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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

DATE: 27-MAR-2013

SUBJECT: Spirotetramat. Human-Health Risk Assessment for the Proposed Uses in/on 

Taro, Leaves; Watercress; Pomegranate; Banana; Vegetable, Bulb, Group 3-07; 

Low growing Berry Subgroup 13-07H, Except Strawberry and Lowbush 

Blueberry; Bushberry Subgroup 13-07B; Artichoke, Globe; Vegetable, Fruiting, 

Group 8-10; Fruit, Pome, Group 11-10; Fruit, Citrus, Group 10-10; Pineapple; 

and Coffee; and Tolerances without U.S. Registration in/on Corn, Sweet, Kernel 

Plus Cob with Husks Removed as Part of the U.S.-Canada Regulatory

Cooperation Council (RCC) Pilot Project.

PC Code: 392201 DP Barcode: D398509

Decision Nos.: 459092; 459087 Registration Nos.: 264-1050, 264-1065, 264-1051

Petition No.: 1E7958 Regulatory Action: Section 3 Registration

Risk Assessment Type: Single Chemical/Aggregate Case No.: 7452

TXR No.: NA CAS No.: 203313-25-1

MRID No.: None 40 CFR: §180.641

FROM: Julie L. Van Alstine, MPH, Environmental Health Scientist 

George F. Kramer, Ph.D., Senior Chemist 

Kelly M. Lowe, Environmental Scientist

Chester E. Rodriguez, Ph.D., Pharmacologist

Risk Assessment Branch 1 (RAB1)

Health Effects Division (HED; 7509P)

THROUGH: Dana M. Vogel, Deputy Director 

RAB1/HED (7509P)

TO: Barbara Madden/Laura Nollen, RM 05

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 the proposed 

Section 3 registration uses of the 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 taro, watercress, 

pomegranates, bananas, bulb vegetables, low-growing berries (except strawberries), bushberries, 

globe artichokes, fruiting vegetables, pome fruit, citrus fruit, pineapples, and coffee and, as part 

of the U.S.-Canada RCC pilot project, the establishment of a tolerance without U.S. registration 

for residues of spirotetramat in/on corn, sweet, kernel plus cob with husks removed.
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A summary of the findings and an assessment of human-health risk resulting from the proposed 

and registered uses of spirotetramat are provided in this document. The risk assessment and 

dietary exposure assessment were provided by Julie Van Alstine (RAB1); the residue chemistry

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

Chester Rodriguez (RAB1); the occupational exposure and residential assessment by Kelly Lowe 

(RAB1); and the drinking water exposure assessment by José Meléndez of the Environmental 

Fate and Effects Division (EFED). 

The most recent human-health risk assessment for spirotetramat was for a Section 18 emergency

exemption registration request for use on watercress in Florida and Tennessee, and was 

completed on 02-AUG-2012 (Memo, J. Van Alstine, et al.; D399022). The most recent Section 

3 human-health risk assessment for spirotetramat was for cotton, legume vegetables including 

soybean (crop groups 6 and 7a), and tropical fruit, and was completed on 22-DEC-2010 (Memo, 

J. Van Alstine, et al.; D368785).
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Table of Contents

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

2.0 HED Recommendations.................................................................................................... 7

2.1 Data Deficiencies ............................................................................................................ 8

2.2 Tolerance Considerations.............................................................................................. 8

2.2.1 Enforcement Analytical Method ............................................................................... 8

2.2.2 Recommended Tolerances......................................................................................... 9

2.2.3 Revisions to Petitioned-For Tolerances.................................................................. 10

2.2.4 International Harmonization................................................................................... 10

2.3 Label Recommendations.............................................................................................. 10

3.0 Introduction...................................................................................................................... 11

3.1 Chemical Identity ......................................................................................................... 11

3.2 Physical/Chemical Characteristics ............................................................................. 12

3.3 Pesticide Use Pattern.................................................................................................... 13

3.4 Anticipated Exposure Pathways................................................................................. 15

3.5 Consideration of Environmental Justice.................................................................... 15

4.0 Hazard Characterization and Dose-Response Assessment.......................................... 16

4.1 Toxicology Studies Available for Analysis................................................................. 16

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME) ............................. 16

4.2.1 Dermal Absorption................................................................................................... 16

4.3 Toxicological Effects .................................................................................................... 17

4.3.1 Summary of Toxicological Effects........................................................................... 17

4.4 Safety Factor for Infants and Children (FQPA SF).................................................. 19

4.4.1 Completeness of the Toxicology Database.............................................................. 19

4.4.2 Evidence of Neurotoxicity........................................................................................ 19

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal........ 19

4.4.4 Residual Uncertainty in the Exposure Database ................................................... 19

4.5 Toxicity Endpoint and Point of Departure Selections.............................................. 20

4.5.1 Dose-Response Assessment...................................................................................... 20

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment..... 21

4.5.3 Cancer Classification and Risk Assessment Recommendation............................ 21

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment............................................................................................................................... 21

5.0 Dietary Exposure and Risk Assessment......................................................................... 22

5.1 Residues of Concern Summary and Rationale.......................................................... 22

5.2 Food Residue Profile .................................................................................................... 23

5.3 Water Residue Profile.................................................................................................. 24

5.4 Dietary Risk Assessment.............................................................................................. 25

5.4.1 Description of Residue Data Used in Dietary Assessment.................................... 25

5.4.2 Percent Crop Treated Used in Dietary Assessment .............................................. 25

5.4.3 Acute Dietary Risk Assessment............................................................................... 25

5.4.4 Chronic Dietary Risk Assessment........................................................................... 25

5.4.5 Cancer Dietary Risk Assessment............................................................................. 26

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 26

6.1 Residential Bystander Post-Application Inhalation Exposure ................................ 26

6.2 Spray Drift.................................................................................................................... 27

7.0 Aggregate Exposure/Risk Characterization.................................................................. 27

7.1 Acute Aggregate Risk................................................................................................... 27

7.2 Chronic Aggregate Risk .............................................................................................. 27

8.0 Cumulative Exposure/Risk Characterization ............................................................... 28
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9.0 Occupational Exposure/Risk Characterization ............................................................ 28

9.1 Short- and Intermediate-Term Handler Risk ........................................................... 28

9.2 Short- and Intermediate-Term Post-Application Risk............................................. 33

9.2.1 Dermal Post-Application Risk................................................................................. 33

9.2.2 Inhalation Post-Application Risk............................................................................ 35

10.0 References......................................................................................................................... 36

Appendix A. Toxicology Profile and Executive Summaries .................................................. 37

A.1 Toxicology Data Requirements................................................................................... 37

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

Appendix B. Physical/Chemical Properties............................................................................. 44

Appendix C. Review of Human Research................................................................................ 44
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1.0 Executive Summary

Background: Spirotetramat is a tetramic acid derivative (ketoenole) and is active against 

sucking insects in a variety of plants. It is systemic (xylem and phloem mobile) and can control 

hidden pests and protect new shoots.

Permanent tolerances for the combined residues of spirotetramat and its metabolites BYI 08330-

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

as spirotetramat equivalents, are currently established in/on a variety of crops (40 CFR 

§180.641). There are no registered residential uses for spirotetramat.

The Interregional Research Project Number 4 (IR-4) has submitted a Section 3 request to register 

a 2 lb ai/gal suspension-concentrate (SC) formulation (Movento®; EPA Reg. No. 264-1050), a 

1.25 lb ai/gal SC formulation (Ultor®; EPA Reg. No. 264-1065), and a 1.25 lb ai/gal oildispersion (OD) formulation (BYI 8330 OD; EPA Reg. No. 264-1051) for use on taro, 

watercress, pomegranates, bananas, bulb vegetables, low-growing berries (except strawberries), 

bushberries, globe artichokes, fruiting vegetables, pome fruit, citrus fruit, pineapples, and coffee. 

The end-use products are proposed for 2 to 5 foliar spray applications at 0.05-0.25 lb 

ai/A/application with minimum retreatment intervals (RTIs) of 7-30 days, for maximum seasonal 

rates of 0.16-1.25 lb ai/A. The proposed labels allow for applications via aerial, groundboom, 

chemigation, and/or airblast equipment, depending on the crop. Preharvest intervals (PHIs) of 1-

14 days are proposed. The rotational crop plantback intervals (PBIs) are 30 days for all nonlabeled crops. In conjunction with this petition, IR-4 has requested the establishment of 

permanent tolerances for the residues of the insecticide spirotetramat, including its metabolites 

and degradates, in or on the commodities summarized in Table 2.2.2.

Additionally, Canada’s Pest Management Regulatory Agency (PMRA) has received a petition 

for the use of spirotetramat on sweet corn in Canada. The Agency has not received a similar 

petition; however, as part of the RCC pilot project, HED has recommended a tolerance without 

U.S. registration for residues of spirotetramat and its metabolites and degradates in/on corn, 

sweet, kernel plus cob with husks removed based on the PMRA’s evaluation of the Canadian 

sweet corn residue data. For more information about the RCC pilot project, please refer to 

http://www.epa.gov/oppfead1/international/naftatwg/us-canada-rcc.html. 

Hazard Assessment: The target organs of toxicity following subchronic and chronic oral 

exposures to spirotetramat were different in rats and dogs. The thyroid and thymus glands were 

the target organs identified in subchronic and chronic toxicity studies in dogs while the testes 

were the target organs identified in rats. The dog was the most sensitive species, and in both 

species, males were more sensitive than females. The thyroid effects in the dog consisted of 

lower circulating levels of thyroid hormones (T3 and/or T4) along with a reduction in follicle 

size, a possible indication of reduced amount of colloid. The effects in the dog thymus were 

described microscopically as involution, which also resulted in decreased organ weight.

In rats, reported testicular effects consisted of abnormal spermatozoa and hypospermia in the 

epididymis, decreased testicular weights, and testicular degenerative vacuolation. An 

investigative subchronic study where rats were dosed with the primary enol metabolite of 

spirotetramat reproduced the same testicular effects as the parent chemical, suggesting that this 

metabolite is at minimum a primary contributor to the observed male reproductive toxicity. 

Consistent with this notion, spirotetramat orally administered to rats was demonstrated to be 

extensively metabolized and males were noted to achieve much higher systemic exposures than 
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their female counterparts, which helps explain the gender dependent differences. Other effects 

reported in a rat chronic toxicity study were associated with kidney effects consisting of 

decreased organ weight and tubular dilatation.

There is no evidence of increased pre- or postnatal susceptibility. Developmental toxicity in the 

rat occurred only in the presence of maternal toxicity at the limit dose. Reduced fetal weight and 

an increased incidence of maltransformations and skeletal variations were reported in the 

presence of impaired food consumption and decreased body weight and body-weight gain. No 

developmental effects were reported in the rabbit study, while similar maternal effects as the rat 

were reported.

