EPA REGISTRATION DIVISION COMPANY 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 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] 

[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 - trimethylphenyl)-1- oxaspiro(4.4)non-3-en-4-yl 3,3-

dimethylbutanoate, 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 [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, middlings, 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 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 are 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. [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 established tolerances.] 

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 pointmutagenic 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, 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 metabolites. These assessments cover 

all established and proposed uses of spiromesifen including the proposed extension 

of sorghum and wheat. These assessments also 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 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 

relevant 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 

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 aggregate 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 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 CropScience 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 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 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 twogeneration 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 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, 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.]