 

  SEQ CHAPTER \h \r 1 FILE NAME:   62719.doc   (11/21/2006)

COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE  (7/1/2006)

EPA Registration Division contact: [Joanne I. Miller 703-305-6224]

 

TEMPLATE:

[Dow AgroSciences]

[Insert petition number]

EPA has received a pesticide petition ([PP  ]) from [Dow AgroSciences
LLC, 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 by establishing a tolerance
for residues of [fluroxypyr MHE and its metabolite fluroxypyr (expressed
as combined residues of total fluroxypyr)] in or on the raw agricultural
commodity [Pome, fruit, group 11] at [0.02] parts per million (ppm); in
or on [millet, grain] at [0.5] parts per million (ppm), [millet, forage]
at [12.0] parts per million (ppm), and [millet, hay] at [20.0] parts per
million (ppm); in or on [millet, proso, grain] at [0.5] parts per
million (ppm), [millet, proso, straw] at [12.0] parts per million (ppm),
[millet, proso, forage] at [12.0] parts per million (ppm); and [millet,
proso, hay] at [20.0] parts per million (ppm); in or on [millet, pearl,
grain] at [0.5] parts per million (ppm), [millet, pearl, forage] at
[12.0] parts per million (ppm); and [millet, pearl, hay] at [20.0] 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 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

	1. Plant metabolism.  [The nature of the residue in plants and animals
is adequately understood for the purpose of this tolerance.  Based on
the findings from these studies, the residues of concern in plants and
animal commodities are the parent, fluroxypyr 1-methylheptly ester (MHE)
and its metabolite fluroxypyr, free and conjugated.  Therefore, the
tolerance expression is the combined residues of total fluroxypyr.]

	2. Analytical method. [Adequate enforcement method for the combined
residues of total fluroxypyr is available to enforce the tolerance
expression in or on food.  The analytical method uses capillary gas
chromatography and mass selective detection (GC-MSD) with limits of
quantitation (LOQ) of 0.01 ppm.  Fluroxypyr has also been tested through
the Food and Drug Administration (FDA), Multi-residue Methodology,
Protocols C, D, and E.  The results have been published in the FDA
Pesticide Analytical Manual, Volume 1.]

	3. Magnitude of residues.  [Geographically representative field trials
on apples, pears, and wheat (representing millet) using an emulsifiable
concentrate formulation of fluroxypyr were conducted according to
proposed use patterns using parameters that would likely result in the
highest residues.  The proposed tolerance of 0.02 ppm pome, fruit, group
11; millet, grain at 0.05 ppm; millet, forage at 12.0 ppm; millet, hay
at 20.0 ppm; millet, proso, grain at 0.05 ppm; millet, proso, straw at
12.0 ppm; millet, proso, forage at 12.0 ppm; millet, proso, hay at 20.0
ppm; millet, pearl, grain at 0.05 ppm; millet, pearl, forage at 12.0
ppm; and millet, pearl, hay at 20.0 ppm was based on the maximum field
trial residue and therefore, would be adequate to cover the highest
residues resulting from these fluroxypyr uses.  Proposed millet
tolerances are based on data developed on wheat due to similarity in
both agronomic practices and crop development.]

B. Toxicological Profile

	1. Acute toxicity.  [Fluroxypyr MHE has low acute toxicity.  The rat
oral LD50 is >5000 mg/kg, the rabbit dermal LD50 is >2000 mg/kg, and the
rat inhalation LC50 is >1.0 mg/l (1000 mg/cubic meter).  In addition,
fluroxypyr MHE is not a skin sensitizer in guinea pigs, has no dermal
irritation in rabbits, and shows mild ocular irritation in rabbits.  The
end use formulation of fluroxypyr MHE has a similar low acute toxicity
profile.  No appropriate endpoint has been identified to quantify a
single exposure.]

	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 fluroxypyr MHE.  These studies show a lack of
genotoxicity.  In addition, short term assays for genotoxicity
consisting of an Ames metabolic activation test, possible induction of
point mutations at the HGPRT-Locus of Chinese hamster ovary cells, in
vivo and in vitro chromosomal aberrations in the Chinese hamster ovary
cells, unscheduled DNA synthesis in human embryonic cells, and an assay
in mouse lymphoma cells have been conducted with fluroxypyr.  These
studies also show a lack of genotoxicity.]

	3. Reproductive and developmental toxicity.  [Developmental studies in
rats and rabbits were conducted with both fluroxypyr MHE and fluroxypyr.
 Studies with fluroxypyr MHE showed maternal and fetal NOELs of 300
mg/kg/day (rat) and 500 mg/kg/day (rabbit).  Studies with fluroxypyr
showed NOAELs in the rat of 250 mg/kg/day for maternal effects and 500
mg/kg/day for fetal effects and a NOEL in the rabbit of 250 mg/kg/day
for both maternal and fetal effects.  These studies show that fluroxypyr
and fluroxypyr MHE are not teratogenic nor will they interfere with in
utero development.  Two multi-generation reproduction studies were
conducted with fluroxypyr in rats.  The first in Wistar rats showed no
effect on fertility or reproductive performance and had a NOAEL of 500
mg/kg/day (highest dose tested).  The second study in Sprague-Dawley
rats showed a parental NOEL for systemic effects of 100 mg/kg/day in
male rats and 500 mg/kg/day in female rats.  The NOEL for reproductive
effects was 750 mg/kg/day for males and 1000 mg/kg/day for females
(highest dose tested).  The NOEL for neonatal effects was 500
mg/kg/day.]

