EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: [insert name and telepho ne 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, 2 TW 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.

(Options (pick one)

1. by amending the current tolerance for residues of

( Spirodiclofen; 3-(2,4-dichlorophenyl)-2-oxo-1-oxaspiro[4,5]dec-3-en-4-yl ester 2,2- dimethylbutanoate] in or on the raw agricultural commodity [citrus oil] from 20 to 35 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 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 metabolism of spirodiclofen in plants is adequately

understood. Studies have been conducted to delineate the metabolism of radiolabeled spirodiclofen in various crops, all showing similar results. The residue of concern is spirodiclofen.]2

2. Analytical method. [Adequate analytical methodology using LC/MS/MS

detection is available fo r enforcement purposes.]

3. Magnitude of residues. [Magnitude of the residue data was conducted on guava, sugar apple and lychee in accordance with OPPTS Guideline 860.1500. The data supports establishing the requested tolerances.]

B. Toxicological Profile

1. Acute toxicity. [Oral and dermal LD50 val ues were >2000 mg/kg bw. Inhalation LC50 values were >5030 mg/m 3 air. Spirodiclofen was not irritating to rabbit skin or eyes but did cause skin sensitization in the Magnusson/Kligman maximization test in guinea pigs. Acute to xicity studies for spirodiclofen support an overall toxicity Category III. Spirodiclofen did not show any evidence of neurotoxicity in an acute neurotoxicity study in rats.]

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 NOELs were 1 000 mg/kg bw/day. An oral developmental toxicity study in rabbits demonstrated a maternal NOEL of 100 mg/kg bw/day and did not reveal any teratogenic potential. A two-generation study in rats, with a parental toxicity NOAEL of 5.2 mg/kg bw/day, did not reveal evidence of a primary reproductive toxicity potential. The re productive NOAEL was 26.2 mg/kg bw/day based on various clinical and histopathological findings at higher dose levels. The results of a second DNT study demonstr ated no changes in developmental/ functional parameters in offspring at the highest dose tested .]

4. Subchronic toxicity. [A subchronic toxicity feeding study with rats over 90 days demonstrated a NOAEL of 32.1 and 8.1 mg/kg bw/day for males and females, respectively, based on effects on the lipid metabolism (decrease of triglycerides and cholesterol), liver effects (increase in transaminases) and adrenal effects (vacuolation) at the higher dose levels. A subchronic feeding study in mice over 13 weeks revealed no clinical toxicological signs. A NOAEL of 30.1 mg/kg bw/day for

females was observed and a NOAEL of 15 mg/kg bw was established for males). A 14-week feeding study in dogs demonstrated a NOAEL of 7.7 mg/kg bw/day for males and <8.4 mg/kg bw/day for females ba sed on adrenal gland effects in 2 out of 4 animals. Spirodiclofen did not show any evidence of neurotoxicity in a subchronic neurotoxicity study in rats. A 28 day im munotoxicity investigation in rats in combination with other guideline studies provide evidence that spirodiclofen does not adversely affect the immune system.]

5. Chronic toxicity. [A 24-month combined chronic feeding/carcinogenicity3

study in rats demonstrated a NOAEL of 14.7 mg/kg bw/day. An oncogenicity study

in the mouse revealed a NOAEL of 4.1 mg/kg bw/day. Uterine and testicular oncogenicity was noted in the rat and hepa tic neoplasia was observed in the mouse. A one-year feeding study with dog demonstrated a NOAEL of 1.38 mg/kg bw day based on adrenal effects (vacuolization) as well as changes in circulating cholesterol and prostate weight at higher dose levels.]

6. Animal metabolism. [Metabolism and pharmacokinetic studies in the rat demonstrate that spirodiclofen residues are rapidly absorbed, metabolized and eliminated. The primary metabolite is the enol, which is formed by cleavage of the alkyl ester group, but numerous ot her metabolites are also formed.]

7. Metabolite toxicology

. [In crop matrices, spirodiclo fen is the only residue of

concern. The residues of concern in livestoc k tissues are spirodiclofen and its enol metabolite. Since the enol is inherently pr esent after administration, toxicology data for this metabolite is completely support ed by data obtained for spirodiclofen

. ]

8. Endocrine disruption

. [The mammalian mode of action for spirodiclofen includes that classified as inhibitory to st eroid biosynthesis, resulting in an indirect and endogenously-mediated toxicological re sponse. Effects do not have an impact on fertility, reproduction, developmental or neuropathological parameters.

