Page 1 of 65 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 

 OFFICE OF 

PREVENTION, PESTICIDES 

AND TOXIC SUBSTANCES 

MEMORANDUM

Date: 14-MAY-2008 

SUBJECT: Spirotetramat. Human-Health Risk Assessment for Proposed Uses on Citrus 

(Crop Group 10); Cucurbit Vegetables (Crop Group 9); Fruiting Vegetables (Crop 

Group 8); Grape (Crop Subgroup 13F); Hops; Leafy Brassica Vegetables (Crop 

Group 5); Leafy Non-Brassica Vegetables (Crop Group 4); Pome Fruit (Crop 

Group 11); Potato and Other Tuberous and Corm Vegetables (Crop Subgroup 

1C); Stone Fruit (Crop Group 12); Tree Nuts (Crop Group 14); Onions; 

Strawberries; Livestock Commodities; and Greenhouses/Nurseries. 

PC Code: 392201 DP#: 333437 and 345276 

Decision No.: 371317 Registration No.: 264-xxx 

Petition No.: 6F7199 Regulatory Action: Section 3 Registration 

Risk Assessment Type: Single Chemical 

Aggregate 

Case No.: None 

TXR No.: None CAS No.: 382608-10-8

MRID No.: 46904479-99, 46904501-27, 

46904529-32, 46904536-39, 46904541-44, 

46904546-58, 46904560-63, 46904565, 46904569, 

46904594-95, 46904597, 46904599, 46904601-02, 

46904604, 47070901, 47151101-05, 47180401-02, 

47281301-07, 47291201, 47143501-02, 47208001 

40 CFR: None

 Ver.Apr.08 

FROM: Jennifer R. Tyler, Risk Assessor 

 George F. Kramer, Ph.D., Chemist 

 Kelly Lowe, Environmental Scientist 

Robert Mitkus, Ph.D., Toxicologist 

Registration Action Branch 1 (RAB1) 

 Health Effects Division (HED; 7509P) 

THROUGH: Dana M. Vogel, Branch Chief 

 RAB1/HED (7509P) 

TO: Rita Kumar/Meredith Laws, PM Team 01 

Registration Division (RD; 7505P) 

The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human 

health from exposure to pesticides. The RD of OPP has requested that HED evaluate hazard and 

exposure data and conduct dietary, occupational, residential and aggregate exposure assessments, 

as needed, to estimate the risk to human health that will result from proposed tolerances for the 
Page 2 of 65 

new active ingredient (ai) spirotetramat (cis-3-(2,5-dimethlyphenyl)-8-methoxy-2-oxo-1-

azaspiro[4.5]dec-3-en-4-yl-ethyl carbonate]) on several agricultural and livestock commodities. 

Spirotetramat is being evaluated as a part of a trilateral review with Canada and Austria. The 

U.S. provided the primary review of the available toxicology studies, and Canada provided the 

primary review of the residue chemistry data. All of the residues of concern for tolerances and 

maximum-residue limits (MRLs) have been harmonized among the participating countries. All 

toxicology endpoints have been harmonized, with the exception of the acute reference dose 

(aRfd), which has been harmonized with Canada. 

A summary of the findings and an assessment of human-health risk resulting from the proposed 

tolerances for spirotetramat are provided in this document. The risk assessment was provided by 

Jennifer Tyler (RAB1); the residue chemistry data review and dietary exposure assessment by 

George Kramer (RAB1); the hazard characterization and endpoint selection by Robert Mitkus 

(RAB1); the occupational exposure assessment by Kelly Lowe (RAB1); and the drinking water 

exposure assessment by José Meléndez of the Environmental Fate and Effects Division (EFED). 

Recommendations for Tolerances: Pending submission of revised Sections B and F and the 

submission of reference standards for the spirotetramat metabolites, there are no residue 

chemistry, toxicology, or occupational exposure issues that would preclude granting an 

unconditional registration for the requested uses of spirotetramat on the requested crops. 

The proposed uses and the submitted data support the following permanent tolerances for 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-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/on 

the following commodities: 

Fruit, citrus, group 10 0.60 ppm Vegetable, fruiting, group 8 2.5 ppm 

Citrus, oil 6.0 ppm Vegetable, cucurbit, group 9 0.30 ppm 

Vegetable, leafy, except Brassica, group 4 9.0 ppm Brassica, head and stem, subgroup 5A 2.5 ppm 

Fruit, pome, group 11 0.70 ppm Brassica, leafy greens, subgroup 5B 8.0 ppm 

Fruit, stone, group 12 4.5 ppm Vegetable, tuberous and corm, subgroup 1C 0.60 ppm 

Small fruit vine climbing subgroup, 

except fuzzy kiwifruit, subgroup 13-07F 

1.3 ppm Potato, flakes 1.6 ppm

Grape, raisin 3.0 ppm Nut, tree, group 14 0.25 ppm 

Strawberry 0.40 ppm Almond, hulls 9.0 ppm 

Onion, bulb, subgroup 3A-07 0.30 ppm Hop, dried cones 10 ppm 

The proposed uses and the submitted data support the following tolerances for the combined 

residues of spirotetramat (cis-3-(2,5-dimethlyphenyl)-8-methoxy-2-oxo-1-azaspiro[4.5]dec-3-en4-yl-ethyl carbonate]) and its metabolite BYI 08330-enol (cis-3-(2,5-dimethylphenyl)-4-

hydroxy-8-methoxy-1-azaspiro[4.5]dec-3-en-2-one), calculated as spirotetramat equivalents, 

in/on the following livestock commodities: 
Page 3 of 65 

Milk 0.01 ppm Sheep, meat 0.02 ppm 

Cattle, meat 0.02 ppm Sheep, fat 0.02 ppm 

Cattle, fat 0.02 ppm Sheep, meat byproducts 0.02 ppm 

Cattle, meat byproducts 0.02 ppm Horse, meat 0.02 ppm 

Goat, meat 0.02 ppm Horse, fat 0.02 ppm 

Goat, fat 0.02 ppm Horse, meat byproducts 0.02 ppm

Goat, meat byproducts 0.02 ppm 

Data Needs/Deficiencies

 The petitioner is requested to submit a revised Section B specifying the following 

o A 30-day plantback interval (PBI) for all non-labeled crops. 

o A 24-hour restricted entry interval (REI). 

 Analytical standards for the metabolites of spirotetramat are currently not available in the 

National Pesticide Standards Repository [Source: personal communication with D. 

Wright Jr. of the Analytical Chemistry Laboratory/Biological and Economics Analysis 

Division (ACL/BEAD), 11/2/2007]. Analytical reference standards (both technical-grade 

and isotopically labeled) of BYI 08330-enol, BYI 08330-ketohydroxy, BYI 08330-monohydroxy, and BYI 08330-enol-Glc should be supplied, and supplies replenished as 

requested by the Repository. 

 The petitioner is requested to submit a revised Section F specifying the following: 

o The tolerance expression for plant commodities should be revised to include the 

combined residues of spirotetramat and its metabolites BYI 08330-enol, BYI 

08330-ketohydroxy, BYI08330-enol-Glc, and BYI 08330-mono-hydroxy, 

expressed as spirotetramat equivalents. 

o Revised tolerance levels and commodity definitions summarized in Appendix C. 
Page 4 of 65 

Table of Contents 

1.0 Executive Summary ............................................................................................................ 5 

2.0 Ingredient Profile .............................................................................................................. 11 

2.1 Summary of Proposed Uses .................................................................................. 12 

2.2 Structure and Nomenclature ................................................................................. 13 

2.3 Physical and Chemical Properties ......................................................................... 15 

3.0 Hazard Characterization/Assessment ................................................................................ 15 

3.1 Hazard and Dose-Response Characterization ....................................................... 15 

3.2 FQPA Considerations ........................................................................................... 18 

3.3 Hazard Identification and Toxicity Endpoint Selection ........................................ 19 

3.4 Endocrine Disruption ............................................................................................ 22 

4.0 Public Health and Pesticide Epidemiology Data .............................................................. 22 

5.0 Dietary Exposure/Risk Characterization ........................................................................... 22 

5.1 Pesticide Metabolism and Environmental Degradation ........................................ 23 

5.2 Dietary Exposure and Risk ................................................................................... 29 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ................................... 31 

6.1 Spray Drift ............................................................................................................ 31

7.0 Aggregate Risk Assessments and Risk Characterization .................................................. 32 

7.1 Acute Aggregate Risk ........................................................................................... 32 

7.2 Chronic Aggregate Risk ........................................................................................ 32 

8.0 Cumulative Risk Characterization/Assessment ................................................................ 32 

9.0 Occupational Exposure/Risk Pathway .............................................................................. 33 

9.1 Short- and Intermediate-Term Handler Risk ........................................................ 33 

9.2 Short-Term Post-application Risk......................................................................... 34 

10.0 Data Needs and Label Recommendations ........................................................................ 36 

10.1 Toxicology ............................................................................................................ 36

10.2 Residue Chemistry ................................................................................................ 36 

Appendix A. Toxicology Assessment ............................................................................ 37 

A.2. Toxicity Profiles .................................................................................................... 38 

A.3. Executive Summaries............................................................................................ 45 

Appendix B. Metabolism Assessment ............................................................................ 59 

Appendix C. Tolerance Summary Table for Spirotetramat ........................................... 65 
Page 5 of 65 

1.0 Executive Summary

Bayer CropSciences has submitted a petition for the use of the new insecticide spirotetramat for 

use on citrus, cucurbit vegetables, fruiting vegetables, grapes, hops, leafy Brassica vegetables, 

leafy non-Brassica vegetables, pome fruit, tuberous and corm vegetables, stone fruit, tree nuts, 

and greenhouse/nurseries. Spirotetramat is a tetramic acid derivative (ketoenole), and is active 

against sucking insects in vegetables, citrus, pome fruit, stone fruit, grapes, cotton and other 

plants. It is systemic (xylem and phloem mobile) and can control hidden pests and protect new 

shoots. 

There are currently no food/feed uses or tolerances for spirotetramat in the U.S. In addition, 

there are currently no registered or proposed residential uses for spirotetramat. Spirotetramat is 

being evaluated as part of a trilateral joint review with Canada and Austria. Spirotetramat will 

be formulated as MoventoTM [EPA Reg. No. 264-xxx; a 2 pound (lb) ai/gallon (gal) suspensionconcentrate (SC) formulation], UltorTM (EPA Reg. No. 264-xxx; a 1.25 lb ai/gal SC 

formulation); BYI 8330 OD [EPA Reg. No. 264-xxx ; a 1.25 lb ai/gal oil-dispersion (OD) 

formulation]; and Spirotetramat 240 SC Greenhouse and Nursery Insecticide/Miticide (EPA Reg. 

No. 264.xxx; a 2 lb ai/gal SC formulation).

Hazard Assessment: The acute, short-term, and long-term toxicity of spirotetramat is well 

understood. Spirotetramat technical demonstrated moderate to low acute toxicity (Toxicity 

Category III or IV) via the oral, dermal, and inhalation routes. Spirotetramat is non-irritating to 

the skin (Toxicity Category IV), although it is an irritant to the eyes (Toxicity Category II) and 

exhibits a skin-sensitization potential in animals and humans. The thyroid and thymus glands 

were target organs in oral subchronic toxicity studies in the dog; whereas, the testesepididymides were the target organs following subchronic oral treatment of rats. Long-term 

toxicity studies reflected the short-term toxicological profile of spirotetramat with the thymus 

and thyroid as target organs following one-year oral exposure of dogs. Chronic exposure of rats 

to spirotetramat also reflected the subchronic pattern of testicular toxicity. No evidence of tumor 

formation was found following long-term studies of rodents, and spirotetramat was also negative 

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

The reproductive and developmental toxicity potential of spirotetramat was tested in rats and 

rabbits. In addition to testicular histopathology observed following subchronic and chronic 

exposure of rats to spirotetramat, male reproductive toxicity was recorded in the 2-generation 

reproductive toxicity study. However, development of the sexual organs of offspring (balanopreputial separation, vaginal opening) was unaffected. In an investigative study designed to 

explore the time of onset of testicular toxicity in rats, decreased epididymal sperm counts were 

noted after 10 days of exposure. Therefore, repeated dosing with spirotetramat is necessary to 

produce male reproductive toxicity in rats. Similar effects were observed after repeated dosing 

with the enol metabolite of spirotetramat. Developmental toxicity was not observed with 

spirotetramat in the absence of maternal toxicity in either the rat or rabbit. 

Dose Response Assessment and Food Quality Protection Act (FQPA) Decision: After review by 

HED’s Risk Assessment Review Committee (RARC) and Toxicology Science Advisory 

Committee (ToxSAC), the spirotetramat risk assessment team recommends that the 10X FQPA 

safety factor (SF) be reduced to 1X since there is a complete toxicity database for spirotetramat 
Page 6 of 65 

and exposure data are complete or are estimated based on data that reasonably account for 

potential exposures. The recommendation is based on the following: 

 There was no evidence of increased susceptibility of offspring following pre- or postnatal exposure in any study. In the rat developmental toxicity study, toxicity to offspring 

was observed at the same dose as maternal toxicity, which was also the limit dose. In the 

developmental toxicity study in the rabbit, only maternal toxicity was observed. In both 

reproductive toxicity studies, toxicity to offspring (decreased body weight) was observed 

at the same dose as parental toxicity. Therefore, no evidence of increased susceptibility 

of offspring was found across four relevant toxicity studies with spirotetramat. 

 Spirotetramat does not operate by way of a neurotoxic mechanism of action in target 

pests. 

 Spirotetramat is not considered a neurotoxic chemical in mammals. Clinical signs of 

toxicity and decreased motor activity were observed in adult rats following a single dose 

of spirotetramat in the acute neurotoxicity study in the rat; however, these effects only 

attained statistical significance at high doses and were not observed at the limit dose in 

the acute oral toxicity study in the rat. 

 There is no concern for neurotoxicity with spirotetramat in the developing animal based 

on the fact that brain dilation in the one-year dog study is most likely a congenital 

anomaly (see section 3.1.2) that was not observed in any other study in the database, and 

the fact that the structurally related Bayer compounds spirodiclofen and spiromesifen are 

not neurotoxic in adults or young. 

 The dietary food exposure assessment utilizes tolerance-level residues and 100% crop 

treated (CT) information for all proposed commodities. By using this screening-level 

assessment, the acute and chronic exposures/risks will not be underestimated. 

 The dietary drinking water assessment (Tier 1 estimates) utilizes values generated by 

model and associated modeling parameters which are designed to provide conservative, 

health-protective, high-end estimates of water concentrations. 

 There are no registered or proposed uses of spirotetramat which would result in 

residential exposure. 

Risk assessments were conducted for the following specific exposure scenarios listed below. 

The acute and chronic reference doses (aRfD and cRfD) were calculated by dividing the noobserved-adverse-effect-level (NOAEL) by 100 (10X for interspecies extrapolation and 10X for 

intraspecies variation). Since the FQPA SF has been reduced to 1X, the acute and chronic 

population-adjusted doses (aPAD and cPAD) are equal to the aRfD and cRfD, respectively. A 

100% oral-equivalent inhalation-absorption factor is assumed. The level of concern (LOC) for 

occupational dermal and inhalation exposures are for margins of exposure (MOEs) <100. 
Page 7 of 65 

Exposure 

Scenario

Point of 

Departure

RfD, PAD, LOC for 

Risk Assessment Study/Effect

Acute dietary NOAEL = 100 

mg/kg/day 

aRfD = aPAD = 

1.0 mg/kg/day 

Acute neurotoxicity in rats (gavage)/Clinical signs (M&F) and decreased motor 

activity (M) seen at the lowest-observed-adverse-effect-level (LOAEL) of 200 

mg/kg/day. 

Chronic 

dietary 

NOAEL = 5 

mg/kg/day 

cRfD = cPAD = 

0.05mg/kg/day 

Chronic toxicity study in dogs (dietary)/Thymus involution seen at LOAEL of 20 

mg/kg/day (M). 

Short- and 

Intermediateterm dermal 

NOAEL = 10 

mg/kg/day 

LOC for MOE < 

100 (occupational) 

Prenatal developmental study in rabbits/ Late abortion (≥GD 22), clinical signs, 

impaired food and water consumption and body weight loss seen at maternal

LOAEL of 40 mg/kg/day.

Short- and 

Intermediateterm 

inhalation 

NOAEL = 10 

mg/kg/day 

LOC for MOE < 

100 (occupational) 

Prenatal developmental study in rabbits/ Late abortion (≥GD 22), clinical signs, 

impaired food and water consumption and body weight loss seen at maternal

LOAEL of 40 mg/kg/day.

Residue Chemistry and Drinking Water Assessments: The residue chemistry and drinking water 

databases are adequate to assess potential human exposure to spirotetramat. 

The residues of concern in plants (primary crops) for tolerance expression and risk assessment 

purposes are spirotetramat and its metabolites BYI 08330-enol, BYI 08330-ketohydroxy, 

BYI08330-enol-Glc, and BYI 08330-mono-hydroxy. The residues of concern for rotational 

crops are spirotetramat and BYI 08330-ketohydroxy and free and conjugated BYI 08330-

desmethyl-ketohydroxy, BYI 08330-desmethyl-di-hydroxy and BYI 08330-ketohydroxyalcohol. Based on the currently proposed uses, the residues of concern for the tolerance 

expression for livestock commodities are spirotetramat and its metabolite BYI 08330-enol and 

the residues of concern for the risk assessment for livestock commodities are spirotetramat and 

its metabolites BYI 08330-enol and BYI 08330-enol-GA. If future proposed uses result in 

significant exposure of livestock to the plant metabolites BYI 08330-ketohydroxy, BYI08330-

enol-Glc, and BYI 08330-mono-hydroxy, then these metabolites may need to be included as 

additional residues of concern for livestock commodities. For drinking water, the residues of 

concern for risk assessment purposes are spirotetramat, BYI 08330-enol, and BYI 08330-

ketohydroxy. 

Adequate crop field trial data have been submitted for citrus, cucurbit vegetables, fruiting 

vegetables, grapes, hops, leafy Brassica vegetables, leafy non-Brassica vegetables, pome fruit, 

tuberous and corm vegetables, stone fruit, and tree nuts and the European residue for 

strawberries and onions data are adequate. For all commodities, the data reflect the maximum 

rates and minimum preharvest intervals (PHIs) requested and have sufficient geographic 

representation to support tolerances for the proposed uses (See Appendix C). All crop field trial 

studies are supported by adequate storage stability data. Adequate processing data indicate that 

tolerances should be established for citrus oil, raisins, potato flakes, and almond hulls. Based on 

the available livestock feeding study, tolerances on several livestock commodities should be 

established (see Appendix C). HED has determined that high-performance liquid 

chromatography with tandem mass spectrometry (HPLC-MS/MS) Methods 00857 and 00966 are 

suitable enforcement methods for plant and livestock commodities, respectively, since the 

methods passed a successful petition method validation (PMV) by Agency chemists at 

ACL/BEAD (E-mail, C. Stafford to D. Vogel; 2/19/08). The existing confined and field 

rotational crop data are adequate to support the proposed rotational crop restrictions. 
Page 8 of 65 

As spirotetremat is a new ai, drinking water monitoring data are not available. The effects of 

water treatment on the pesticide and degradates is uncertain. Spirotetramat and its metabolites, 

BYI 08330-enol, BYI 08330-ketohydroxy and BYI 08330-MA-amide, were highly mobile to 

moderately mobile, and low levels of binding are expected. It appears that spirotetramat 

metabolites BYI 08330-enol and BYI 08330-ketohydroxy are of high concern because the parent 

and BYI 08330 degrade relatively fast in most environments. EFED provided Tier 1 estimated 

drinking water concentrations (EDWCs) for surface and ground water which were generated 

using the FQPA Index Reservoir Screening Tool (FIRST) and Screening Concentration in 

Ground Water (SCI-GROW) models, respectively. 

Dietary (Food and Drinking Water) Exposure Estimates: Acute and chronic dietary exposure 

analyses were conducted using the Dietary Exposure Evaluation Model-Food Commodity Intake 

Database (DEEM-FCID; ver. 2.03) program which incorporates consumption data from the 

United States Department of Agriculture’s (USDA’s) Continuing Surveys of Food Intakes by 

Individuals (CSFII), 1994-1996/1998. For acute and chronic dietary risk estimates, HED’s level 

of concern is for estimates that exceed 100% aPAD or cPAD, respectively. 

The acute analysis assumed 100% CT and tolerance-level residues for all foods. Empirical and 

DEEMTM (ver. 7.81) default processing factors were used for processed commodities. A 

conservative chronic dietary assessment assuming average field-trial residues, empirical and 

DEEMTM (ver. 7.81) default processing factors, and 100% CT was also conducted. Drinking 

water was incorporated directly in the dietary assessment using the acute or chronic 

concentrations for surface water generated by the FIRST model. The acute dietary exposure 

estimates (95th percentile) are not of concern to HED (<100% of the aPAD) for the general U.S. 

population (4.2% of the aPAD) and all other population subgroups. The most highly exposed 

population subgroup is children 1-2 years old at 10% of the aPAD. The chronic dietary exposure 

estimates are not of concern to HED (<100% of the cPAD) for the general U.S. population (28% 

of the cPAD) and all population subgroups. The most highly exposed population subgroup is 

children 1-2 years old at 77% of the cPAD. 

Aggregate Exposure Scenarios and Risk Conclusions: For the proposed uses, human-health 

aggregate risk assessments have been conducted for the following exposure scenarios: acute 

aggregate exposure (food + drinking water), and chronic aggregate exposure (food + drinking 

water). Short- and intermediate-term aggregate risk assessments were not performed because 

there are no registered or proposed residential uses for spirotetramat. A cancer aggregate risk 

assessment was not performed because spirotetramat is classified as “Not Likely to be 

Carcinogenic to Humans.” All potential exposure pathways were assessed in the aggregate risk 

assessment. All aggregate exposure and risk estimates are not of concern to HED for the 

scenarios listed above.

Occupational Exposure Estimates: Based on the proposed use patterns, HED believes short-term 

(1-30 days) dermal and inhalation exposures are expected for commercial and private 

applicators. However, the short- and intermediate-term toxicological endpoints are the same; 

therefore, the estimates of risk for short-term duration exposures are protective of those for 

intermediate-term duration exposures. The most highly exposed occupational workers are 

expected to be mixer/loaders of liquids for aerial applications, applicators using airblast 

equipment, and mixer/loader/applicators of liquid concentrates using high-pressure handwand 

equipment. No chemical-specific data are available with which to assess potential exposure to 
Page 9 of 65 

pesticide handlers; therefore, estimates of exposure are based on data available in the Pesticide 

Handler Exposure Database Version 1.1 (PHED Surrogate Exposure Guide, 8/98). 