In one- and two-generation rat reproductive toxicity studies, male reproductive toxicity

(abnormal sperm cells and reproductive performance) similar to that reported in subchronic 

toxicity studies with adult rats was reported in the first generation (F1) males. The effects were 

reported at relatively high dose levels: sperm abnormalities and testicular toxicity were seen at 

419 and 616 mg/kg/day, respectively in the two-generation reproduction study and at 1000 

mg/kg/day (limit dose) in a special male reproductive toxicity study to determine the onset of 

testicular toxicity. In all cases, a well-defined no-observed adverse-effect level (NOAEL) was 

established.

No evidence of tumor formation was found in long-term carcinogenicity studies in mice and rats. 

Spirotetramat was also negative for mutagenicity and clastogenicity in several standard in vivo

and in vitro assays.

Although the toxicology database for spirotetramat shows effects in the thymus gland in dog 

studies, the results of a recently submitted and reviewed immunotoxicity study in rats does not 

indicate any functional deficits in immune function. Thymus involution has been demonstrated 

to occur when hypothyroidism is induced in animals, so it is reasonable to conclude that the 

thymus involution in dogs was secondary to the thyroid effects, rather than a direct effect on the 

immune system.

Consistent with previous risk assessments for spirotetramat (Memo, J. Tyler, et al., 14-MAY2008, D333437; Memo, J. Van Alstine, et al., 22-DEC-2010, D368785; Memo, J. Van Alstine, et 

al., 02-AUG-2012, D399022), the spirotetramat risk assessment team recommends that the 10X 

Food Quality Protection Act Safety Factor (FQPA SF) be reduced to 1X for all exposure 

scenarios, as discussed in Section 4.4.

Food Residue Profile: The nature of the residue in plants and livestock is adequately 

understood. Organization for Economic Co-operation and Development (OECD) tolerancecalculation procedures and the submitted residue data sets were used to calculate the HEDrecommended tolerances. Additionally, as part of the RCC pilot project, HED has recommended 

a tolerance without U.S. registration for residues of spirotetramat and its metabolites in/on corn, 

sweet, kernel plus cob with husks removed based on PMRA’s evaluation of the Canadian residue 

data for sweet corn. There is an adequate residue analytical method for the purposes of tolerance 

enforcement. The submitted field trial residue data are adequate and, provided that the data 

deficiencies identified in Section 2.1 are addressed, there are no residue chemistry issues that 

would preclude establishing unconditional tolerances for residues of spirotetramat and its 

metabolites, as outlined in Table 2.2.2.

Exposure/Risk Assessment Characterization: Acute and chronic risk assessments were 
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conducted for dietary exposure based on the existing and proposed uses. The acute and chronic 

assessments directly incorporated drinking water estimates. Assumptions for the acute 

assessment included tolerance-level residues for all foods, Dietary Exposure Evaluation Model 

(DEEM) 7.81 default processing factors (where provided), and 100% crop-treated (CT). 

Assumptions for the chronic dietary assessment included average field trial residues for some 

commodities, tolerance-level residues for the remaining commodities, and 100% CT. Some 

empirical processing factors were used in the chronic assessment along with DEEM 7.81 default 

processing factors (where provided). All exposure and risk estimates were not of concern. A 

cancer dietary assessment was not conducted because spirotetramat is classified as “not likely to 

be carcinogenic to humans.”

There are no registered or proposed residential uses for spirotetramat; therefore, a residentialexposure assessment was not conducted.

Since there are no residential uses, the acute and chronic aggregate risks are made up only of 

dietary sources (food and drinking water) and the dietary exposure analyses represent acute and 

chronic aggregate exposure, respectively. 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.

The occupational handler and post-application assessments were completed assuming the 

maximum label application rate. Based on the proposed use patterns, there is potential for shortand intermediate-term occupational exposure to spirotetramat during mixing, loading, applying, 

and other handling tasks; and during post-application activities. Additionally, since the same 

endpoint and point of departure (POD) were selected for short- and intermediate-term durations, 

short-term exposure and risk estimates are considered to be protective of potential longer-term 

exposure and risk. Chronic exposure is not expected for the proposed agricultural uses. The 

level of concern (LOC) for occupational dermal and inhalation exposures are for margins of 

exposure (MOEs) <100. For the proposed uses, all occupational short- and intermediate-term 

handler (with baseline attire) and post-application (on Day 0) MOEs were >100. The 

spirotetramat label includes a personal-protective equipment (PPE) requirement that applicators 

and other handlers wear long-sleeved shirts, long pants, chemical-resistant gloves, shoes plus 

socks, and protective eyewear.

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. Please refer to Appendix C for a 

discussion of the human study data used in this risk assessment. 

2.0 HED Recommendations

Pending resolution of the deficiencies outlined below, there are no other residue chemistry, 

occupational, or toxicology data deficiencies that would preclude the establishment of permanent 

tolerances for residues of spirotetramat and it metabolites and degradates as outlined in Table 

2.2.2. 
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2.1 Data Deficiencies

860.1200 Directions for Use

 Currently the label specifies a 30-day PBI for all crops; however, a 260-day PBI for 

rotational crops is required to support the proposed use on watercress. 

 As no residue data were submitted for an OD or equivalent formulation, the use 

directions for the subject crops should be removed from the BYI 8330 OD label.

 Since all of the banana field trials were performed in HI, the registration for use on this 

crop should be limited to the state of HI.

860.1550 Proposed Tolerances

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

 Revised tolerance levels and commodity definitions, as presented in Table 2.2.2.

860.1650 Submittal of Analytical Reference Standards

 The analytical reference standard for BYI 08330-ketohydroxy has expired and the 

standards for the isotopically labeled internal standards of BYI 08330-enol and BYI 

08330-ketohydroxy will soon expire (7/11/2013). The registrant should either recertify

the lot in the repository and send an updated certificate of analysis (COA), or submit new 

standards (different lot #) if the previous lots will not be recertified. If new standards are 

being submitted, then they should be sent to the Analytical Chemistry Lab, which is 

located at Fort Meade, to the attention of either Theresa Cole or Thuy Nygen at the 

following address:

USEPA

National Pesticide Standards Repository/Analytical Chemistry Branch/OPP

701 Mapes Road

Fort George G. Meade, MD 20755-5350

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Several high-performance liquid chromatography with tandem mass spectrometry (HPLCMS/MS) residue analytical methods have been submitted 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. 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. 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. 

There is an adequate residue analytical method for the purposes of tolerance enforcement. For 

the current petition, samples were analyzed for residues of spirotetramat and its metabolites BYI 
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08330-enol, BYI 08330-ketohydroxy, BYI 08330-mono-hydroxy, and BYI 08330-enolglucoside using a HPLC-MS/MS method, Method 00857, which is the current enforcement 

method for crop commodities. Residues of each metabolite were reported in parent equivalents. 

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 using isotopically labeled internal standards. 

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

08330-enol-Glc were extracted from the plant commodity using a blender with acidic 

acetonitrile/water (4/1, v/v). After subsequent clean-up of the extract through a Bond Elut clean 

polyethylene frit, the corresponding internal standards were added. The solution was made up to 

volume, diluted, and subjected to HPLC-MS/MS with multiple-reaction monitoring of two 

transitions for each matrix and analyte for quantitation and confirmation purposes. The limit of 

quantitation (LOQ) was 0.01 ppm for each analyte on all tested plant commodities with the 

exception of roasted coffee bean (BYI 08830-glucoside had an LOQ of 0.05 ppm) and freezedried coffee (the LOQ was 0.1 ppm for each analyte). The method was adequate for data 

collection based on acceptable concurrent method recovery data. 

2.2.2 Recommended Tolerances

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

residues of the insecticide spirotetramat, including its metabolites and degradates, in or on the 

commodities in the table below. Compliance with the tolerance levels specified below is to be 

determined by measuring only the sum of spirotetramat (cis-3-(2,5-dimethlyphenyl)-8-methoxy2-oxo-1-azaspiro[4.5]dec-3-en-4-yl-ethyl carbonate]) and its metabolites cis-3-(2,5-

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

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

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

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

stoichiometric equivalent of spirotetramat, in or on the following commodities summarized in 

Table 2.2.2.

Table 2.2.2. Tolerance Summary for Spirotetramat.

Commodity Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity 

Definition

Taro, leaves 9 9.0

Watercress 1.5 2.0

Pomegranate 0.5 0.50

Banana14 4.0

Vegetable, bulb, group 3-07 0.6 0.80

Low growing berry subgroup 

13-07H, except strawberry 0.3 0.30

Low growing berry subgroup 13-

07H, except strawberry and 

lowbush blueberry

Bushberry subgroup 13-07B 3 3.0

Artichoke, globe 2 1.5

Vegetable, fruiting, crop 

group 8-10 2.5 2.5 Vegetable, fruiting, group 8-10

Fruit, pome, crop group 11-

10 0.7 0.70 Fruit, pome, group 11-10 

Fruit, citrus, crop group 10-

10 0.6 0.60 Fruit, citrus, group 10-10

Pineapple 0.3 0.30

Pineapple, process residue 0.36 -
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Table 2.2.2. Tolerance Summary for Spirotetramat.

Commodity Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity 

Definition

Coffee, green bean 0.2 0.20

Coffee, instant - 0.50

Coffee, roasted bean 0.32 -

Corn, sweet, kernel plus cob 

with husks removed2 - 1.5

1 This tolerance should be established under 40 CFR §180.641(c) Tolerances with regional registrations.

2 There are no U.S. registrations as of [date] for use on corn, sweet.

2.2.3 Revisions to Petitioned-For Tolerances

The OECD tolerance calculation procedures were utilized to determine appropriate tolerance 

levels. Based on these procedures, HED has recommended tolerances for residues of 

spirotetramat and its metabolites that are different than the IR-4-proposed tolerances in/on 

watercress, vegetable, bulb, group 3-07, and artichoke, globe. 

IR-4 has proposed tolerances for residues of spirotetramat and its metabolites in/on pineapple, 

process residue and coffee, roasted bean. Since the HED-calculated tolerance values for these 

processed commodities are less than the HED-recommended tolerances for residues of 

spirotetramat in/on pineapple and coffee, green bean, separate tolerances for these processed 

commodities are not required. 

Although IR-4 has not requested a tolerance for coffee, instant, based on the available processing 

data, an LOQ-level tolerance of 0.50 ppm is required for this commodity. HED has also 

recommended a tolerance for residues of spirotetramat in/on corn, sweet, kernel plus cob with 

husks removed as part of the U.S.-Canada RCC pilot project.