	4. Subchronic toxicity.  [Fluroxypyr MHE showed a NOEL of 1000
mg/kg/day in a 90-day rat dietary study and a 21-day rabbit dermal
study.  Ninety day feeding studies with fluroxypyr showed NOELs of 80
mg/kg/day (Wistar rats), 700 mg/kg/day (Fischer 344 rats), 1342
mg/kg/day (male mice), and 1748 mg/kg/day (female mice).  In a 4-week
dietary, range finding study with fluroxypyr in dogs the NOEL found was
>50 mg/kg/day.]

	5. Chronic toxicity. [NOAELs found in the chronic dietary studies are
as follows: 150 mg/kg/day (dog), 300 mg/kg/day (mouse), 100 mg/kg/day
(male Fischer 344 rats), and 500 mg/kg/day (female Fischer 344 rats). 
Based on the chronic/carcinogenicity study on rat, EPA has established a
chronic reference dose (cRFD) of 1 mg/kg/day.  The NOAEL of 100
mg/kg/day was based on increased kidney weight in both sexes and an
increase in the severity of chronic progressive glomerulo-nephropathy in
the kidney in both sexes at the LOAEL of 500 mg/kg/day.  No additional
FQPA factor was required, therefore, the chronic population adjusted
dose (cPAD) is equal to cRfD.   Fluroxypyr is classified as "not likely"
a human carcinogen and there was no concern for its mutagenicity
potential.]

	6. Animal metabolism.  [Both fluroxypyr and fluroxypyr MHE have been
evaluated in rat metabolism studies.  In summary, these studies show
that fluroxypyr MHE is rapidly hydrolyzed and the fate of the hydrolysis
products, fluroxypyr and 1-methylheptanol, are independent of whether
they were given as the ester or the acid.  Fluroxypyr, per se, was
extensively absorbed and rapidly excreted principally unchanged in the
urine; 1-methylheptanol also was rapidly absorbed and rapidly
eliminated.  Repeated administration of fluroxypyr MHE was not
associated with accumulation in tissues.  Also, the metabolism and
pharmacokinetics of 1-methylheptanol are comparable to that of the
methylheptyl portion of fluroxypyr MHE.]

7. Metabolite toxicology.  [Administration of fluroxypyr, as the acid or

methylheptyl ester, in a variety of toxicological studies has produced
similar effects.  The principal response to sufficiently high dosages,
whether administered over the short-term or, in some cases, over a
lifetime, was nephrosis.  Fluroxypyr is an organic acid that is actively
excreted into the urine by the kidney. Thus, the target organ and dose
response relationship for fluroxypyr toxicity is entirely consistent
with the data on the toxicokinetics of fluroxypyr.  Metabolism studies
have shown that fluroxypyr MHE is rapidly and completely hydrolyzed to
fluroxypyr acid and methylheptanol.]

	8. Endocrine disruption.  [There is no evidence to suggest that
fluroxypyr and 

MHE have an effect on any endocrine system.]

C. Aggregate Exposure

1. Dietary exposure 	

	i. Food. [Tolerances have been established (40 CFR 180.535) for the
combined residues of fluroxypyr in or on a variety of raw agricultural
commodities, milk, meat and meat by-products.  In this petition,
tolerances of 0.02 ppm in or on pome, fruit, group 11; 0.5 ppm in or on
millet, grain; millet, proso, grain; and millet, pearl, grain are being
proposed. 

An acute dietary exposure is not required because no adverse effect
attributable to a single exposure of fluroxypyr was observed in the
available toxicity studies.  Therefore, EPA did not identify an acute
dietary endpoint and no acute risk is expected. 

In conducting the chronic dietary assessment, Dow AgroSciences used the
Dietary Exposure Evaluation Model software with the Food Commodity
Intake Database (DEEM-FCID, Version 2.0) which incorporates food
consumption data as reported in the CSFII Survey 1994-1996 and 1998.  A
conservative analysis (Tier 1) was performed with the assumptions that
100% of crops with approved and proposed uses of fluroxypyr would be
treated with the pesticide and that the residues would be present at the
tolerance levels.  Additionally, the processing factors were used in
DEEM-FCID for all processed commodities.  Based on these conservative
assumptions and using a cPAD of 1 mg/kg/day, the exposure to fluroxypyr
from food will utilize <1% of the cPAD for the U. S. population, <1% of
the cPAD for all infants, and 1.4% of the cPAD for children (1-2 years
old), the population subgroup with the highest potential for exposure.
Adverse effects are not expected for exposures utilizing less than 100%
of the RfD, therefore, chronic dietary exposure and risk for the general
U.S. population and children are well within the acceptable levels.]

ii. Drinking Food. [Since the Agency lacks sufficient monitoring data to
complete a comprehensive exposure and risk assessment for fluroxypyr in
drinking water, drinking water concentration estimates are made on
simulation taking into account data on the physical characteristics of
fluroxypyr. 