Exposure/risks for short-term dermal and inhalation handler mixer/loader exposures were 

presented at baseline (workers wearing a single layer of work clothing consisting of a longsleeved shirt, long pants, shoes plus socks and no protective gloves). Provided workers wear 

protective gloves as recommended on the label, all occupational handler MOEs are >100; and, 

therefore, are not of concern to HED (i.e., MOE>100). 

Short- and intermediate-term (1-30 days and 1-6 months, respectively) dermal exposures are 

expected for post-application agricultural activities. Post-application inhalation exposure is 

expected to be negligible due to the low vapor pressure of spirotetramat. There are no chemicalspecific data with which to estimate post-application exposure of agricultural workers to 

dislodgeable residues of spirotetramat. Therefore, post-application worker exposure was 

estimated using Agency default assumptions for dislodgeable residues, which lists scouting and 

irrigating as the activities with the highest (i.e., most conservative) transfer coefficients (TCs) 

related to the proposed uses. All MOEs are >100; therefore, post-application dermal exposure to 

agricultural workers is not of concern to HED (i.e., MOE >100). 

Based on the acute Toxicity Category classification for spirotetramat, the interim Worker 

Protection Standard (WPS) REI of 24 hours is adequate to protect agricultural workers from 

post-application exposures. The proposed end-use product labels list an REI of 12 hours. The 

labels should be revised to include a 24-hour REI. 

Environmental Justice Considerations: Potential areas of environmental justice concerns, to the 

extent possible, were considered in this human-health risk assessment, in accordance with U.S. 

Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority 

Populations and Low-Income Populations," 

(http://homer.ornl.gov/nuclearsafety/nsea/oepa/guidance/justice/eo12898.pdf). 

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, HED estimates 

risks to population subgroups from pesticide exposures that are based on patterns of that 

subgroup’s food and water consumption, and activities in and around the home that involve 

pesticide use in a residential setting. Extensive data on food consumption patterns are compiled 

by the USDA under CSFII and are used in pesticide risk assessments for all registered food uses 

of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the 

year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary 

exposure to smaller, specialized subgroups and exposure assessments are performed when 

conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on 

home use of pesticide products and associated risks for adult applicators and for toddlers, youths, 

and adults entering or playing on treated areas post-application are evaluated. Further 

considerations are currently in development as OPP has committed resources and expertise to the 

development of specialized software and models that consider exposure to bystanders and farm 

workers as well as lifestyle and traditional dietary patterns among specific subgroups. 

Review of Human Research: This risk assessment relies in part on data from PHED studies in 

which adult human subjects were intentionally exposed to a pesticide or other chemical. These 

studies have been determined to require a review of their ethical conduct, and have received that 
Page 10 of 65 

review. 

Recommendations for Tolerances: Pending submission of revised Sections B and F and the 

submission of reference standards for the spirotetramat metabolites, there are no residue 

chemistry, toxicology, or occupational exposure issues that would preclude granting an 

unconditional registration for the requested uses of spirotetramat on the requested crops. 

The proposed uses and the submitted data support the following permanent tolerances for 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-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/on 

the following commodities: 

Fruit, citrus, group 10 0.60 ppm Vegetable, fruiting, group 8 2.5 ppm 

Citrus, oil 6.0 ppm Vegetable, cucurbit, group 9 0.30 ppm 

Vegetable, leafy, except Brassica, group 4 9.0 ppm Brassica, head and stem, subgroup 5A 2.5 ppm 

Fruit, pome, group 11 0.70 ppm Brassica, leafy greens, subgroup 5B 8.0 ppm 

Fruit, stone, group 12 4.5 ppm Vegetable, tuberous and corm, subgroup 1C 0.60 ppm 

Small fruit vine climbing subgroup, 

except fuzzy kiwifruit, subgroup 13-07F 

1.3 ppm Potato, flakes 1.6 ppm

Grape, raisin 3.0 ppm Nut, tree, group 14 0.25 ppm 

Strawberry 0.40 ppm Almond, hulls 9.0 ppm 

Onion, bulb, subgroup 3A-07 0.30 ppm Hop, dried cones 10 ppm 

The proposed uses and the submitted data support the following tolerances for the combined 

residues of spirotetramat (cis-3-(2,5-dimethlyphenyl)-8-methoxy-2-oxo-1-azaspiro[4.5]dec-3-en4-yl-ethyl carbonate]) and its metabolite BYI 08330-enol (cis-3-(2,5-dimethylphenyl)-4-

hydroxy-8-methoxy-1-azaspiro[4.5]dec-3-en-2-one), calculated as spirotetramat equivalents, 

in/on the following livestock commodities: 

Milk 0.01 ppm Sheep, meat 0.02 ppm 

Cattle, meat 0.02 ppm Sheep, fat 0.02 ppm 

Cattle, fat 0.02 ppm Sheep, meat byproducts 0.02 ppm 

Cattle, meat byproducts 0.02 ppm Horse, meat 0.02 ppm 

Goat, meat 0.02 ppm Horse, fat 0.02 ppm 

Goat, fat 0.02 ppm Horse, meat byproducts 0.02 ppm

Goat, meat byproducts 0.02 ppm 

Data Needs/Deficiencies

 The petitioner is requested to submit a revised Section B specifying the following 

o A 30-day PBI for all non-labeled crops. 

o A 24-hour REI. 

 Analytical standards for the metabolites of spirotetramat are currently not available in the 

National Pesticide Standards Repository [Source: personal communication with D. 

Wright Jr. of ACL/BEAD, 11/2/2007]. Analytical reference standards (both technicalgrade and isotopically labeled) of BYI 08330-enol, BYI 08330-ketohydroxy, BYI 08330-
Page 11 of 65 

mono-hydroxy, and BYI 08330-enol-Glc should be supplied, and supplies replenished as 

requested by the Repository. 

 The petitioner is requested to submit a revised Section F specifying the following: 

o The tolerance expression for plant commodities should be revised to include the 

combined residues of spirotetramat and its metabolites BYI 08330-enol, BYI 

08330-ketohydroxy, BYI08330-enol-Glc, and BYI 08330-mono-hydroxy, 

expressed as spirotetramat equivalents. 

o Revised tolerance levels and commodity definitions summarized in Appendix C. 

2.0 Ingredient Profile

Spirotetramat is a tetramic acid derivative (ketoenole) developed by Bayer CropScience AG. 

This foliar insecticide is active against sucking insects in vegetables, citrus, pome fruit, stone 

fruit, grapes, cotton and other plants. It is systemic (xylem and phloem mobile) and can control 

hidden pests and protect new shoots. 

As spirotetramat is a new ai, there are no tolerances currently established under 40 CFR. 

Spirotetramat is being evaluated as part of a trilateral joint review with Canada and Austria. 

The petitioner has submitted draft labels dated 10/5/07 for the 2 lb ai/gal SC formulation 

(MoventoTM; EPA Reg. No. 264-xxx), the 1.25 lb ai/gal SC formulation (UltorTM; EPA Reg. No. 

264-xxx), the 1.25 lb ai/gal OD formulation (BYI 8330 OD; EPA Reg. No. 264-xxx); and the 2 

lb ai/gal SC formulation (Spirotetramat 240 SC Greenhouse and Nursery Insecticide/Miticide; 

EPA Reg. No. 264.xxx). A summary of the proposed use patterns on citrus, cucurbit vegetables, 

fruiting vegetables, grapes, hops, leafy Brassica vegetables, leafy non-Brassica vegetables, pome 

fruit, tuberous and corm vegetables, stone fruit, tree nuts, and greenhouse/nurseries is detailed in 

Table 2.1. 
Page 12 of 65 

2.1 Summary of Proposed Uses

Table 2.1. Summary of Directions for Use of Spirotetramat. 

Trade Names 

Application 

Timing, 

Type, and 

Equipment 

Applic. 

Rate 

(lb ai/A) 

Maximum 

Number 

Applications 

per Season 

Maximum 

Seasonal 

Application Rate 

(lb ai/A) 

PHI 

(days) Use Directions and Limitations 

CITRUS (Crop Group 10) 

BYI 8330 OD 

MoventoTM 

UltorTM

Ground & 

aerial 0.12-0.16 2 0.32 1 

Minimum RTI: 21 days 

Minimum spray volume: 15 

gallons per acre (GPA) ground, 10 

GPA aerial 

GRAPE and SMALL FRUIT VINE CLIMBING (except kiwifruit) 

BYI 8330 OD 

MoventoTM 

UltorTM

Ground & 

aerial 0.08-0.12 2 0.20 7 

Minimum RTI: 30 days 

Minimum spray volume: 15 GPA 

ground, 10 GPA aerial 

POME FRUIT (Crop Group 11) 

BYI 8330 OD 

MoventoTM 

UltorTM

Ground & 

aerial 0.10-0.14 4 0.40 7 

Minimum RTI: 14 days 

Minimum spray volume: 15 GPA 

ground, 10 GPA aerial 

STONE FRUIT (Crop Group 12) 

BYI 8330 OD 

MoventoTM 

UltorTM

Ground & 

aerial 0.10-0.14 2 0.24 7 

Minimum RTI: 14 days 

Minimum spray volume: 15 GPA 

ground, 10 GPA aerial 

TREE NUTS (Crop Group 14) 

BYI 8330 OD 

MoventoTM 

UltorTM

Ground & 

aerial 0.10-0.14 3 0.34 7 

Minimum RTI: 14 days 

Minimum spray volume: 15 GPA 

ground, 10 GPA aerial 

HOPS 

BYI 8330 OD 

MoventoTM 

UltorTM

Ground & 

aerial 0.08-0.10 2 0.20 7 

Minimum RTI: 14 days 

Minimum spray volume: 10 GPA 

ground, 10 GPA aerial 

CUCURBIT VEGETABLES (Crop Group 9) 

BYI 8330 OD 

MoventoTM 

UltorTM

Ground, 

chemigation, 

& aerial 

0.05-0.08 3 0.16 1 

Minimum RTI: 7 days 

Minimum spray volume: 15 GPA 

ground, 5 GPA aerial 

FRUITING VEGETABLES (Crop Group 8) + OKRA 

BYI 8330 OD 

MoventoTM 

UltorTM

Ground, 

chemigation, 

& aerial 

0.05-0.08 3 0.16 1 

Minimum RTI: 7 days 

Minimum spray volume: 15 GPA 

ground, 5 GPA aerial 

LEAFY VEGETABLES - NON-BRASSICA (Crop Group 4) 

BYI 8330 OD 

MoventoTM 

UltorTM

Ground, 

chemigation, 

& aerial 

0.05-0.08 3 0.16 3 

Minimum RTI: 7 days 

Minimum spray volume: 15 GPA 

ground, 5 GPA aerial 

BRASSICA (COLE) LEAFY VEGETABLES (Crop Group 5) 

BYI 8330 OD 

MoventoTM 

UltorTMTM

Ground, 

chemigation, 

& aerial 

0.05-0.08 3 0.16 1 

Minimum RTI: 7 days 

Minimum spray volume: 15 GPA 

ground, 5 GPA aerial 

POTATO and OTHER TUBEROUS AND CORM VEGETABLES (Crop Group 1C) 

BYI 8330 OD 

MoventoTM 

UltorTM

Ground, 

chemigation, 

& aerial 

0.06-0.08 2 0.16 7 

Minimum RTI: 7 days 

Minimum spray volume: 15 GPA 

ground, 5 GPA aerial 

GREENHOUSES, NURSERIES, INTERIOR PLANTSCAPES 

Spirotetramat 

240 SC 

Greenhouse 

and Nursery 

Insecticide/ 

Miticide 

Chemigation, 

Groundboom, 

Airblast, High 

Pressure 

Handwand 

0.16 - 0.39 N/A Minimum RTI: 14 days 

REI: 24 hours. 

Additional Restrictions for all Crops: 

MOVENTOTM and UltorTM must be tank-mixed with a spray adjuvant/additive. BYI 8330 OD may be tank-mixed with a 

spray adjuvant/additive. 

Use in enclosed structures, such as greenhouses or planthouses, is not permitted unless specified otherwise by state-specific 

supplemental labeling. 

Rotational PBIs: Immediate plant-back: All crops
Page 13 of 65 

HED Conclusions: The submitted use directions for MoventoTM, UltorTM, BYI 8330 OD, and 

Spirotetramat 240 SC Greenhouse and Nursery Insecticide/Miticide are adequate to allow 

evaluation of the residue data relative to the proposed use. The specified rotational PBIs allow 

immediate plantback of all crops. However, the rotational crop data support a rotational crop 

restriction of 30 days for all non-labeled crops. The labels should thus be amended to specify 

the 30-day PBI.

2.2 Structure and Nomenclature

Table 2.2. Test Compound Nomenclature.

Compound 

Chemical Structure 

Common name Spirotetramat 

Company experimental name BYI 08330 

IUPAC name cis-4-(ethoxycarbonyloxy)-8-methoxy-3-(2,5-xylyl)-1-azaspiro[4.5]dec-3-en-2-one 

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

carbonate 

CAS # 382608-10-8 

End-use product/EP MoventoTM, UltorTM, BYI 8330 OD 

Compound: BYI08330-enol 

Chemical Structure 

Common name BYI08330-enol 

Company experimental name BYI08330-enol 

IUPAC name None provided 

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

CAS # None provided 

Compound: BYI08830-

ketohydroxy 

Chemical Structure 

Common name BYI08830-ketohydroxy 

Company experimental name BYI08830-ketohydroxy 

IUPAC name None provided 

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

CAS # None provided 

Compound: BYI08330-enol-Glc Chemical Structure 
Page 14 of 65 

Common name BYI08330-enol-Glc 

Company experimental name BYI08330-enol-Glc 

IUPAC name None provided 

CAS name cis-3-(2,5-dimethylphenyl)-8-methoxy-2-oxo-1-azaspiro[4.5]dec-3-en-4-yl beta-Dglucopyranoside 

CAS # None provided 

Compound: BYI 08330-monohydroxy 

Chemical Structure 

Common name BYI 08330-mono-hydroxy 

Company experimental name BYI 08330-mono-hydroxy 

IUPAC name None provided 

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

CAS # None provided 

Compound: BYI 08330-enolGA 

Chemical Structure 

Common name BYI 08330-enol-GA 

Company experimental name BYI 08330-enol-GA 

IUPAC name None provided 

CAS name cis-3-(2,5-dimethylphenyl)-4-(β-D-glucopyranosyloxy)-8-methoxy-1-azaspiro[4.5]dec-3-

en-2-one 

CAS # None provided 
Page 15 of 65 

2.3 Physical and Chemical Properties

Table 2.3 Physicochemical Properties of the Technical Grade Spirotetramat. 

Parameter Value Reference 

Melting Point (°C) 142 Bayer CropScience AG 

Report M-063268-01-1 

pH 6.3 Bayer CropScience AG 

Report M-269907-01-1 

Density D4

20 = 1.22 Bayer CropScience AG 

Report M-270041-01-1 

Solubility in water at 20oC pH 4 - 33.5 mg/L 

pH 7 - 29.9 mg/L 

pH9 - 19.1 mg/L 

Bayer CropScience AG 

Report M-103256-01-1 

Solubility in organic solvent at 20oC Solvent g/L

n-hexane 0.055 

Dichloromethane >600 

Dimethyl Sulfoxide 200-300 

Toluene 60 

Acetone 100–120 

Ethyl acetate 67 

Ethanol 44 

Bayer CropScience AG 

Report M-122802-01-1 

Partition Coefficient n-octanol/water 

(log Kow) 

pH 4 - 2.51 

pH 7 - 2.51 

pH 9 - 2.50 

Bayer CropScience AG 

Report M-103244-01-1 

Vapor pressure (Pa) Extrapolated Values: 

5.6 x 10-9 (20oC) 

1.5 x 10-8 (25oC) 

1.5 x 10-6 (50oC) 

Bayer CropScience AG 

Report M-066171-01-1 

UV/Visible Absorption Spectra Peak Maxima Molar Absorptivity 

 (nm) (1000 cm2

/ mol) 

 211 22.0 x 103 

 276 0.8 x 103

Bayer CropScience AG 

M-182543-02-1 

3.0 Hazard Characterization/Assessment

3.1 Hazard and Dose-Response Characterization

3.1.1 Database Summary

Data from the following studies were used to evaluate the hazard potential of spirotetramat: 

 Acute: One acute neurotoxicity study (rat), in addition to standard acute toxicity battery.

 Subchronic: Six oral (mouse, rat, dog) and one dermal (rat) toxicity studies. 

 Long-term: Two oral toxicity (dog, rat) and two oral carcinogenicity (rat, mouse) 

studies. 

 Reproduction/developmental: Two developmental (rat, rabbit), one single-generation 

(rat), and one two-generation reproduction (rat) studies. 

 Other: Eight genotoxicity screens (in vivo/in vitro), two disposition studies (rat), and 

one in vivo dermal penetration study (rat). 

The submitted acute, subchronic, and chronic studies were sufficient to evaluate human hazard 

potential, and data quality is acceptable. 
Page 16 of 65 

3.1.2 Mammalian Toxicology

Spirotetramat is an insecticidal compound and belongs to the chemical class of cyclic ketoenols. 

In insects, spirotetramat is an inhibitor of acetyl-CoA carboxylase, which is a key enzyme in 

fatty acid biosynthesis in eukaryotes and prokaryotes. The insecticidal mode of action of 

spirotetramat correlates with inhibition of lipogenesis in treated insects, resulting in decreased 

lipid contents (notably triglycerides and free fatty acids), inhibition of the ability of younger 

insects to develop through the various growth stages, and ultimately culminating in a diminished 

capacity of the insects to reproduce as adults. Changes in plasma lipid parameters such as 

plasma triglycerides and plasma cholesterol were not observed in any animal study in the 

toxicology database for spirotetramat. 

Absorption, Distribution, Metabolism, and Excretion: Absorption of spirotetramat by the rat was 

89-98% 48 hrs after single low (2 mg/kg bw) and higher (100 mg/kg bw) doses, as well as 

repeated low doses (2 mg/kg bw). Systemic exposure, as estimated by AUC0-∞, was slightly 

higher for males than females. Less than 0.2% of the administered dose was detected in the body 

48 hrs after sacrifice, and the highest equivalent concentrations were detected in the liver and 

kidney, a fact that is consistent with the detoxification/excretory functions of these organs. 

Spirotetramat was completely metabolized by the rat, since no parent compound was detected in 

the excreta. The main metabolic reaction was cleavage of the ester group which resulted in 

formation of the major metabolite BYI 08330-enol (53-87% of administered dose). All other 

identified metabolites could be derived from enol. Male rats exhibited much higher rates of 

demethylation of BYI 08330-enol to BYI 08330-desmethyl-enol (25-37%) when compared to 

female rats (5-10 %). Spirotetramat was excreted quickly with 88-95% of the administered dose 

eliminated via urine and 2-11% via feces within 48 hrs of exposure. 

Absorption and excretion in animals treated one time with 1000 mg/kg bw was less than that at 

the lower doses, with 27% of dose excreted in urine after 24 hours and 18% in feces. Plasma 

radioactivity was slightly higher than that for liver and kidney, thereby suggesting saturation of 

cellular transport mechanisms at this high dose. Tissue radioactivity decreased from 1 h to 24 h 

post dose. The metabolism profile was qualitatively similar to that of the low dose studies. 

Similar to the low-dose studies, BYI 08330-enol was the most prominent metabolite in the highdose study. Physiologically based pharmacokinetic (PBPK) simulations with the enol metabolite 

suggest that repeated daily doses ≥300 mg/kg bw spirotetramat leads to non-linear elimination 

kinetics, possibly due to saturation of uptake processes in the liver and kidney. 

Acute toxicity: Spirotetramat technical demonstrated moderate to low acute toxicity (Toxicity 

Category III or IV) via the oral, dermal, and inhalation routes. Spirotetramat is non-irritating to 

the skin (Toxicity Category IV), although it is an irritant to the eyes (Toxicity Category II) and 

exhibits a skin-sensitization potential under the conditions of the guinea pig maximization test 

and the local lymph node assay, but not the Buehler patch test. The sensitization potential of 

spirotetramat was supported by two cases of Type IV hypersensitivity that were reported in 

spirotetramat manufacturing plant personnel. 

Subchronic toxicity: A summary of the prechronic and chronic toxicity and genotoxicity 

databases for spirotetramat is found in Appendix A.2. The thyroid and thymus glands were 

target organs in oral subchronic toxicity studies in the dog. Subchronic (90-day) exposure of 

dogs to spirotetramat was characterized by statistically significant declines in circulating thyroid 
Page 17 of 65 

hormones (T4) at ≥1200 ppm (32 mg/kg bw/day); decreased T3 was observed at the highest dose 

tested only (2500 ppm; 72 mg kg bw/day). However, correlative changes in thyroid weight, 

thyroid histopathology, or thyroid-stimulating hormone (TSH) were not observed in either sex. 

In rats, the testes were the target organ following subchronic oral treatment at a high dose. 

Abnormal spermatozoa and hypospermia in the epididymis, decreased testicular weight, and 

testicular degeneration and vacuolation were observed in males after 90 days of exposure at 

10,000 ppm (616 mg/kg bw/day). These effects proved to be reversible in most animals after 

cessation of treatment. It is noteworthy that the thyroid and thymus were unaffected in rats at 

any dose, while testicular histopathology was unobserved in dogs. No adverse effects of any 

kind were observed in mice following oral exposure. Subchronic exposure of rats by the dermal 

route yielded no evidence of systemic toxicity. 

Long-term toxicity: The thymus and thyroid were also target organs following one-year oral 

exposure of dogs to spirotetramat. Thymus involution and brain dilation with dose-related 

severity were observed in one male each at 600 ppm (20 mg/kg bw/day) and 1800 ppm (55 

mg/kg bw/day). Brain dilation has been observed by veterinary pathologists in up to 5% of 

Beagle dog colonies and is considered a congenital anomaly by Bayer CropScience. Brain 

dilation was not observed in any other study in the dog or in any other species tested with 

spirotetramat. For these reasons, and since brain dilation was also observed sporadically in 

several other Bayer dog studies with other chemicals of varying durations (from four weeks up to 

one year), this observation was considered to be an equivocal effect and not likely treatmentrelated. Declines in circulating thyroid hormone (T4) were observed in males and females at 

≥600 ppm (20 mg/kg bw/day). Reduction in follicle size, a possible indication of a reduced 

amount of colloid in the organ, and decreased T3 levels were observed in 1800-ppm males (55 

mg/kg bw/day) only. Correlative changes in thyroid weight or TSH were not observed in either 

sex. No morphological changes in the testes were observed in dogs at any dose. 