Note to RD: With the establishment of these tolerances, the tolerances for the following 

commodities should be deleted from 40 CFR §180.641(a)(1): onion, bulb, subgroup 3A-07; 

vegetable, fruiting group 8; fruit, citrus, group 10; fruit, pome, group 11; and okra. HED also 

notes that the established tolerances for residues in/on feijoa, papaya, and Spanish lime in 40 

CFR §180.641(a)(1) are incorrect and the previously recommended tolerance for residues in/on 

persimmon is missing. The correct tolerances are: 2.5 ppm for residues in/on feijoa, 0.35 ppm 

for residues in/on papaya, 13 ppm for residues in/on Spanish lime, and 2.5 ppm for residues 

in/on persimmon (Memo, J. Van Alstine et al., 22-DEC-2010; D368785). 40 CFR 

§180.641(a)(1) should be updated to reflect the recommended tolerances.

2.2.4 International Harmonization

The Codex tolerances/maximum residue limits (MRLs) for residues of spirotetramat in/on bulb 

vegetables, fruiting vegetables, and citrus and pome fruits cannot be harmonized as the 

U.S./Canadian residue definition includes metabolites not included in the Codex residue 

definition. The U.S. and Canadian tolerance/MRL levels for the subject crops are being 

harmonized as part of the RCC pilot project.

2.3 Label Recommendations

The submitted use directions for Movento®and Ultor®are adequate to allow evaluation of the 

residue data relative to the proposed uses except that a 260-day PBI is required to support the 
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proposed use on watercress. Since all of the banana field trials were performed in HI, the 

registration for use on this crop should be limited to the state of HI. In addition, as no residue 

data were submitted for an OD or equivalent formulation, the use directions for the subject crops 

should be removed from the BYI 8330 OD label. Revised labels are required.

3.0 Introduction

3.1 Chemical Identity

Table 3.1. 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 # 203313-25-1

End-use product/EP Movento®, Ultor®, BYI 8330 OD

Compound: BYI08330-enol

Chemical Structure

Common name BYI 08330-enol

Company experimental name BYI 08330-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 BYI 08830-ketohydroxy

Company experimental name BYI 08830-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
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Table 3.1. Test Compound Nomenclature.

Compound: BYI08330-enol-Glc

Chemical Structure

Common name BYI 08330-enol-Glc

Company experimental name BYI 08330-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

3.2 Physical/Chemical Characteristics

Spirotetramat is a systemic broad-spectrum tetramic acid insecticide (ketoenol class) that is 

applied as a preventative treatment during an early threshold of developing chewing insect 

population when sufficient leaf tissue is present for uptake and translocation to occur within 

agricultural crops. It is systemic (xylem and phloem mobile) and can control hidden pests and 

protect new shoots. Its vapor pressure is 5.6 x 10-9Pa at 20 oC. The mobility of spirotetramat is 

moderately high [partition coefficient (Kd) range 3.58-5.52 L/Kg, soil organic carbon partition 

coefficient (KOC) range 184-437 L/KgOC, moderately mobile, FAO 2000]. Spirotetramat is 
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labile, especially under aerobic soil metabolism conditions. Nonetheless, its total residues are 

relatively persistent. A table of the physicochemical properties can be found in Appendix B. 

3.3 Pesticide Use Pattern

The petitioner has submitted draft labels for the 2 lb ai/gal SC formulation (Movento®; EPA Reg. 

No. 264-1050), for the 1.25 lb ai/gal SC formulation (Ultor®; EPA Reg. No. 264-1065), and the 

1.25 lb ai/gal OD formulation (BYI 8330 OD; EPA Reg. No. 264-1051). Information pertaining 

to the proposed end-use product is listed in Table 3.3.1. A summary of the proposed use patterns 

on taro, watercress, pomegranates, bananas, bulb vegetables, low-growing berries (except 

strawberries), bushberries; globe artichokes, fruiting vegetables, pome fruit, citrus fruit, 

pineapples, and coffee is detailed in Table 3.3.2. A summary of the recommended label changes 

can be found in Section 2.3. 

Permanent tolerances for the combined residues of spirotetramat and its metabolites BYI 08330-

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

as spirotetramat equivalents, are currently established in/on a wide variety of crops and crop 

groups in 40 CFR §180.641(a)(1), ranging from 0.25 ppm in tree nut crop group 14 to 16 ppm in 

soybean hay. Tolerances are established in 40 CFR §180.641(a)(2) for the combined residues of 

spirotetramat and its BYI 08330-enol metabolite, calculated as spirotetramat equivalents, in/on 

the fat, meat, and meat byproducts of cattle, goat, horse, and sheep; the meat byproducts of hog 

and poultry; milk; and eggs. Additionally, time-limited tolerances are established in 40 CFR

§180.641(b) for the combined residues of spirotetramat and its metabolites BYI 08330-enol, BYI 

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

spirotetramat equivalents, in/on onion, dry bulb and watercress that expire on 31-DEC-2014 and 

31-DEC-2015, respectively. 

Table 3.3.1. Summary of Proposed End-Use Products.

Trade 

Name

Reg. 

No.

ai (% of 

formulation)

Formulation 

Type

Target Crops Target 

Pests Label Date

Movento® 264-

1050 22.4 SC taro, watercress, pomegranates, bananas, bulb vegetables, lowgrowing berries (except 

strawberries), bushberries, 

globe artichokes, fruiting 

vegetables, pome fruit, citrus 

fruit, pineapples, and coffee.

sucking 

insects

Draft labels 

submitted 

7/24/12

Ultor® 264-

1065 14.5 SC

BYI 8330 

OD

264-

1051 15.3 OD

Table 3.3.2. Summary of Directions for Use of Spirotetramat.

Application 

Timing, Type, 

and Equipment

Formulation [EPA 

Reg. No.]

Application 

Rate (lb 

ai/A)

Max. No. Applic. per Season1

Maximum 

Seasonal 

Application 

Rate (lb ai/A)

PHI

(days)

Use Directions and 

Limitations

Banana and Plantain

Aerial and 

Airblast

SC liquid [264-

1050; 264-1065]

OD liquid [264-

1051]

0.16 – 0.25

Not specified on label: assume 

maximum of 5 apps/crop season 

at maximum rate and maximum 

of 7 apps/crop season at 

minimum rate

1.25 1

RTI = 14 days

REI = 24 hrs

Minimum spray volume: 

50 gallons per acre (GPA) 

ground, 10 GPA aerial
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Table 3.3.2. Summary of Directions for Use of Spirotetramat.

Application 

Timing, Type, 

and Equipment

Formulation [EPA 

Reg. No.]

Application 

Rate (lb 

ai/A)

Max. No. Applic. per Season1

Maximum 

Seasonal 

Application 

Rate (lb ai/A)

PHI

(days)

Use Directions and 

Limitations

Bushberry subgroups 13-07B and 13-07H

Aerial and 

Groundboom

SC liquid [264-

1050; 264-1065]

OD liquid [264-

1051]

0.13-0.16

Not specified on label: assume 

maximum of 2 apps/crop season 

at maximum rate and maximum 

of 3 apps/crop season at 

minimum rate 

0.47 7

Do not apply until after 

petal fall.

RTI = 7 days

REI = 24 hrs

Minimum spray volume: 

30 GPA ground, 10 GPA 

aerial

Coffee

Aerial and 

Airblast

SC liquid [264-

1050; 264-1065]

OD liquid [264-

1051]

0.13-0.16

Not specified on label: assume 

maximum of 2 apps/crop season 

at maximum rate and maximum 

of 3 apps/crop season at 

minimum rate

0.47 14

Do not apply until after 

petal fall.

RTI = 21 days

REI = 24 hours

Minimum spray volume: 

30 GPA ground, 10 GPA 

aerial

Pineapple

Aerial and 

Groundboom

SC liquid [264-

1050; 264-1065]

OD liquid [264-

1051]

0.16

Not specified on label: assume 

maximum of 2 apps/crop season 

at maximum rate 0.32 1

RTI = 14 days

REI = 24 hours

Minimum spray volume: 

30 GPA ground, 10 GPA 

aerial

Pomegranate

Aerial and 

Airblast

SC liquid [264-

1050; 264-1065]

OD liquid [264-

1051]

0.13-0.16

Not specified on label: assume 

maximum of 2 apps/crop season 

at maximum and minimum rate

0.32 1

RTI = 14 days

REI = 24 hours

Minimum spray volume: 

50 gallons per acre (GPA) 

ground, 10 GPA aerial

Bulb vegetables subgroups 3-07A and 3-07B

Aerial, 

Groundboom, 

Chemigation

SC liquid [264-

1050; 264-1065]

OD liquid [264-

1051]

0.08

Not specified on label: assume 

maximum of 2 apps/crop season 

at maximum rate 0.16

3-07A: 

3

3-07B: 

7 

RTI = 7 days

REI = 24 hours

Minimum spray volume: 

15 GPA ground, 5 GPA 

aerial

Globe artichoke

Aerial, 

Groundboom, 

Chemigation

SC liquid [264-

1050; 264-1065]

OD liquid [264-

1051]

0.08-0.13

Not specified on label: assume 

maximum of 3 apps/crop season 

at maximum rate and maximum 

of 6 apps/crop season at 

minimum rate 

0.5 3

RTI = 7 days

REI = 24 hours

Minimum spray volume: 

15 GPA ground, 5 GPA 

aerial

Watercress

Aerial, 

Groundboom, 

Chemigation

SC liquid [264-

1050; 264-1065]

OD liquid [264-

1051]

0.06-0.2

Not specified on label: assume 

maximum of 2 apps/crop season 

at maximum rate and maximum 

of 6 apps/crop season at 

minimum rate 

0.4 3

RTI = 7 days

REI = 24 hours

Minimum spray volume: 

15 GPA ground, 5 GPA 

aerial
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Table 3.3.2. Summary of Directions for Use of Spirotetramat.

Application 

Timing, Type, 

and Equipment

Formulation [EPA 

Reg. No.]

Application 

Rate (lb 

ai/A)

Max. No. Applic. per Season1

Maximum 

Seasonal 

Application 

Rate (lb ai/A)

PHI

(days)

Use Directions and 

Limitations

Additional Restrictions for all Crops:

Movento®and Ultor® must be tank-mixed with a spray adjuvant/additive. BYI 8330 OD may not be tank-mixed with a spray adjuvant/additive 

having sticking properties. 

Use in enclosed structures, such as greenhouses or planthouses, is not permitted.

Rotational crop PBIs: 30 days for all non-labeled crops.

1 The submitted labels did not include a maximum number of applications per season. The maximum number of 

applications was calculated by dividing the maximum seasonal application rate by the individual application rates. 