Guidance from EPA has indicated that Tier 1 screening level models, such
as GENEEC and SCI-GROW, may be used to estimate upper-bound pesticide
residues in surface water and ground water when assessing potential
exposure through drinking water.  The main inputs and outputs into each
model, as well as the resulting Estimated Environmental Concentrations
(EEC) are shown in the table below. Estimated environmental
concentrations (EEC) of pesticide in surface water or ground water were
then inputted into DEEM model for estimation of dietary exposure from
water both direct and indirect sources.  The input of water residues
along with food into the DEEM model provides a conservative estimate of
the total exposure from food and water sources. 

In a recent assessment (Federal Register Vol. 68, No. 250 December 31,
2003, FRL-7340-5), EPA used PRZM/EXAMS and SCI-GROW models to estimate
the environmental concentrations (EECs) of fluroxypyr in surface water
and ground water. The EECs for chronic exposures are estimated to be 3.3
ppb in surface water and 0.062 ppb in ground water. For the U.S.
population and all infants, the exposures from food and water represent
less than 1% of the cPAD. Additionally, for children age 1-2 years, the
population with the highest exposure, the exposures represent
approximately 1% of the cPAD. EPA has no concern for aggregate chronic
exposure below 100% of the cPAD.]>

<2. Non-dietary exposure.  [Fluroxypyr is currently registered for use
on residential turfgrass and recreational sites such as golf courses and
sports fields.  Short- and intermediate-term exposures to fluroxypyr may
occur during post-application activities for adults and children. The
risk assessment was conducted using the following assumptions: Adults
and children may be exposed from dermal contact with turf during
post-application activities. Toddlers may experience short- and
intermediate-term oral exposure from incidental non-dietary ingestion
during post-application activities.  Residential handlers may receive
short-term dermal and inhalation exposure during mixing, loading and
applying the formulations. The HED's Draft Standard Operating Procedures
for Residential Exposure Assessments and Recommended Revisions (HED
Policy Number 11, February 22, 2001) along with the ORETF and turf
transferable residue data were used as the basis for exposure
calculations. 

Using the above assumptions, the aggregated food and residential
exposures resulted in estimated MOEs of 31,000 for the U. S. population
and 4,500 for children 1-2 years old.  These MOEs are substantially
greater than 100, indicating that the risk from potential
non-dietary/residential exposures is well within an acceptable level.]>

D. Cumulative Effects

[The potential for cumulative effects of fluroxypyr MHE and fluroxypyr
and other substances that have a common mechanism of toxicity is also
considered.  There is no reliable information to indicate that toxic
effects produced by fluroxypyr MHE and fluroxypyr would be cumulative
with those of any other pesticide chemical.  Thus, it is appropriate to
consider only the potential risks of fluroxypyr MHE and fluroxypyr in an
aggregate exposure assessment.]

E. Safety Determination

1. U.S. population.  [Chronic dietary exposure for the general U.S.
population                   to residues of fluroxypyr from current and
proposed uses were estimated to occupy <1% of the cPAD.  Thus, the
aggregated chronic exposure to fluroxypyr resulting from current and
proposed uses is well within the acceptable levels of risk. 

Use of fluroxypyr on turf results in potential short-and
intermediate-term exposures. Potential food dietary and residential
exposures were combined into an aggregate MOE value, which was
calculated to be 31,000 for the U.S. population.  The aggregate MOE is
well above 100, indicating risk is well within acceptable levels. 

Thus, based on the completeness and reliability of the toxicity data and
the conservative exposure assessment, it is concluded that there is a
reasonable certainty that no harm will result to the U.S. population
from chronic, short- and intermediate-term aggregate exposures to
fluroxypyr residues from current and proposed uses.]>

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 fluroxypyr MHE relative to pre- and
post-natal effects for children is complete. There were no indications
of neurotoxicity and developmental toxicity was not observed in the
absence of maternal toxicity.  It is concluded that there is no
indication of increased sensitivity of infants and children relative to
adults and that an additional FQPA safety factor is not required. 

Chronic dietary exposure to residues of fluroxypyr from current and
proposed uses was estimated to occupy only 1.4% of the chronic PAD for
children 1-2 years old, the population subgroup predicted to be most
highly exposed. 

Potential food dietary and residential exposures to children 1-2 years
old were combined into an aggregate MOE value. The aggregate MOE was
estimated to be 4,500 and well above 100, indicating risk is well within
acceptable levels. 

Thus, based on the completeness and reliability of the toxicity data and
the conservative exposure assessment, it is concluded that there is a
reasonable certainty that no harm will result to infants and children
from chronic, short- and intermediate-term aggregate  exposures to
fluroxypyr residues from current and proposed uses.] 

F. International Tolerances

	[There are no Codex maximum residue levels established for residues of
fluroxypyr MHE and fluroxypyr on any food or feed crop.]>

	