In rats, abnormal sperm or spermatid degeneration in the testes and germ cell exfoliated debris in 

the epididymis were observed in male rats at the high dose only (7500 ppm; 414 or 373 mg/kg 

bw/day) following 12 (not statistically significant) or 24 months of oral exposure. Other target 

organs in rats following exposure for 2 years were the kidney (both sexes) at mid and high doses 

and the liver (females) at the highest dose only. These results are consistent with the excretory 

and/or detoxification roles of the kidney and liver. Similar kidney toxicity was also observed at 

higher doses (419.3 or 484.7 mg/kg bw/day) in parental animals of the F1 generation in the 2-

generation reproductive toxicity study in rats. No adverse findings were observed in mice up to 

the limit dose following long-term treatment with spirotetramat. 

 

Carcinogenicity and 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. 

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 
Page 18 of 65 

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. 

Reproductive Toxicity: 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 (balano-preputial separation, vaginal opening) was unaffected in either study, and no 

treatment-related 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. 

3.2 FQPA Considerations

After review by HED’s Hazard Science Policy Council (HASPOC), the spirotetramat risk 

assessment team recommends that the FQPA SF be reduced to 1X for the following reasons: 

 There was no evidence of increased susceptibility of offspring following pre- or postnatal exposure in any study. In the rat developmental toxicity study, toxicity to offspring 

was observed at the same dose as maternal toxicity, which was also the limit dose. In the 

developmental toxicity study in the rabbit, only maternal toxicity was observed. In both 

reproductive toxicity studies, toxicity to offspring (decreased body weight) was observed 

at the same dose as parental toxicity. Therefore, no evidence of increased susceptibility 

of offspring was found across four relevant toxicity studies with spirotetramat. 

 Spirotetramat does not operate by way of a neurotoxic mechanism of action in target 

pests. 

 Spirotetramat is not considered a neurotoxic chemical in mammals. Clinical signs of 

toxicity and decreased motor activity were observed in adult rats following a single dose 

of spirotetramat in the acute neurotoxicity study in the rat; however, these effects only 

attained statistical significance at high doses and were not observed at the limit dose in 

the acute oral toxicity study in the rat. 

 There is no concern for neurotoxicity with spirotetramat in the developing animal based 

on the fact that brain dilation in the one-year dog study is most likely a congenital 

anomaly (see section 3.1.2) that was not observed in any other study in the database, and 

the fact that the structurally related Bayer compounds spirodiclofen and spiromesifen are 

not neurotoxic in adults or young. 
Page 19 of 65 

 There are no residual uncertainties with respect to exposure data. The dietary food 

exposure assessment utilizes recommended tolerance-level residues and 100% CT 

information for all proposed commodities. By using this screening-level assessment, the 

acute and chronic exposures/risks will not be underestimated. 

 The dietary drinking water assessment (Tier 1 estimates) utilizes values generated by 

model and associated modeling parameters which are designed to provide conservative, 

health-protective, high-end estimates of water concentrations. 

 There are no registered or proposed uses of spirotetramat which would result in 

residential exposure. 

3.3 Hazard Identification and Toxicity Endpoint Selection

3.3.1 Acute Reference Dose (aRfD)

The aRfD for the general population, including females 13-49 years of age, was established 

based on the NOAEL (100 mg/kg/day) from the acute neurotoxicity study in rats. The LOAEL 

of 200 mg/kg/day is based on clinical signs of toxicity in males and females and decreased motor 

activity in males. This study and endpoint are the most appropriate single-dose effects for the 

general population, including women of childbearing age. For reasons outlined in Section 3.2, 

the 10X FQPA SF has been reduced to 1x. 

3.3.2 Chronic Reference Dose (cRfD) 

The cRfD was established based on the NOAEL (5 mg/kg/day) from the 1-year toxicity study in 

the dog. The LOAEL of 20 mg/kg/day is based on thymus involution in males. The NOAEL of 

5 mg/kg is the lowest in the database. In addition, the study duration is appropriate for the 

duration of exposure. For reasons outlined in Section 3.2, the 10X FQPA SF has been reduced to 

1x. 

3.3.3 Incidental Oral Exposure (Short- and Intermediate-Term)

No residential uses are proposed for the current action. Therefore, an endpoint for incidental oral 

exposure was not chosen. 

3.3.4 Dermal Absorption

An in vivo dermal penetration study was performed in the rat using the OD150 formulation. 

Dermal absorption was estimated to be 10%, based on the directly absorbed dose and compound 

remaining at the dose site (including stratum corneum) 168 hrs following a 10-hr exposure. 

Compound retained in the stratum corneum was included in this calculation, because 

radioactivity in the feces increased over the 168-hr time period, which suggested that compound 

measured in the stratum corneum immediately after the 10-hr exposure continued to be absorbed. 

3.3.5 Dermal Exposure (Short- and Intermediate-Term)

There are no registered or proposed residential uses for spirotetramat. The oral developmental 

toxicity study in the rabbit was considered the most relevant study for short- and intermediateterm dermal occupational exposure scenarios, because it is protective of potential exposure to 
Page 20 of 65 

pregnant workers. Dose-dependent systemic toxicity (including body weight loss, decreased 

food consumption, clinical signs of toxicity, abortion) was observed in one dam at the LOAEL of 

40 mg/kg bw/day (NOAEL = 10 mg/kg bw/day). The route of exposure of this study is not ideal 

for these dermal exposure scenarios; however, the NOAEL in this study is protective of potential 

systemic toxicity in pregnant workers. 

3.3.6 Dermal Exposure (Long-Term) 

There are no registered or proposed residential uses for spirotetramat. The 1-year toxicity study 

in the dog was chosen for the long-term dermal occupational exposure scenario. The LOAEL of 

20 mg/kg/day is based on thymus involution in males. The NOAEL of 5 mg/kg is the lowest in 

the database. Although the route of exposure is not ideal, the study duration is ideal for the 

duration of exposure. 

3.3.7 Inhalation Exposure (Short- and Intermediate-Term)

There are no registered or proposed residential uses for spirotetramat. The effects of concern 

that are relevant to the selection of the short- and intermediate-term occupational inhalation 

doses are dose-dependent systemic toxicity (including body weight loss, decreased food 

consumption, clinical signs of toxicity, abortion) observed in one dam at 40 mg/kg bw/day 

(NOAEL = 10 mg/kg bw/day). The route of exposure of this study is not ideal for these 

inhalation exposure scenarios; however, the NOAEL in this study is protective of potential 

toxicity to pregnant workers. 

3.3.8 Inhalation Exposure (Long-Term) 

There are no registered or proposed residential uses for spirotetramat. The 1-year toxicity study 

in the dog was chosen for the long-term inhalation occupational exposure scenario. The LOAEL 

of 20 mg/kg/day is based on thymus involution in males. The NOAEL of 5 mg/kg is the lowest 

in the database. Although the route of exposure is not ideal, the study duration is ideal for the 

duration of exposure. 

3.3.9 Level of Concern for Margin of Exposure

There are no registered or proposed residential uses for spirotetramat. A summary of the levels 

of concern for occupational (worker) exposure is listed in Table 3.3.9. 

Table 3.3.9. Summary of Levels of Concern for Occupational (Worker) Exposure Risk Assessment. 

Route Short-Term (1-30 Days) Intermediate-Term (1-6 Months) Long-Term (>6 Months) 

Dermal 100 100 100 

Inhalation 100 100 100 

3.3.10 Recommendation for Aggregate Exposure Risk Assessments

For oral exposure, dietary and drinking water exposures were combined. For occupational 

exposure dermal and inhalation exposures were combined since the toxicological effects of 

concern are the same and identified from the same study. 
Page 21 of 65 

3.3.11 Classification of Carcinogenic Potential

Spirotetramat was determined to be non-mutagenic in bacteria and mammalian cells, as well as 

non-clastogenic in in vivo mammalian assays. No evidence of carcinogenicity was observed in 

carcinogenicity studies in the rat and mouse. Based on these results, RAB1 toxicologists 

classified spirotetramat as “Not Likely to be Carcinogenic to Humans.” 

3.3.12 Summary of Toxicological Doses and Endpoints for Spirotetramat for Use in 

Human-Health Risk Assessments

Summaries of the toxicological doses and endpoints for spirotetramat for use in dietary/nonoccupational risk assessments and occupational risk assessment are listed below in Tables 

3.3.12a and 3.3.12b, respectively. 

Table 3.3.12a. Summary of Toxicological Doses and Endpoints for Spirotetramat for Use in Dietary Human Health Risk 

Assessments. 

Exposure Scenario Point of 

Departure 

Uncertainty/FQPA 

Safety Factors 

RfD, PAD, LOC for 

Risk Assessment 

Study and Relevant 

Toxicological Effects 

Acute Dietary (General 

Population, including 

Infants and Children) 

NOAEL = 

100 

mg/kg/day 

UFA = 10X 

UFH = 10X 

UFFQPA = 1X 

aRfD = aPAD = 1.0 

mg/kg/day 

Acute neurotoxicity (rat; 

gavage)

LOAEL = 200 mg/kg based on 

clinical signs (M&F) and 

decreased motor activity (M). 

Chronic Dietary (All 

populations) 

NOAEL = 5 

mg/kg/day 

UFA = 10X 

UFH = 10X 

UFFQPA = 1X 

cRfD = cPAD = 0.05 

mg/kg/day1 

Chronic toxicity (dog; dietary)

LOAEL = 20 mg/kg/day (M) 

based on thymus involution.

Cancer (oral, dermal, 

inhalation) 

Classification: “Not Likely to be Carcinogenic to Humans” based on lack of evidence of 

carcinogenicity in two oral rodent carcinogenicity studies.

Abbreviations: UF = uncertainty factor, UFA = extrapolation from animal to human (interspecies), UFH = potential variation in sensitivity among 

members of the human population (intraspecies), UFFQPA = FQPA Safety Factor, NOAEL = no-observed adverse-effect level, LOAEL = lowestobserved adverse-effect level, RfD = reference dose (a = acute, c = chronic), PAD = population-adjusted dose, MOE = margin of exposure, LOC 

= level of concern. 

1

 The cRfD has been harmonized across American (USEPA), Canadian (PMRA), and Austrian (AGES) regulatory agencies. However, it is noted 

that USEPA considered a NOAEL=6 mg/kg/day in males and a NOAEL=19 mg/kg/day in females to more accurately reflect the toxicological 

data. The difference between 5 mg/kg/day (NOAEL in females for PMRA and AGES) and 6 mg/kg/day was considered negligible for risk 

assessment. 

Table 3.3.12b. Summary of Toxicological Doses and Endpoints for Spirotetramat for Use in Occupational Human Health 

Risk Assessments. 

Exposure 

Scenario 

Point of 

Departure 

Uncertainty Factors Level of Concern for Risk 

Assessment 

Study and Toxicological 

Effects 

Dermal 

Short- and 

IntermediateTerm (1-30 

days and 1-6 

months) 

NOAEL = 10 

mg/kg/day 

Dermal 

absorption 

factor = 10% 

UFA = 10X 

UFH = 10X 

Occupational LOC for MOE 

<100 

Prenatal developmental 

toxicity (rabbit) Maternal

LOAEL = 40 mg/kg/day based 

on late abortion (≥GD 22), 

clinical signs, impaired food 

and water consumption and 

body weight loss.

Dermal 

Long-Term (>6 

months) 

NOAEL = 5 

mg/kg/day 

Dermal 

absorption 

factor = 10% 

UFA = 10X 

UFH = 10X 

Occupational LOC for MOE 

<100 

Chronic toxicity (dog; 

dietary) LOAEL = 20 

mg/kg/day (M) based on 

thymus involution.

Inhalation 

Short- and 

IntermediateTerm (1-30 

days and 1-6 

NOAEL = 10 

mg/kg/day 

100% 

inhalation 

UFA = 10X 

UFH = 10X 

Occupational LOC for MOE 

<100 

Prenatal developmental 

toxicity (rabbit) Maternal

LOAEL = 40 mg/kg/day based 

on late abortion (≥GD 22), 

clinical signs, impaired food 
Page 22 of 65 

Table 3.3.12b. Summary of Toxicological Doses and Endpoints for Spirotetramat for Use in Occupational Human Health 

Risk Assessments. 

Exposure 

Scenario 

Point of 

Departure 

Uncertainty Factors Level of Concern for Risk 

Assessment 

Study and Toxicological 

Effects 

months) assumed and water consumption and 

body weight loss. 

Inhalation 

Long-Term (>6 

months) 

NOAEL = 5 

mg/kg/day 

100% 

inhalation 

assumed 

UFA = 10X 

UFH = 10X 

Occupational LOC for MOE 

<100 

Chronic toxicity (dog; 

dietary) LOAEL = 20 

mg/kg/day (M) based on 

thymus involution.

Cancer (oral, 

dermal, 

inhalation) 

Classification: Not likely to be carcinogenic to humans based on lack of evidence of carcinogenicity in two 

oral rodent carcinogenicity studies.

Abbreviations: UF = uncertainty factor, UFA = extrapolation from animal to human (interspecies), UFH = potential variation in sensitivity among 

members of the human population (intraspecies), UFFQPA = FQPA Safety Factor, NOAEL = no-observed adverse-effect level, LOAEL = lowestobserved adverse-effect level, RfD = reference dose (a = acute, c = chronic), LOC = level of concern. 

3.4 Endocrine Disruption 

EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to 

determine whether certain substances (including all pesticide active and other ingredients) “may 

have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, 

or other such endocrine effects as the Administrator may designate.” Following 

recommendations of its Endocrine Disruptor and Testing Advisory Committee (EDSTAC), EPA 

determined that there was a scientific basis for including, as part of the program, the androgen 

and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted 

EDSTAC’s recommendation that the Program include evaluations of potential effects in wildlife. 

For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help 

determine whether a substance may have an effect in humans, FFDCA authority to require the 

wildlife evaluations. As the science develops and resources allow, screening of additional 

hormone systems may be added to the Endocrine Disruptor Screening Program (EDSP). 

When additional appropriate screening and/or testing protocols being considered under the 

Agency’s EDSP have been developed, spirotetramat may be subjected to further screening 

and/or testing to better characterize effects related to endocrine disruption. 

4.0 Public Health and Pesticide Epidemiology Data 

Literature searches performed by the registrant did not yield any epidemiology data for 

spirotetramat. Two cases of Type IV hypersensitivity (facial) were reported and confirmed by 

patch testing in spirotetramat manufacturing plant personnel in 2004. 

5.0 Dietary Exposure/Risk Characterization 

The residue chemistry data submitted in support of the proposed uses were summarized in the 

HED memorandum by G. Kramer (DP# 339694). The drinking water assessment was provided 

by EFED in a memo dated 01/22/08 (J. Meléndez; DP# 345275). The acute and chronic dietary 

exposure assessments were completed in a HED memorandum by G. Kramer (DP# 339710). 
Page 23 of 65 

5.1 Pesticide Metabolism and Environmental Degradation

5.1.1 Metabolism in Primary Crops

The submitted metabolism data for apple, lettuce, cotton and potato are adequate to elucidate the 

nature of the residue in plants. Major metabolic reaction involved the hydrolytic cleavage of the 

carbonate ester parent bond of the parent compound to form BYI 08330-enol. Further reduction 

of the double bond in the tetramic acid moiety of BYI 08330-enol occurred to form the BYI 

08330-mono-hydroxy metabolite. Hydroxylation in the tetramic acid moiety resulted in BYI 

08330-ketohydroxy. Demethylation of the methoxy group of the cyclohexyl ring resulted via a 

proposed intermediate (BYI 08330-desmethyl-enol) in BYI 08330-desmethyl-ketohydroxy (after 

the corresponding hydroxylation). Oxidation of the methoxy group resulted in BYI 08330-

ketohydroxy-formiate. Partly, metabolites bearing a hydroxy group were conjugated with 

glucose. 

5.1.2 Metabolism in Rotational Crops

It appears that two major metabolic routes in rotational crops start with the soil metabolites BYI 

08330-ketohydroxy and BYI 08330-enol. The first metabolic route proceeds by demethylation 

of the cyclohexyl ring or hydroxylation of one methyl group of the xylol ring. Another 

metabolic route starts with the addition of water to the tetramic acid ring of BYI 08330-enol 

resulting in the formation of BYI 08330-di-hydroxy, followed by the demethylation of the 

metabolite. Additionally, hydroxylation of one methyl group of the xylol ring of BYI 08330-

enol followed by demethylation of the cyclohexyl ring results in BYI 08330-desmethyl-enolalcohol, which was detected in all matrices. Most of the metabolites were rapidly conjugated. 

Glucosides and/or glucosyl malonic acid conjugates were detected for BYI 08330-enol, BYI 

08330-desmethyl-di-hydroxy, BYI 08330-desmethyl-ketohydroxy and BYI 08330-ketohydroxyalcohol. The percentage of conjugates increased from the 30-day to the 260-day rotation. 

5.1.3 Metabolism in Livestock 

The submitted goat and poultry metabolism data are adequate to satisfy data requirements. The 

biodegradation of spirotetramat in livestock can be characterized as cleavage of the carbonate 

ester group to the primary metabolite BYI 08330-enol followed by conjugation of the enol 

hydroxy group with glucuronic acid to BYI 08330-enol-GA. Oxidation of the azaspirodecenyl 

moiety to BYI 08330-ketohydroxy and demethylation of the methoxy group to BYI 08330-

desmethyl-enol were minor metabolic reactions in ruminants as well as reduction of the 

azaspirodecenyl moiety to BYI 08330-monohydroxy. 

5.1.4 Analytical Methodology 

The petitioner has submitted several HPLC-MS/MS residue analytical methods for the 

determination of residues of the parent and its metabolites in/on plant and livestock commodities. 

Analytical method 00857 was developed for the determination of residues of spirotetramat, the 

metabolites BYI 08330-enol, BYI 08330-ketohydroxy, BYI 08330-mono-hydroxy and BYI 

08330-enol-Glc in plant matrices by HPLC-MS/MS. The analytical method 00966 was 

developed for the determination of residues of spirotetramat and the metabolites BYI 08330-enol 

and BYI 08330-enol-GA in livestock matrices by HPLC-MS/MS. These methods were used as 
Page 24 of 65 

the data-collection methods in the analysis of samples for residues of concern from the various 

studies associated with the current petition. Each method has been adequately validated by the 

petitioner as well as by independent laboratories. Methods 00857 and 00966 were also 

adequately radiovalidated using weathered samples obtained from metabolism studies. 

HED has determined that Methods 00857 and 00966 are suitable enforcement methods for plant 

and livestock commodities, respectively, since the methods passed a successful PMV by Agency 

chemists at ACL/BEAD (E-mail, C. Stafford to D. Vogel; 2/19/08). 

Spirotetramat and five metabolites BYI 08330-enol, BYI 08330-ketohydroxy, BYI 08330-monohydroxy, BYI 08330-enol-Glc, and BYI 08330-enol-GA were screened through multiresidue 

methods described in the U.S. Food and Drug Administration (FDA) Pesticide Analytical 

Manual, Vol. I (PAM I). The multiresidue methods (MRMs) are not suitable for the analysis of 

spirotetramat or its metabolites. The multiresidue methods testing data will be forwarded to 

FDA for further evaluation and inclusion of results in PAM Vol. I. 

5.1.5 Environmental Degradation

The hydrolysis of spirotetramat is pH and temperature dependent. The rate of reaction increased 

with increasing pH. At 25°C, the experimental half-lives for the chemical were 32.5, 8.6 and 

0.32 days at pHs of 4, 7 and 9, respectively. In addition, hydrolysis rates increased with 

increasing temperature. The major hydrolysate is BYI 08330-enol, which appeared to be stable 

to hydrolysis. Spirotetramat photolyzes with hydrolysis-corrected DT50’s of 3.0 and 0.22 days, 

in sterile buffer (pH 5) solution and natural water (pH 7.9), respectively. These half-lives 

correspond to 14.4 and 0.74 days, respectively, under environmental conditions (summer light in 

Phoenix, AZ). In sterilized natural water the major products observed were BYI 08330-enol 

(81.9% at 1 day), methoxycyclohexanone (17.5% at 8 days) and methoxy-cyclohexylamino 

carboxylic acid (11.3 % at 10 days). In sterile buffer solution (pH 5), four major photoproducts 

(at up to 42.9%) are the result of rearrangement of the parent. Definite conclusions on the rate of 

soil photodegradation could not be derived from the available study. However, useful 

information on the identity of the degradates in the study may be obtained from it. The 

following degradates were identified only in the irradiated samples: methoxycyclohexanone and 

dimethyl-benzoic acid. 

Spirotetramat degraded quickly, with DT50’s of <1 day in four aerobic soils. Furthermore, 

spirotetramat-enol also degraded relatively quickly, with calculated DT50’s of <1 day, in four 

aerobic soils. DT50’s for BYI 08330-ketohydroxy (at a maximum of 24.0% of the applied, 

range of DT50’s 1.5-16.7 days) and spirotetramat-amide (maximum 5.2% of the applied, range 

of DT50’s 0.03-5.4 days) were derived from the study conducted on BYI 08330-enol. Carbon 

dioxide formation was 9.7-19.4% by 50 days in the study conducted with spirotetramat and 10.9-

34.9 by 60 days in the study conducted with BYI 08330-enol. Volatiles were insignificant while 

non-extractable residues were important (both cases). In an outdoor metabolism study 

spirotetramat degraded with calculated DT50’s of 1.2 and 2.9 days. BYI 08330-enol was a 

maximum of 7.8%. The degradates spirotetramat-glyoxylic amide and dimethyl-benzoic acid 

were observed besides the aerobic soil metabolites observed in the laboratory. The latter two 

compounds were also observed in the marginally supplemental soil photodegradation studies. 
Page 25 of 65 

In aquatic environment, under aerobic aquatic conditions, spirotetramat degraded with calculated 

half-lives (DT50’s) of 0.7 and 0.9 days in the total system. Spirotetramat was initially mostly 

associated with the aqueous phase. The metabolite BYI 08330-enol reached a maximum at 14 

days at 99.0%, and decreased to less than the limit of quantitation (<LOQ) to 21.0% at 120 days. 

The degradate BYI 08330-ketohydroxy was a maximum of 50.8% at study termination. It 

appeared to be relatively stable in the aerobic aquatic system. Non-extractable residues 

increased throughout the study to a maximum of 33.9% at 120 days. Mineralization was a 

maximum of 13.5-24.0% at 120 days. 

In the anaerobic soil metabolism study, the metabolites observed were consistent with the ones 

for the aerobic soil metabolism studies for spirotetramat and BYI 08330-enol. Under anaerobic 

soil conditions, spirotetramat dissipated quickly with a calculated half-life of <<1 day. The 

major degradates were BYI 08330-enol, which increased throughout the study (maximum 54.6% 

at 180 days) and BYI 08330-ketohydroxy (maximum 19.3% at 1 day). Mineralization was very 

low. Non-extractable residues were a maximum of 17.5% at 0.6 days. In an anaerobic aquatic 

metabolism system, spirotetramat completely degraded to BYI 08330-enol, which was found to 

be stable thereafter. The half-life for (DT50) the transformation of spirotetramat was calculated 

to be 2.8 days in the total anaerobic system. 