3.4 Anticipated Exposure Pathways

RD has requested an assessment of human-health risk to support the IR-4 proposed new uses of 

spirotetramat on watercress, pomegranates, bananas, bulb vegetables, low-growing berries 

(except strawberries), bushberries, globe artichokes, fruiting vegetables, pome fruit, citrus fruit, 

pineapples, and coffee and the RCC pilot project tolerance without U.S. registration for residues 

of spirotetramat and its metabolites in/on corn, sweet, kernel plus cob with husks removed. 

Humans may be exposed to spirotetramat in food and drinking water, since spirotetramat may be 

applied directly to growing crops and application may result in spirotetramat reaching surface 

and ground water sources of drinking water. There are no residential uses of spirotetramat, so 

exposure in residential or non-occupational settings is not likely. In an occupational setting, 

applicators may be exposed while handling the pesticide prior to application, as well as during 

application. There is also a potential for post-application exposure for workers re-entering 

treated fields. 

This risk assessment considers all of the aforementioned exposure pathways based on the 

proposed new uses of spirotetramat, but also considers the existing registered uses as well, 

particularly for the dietary exposure assessment. 

3.5 Consideration of Environmental Justice

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://www.hss.energy.gov/nuclearsafety/env/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 U.S. Department of 

Agriculture (USDA) under the National Health and Nutrition Examination Survey, What We Eat 

in America, (NHANES/WWEIA; 2003-2008) 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 postapplication are evaluated. 

Further considerations are currently in development as OPP has committed resources and 
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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.

4.0 Hazard Characterization and Dose-Response Assessment

Spirotetramat belongs to the class of cyclic ketoenol insecticides. The proposed insecticidal 

mode of action for these agents is based on inhibition of acetyl-CoA carboxylase, a key enzyme 

in fatty acid biosynthesis in eukaryotes and prokaryotes. Inhibition of lipogenesis, resulting in 

decreased lipid content (notably triglycerides and free fatty acids) in treated insects, hinders the 

ability of younger insects to develop and ultimately their ability to reproduce as adults. The 

mammalian toxicity database for spirotetramat does not indicate changes in plasma lipid 

parameters such as plasma levels of triglycerides and cholesterol; therefore, it is unclear if a 

lipogenesis-inhibiting mode of action also operates in mammals.

4.1 Toxicology Studies Available for Analysis

The toxicology database for spirotetramat is adequate for characterization of its hazard, toxicity

endpoint selection, and FQPA SF consideration. In the last Section 3 risk assessment (J. Van 

Alstine et al., 22-DEC-2010; D368785), immunotoxicity and subchronic neurotoxicity studies 

were reported as data gaps. Since then, an immunotoxicity study (MRID# 48525901) has been 

submitted and reviewed by the Agency. The results of the study are included in this hazard 

characterization. The Hazard and Science Policy Council (HASPOC) met on 04-OCT-2012 

(TXR# 0056480) and concluded that repeated exposure inhalation toxicity and subchronic 

neurotoxicity (SCN) studies are not required for spirotetramat at this time. 

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME)

Absorption of orally-administered spirotetramat in rats was rapid and nearly complete. In 

females, the time to maximum plasma levels (tmax) at the low dose tested of 2 mg/kg bw was 

estimated to be about 10 minutes, while at the high dose of 100 mg/kg bw, tmax was prolonged to 

42 minutes. In males, tmax was between 0.7 and 1 hour at both dose levels. The extent of 

absorption was 89-98% by 48 hours following single low (2 mg/kg bw) and higher (100 mg/kg 

bw) gavage doses, as well as repeated low doses (2 mg/kg bw). Systemic exposure estimated by

the area under the plasma concentration-time curve (AUC0-∞) was higher for male than female 

rats. At 2 mg/kg bw (single or repeated dosing), the AUC for males was about 60% higher than 

females, and much greater at the high dose. Less than 0.2% of the administered dose was 

detected in the body at 48 hours after sacrifice, and the highest concentrations were detected at 

similar levels in the liver and kidney. Spirotetramat was completely metabolized in 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 the primary enol 

metabolite. 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 %). Excretion of 

radioactivity was relatively rapid with 88-95% of the administered dose eliminated via urine and 

2-11% via feces by 48 hours of exposure.

4.2.1 Dermal Absorption

An in vivo dermal-penetration study in the rat was performed using the formulation OD150. A 
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dermal-absorption factor (DAF) of 10% was estimated based on the fraction absorbed and the 

fraction remaining at the application site (including stratum corneum) at 168 hours following a 

10-hour exposure. The fraction retained in the stratum corneum was included because 

radioactivity in the feces increased over the 168-hour time period, indicating that absorption 

continued after the 10-hour exposure.

4.3 Toxicological Effects

4.3.1 Summary of Toxicological Effects

The targets of toxicity following spirotetramat exposure were different for rats and dogs. The

thyroid and thymus glands were target organs in oral subchronic and chronic toxicity studies in 

the dog. In a 28-day study, male dogs exhibited lower circulating levels of the thyroid hormones 

T3 and T4 at a lower dose level than females. In a 90-day study, circulating levels of T4 were 

decreased in both sexes at a lower dose than were T3 levels. Decreases in T4 were also observed 

at a lower dose as compared to subchronic exposures (above) in male and female dogs in a oneyear study. The only histopathological change in the thyroid was a reduction in follicle size in 

the high-dose group, a possible indication of reduced amount of colloid. There were no 

correlative changes in thyroid weight, thyroid histopathology, or thyroid-stimulating hormone 

(TSH) in either sex. In all three dog studies (28-day, 90-day, and 1-year), there were decreases 

in thymus weights described microscopically as involution. In the one-year chronic study, the 

thymus involution was only observed in males.

In rats, the testes were the target organ following subchronic and chronic studies. 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. 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, which may be related to the excretory

and/or detoxification roles of the kidney and liver. Kidney toxicity consisted of decreased organ 

weight and tubular dilation. Similar kidney toxicity (decreased weight and histopathology) was 

also observed at higher doses (419.3 or 484.7 mg/kg bw/day) in parental animals of the F1

generation in the two-generation reproductive toxicity study in rats.

It should be noted that the thyroid and thymus were unaffected in rats at any dose tested, while 

testicular histopathology was unobserved in dogs.

No adverse findings were observed in mice up to the limit dose following long-term treatment 

with spirotetramat.

Developmental toxicity only occurred in the presence of maternal toxicity in both rats and 

rabbits. Reduced fetal weight and increased incidences of malformations and skeletal deviations 

were observed along with decreased maternal body weight and food consumption at the limit 

dose in a rat developmental toxicity study. In the rabbit, maternal toxicity included a dosedependent increase in late abortions and other clinical signs of systemic toxicity such as 

increased weight loss and impaired food and water consumption.
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The two-generation reproductive toxicity study showed evidence of male reproductive toxicity

similar to chronic and subchronic studies with adult rats. 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 one-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 spirotetramat by oral gavage. Although the data demonstrate that the decreased 

sperm counts were the result of repeated dosing with spirotetramat, it is noted that since sperm 

development is a lengthy process (approximately 8 weeks in rats and 10 weeks in humans), the 

decreased sperm counts may have resulted from single-dose toxicity to an immature precursor 

that did not manifest until 10 days later. However, while plausible, this hypothesis is unproven 

in the absence of additional mechanistic data.

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. In 

conjunction with the ADME data, which indicates that the parent chemical is completely

metabolized to the enol metabolite, these data support the conclusion that male reproductive 

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

In a 28-day dermal toxicity study in rats, there were no effects (local or systemic) reported at the 

limit dose. Spirotetramat tested positive for dermal sensitization, which was supported by two 

cases of Type IV hypersensitivity that were reported in spirotetramat manufacturing plant 

personnel.

An inhalation toxicity study based on repeated exposures to spirotetramat is not available. Based 

on an acute inhalation toxicity study in rats, spirotetramat was classified as Toxicity Category

IV, the lowest category for acute toxicity. The HASPOC concluded that a 28-day inhalation 

toxicity study is not required as a condition of registration for spirotetramat at this time (TXR# 

0056480). 

In the available acute neurotoxicity study, the only evidence of neurotoxicity was based on 

decreased motor and locomotor activity which occurred only at relatively high-dose levels (200 

mg/kg bw). As a result of the low concern for neurotoxicity in the available toxicity database, 

the HASPOC also concluded that an SCN study was not required as condition of registration 

(TXR# 0056480). Consistent with a low LOC for neurotoxicity, a preliminary review of a 

recently submitted SCN study where spirotetramat was administered to rats via the diet does not 

indicate neurotoxicity even at the highest doses tested of 585 and 707 mg/kg bw/day for males 

and females, respectively.

Although the toxicology database for spirotetramat shows effects in the thymus gland in dogs, 

the results of a recently submitted and reviewed immunotoxicity study in rats do not indicate any

functional deficits in immune function. Thymus involution has been demonstrated to occur 

when hypothyroidism is induced in animals, so it is reasonable to conclude that the thymus 
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involution in dogs was secondary to the thyroid effects, rather than a direct effect on the immune 

system.

There is no evidence of carcinogenicity; 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.

4.4 Safety Factor for Infants and Children (FQPA SF)

The RAB1 risk assessment team recommends that the FQPA SF be reduced to 1X for all 

exposure scenarios. The rationale is provided below.

4.4.1 Completeness of the Toxicology Database

The existing toxicology database for spirotetramat is complete for FQPA SF evaluation. The 

following acceptable studies are available: developmental toxicity studies in rats and rabbits, a 

one- and two-generation reproductive toxicity studies in rats, and an acute neurotoxicity study in 

rats.

4.4.2 Evidence of Neurotoxicity

There is evidence of neurotoxicity from the acute neurotoxicity study at high dose levels (200 

mg/kg bw) based on decreased motor and locomotor activity in both sexes, with males being 

more sensitive than females. However, the existing toxicological database indicates that 

spirotetramat is not a neurotoxic chemical in mammals. The decreased motor activity observed 

is not considered evidence of direct neurotoxicity because there were no effects on movement or 

gait and there were no confirmatory findings of neurological pathology observed at relatively 

high doses [lowest-observed adverse-effect level (LOAEL) of 200 mg/kg bw]. In addition, a 

preliminary review of the recently submitted SCN does not indicate a concern for neurotoxicity

even at very high dose levels administered to rats through the diet. Finally, the conclusion that 

spirotetramat is not a neurotoxic chemical is supported by the fact that the acute, subchronic, and 

developmental neurotoxicity studies available for structurally-related compounds (spirodiclofen 

and spiromesifen) do not show evidence of neurotoxicity in adults or the young.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

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.

