EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: Mark Suarez, (703) 305-0120

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 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. 

(Options (pick one)

by establishing a tolerance for residues of 

Spirotetramat (cis-3-(2,5-dimethlyphenyl)-8-methoxy-2-oxo-1-azaspiro[4.5]dec-3-en-4-

yl-ethyl carbonate]) and its metabolites BYI 08330-enol (cis-3-(2,5-dimethylphenyl)-4-

hydroxy-8-methoxy-1-azaspiro[4.5]dec-3-en-2-one), BYI 08330-ketohydroxy (cis-3-(2,5-

dimethylphenyl)-3-hydroxy-8-methoxy-1-azaspiro[4.5]decane-2,4-dione), BYI08330-

enol-Glc (cis-3-(2,5-dimethylphenyl)-8-methoxy-2-oxo-1-azaspiro[4.5]dec-3-en-4-yl 

beta-D-glucopyranoside), and BYI 08330-mono-hydroxy (cis-3-(2,5-dimethylphenyl)-4-

hydroxy-8-methoxy-1-azaspiro[4.5]decan-2-one), calculated as spirotetramat 

equivalents,] in or on the raw agricultural commodities [asparagus, spears (stems)] at

[0.10 ] 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 nature of the spirotetramat residues in plants and 

M-526170-01-1
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livestock is adequately understood. The plant residues of concern for tolerance 

enforcement are the combined residues of spirotetramat (cis-3-(2,5-dimethlyphenyl)-8-

methoxy-2-oxo-1-azaspiro[4.5]dec-3-en-4-yl-ethyl carbonate]) and its metabolites BYI 

08330-enol (cis-3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]dec-3-en2-one), BYI 08330-ketohydroxy (cis-3-(2,5-dimethylphenyl)-3-hydroxy-8-methoxy-1-

azaspiro[4.5]decane-2,4-dione), BYI08330-enol-Glc (cis-3-(2,5-dimethylphenyl)-8-

methoxy-2-oxo-1-azaspiro[4.5]dec-3-en-4-yl beta-D-glucopyranoside), and BYI 08330-

mono-hydroxy (cis-3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]decan2-one), calculated as spirotetramat equivalents.

2. Analytical method. Spirotetramat residues are quantified in raw agricultural 

commodities by high pressure liquid chromatography/triple stage quadrupole mass 

spectrometry (LC/MS/MS) using the stable isotopically labeled analytes as internal 

standards. The limit of quantification (LOQ) for each analyte was 0.01 ppm for all 

commodities.

3. Magnitude of residues. [Residue trials were conducted to support the tolerances 

requested above including the following: 

- Asparagus: A total of eight field trials were conducted in Mexico and Peru.

B. Toxicological Profile

1. Acute toxicity. Spirotetramat has a low acute oral (LD50 > 2,000 mg/kg bw; 

Category III), dermal (LD50: > 2,000 mg/kg bw; Category III) and inhalative toxicity 

(LC50: > 4.183 mg/L air; Category IV) in male and female rats. Though a Category II 

irritant to the eye, spirotetramat is not a skin irritant (Category IV) but does exhibit skin 

sensitizing potential.

2. Genotoxicity. Treatment-related increases in tumor incidence were not 

observed in either sex in rats or mice. Spirotetramat was also negative for mutagenicity 

and clastogenicity in several standard in vivo and in vitro assays.

3. Reproductive and developmental toxicity. Developmental toxicity in the 

absence of maternal toxicity was not observed in either the rat or rabbit. In the rat, 

decreased body weight and food consumption were observed in dams at the limit dose in 

a developmental toxicity study. Developmental toxicity (reduced fetal weight and 

increased incidences of malformations and skeletal deviations) was also observed at the 

limit dose. The NOAEL was established at the next lower dose (140 mg/kg bw/day) in 

both dams and offspring. In the rabbit, developmental toxicity was not observed up to the 

highest dose tested (160 mg/kg bw/day). However, maternal toxicity was observed at ≥40 

mg/kg bw/day, including a dose-dependent increase in abortion and other clinical signs of 

systemic toxicity in affected animals.
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In addition to testicular histopathology observed following subchronic and chronic 

exposure of male rats to spirotetramat, evidence of male reproductive toxicity was 

provided in the 2-generation reproductive toxicity study. Abnormal sperm cells were 

reported in F1-generation male rats treated with 6000 ppm (419 mg/kg bw/day) 

spirotetramat in the diet, and decreased reproductive performance was also observed in 

one of these males. Similar results were obtained in the 1-generation reproductive 

toxicity range-finding study, in which decreased sperm motility and progression and 

increased abnormal sperm cells in the epididymides were observed in F1 males at ≥6000 

ppm (320 mg/kg bw/day). Development of the sexual organs of offspring (balanopreputial separation, vaginal opening) was unaffected in either study, and no treatmentrelated effects were observed at lower doses.