5.1.6 Comparative Metabolic Profile

Spirotetramat was completely metabolized by the rat; no parent compound was detected in the 

excreta. Identified metabolites accounted for 87-95% of the administered dose. Only very minor 

metabolites (<0.7% of the dose) were not identified. The main metabolic reaction was cleavage 

of the ester group which resulted in the formation of the primary and most predominant 

metabolite BYI 08330-enol (53-87% of the administered dose). All other identified metabolites 

could be derived from the enol intermediate. The second prominent metabolic transformation 

was oxidative demethylation of the 8-methoxy group to BYI 08330-desmethyl-enol (5-37% of 

the administered dose). Oxidation of the azaspiro moiety to BYI 08330-ketohydroxy and BYI 

08330-desmethyl-ketohydroxy were detected as minor pathways. Other minor metabolic 

transformations were conjugation of the enol with glucuronic acid to BYI 08330-enol-GA and 

oxidation of the aromatic methyl group of the enol metabolite to BYI 08330-enol-alcohol. A 

sex-related difference was observed in metabolism with male rats showing much higher rates of 

demethylation to BYI 08330-desmethyl-enol compared to female rats. 

The metabolism of spirotetramat in plants and livestock appears to be similar to its metabolism 

in rats. The primary metabolic pathway in animals (rats, goats and hens) and plants involves the 

hydrolytic cleavage of the carbonate ester parent bond of the parent compound to form BYI 

08330-enol. All other identified metabolites are derived from the enol intermediate. 

Hydroxylation in the tetramic acid moiety of BYI 08330-enol resulted in BYI 08330-

ketohydroxy (animals and plants) and oxidative demethylation of the 8-methoxy group to BYI 

08330-desmethyl-enol (animals and plants). Further reduction of the double bond in the teramic 

acid moiety of BYI 08330-enol occurred to form the BYI 08330-mono-hydroxy metabolite 

(ruminants and plants). Conjugation of BYI 08330-enol was also a significant pathway in both 

plants and animals. Minor pathways include hydroxylation of one methyl group of the xylol ring 

of BYI 08330-enol followed by demethylation of the cyclohexyl ring resulting in BYI 08330-

desmethyl-enol-alcohol (rotational crops), oxidation of the methoxy group of BYI 08330-

ketohydroxy resulted in BYI 08330-ketohydroxy-formiate (plants), conjugation with glucose of 
Page 26 of 65 

various metabolites bearing a hydroxy group (plants). 

5.1.7 Toxicity Profile of Major Metabolites and Degradates 

Limited information is available on the toxicity of the major spirotetramat metabolites (BYI 

08330-enol, BYI 08330-ketohydroxy, BYI08330-enol-Glc/GA, and BYI 08330-mono-hydroxy). 

However, based on the structural similarity of the parent and these metabolites, and in the 

absence of toxicological evidence to the contrary, they are assumed to be of comparable toxicity 

to the parent. 

5.1.8 Pesticide Metabolites and Degradates of Concern 

Table 5.1.8. Summary of Metabolites and Degradates to be included in Risk Assessment and Tolerance Expression.

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression 

Plants Primary 

Crop 

Spirotetramat, BYI 08330-enol, BYI 08330-

ketohydroxy, BYI08330-enol-Glc, and BYI 08330-

mono-hydroxy

Spirotetramat, BYI 08330-enol, BYI 

08330-ketohydroxy, BYI08330-enolGlc, and BYI 08330-mono-hydroxy

Rotational 

Crop 

Not Applicable1 Not Applicable1

Livestock (Ruminant and 

Poultry) 

Spirotetramat, BYI 08330-enol, and BYI 08330-enolGA2Spirotetramat and BYI 08330-enol2

Drinking Water Spirotetramat, BYI 08330-enol, and BYI 08330-

ketohydroxy

Not Applicable

1

 The following potential residues of concern were identified in the confined rotational crop study: Spirotetramat, BYI 08330-

ketohydroxy and free and conjugated BYI 08330-desmethyl-ketohydroxy, BYI 08330-desmethyl-di-hydroxy and BYI 08330-

ketohydroxy-alcohol. None of these residues were found in the limited rotational crop field trials at a 30-day PBI. Provided a 30-day PBI 

is specified on the spirotetramat labels, residues in rotational crops are not currently of concern for the risk assessment or for tolerance 

setting. 

2

 If future proposed uses result in significant exposure of livestock to the plant metabolites BYI 08330-ketohydroxy, BYI08330-enol-Glc, 

and BYI 08330-mono-hydroxy, then these metabolites may need to be included as additional residues of concern for livestock 

commodities. 

Plants (Primary Crops): The risk assessment team determined that the residues of concern for 

both tolerance and risk assessment purposes are spirotetramat and its metabolites BYI 08330-

enol, BYI 08330-ketohydroxy, BYI08330-enol-Glc, and BYI 08330-mono-hydroxy. This 

decision was based on the following: 

 BYI 08330-enol was a major metabolite in apple leaves; lettuce; cotton gin trash & seed, 

and in rat tissues and excreta. Based on the structural similarity to the parent, BYI 

08330-enol is assumed to be of comparable toxicity to the parent. 

 BYI 08330-ketohydroxy was a major metabolite in cotton gin trash and lint; and potato 

tops. Also, in the cauliflower field trials, BYI 08330-ketohydroxy (0.32 ppm) accounted 

for >80% of the total spirotetramat residue in some samples. Based on the structural 

similarity to the parent, BYI 08330-ketohydroxy is assumed to be of comparable toxicity 

to the parent. 

 BYI08330-enol-Glc was a major metabolite in lettuce. Also, in the hop field trials, 

BYI08330-enol-Glc (0.79 ppm) accounted for ~20% of the total spirotetramat residue in 

some samples. Based on the structural similarity to the parent, BYI08330-enol-Glc is 

assumed to be of comparable toxicity to the parent. 
Page 27 of 65 

 BYI 08330-mono-hydroxy was a major metabolite in apple fruit. Also, in the plum field 

trials, BYI 08330-mono-hydroxy (0.18 ppm) accounted for >50% of the total 

spirotetramat residue in some samples. Based on the structural similarity to the parent, 

BYI 08330-mono-hydroxy is assumed to be of comparable toxicity to the parent. 

 The data collection method, Method 00857 is a HPLC-MS/MS method for residues of 

spirotetramat, BYI 08330-enol, BYI 08330-ketohydroxy, BYI08330-enol-Glc, and BYI 

08330-mono-hydroxy in crop matrices. The analytes are all determined in a single 

chromatographic analysis. All samples in the crop residue trials were analyzed with this 

method. 

Plants (Rotational Crops): The risk assessment team determined that the residues of concern 

are spirotetramat and its metabolites BYI 08330-ketohydroxy and free and conjugated BYI 

08330-desmethyl-ketohydroxy, BYI 08330-desmethyl-di-hydroxy and BYI 08330-ketohydroxyalcohol. This decision was based on the following: 

 BYI 08330-ketohydroxy was a major metabolite in wheat forage, chard, and turnip roots. 

Based on the structural similarity to the parent, BYI 08330-ketohydroxy is assumed to be 

of comparable toxicity to the parent. 

 BYI 08330-desmethyl-ketohydroxy (conjugated) was a major metabolite in wheat forage, 

hay, and straw; and chard. Based on the structural similarity to the parent, BYI 08330-

desmethyl-ketohydroxy is assumed to be of comparable toxicity to the parent. 

 BYI 08330-desmethyl-di-hydroxy (conjugated) was a major metabolite in wheat straw, 

forage, and hay. Based on the structural similarity to the parent, BYI 08330-desmethyldi-hydroxy is assumed to be of comparable toxicity to the parent. 

 BYI 08330-ketohydroxy-alcohol (conjugated) was a major metabolite in wheat straw, 

hay, and grain; chard, and turnip leaves. Based on the structural similarity to the parent, 

BYI 08330-ketohydroxy-alcohol is assumed to be of comparable toxicity to the parent. 

 The data collection method, Method 00929 is a HPLC-MS/MS method for residues of 

spirotetramat, BYI 08330-ketohydroxy and free and conjugated BYI 08330-desmethylketohydroxy, BYI 08330-desmethyl-di-hydroxy and BYI 08330-ketohydroxy-alcohol in 

crop matrices. The analytes are all determined in a single chromatographic analysis. All 

samples in the limited field rotational crop residue trials were analyzed with this method. 

Livestock: The risk assessment team determined that, based on the currently proposed uses, the 

residues of concern for the tolerance expression for livestock commodities are spirotetramat and 

its metabolite BYI 08330-enol and the residues of concern for the risk assessment for livestock 

commodities are spirotetramat and its metabolites BYI 08330-enol and BYI 08330-enol-GA. 

This decision was based on the following: 

 BYI 08330-enol was a major metabolite in all ruminant commodities and in rat tissues 

and excreta. Based on the structural similarity to the parent, BYI 08330-enol is assumed 

to be of comparable toxicity to the parent. 

 BYI 08330-enol-GA was a major metabolite in ruminant fat, liver, kidney, milk; and 

poultry liver. Based on the structural similarity to the parent, BYI 08330-enol-GA is 

assumed to be of comparable toxicity to the parent. However, as the low dietary burden 

associated with the currently proposed uses is expected to result in non-quantifiable 

residues and BYI 08330-enol can serve as a marker for potential misuse, BYI 08330-

enol-GA does not need to be included in the tolerance expression. 
Page 28 of 65 

 If future proposed uses result in significant exposure of livestock to the plant metabolites 

BYI 08330-ketohydroxy, BYI08330-enol-Glc, and BYI 08330-mono-hydroxy, then these 

metabolites may need to be included as additional residues of concern for livestock 

commodities. 

Drinking Water: The risk assessment team determined that the residues of concern in drinking 

water for risk assessment purposes are spirotetramat, BYI 08330-enol, and BYI 08330-

ketohydroxy. BYI 08330-enol and BYI 08330-ketohydroxy were the major metabolites in the 

aerobic soil outdoor metabolism studies. BYI 08330-MA-amide was excluded as a residue of 

concern since it was never found at a level of >10% of the total residue. 

5.1.9 Drinking Water Residue Profile

All the following appear to be important routes of degradation/transformation for spirotetramat: 

hydrolysis in basic media, photolysis in sterile natural water and biodegradation in aerobic and 

anaerobic environments (DT50s range <1-2.8 days). Hydrolysis in neutral and acidic 

environments and photolysis in sterile buffered solution (half-lives 8.6-32.5 days) appear to be 

routes of transformation of relatively low importance for spirotetramat. Spirotetramat degrades 

to BYI 08330-enol (product of cleavage of the ester link), which also degrades relatively rapidly 

in aerobic environments and under photolytic conditions, and subsequently forms numerous 

degradates most of which have the basic backbone structure of spirotetramat. It appears that the 

metabolites BYI 08330-enol and BYI 08330-ketohydroxy are of high concern in soils, sediments 

and water. The parent spirotetramat appears to be labile in most environments (particularly in 

aerobic media). Total residues (spirotetramat + BYI 08330-enol + BYI 08330-ketohydroxy) 

have a potential to contaminate surface waters for a period of weeks to months post-treatment, 

and a potential to move subsurface and contaminate groundwater. There is also the chance that 

spirotetramat would be deposited off-target by spray drift (the chemical may be applied by 

ground and aerial methods or via airblast). In addition, given the relatively high solubility of 

BYI 08330-enol and BYI 08330-ketohydroxy and their relatively low level of binding, these 

particular transformation products could be released via plant wash-off to soils in large rain 

events, especially if they occur shortly after application. It appears that the residues could reach 

adjacent bodies of water in runoff events both via dissolution or bound to the soils (high levels of 

bound residue were observed in most laboratory studies). 

Since this is a new chemical, there are no monitoring data available. The effects of water 

treatment on the pesticide and degradates is uncertain. Spirotetramat and its metabolites, BYI 

08330-enol, BYI 08330-ketohydroxy and BYI 08330-MA-amide, were highly mobile to 

moderately mobile, and low levels of binding are expected. It appears that spirotetramat 

metabolites BYI 08330-ketohydroxy and BYI 08330-MA-amide are of higher concern because 

the parent degrades relatively fast in most environments. 

EFED provided Tier 1 ground and surface water EDWCs for spirotetramat and its major 

transformation products spirotetramat-enol and spirotetramat-ketohydroxy. The ground and 

surface water EDWCs were generated using SCI-GROW and FIRST, respectively. The ground 

water EDWCs are based on the use of spirotetramat on pome fruit (0.4 lb ai/A/year); and the 

surface water EDWCs are based on the use of spirotetramat on Christmas trees (0.32 lb 

ai/A/year). The total surface water EDWCs (spirotetramat and transformation products of 

concern) are 0.212 ppb (acute) and 1.37x10-3 ppb (chronic). The acute and chronic groundwater 
Page 29 of 65 

EDWC is 3.96x10-4 ppb. Table 5.1.9 lists the summary of estimated ground and surface water 

EDWCs for spirotetramat. 

Table 5.1.9. Summary of Surface Water and Groundwater EDWCs for Spirotetramat. 

Drinking Water 

Source (Model) 

Type of 

Risk 

EDWC (ppb) 

Spirotetramat Spirotetramatenol 

Spirotetramatketohydroxy Maximum Total 

Residues3

Ground-water 

(SCI-GROW)1

Acute and 

Chronic 2.25x10-5 1.64x10-5

3.57x10-4 3.96x10-4 

Surface Water 

(FIRST)2 Acute 0.208 8.0x10-5

3.60x10-3 0.212

Chronic 1.1x10-3 1.7x10-5

2.50x10-4 1.37x10-3 

1

 From the SCI-GROW model. Input parameters are based on application to pome fruit at a rate of 0.4 lb ai/A/year. 2

 From the Tier 1 FIRST model. Input parameters are based on application to Christmas trees at a rate of 0.32 lb ai/A/year. 3

 Total residues = spirotetramat + spirotetramat-enol + spirotetramat-ketohydroxy.

5.1.10 Food Residue Profile

The submitted magnitude of the residue data for the raw agricultural commodities (RACs) of 

citrus, cucurbit vegetables, fruiting vegetables, grapes, hops, leafy Brassica vegetables, leafy 

non-Brassica vegetables, pome fruit, tuberous and corm vegetables, stone fruit, and tree nuts and 

the European residue for strawberries and onions data are adequate. There are adequate storage 

stability data to validate the storage conditions and intervals of samples collected from the field 

trials. 

Acceptable apple, orange, grape, plum, potato, and tomato processing studies are available. The 

processing studies show that following processing of RAC samples bearing quantifiable residues, 

total residues of spirotetramat and its metabolites concentrated in apple wet pomace (1.9X), 

citrus oil (13.5X), raisins (2.6X), prunes (2.2X), potato flakes (3.5X), potato chips (1.2X), 

tomato paste (7.4X) and tomato purée (3.5X). 

An adequate dairy cow feeding study has been submitted; this study is acceptable for 

determining tolerance levels for livestock commodities. Based on the submitted data, HED has 

concluded that the tolerances, expressed as spirotetramat and its metabolite BYI 08330-enol, are 

required for some livestock commodities. As none of the proposed target crops are considered as 

a commodity for poultry feed, data depicting residues in laying hens are not required. 

The Agency’s Guidance for Setting Pesticide Tolerances Based on Field Trial Data was utilized 

for determining appropriate tolerance levels listed in Appendix C. 

5.1.11 International Residue Limits

There are no Codex, Canadian, or Mexican MRLs established for residues of spirotetramat and 

its metabolites in crop or livestock commodities. Harmonization is not an issue at this time. 

5.2 Dietary Exposure and Risk

Spirotetramat acute and chronic dietary exposure assessments were conducted using DEEMFCID, Version 2.03), which incorporates consumption data from USDA’s CSFII, 1994-1996 

and 1998. The 1994-96, 98 data are based on the reported consumption of more than 20,000 
Page 30 of 65 

individuals over two non-consecutive survey days. Foods “as consumed” (e.g., apple pie) are 

linked to EPA-defined food commodities (e.g., apples, peeled fruit - cooked; fresh or N/S; baked; 

or wheat flour - cooked; fresh or N/S, baked) using publicly available recipe translation files 

developed jointly by USDA/ARS and EPA. Consumption data are averaged for the entire U.S. 

population and within population subgroups for chronic exposure assessment, but are retained as 

individual consumption events for acute exposure assessment. Based on analysis of the 1994-96, 

98 CSFII consumption data, which took into account dietary patterns and survey respondents, 

HED concluded that it is most appropriate to report risk for the following population subgroups: 

the general U.S. population, all infants (<1 year old), children 1-2, children 3-5, children 6-12, 

youth 13-19, adults 20-49, females 13-49, and adults 50+ years old. 

For chronic exposure and risk assessment, an estimate of the residue level in each food or foodform (e.g., orange or orange juice) on the food commodity residue list is multiplied by the 

average daily consumption estimate for that food/food form. The resulting residue consumption 

estimate for each food/food-form is summed with the residue consumption estimates for all other 

food/food-forms on the commodity residue list to arrive at the total average estimated exposure. 

Exposure is expressed in mg/kg body weight/day and as a percent of the cPAD. This procedure 

is performed for each population subgroup. 

For acute exposure assessments, individual one-day food consumption data are used on an 

individual-by-individual basis. The reported consumption amounts of each food item can be 

multiplied by a residue point estimate and summed to obtain a total daily pesticide exposure for a 

deterministic exposure assessment, or “matched” in multiple random pairings with residue values 

and then summed in a probabilistic assessment. The resulting distribution of exposures is 

expressed as a percentage of the aPAD on both a user (i.e., those who reported eating relevant 

commodities/food forms) and a per-capita (i.e., those who reported eating the relevant 

commodities as well as those who did not) basis. In accordance with HED policy, per capita 

exposure and risk are reported for all tiers of analysis. However, for Tiers 1 and 2, significant 

differences in user vs. per capita exposure and risk are identified and noted in the risk 

assessment. 

HED’s level of concern is when the exposure is greater than 100% of the PAD. That is, 

estimated exposures above this level are of concern, while estimated exposures at or below this 

level are not of concern. The DEEM-FCIDTM analysis estimates the dietary exposure of the U.S. 

population and 26 population subgroups. The results reported in Table 5.2 are for the U.S. 

population, all infants (<1 year old), children 1-2, children 3-5, children 6-12, youth 13-19, 

females 13-49, males 20-49, and adults 50+ years. 

5.2.1 Acute Dietary Exposure/Risk

The acute analysis assumed 100% CT and tolerance-level residues for all foods. Empirical and 

DEEMTM (ver. 7.81) default processing factors were used for processed commodities. Drinking 

water was incorporated directly in the dietary assessment using the acute concentration for 

surface water generated by the FIRST model. The results of this assessment indicate that the 

acute dietary exposure estimates (95th percentile) are not of concern to HED (<100% of the 

aPAD) for the general U.S. population (4.2% of the aPAD) and all other populations subgroups. 

The most highly exposed population subgroup is children 1-2 years old at 10% of the aPAD. 
Page 31 of 65 

5.2.2 Chronic Dietary Exposure/Risk

A conservative chronic dietary assessment assuming average field-trial residues, empirical and 

DEEMTM (ver. 7.81) default processing factors, and 100% CT was also conducted. Drinking 

water was incorporated directly into the dietary assessment using the chronic concentration for 

surface water generated by the FIRST model. The results of the assessment conclude that the 

chronic dietary exposure estimates are below HED’s level of concern (<100% of the cPAD) for 

the general U.S. population (28% of the cPAD) and all population subgroups. The most highly 

exposed population subgroup is children 1-2 years old at 77% of the cPAD. 

Table 5.2. Summary of Dietary (Food and Drinking Water) Exposure Risk for Spirotetramat. 

Population Subgroup 

Acute Dietary (95th Percentile) Chronic Dietary 

Dietary Exposure 

(mg/kg/day) % aPAD Dietary Exposure 

(mg/kg/day) % cPAD 

General U.S. Population 0.042364 4.2 0.013768 28 

All Infants (<1 year old) 0.081433 8.1 0.019464 39 

Children 1-2 years old 0.102892 10 0.038373 77 

Children 3-5 years old 0.080506 8.1 0.029638 59

Children 6-12 years old 0.050723 5.1 0.018032 36 

Youth 13-19 years old 0.035371 3.5 0.011795 24 

Adults 20-49 years old 0.033504 3.4 0.011145 22 

Adults 50+ years old 0.033253 3.3 0.011139 22 

Females 13-49 years old 0.033564 3.4 0.011180 22 

*The values for the highest exposed population for each type of risk assessment are bolded. 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization 

As there are currently no registered or proposed residential uses for spirotetremat, a residential 

exposure assessment was not conducted. 

6.1 Spray Drift 

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for spirotetramat. 

The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State 

Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices. On a chemical by chemical basis, the Agency is now requiring interim 

mitigation measures for aerial applications that must be placed on product labels/labeling. The 

Agency has completed its evaluation of the new database submitted by the Spray Drift Task 

Force, a membership of U.S. pesticide registrants, and is developing a policy on how to 

appropriately apply the data and the AgDRIFT® computer model to its risk assessments for 
Page 32 of 65 

pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in 

place, the Agency may impose further refinements in spray drift management practices to reduce 

off-target drift with specific products with significant risks associated with drift. 

7.0 Aggregate Risk Assessments and Risk Characterization

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks 

from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure. 

For spirotetramat, aggregate exposure risk assessments were performed for the following 

scenarios: acute aggregate exposure (food and drinking water), and chronic aggregate exposure 

(food and drinking water). Short- and intermediate-term assessments, which are used to evaluate 

aggregate dietary and residential exposures, were not performed because there are no registered 

or proposed residential non-food uses. Spirotetramat is classified as “Not Likely to be 

Carcinogenic to Humans;” therefore, cancer aggregate risk assessments were not performed. 

 

7.1 Acute Aggregate Risk 

The acute aggregate risk assessment takes into account exposure estimates from dietary 

consumption of spirotetremat (food and drinking water). The acute dietary exposure estimates 

are not of concern to HED (<100% aPAD) at the 95th exposure percentile for the general U.S. 

population and all other population subgroups (see Table 5.2). The dietary exposure assessment 

was a screening-level assessment, utilizing tolerance-level residues and 100% CT information 

for all proposed agricultural uses and a Tier 1 acute surface water EDWCs generated by FIRST. 

Therefore, the acute aggregate risk associated with the proposed uses of spirotetramat is not of 

concern to HED for the general U.S. population or any population subgroups.

7.2 Chronic Aggregate Risk

The chronic aggregate risk assessment takes into account average exposure estimates from 

dietary consumption of spirotetramat (food and drinking water). The chronic dietary exposure 

estimates are not of concern to HED (<100% cPAD) for the general U.S. population and all 

population subgroups (see Table 5.2). The dietary exposure assessment was a conservative 

assessment, utilizing average field-trial residues and 100% CT information for all proposed 

agricultural uses and a Tier 1 chronic surface water EDWCs generated by FIRST. Therefore, the 

chronic aggregate risk associated with the proposed uses of spirotetramat is not of concern to 

HED for the general U.S. population or any population subgroups. 