4.4.4 Residual Uncertainty in the Exposure Database

The acute dietary food exposure assessment utilizes existing and proposed tolerance-level 

residues, DEEM 7.81 default processing factors (where provided), and 100% CT information for 

all commodities. By using these screening-level assessments, actual exposures/risks will not be 

underestimated.
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The chronic dietary food exposure assessment utilizes average field trial residues for some 

commodities, tolerance-level residues for the remaining commodities, and 100% CT. Some 

empirical processing factors were used in the chronic assessment along with DEEM 7.81 default 

processing factors (where provided). The chronic assessment is somewhat refined; however,

since it is based on reliable data, it will not underestimate exposure/risk.

The dietary drinking water assessments utilize water concentration values generated by the Tier 

1 Rice Model v.1.0. The resulting screening-level estimated drinking water concentrations 

(EDWCs) provide conservative, health-protective, high-end estimates of water concentrations 

that will not likely be exceeded.

There are no registered residential uses of spirotetramat; therefore, residential exposures are not 

anticipated. 

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

Tables 4.5.4.1 and 4.5.4.2 summarize the toxicological doses and endpoints selected for humanhealth risk assessment. Acute and chronic dietary and short- and intermediate-term inhalation 

and dermal exposure scenarios were assessed. There are no registered residential uses of 

spirotetramat.

Acute Dietary Endpoint (General Population): This dietary endpoint was based on clinical signs 

and decreased motor activity observed in the acute neurotoxicity study at the LOAEL of 200 

mg/kg bw (NOAEL = 100 mg/kg bw). The standard combined uncertainty factor (UF) of 100X 

is being applied to account for interspecies (10X) and intraspecies (10X) extrapolation. The 

FQPA SF was reduced to 1X for this exposure scenario since the toxicology database is 

complete and there were no residual uncertainties for pre- and/or postnatal susceptibility. Thus, 

the acute reference dose (aRfD) and population-adjusted dose (aPAD) are equivalent at 1.0

mg/kg bw.

Chronic Dietary (All Populations): This dietary endpoint was based on the thymus involution in 

males in the dog chronic study at the LOAEL of 20 mg/kg bw/day (NOAEL = 5 mg/kg bw/day). 

The standard combined UF of 100X is being applied to account for interspecies (10X) and 

intraspecies (10X) extrapolation. The FQPA SF was reduced to 1X for this exposure scenario 

since the toxicology database is complete and there were no residual uncertainties for pre-and or 

postnatal susceptibility. Thus, the chronic reference dose (cRfD) and population-adjusted dose 

(cPAD) are equivalent at 0.05 mg/kg bw.

Dermal [Short- (1-30 days) and Intermediate- (1-6 months) Term]- Occupational: This endpoint 

was based on late abortions (≥GD 22), clinical signs, impaired food and water consumption, and 

body-weight loss in the rabbit prenatal developmental toxicity study at the LOAEL of 40 mg/kg 

bw/day (NOAEL = 10 mg/kg bw/day). Although a 21-day rabbit dermal toxicity study was 

performed and no toxic effects were observed, such studies are based on non-pregnant adult 

animals and thus do not account for potential developmental effects.

A DAF of 10% was previously estimated based on an in vivo rat dermal-penetration study with 

an OD formulation containing spirotetramat. A LOC for MOEs <100, based on interspecies 

(10X) and intraspecies (10X) extrapolation, is adequate for this scenario. 
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Inhalation [Short- (1-30 days) and Intermediate- (1-6 months) Term]- Occupational: This 

endpoint was also based on late abortions (≥GD 22), clinical signs, impaired food and water 

consumption, and body-weight loss in the rabbit prenatal developmental toxicity study at the 

LOAEL of 40 mg/kg bw/day (NOAEL = 10 mg/kg bw/day). A LOC for MOEs <100, based on 

interspecies (10X) and intraspecies (10X) extrapolation, is adequate for this scenario. 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

For occupational exposure, dermal and inhalation exposures can be combined since the 

toxicological effects of concern are the same and were identified from the same study. Currently

there are no registered residential uses of spirotetramat.

4.5.3 Cancer Classification and Risk Assessment Recommendation

There is no evidence of carcinogenicity in chronic toxicity/carcinogenicity studies performed in 

rats and mice. Spirotetramat has been classified as “not likely to be carcinogenic to humans” 

based on lack of evidence for carcinogenicity in rodent studies. 

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Spirotetramat for Use in Dietary HumanHealth Risk Assessments. 

Exposure Scenario POD 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; oral 

gavage)

LOAEL = 200 mg/kg based on 

clinical signs and decreased motor 

activity.

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 based on 

thymus involution in males.

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, 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.
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Table 4.5.4.2. Summary of Toxicological Doses and Endpoints for Spirotetramat for Use in Occupational 

Human-Health Risk Assessments.

Exposure 

Scenario POD Uncertainty Factors LOC for Risk Assessment Study and Toxicological Effects

Dermal

Short- and 

IntermediateTerm (1-30 

days and 1-6 

months)

NOAEL = 10

mg/kg/day 

Dermalabsorption 

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.

Inhalation

Short- and 

IntermediateTerm (1-30 

days and 1-6 

months)

NOAEL = 10

mg/kg/day 

100% 

absorption 

assumed

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.

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), NOAEL = no-observed adverse-effect level, LOAEL = lowest-observed adverse-effect level, 

MOE = margin of exposure, LOC = level of concern.

5.0 Dietary Exposure and Risk Assessment 

An overview of the metabolism and environmental degradation of spirotetramat can be found in 

the August 2012 human-health risk assessment (Memo, J. Van Alstine, et al.; D399022).

5.1 Residues of Concern Summary and Rationale

The nature of the residue in plants, rotational crops, and livestock is adequately understood based 

on acceptable metabolism studies conducted with apple, lettuce, cotton, potato, rotational crops, 

lactating goats, and laying hens.

Plants (Primary Crops): 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 (Memo, J. Tyler, et al., 14-MAY-2008; 

D333437).

Plants (Rotational Crops): 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-ketohydroxy-alcohol (Memo, J. Tyler, et al., 14-MAY2008; D333437).

Livestock: 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 (Memo, J. Tyler, et al., 14-MAY-2008; D333437). 

Drinking Water: The residues of concern in drinking water for risk assessment purposes are 

spirotetramat, BYI 08330-enol, and BYI 08330-ketohydroxy (Memo, J. Tyler, et al., 14-MAY2008; D333437). 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 
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of concern since it was never found at a level of >10% of the total residue.

Table 5.1. Summary of Metabolites and Degradates to be included in Risk Assessment and Tolerance 

Expression1.

Matrix Residues Included in Risk Assessment Residues Included in Tolerance Expression 

for Compliance Monitoring

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-enol-Glc, and BYI 

08330-mono-hydroxy

Rotational 

Crop Not Applicable2 Not Applicable2

Livestock (Ruminant 

and Poultry)

Spirotetramat, BYI 08330-enol, and BYI 08330-enolGA2 Spirotetramat and BYI 08330-enol3

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

ketohydroxy Not Applicable

1 Memo, J. Tyler, et al., 14-MAY-2008; D333437.

2 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 and use rates in are below 0.16 lb ai/A for annual crops, residues in rotational 

crops are not currently of concern for the risk assessment or for tolerance setting.

3

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.

5.2 Food Residue Profile

Spirotetramat is systemic (xylem and phloem mobile). The submitted magnitude of the residue 

data for the raw agricultural commodities (RACs) of watercress, pomegranates, bananas, bulb 

vegetables, low-growing berries (except strawberries), bushberries, globe artichokes, pineapples, 

and coffee will support the proposed use patterns. As no residue data were submitted for an OD 

or equivalent formulation and higher residues result from this formulation type (Memo, G. 

Kramer, 17-APR-2008; D339694), the use directions for the subject crops should be removed 

from the BYI 8330 OD label. In addition, as all of the banana field trials were performed in HI, 

the registration for use on this crop should be limited to the state of HI. 

Residue-decline data show that residues of concern decreased in blueberries, cranberries, 

pomegranate, globe artichoke, green onions, pineapple, and sweet corn forage with increasing 

PHIs. The residue-decline data indicate that the residues of concern increased with increasing 

PHIs for coffee, and remained fairly stable for dry bulb onion and sweet corn stover. For 

pomegranate and pineapple, residues of the metabolites BYI 08330-enol, BYI 08330-

ketohydroxy, BYI 08330-monohydroxy, and BYI 08330-glucoside were <LOQ at each sampling 

interval; therefore, residue decline could not be assessed for these metabolites in these 

commodities. Average combined residues of spirotetramat and its metabolites in banana were 

<1.5 ppm at the 1-day PHI, decreased to <0.49 ppm at the 7-day PHI, and increased to <0.63 

ppm at the 14-day PHI. 

Acceptable coffee and pineapple 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 roasted coffee bean (<1.9X), instant coffee 

(<10X), and pineapple process residue (1.2X). 

Freezer storage stability data are available for five diverse crops (i.e., a fruiting vegetabletomato; a root crop-potato, a leafy vegetable-head lettuce; a nut-almond nutmeat; and a legume-
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bean with pod) which demonstrate stability of residues of spirotetramat, BYI 08330-enol, BYI 

08330-enol-Glc, BYI 08330-ketohydroxy, and BYI 08330-mono-hydroxy for up to 718 days of 

frozen storage. These data support the storage conditions and intervals of samples collected 

from the various crop field trials. There are no unresolved storage stability issues, and no 

corrections need to be applied to the various residue crop studies. 

The only feedstuff associated with the proposed new uses is pineapple process residue, a minor 

feed item. As the calculated maximum residue calculated for pineapple process residue (0.14 

ppm) is very low relative to the reasonably balanced dietary burdens (RBDBs) for spirotetramat

and its metabolites, addition of this feed item to the livestock diets would not have a significant 

effect on the estimated residue levels in livestock. The established tolerances for residues of 

spirotetramat and its metabolite in livestock commodities are thus adequate to support the 

proposed new uses.

The metabolism of spirotetramat in rotational crops appears to be consistent with the pathway

observed in the plant metabolism studies. The available field accumulation data indicate that 

residues of the parent and its metabolites (BYI 08330-ketohydroxy, BYI 08330-desmethylketohydroxy, BYI 08330-desmethyl-di-hydroxy and BYI 08330-ketohydroxy-alcohol) were each 

<0.020 ppm in/on all rotational crop matrices at a 30-day PBI. Unless the petitioner requests 

PBIs shorter than 30 days or use rates in excess of 0.16 lb ai/A for annual crops, no additional 

data are required, and tolerances for inadvertent residues in/on rotational crops need not be 

established in conjunction with the currently proposed uses. The proposed use rate for 

watercress is 0.4 lb ai/A; therefore, based on the results of the confined rotational crop study 

(conducted at an application rate of 0.36 lbs. ai/A), a 260-day PBI is required to support the 

proposed use on watercress. 

