 

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  (7/1/2007)

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
[Spiromesifen; butanoic acid, 3,3-dimethyl-,
2-oxo-3-(2,4,6-trimethylphenyl)-1-oxaspiro[4.4]non-3-en-4-yl ester, and
its enol metabolite;
4-hydroxy-3-(2,4,6-trimethylphenyl)-1-oxaspiro[4.4]non-3-en-2-one,
calculated as parent compound equivalents] in or on the raw agricultural
commodity [tomato, paste] at [0.8] 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 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 uptake and metabolism of spiromesifen in
primary crops is adequately understood. Radiolabeled studies have been
conducted in various plants all showing similar results. The residues of
concern are spiromesifen and its enol metabolite.]

	2. Analytical method. [Adequate analytical methodology using LC/MS/MS
detection is available for enforcement purposes.]

	3. Magnitude of residues. [The concentration of residues in tomato
paste produced from tomatoes is known]

B. Toxicological Profile

	1. Acute toxicity.  [Oral and dermal LD50 values were >2000 mg/kg bw. 
Inhalation LC50 values were >4873 mg/m3 air.  Spiromesifen was not
irritating to rabbit skin or eyes but did cause skin sensitization in
the Magnusson/Kligman maximization test in guinea pigs.  Acute toxicity
studies for spiromesifen support an overall toxicity Category III]

	2. Genotoxicty. [Several genotoxicity tests were conducted to test for
point-mutagenic activity, chromosome aberration in vitro and in vivo,
and for DNA repair.  All tests conducted were negative, indicating no
evidence of mutagenic or genotoxic potential.]

	3. Reproductive and developmental toxicity. [An oral developmental
toxicity study in rat did not reveal any evidence of teratogenic
potential.  The maternal and developmental NOAELs were 10 mg/kg bw/day. 
An oral developmental toxicity study in rabbits demonstrated a maternal
NOAEL of 5 mg/kg bw/day, a developmental NOAEL of 35 mg/kg bw/day and
did not reveal any teratogenic potential.  A two-generation study in
rats, with a parental systemic toxicity NOAEL of 3.3 mg/kg bw/day for
males and 4.6 mg/kg bw/day for females (based on the F1 generation), did
not reveal evidence of a primary reproductive toxicity potential.  The
reproductive NOAEL was 36.6 mg/kg bw/day for males and 14.2 mg/kg bw/day
in females.]

	4. Subchronic toxicity. [A subchronic toxicity feeding study with rats
over 90 days demonstrated a NOAEL of 6.3 and 7.7 mg/kg bw/day for males
and females, respectively, based on reduced body weights, effects on the
lipid metabolism (decrease of triglycerides and cholesterol) and thyroid
effects (colloidal alteration, hypertrophy) at the higher dose levels. 
A subchronic feeding study in mice over 14 weeks demonstrated a NOAEL of
3.2 and 5.1 mg/kg bw/day based on effects on lipid metabolism (decrease
of cholesterol) and adrenal effects (cytoplasmic eosinophilia).  A
14-week feeding study in dogs demonstrated a NOAEL of 9.2 and 9.3 mg/kg
bw/day based on liver effects (enzyme induction, increased liver weights
and cytoplasmic change) and thyroid effects (decreased T4).]

	5. Chronic toxicity. [A 12-month chronic feeding study in rats
demonstrated a NOAEL of 6.5 and 19.3 mg/kg bw/day for males and females,
respectively.  A 24-month oncogenicity study in rats demonstrated a
NOAEL of 6.1 and 19.5 mg/kg bw/day for males and females, respectively.
An oncogenicity study in the mouse revealed a NOAEL of 3.3 and 3.8 mg/kg
bw/day for males and females, respectively based on macroscopic and
microscopic adrenal effects.  There was no indication in the rat or
mouse for an oncogenic effect of spiromesifen.  A one-year feeding study
with dogs demonstrated a NOAEL of 11.5 and 10.8 mg/kg bw day for males
and females, respectively based on decreased body weights, liver effects
(increased liver weight, hepatocellular cytoplasmic change, vacuoles)
and adrenal effects (increased incidence of small cell types).]

	6. Animal metabolism. [Metabolism and pharmacokinetic studies in the
rat demonstrate that spiromesifen residues are rapidly absorbed,
metabolized and eliminated.  There was no evidence of accumulation of
residues in any tissues or organs.  The primary metabolites are the
enol, which is formed by cleavage of the alkyl ester group, and the
4-hydroxymethyl metabolite.  Several other metabolites are also formed.]

	7. Metabolite toxicology. [In addition to parent, the metabolites of
concern are those containing the enol and 4-hydroxymethyl moieties. 
Since both moieties are primary metabolites in mammalian systems
following the oral administration of spiromesifen to rats, the
toxicology data for spiromesifen adequately covers the metabolites.]

	8. Endocrine disruption. [There is no evidence to suggest that
spiromesifen has any primary endocrine disruptive potential. 
Reproductive and developmental findings provided no evidence of an
enhanced sensitivity of the young.  All prospective endocrine and
endocrine-related changes which were noted were considered a function of
the chemical's biological mode of action, the degree of exposure, a
response secondary to other changes (e.g. enhanced liver metabolism), an
aging or strain-specific phenomenon, or some combination of these
factors.]