In an investigative study designed to explore the time of onset of testicular toxicity in 

rats, decreased epididymal sperm counts were observed after 10 days or more of 

treatment with 1000 mg/kg bw/day by gavage. Repeated dosing, therefore, is necessary to 

produce male reproductive toxicity in rats. In a second investigative study, male rats were 

treated by gavage with the enol metabolite of spirotetramat for 21 days at a dose of 800 

mg/kg bw/day. Spermatotoxicity, abnormal sperm, and Sertoli cell vacuolation were 

observed in the testes-epididymides of treated animals. Therefore, male reproductive 

toxicity in rats is likely due to the enol metabolite of spirotetramat.

4. Subchronic toxicity. In the rat, spirotetramat-induced testicular changes were 

characterized by increases in tubular degeneration and decreased testicle weight at the 

highest dose tested (616 mg/kg bw/day). Increases in abnormal spermatozoa and 

hypospermia were also identified in the rat epididymis. Unlike the rat, no effects of any 

kind emerged in the mouse, which was tested up to the limit dose. Nonadverse declines 

in circulating thyroid hormones were identified exclusively in the dog; however, no other 

thyroid-related changes were noted following subchronic exposure.

5. Chronic toxicity. In the dog, prolonged exposure to spirotetramat was 

characterized by nonadverse declines in circulating thyroid hormones. Below the highest 

dose tested, no changes in thyroid weight, thyroid pathology, compensating increases in 

thyrotropin (TSH), or clinical observations (e.g., neurological signs) suggestive of thyroid 

compromise and/or hypothyroidism were detected in either sex. In contrast to the dog, 

the rat showed no signs of thyroid involvement; slight increases in liver weight and 

alveolar macrophage accumulation in the lung, characterized the one-year chronic 

response in the rat. No significant effects were observed in the mouse up to the limit 

dose.

6. Animal metabolism. The pharmacokinetic behavior of spirotetramat is 

characterized by a rapid and complete absorption and rapid elimination from the plasma 

in rats. Following oral administration, 88% to 98% of the administered dose was excreted 

within 24 hours. The predominant route of excretion was by urine, accounting for 88% 

to 95% of the administered dose. Less than 0.2 % of the dose was detected in the body 

and the gastro-intestinal tract at 48 hours after the dose. Dose rate and frequency did not 

have any significant effects on the rates of absorption and excretion.
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The maximum of plasma concentration was reached for all dose groups within 0.09 to 

2.03 hours after administration. From the maximum, the radioactivity concentrations in 

plasma declined steadily by several orders of magnitude within 48 hours for all dose 

groups. Concentrations of radioactivity detected in tissues and organs at the time of 

sacrifice 48 hours post dose administration were very low and below the limit of 

detection for some organs/tissues.

Spirotetramat was completely metabolized by the rat and no parent compound was 

detected in the excreta. The major metabolic reaction was cleavage of the ester group 

leading to the formation of the primary and most predominant metabolite BYI08330-enol 

(53 – 87 % of the dose administered). All other identified metabolites could be derived 

from the enol intermediate. The second prominent metabolic transformation was 

demethylation of the 8-methoxy group to BYI08330-desmethyl-enol (5 – 37 % of the 

dose administered). Oxidation of the pyrroline moiety to BYI08330-ketohydroxy and 

BYI08330-desmethyl-ketohydroxy were detected as minor pathways. Other very minor 

metabolic transformations were conjugation of the enol with glucuronic acid to 

BYI08330-enol-GA and oxidation of the aromatic methyl group of the enol metabolite to 

BYI08330-enol-alcohol.

7. Metabolite toxicology. Acute (oral rat) and genotoxicity (bacterial reverse 

mutation) testing was conducted on four plant metabolites of spirotetramat not identified 

in the rat or identified to a minor degree: BYI 08330-cis-ketohydroxy, BYI 08330-

desmethyl-ketohydroxy, BYI 08330-desmethyl-di-hydroxy, and BYI 08330-monohydroxy. With all four metabolites, the results were equivalent to that observed with the 

parent compound (LD50 > 2000 mg/kg; negative = no evidence of mutagenicity).

