UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

Date: February 02, 2011

SUBJECT: Spirotetramat; Response to comments on human health effects submitted by

Mayra Quirindongo ofthe NRDC

PC Code: 39220 I

Decision No.: 406300

Petition No.: NA

Risk Assessment Type: NA

TXR No.: 0055644

MRID No.: NA

FROM Dana Vogel, Branch Chief

Registration Action Branch 1

Health Effects Division (7509P)

TO: John Hebert

Risk Manager

Registration Division (7505P)

I. CONCLUSIONS

DP Barcode: D38637!

Registration No.: . J V.J - 10 'i q

Regulatory Action: NA

Case No.: NA

CAS No.: NA

40 CFR: NA

Ver.Apr.08

In a submission to the Agency, Ms. Quirindongo of the Natural Resources Defense Council

stated that spirotctramat presents risks of developmental, reproductive and neurological toxicity.

As stated in the Federal Register for July 9, 2008 (Volume 73, Number 132), EPA detennined

that reliable data show that the safety of infants and children would be adequately protected ifthe

FQPA SF were reduced to 1X for spirotetramat. That decision was based on the available

toxicity and exposure data. The Agency is regulating at a dose that is 100-200 times lower than

the doses at which toxicity of concern was seen and then applying the IDO-fold uncertainty factor

to the Point of Departure results in a margin of exposure of 10,000-20,000. Therefore, the

Agency's assessment is highly protective ofthe developmental, reproductive and neurotoxic

effects observed with spirotetramat.

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

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 data 

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

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

water exposure assessment by José Meléndez of the Environmental Fate and Effects Division 

(EFED). The most recent human-health risk assessment for spirotetramat was completed on 14-

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

Table of Contents 

1.0 Executive Summary 3

2.0 Ingredient Profile 9

2.1 Summary of Proposed Uses 10

2.2 Structure and Nomenclature 11

2.3 Physical and Chemical Properties 13

3.0 Hazard Characterization/Assessment 13

3.1 Hazard and Dose-Response Characterization 13

3.2 FQPA Considerations 16

3.3 Hazard Identification and Toxicity Endpoint Selection 18

3.4 Endocrine Disruption 21

4.0 Public Health and Pesticide Epidemiology Data 22

5.0 Dietary Exposure/Risk Characterization 22

5.1 Pesticide Metabolism and Environmental Degradation 22

5.2 Dietary Exposure and Risk 29

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

6.1 Spray Drift 31

7.0 Aggregate Risk Assessments and Risk Characterization 31

7.1 Acute Aggregate Risk 32

7.2 Chronic Aggregate Risk 32

8.0 Cumulative Risk Characterization/Assessment 32

9.0 Occupational Exposure/Risk Pathway 32

9.1 Short- and Intermediate-Term Handler Risk 33

9.2 Short-Term Post-application Risk 36

10.0 Data Needs and Label Recommendations 37

10.1 Toxicology 37

10.2 Residue Chemistry 38

10.3 Occupational Exposure 38

Appendix A. Toxicology Assessment 39

Appendix B. Tolerance Summary Table for Spirotetramat 47
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1.0 Executive Summary

Bayer CropScience has submitted a Section 3 request to register a 2 lb a.i./gal suspensionconcentrate (SC) formulation (MoventoTM; EPA Reg. No. 264-1050), a 1.25 lb a.i./gal SC 

formulation (UltorTM; EPA Reg. No. 264-1065), and a 1.25 lb a.i./gal oil-dispersion (OD) 

formulation (BYI 8330 OD; EPA Reg. No. 264-1051) of spirotetramat for use on cotton, legume 

vegetables including soybean (crop groups 6 and 7a), and tropical fruit. Spirotetramat is a 

tetramic acid derivative (ketoenole), and is active against sucking insects in vegetables, citrus, 

pome fruit, stone fruit, grapes, cotton, and other plants. It is systemic (xylem and phloem 

mobile) and can control hidden pests and protect new shoots. 

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 citrus, cucurbit vegetables, fruiting 

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

tuberous and corm vegetables, stone fruit, and tree nuts (40 CFR §180.641). Spirotetramat is 

being evaluated as part of a trilateral joint review with Canada and Austria. The most recent 

human-health risk assessment for spirotetramat was completed on 14-MAY-2008 (Memo, J. 

Tyler, et al.; D333437). There are currently no registered or proposed residential uses for 

spirotetramat. 

 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

noted after 10 days of exposure. Similar effects were observed after repeated dosing with the 

enol metabolite of spirotetramat. Although reproductive effects manifested as testicular toxicity 

and sperm abnormalities in a 90-day rat study, in a two-generation reproductive toxicity study 

and in a special reproductive toxicity, the reproductive effects were seen at very high doses. 

Testicular toxicity was seen at 616 mg/kg/day and the sperm abnormalities were seen at 419 

mg/kg/day in the two generation reproduction study and at 1000 mg/kg/day (Limit Dose) in the 

special male reproductive toxicity study. Developmental toxicity was not observed with 

spirotetramat in the absence of maternal toxicity in either the rat or rabbit. 
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Dose Response Assessment and Food Quality Protection Act (FQPA) Decision: Consistent with 

the last risk assessment for spirotetramat (Memo, J. Tyler, et al., 14-MAY-2008; D333437), the 

spirotetramat risk assessment team recommends that the 10X FQPA Safety Factor (SF) be 

reduced to 1X based on the following: 

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

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

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

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

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

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

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

pests. 