5.3 Water Residue Profile

EFED provided Tier 1 ground and surface EDWCs for spirotetramat and the major 

transformation products, spirotetramat-enol and spirotetramat-ketohydroxy (Memo, J. Meléndez, 

19-JUL-2012; D398507). The EDWCs were calculated using SCI-GROW v.2.3 (groundwater, 

applications to bananas and plantains) and the Tier 1 Rice Model v.1.0 (surface water, as a 

surrogate for applications to watercress). The Tier 1 Rice Model v.1.0 resulted in the highest 

EDWC for use in the acute and chronic assessments. Therefore, the surface water EDWC value 

of 0.395 ppm was incorporated in DEEM-FCID, Version 3.16, into the food categories “water, 

direct, all sources” and “water, indirect, all sources” for both the acute and chronic assessments. 

The Tier 1 Rice Model v.1.0 provides a conservative, screening-level estimate. Crop 

interception, pesticide degradation, stream flow, and runoff dilution from the areas in the 

watershed which are not treated all have the potential to reduce the conservative EDWCs 

generated by the Tier 1 Rice Model. 
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Table 5.3. Maximum Tier I EDWCs Based on Ground or Aerial Application of Spirotetramat on 

Plantains and Bananas (for Groundwater) at 1.25 lb ai/A/Season, and Ground, Aerial, or 

Chemigation Applications on Watercress (for Surface Water) at 0.4 lb ai/A/Season.

Drinking Water 

Source 

(MODEL)

Estimated Drinking Water Concentration (EDWC)

Chemical: Parent

Spirotetramat

SpirotetramatenolSpirotetramatketohydroxyTotal Toxic 

Residues (TTR)1

Risk \ Units (ppb) (ppb) (ppb) (ppb)

Ground-water 

(SCI-GROW)

Acute and 

Chronic 2 7.06 x 10-5

5.15 x 10-51.12 x 10-31.24 x 10-3

Surface Water 

(Tier 1 Rice 

Model v.1.0)

Acute and 

Chronic 2 N/A N/A N/A 395

1 TTR = total toxic residue (sum of spirotetramat + spirotetramat-enol + spirotetramat-ketohydroxy).

2

Surface-water concentrations calculated by the Tier I Rice Model v1.0 and ground water concentrations calculated by SCIGROW do not distinguish between peak and chronic concentrations.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Acute and chronic dietary-exposure (food plus water) and risk assessments were conducted using 

DEEM-FCID, Version 3.16, which uses food consumption data from the USDA’s 

NHANES/WWEIA survey from 2003 through 2008. The assessments were performed for the 

general U.S. population and all population subgroups. Assumptions for the acute assessment 

included tolerance-level residues for all foods, DEEM 7.81 default processing factors (where 

provided), and 100% CT. Assumptions for the chronic dietary assessment included average field 

trial residues for some commodities, tolerance-level residues for the remaining commodities, and 

100% CT. Some empirical processing factors were used in the chronic assessment along with 

DEEM 7.81 default processing factors (where provided). Drinking water estimates were 

provided by EFED. The EDWC values were generated using the watercress use pattern and the 

Tier 1 Rice Model v.1.0. The resulting screening-level EDWC estimate of 0.395 ppm was used 

for both the acute and chronic assessments. 

5.4.2 Percent Crop Treated Used in Dietary Assessment

The acute and chronic dietary analyses assumed 100% CT for all commodities. 

5.4.3 Acute Dietary Risk Assessment

Acute dietary risk estimates (food and drinking water) are not of concern for the general 

population or any other population subgroup. The assessment was unrefined and the highest 

exposure estimate was for the population subgroup children 1-2 years old, which utilized 16% of 

the aPAD for spirotetramat. The acute exposure estimate for the general U.S. population utilized 

7% of the aPAD. A summary table of dietary exposure and risk for spirotetramat can be found 

in Section 5.4.6. 

5.4.4 Chronic Dietary Risk Assessment

Chronic dietary risk estimates (food and drinking water) are not of concern for the general 

population or any other population subgroup. The assessment was somewhat refined and the 

highest exposure and risk estimates were for the population subgroup children 1-2 years old, 

which utilized 76% of the cPAD for spirotetramat. The chronic exposure estimate for the 
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general U.S. population utilized 36% of the cPAD. A summary table of dietary exposure and 

risk for spirotetramat can be found in Section 5.4.6. Although further refinement to the analysis 

is not required at this time, future assessments could be refined through the use of additional 

average field trial values and translation of average field trial residues to other commodities 

using HED SOP 2000.1, additional empirical processing factors, incorporation of % CT data, or 

monitoring data. 

5.4.5 Cancer Dietary Risk Assessment

A cancer dietary assessment was not performed because spirotetramat was classified as “not 

likely to be carcinogenic to humans.”

5.4.6 Summary Table

Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure Risk for Spirotetramat1.

Population Subgroup

Acute Dietary (95th Percentile) Chronic Dietary

Dietary Exposure 

(mg/kg/day) % aPAD Dietary Exposure(mg/kg/day) % cPAD

General U.S. Population 0.066115 7 0.017785 36

All Infants (<1 year old) 0.137642 14 0.036886 74

Children 1-2 years old 0.155241 16 0.038038 76

Children 3-5 years old 0.125606 13 0.030925 62

Children 6-12 years old 0.075624 8 0.019418 39

Youth 13-19 years old 0.046354 5 0.013149 26

Adults 20-49 years old 0.053000 5 0.016159 32

Adults 50-99 years old 0.050326 5 0.016494 33

Females 13-49 years old 0.052999 5 0.015902 32

1 The values for the highest exposed population for each type of risk assessment are bolded.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

The proposed uses are not expected to result in residential exposure, and there are no currently

registered residential uses of spirotetramat; therefore, a quantitative residential exposure 

assessment was not conducted.

6.1 Residential Bystander Post-Application Inhalation Exposure

Based on the Agency’s current practices, a quantitative post-application inhalation exposure 

assessment was not performed for spirotetramat at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV), low vapor pressure (5.6 x 10-9Pa at 20 oC), and the 

low proposed use rate (0.25 lb ai/A). However, volatilization of pesticides may be a source of 

post-application inhalation exposure to individuals nearby pesticide applications. The Agency 

sought expert advice and input on issues related to volatilization of pesticides from its Federal 

Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in 

December 2009, and received the SAP’s final report on March 2, 20101. The Agency is in the 

process of evaluating the SAP report and may, as appropriate, develop policies and procedures to 

identify the need for and, subsequently, the way to incorporate post-application inhalation 

exposure into the Agency's risk assessments. If new policies or procedures are developed, then 

the Agency may revisit the need for a quantitative post-application inhalation exposure 

 

1 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
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assessment for spirotetramat.

6.2 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-driftmanagement practices (see the Agency’s Spray Drift website for more information2

. 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 

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 risk estimates associated with drift.

7.0 Aggregate Exposure/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 spirotetramat (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 5.4.6). The dietary exposure 

assessment utilized tolerance-level residues, 100% CT information for all proposed agricultural 

uses, DEEM 7.81 default processing factors (where provided), and a Tier 1 surface water EDWC 

generated by the Tier 1 Rice Model v.1.0. 

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 

 

2 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm 
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population subgroups (see Table 5.4.6). The dietary exposure assessment utilized average field 

trial residues for some commodities, tolerance-level residues for the remaining commodities, 

100% CT, some empirical processing factors, DEEM 7.81 default processing factors (where 

provided), and a Tier 1 chronic surface water EDWC generated by the Tier 1 Rice Model v.1.0. 

8.0 Cumulative Exposure/Risk Characterization

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, 

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 Characterization

An occupational exposure assessment of the proposed uses was provided in a HED 

memorandum dated 26-MAR-2013 (K. Lowe; D398857). For the proposed use sites, there is a 

potential for short- and intermediate-term occupational exposure to spirotetramat during mixing, 

loading, applying, and other handling tasks; and during post-application activities. Additionally, 

since the same endpoint and POD were selected for short- and intermediate-term durations, 

short-term exposure and risk estimates are considered to be protective of potential longer-term 

exposure and risk. Chronic exposure is not expected for the proposed agricultural uses. 

9.1 Short- and Intermediate-Term Handler Risk

The scenarios assessed for occupational handlers include mixing/loading liquids to support 

aerial, airblast, groundboom, and chemigation applications, applying sprays with aerial, airblast, 

and groundboom equipment, and flagging for liquid aerial applications. 

It is the policy of HED to use the best available data to assess handler exposure. Sources of 

generic handler data, used as surrogate data in the absence of chemical-specific data, include the 

Pesticide Handlers Exposure Database (PHED) 1.1, the Agricultural Handler Exposure Task 

Force (AHETF) database, the Outdoor Residential Exposure Task Force (ORETF) database, or 

other registrant-submitted occupational exposure studies. Some of these data are proprietary

(e.g., AHETF data), and subject to the data protection provisions of FIFRA. The standard values 

recommended for use in predicting handler exposure that are used in this assessment, known as 

“unit exposures,” are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate 

Reference Table3,” which, along with additional information on HED policy on use of surrogate 

data, including descriptions of the various sources, can be found at the Agency website4. 

Estimates of dermal and inhalation exposure were calculated for various levels of PPE. Results 

are presented for “baseline,” defined as a single layer of clothing consisting of a long-sleeved 

 

3 Available: http://www.epa.gov/opp00001/science/handler-exposure-table.pdf

4 Available: http://www.epa.gov/pesticides/science/handler-exposure-data.html
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shirt, long pants, shoes plus socks, no protective gloves, and no respirator, as well as baseline 

with various levels of PPE as necessary (e.g., gloves, respirator, etc.). The spirotetramat product 

labels direct mixers, loaders, applicators and other handlers to wear long-sleeved shirts, long 

pants, chemical-resistant gloves, shoes plus socks, and protective eyewear. 

The occupational handler exposure and risk estimates indicate that short- and intermediate-term 

dermal and inhalation combined MOEs are not of concern to HED (i.e., MOEs > 100) with 

baseline attire. With baseline attire, the dermal plus inhalation MOEs range from 360 to 43,000 

(see Table 9.1.1). HED has no data to assess exposures to pilots using open cockpits. The only 

data available is for exposure to pilots in enclosed cockpits. Therefore, risks to pilots are 

assessed using the engineering control (enclosed cockpits) and baseline attire (long-sleeved shirt, 

long pants, shoes, and socks); pilots are not required to wear protective gloves. With this level of 

protection, there are no risk estimates of concern for applicators.