8. Endocrine disruption. Evidence of thyroid- and testicular-related changes 

emerged in the dog and rat, respectively, following exposure to spirotetramat. During 

both the 90-day and 1-year feeding studies, decreases in circulating T3 and T4 were 

observed exclusively in the dog. Ultimately, based on the total response of the animals to 

the thyroid profile that emerged in both the 90-day and 1-year dog studies, the changes in 

circulating thyroid hormones in the dog were judged to be nonadverse. No thyroid 

effects of any form were observed in either the rat or the mouse. Though effects on 

sperm development in the testes of the rat were identified, there were no data to suggest 

the effect was mediated through some form of spirotetramat-induced hormonal 

interference.

C. Aggregate Exposure

1. Dietary exposure. The toxicology database for spirotetramat is complete for the 

purposes of this risk assessment and the characterization of potential pre- and postnatal 

risks to infants and children. Acute exposure estimates for spirotetramat were based on 

an acute reference dose (aRfD) of 1.0 mg/kg body weight/day. This aRfD was based on a 

no observed adverse effect level (NOAEL) of 100 mg/kg body weight/day from an acute 

oral neurotoxicity screening study with technical grade spirotetramat in rats, applying an 

uncertainty factor of 100 to account for interspecies extrapolation (10X) and intraspecies 
5

variation (10X). No additional FQPA safety factor was applied; therefore, the aRfD and 

the acute population adjusted dose (aPAD) are the same. Chronic exposure estimates for 

spirotetramat were based on a chronic reference dose (cRfD) of 0.05 mg/kg body 

weight/day. This cRfD is based on a no observed adverse effect level (NOAEL) of 5

mg/kg body weight/day from the chronic dog toxicity study for spirotetramat, applying 

an uncertainty factor of 100 to account for interspecies extrapolation (10X) and 

intraspecies variation (10X). No additional FQPA safety factor was applied; therefore, 

the cRfD and the chronic population adjusted dose (cPAD) are the same.

Assessments were conducted to evaluate potential risks due to acute and chronic dietary 

exposure of the U.S. population and selected population subgroups to residues of 

spirotetramat. These analyses included the existing uses of spirotetramat on taro leaves, 

watercress, pomegranate, banana, bulb vegetables (3-07), low growing berry (13-07H), 

bushberry (13-07B), globe artichoke, fruiting vegetables (8-10), pome fruit (11-10), citrus 

fruit (10-10), pineapple, coffee, and corn import tolerance. The following analysis was 

based on the most recent EPA dietary assessment on March 26, 2013 (D398858) with 

additional proposed uses of spirotetramat on asparagus import tolerance. Potential 

exposure from drinking water is also included in these assessments. Potential 

concentrations of spirotetramat residues in drinking water were determined by EPA using 

SCI-GROW and Tier 1 Rice Model v1.0. These conservative surface water estimates 

were added to the potential exposure from food. Dietary exposure was determined using 

DEEM-FCID Ver. 3.16. Consumption data used in this program were taken from 

NHANES WWEIA 2003 to 2008.

i. Food. Food exposure estimates were calculated using DEEM-FCID Ver. 3.16 

software, with NHANES WWEIA 2003 to 2008 consumption data. The acute 

assessment assumed that 100% of crops with registered and pending uses of spirotetramat

are treated, default processing factors were used, and that all treated crops contain 

residues at tolerance level. The refined chronic assessment assumed that 100% of crops

with registered and pending uses of spirotetramat are treated, empirical processing factors 

were used, and that some treated crops contain residues at the average residue levels 

found in crop field trials while the remaining treated crops were at tolerance-level 

residues. In addition, tolerance level residues for livestock commodities were also 

included in the analyses to account for the potential transfer of plant residues to livestock 

tissues. The addition of asparagus residues at tolerance-levels had negligible effects on 

the previous risk assessment. Tier 1 acute exposure (95th percentile) for food only 

utilizes 5% of the aPAD for the US Population and 14% for Children 1-2 yrs., the most 

highly exposed subpopulation. Refined chronic exposure for food only utilizes 19% of 

the cPAD for the US Population and 53% of the cPAD for Children 1-2 yrs., the most 

highly exposed subpopulation.

ii. Drinking water. The Tier 1 Estimated Drinking Water Concentrations

(EDWCs) associated with spirotetramat use on all crops were calculated using 

SCI-GROW v.2.3 (ground water) and Tier 1 Rice Model v.1.0 (surface water). The 

highest potential drinking water exposure from registered and pending uses of 

spirotetramat was from surface water scenario. For acute and chronic exposure, the 
6

EDWC of 395 μg/L was used in the assessments. EDWCs were incorporated into 

exposure assessments using DEEM-FCID v.3.16. The addition of asparagus residues at 

tolerance-levels had negligible effects on the previous risk assessment. Acute aggregate 

dietary exposure (food and water) was 7% aPAD for the overall U.S. population. For the 

most highly exposed population subgroup, children 1 -2 yrs., acute aggregate exposure 

(food and water) was 16% of the aPAD. Chronic aggregate dietary exposure (food and 

water) was 36% cPAD for the overall U.S. population. For the most highly exposed 

population subgroup, children 1 -2 yrs., chronic aggregate exposure (food and water) was 

76% of the cPAD.

