EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITION

Docket ID Number: EPA-HQ-OPP-2016-0255

EPA Registration Division Contact: Sidney Jackson (703-305-7610)

Pesticide Petition Number: 6E8467 

EPA has received a pesticide petition (6E8467) from Interregional Research Project 

Number 4 (IR-4), IR-4 Project Headquarters, Rutgers, The State University of NJ, 500

College Road East, Suite 201 W, Princeton, NJ 08540 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 180.641 by establishing a tolerance for residues of the insecticide 

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

yl-ethyl carbonate) and its metabolites cis-3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy1-azaspiro[4.5]dec-3-en-2-one, cis-3-(2,5-dimethylphenyl)-3-hydroxy-8-methoxy-1-

azaspiro[4.5]decane-2,4-dione, cis-3-(2,5-dimethylphenyl)-8-methoxy-2-oxo-1-

azaspiro[4.5]dec-3-en-4-yl beta-D-glucopyranoside, and cis-3-(2,5-dimethylphenyl)-4-

hydroxy-8-methoxy-1-azaspiro[4.5]decan-2-one, calculated as the stoichiometric 

equivalent of spirotetramat, in or on the raw agricultural commodities carrot, roots at 0.15

parts per million (ppm); nut, tree, group 14-12 at 0.25 ppm; and fruit, stone, group 12-12

at 4.5 ppm. Upon establishment of the aforementioned tolerances, the petitioner proposes 

to be deleted the following existing tolerances in order to eliminate redundancies: fruit, 

stone, group 12 at 4.5 ppm; nut, tree, group 14 at 0.25 ppm; and pistachio at 0.25 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 support 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 

livestock is adequately understood. The plant residues of concern for tolerance 

enforcement are the combined residues of (cis-3-(2,5-dimethlyphenyl)-8-methoxy-2-oxo1-azaspiro[4.5]dec-3-en-4-yl-ethyl carbonate) and its metabolites cis-3-(2,5-

dimethylphenyl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]dec-3-en-2-one, cis-3-(2,5-

dimethylphenyl)-3-hydroxy-8-methoxy-1-azaspiro[4.5]decane-2,4-dione, cis-3-(2,5-

dimethylphenyl)-8-methoxy-2-oxo-1-azaspiro[4.5]dec-3-en-4-yl beta-D-glucopyranoside, 

and cis-3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]decan-2-one, 

calculated as the stoichiometric equivalent of spirotetramat.

2. Analytical method. Spirotetramat residues are quantified in raw agricultural 
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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. A total of 8 residue field trials were conducted to 

support the tolerances requested above including carrots. 

B. Toxicological Profile

1. Acute toxicity. Spirotetramat has a low acute oral (lethal dose (LD)50 > 2,000 

milligrams (mg)/kilogram (kg) body weight (bw); Category III), dermal (LD50: > 2,000 

mg/kg bw; Category III) and inhalation toxicity (lethal concentration (LC)50: > 4.183 

mg/liter (L) air; Category IV) in male and female rats. Although the technical material is 

slightly irritating to the eye (Category II), spirotetramat is not a skin irritant (Category 

IV), but did exhibit a skin sensitizing potential under the conditions of the guinea pig 

maximization test.

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. In both the rabbit developmental 

toxicity study and rat two-generation reproductive study, changes in developmental 

endpoints were observed at equivalent or higher doses than those resulting in maternal 

toxicity. No treatment-related developmental effects were seen in the rabbit, while 

maternal animals exhibited clinical signs and an increase in sacrifice of moribund animals 

at the highest dose tested (HDT) of 160 mg/kg/day. In the two-generation reproduction 

study in rats, effects were observed only at the HDT of 419.3/484.7 mg/kg/day (m/f, 

premating P-generation). The incidence of abnormal sperm cells increased to a minimal 

degree and decreased reproductive performance was observed in F1 males, but overall 

fertility was unaffected since fertility was compromised in only 1 male. The effects on 

sperm cells confirm similar findings seen in the one-generation reproduction study at the 

same dose level. The reproductive changes, as well as kidney effects (i.e. decreased 

absolute and relative weights with minimal to moderate multifocal tubular dilatation) and 

decreased pup body weight (F1 and F2 during lactation) were accompanied by decreased 

parental body weight (F1; males throughout premating, females during premating and 

lactation) and food consumption (P and F1 females). Evidence of qualitative 

susceptibility was observed in the rat developmental study, where reduced fetal weight (-

14% compared to control) and increased incidences of malformations and skeletal 

variations were observed in the presence of maternal toxicity (i.e. significantly reduced 

final body weight and body weight gain (BWG) during the overall treatment period and 

gestation, decreased corrected BWG and significantly decreased food consumption 

through most of gestation). The developmental changes, however, were within historical 

control values for fetal incidence, occurred only at the limit dose. 
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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/day spirotetramat 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. Based on these 

findings, male reproductive toxicity observed in rats is likely due to the enol metabolite 

of spirotetramat and not the parent compound.