The Agency matches quantitative occupational exposure assessment with appropriate 

characterization of exposure potential. While HED presents quantitative risk estimates for 

human flaggers where appropriate, agricultural aviation has changed dramatically over the past 

two decades. According the 2012 National Agricultural Aviation Association (NAAA) survey of 

their membership, the use of the Global Positioning System (GPS) for swath guidance in 

agricultural aviation has grown steadily from the mid 1990s. Over the same time period, the use 

of human flaggers for aerial pesticide applications has decreased steadily from ~15% in the late 

1990s to only 1% in the most recent (2012) NAAA survey. The Agency will continue to monitor 

all available information sources to best assess and characterize the exposure potential for human 

flaggers in agricultural aerial applications.
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Table 9.1.1. Short-/Intermediate-Term Occupational Exposure and Risk Estimates for Spirotetramat. 

Exposure 

Scenario Crop or Target

Dermal Unit 

Exposure 

(μg/lb ai)1

Inhalation Unit 

Exposure 

(μg/lb ai)1

Maximum 

Application 

Rate 

(lb ai/A)2

Area 

Treated 

Daily

(acres)3

Dermal Inhalation Total

Mitigation 

Level

Mitigation 

Level

Dose 

(mg/kg/day)4 MOE5 Dose (mg/kg/day)6 MOE7 MOE8

Mixer/Loader

Aerial 

Applications 

of Liquid 

Formulations

Banana, Plantain

220 (baseline) 0.219 

(baseline)

0.25

350

0.028 360 0.000278 36,000 360

Watercress 0.2 0.0223 450 0.000222 45,000 450

Bushberry subgroups 

13-07B and 13-07H, 

Coffee, Pineapple, 

Pomegranate, 

0.16 0.0178 560 0.000178 56,000 550

Globe artichoke 0.13 0.0145 690 0.000144 69,000 680

Bulb vegetables 

subgroups 3-07A and 

3-07B

0.08 0.00893 1,100 0.0000888 110,000 1,100

Airblast 

Applications 

of Liquid 

Formulations

Banana, Plantain

220 (baseline) 0.219 

(baseline)

0.25

40

0.00319 3,100 0.0000317 320,000 3,100

Bushberry subgroups 

13-07B and 13-07H, 

Coffee, Pomegranate

0.16 0.00204 4,900 0.0000203 490,000 4,900

Chemigation 

Applications 

of Liquid 

Formulations

Watercress

220 (baseline) 0.219 

(baseline)

0.2

350

0.0223 450 0.000222 45,000 450

Globe artichoke 0.13 0.0145 690 0.000144 69,000 680

Bulb vegetables 

subgroups 3-07A and 

3-07B

0.08 0.00893 1,100 0.0000888 110,000 1,100

Groundboom 

Application of 

Liquid 

Formulations

Watercress

220 (baseline) 0.219 

(baseline)

0.2

80

0.0051 2,000 0.0000507 200,000 2,000

Bushberry subgroups 

13-07B and 13-07H, 

Pineapple

0.16 0.00409 2,400 0.0000406 250,000 2,400

Globe artichoke 0.13 0.00332 3,000 0.000033 300,000 3,000

Bulb vegetables 

subgroups 3-07A and 

3-07B

0.08 0.00204 4,900 0.0000203 490,000 4,900
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Table 9.1.1. Short-/Intermediate-Term Occupational Exposure and Risk Estimates for Spirotetramat. 

Exposure 

Scenario Crop or Target

Dermal Unit 

Exposure 

(μg/lb ai)1

Inhalation Unit 

Exposure 

(μg/lb ai)1

Maximum 

Application 

Rate 

(lb ai/A)2

Area 

Treated 

Daily

(acres)3

Dermal Inhalation Total

Mitigation 

Level

Mitigation 

Level

Dose 

(mg/kg/day)4 MOE5 Dose (mg/kg/day)6 MOE7 MOE8

Applicator

Aerial 

Applications 

of Liquid 

Formulations

Banana, Plantain

5 

(engineering 

control)

0.068 

(engineering 

control)

0.25

350

0.000635 16,000 0.0000862 120,000 14,000

Watercress 0.2 0.000507 20,000 0.000069 140,000 18,000

Bushberry subgroups 

13-07B and 13-07H, 

Coffee, Pineapple, 

Pomegranate, 

0.16 0.000406 25,000 0.0000552 180,000 22,000

Globe artichoke 0.13 0.00033 30,000 0.0000448 220,000 26,000

Bulb vegetables 

subgroups 3-07A and 

3-07B

0.08 0.000203 49,000 0.0000275 360,000 43,000

Airblast 

Applications 

of Liquid 

Formulations

Banana, Plantain

1770 

(baseline) 4.71 (baseline)

0.25

40

0.0257 390 0.000683 15,000 380

Bushberry subgroups 

13-07B and 13-07H, 

Coffee, Pomegranate

0.16 0.0164 610 0.000436 23,000 590

Groundboom 

Application of 

Liquid 

Formulations

Watercress

78.6 

(baseline) 0.34 (baseline)

0.2

80

0.00183 5,500 0.0000788 130,000 5,300

Bushberry subgroups 

13-07B and 13-07H, 

Pineapple

0.16 0.00146 6,800 0.000063 160,000 6,500

Globe artichoke 0.13 0.00118 8,500 0.0000513 190,000 8,100

Bulb vegetables 

subgroups 3-07A and 

3-07B

0.08 0.000729 14,000 0.0000316 320,000 13,000
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Table 9.1.1. Short-/Intermediate-Term Occupational Exposure and Risk Estimates for Spirotetramat. 

Exposure 

Scenario Crop or Target

Dermal Unit 

Exposure 

(μg/lb ai)1

Inhalation Unit 

Exposure 

(μg/lb ai)1

Maximum 

Application 

Rate 

(lb ai/A)2

Area 

Treated 

Daily

(acres)3

Dermal Inhalation Total

Mitigation 

Level

Mitigation 

Level

Dose 

(mg/kg/day)4 MOE5 Dose (mg/kg/day)6 MOE7 MOE8

Flagger

Flagging for 

Aerial 

Applications

Banana, Plantain

11 (baseline) 0.35 (baseline)

0.25

350

0.0014 7,100 0.000443 23,000 5,400

Watercress 0.2 0.00112 8,900 0.000355 28,000 6,800

Bushberry subgroups 

13-07B and 13-07H, 

Coffee, Pineapple, 

Pomegranate, 

0.16 0.000893 11,000 0.000284 35,000 8,400

Globe artichoke 0.13 0.000726 14,000 0.00023 43,000 11,000

Bulb vegetables 

subgroups 3-07A and 

3-07B

0.08 0.000446 22,000 0.000142 70,000 17,000

1 Based on “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2012); includes data from PHED/ORETF/AHETF (level of mitigation: Baseline for all scenarios except 

for aerial applicators which is assessed using eng. controls).

2 Based on proposed labels (Reg. Nos. 264-1050, 264-1065, 264-1051).

3 Exposure Science Advisory Council (ExpoSAC) Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre) x Area Treated (A/day) x DAF (10%) / BW (69 kg).

5 Dermal MOE = Dermal NOAEL (10 mg/kg/day)/Dermal Dose (mg/kg/day).

6

Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre) x Area Treated (A/day) / BW (69 kg).

7

Inhalation MOE = Inhalation NOAEL (10 mg/kg/day)/Inhalation Dose (mg/kg/day).

8 Total MOE = NOAEL (10 mg/kg/day)/Dermal Dose + Inhalation Dose.
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9.2 Short- and Intermediate-Term Post-Application Risk

9.2.1 Dermal Post-Application Risk

HED expects that post-application exposure will occur since spirotetramat is applied as a foliar 

spray. For spirotetramat, based on the proposed uses, short- and intermediate-term exposures are 

expected since there is the potential for multiple applications at the maximum application rate for 

most crops (range of 2 to 7 applications with RTIs ranging from 7 to 21 days). In addition, both 

the short-term and intermediate-term endpoints are the same; therefore, estimates of short-term 

exposure/risk are protective of any potential longer-term exposures. 

No post-application exposure data were submitted in support of this registration action. It is the 

policy of HED to use the best available data to assess post-application exposure. Sources of 

generic post-application data, used as surrogate data in the absence of chemical-specific data, are 

derived from ARTF exposure monitoring studies, and, as proprietary data, are subject to the data 

protection provisions of FIFRA. The standard values recommended for use in predicting postapplication exposure that are used in this assessment, known as “transfer coefficients,” are 

presented in the “Science Advisory Council for Exposure (ExpoSAC) Policy 3” 

(http://www.epa.gov/pesticides/science/exposac_policy3.pdf), which, along with additional 

information about the ARTF data, can be found at http://www.epa.gov/pesticides/science/postapp-exposure-data.html. 

Coffee is not currently assigned a crop group and/or transfer coefficients in ExpoSAC Policy 3. 

According to USDA’s Crop Profiles for coffee, this crop is described as a small evergreen tree.5 

Therefore, the activities and transfer coefficients assigned to trees, “fruit,” evergreen/Christmas 

trees were used as a surrogate for the occupational post-application exposure assessment for 

coffee.

The fraction of ai retained on foliage surfaces is assumed to be 25% (0.25) of the application rate 

on the day of initial treatment. This fraction is assumed to further dissipate at the rate of 10% 

(0.1) per day. These are standard values established by HED ExpoSAC when no information is 

known about possible bonding to foliar surfaces and dissipation of the ai over time.

In accordance with the updated Part 158 data requirements (2007), one or more dislodgeablefoliar residue (DFR) studies are required when a pesticide has residential or occupational uses 

that could result in post-application dermal exposure. As part of the recent revision to the Health 

Effects Division’s 2012 Standard Operating Procedures for Residential Pesticide Exposure 

Assessment, HED analyzed a number of DFR studies and selected a new default value for the 

fraction of the application rate available to be dislodged after a foliar application (FAR). This 

default value is 25% and is based on an analysis of 19 DFR studies where the FAR value ranged 

from 2% to 89%. This value is recommended for use in both residential and occupational postapplication assessments. Of the analyzed DFR studies, the maximum FAR value seen was 89% 

or 3.6 times higher than the default residue transfer value. Therefore, the HED has decided that a 

calculated MOE of approximately 4 times higher than the LOC (e.g., an MOE > 400 if the LOC 

= 100) using the default dislodged residue values would provide an adequate margin of safety for 

 

5 Available: http://www.ipmcenters.org/cropprofiles/docs/hicoffee.pdf
Spirotetramat Human-Health Risk Assessment DP# 398509

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any potentially higher residues seen in a chemical-specific DFR study (Guidance for 

Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar Residue (DFR) 

Studies. Memo, J. Housenger, 12/12/12). A DFR study is not required for spirotetramat at this 

time since the dermal MOEs are greater than 400 on Day 0 based on default values for the 

fraction of application rate available for transfer after a foliar application.