8.0 Cumulative Risk Characterization/Assessment

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to spirotetramat and any other substances and spirotetramat does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 
Page 33 of 65 

EPA has not assumed that spirotetramat has a common mechanism of toxicity with other 

substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Pathway

An occupational exposure assessment was provided in a HED memorandum dated 3/13/08 (K. 

Lowe; DP# 338101). Based on the proposed use patterns, occupational handler and postapplication exposure to spirotetramat is expected. 

9.1 Short- and Intermediate-Term Handler Risk

The proposed use patterns indicate that the most highly-exposed occupational pesticide handlers 

are likely to be mixer/loaders of liquids for aerial applications, applicators using airblast 

equipment, and mixers/loaders/applicators of liquid concentrates using a high-pressure 

handwand. 

As no chemical-specific data were available with which to assess potential exposure of 

spirotetramat to pesticide handlers, the estimates of exposure to pesticide handlers are based 

upon surrogate study data available in the PHED Surrogate Exposure Guide (August 1998). For 

pesticide handlers, it is HED standard practice to present estimates of dermal exposure for 

“baseline;” that is, for workers wearing a single layer of work clothing consisting of a longsleeved shirt, long pants, shoes plus socks and no protective gloves, as well as for “baseline” and 

the use of protective gloves or other personal protective equipment (PPE) as might be necessary. 

The proposed product labels direct applicators and other handlers to wear a long-sleeved shirt, 

long pants, socks, shoes, chemical-resistant gloves and protective eyewear. 

HED believes most exposure durations will be short-term (1-30 days). However, HED’s Science 

Advisory Council for Exposure (ExpoSAC) maintains it is possible for commercial applicators to 

be exposed to intermediate-term exposure durations (1-6 months). In addition, the short- and 

intermediate-term toxicological endpoints are the same; therefore, the estimates of risk for shortterm duration exposures are protective of those for intermediate-term duration exposures. Longterm exposures are not expected; therefore, a long-term assessment was not conducted. 

Table 9.1 presents the exposure/risks for short and intermediate-term dermal and inhalation 

exposures at baseline and with gloves. A MOE of 100 is adequate to protect occupational 

pesticide handlers. HED has determined that risks are not of concern (i.e., MOEs >100), 

provided workers wear protective gloves as recommended on the label. 
Page 34 of 65 

Table 9.1. Occupational Handler Dermal and Inhalation Exposures and Risks. 

Dermal and 

Inhalation Unit 

Exposures 

(mg/lb ai) 

Application 

rate 

(lb ai/A)a

Area 

Treated 

Daily (A)b 

Short- and 

Intermediate-term 

Doses (mg/kg/day)c 

Short- and 

Intermediate-term 

MOEsd

Combined Short- and 

Intermediate-term 

MOEsi

Mixer/Loader – Aerial Application 

Dermal

Baselinee: 2.9 (HC)h 

Single layer w/glovesg

: 

0.023 (HC) 

Inhalation

Baselinef

: 0.0012 (HC) 

0.16 350 

Dermal

Baseline: 0.27 

Single layer w/gloves: 

0.0021 

Dermal

Baseline: 37 

Single layer w/gloves: 

4700 

Baseline: 37 

Single layer w/gloves: 

3100 Inhalation

Baseline: 0.0011 

Inhalation

Baseline: 8,900 

Applicator –Airblast Application 

Dermal

Baseline: 0.36 (HC) 

Single layer w/glovesg

: 

0.24 

Inhalation

Baseline: 0.0045 (HC) 

0.16 40 

Dermal

Baseline: 0.0038 

Single layer w/gloves: 

0.0026 

Dermal

Baseline: 2,600 

Single layer w/gloves: 

3900 

Baseline: 2,300 

Single layer w/gloves: 

3,200 Inhalation

Baseline: 0.00048 

Inhalation

Baseline: 21,000 

Mixer/Loader – High Pressure Handwand 

Dermal

Baseline: No Data 

Single layer w/glovesg

: 2.5 

(LC) 

Inhalation

Baseline: 0.12 (LC) 

0.00125 lb 

ai/gallon 

1000 

gallons 

Dermal

Single layer w/gloves: 

0.0052 

Dermal

Single layer w/gloves: 

1,900 

Single layer w/gloves: 

1300 

Inhalation

Baseline: 0.0025 

Inhalation

Baseline: 4,000 

a Application rates are the maximum recommended rates provided on the spirotetramat product labels. 

b Area treated per day and amount handled values are HED estimates based on ExpoSAC Policy #9 “Standard Values for Daily Acres 

Treated in Agriculture,” industry sources, and HED estimates. 

c Dose (mg/kg/day) = Unit exposure(mg/lb ai) x App Rate (lb ai/acre or lb ai/gallon) x Area Treated/Amount Handled 

(acres/day or gallons/day) x %Absorption (10% dermal and 100% inhalation assumed) / Body weight (60 kg). 

d MOE = NOAEL/Dose; where the short- and intermediate-term dermal and inhalation NOAEL = 10 mg/kg/day . 

e Baseline Dermal: Long-sleeve shirt, long pants, and no gloves. 

f Baseline Inhalation: no respirator. 

g Single layer w/gloves: Single layer baseline attire plus chemical-resistant gloves. 

h Data Confidence for PHED unit exposures: LC = Low Confidence, MC = Medium Confidence, HC = High Confidence. 

i. Combined MOE = NOAEL / (dermal + inhalation daily dose). 

9.2 Short-Term Post-application Risk

HED expects that post-application exposure will occur since spirotetramat is applied as a foliar 

spray. Since no post-application data were submitted in support of this registration action, 

exposures during post-application activities were estimated using dermal TCs from HED’s 

ExpoSAC Policy Number 3.1 “Agricultural Transfer Coefficients” (August, 2000). 

The activities with the highest (i.e., most conservative) TCs related to the proposed uses were 

tying (cane turning), turning (cane turning), and girdling grapes (with an application rate of 

0.125 lb ai/A and a high TC of 10,000 cm2/hr); and hand-harvesting, skating, topping and 
Page 35 of 65 

training Christmas trees (with an application rate of 0.16 lb ai/A and a high TC of 8,000 cm2

/hr). 

In addition, the following assumptions were used in the calculations: 

Assumptions: 

• Exposure Duration = 8 hours per day 

• Body Weight = 60 kg 

• Dermal Absorption = 10% 

• Fraction of ai retained on foliage = assumed to be 20% on day zero (= % dislodgeable 

foliar residue, DFR, after initial treatment). This fraction is assumed to further dissipate at the rate of 10% 

per day on following days. These are default values established by ExpoSAC. 

Daily dermal exposures were calculated on each post-application day after application using the following equation: 

DE(t) (mg/day) = (TR(t) (μg/cm2

) x TC (cm2/hr) x Hr/Day)/1000 (μg/mg) 

Where: 

DE(t) = Daily exposure or amount deposited on the surface of the skin at time (t) attributable for 

activity in a previously treated area, also referred to as potential dose (mg ai/day); 

 TR(t) = Transferable residues that can be dislodgeable foliar residue at time “t” (μg/cm2

); 

 TC = Transfer Coefficient (cm2

/hour); and 

 Hr/day = Exposure duration meant to represent a typical workday (8 hours). 

Note that the (TR(t)) input may represent levels on the day of application in the case of short-term risk calculations. 

Once daily exposures are calculated, the calculation of daily absorbed dose and the resulting MOEs use the same 

algorithms that are described above for the handler exposures. These calculations are completed for each day or 

appropriate block of time after application. 

HED has determined that risks are not of concern (i.e., MOEs >100) on the day of treatment (i.e., 

Day 0) for all post-application exposure activities. Table 9.2 presents a summary of occupational 

short-and intermediate-term post-application risks associated with the proposed uses of 

spirotetramat. 

Table 9.2. Summary of Occupational Post-application Risks for Spirotetramat. 

Crop 

Grouping 

Application rate 

(lb ai/A) TC (μg/cm2

) Day after 

Treatment

Short- and Intermediate-term 

MOE at Day 0 

(Level of Concern = 100) 

Vine / trellis 0.125 10,000 (Tying (Cane turning); 

Turning (Cane turning); Girdling) 0 

(12 hours)

270 

Tree, "fruit", 

evergreen 

0.16 8,000 (Hand-harvest; Staking; 

Topping; Training) 260 

Spirotetramat is classified as Toxicity Category III for acute oral and acute dermal; Toxicity 

Category II for primary eye irritation; and as Toxicity Category IV for acute inhalation and 

primary dermal irritation. It is a positive dermal sensitizer. Therefore, while an assessment of 

systemic toxicity from post-application exposure would indicate acceptable MOEs on the day of 

treatment, the acute toxicity categories for this chemical require a 24-hour REI under the WPS. 

HED recommends that all spirotetramat labels have a 24-hour REI. The proposed end-use 

labels specify a 12-hour REI. The labels should be revised to include a 24-hour REI. 
Page 36 of 65 

10.0 Data Needs and Label Recommendations

10.1 Toxicology

 None. 

10.2 Residue Chemistry

860.1200 Directions for Use

 The labels should be amended to specify a 30-day PBI for all non-labeled crops. 

860.1650 Submittal of Analytical Reference Standards

 Analytical standards for the metabolites of spirotetramat are currently not available in the 

National Pesticide Standards Repository [Source: personal communication with D. 

Wright Jr. of ACL/BEAD, 11/2/2007]. Analytical reference standards (both technicalgrade and isotopically labeled) of BYI 08330-enol, BYI 08330-ketohydroxy, BYI 08330-

mono-hydroxy, and BYI 08330-enol-Glc should be supplied, and supplies replenished as 

requested by the Repository. 

860.1550 Proposed Tolerances

 The petitioner is requested to submit a revised Section F specifying the following: 

o The tolerance expression for plant commodities should be revised to include the 

combined residues of spirotetramat and its metabolites BYI 08330-enol, BYI 

08330-ketohydroxy, BYI08330-enol-Glc, and BYI 08330-mono-hydroxy, 

expressed as spirotetramat equivalents. 

o Revised tolerance levels and commodity definitions presented in Appendix C. 

10.3 Occupational Exposure

 Based on the acute toxicity categories for this chemical, 24-hour REI is needed under the 

Worker Protection Standard. As the proposed end-use labels specify a 12-hour REI, the 

labels should be revised to include a 24-hour REI.
Page 37 of 65 

Appendix A. Toxicology Assessment 

A.1. Toxicology Data Requirements

The requirements (40 CFR 158.340) for the use of spirotetramat on food at the time of data submission are listed in 

Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used. 

Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity ....................................................... 

870.1200 Acute Dermal Toxicity .................................................. 

870.1300 Acute Inhalation Toxicity .............................................. 

870.2400 Primary Eye Irritation .................................................... 

870.2500 Primary Dermal Irritation .............................................. 

870.2600 Dermal Sensitization...................................................... 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

870.3100 Oral Subchronic (rodent) ............................................... 

870.3150 Oral Subchronic (nonrodent) ......................................... 

870.3200 21-Day Dermal .............................................................. 

870.3250 90-Day Dermal .............................................................. 

870.3465 90-Day Inhalation .......................................................... 

yes 

yes 

yes 

no 

no 

yes 

yes 

yes 

- 

- 

870.3700a Developmental Toxicity (rodent) ................................... 

870.3700b Developmental Toxicity (nonrodent)............................. 

870.3800 Reproduction ................................................................. 

yes 

yes 

yes 

yes 

yes 

yes 

870.4100a Chronic Toxicity (rodent) .............................................. 

870.4100b Chronic Toxicity (nonrodent) ........................................ 

870.4200a Oncogenicity (rat) .......................................................... 

870.4200b Oncogenicity (mouse) .................................................... 

870.4300 Chronic/Oncogenicity .................................................... 

yes 

yes 

yes 

yes 

no 

yes 

yes 

yes 

yes 

- 

870.5100 Mutagenicity—Gene Mutation - bacterial ..................... 

870.5300 Mutagenicity—Gene Mutation - mammalian ................ 

870.5xxx Mutagenicity—Structural Chromosomal Aberrations ... 

870.5xxx Mutagenicity—Other Genotoxic Effects ....................... 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

870.6100a Acute Delayed Neurotox. (hen) ..................................... 

870.6100b 90-Day Neurotoxicity (hen) ........................................... 

870.6200a Acute Neurotox. Screening Battery (rat) ....................... 

870.6200b 90-Day Neuro. Screening Battery (rat) .......................... 

870.6300 Develop. Neuro .............................................................. 

no 

no 

yes 

no 

no 

- 

- 

yes 

- 

- 

870.7485 General Metabolism ...................................................... 

870.7600 Dermal Penetration ........................................................ 

yes 

yes 

yes 

yes 
Page 38 of 65 

A.2. Toxicity Profiles

Table A.2.1 Acute Toxicity Profile – Spirotetramat Technical 

Guideline No. Study Type MRID(s) Results Toxicity Category 

870.1100 Acute oral (rat) 46904527 LD50 >2000 

mg/kg (F) 

III 

870.1200 Acute dermal (rat) 46904529 LD50 >2000 

mg/kg (M&F) 

III 

870.1300 Acute inhalation (rat) 46904530 LC50 >4.183 mg/L 

(M&F) 

IV 

870.2400 Primary eye irritation (rabbit) 46904531 Corneal opacity 

and iritis (grade 

1); cleared by day 

8 

II 

870.2500 Primary dermal irritation (rabbit) 46904532 Negative IV 

870.2600 Dermal sensitization (mouse) 46904565 Positive (LLNA) N/A 
Page 39 of 65 

Table A.2.2 Subchronic and Chronic Toxicity and Genotoxicity Profile – Spirotetramat 

Technical

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3100 28-Day oral 

toxicity (mouse) 

46904536 (2001) 

Acceptable/non-guideline 

0, 500 or 5000 ppm 

(equivalent to 0, 136.5 or 

1415 mg/kg bw/day [M]) 

NOAEL = 5000 ppm (1415 mg/kg/day [M]). 

LOAEL not observed. 

870.3100 90-Day oral 

toxicity (mouse) 

46904539 (2005) 

Acceptable/guideline 

0, 70, 350, 1700, or 7000 

ppm (equivalent to 0/0, 

12.8/16, 59.6/72.4, 

300/389 or 1305/1515 

mg/kg bw/day [M/F]) 

NOAEL = 7000 ppm (1305/1515 mg/kg/day

[M/F]). 

LOAEL not observed. 

870.3100 28-Day oral 

toxicity (rat) 

46904537 (1998) 

Acceptable/non-guideline 

0, 500 or 5000 ppm 

(equivalent to 0, 47.3 or 

501.8 mg/kg bw/day [F]) 

NOAEL = 5000 ppm (501.8 mg/kg/day [F]). 

LOAEL not observed. 

870.3100 90-Day oral 

toxicity (rat) 

46904538 (2005) 

Acceptable/guideline 

0, 150, 600, 2500, or 

10000 ppm (equivalent to 

0/0, 9/11, 26/46, 148/188 

or 616/752 mg/kg bw/day 

[M/F]) 

NOAEL = 2500 ppm (148/188 mg/kg/day 

[M/F]). 

LOAEL = 10000 ppm (616/752 mg/kg/day 

[M/F]), based on decreased body weight, 

abnormal spermatozoa and hypospermia in the 

epididymis, decreased testicular weight, and 

testicular degeneration and vacuolation in 

males; and alveolar macrophages in both sexes. 

870.3150 28-Day oral 

toxicity (dog) 

46904572 (2004) 

Acceptable/non-guideline 

0, 100, 400, 1600, or 6400 

ppm (equivalent to 0/0, 

3/3, 13/12, 42/70, or 

104/127 mg/kg/day 

[M/F]) 

NOAEL = 1600 ppm (42/70 mg/kg/day [M/F]). 

LOAEL = 6400 ppm (104/127 mg/kg/day 

[M/F]) based on decreased thymus size and 

weight as well as decreased body weight and 

food consumption, which resulted in 

emaciation. 

870.3150 90-Day oral 

toxicity (dog) 

46904541 (2005) 

Acceptable/guideline 

0, 150, 300, 1200, or 

4000/2500 ppm 

(equivalent to 0/0, 5/6, 

9/10, 33/32, or 81/72 

mg/kg bw/day) 

NOAEL = 1200 (32 mg/kg/day)[F] & 2500 

ppm (81 mg/kg/day)[M]. 

LOAEL = 2500 ppm (72 mg/kg/day)[F] based 

on decreased body-weight gain and food 

consumption, depressed RBC parameters (red 

blood cell count, hemoglobin level and 

hematocrit), and thymus atrophy. 
Page 40 of 65 

870.3200 28-Day dermal 

toxicity (rat) 

46904542 (2006) 

Acceptable/guideline 

0, 100, 300, or 

1000 mg/kg bw/day (limit 

dose) 

NOAEL = 1000 mg/kg/day. 

LOAEL not established. 

870.3700a Prenatal 

developmental (rat) 

46904543 (2004) 

Acceptable/guideline 

0, 20, 140, or 1000 mg/kg 

bw/day 

Maternal NOAEL = 140 mg/kg/day. 

LOAEL = 1000 mg/kg/day based on impaired 

food consumption, transient body weight loss, 

impaired body-weight gain, and reduced final 

body weight. 

Developmental NOAEL = 140 mg/kg/day. 

LOAEL = 1000 mg/kg/day based on reduced 

fetal weight and increased incidences of 

malformations and skeletal variations. 

870.3700b Prenatal 

developmental 

(rabbit) 

46904544 (2004) 

Acceptable/guideline 

0, 10, 40 or 160 mg/kg 

bw/day 

Maternal NOAEL = 10 mg/kg/day. 

LOAEL = 40 mg/kg/day based on late abortion 

(≥GD 22), clinical signs, impaired food and 

water consumption and body weight loss. 

Developmental NOAEL = 160 mg/kg/day. 

LOAEL not observed. 

870.3800 1-gen. reproduction 

and fertility effects 

(rat) – range 

finding 

46904571 (2006) 

Acceptable/non-guideline 

0, 200, 500, 6000 or 

10000 ppm (equivalent to 

0/0, 10.5/12.8, 27.8/31.4, 

320.1/384.1, or 

537.9/645.7 mg/kg 

bw/day [M/F]) 

Parental/Systemic NOAEL = 500 ppm (27.8 

and 31.4 mg/kg bw/day [M/F]). 

LOAEL =6,000 ppm (320.1 and 384.1 mg/kg 

bw/day [M/F]) based on decreased body-weight 

gain (P females) and terminal body weight (F1

males). 

Reproductive NOAEL = 500 ppm (27.8 mg/kg 

bw/day [M]) and 10,000 ppm (645.7 

mg/kg/day) [F]. 

LOAEL = 6,000 ppm (320.1 mg/kg bw/day 

[M]) based on decreased sperm motility and 

progression and increased abnormal sperm cells 

in the F1 males. 

Offspring NOAEL = 500 ppm (27.8 and 31.4 

mg/kg bw/day [M/F]). 

LOAEL = 6,000 ppm (320.1 and 384.1 mg/kg 

bw/day [M/F]) based on decreased body weight 

and body-weight gain during lactation in F1

pups. 
Page 41 of 65 

870.3800 2-gen. reproduction 

and fertility effects 

(rat) 

46904546 (2006) 

Acceptable/guideline 

0, 250, 1,000 or 6,000 

ppm (equivalent to 0/0, 

17.2/20, 70.7/82.5 or 

419.3/484.7 mg/kg 

bw/day [M/F]) 

Parental/Systemic NOAEL = 1000 ppm 

(70.7/82.5 mg/kg/day [M/F]). 

LOAEL = 6000 ppm (419.3/484.7 mg/kg/day 

[M/F]) based on decreases in body weight (F1

males and females), weight gain (P males, F1

males and females), and food consumption 

during lactation (P- and F1-generation females); 

and kidney histopathology and decreased 

kidney weights (F1 males and females). 

Reproductive NOAEL = 1000 ppm (70.7 

mg/kg/day)[M] & 6000 ppm (484.7 

mg/kg/day)[F]. 

LOAEL = 6000 ppm (419.3 mg/kg/day)[M] 

based on abnormal sperm cells and decreased 

reproductive performance in the F1 males. 

Offspring NOAEL = 1000 ppm (70.7/82.5 

mg/kg/day [M/F]). 

LOAEL = 6000 ppm (419.3/484.7 mg/kg/day 

[M/F]) based on decreased body weight and 

body-weight gain during lactation in both F1

and F2 generations. 

870.4100 Chronic toxicity (1 

year; dog) 

46904548 (2006) 

Acceptable/guideline 

0, 200, 600 or 1800 ppm 

(equivalent to 0/0, 6/5, 

20/19, or 55/48 mg/kg/day 

[M/F]) 

NOAEL = 200 ppm (6 mg/kg/day)[M] & 1800 

ppm (48 mg/kg/day)[F]. 

LOAEL = 600 ppm (20 mg/kg/day)[M] based 

on thymus involution [M] and not observed 

[F].. 

870.4100 Chronic toxicity 

(1 year; rat) 

46904547 (2005) 

Acceptable/guideline 

0, 250, 3500, or 

7500/12000 ppm (M/F) 

(equivalent to 0/0, 

13.2/18, 189/255, or 

414/890 mg/kg bw/day 

[M/F]) 

NOAEL = 250 ppm (13.2 mg/kg/day)[M] & 

3500 ppm (255 mg/kg/day)[F]. 

LOAEL = 3500 ppm (189 mg/kg/day)[M] 

based on dose-dependent increase in alveolar 

macrophages; & 12000 ppm (890 

mg/kg/day)[F] based on decreased body weight 

and body-weight gain, alveolar macrophages, 

discoloration of the lung, and yellow/brown 

staining of the perigenital area and tail. 

870.4200 Carcinogenicity 

(rat) 

46904549 (2006) 

Acceptable/guideline 

0, 250, 3500, or 

7500/12000 ppm (M/F) 

(equivalent to 0/0, 

12.5/16.8, 169/229, or 

373/823 mg/kg bw/day 

[M/F]) 

NOAEL = 250 ppm (12.5/16.8 mg/kg/day 

[M/F]). 

LOAEL = 3500 ppm (169/229 mg/kg/day 

[M/F]) based on decreased kidney weight and 

renal tubular dilation. 

No evidence of carcinogenicity. 

870.4200 Carcinogenicity 

(mouse) 

46904550 (2006) 

Acceptable/guideline 

0, 70, 1700 or 7000/6000 

ppm (M/F) (equivalent to 

0/0, 10.9/13.7, 263/331, or 

1022/1319 mg/kg/day 

[M/F]) 

NOAEL = 7000/6000 ppm (1022/1319 

mg/kg/day [M/F]). 