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

characterized by increases in tubular degeneration and decreased testicle weight. Increases in 

abnormal spermatozoa and hypospermia were also identified in the rat epididymis. Unlike the 

rat, no effects of any kind were seen in the mouse up to the limit dose. Non-adverse decreases in 

circulating thyroid hormones were identified exclusively in the dog without any other 

corresponding thyroid-related changes.

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

non-adverse decreases 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. Similar male reproductive findings as those seen after subchronic exposure 

were observed after chronic exposure. Abnormal spermatozoa, hypospermia, and germ cell 

exfoliated debris in the epididymis, decreased testicular weight, and testicular degeneration and 

vacuolation were seen in males only at the HDT (616 mg/kg/day, 90 days; 373 mg/kg/day, 24 

months) and were largely reversible after cessation of treatment. The lung and kidney were also 

target organs in the rat. An increased incidence of alveolar macrophages was observed 

(≥189/890 mg/kg/day, m/f) and a complex of changes in the lung described as interstitial 

pneumonia occurred after chronic exposure at the HDT in both sexes. Decreased kidney weights 

correlated with an increased incidence of tubular dilatation in the carcinogenicity study in both 

sexes (≥169/229 mg/kg/day, m/f).

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.

The maximum plasma concentration was reached for all dose groups within 0.09 to 2.03 

hours after administration; radioactivity concentrations in plasma then 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.
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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 were 

observed 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 lack of dose-related thyroid 

changes in the 90-day and 1-year dog studies, the changes in circulating thyroid 

hormones in the dog were determined to be non-adverse. No thyroid effects 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 changes were mediated 

through 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 

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 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.
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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 for all existing registered uses. These analyses also included additional 

proposed uses of spirotetramat on sugar beets and carrots, and import tolerance on

asparagus and strawberries. Potential exposure from drinking water is also included in 

these assessments. Potential concentrations of spirotetramat residues in drinking water 

were determined by EPA using the Tier I Screening Concentration in Ground Water 

(SCI-GROW) model 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 Dietary Exposure Evaluation Model using the Food Commodity Intake 

Database (DEEM-FCID) Ver. 4.02. Consumption data used in this program were taken 

from the U.S. Department of Agriculture’s National Health and Nutrition Examination 

Survey, What We Eat in America, (NHANES/WWEIA), 2005 to 2010.

i. Food. Food exposure estimates were calculated using DEEM-FCID Ver. 4.02

software, with NHANES WWEIA 2005 to 2010 consumption data. Acute assessments 

assumed that 100% of crops with registered and pending uses of spirotetramat are treated, 

and that all treated crops contain residues at tolerance level. 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 refined chronic assessments 

assumed 100% of crops are treated with average field trial residues for some 

commodities and tolerance-level residues for the remaining residues. For acute 

assessment the default processing factors were used, while for chronic assessment 

experimentally determined processing factors were incorporated, where available. 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 57% of the cPAD for Children 1-2 yrs., the most highly exposed subpopulation.

ii. Drinking water. The Tier 1 Estimated Drinking Water Concentration (EDWCs) 

associated with spirotetramat use on all crops was 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 EDWC of 395 μg/L was 

used in the assessments. EDWCs were incorporated into exposure assessments using 

DEEM-FCID v.4.02. 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 35% 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 90% of the cPAD.

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

registered uses on turf (sod farms and golf courses) and citrus grown in residential areas 
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[12ESP703 SC Insecticide (Reg No. 432-1530) and 14ACP703 SC Insecticide/Miticide 

(Reg No. 264-1050)]. 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. EPA

conducted a human health risk assessment for the turfgrass use. 

14ACP703 SC Insecticide/Miticide is intended for application citrus trees grown in 

residential areas. There is potential for short-term residential handler and postapplication exposures from the ornamental use. The residential handler exposure and risk 

estimates indicate that the short-term inhalation margin of exposures (MOE)s are not of 

concern (MOE≥100). While residential post-application exposure may potentially occur 

for adults and children 6<11 yrs.), there is no dermal Point of Departure (POD) identified

for spirotetramat, therefore, a quantitative assessment was not conducted. EPA

conducted a human health risk assessment for the citrus grown in residential areas use. 

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 35% 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. 

Short-term aggregate assessment for adults combines dietary (food + drinking water) 

exposures with inhalation exposures due to potential handler exposure from residential 

use on citrus trees. The aggregate MOE for adults was 2,000, which is above the level of 

concern (100). Therefore, the aggregate assessment for all proposed uses for 

spirotetramat demonstrates that there is a reasonable certainty that no harm will result to 

the U.S. Population from the 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 
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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 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

90% of the cPAD for the most sensitive population subgroup. 

F. International Tolerances

International and Codex tolerances or Maximum Residue Limits (MRLs) for 

spirotetramat are established for many crops in various countries. At this time, no Codex 

MRL has been established for spirotetramat residues in/on carrot. MRLs of 0.10 ppm 

and 0.30 ppm have been established by the EU and S. Korea, respectively.