Table 9.2.1. Summary of Short- and Intermediate-term Occupational/Commercial Post-application Risk 

Estimates for Spirotetramat.

Crop/Site Activities

Transfer 

Coefficient 

(cm2/hr)

DFR/TTR1 Dermal Dose 

(mg/kg/day)2 MOE3

Banana/Plantain Hand weeding 100 0.701 0.000813 12,000

Hand harvesting 1,400 0.0114 880

Bushberry subgroups

13-07B and 13-07H

Hand weeding, Pruning, 

Hand (shears) 70

0.449

0.000364 27,000

Transplanting 230 0.0012 8,300

Scouting, Hand pruning, 

Hand weeding, Bird 

control, Frost control

640 0.00333 3,000

Hand harvesting, 

Scouting 1,100 0.00573 1,700

Hand harvesting 1,400 0.00729 1,400

Handset irrigation 1,900 0.00989 1,000

Coffee

Hand weeding 100

0.449

0.000521 19,000

Transplanting 230 0.0012 8,300

Scouting 580 0.00302 3,300

Hand harvesting 1,400 0.00729 1,400

Handset irrigation 1,900 0.00989 1,000

Pineapple and Globe 

Artichoke4

Hand weeding, Hand 

pruning (artichoke only), 

Thinning plants 

(artichoke only)

70

0.365 

(artichoke)

0.449 

(pineapple)

0.000364 27,000

Scouting 210 0.00109 9,200

Transplanting (artichoke 

only) 230 0.000973 10,000

Hand harvesting 1,100 0.00573 1,700

Handset irrigation 

(artichoke only) 1,900 0.00804 1,200

Pomegranate

Orchard maintenance 100

0.449

0.000521 19,000

Transplanting 230 0.0012 8,300

Scouting, Hand pruning 580 0.00302 3,300

Hand harvesting 1,400 0.00729 1,400

Bulb Vegetables 

subgroups 3-07A and 

3-07B

Scouting, Thinning plants 330

0.224

0.000857 12,000

Scouting, Hand weeding, 

Hand harvesting 1,400 0.00364 2,700

Hand set irrigation 1,900 0.00493 2,000

Hand weeding 4,200 0.0109 920

Watercress

Thinning plants, Hand 

weeding 70

0.561

0.000455 22,000

Scouting 210 0.00137 7,300

Transplanting 230 0.0015 6,700

Hand harvesting 1,100 0.00715 1,400
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Table 9.2.1. Summary of Short- and Intermediate-term Occupational/Commercial Post-application Risk 

Estimates for Spirotetramat.

Crop/Site Activities

Transfer 

Coefficient 

(cm2/hr)

DFR/TTR1 Dermal Dose 

(mg/kg/day)2 MOE3

Hand set irrigation 1,900 0.0124 810

1 DFR = Application Rate × F × (1-D)t

× 4.54E8 μg/lb × 2.47E-8 acre/cm2; where F = 0.25 and D = 0.10 per day. 

2 Daily Dermal Dose = [DFR (μg/cm2

) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (%)]  BW (kg).

3 MOE = POD (mg/kg/day) / Daily Dermal Dose. Daily Dermal Dose = [DFR/TTR (μg/cm2

) × TC × 0.001 mg/μg x 8 hrs/day × 

dermal absorption]  BW (kg).

4

For activities common to both pineapple and globe artichoke, only doses and MOE for the higher pineapple rate are shown. 

All scenarios resulted in MOEs greater than the LOC of 100 (ranging from 810 to 27,000) on day

0 (12 hours after application) and, therefore, are not of concern to HED. Under 40 CFR 156.208 

(c) (2) (iii), active ingredients classified as Toxicity Category II for acute dermal, eye irritation or 

primary skin irrigation are assigned a 24-hour REI. Therefore, the [156 subpart K] Worker 

Protection Statement interim REI of 24 hours is adequate to protect agricultural workers from 

post-application exposures to spirotetramat. The proposed labels for spirotetramat include an 

REI of 24 hours.

9.2.2 Inhalation Post-Application Risk

Based on the Agency’s current practices, a quantitative post-application inhalation exposure 

assessment was not performed for spirotetramat at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV), low vapor pressure (5.6 x 10-9Pa at 20 oC), and the 

low proposed use rate (0.25 lb ai/A). However, there are multiple potential sources of postapplication inhalation exposure to individuals performing post-application activities in 

previously treated fields. These potential sources include volatilization of pesticides and 

resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert 

advice and input on issues related to volatilization of pesticides from its FIFRA SAP in 

December 2009, and received the SAP’s final report on March 2, 20106. The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the ARTF and may, as appropriate, develop policies and procedures, to 

identify the need for and, subsequently, the way to incorporate occupational post-application 

inhalation exposure into the Agency's risk assessments. If new policies or procedures are put 

into place, then the Agency may revisit the need for a quantitative occupational post-application 

inhalation exposure assessment for spirotetramat.

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

higher exposure than post-application exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of most occupational post-application 

inhalation exposure scenarios.

 

6 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
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10.0 References

Previous Risk Assessments: J. Tyler, et al., 14-MAY-2008, D333437; J. Van Alstine, et al. 22-

DEC-2010, D368785; J. Van Alstine, et al. 02-AUG-2012, D399022

HASPOC Memo: K. Rury; 4-OCT-2012; TXR# 0056480

Chemistry Memo: G. Kramer; 26-MAR-2013; D398856

Drinking Water Memo: J. Meléndez; 19-JUL-2012; D398507

Dietary Memo: J. Van Alstine; 26-MAR-2013; D398858

Occupational Exposure Memo: K. Lowe; 26-MAR-2013; D398857

List of Appendices:

Appendix A. Toxicology Profile and Executive Summaries

Appendix B. Physical/Chemical Properties

Appendix C. Review of Human Research

cc: J. Van Alstine, G. Kramer, K. Lowe, C. Rodriguez

RDI: RAB1 (30-JAN-2013), C. Smith (30-JAN-2013)

J. Van Alstine: S-10951: Potomac Yard 1 (PY1): (703)603-8866: 7509P: RAB1
Spirotetramat Human-Health Risk Assessment DP# 398509

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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for Food Use for spirotetramat are presented below.

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

-

no1

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

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial

870.5300 Mutagenicity—Gene Mutation - mammalian

870.5400 Mutagenicity—Structural Chromosomal Aberrations

870.5500 Mutagenicity—Other Genotoxic Effects

yes

yes

yes

no

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. Neurotoxicity

no

no

yes

no

no

-

-

yes

yes

-

870.7485 General Metabolism

870.7600 Dermal Penetration

yes

yes

yes

yes

Special Studies for Ocular Effects

Acute Oral (rat)...........................................................

Subchronic Oral (rat) ..................................................

Six-month Oral (dog)..................................................

no

no

no

-

-

-

1 The Hazard and Science Policy Council (HASPOC) met on 04-OCT-2012 (TXR# 0056480) and concluded that a 

repeated exposure inhalation toxicity study is not required for spirotetramat at this time. 
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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

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

NOAEL = 1200 (32 mg/kg/day) [F] & 2500 

ppm (81 mg/kg/day) [M].
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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)

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.

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.

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 
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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.

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 

Negative.
Spirotetramat Human-Health Risk Assessment DP# 398509

Page 41 of 44

g/mL (+S9)

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.

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).

870.6200b Subchronic 

neurotoxicity 

screening battery

48958802 (2012) Pending formal review.

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

46904561 (2006)

Acceptable/guideline

At 1000 mg/kg bw: Absorption and 

excretion less than low dose, with 27% of 
Spirotetramat Human-Health Risk Assessment DP# 398509

Page 42 of 44

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 body-weight gain; 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 bodyweight gain, 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.

(rat) 2 or 1000 mg/kg bw (single) 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 to 24 hours post dose. 

Metabolism profile qualitatively similar to 

that of the low-dose group; 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%.

870.7800 Immunotoxicity

(rat)

48525901 (2011)

Acceptable/guideline

500, 2500, or 12,000 ppm 

(equivalent to 33, 164, or 795 

mg/kg/day)

The functional immunotoxicity NOAEL is 

12,000 ppm (equivalent to 795 mg/kg/day, 

the highest dose tested); the LOAEL was not 

established.

The systemic toxicity LOAEL for 

Spirotetramat in male rats is 12,000 ppm 

(equivalent to 795 mg/kg bw/day) based on 

decreased body weights, decreased bodyweight gains, lowered food consumption, 

lower thymus weight, and observations of 

atrophic thymus. The NOAEL for systemic 

toxicity is 2500 ppm (equivalent to 164 

mg/kg bw/day)

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.
Spirotetramat Human-Health Risk Assessment DP# 398509

Page 43 of 44

Table A.2.3. USEPA Toxicity Profile – Metabolites.

Guideline 

No. Study Type

MRID No. (year)/ 

Classification /Doses Results

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 tract, 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.

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. 
Spirotetramat Human-Health Risk Assessment DP# 398509

Page 44 of 44

Appendix B. Physical/Chemical Properties

Table B.1. Physicochemical Properties of the Spirotetramat.

Parameter Value Reference

Melting point 142 °C EPA Chemical Fact Sheet for 

Spirotetramat, June 2008 pH 6.3

Density D4

20 = 1.22

Water solubility (20 oC) pH 4: 33.5 mg/L

pH 7: 29.9 mg/L

pH 9: 19.1 mg/L

Solvent solubility (20 oC) Solvent g/L

n-hexane 0.055

Dichloromethane >600

Dimethyl Sulfoxide 200-300

Toluene 60

Acetone 100-120

Ethyl acetate 67

Ethanol 44

Vapor pressure Extrapolated Values:

5.6 x 10-9Pa (20 oC)

1.5 x 10-8Pa (25 oC)

1.5 x 10-6Pa (50 oC)

Dissociation constant, pKa 10.7 Included in MRID 47648203

Octanol/water partition coefficient, Log(KOW) pH 4: 2.51

pH 7: 2.51

pH 9: 2.50

EPA Chemical Fact Sheet for 

Spirotetramat, June 2008

UV/visible absorption spectrum Peak Maxima Molar Absorptivity 

 (nm) (1000 cm2/ mol)

 211 22.0 x 103 

 276 0.8 x 103

Appendix C. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These data, which include studies from 

the PHED 1.1, the AHETF database, and the ARTF database are (1) subject to ethics review 

pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable 

ethics requirements. For certain studies, the ethics review may have included review by the 

Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, 

can be found at the Agency website7. 

 

7

http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html