Additional mechanistic studies with the chemical indicated that there is no direct effect on the endocrine system as there is no interaction with hormone receptors. ]

C. Aggregate Exposure

1. Dietary exposure. [Spirodiclofen has a low acute toxicity via the oral, dermal or inhalation route. An endpoint of concern attributable to a single dose was not identified in the hazard database; therefore an acute reference dose was not

established. Chronic dietary analysis was con ducted to estimate exposure to potential spirodiclofen residue s for the proposed use on sugar apple, cherimoya, atemoya, custard apple, ilama, soursop, briba, guava, fejoa, jaboticaba, wax jambu, starfruit, passionfruit, acerola, persimmo n, lychee, longan, Spanish lime, rambutan and pulasan and all registered and pending us es. DEEM-FCIDTM software (Version 2.14) utilizing the 94-96-98 CSFII consum ption database was used to estimate exposure. Average anticipated residues, processing factors (where available) and average percent crop treated values were used in the chronic assessment. The chronic reference dose of 0.014 mg/kg bw/day is based on the one year dog study NOAEL of 1.38 mg/kg bw/day and an applied uncertainty factor of 100X (10x for interspecies extrapolation and 10x for intraspecies variations). Spirodiclofen has been classified by EPA as “likely to be carcinogenic to humans” by the oral route. The unit risk, Q 1 * (mg/kg/day) -1 for spirodiclofen is 1.49 x 10 -2 based on male rat testes Leydig cell adenoma. Chronic and cancer aggregate risk estimates include exposure from drinking water and from food sources.)

i. Food. [Chronic dietary exposure estimates from residues of spirodiclofen for the U.S. population is 0.3% of th e cPAD. The population with the highest4

exposure is children 1-2 years with 0.9% of the cPAD utilized. The chronic cancer dietary exposure estimate for the general population is 5.88 x 10

- 7 .]

ii. Drinking water. [To assess chronic risk, drinking water estimates were incorporated directly into the dietary analysis (DEEM-FCID residue file). The

chronic estimated environmental concentrat ion (EEC) for drinki ng water was based on the PRZM/EXAMS model. The water exposure assessment was done using the latest EPA modeling tool PE5 and the latest modeling scenarios. In the assessment, regional percent crop areas were used. The chronic (non-cancer) exposure for spirodiclofen (total residue including its three metabolites: spirodiclofen-enol, spirodiclofen-ketohydroxy, and spirodiclofen- dihydroxy) in surface water was estimated to be 0.98 ppb in surface water. The EEC for chronic (cancer) exposure in surface water was estimated to be 0.67 ppb. Combined chronic dietary exposure estimates from residues of spirodiclofen in food and drinking water for the U.S. population is 0.4% of the cPAD. The po pulations with the highest potential; exposures are infants and children 1-2 years with 1.1% of the cPAD utilized. The chronic cancer dietary exposure estimate for the general population is 8.96 x 10

- 7

. ]

2. Non-dietary exposure

. [There are no indoor resi dential, indo or commercial or outdoor residential uses for spirodiclofen.]

D. Cumulative Effects

[Spirodiclofen represents a new class of chemistry, ketoenols. There are no

data available to indicate that toxic effect s produced by spirodiclofen are a result of

a common mechanism and should be cumula ted with those of any other compound.

EPA has not made a common mechanism of to xicity finding as to spirodiclofen and any other substances and spirodiclofen does not appear to product a toxic metabolite produced by other substa nces. Bayer CropScience will submit information, if necessary, for EPA to co nsider concerning potential cumulative effects of spirodiclofen 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 toxi city data, it can be concluded that total aggregate exposure to spirodiclofen residues in food and drinking water resulting from all label and pending uses as well as the proposed tropical fruit uses will utilize 0.4 percent of the cPAD for chronic dietary exposures to the U.S. Population. EPA generally has no concerns for exposures below 100 percent of the cPAD, because it represents the level at or below which daily aggregate exposure over a lifetime will not pose appreciable risks to human heal th. Cancer aggregate risk was calculated for the U.S. population only. The cancer risk estimate with drinking water included

is 8.96 x 10 -7 . Since EPA considers a cancer risk to be greater than negligible when5

it exceeds the range of 1-3 in a million, the estimated cancer risk for spirodiclofen is not likely to exceed the Agency’s level of concern. 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 spirodiclofen residues.]

2. Infants and children

. [ The Agency has concluded that there is no evidence of increased susceptibility following the in utero and/or prenatal/postn atal exposure in the developmental toxicity st udies in rabbits and 2-generation reproduction studies in rats. The results from developmental, reproduction and 2 DNT studies do not indicate a significant concern for increase d susceptibility, and therefore the FQPA safety factor has not been retained in calc ulating the reference dose for chronic risk. The most highly exposed population subgroups are infants and children 1-2 years with a total aggregate (food and water) exposure to spirodiclofen from all the registered and pending uses and the proposed tropical fruit uses being 1.1% of the cPAD for chronic dietary exposures. EPA generally has no concerns for exposures below 100 percent of the cPAD, because it represents the level at or below which daily aggregate exposure over a lifetime will not pose appreciable risks to human

health.

F. International Tolerances

[At the July 2010 Codex meeting, the Committee decided to advance the proposed draft MRLs for adoption at Step 5/8 as follows:

Commodity MRL (mg/kg) Dried grapes (= currants, sultanas, raisins) 0.3

Tree nuts 0.05

Tomato 0.5 Strawberry 2

Stone fruits 2

Pome fruits 0.8 Papaya 0.03* Meat (from mammals other than marine mammals) 0.01*

Milks 0.004* Hops, Dry 40

Gherkins 0.07 Edible offal (mammalian) 0.05* Currants (red, black, white) 1

Cucumber 0.07

Citrus fruits 0.4

Coffee beans 0.03* Apple pomace, Dry 4

Almond hulls 15 Peppers, sweet (including pimento, pimiento) 0.2 Grapes 0.26