LOAEL not observed. 

No evidence of carcinogenicity. 
Page 42 of 65 

870.5100 Bacterial Gene 

Mutation 

46904551 (2006) 

Acceptable/guideline 

0, 16, 50, 158, 500, 1581 

or 5000 μg/plate +/- S9 

activation 

Negative. 

870.5100 Bacterial Gene 

Mutation 

46904552 (2002) 

Acceptable/guideline 

0, 16, 50, 158, 500, 1581 

or 5000 μg/plate +/- S9 

activation 

Negative. 

870.5300 Mammalian Gene 

Mutation 

46904553 (2002) 

Acceptable/guideline 

0, 2.5, 5, 10, 20, 30, 40, 

50, 60, 70, or 80 g/mL (-

S9) 

0, 20, 40, 60, 80, 92, 100, 

108, 116, 120, 124, 132, 

or 140 g/mL (+S9) 

Negative. 

870.5375 In vitro mammalian 

chromosome 

aberration 

46904554 (2002) 

Acceptable/guideline 

0, 10, 12, 24, 30, 48, or 50 

μg/mL (-S9) 

0, 20, 40 or 80 μg/mL 

(+S9) 

Weakly clastogenic at cytotoxic concentrations 

only. 

870.5375 In vitro mammalian 

chromosome 

aberration 

46904555 (2003) 

Unacceptable/guideline 

0, 30, 50, 70, 90 or 110 

μg/mL (-S9) 

0, 40, 60, 80, 100 or 120 

μg/mL (+S9) 

N/A 

870.5395 In vivo erythrocyte 

micronucleus assay 

(mouse) 

46904556 (2002) 

Acceptable/guideline 

0, 125, 250, or 500 mg/kg 

bw 

Negative. 

870.5385 In vivo bone 

marrow 

chromosomal 

aberration assay 

(mouse) 

46904558 (2003) 

Acceptable/guideline 

0, 125, 250 or 500 mg/kg 

bw 

Negative. 

870.5550 In vivo/in vitro

UDS assay (rat 

hepatocytes) 

46904557 (2003) 

Acceptable/guideline 

0, 1000, or 2000 mg/kg 

bw 

Negative. 
Page 43 of 65 

870.6200a Acute neurotoxicity 

screening battery 

46904560 (2005) 

Acceptable/guideline 

0, 50, 100, 200, 500 or 

2000 mg/kg bw 

NOAEL = 100 mg/kg/day. 

LOAEL = 200 mg/kg/day based on clinical 

signs (males and females) and decreased motor 

activity (males). 

870.7485 Metabolism and 

pharmacokinetics 

(rat) 

46904504 (2006) 

Acceptable/guideline 

2 or 100 mg/kg bw 

(single) 

2 mg/kg bw (repeat) 

Absorption: 89-98% after 48 hrs (no significant 

differences among low dose, high dose, and 

repeated dose tests). 

Distribution: AUC0-∞ (measure of systemic 

exposure) slightly higher for males than 

females; <0.2% of administered dose detected 

in body 48 hrs after sacrifice; highest 

equivalent concentrations detected in liver and 

kidney. 

Metabolism: parent compound undetected in 

urine and feces of all tests; main metabolic 

reaction was cleavage of the ester group which 

resulted in formation of the primary metabolite 

BYI 08330-enol (53-87% of administered 

dose); all other identified metabolites could be 

derived from enol; male rats exhibited much 

higher rates of demethylation of BYI 08330-

enol to BYI 08330-desmethyl-enol (25-37%) 

vs. females rats (5-10 %). 

Excretion: 88-95% of administered dose 

eliminated via urine and 2-11% via feces within 

48 hrs. 

870.7485 Metabolism and 

pharmacokinetics 

(rat) 

46904561 (2006) 

Acceptable/guideline 

2 or 1000 mg/kg bw 

(single) 

At 1000 mg/kg bw: Absorption and excretion 

less than low dose, with 27% of dose excreted 

in urine after 24 hours (18% in feces); plasma 

radioactivity slightly higher than in liver and 

kidney; these results are consistent with 

saturation of cellular transport mechanisms. 

Tissue radioactivity decreased from 1 h to 24 h 

post dose. Metabolism profile qualitatively 

similar to that of the low dose; BYI 08330-enol 

was most prominent metabolite; similar to low 

dose group, BYI 08330-desmethyl-enol levels 

greater in urine than in plasma and organs. 

870.7600 In vivo dermal 

penetration 

(rat) 

46904563 (2006) 

Acceptable/guideline 

100, 15, or 5 μg ai/cm2

(OD150 formulation) 

Dermal absorption = 10%. 

Special 

study 

Male reproductive 

toxicity 

46904569 (2005) 

Acceptable/non-guideline 

1000 mg/kg bw/day (3, 

10, 21 or 41 days) 

Primary testicular effects on or after day 10 

were degeneration of round and elongating 

spermatids (stage 7-8 and 9-14, respectively), 

decreased sperm count, and increased numbers 

of aberrant/abnormal spermatozoa in the 

epididymis. 
Page 44 of 65 

Table A.2.3 USEPA Toxicity Profile – Metabolites

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

Exploratory 

study

10-day gavage 

(enol metabolite) 46904601 (2006) 

Acceptable/non-guideline 

800 mg/kg bw/day 

Decreased BWG; histopathology not evaluated. 

Special 

study

21-day gavage 

(enol metabolite) 47070901 (2006) 

Acceptable/non-guideline 

800 mg/kg bw/day 

Clinical signs of toxicity, decreased BWG, 

Testicular/spermatotoxicity. 

870.5100 Bacterial Gene 

Mutation 

(ketohydroxy 

metabolite) 

46904594 (2005) 

Acceptable/guideline 

0, 16, 50, 158, 500, 1581 

or 5000 μg/plate +/- S9 

activation 

Negative. 

870.7485 Metabolism and 

Pharmacokinetics 

(rat) 

(ketohydroxy 

metabolite) 

46904595 (2006) 

Acceptable/guideline 

2 mg/kg bw (single) 

Absorption: ≥55% after 48 hrs. 

Distribution: highest concentrations detected in 

GI, liver, and kidney; <0.2% of administered 

dose detected in body 48 hrs post dose. 

Metabolism: parent compound undetected in 

urine and trace amounts in feces; main 

metabolic reaction was oxidative demethylation 

of cyclohexyl-O-methyl group to form 

desmethyl-ketohydroxy metabolite (15% of 

administered dose); all other identified 

metabolites could be derived from desmethylketohydroxy metabolite. 

Excretion: 54% of administered dose 

eliminated via urine and 44% via feces within 

48 hrs. 

870.5100 Bacterial Gene 

Mutation 

(desmethylketohydroxy 

metabolite) 

46904597 (2006) 

Acceptable/guideline 

0, 16, 50, 158, 500, 1581 

or 5000 μg/plate +/- S9 

activation 

Negative. 

870.5100 Bacterial Gene 

Mutation 

(dihydroxy 

metabolite) 

46904599 (2005) 

Acceptable/guideline 

0, 16, 50, 158, 500, 1581 

or 5000 μg/plate +/- S9 

activation 

Negative. 
Page 45 of 65 

Table A.2.3 USEPA Toxicity Profile – Metabolites

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.7485 Metabolism and 

Pharmacokinetics 

(rat) 

(enol glucoside 

metabolite) 

46904602 (2006) 

Acceptable/non-guideline 

0.1 mg/kg bw (single; 1 

rat) 

Absorption: 54% after 48 hrs. 

Distribution: plasma concentrations peaked 4 

hrs post dose; 1% of administered dose 

detected in body 48 hrs post dose. 

Metabolism: parent compound detected in feces 

(21%); main metabolite was enol (64% of 

administered dose). 

Excretion: 53% of administered dose 

eliminated via urine and 44% via feces within 

48 hrs. 

870.5100 Bacterial Gene 

Mutation 

(monohydroxy 

metabolite) 

46904604 (2005) 

Acceptable/guideline 

0, 16, 50, 158, 500, 1581 

or 5000 μg/plate +/- S9 

activation 

Negative. 

A.3. Executive Summaries 

A.3.1 Subchronic Toxicity

 870.3100 90-Day Oral Toxicity – Rat 

In a 14-week oral toxicity study (MRID 46904538) spirotetramat (batch NLL 6425-9, 93.1 to 

96.5%) was administered to 10 Wistar Hanover strain rats/sex/dose in the diet at dose levels of 0, 

150, 600, 2500 or 10000 ppm (equivalent to 0, 9, 26, 148 and 616 mg/kg bw/day in males and 0, 

11, 46, 188 and 752 mg/kg/day in females, respectively). A satellite group of 10 rats/sex for the 

control and high dose groups was also included for a four-week recovery period. Special 

assessments of hepatic enzymes (N-demethylase, O-demethylase, UDP glucuronyltransferase 

and hepatic cytochrome P450) were included. 

All animals survived the dosing and recovery periods, and there were no clinical signs or 

changes in hematology, clinical chemistry or urinalysis parameters attributed to treatment. The 

hepatic enzyme profile was unchanged. Week 14 body weights in males were 3%, 5%, 2% and 

8.4% lower than controls and net body-weight gain for the dosing period was decreased by 4.4%, 

12%, 1% and 17.6% (p < 0.05) for the 150, 600, 2500 and 10000 ppm dose groups, respectively. 

Only the high dose group was considered affected. Female high dose body weight was only 

3.5% (not statistically significant) less than the control, while net body-weight gain was 13% less 

than the control indicating a possible effect. Other treatment-related effects in the high dose 

were decreased kidney (11%) and testicular (6.5%) weights in males. Kidney weight for high 

dose males was similar to controls after recovery. Kidney weight in females was decreased by 

6% (NSS) at termination and equivalent to the control group after recovery. No treatmentrelated histopathological changes in the kidney were reported. Histopathological findings in the 

epididymis (abnormal spermatozoa: 9 animals; hypospermia: 5 animals) and testis (tubular 
Page 46 of 65 

degeneration and vacuolization: 5 animals each) were observed in high dose males. Following 

recovery, the control and high dose group testis weights were essentially equal. The lungs of 

both sexes had increased incidences of alveolar macrophages. Partial recovery of body weight, 

epididymal and testicular weights, and lungs conditions was evident after four weeks. 

The LOAEL is 10000 ppm (616/752 mg/kg/day [M/F]), based on decreased body weight, 

abnormal spermatozoa and hypospermia in the epididymis, decreased testicular weight, 

and testicular degeneration and vacuolation in males; and alveolar macrophages in both 

sexes. The NOAEL is 2500 ppm (148/188 mg/kg/day [M/F]). 

This 90-day oral toxicity study in the rat is Acceptable/Guideline and satisfies the guideline 

requirement for a 90-day oral toxicity study (OPPTS 870.3100; OECD 408) in the rat. 

 870.3100 90-Day Oral Toxicity - Mouse

In a 90-day feeding study (MRID 46904539), groups of 15 CD-1 mice/sex were dosed with 0, 

70, 350, 1700 or 7000 ppm of spirotetramat (BYI08330, purity 96.5 to 93.1%, batch no.: NLL 

6425-9) for approximately 14 weeks. These doses correspond to 12.8, 59.6, 300 and 1305 

mg/kg/day in males and 0, 16, 72.4, 389 and 1515 mg/kg/day in females, respectively. 

Assessments for clinical signs, mortality, body weight and food consumption, hematology, 

limited clinical chemistry, urinalysis, organ weight and gross and histopathology (on the control 

and high dose) were made. 

 

There were no adverse reactions to treatment of any kind noted. The LOAEL was not 

established. The NOAEL was 7000 ppm (1305/1515 mg/kg/day [M/F]). 

 

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a 

90-day feeding study in mice [OPPTS 870.3100; OECD 408]. 

 870.3150 90-Day Oral Toxicity - Dog

In a subchronic oral toxicity study (MRID 46904541), BYI 08330 (97.6-97.8%, Batch No. 08045/0014) 

was initially administered to 4 beagle dogs/sex/group at dietary levels of 0, 150, 300, 1200 and 4000 

ppm. During the first two weeks of the study, males and females in the 4000 ppm dietary groups lost 

body weight; therefore, the dietary level of test material was reduced from 4000 to 2500 ppm beginning 

on test day 15 and was maintained at that level for the remaining duration of the 90-day study. 

Consequently, the equivalent dosages (excluding 4000 ppm during the first 2 weeks) were 0, 5, 9, 33 

and 81 mg/kg/day, respectively, in males and 0, 6, 10, 32 and 72 mg/kg/day, respectively, in females. 

There were no significant compound-related effects based on the assessment of mortality, 

clinical chemistry, urine, eyes and organ weights. 

Compound-related decreases in the circulating levels of T4 at 1200 and 2500 ppm and T3 at 2500 

ppm were observed in both sexes. These changes were not considered toxicologically significant 

since there were no related changes in thyroid weight or histopathology, and no compensatory 

increases in TSH were seen. 

Compound-related inhibition of body-weight gain and food consumption, depressed RBC 
Page 47 of 65 

parameters (red blood cell count, hemoglobin level and hematocrit) and reduced thymus size 

were observed at 2500 ppm in females; these were considered adverse effects. 

The LOAEL for BYI 08330 in this study for female dogs is 2500 ppm (72 mg/kg/day) based 

on decreased body-weight gain and food consumption, depressed RBC parameters (red 

blood cell count, hemoglobin level and hematocrit) and thymus atrophy; a LOAEL was not 

established for males. The NOAELs for males and females are 2500 ppm (81 mg/kg/day) 

and 1200 ppm (32 mg/kg/day), respectively. 

This 90-day oral toxicity study in dogs is Acceptable/Guideline and satisfies the guideline 

requirement [OPPTS 870.3150, OECD 409] for a 90-day oral toxicity study in a non-rodent 

species. 

 870.3200 21/28-Day Dermal Toxicity – Rat

In a 28-day dermal toxicity study, BYI 08330 (MRID 46904542), batch no. 08045/0014, purity: 

97.6 % to 98.5%, was administered to groups of 10 male and 10 female Wistar Hanover rats of 

the strain Crl:WI[G1x/BRL/Han]IGS BR at dose levels of 0, 100, 300, and 1,000 mg/kg (limit 

dose) by dermal application. The doses were administered for a minimum of six hours/day for 

five consecutive days/week for four weeks. Analytical determinations of stability and 

homogeneity were not performed because the test substance was applied undiluted and only 

moistened with water immediately before application. One mortality of a female at 100 mg/kg 

occurred on Day 22 during blood collection due to isoflurane anesthesia and was not treatmentrelated. There were no treatment-related effects on body weight, organ weight, or body 

weight:organ weight ratios. Statistically significant differences (p≤0.05) observed in treated 

groups in hematology (increased white blood cell count, activated partial prothromboblastin 

time, prothrombin time, differential cell counts) and clinical chemistry (decreased creatine 

kinase, lactate dehydrogenase, aspartate aminotransferase) measurements were not considered 

toxicologically or biologically significant since they did not have a clear dose-response pattern, 

were within historical control ranges, and/or no histological correlations were found. Only 

tissues from the control and high dose groups were examined microscopically, and no treatmentrelated findings were reported. 

A systemic LOAEL for male and female rats was not established. The NOAEL for male 

and female rats is 1000 mg/kg/day. 

A dermal LOAEL for male and female rats was not established. The NOAEL for male and 

female rats is 1000 mg/kg/day. 

This 28-day dermal toxicity study in the rat is Acceptable/Guideline and satisfies the guideline 

requirement for a 28-day dermal toxicity study (OPPTS 870.3200).

A.3.2 Prenatal Developmental Toxicity

 870.3700a Prenatal Developmental Toxicity Study – Rat 

In a developmental toxicity study (MRID 46904543), BYI 08330 (99.0% ai, batch # NLL 6425-

14-a), suspended in 0.5% aqueous carboxymethylcellulose, was administered to 25 mated female 
Page 48 of 65 

Wistar (Hsd Cpb:WU) rats/dose by oral gavage at dose levels of 0, 20, 140, or 1000 mg/kg 

bw/day from days 6 through 19 of gestation (GD 6-19). The fetuses were delivered by cesarean 

section on day 20 of gestation. The total numbers of fetuses examined (number of litters) was 

247 (20), 301 (24), 253 (23), and 270 (22) for the 0, 20, 140, and 1000 mg/kg bw/day groups, 

respectively. All live fetuses were weighed, sexed, and examined for external abnormalities. 

Every other fetus within a litter was prepared for either skeletal or visceral evaluation. The doses 

were selected based on the results of a pilot developmental toxicity study in rats in which doses 

of 0, 50, 200, 800 and 1000 mg/kg bw/day were tested. 

Maternal mortality, appearance and behavior were not affected by treatment with BYI 08330. 

Treatment-related effects at 1000 mg/kg bw/day included impaired food consumption, transient 

marginal body weight loss, impaired body-weight gain, reduced final body weight and reduced 

carcass weight. Light colored feces were observed in the 1000 mg/kg bw/day dose group, 

although this finding may be related to the high amount of white test substance given. Body 

weight gain during treatment and final body weight were slightly impaired at the 140 mg/kg 

bw/day dose level; however, corrected body-weight gain remained unaffected. Because of this 

and since the finding was not replicated in a supplementary study, a treatment related effect on 

body weight was not concluded. Necropsy revealed no treatment-related findings at a dose level 

up to and including 1000 mg/kg bw/day. 

The oral maternal toxicity LOAEL for BYI 08330 in rats is 1000 mg/kg bw/day, based on 

impaired food consumption, transient body weight loss, impaired body-weight gain, and 

reduced final body weight. The maternal NOAEL is 140 mg/kg bw/day. 

A marginal reduction of placental weight together with a more distinct reduction of fetal weight 

(86% of control) was observed in the 1000 mg/kg bw/day dose group. Treatment related effects 

were not evident for mean post-implantation loss, litter size, fetal sex distribution and placental 

appearance at a dose level up to and including 1000 mg/kg bw/day. 

External, visceral and skeletal evaluation of fetuses revealed a slightly increased number of 

fetuses and litters with generally common unspecific malformations at the maternally toxic 1000 

mg/kg bw/day dose level, including single cases of cleft palate, co-arctation of aortic arch, atrial 

septal defect of the heart, microphthalmia, supernumerary lumbar vertebra and 4 cases of 

dysplastic forelimb bones and 3 cases of malformed sacral vertebral arches with pelvic shift. A 

potential of BYI 08330 to induce a specific type of malformation was not deduced from these 

findings. Overall incidence and type of malformations at the 20 and 140 mg/kg bw/day dose 

level did not indicate a treatment related effect. Fetal external deviations were not observed in 

this study and incidence and type of visceral deviations of fetuses revealed no treatment-related 

effects at a dose level up to and including 1000 mg/kg bw/day. Skeletal evaluation of fetuses 

revealed retarded ossification of skull bones, fore- and hindlimbs, sternum and vertebral column 

at the 1000 mg/kg bw/day dose level in the osseous and cartilaginous parts. Increased incidence 

of skeletal variations (wavy ribs, 14th ribs, and combined osseous and cartilaginous findings) also 

was observed. Furthermore, retarded ossification of single localisations and increased incidence 

of wavy ribs were noted in the 140 mg/kg bw/day dose group and at the 20 mg/kg bw/day dose 

level without clear dose relation. 

Based on the results of a supplementary study with BYI 08330 (MRID 46904545) which 

revealed no evidence for a treatment-related increase of wavy ribs at a dose level up to and 
Page 49 of 65 

including 140 mg/kg bw/day and no evidence for effects on degree of ossification at a dose level 

up to and including 140 mg/kg bw/day, treatment relationship was excluded in the present study 

for retarded ossification and for incidence of wavy ribs at a dose level up to and including 140 

mg/kg bw/day. 

The oral developmental toxicity LOAEL for BYI 08330 in rats is 1000 mg/kg bw/day (limit 

dose), based on reduced fetal weight, increased incidence of malformations, and increased 

incidence of skeletal deviations (incomplete ossification of skull bones, fore- and hindlimbs, 

sternum and vertebral column; wavy ribs, 14th ribs, and combined osseous and 

cartilaginous findings). The developmental toxicity NOAEL is 140 mg/kg bw/day.

The developmental toxicity study in the rat is classified Acceptable/Guideline and does satisfy 

the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in 

the rat. 

 870.3700b Prenatal Developmental Toxicity Study - Rabbit

In a developmental toxicity study (MRID 46904544), BYI 08330 (98.9% ai, batch # 

08045/0004), suspended in 0.5% aqueous carboxymethylcellulose, was administered to groups 

of 22, 22, 24 or 30 mated female Himalayan rabbits (CHBB.HM) by oral gavage at dose levels 

of 0, 10, 40 or 160 mg/kg bw/day, respectively, from days 6 through 28 of gestation (GD6-28).

The fetuses were delivered by cesarean section on day 29 of gestation; the dams were killed and 

subjected to necropsy. The total numbers of fetuses (litters) examined was 170 (22), 152 (22), 

172 (21) and 132 (19) for the 0, 10, 40 and 160 mg/kg bw/day groups, respectively. All live 

fetuses were weighted, sexed, and examined for external, visceral and skeletal abnormalities. The 

doses were selected based on the results of a pilot developmental toxicity study in rabbits in 

which doses of 0, 5, 25, 100, 160, 250 or 500 mg/kg bw/day were tested (MRID 46904570). 

One female of the 160 mg/kg bw/day group was found dead and 5 females were sacrificed in 

moribund condition with severely reduced food consumption, severe body weight loss, cold ears, 

alopecia, reduced amount of feces, diarrhea or soft and light colored feces, reddish excretion, 

decreased water intake and decreased/discolored urination. Females at necropsy revealed fluid 

and/or gaseous contents in caecum, discolored liver and mottled gall bladder. Late abortion 

(≥GD 22) was observed, most likely as a consequence of maternal toxicity, in two other females 

of the 160 mg/kg bw/day group and in one female of the 40 mg/kg bw/day group showing 

clinical signs, impaired food consumption and body weight loss before abortion. The remaining 

females of the 160 mg/kg bw/day dose group exhibited cold ears, alopecia and soft, mucoid and 

light colored feces. 

