EPA REGISTRATION DIVISION CO MPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER (7/1/2007)

EPA Registration Division contact: [Jennifer Gaines, (703) 305–5967]

INSTRUCTIONS: Please utilize this outline in p reparing the pesticide petition. In

cases where the outline element does not apply, please insert “NA-Remove” and

maintain the outline. Please do not chan ge 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]

[0F7691]

EPA has received a pesticide petition (0F7691) 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; 2-oxo-3-(2, 4, 6 - trimethy lphenyl)-1- oxaspiro( 4.4)non-3-en-4-yl 3,3- dimethylbutanoate, and its enol metabolite; 4-hy droxy-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 [sorghum grain] at [0.80] parts per million (ppm)

, [sorghum fodder] at [1.30] parts per million (ppm)

, [sorghum forage] at [9.0] parts per million (ppm) and in or on [sorghum aspirated grain fraction] at [11] parts per million (ppm) ; in or on the raw agricultural commodity [wheat grain and the corresponding processed fractions flour, midd lings, shorts, germ and bran ] at [0.10] parts per million (ppm) , in or on the raw agricultural commodity [wheat forage] at [19] parts per million (ppm), in or on the raw agricultural commodity [wheat hay ] at [16] parts per million (ppm), in or on the raw agricultural commodity [wheat straw ] at [4.5] parts per million (ppm) and in or on the raw agricultural commodity [wheat aspirated grain fraction] at [30] parts per million (ppm) . EPA has de termined 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 peti tion. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry1. Plant metabolism. [The uptake and metabolism of spiromesifen in primary crops are adequately understood. Radiolab eled 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. [ Magnitude of the residue data, conducted according to OPPTS Guideline 860.1500, are available for all required sorghum and wheat raw agricultural and processed commodities which support esta blished tolerances .]

B. Toxicological Profile

1. Acute toxicity. [Oral and dermal LD50 values were >2000 mg/kg bw. Inhalation LC50 values were >4873 mg/m 3 air. Spiromesifen was not irritating to rabbit skin or eyes but di d cause skin sensitization in the Magnusson/Kligman maximization test in guinea pigs. Acute t oxicity studies for spir omesifen support an overall toxicity Category III]

2. Genotoxicty. [Several genotoxicity tests were conducted to test for pointmutagenic activity, chromosome aberrati on 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 ma ternal 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 ad renal effects (cytopla smic eosinophilia). A 14-week feeding study in dogs demo nstrated 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 thyr oid effects (decreased T4).]

5. Chronic toxicity. [A 12-month chronic feeding st udy in rats demonstrated aNOAEL of 6.5 and 19.3 mg/kg bw/day for ma les 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, respectivel y. 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 accu mulation of residues in any tissues or organs. The primary metabolites are the en ol, which is formed by cleavage of the alkyl ester group, and the 4-hydroxymethy l metabolite. Several other metabolites are also formed.]

7. Metabolite toxicology

. [In addition to parent, metabolites of concern are those containing the enol and 4-hydroxymet hyl 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 potentia l. Reproductive and developmental findings provided no evidence of an enhanced sensitivity of the young. All prospective endocrine and endocrine-rel ated 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 limi ts for all populations, including infants and children, are not n ecessary because an endpoint of concern attributable to a single exposure (dose) wa s not identified from the oral toxicity studies. In addition, there are no deve lopmental 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 th e 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 conductingthe assessments.]

i. Food. [Assessments were conducted to eval uate the potential risks due to chronic dietary exposure of the entire U.S. population and selected population subgroups to residues of spiromesifen and its metabolites. These assessments cover all established and proposed uses of spir omesifen including the proposed extension of sorghum and wheat. These assessments al so include secondary residues in animal tissues resulting from registered and proposed uses. Tier 3 chronic dietary exposure, calculated using DEEM-FCID Version 2.14, equated to 4.4% of the cPAD for the most exposed subpopulation, Children 1-2 years. The exposure to the U.S. population equated to 1.5% of the cPAD. These Tier 3 exposure estimates assume 100% crop treated for wheat, sorghum and crops pending registration and assume a percent crop treated for already registered commodities. Exposures 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 for wheat and sorghum 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 usin g 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

relevant value for a chronic assessment resulted from the Florida strawberry,

surface water scenario. The EDWC for comb ined 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 wat er level of comparison (DWLOC) value

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, the Tier 3 chronic aggregat e dietary exposure (food and water) calculated using DEEM-FCID Version 2.14 was 4.9% of the cPAD. For the overall U.S. population, chronic aggregate dietary exposure was 1.8% of the cPAD. Aggregate exposures are based on an esti mated 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 sp iromesifen are a result of

a common mechanism and should be cumulated with thos e of any other compound.

EPA has not made a common mechanism of t oxicity finding as to spiromesifen and any other substances and spiromesifen does not appear to produce a toxicmetabolite produced by other substances. Bayer CropScience will submit information, if necessary, for EPA to co nsider concerning any potential cumulative effects of spiromesifen cons istent 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 asse ssments described above and on the completeness and reliability of the toxi city data, it can be concluded that total aggregate exposure to spiromesifen from all label and proposed 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 represen ts the level at or below which daily aggregate exposure over a lifetime will not po se 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 aggre gate 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 subchr onic neurotoxicity studies in rats. In the prenatal developmental toxi city studies in rats and rabbits and in the twogeneration reproduction study in rats, de velopmental toxicity to the offspring occurred at equivalent or higher doses than maternal toxicity. There are no neurotoxicity concerns based on acute a nd subchronic neurotoxicity studies. The most highly exposed population subgroup was children 1-2 with a total aggregate exposure to spiromesifen from all label and proposed 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, beca use the RfD represents the level at or below which daily aggregate exposure over a li fetime will not pose appreciable risks to human health. Thus, it can be conclude d 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 (M RLs) are not yet established for spiromesifen.]