potential exposure is children (1-2 years old) with a TMRC of 0.00210
mg/kg/day that represents only 0.4% of the cPAD. The % of the cPAD is
significantly below the acceptable 100%, therefore, demonstrates no
chronic dietary concern.

No appropriate toxicological endpoint attributable to a single exposure
was identified in the available toxicological studies on aminopyralid.
Thus, the risk from acute exposure is considered negligible and no acute
risk assessment was performed.]

>

<	ii. Drinking water. [No monitoring exposure data is available to
complete a

o addresses total aggregate exposure to aminopyralid, the most
conservative value of 1.937 ppb is used as an input to DEEM-FCID™,
Version 2.14 as water EEC from direct and indirect exposure so as to be
included in the dietary exposure and risk assessment.  Potential
exposure to aminopyralid in drinking water would not result in
unacceptable levels of aggregate human health risk.]>

<	2. Non-dietary exposure. [Aminopyralid is not currently registered for
use on any sites that would result in residential exposure. Therefore,
considerations of aggregate exposure to aminopyralid will not include
non-dietary or residential exposures.]

>

<D. Cumulative Effects>

<	[At this time, no data is available to determine whether aminopyralid
has a common mechanism of toxicity with other substances. Unlike other
pesticides for which EPA has followed a cumulative risk approach based
on a common mechanism of toxicity, aminopyralid  does not appear to
produce a common toxic metabolite generated by other substances. For
purposes of this tolerance action, therefore, it is assumed that
aminopyralid does not have a mechanism of toxicity common with other
substances]

E. Safety Determination>

<	1. U.S. population. [Using the above conservative exposure
assumptions, aggregate exposure to aminopyralid from the proposed
tolerances in corn commodities will utilize less than 1% of the cPAD for
the general U. S. population. The population subgroup with the highest
exposure of 0.4% of the cPAD is children (1-2 yrs old). Generally, EPA
has no concern for exposures below 100% of the cPAD because the cPAD
represents the level at or below which daily aggregate dietary exposures
over a lifetime will not pose appreciable risks to human health. No
endpoint of concern was identified to quantitate acute-dietary risk to
the general population, therefore, acute risk exposure is considered to
be negligible. Additionally, the potential contribution of aminopyralid
residues in drinking water to aggregate exposure is expected to be
minimal. Therefore, based on these risk assessments, Dow AgroSciences
concludes that there is reasonable certainty that no harm will result to
the U. S. population from aggregate exposure to aminopyralid residues.]

>

<	2. Infants and children. [FFDCA Section 408 provides that EPA may
apply an additional safety factor for infants and children in the case
of threshold effects to account for pre- and post-natal toxicity and the
completeness of the database. Based on the current toxicological data
requirements, the database for aminopyralid relative to pre- and
post-natal effects for children is complete. Overall, aminopyralid had
no effect on reproduction or embryo-fetal development at any dosage
tested. No quantitative or qualitative susceptibility was seen following
pre- and post-natal exposures. In a 2-generation reproductive toxicity
study in rats, no effects on reproductive performance or neonatal
development were observed. Dow

AgroSciences concluded that there is no indication of increased
sensitivity of infants and children relative to adults and that no
additional FQPA safety factor is required.

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摧㤲p᠀d 0.3% of the cPAD for children 6-12 yrs old. Even when
considering the potential exposure to drinking water, the aggregate
exposure is not expected to exceed 100% of the cPAD. Therefore, based on
the completeness and reliability of the toxicity data and the
conservative exposure assessment, Dow AgroSciences concludes with
reasonable certainty that no harm will result to infants and children
from the aggregate exposure to aminopyralid residues.]

>

<F. International Tolerances>

<	[Temporary Codex maximum residue levels (MRL) are established for
residues of aminopyralid on a number of food and feed commodities other
than corn forage, grain and stover. Therefore, no compatibility problems
exist for the proposed tolerances on corn commodities.]

>

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