The gestation rate was decreased by one abortion in the 40 mg/kg bw/day dose group for which a 

treatment related effect cannot be excluded and two abortions in the 160 mg/kg group most 

likely as a consequence of severe maternal toxicity. There were no treatment-related effects in 

the remaining females on postimplantation loss, number of fetuses, or placental weight and 

appearance; fetal weight and fetal sex distribution were unaffected by treatment at dose levels up 

to and including 160 mg/kg bw/day. Teratogenic effects of BYI 08330 were excluded at a dose 

level up to and including 160 mg/kg bw/day. Malformations were different in type, scattered 

within the different dose groups and revealed no dose dependency. Malformations of 

cartilaginous parts of ribs, cardiac ventricular septal defects and malpositioned forelimbs were 
Page 50 of 65 

not dose related and single malformations which appeared only once in the 160 mg/kg bw/day 

dose group (domed head together with encephalomeningocele, cleft palate, microphthalmia) 

were different in type and comparable with historical control data. There was an increased 

incidence of fetuses with distinct liver lobulation in the 160 mg/kg bw/day group (8 fetuses in 2 

litters). No other treatment related effects on fetal external and visceral deviations were observed 

at dose levels up to and including 160 mg/kg bw/day. Fetal skeletal evaluation did not reveal 

treatment related effects at a dose level up to and including 160 mg/kg bw/day. Findings on the 

progeny (abortions at the 40 mg/kg bw/day and 160 mg/kg bw/day dose level; possibly distinct 

fetal liver lobulation at the 160 mg/kg bw/day dose level) occurred only at dose levels with signs 

of distinct to severe maternal toxicity. 

The oral maternal toxicity LOAEL for BYI 08330 in rabbits is 40 mg/kg bw/day, based on 

late abortion, clinical signs, impaired food and water consumption and body weight loss in 

one animal. The maternal NOAEL is 10 mg/kg bw/day. 

The oral developmental toxicity LOAEL for BYI 08330 in rabbits was not established. The 

developmental NOAEL is 160 mg/kg bw/day. 

The developmental toxicity study in the rabbit is classified Acceptable/Guideline and does 

satisfy the guideline requirement for a developmental toxicity study (OPPTS 870.3700b; OECD 

414) in the rabbit. 

A.3.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects – Rat 

In the present two-generation study (MRID 46904546), groups of 30 male and 30 female Wistar 

Hanover rats (strain: Crl:WI(Glx/BRL/Han)IGS BR) were exposed to BYI 08330 (batch no. 

08045/0014, purity: 97.4 – 98.5%) at dietary concentrations of 0, 250, 1,000 or 6,000 ppm. The 

dietary concentrations were equal to premating doses of 0, 17.2, 70.7 and 419.3 mg/kg bw/day in 

P-generation males; 0, 20.0, 82.5 and 484.7 mg/kg bw/day in P-generation females; 0, 19.3, 79.5 

and 486.7 mg/kg bw/day in F1-generation males; and 0, 21.7, 90.3 and 539.5 mg/kg bw/day in 

F1-generation females, respectively. P-generation rats were approximately 8-9 weeks of age at 

the time of study initiation, corresponding to body weights of 240.9 - 307.7 g. They were 

pretreated for ten weeks, during the subsequent mating period and until the last litters were 

produced (males) or until lactation day 21 (females). F1 offspring were nursed up to an age of 

three weeks. Some of them were selected for further treatment and for breeding an F2 generation 

at 5-9 weeks of age. 

No treatment-related mortalities or clinical signs of toxicity were observed in parental animals of 

either generation. A decline in body-weight gain (Wk 1-10) was noted in P-generation males 

(13.2%) of the 6,000 ppm group. In the F1-generation, the males of the 6,000 ppm group 

exhibited statistically significant declines in body weight (mean of 6.4%) from premating days 

14-70 and declines in overall body-weight gain (8%). In F1-generation females of the 6,000 ppm 

group, statistically significant declines in body weight (6%, week 10 of premating) and declines 

in overall body-weight gain (11%) were observed at the end of the premating phase. The 

premating effects on F1 females in the 6,000 ppm group continued into gestation and lactation as 

a decline in body-weight gain (8%) accompanied by statistically significantly lower body weight 
Page 51 of 65 

means (7%) from day 0-20 of gestation and statistically significant body weight declines (6-8%) 

throughout lactation. Food consumption during premating was not affected by treatment in 

either sex of either generation. P-generation females of the 6,000 ppm group showed statistically 

significant declines in food consumption throughout lactation on both a g/kg/day (11.5 %) and 

g/animal/day (13.4 %) basis. In the F1-generation, females of the 6,000 ppm group exhibited 

significantly declined food consumption (lactation days 7-21) on both a g/kg/day (8.6 %) and 

g/animal/day (13.9 %) basis. This effect could not be attributed to less food consumed by the 

pups since it occurred prior to the time when the pups would start eating the treated diet. 

Gross necropsy was unremarkable for both generations. No treatment-related microscopic 

changes were observed in P-generation rats. In F1-generation male and female rats of the 6,000 

ppm group, a minimal to moderate multifocal tubular dilatation was observed in the outer portion 

of the medulla, containing occasional proteinaceous material. In general, both kidneys were 

affected with the incidences (severity) of 23/30 (1.7) in males and 15/30 (1.5) in females; this 

finding was not seen in animals from the control or other treated groups. Decreased absolute 

(11%) and relative (5%) kidney weights in males and females at 6000 ppm were considered 

toxicologically significant in the presence of renal histopathology. 

The parental systemic LOAEL for BYI 08330 in male and female Wistar rats is 6000 ppm 

(419.3 and 484.7 mg/kg bw/day in males and females, respectively) based on decreases in 

body weight (F1 males and females), weight gain (P males, F1 males and females), and food 

consumption during lactation (P- and F1-generation females), and kidney histopathology 

and decreased kidney weights (F1 males and females). The parental systemic NOAEL is 

1000 ppm (70.7 and 82.5 mg/kg bw/day in males and females, respectively).

Evaluation of female reproductive performance revealed no effects on any parameter measured 

in either parental generation at 6,000 ppm and below. The litter parameters determined at birth 

were not affected in either generation. Histopathology of the reproductive tract of females of 

either generation showed no treatment-related findings. Ovarian follicle counts of 6,000 ppm F1-

generation females showed no difference from controls. Female reproductive function (estrus 

cycle staging) was not affected in the P- or F1-generation at any dietary level tested. 

In P-generation males, reproductive function (sperm analysis: sperm count, motility, progression, 

and morphology as well as gross examination, weight and histopathology of reproductive 

organs) was not affected by treatment. In F1-generation males, sperm motility, epididymal and 

testicular sperm count were also not affected at 6,000 ppm. However, abnormal sperm cells were 

noted at 6,000 ppm, with a high degree of variation as 9/30 males exhibited a minimal effect (1 

to 4 abnormal sperm was noted out of 200 cells viewed). One of these males presented with 

82% total abnormal sperm with 77% of these sperm presenting as amorphous heads and had 

decreased reproductive performance. At histopathology, this same male showed abnormal sperm 

in the epididymis. Reproductive function was not affected in F1-generation males at 1,000 and 

250 ppm. 

The reproductive toxicity LOAEL for BYI 08330 in male Wistar rats is 6000 ppm (419.3 

mg/kg bw/day) based on abnormal sperm cells and decreased reproductive performance in 

the F1 males. The reproductive toxicity NOAEL is 1000 ppm in males (70.7 mg/kg bw/day). 

The reproductive toxicity LOAEL was not observed in females; the reproductive toxicity 

NOAEL in females was 6000 ppm (484.7 mg/kg bw/day).
Page 52 of 65 

There were no treatment-related effects on the viability parameters (viability index, lactation 

index), and no clinical signs and no malformations were observed in F1 and F2 pups. Offspring 

toxicity was limited to decreased body weights in F1 and F2 litters. Pup weights at birth were not 

affected (F1 and F2). On lactation day 21, the F1 pup body weights for both sexes in the 6,000 

ppm group was significantly lower than control (8.2%) with females also significantly lower on 

day 14 (6%). The pup body-weight gains for the 6,000-ppm group was statistically decreased 

(9.1%) during days 4-21 of lactation. On lactation days 14 and 21, the F2 pup body weights for 

both sexes in the 6,000-ppm group were significantly less than control (7.5% and 10.3%, 

respectively). The pup body-weight gains for the 6,000-ppm group were statistically decreased 

(12.0%) during days 4-21 of lactation. 

Gross necropsy, organ weights (brain, thymus, spleen, uterus) and histopathology of the 

reproductive organ system revealed no direct compound-related findings at any dietary levels 

tested. Statistically significant decreases in brain, spleen, and thymus weights were considered 

secondary to the lower mean body weights of the 6,000 ppm dose groups. Maturation of external 

sexual organs (balano-preputial separation, vaginal opening) was not affected in F1 weanlings. 

The offspring toxicity LOAEL for BYI 08330 in male and female Wistar rats is 6000 ppm 

(419.3 and 484.7 mg/kg bw/day in males and females, respectively) based on decreased 

body weight and body-weight gain during lactation in both F1 and F2 generations. The 

offspring NOAEL is 1000 ppm (70.7 and 82.5 mg/kg/ bw/day in males and females, 

respectively).

This study is Acceptable/Guideline and satisfies the guideline requirement for a two-generation 

reproductive toxicity study (OPPTS 870.3800); OECD 416 in rats. 

A.3.4 Chronic Toxicity

 870.4100a (870.4300) Chronic Toxicity – Rat 

In a chronic toxicity study (MRID 46904547), spirotetramat (97.5-98.5% purity, batch no. 

0845/0014) was administered to 25 Wistar Hanover strain rats/sex/dose in the diet at dose levels 

of 0, 250 and 3500 ppm for both sexes and 7,500 ppm for males and 12,000 ppm for females 

(equivalent to 0, 13.2, 189, or 414 mg/kg bw/day for males and 0, 18, 255, or 890 mg/kg bw/day 

for females) for 12 months. In the last month of the study, 10 rats/sex/dose were evaluated in an 

FOB assessment that included evaluation of motor activity and responses to sensory stimuli. 

Consistent with the subchronic study (MRID 46904538) the lung demonstrated treatment-related 

presence of alveolar macrophages in mid (6/25, severity 1) and high (11/25, severity 1.2) dose 

males and high dose females (21/25, severity 1.3) relative to 1/25 control males and 5/25 control 

females (severity 1 for both sexes). Clinical signs were limited to yellow/brown staining of the 

perigenital area and tail in females in the high dose group. Body weight and body-weight gain 

were decreased by 7% and 14%, respectively in high dose females at termination. Other findings 

include slightly elevated (8%) relative kidney weight in females and relative liver weight in 

males (9%) and females (15%); however neither the kidney nor the liver had related 

histopathological changes. The lung showed some discoloration in high-dose females. Although 

not statistically significant, histopathology of the testis (abnormal spermatozoa) and epididymis 

(germ cell debris) was observed in high-dose males. These findings were considered 
Page 53 of 65 

toxicologically significant, since histopathology of both of these organs was also observed 

following 24 months of treatment. There were no obvious treatment-related effects in the FOB 

assessments. 

The LOAEL is 3500 ppm (189 mg/kg/day) in males, based on alveolar macrophages; and 

12000 ppm (890 mg/kg/day) in females based on decreased body weight and body-weight 

gain, alveolar macrophages, discoloration of the lung, and yellow/brown staining of the 

perigenital area and tail. The NOAEL is 250 ppm (13.2 mg/kg/day) in males and 3500 ppm 

(255 mg/kg/day) in females. 

This chronic study in the rat is Acceptable/Guideline and satisfies the guideline requirement for 

a chronic oral toxicity study (OPPTS 870.4100, OECD 452) in the rat. 

 870.4100b Chronic Toxicity – Dog 

In a chronic oral toxicity study (MRID 46904548), BYI 08330 (97.6-98.5%, Batch No. 08045/0014) 

was administered to 4 beagle dogs/sex/group at dietary levels of 0, 200, 600 and 1800 ppm (equivalent 

to 0, 6, 20 or 55 mg/kg/day, respectively in males and 0, 5, 19 or 48 mg/kg/day, respectively, in 

females). There were no significant compound-related effects based on the assessment of mortality, 

urine, eyes or organ weights. Compound-related decreases in the circulating levels of T4 at 600 and 

1800 ppm in both sexes and T3 at 1800 ppm in males were observed. Changes at ≤600 ppm were not 

considered toxicologically significant since there were no correlative changes in thyroid weight or 

histopathology, no compensatory increases in TSH, and there were no clinical signs of toxicity or 

changes in body weight at these doses that might result from decreased thyroid output. The only 

histopathological change in thyroid was a reduction in follicle size at 1800 ppm in males, a possible 

indication of a reduced amount of colloid in the organ. Notable gross observations were reduced thymus 

size in 1 male each at 600 and 1800 ppm. Histopathology of the thymus (thymus involution) was 

observed with dose-related severity in 1 male each at 600 and 1800 ppm. 

The LOAEL for BYI 08330 in this study for male dogs is 600 ppm (20 mg/kg/day) based on 

thymus involution and was not observed in females. The NOAELs for males and females 

are 200 ppm (6 mg/kg/day) and 1800 ppm (48 mg/kg/day), respectively. 

This one-year oral toxicity in dogs is Acceptable/Guideline and satisfies the guideline 

requirement [OPPTS 870.4100b, OECD 452] for a one-year oral toxicity study in a non-rodent 

species. 

A.3.5 Carcinogenicity

 870.4200a Carcinogenicity Study – rat 

In a carcinogenicity study (MRID 46904549), spirotetramat (BYI 08330, batch no.: 08045/0014, 

purity: 97.4 – 98.5 %) was administered to 55 Wistar Hanover rats (strain: 

Crl:WI[Glx/BRL/Han] IGS BR)/sex/dose in the diet at dose levels of 0, 250, or 3500 ppm for 

both males and females and 7500 ppm for males and 12,000 ppm for females (equivalent to 0, 

12.5, 169 or 373 mg/kg bw/day for males and 0, 16.8, 229 or 823 mg/kg bw/day for females) for 

two years. 
Page 54 of 65 

Survival was not affected by treatment since there were 40, 34, 44 and 35 males and 39, 39, 37 

and 42 females that survived to termination at each increasing dose level. Clinical signs were 

limited to yellow and/or brown perigenital staining in the mid (females) and high dose groups 

(both sexes) and body scaling in high dose animals. Terminal body weight was statistically 

significantly (p< 0.05) decreased in high dose males (10.2%) and females (14.2%). 

Correspondingly lower interim body-weight gains -- e.g., at week 13 where gains were 10% 

lower for males and 17% lower for females -- were also noted at the high dose. The kidney 

demonstrated statistically significant lower absolute weights in the low (9.7%), mid (10.2%) and 

high (14.6%) dose males and in mid (10.8%) and high (13.7%) dose females. Tubular dilation of 

the kidneys of mid (8/54 males and 16/55 females) and high (19/54 males and 42/55 females) 

dose animals was also observed. Because there was no corresponding pathology, the decrease in 

absolute kidney weight at the low dose was not considered toxicologically significant. In males, 

the high dose caused spermatid degeneration in the testes (9/55 vs. 0/55 in other groups) and 

germ cell exfoliated debris in the epididymis (31/55 vs. ≤10/55 in the other groups). Relative 

liver weight was increased in the high dose females (11.8%), and high dose (32/55, severity 1.7) 

females had an increased incidence (NSS) of biliary hyperplasia/fibrosis relative to the control 

group (18/55, severity 1.9). 

Increased incidences of alveolar macrophages were observed in males at the low and mid doses 

only. Females did not demonstrate a pattern of increased alveolar macrophages. High dose 

males demonstrated an increased incidence and severity of interstitial pneumonia, while 

increased incidences and/or severity of interstitial pneumonia were observed in all treated 

females. It is unclear how treatment with spirotetramat and interstitial pneumonia are linked, if 

at all. Relative lung weight was increased in females in the high dose group. High-dose females 

also had more incidents of discolored zones in their lungs. It is noted that the subchronic (MRID 

46904538) and chronic (MRID 46904547) studies in the rat demonstrated the presence of 

alveolar macrophages following treatment with spirotetramat. 

The systemic LOAEL is 3500 ppm (169/229 mg/kg/day [M/F]), based on decreased kidney 

weight and renal tubular dilation. The NOAEL is 250 ppm (12.5/16.8 mg/kg/day [M/F]). 

There were no treatment-related increases in tumor incidence. Dosing was considered adequate 

based on pathological findings in the kidney (tubular dilation) and decreases in absolute kidney 

weight at the mid and high doses. At the highest dose tested, there were also indications of 

testicular (males) and liver histopathologies (females). 

This carcinogenicity study in the rat is Acceptable/Guideline and satisfies the guideline 

requirement for a carcinogenicity study [OPPTS 870.4200; OECD 451] in rats. 

 870.4200b Carcinogenicity (feeding) - Mouse

In a carcinogenicity study (MRID 46904550), spirotetramat (BYI08330, 97.4 to 98.3% purity, 

batch 90945/0014) was administered to 55 CD-1 mice/sex via their diets for a period of 18 

months at dose levels of 0, 70, 1,700 or 7000 (for males) or 6000 (for females) ppm. These doses 

correspond to 0, 10.9, 263 or 1022 mg/kg/day for males and 0, 13.7, 331 or 1319 mg/kg/day for 

females. 
Page 55 of 65 

There were no adverse reactions to treatment of any kind. There were 43, 42, 41 and 44 males 

and 36, 35, 41, and 37 females that survived to terminal sacrifice in the control, low, mid and 

high dose groups, respectively. The LOAEL was not established. The NOAEL was 

7000/6000 ppm (1022/1319 mg/kg/day [M/F]). 

At the doses tested, there were no treatment related increases in tumor incidence. Dosing was 

considered adequate since the limit dose of 1000 mg/kg/day was achieved. 

This carcinogenicity study in mice is Acceptable/Guideline and satisfies the guideline 

requirement for a carcinogenicity study [OPPTS 870.4200; OECD 451] in mice. 

A.3.6 Neurotoxicity

 870.6200 Acute Neurotoxicity Screening Battery 

In an acute neurotoxicity study (MRID 46904560), groups of nonfasted Wistar Hanover 

(Crl:WI[Glx/BRL/Han]IGS BR) rats (12/sex/dose), at least 9 weeks old, were given a single oral 

gavage dose of BYI 08330 (spirotetramat) technical (97.8-98.5%, mix batch 08045/0014) in 

0.5% methylcellulose/0.4% Tween 80 in deionized water at nominal doses of 0, 200, 500 or 

2000 mg/kg bw and observed for 14 days. Since treatment-related effects were observed at 200 

mg/kg, a follow-up study with 12 animals/sex/dose was conducted at nominal doses of 0, 50, 100 

and 500 mg/kg. In the initial study, neurobehavioral assessment (functional observational 

battery and motor activity testing) was performed on all animals/sex/ group pre-dosing and on 

days 0 (day of treatment), 7 and 14. Body weight was measured weekly throughout the study. 

At study termination, 6 animals/sex/group were euthanized and perfused in situ for 

neuropathological examination; brain weight was recorded from these animals. Of the perfused 

animals, 6 animals/sex from the control and high dose groups were subjected to histo–

pathological evaluation of brain and peripheral nervous system tissues. In the follow-up study, 

the following parameters were measured: clinical observations, body weight, FOB testing (pretreatment and day 0) and motor activity (pre-treatment and day 0); no necropsies were 

conducted. 

In the initial study, treatment-related observations involved urine stain in males and females at 

200 mg/kg and above and perianal stain in males at 500 mg/kg and above. Total motor and 

locomotor activity in the initial study were significantly reduced at 2,000 mg/kg in males (48 % 

and 64 %, respectively) and females (40% and 65%, respectively) on day 0. At 500 mg/kg, 

motor activity was reduced (32%) and locomotor activity was significantly reduced (44 %) in 

males only on day 0. Locomotor activity was slightly reduced (29 %) in males of the low dose 

group (200 mg/kg). In addition, interval motor activity on day 0 was significantly reduced in 

males at several intervals at 500 and 2,000 mg/kg; interval locomotor activity was decreased in 

males at 200 mg/kg. A similar trend was evident in females, but the difference from control was 

not statistically significant. In the follow-up study, total motor and locomotor activity was 

slightly reduced (21 % and 30 %, respectively) on day 0 in males dosed at 500 mg/kg, but not in 

lower levels (50 and 100 mg/kg) or in females at any dose. Interval motor and locomotor 

activity was reduced at several intervals in both sexes at 500 mg/kg on day 0. 
Page 56 of 65 

The LOAEL for acute neurotoxicity of spirotetramat technical in rats was 200 mg/kg 

based on clinical signs (urine stain; males and females) and decreased motor activity 

(males). The NOAEL was 100 mg/kg. 

This neurotoxicity study is classified as Acceptable/Guideline and satisfies the guideline 

requirement for an acute neurotoxicity study in rats (870.6200a; OECD 424). 

A.3.7 Special

870.7485 Metabolism – Rat 

I. In a metabolism and pharmacokinetic study (MRID 46904504), four groups of 4 male and 4 

female Wistar rats were administered a single gavage dose of [azaspirodecenyl-3-14C]BYI 08330 

(Lot/Batch Nos. BECH 0826, 0834, 0843, 0906, 0948, radiochemical purity >99%) in aqueous 

Tragacanth® and nonlabelled azaspirodecenyl-BYI 08330 (Lot/Batch No. 08045/0003, chemical 

purity >99%) at target doses of 2 or 100 mg/kg body weight. Two groups of 4 male or female 

rats were also pre-treated for 14 days with 2 mg/kg non-radiolabelled BYI 08330 followed by a 

single radiolabelled dose of 2 mg/kg. The animals of all groups were sacrificed 2 days after 

dosing. The total radioactivity which included the test item and metabolites was determined in 

plasma samples, the excreta (urine and feces) as well as in organs and tissues. The metabolism 

was investigated by radio-HPLC, normal phase TLC and spectroscopic methods in selected urine 

samples and feces extracts. 

Radioactivity inventory showed total recovery of 91.4% to 99.8% of the administered dose. 

[Azaspirodecenyl-3-14C]BYI 08330 was rapidly absorbed from the gastrointestinal tract of male 

and female rats in all test groups. The absorption rate in all tests was between 89 and 98% of the 

total recovered radioactivity, based upon recovery from the urine and carcass (without the 

gastrointestinal tract). No significant differences in the absorption rate were observed among 

any of the dose groups. The absorption rate in the single low dose test was 95% for male rats and 

96% for female rats. 

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

after administration (values calculated by pharmacokinetic modelling). The radioactivity 

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

dose groups. Radioactivity in tissues and organs at the 48-hour termination were very low 

(<0.2% and below the limit of detection for some organs/tissues). 

Urinary excretion was very rapid and was the major excretion route. Faecal excretion accounted 

for 2-11% of the dose in male and female rats. The excretion behaviour was similar for all dose 

groups. 

BYI 08330 was completely metabolized by the rat; no parent compound was detected in the 

excreta. Identified metabolites accounted for 87-95% of the administered dose. Only very minor 

metabolites (<0.7% of the dose) were not identified. The main metabolic reaction was cleavage 

of the ester group which resulted in the formation of the primary and most predominant 

metabolite BYI 08330-enol (53-87% of the administered dose). All other identified metabolites 

could be derived from the enol intermediate. The second prominent metabolic transformation 

was oxidative demethylation of the 8-methoxy group to BYI 08330-desmethyl-enol (5-37% of 
Page 57 of 65 

the administered dose). Oxidation of the azaspiro moiety to BYI 08330-ketohydroxy and BYI 

08330-desmethyl-ketohydroxy were detected as minor pathways. Other minor metabolic 

transformations were conjugation of the enol with glucuronic acid to BYI 08330-enol-GA and 

oxidation of the aromatic methyl group of the enol metabolite to BYI 08330-enol-alcohol. A 

sex-related difference was observed in metabolism with male rats showing much higher rates of 

demethylation to BYI 08330-desmethyl-enol compared to female rats. 