C. Aggregate Exposure

	1. Dietary exposure. [Acute dietary exposure limits for all
populations, including infants and children, are not necessary because
an endpoint of concern attributable to a single exposure (dose) was not
identified from the oral toxicity studies.  In addition, there are no
developmental concerns based on rat and/or rabbit developmental toxicity
studies. For the chronic dietary analysis, the chronic reference dose
(cRfD), of 0.033 mg/kg/day was derived from a parental systemic NOAEL of
3.3 mg/kg/day (based on the F1 generation) in a 2-generation
reproduction toxicity study in rats and the application of an UF of 100.
As the toxicology database is adequate for Food Quality Protection Act
(FQPA) purposes and there are no concerns or residual uncertainties for
pre-/post-natal toxicity, an FQPA safety factor of 1 was applied to the
chronic toxicology values, resulting in a chronic population adjusted
dose (cPAD) of 0.033 mg/kg/day.  As a conservative measure, the cPAD
values were used for all population sub-groups when conducting the
assessments.]

	i. Food. [Assessments were conducted to evaluate the potential risks
due to chronic dietary exposure of the entire U.S. population and
selected population subgroups to residues of spiromesifen and its enol
metabolite.  These assessments cover all the established and proposed
uses of spiromesifen, including residues from primary crops, rotational
crops and secondary residues in animal tissues resulting from registered
and proposed uses.  Chronic exposure, calculated using DEEM-FCID Version
2.16, for the most exposed subpopulation, Children 1-2 years, equated to
3.3% of the cPAD.  The exposure to the U.S. population equated to 0.9%
of the cPAD. These Tier 3 chronic dietary exposure estimates,
incorporating Bayer CropScience estimates of  percent crop treated, are
well below EPA’s level of concern for the overall U.S. population as
well as the various population subgroups.]

	ii. Drinking Water. [The tolerances requested in tomato paste will not
alter potential risks from exposure to residues of spiromesifen or
degradates through drinking water. A Tier II drinking water assessment
for spiromesifen and its enol metabolite was conducted using PRZM/EXAMS
(Pesticide Root Zone Model/Exposure Analysis Modeling System) to
calculate surface water estimated drinking water concentrations (EDWCs).
 The Screening Concentration in Ground Water (SCI-GROW) model was used
to calculate ground water EDWCs. The highest value for a chronic
assessment resulted from the Florida strawberry, surface water scenario.
The EDWC for combined residues of spiromesifen and its enol metabolite,
expressed as parent equivalents, was 5.4 ppb. The chronic EDWC
represents the upper 1-in-10 year mean annual concentration. All EDWCs
values are much lower than the drinking water level of comparison
(DWLOC) value of 326 µg/L (children 1-2 years old) determined for the
chronic scenario. Therefore, the EDWCs do not exceed the Agency’s
level of concern. For the most highly exposed population subgroup,
children 1-2, chronic aggregate dietary exposure (food and water)
calculated using DEEM-FCID Version 2.16 was 3.8% of the cPAD. For the
overall U.S. population, chronic aggregate dietary exposure was 1.2% of
the cPAD. Aggregate exposures are based on an estimated drinking water
concentration of 5.4 µg/L.]

  

	2. Non-dietary exposure. [There are no indoor or outdoor residential
uses associated with this product.]

D. Cumulative Effects

	[Spiromesifen represents a new class of chemistry, ketoenoles.  There
are no data available to indicate that toxic effects produced by
spiromesifen are a result of a common mechanism and should be cumulated
with those of any other compound. EPA has not made a common mechanism of
toxicity finding as to spiromesifen and any other substances and
spiromesifen does not appear to produce a toxic metabolite produced by
other substances. Bayer will submit information, if necessary, for EPA
to consider concerning any potential cumulative effects of spiromesifen
consistent with the schedule established by EPA at 62 Federal Register
42020 (Aug. 4, 1997) and other EPA publications pursuant to the Food
Quality Protection Act.]

E. Safety Determination

	1. U.S. population. [Based on the exposure assessments described above
and on the completeness and reliability of the toxicity data, it can be
concluded that total aggregate exposure to spiromesifen from all label
uses will utilize less than 2 percent of the RfD for chronic dietary
exposures to the U.S. population and all population subgroups. EPA
generally has no concerns for exposures below 100 percent of the RfD,
because the RfD represents the level at or below which daily aggregate
exposure over a lifetime will not pose appreciable risks to human
health.  Thus, it can be concluded that there is a reasonable certainty
that no harm will result to the U.S. population from aggregate exposure
to spiromesifen residues.]

	2. Infants and children. [The Agency has previously concluded that the
toxicology database is adequate for Food Quality Protection Act (FQPA)
purposes and that there are no concerns or residual uncertainties for
pre-/post-natal toxicity. Therefore, a FQPA factor of 1X was selected.
Available studies include developmental toxicity studies in rats and
rabbits, a two-generation reproductive toxicity study in rats, and acute
and subchronic neurotoxicity studies in rats. In the prenatal
developmental toxicity studies in rats and rabbits and in the
two-generation reproduction study in rats, developmental toxicity to the
offspring occurred at equivalent or higher doses than maternal toxicity.
There are no neurotoxicity concerns based on acute and subchronic
neurotoxicity studies. The most highly exposed population subgroup was
children 1-2 with a total aggregate exposure to spiromesifen from all
label uses utilizing less than 5 percent of the RfD for chronic dietary
exposures. EPA generally has no concerns for exposures below 100 percent
of the RfD, because the RfD represents the level at or below which daily
aggregate exposure over a lifetime will not pose appreciable risks to
human health.  Thus, it can be concluded that there is a reasonable
certainty that no harm will result to infants and children from
aggregate exposure to spiromesifen residues.]

F. International Tolerances

	[Codex maximum residue levels (MRLs) are not yet established for
spiromesifen.]

