EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

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, 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 for 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 values were >2000 mg/kg bw. 

Inhalation LC50 values were >5030 mg/m3 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 toxicity 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 1000 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 reproductive 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 demonstrated 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 based 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 immunotoxicity 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/carcinogenicity 
3

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 hepatic 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 other metabolites are also formed.]

 7. Metabolite toxicology. [In crop matrices, spirodiclofen is the only residue of 

concern. The residues of concern in livestock tissues are spirodiclofen and its enol 

metabolite. Since the enol is inherently present after administration, toxicology data 

for this metabolite is completely supported by data obtained for spirodiclofen.]

 8. Endocrine disruption. [The mammalian mode of action for spirodiclofen 

includes that classified as inhibitory to steroid biosynthesis, resulting in an indirect 

and endogenously-mediated toxicological response. 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 conducted to estimate exposure to 

potential spirodiclofen residues for the proposed use on sugar apple, cherimoya, 

atemoya, custard apple, ilama, soursop, briba, guava, fejoa, jaboticaba, wax jambu, 

starfruit, passionfruit, acerola, persimmon, lychee, longan, Spanish lime, rambutan 

and pulasan and all registered and pending uses. DEEM-FCIDTM software (Version 

2.14) utilizing the 94-96-98 CSFII consumption 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, Q1

*(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 the cPAD. The population with the highest 
4

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 concentration (EEC) for drinking 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 populations 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 residential, indoor 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 effects produced by spirodiclofen 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 spirodiclofen and 

any other substances and spirodiclofen does not appear to product a toxic 

metabolite produced by other substances. Bayer CropScience will submit 

information, if necessary, for EPA to consider 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 toxicity 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 health. 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 when 
5

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/postnatal exposure in 

the developmental toxicity studies 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 increased susceptibility, and therefore the FQPA 

safety factor has not been retained in calculating 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 0.2 
6