2. Non-dietary exposure. There is a potential for exposure from non-dietary turf 

and ornamental uses previously submitted [12ESP703 SC Insecticide (Reg No. 432-

1530) and 14ACP703 SC Insecticide/Miticide (pending registration)]. 12ESP703 SC 

Insecticide is intended for professional use by lawn care operators for application to golf 

course turf and sod farms. Typical application equipment consists of handgun 

applications by LCOs and to golf course greens and tees, and boom applications to 

fairways and sod farms. There is a potential for short-term post-application dermal 

exposure for golfers (adults, 11<16 yrs, and 6<11 yrs), however, a reevaluation of the 

toxicological database was conducted by EPA and yielded no dermal hazard. Therefore, 

a quantification of dermal risk is not necessary. HED conducted a human health risk 

assessment for the turfgrass use (D413575, 10/16/14). 

14ACP703 SC Insecticide/Miticide (pending registration) is intended for professional 

application citrus trees grown in residential areas. There is a potential for short-term 

post-application dermal exposure for adults and children 6<11 yrs), however, a 

reevaluation of the toxicological database was conducted by EPA and yielded no dermal 

hazard. Therefore, a quantification of dermal risk is not necessary. 

D. Cumulative Effects Spirotetramat is a ketoenol tetramic acid insecticide. At this time, 

the EPA has not made a determination that spirotetramat and other substances that may 

have a common mechanism of toxicity would have cumulative effects. Therefore, for 

these tolerance petitions, it is assumed that spirotetramat does not have a common 

mechanism of toxicity with other substances and only the potential risks of spirotetramat 

in its aggregate exposure are considered. 

E. Safety Determination

1. U.S. population. Using the conservative exposure assumptions described above 

and based on the completeness of the toxicity data, it can be concluded that aggregate 

exposure to residues of spirotetramat present a reasonable certainty of no harm. 

Exposure from residues in crops utilizes about 7% of the aPAD and 36% of the cPAD. 

These values include potential exposure from both food and drinking water. EPA 

generally has no concerns for exposures below 100% of the Population Adjusted Doses. 

Therefore, the aggregate assessment for all proposed uses for spirotetramat demonstrates 

that there is a reasonable certainty that no harm will result to the US Population from the 
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use of spirotetramat. 

2. Infants and children. The developmental and reproductive toxicity of 

spirotetramat was evaluated in developmental toxicity studies in the rat and rabbit and a 

2-generation reproduction study in the rat. These studies are discussed under Section B 

(Toxicology Profile) above. The developmental toxicity data demonstrated no increased 

sensitivity of rats or rabbits to in utero exposure to spirotetramat. In addition, the 

multi-generation reproductive toxicity study did not identify any increased sensitivity of 

rats to in utero or post-natal exposure. Non-maternal toxicity was identified at equivalent 

or higher doses than maternal toxicity in both the rat and the rabbit. The developmental 

toxicity studies are designed to evaluate adverse effects on the developing organism 

resulting from maternal pesticide exposure during gestation. Reproduction studies 

provide information relating to effects from exposure to the pesticide on the reproductive 

capability of mating animals and data on systemic toxicity.

FFDCA section 408 provides that EPA shall apply an additional tenfold margin of safety 

for infants and children in the case of threshold effects to account for pre-and post-natal 

toxicity and the completeness of the data base unless EPA determines that a different 

margin of safety will be safe for infants and children. The spirotetramat database is 

complete for FQPA purposes and there are no residual uncertainties for pre-/post-natal 

toxicity for spirotetramat. Therefore, the Special FQPA Safety Factor can be reduced to 

1x. 

Based on the exposure assessments described above and on the completeness and 

reliability of the toxicity data, it can be concluded that the dietary exposure from all 

proposed uses of spirotetramat accounts for 16% of the aPAD at the 95th percentile and 

76% of the cPAD for the most sensitive population subgroup. Aggregate dietary and 

residential exposures were not performed because there are no registered or proposed 

residential non-food uses of spirotetramat, Thus, it can be concluded that there is a 

reasonable certainty that no harm will result from aggregate exposure to spirotetramat 

residues.

F. International Tolerances

 Peru has established a national MRL for spirotetramat residues in/on asparagus at 0.1 

ppm. Therefore we proposed to establish the US tolerance at 0.1 ppm to harmonize and 

minimize any potential trade irritant.