This study in the rat is considered Acceptable/Guideline and meets the guideline requirement 

for a metabolism and pharmacokinetics study (870.7485) in rats.

II. In a metabolism study (MRID 46904561), three groups of 4 male Wistar rats were 

administered by oral gavage a single dose of [azaspirodecenyl-3-14C]BYI 08330 (Lot/batch No. 

BECH 1943, radiochemical purity >98%) and non-radiolabelled BYI 08330 (Lot/Batch No. 

08045/0003, chemical purity >98%) in aqueous Tragacanth® at a target dose level of 2 mg/kg 

body weight. Three additional groups received a dose of 1000 mg/kg body weight. One group of 

animals from each test group was sacrificed at 1 h, 8 h, and 24 h after dosage, respectively. The 

total radioactivity (parent compound and metabolites) was determined in the urine and feces over 

the test period. Radioactivity in plasma, testis, liver and kidney were determined following 

terminal sacrifice. 

Recovery of administered radioactivity was excellent; 100.3-121.8% (tests 1–3) and 94.8-98.9 % 

(tests 4–6). Metabolites were identified and characterized in urine, plasma, testis, liver, and 

kidney. Metabolites accounted for more than 89% of the total recovered radioactivity for all 

samples. 

 

For the 2 mg/kg dose, the administered radioactivity was rapidly absorbed, widely distributed 

and rapidly excreted. Excretion was primarily via the urine and nearly complete at 24 hours post 

dose. Absorption and excretion rate and amount were less for the 1000 mg/kg dose with only 27 

% of the dose excreted in the urine after 24 hours. Radioactivity in plasma and organs declined 

rapidly after dosing resulting in low plasma residues at 24 hours post dose. For all time points, 

the residues in liver and kidney were distinctively higher than in plasma while residues in testis, 

carcass and skin were distinctively lower than in plasma. The ratio of the two main metabolites, 

BYI 08330-enol and BYI 08330-desmethyl-enol, in urine was about 2:1. Due to its greater 

polarity, BYI 08330-desmethyl-enol was found at higher percentages in urine than in plasma and 

organs. The highest percentages of BYI 08330-desmethyl-enol were detected in liver, where the 

compound is formed by metabolic transformation of BYI 08330-enol. BYI 08330-enol levels in 

the plasma, kidney and testis were comparable but significantly lower than in liver. 

For the 1000 mg/kg dose, excretion rate was distinctively less than for the low-dose while 

plasma radioactivity was slightly higher than in liver and kidney. This is consistent with 

saturation of cellular transport mechanisms. Decline of tissue radioactivity was minimal from 1 

h to 8 h post dose and increased only slightly to 24 hours. The residues in testis, carcass and skin 

were lower than in plasma. The metabolism profile was qualitatively similar to that of the low 

dose; however, BYI 08330-desmethyl-enol occurred at lower levels at the high dose and is likely 

a reflection of the decreased absorption at the high dose. Similar to the low dose group, BYI 

08330-desmethyl-enol levels were greater in urine than in plasma and organs. The highest 

percentage of BYI 08330-desmethyl-enol was detected in liver and kidney. The percentage in 

plasma, kidney and testis was lower. 
Page 58 of 65 

For all dose regimens, the most prominent metabolic reaction was the cleavage of the ester bond 

of the side chain yielding the BYI 08330-enol. The demethylation of the cyclohexyl-O-methyl 

group to the respective alcohol (BYI 08330-desmethyl-enol) was a further important metabolic 

reaction as well as the hydroxylation in the azaspiro ring of BYI 08330-enol resulting in BYI 

08330-ketohydroxy, which was mainly detected in liver and kidney. Other metabolic reactions 

(e.g., conjugation of the BYI 08330-enol with glucuronic acid, oxidation of one of the methyl 

groups of the phenyl ring forming the BYI 08330-enol-alcohol, and demethylation of BYI 

08330-ketohydroxy to BYI 08330-desmethyl-ketohydroxy) were of minor importance. 

Results of this study indicate that saturation of active transport mechanisms occurs at a dose of 

1000 mg/kg but not 2 mg/kg. This results in decreased excretion via urine and feces and a 

potential for accumulation of BYI 08330 related residues in the body following repeated high 

doses.

This study in rats does meet current OPPTS 870.7485 Guidelines for a metabolism and 

pharmacokinetics study. This study in the rat is considered Acceptable/Guideline and meets the 

guideline requirement for a metabolism and pharmacokinetics study (870.7485) in rats. 

 870.7600 Dermal Absorption - Rat

In an in vivo dermal absorption study (MRID No.46904563), male Wistar rats were administered 

nominal doses of 100, 15, or 5 μg ai/cm2

 of [14C]-BY1 08330 (synthesis ref. No. KML 2978-2; 

>99% radiopurity) to approximately 12 cm2

 of body surface and monitored up to 168 hr postdosing. Mean dermal absorption values (excluding skin), for the groups for which the skin site 

was washed and the animals sacrificed after 10 hours exposure (n=4), were 1.73%, 1.92%, and 

1.43%, respectively, for the high, medium, and low dose levels. Ten hours is considered most 

applicable to the typical worker exposure time. When the animals were skin washed after 10 hrs 

exposure and sacrificed at 168 hrs, the mean dermal absorption values (excluding skin) were 

7.69%, 2.99%, and 3.99% for the high, medium, and low dose (n=4) exposure groups, 

respectively. Mean radioactivity (percent of the applied dose) remaining at the dose site (treated 

skin and stratum corneum) after 10 hours exposure was 15.89%, 8.43%, and 10.60% for the 

high, medium, and low dose rats. The respective values decreased to 2.87%, 1.72%, and 1.82% 

at the 168 hr sacrifice following a 10 hour exposure, indicating that the activity remaining at the 

application site decreased with time. Because the amount of radioactivity at the dose site 

(including stratum corneum) decreased during this time period and the amount of radioactivity in 

excreta increased, the small amount of the active ingredient (2.87% 1.72%, and 1.82%, 

respectively, for the high, medium, and low dose groups) retained at the skin site after 168 hours 

was considered part of the absorbed dose. Therefore, mean dermal absorption values (including 

skin) for the animals sacrificed 168 hrs after a 10-hr exposure were 10.57%, 4.71%, and 5.81% 

for the high, medium, and low dose (n=4) exposure groups, respectively. 

This study in the rat is acceptable/guideline and satisfies the guideline requirement for an in

vivo dermal penetration study. 
Page 59 of 65 

Appendix B. Metabolism Assessment 

Table B.2. Tabular Summary of Metabolites and Degradates

Chemical Name 

(other names in 

parenthesis) 

Matrix 

Percent TRR (PPM)1

Matrices - Major Structure 

Residue 

(>10%TRR) 

Matrices - Minor 

Residue 

(<10%TRR) 

Spirotetramat 

(cis-3-(2,5-

dimethylphenyl)-8-

methoxy-2-oxo-1-

azaspiro[4.5]dec-3-

en-4-yl ethyl 

carbonate)

Plants Apple Fruit & 

Leaves; Lettuce; 

Cotton Gin Trash 

& Lint; Potato 

Tops 

Cotton Seed 

Rotational Crops - - 

Ruminant - - 

Poultry - - 

Rat - - 

Water - - 

BYI08330-enol 

(cis-3-(2,5-

dimethylphenyl)-4-

hydroxy-8-methoxy1-azaspiro[4.5]dec3-en-2-one) 

Plants Apple Leaves; 

Lettuce; Cotton 

Gin Trash & Seed 

Apple Fruit, 

Cotton Lint, 

Potato Tops 

Rotational Crops Wheat Grain 

Ruminant Muscle, Fat, 

Liver, Kidney, 

Milk 

Poultry Muscle, Eggs, Fat, 

Liver 

Rat Liver, Kidney, 

Excreta, Plasma 

Water Aerobic Soil, 

Aerobic Outdoor 

BYI08830-

ketohydroxy 

(cis-3-(2,5-

dimethylphenyl)-3-

hydroxy-8-methoxy1-

azaspiro[4.5]decane2,4-dione)

Plants Cotton Gin 

Trash& Lint; 

Potato Tops 

Apple Fruit & 

Leaves, Lettuce, 

Cotton Seed 

Rotational Crops Wheat Forage; 

Chard; Turnip 

Roots

Wheat Straw, 

Hay; Turnip 

Leaves 

Ruminant Muscle, Liver, 

Kidney, Milk 

Poultry - - 

Rat Kidney, Liver Excreta, Plasma 

Water Aerobic Soil, 

Aerobic Outdoor 

BYI08330-enolGlc 

(cis-3-(2,5-

dimethylphenyl)-8-

methoxy-2-oxo-1-

azaspiro[4.5]dec-3-

en-4-yl beta-Dglucopyranoside)

Plants Lettuce Apple Fruit, 

Potato Tops 

Rotational Crops Wheat Hay, 

Straw 

Ruminant - - 

Poultry - - 

Rat - - 

Water - - 
Page 60 of 65 

Table B.2. Tabular Summary of Metabolites and Degradates

Chemical Name 

(other names in 

parenthesis) 

Matrix 

Percent TRR (PPM)1

Matrices - Major Structure 

Residue 

(>10%TRR) 

Matrices - Minor 

Residue 

(<10%TRR) 

BYI 08330-

mono-hydroxy 

(cis-3-(2,5-

dimethylphenyl)-4-

hydroxy-8-methoxy1-

azaspiro[4.5]decan2-one)

Plants Apple Fruit - 

Rotational Crops - - 

Ruminant Liver, Milk 

Poultry - - 

Rat - - 

Water - - 

BYI 08330-

enol-GA (cis-3-(

cis-3-(2,5-

dimethylphenyl)-4-

(β-Dglucopyranosyloxy)-

8-methoxy-1-

azaspiro[4.5]dec-3-

en-2-one)

Plants - - 

Rotational Crops 

Ruminant Fat, Liver, 

Kidney, Milk 

Poultry Liver, Muscle, Eggs 

Rat Liver, Kidney, 

Excreta 

Water - - 

BYI 08330-

desmethylketohydroxy (cis3-(2,5-

dimethylphenyl)-3,8-

dihydroxy-1-

azaspiro[4.5]decane

-2,4-dione)

Plants Apple Fruit, 

Cotton Gin Trash 

Rotational Crops Wheat Forage, 

Straw, Hay; 

Chard, Turnip 

Leaves, Roots 

Ruminant - - 

Poultry - - 

Rat Liver, Kidney, 

Excreta 

Water - - 

BYI 08330-dihydroxy (cis-3-

(2,5-

dimethylphenyl)-

3,4-dihydroxy-8-

methoxy-1-

azaspiro[4.5]decan2-one)

Plants - Apple Fruit 

Rotational Crops Wheat Straw, 

Chard 

Wheat Forage, 

Hay, Grain; 

Turnip Leaves, 

Roots 

Ruminant - - 

Poultry - - 

Rat - - 

Water - - 

BYI 08330-

desmethylketohydroxyglucoside 

(isomers), in 

leaves also 

+BYI 08330-

ketohydroxyformiatePlants - Apple Fruit & 

Leaves; Cotton 

Gin Trash & Lint 

+ 

Rotational Crops Wheat Forage, 

Hay, Straw; Chard 

Wheat Grain; 

Turnip Leaves 

Ruminant - - 

Poultry - - 

Rat - - 
Page 61 of 65 

Table B.2. Tabular Summary of Metabolites and Degradates

Chemical Name 

(other names in 

parenthesis) 

Matrix 

Percent TRR (PPM)1

Matrices - Major Structure 

Residue 

(>10%TRR) 

Matrices - Minor 

Residue 

(<10%TRR) 

glycoside Water - - 

BYI 08330-

desmethyl-enol 

Or 

BYI 08330-4-

hydroxy-enol 

(cis-3-(2,5-

dimethylphenyl)-4,8-

dihydroxy-1-

azaspiro[4.5]dec-3-

en-2-one)

Plants - Potato Tops 

Rotational Crops - - 

Ruminant Goat Muscle, 

Liver, Kidney, 

Milk; 

Poultry - - 

Rat Excreta Liver, Kidney, 

Plasma 

Water Aerobic Soil 

BYI 08330-

desmethyl-enolGlc (Glucoside of 

3-(2,5-

dimethylphenyl)-

4,8-dihydroxy-1-

azaspiro[4.5]dec-3-

en-2-one)

Plants Cotton Gin Trash 

& Seed; Potato 

Tops 

Rotational Crops - - 

Ruminant - - 

Poultry - - 

Rat - - 

Water - - 

BYI 08330-MAamide (1-{[(2,5-

dimethylphenyl)(hyd

roxy)acetyl]amino}-

4-

methoxycyclohexan

ecarboxylicacid)

Plants - Cotton Gin Trash 

Cotton Lint 

Rotational Crops - - 

Ruminant - - 

Poultry - - 

Rat - - 

Water Aerobic Soil, 

Aerobic Outdoor 

BYI 08330-

mandelic acid 

amide (2-(2,5-

dimethylphenyl)-2- 

hydroxyacetamide)

Plants Cotton Lint Cotton Gin Trash 

Cotton Seed 

Rotational Crops - - 

Ruminant - - 

Poultry - - 

Rat - - 

Water - - 

BYI 08330-

mandelic acid 

((2,5-

dimethylphenyl)(hyd

roxy) 

Plants - Cotton Lint 

Rotational Crops - - 

Ruminant - - 

Poultry - - 
Page 62 of 65 

Table B.2. Tabular Summary of Metabolites and Degradates

Chemical Name 

(other names in 

parenthesis) 

Matrix 

Percent TRR (PPM)1

Matrices - Major Structure 

Residue 

(>10%TRR) 

Matrices - Minor 

Residue 

(<10%TRR) 

acetic acid) Rat - - 

Water - - 

BYI 08330-

hydroxymorphol

inedion (3-(2,5-

dimethylphenyl)-3- 

hydroxy-9-methoxy4-oxa1-

azaspiro[5.5]undeca

ne-2,5- 

dione)

Plants Cotton Gin Trash 

Rotational Crops - - 

Ruminant - - 

Poultry - - 

Rat - - 

Water - - 

BYI 08330-

olefine (2-(2,5-

dimethylphenyl)-2-

hydroxy-N-(4-

methoxycyclohex-1-

en-1-yl)acetamide 

or 

2-(2,5-

dimethylphenyl)-2-

hydroxy-N-(4-

methoxycyclohexyli

dene) acetamide)

Plants - Cotton Gin Trash 

Cotton Lint 

Rotational Crops - - 

Ruminant - - 

Poultry - - 

Rat - - 

Water - - 

BYI 08330-

ketohydroxyalcohol (cis-3-

hydroxy-3-[5-

(hydroxymethyl)-2-

methylphenyl]-8-

methoxy-1-

azaspiro[4.5]decane2,4-dione)

Plants - - 

Rotational Crops Wheat Straw, 

Hay, Grain; 

Chard, Turnip 

Leaves 

Ruminant - - 

Poultry - - 

Rat - - 

Water - - 

BYI 08330-

ketohydroxyalcoholglycoside 

(glycoside of cis-3-

hydroxy-3-[5-

(hydroxymethyl)-2-

methylphenyl]-8-

methoxy-1-

azaspiro[4.5]decane2,4-dione)

Plants - - 

Rotational Crops Wheat Forage, 

Straw, Hay, 

Grain; Turnip 

Leaves 

Ruminant - - 

Poultry - - 

Rat - - 

Water - - 

BYI 08330- 

enol-alcohol (cis4-hydroxy-3-[5-

(hydroxymethyl)-2-

methylphenyl]-8-

methoxy-1-

azaspiro[4.5]dec-3-

en-2-one)

Plants - Potato Tops 

Rotational Crops - - 

Ruminant - - 

Poultry - - 

Rat Liver, Kidney, 

Excreta 
Page 63 of 65 

Table B.2. Tabular Summary of Metabolites and Degradates

Chemical Name 

(other names in 

parenthesis) 

Matrix 

Percent TRR (PPM)1

Matrices - Major Structure 

Residue 

(>10%TRR) 

Matrices - Minor 

Residue 

(<10%TRR) 

Water - - 

BYI 08330-

desmethyl-dihydroxy-Glc 

(glucoside of 

(5s,8s)-3-(2,5-

dimethylphenyl)-

3,4,8-trihydroxy-1-

azaspiro[4.5]decan2-one)

Plants - - 

Rotational Crops Wheat Straw, 

Forage, Hay 

Wheat Grain; 

Chard, Turnip 

Leaves 

Ruminant - - 

Poultry - - 

Rat - - 

Water - - 

BYI 08330-

desmethyl-dihydroxy 

((5s,8s)-3-(2,5-

dimethylphenyl)-

3,4,8-trihydroxy-1-

azaspiro[4.5]decan2-one)

Plants - - 

Rotational Crops Wheat Straw, 

Hay, Grain, 

Turnip Leaves 

Ruminant - - 

Poultry - - 

Rat - - 

Water - - 

BYI 08330-

desmethyldihydroxy-GlcMA (glucosylmalonic acid 

conjugate of (5s,8s)-

3-(2,5-

dimethylphenyl)-

3,4,8-trihydroxy-1-

azaspiro[4.5]decan2-one)

Plants - - 

Rotational Crops Wheat Hay Wheat Straw, 

Grain; Chard, 

Turnip Leaves, 

Roots 

Ruminant - - 

Poultry - - 

Rat - - 

Water - - 

BYI 08330-

desmethyl-enol -

alcohol ((5s,8s)-

4,8-dihydroxy-3-[5-

(hydroxymethyl)-2-

methylphenyl]-1-

azaspiro[4.5]dec-3-

en-2-one)

Plants - - 

Rotational Crops Wheat Forage, 

Straw, Hay, 

Grain; Chard, 

Turnip Leaves, 

Roots 

Ruminant - - 

Poultry - - 

Rat - - 

Water - - 

BYI 08330-

desmethylketohydroxyGlc-MA (isomer 

1 & isomer 2) 

(glucosyl-malonic 

acid conjugate of 

Plants - - 

Rotational Crops Wheat Forage, 

Hay, Straw 

Wheat Grain; 

Turnip Leaves 

Ruminant - - 

Poultry - - 

Rat - - 
Page 64 of 65 

Table B.2. Tabular Summary of Metabolites and Degradates

Chemical Name 

(other names in 

parenthesis) 

Matrix 

Percent TRR (PPM)1

Matrices - Major Structure 

Residue 

(>10%TRR) 

Matrices - Minor 

Residue 

(<10%TRR) 

(5s,8s)-3-(2,5-

dimethylphenyl)-

3,8-dihydroxy-1-

azaspiro[4.5]decane2,4-dione)

Water - - 

Apple, 46904480; 0.982 lb ai/A; 2.5X rate; first application at growth stage 69 BBCH and the second application 

at growth stage 71; 63 days (fruit & leaves). 

Lettuce, 46695529; 0.15 lb ai/A; 0.9X rate; two applications at a 14-day RTI; 7 days. 

Cotton, 46904479; 0.23 lb ai/A; first application at growth stage 15 BBCH and the second application at growth 

stage 85; 39 days (gin trash, lint and undelinted seed). 

Potato, 46904484; 0.275 lb ai/A; 1.7X rate; three applications at a 21-day RTI; 14 days. 

Cow (PH label); 46695532; 8.01 ppm; 6.8X MTDB; 7 days; 23 hour PSI 

Hen (PH label); 46695534; 11.33 ppm; 470X MTDB; 14 days; 24 hour PSI 

Rotational Crops; 46695612; Swiss chard, turnips, and spring wheat; 1.2X, applied to bare soil;90-day PBI

Rat Metabolism; 46904504, 46904561; 2, 100, 1000 mg/kg oral dose; Wistar, 2-day depuration.
Page 65 of 65 

Appendix C. Tolerance Summary Table for Spirotetramat 

Commodity 

Proposed 

Tolerance 

(ppm) 

Recommended 

Tolerance 

(ppm) 

Correct Commodity Definition 

Citrus, crop group 10 0.5 0.60 Fruit, citrus, group 10

Citrus, oil 4 6.0 

Leafy vegetables, crop group 4 5 9.0 Vegetable, leafy, except Brassica, group 4

Pome fruit, crop group 11 0.5 0.70 Fruit, pome, group 11

Apple pomace, wet 0.6 - 

Stone fruit, crop group 12 2 4.5 Fruit, stone, group 12

Grape, wine and table grape, Crop 

Group 13F 1 1.3 

Small fruit vine climbing subgroup, 

except fuzzy kiwifruit, subgroup 13-

07F

Grapes, raisins 2.5 3.0 Grape, raisin

Strawberry 0.5 0.40 

Bulb vegetables, onion, crop group 3A 0.3 0.30 Onion, bulb, subgroup 3A-07 

Fruiting vegetables, crop group 8 1 2.5 Vegetable, fruiting, group 8

Tomato, dried 2.5 - 

Cucurbits, crop group 9 0.2 0.30 Vegetable, cucurbit, group 9

Brassica, head and stem, crop group 5A 1 2.5 Brassica, head and stem, subgroup 5A

Leafy Brassica, crop group 5B 16 8.0 Brassica, leafy greens, subgroup 5B

Potato, crop group 1C 1 0.60 Vegetable, tuberous and corm, subgroup 1C

Potato, flakes 2.5 1.6 

Tree Nuts, Crop Group 14 0.5 0.25 Nut, tree, group 14

Almond, hulls 9 9.0 

Hop (dried cones) 10 10 Hop, dried cones 

- - 0.01 Milk 

Cattle, meat 0.01 0.02 

Cattle, fat 0.01 0.02 

Cattle, liver 0.01 - 

Cattle, meat byproducts, except liver 0.02 0.02 Cattle, meat byproducts 

Goat, meat 0.01 0.02 

Goat, fat 0.01 0.02 

Goat, liver 0.01 

Goat, meat byproducts, except liver 0.02 0.02 Goat, meat byproducts 

Hog, meat 0.01 - 

Hog, fat 0.01 - 

Hog, liver 0.01 - 

Hog, meat byproducts, except liver 0.02 - 

Sheep, meat 0.01 0.02 

Sheep, fat 0.01 0.02 

Sheep, liver 0.01 - 

Sheep, meat byproducts, except liver 0.02 0.02 Sheep, meat byproducts 

Horse, meat 0.01 0.02 

Horse, fat 0.01 0.02 

Horse, liver 0.01 - 

Horse, meat byproducts, except liver 0.02 0.02 Horse, meat byproducts