• Although a subchronic neurotoxicity study is now required as part of the revisions to 40 

CFR Part 158, the existing toxicological database indicates that spirotetramat is not a 

neurotoxic chemical in mammals. Clinical signs of toxicity and decreased motor activity 

were observed in adult rats following a single dose of spirotetramat in the acute 

neurotoxicity study in the rat; however, these effects only attained statistical significance 

at high doses and were not observed at the limit dose in the acute oral toxicity study in 

the rat. 

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

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

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

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

not neurotoxic in adults or young animals. 

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

organ of the immune system, this finding does not raise uncertainty given the lack of an 

immunotoxicity study. The endpoint selected for risk assessment was based on 

accelerated thymus involution and hypothyroid effects in the dog. Thymus involution 

has been demonstrated to occur when hypothyroidism is induced in animals, so it is 

reasonable to conclude that the thymus involution in these dogs was secondary to the 

thyroid effects, rather than a direct effect on the immune system. With respect to 

immunotoxicity, no immunotoxic effects were seen in rats or mice, the species in which 

immunotoxicity studies are conducted. Thus, HED does not believe that conducting a 

functional immunotoxicity study in any rodent species will result in a lower point of 

departure (POD) than that currently used for overall risk assessment. For this reason and 

because the current POD is considered extremely protective, a database uncertainty factor 

(UFDB) is not needed to account for the lack of this study. 

• There are no residual uncertainties with respect to the exposure database which will result 

in underestimation of exposure. The dietary food exposure assessment utilizes 

recommended tolerance-level or average field-trial residues and 100% crop treated (CT) 

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

acute and chronic exposures/risks will not be underestimated. Additional residue data for 

tropical fruits are being requested. However, the recommended tolerances are based on 

exaggerated-rate data; the additional field trials will be used to determine whether these 

tolerances are being set at a level higher than necessary. 
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• The dietary drinking water assessment (Tier 1 estimates) utilizes values generated by 

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

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

• The registered and/or proposed uses of spirotetramat are not expected to result in 

residential exposures. 

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

The acute and chronic reference doses (aRfD and cRfD) were calculated by dividing the NOAEL 

by 100 (10X for interspecies extrapolation and 10X for intraspecies variation). Since the FQPA 

SF has been reduced to 1X, the acute and chronic population-adjusted doses (aPAD and cPAD) 

are equal to the aRfD and cRfD, respectively. A 100% oral-equivalent inhalation-absorption 

factor is assumed. The level of concern (LOC) for occupational dermal and inhalation exposures 

are for margins of exposure (MOEs) <100. 

Exposure 

Scenario POD RfD, PAD, LOC for Risk Assessment Study/Effect

Acute Dietary 

NOAEL = 

100 

mg/kg/day 

aRfD = aPAD = 

1.0 mg/kg/day 

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

motor activity (M) seen at the lowest-observed-adverse-effect-level 

(LOAEL) of 200 mg/kg/day. 

Chronic Dietary NOAEL = 5 

mg/kg/day 

cRfD = cPAD = 0.05 

mg/kg/day 

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

of 20 mg/kg/day (M). 

Short- and 

Intermediateterm Dermal 

NOAEL = 10 

mg/kg/day 

LOC for MOE <100 

(occupational) 

Prenatal developmental study in rabbits/Late abortion [≥gestation day (GD) 

22], clinical signs, impaired food and water consumption, and body-weight 

loss seen at maternal LOAEL of 40 mg/kg/day. 

Short- and 

Intermediateterm Inhalation 

NOAEL = 10 

mg/kg/day 

LOC for MOE <100 

(occupational) 

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

signs, impaired food and water consumption, and body-weight loss seen at 

maternal LOAEL of 40 mg/kg/day. 

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

databases are adequate to assess potential human exposure to spirotetramat. Adequate data have 

been submitted to determine the residues of concern in primary crops, rotational crops, and 

livestock. 

Adequate crop field trial data have been submitted for the following proposed crops: cotton; 

soybean; edible-podded legume vegetables; succulent shelled peas and beans; dried shelled peas 

and beans (except soybeans), subgroup 6C; and foliage of legume vegetables (except soybean) 

7A. For these commodities, the data reflect the maximum rates and minimum preharvest 

intervals (PHIs) requested and have sufficient geographic representation to support tolerances for 

the proposed uses. The submitted residue data for tropical fruit are not adequate to fulfill data 

requirements. The number and locations of the crop field trials for tropical fruit are in 

accordance with OPPTS Guideline 860.1500. However, the available data will not support the 

proposed use pattern as the trials were conducted at a ~2X use rate. Field trial data were not 

submitted for pistachio and okra; however, the existing tree nut crop group tolerance may be 

translated to pistachio and the existing fruiting vegetable crop group tolerance may be translated 

to okra. All crop field trial studies are supported by adequate storage stability data. Adequate 

processing data indicate that separate tolerances do not need to be established for cotton meal 

and hulls, soybean meal, and dried plum, prune. However, a separate tolerance is required for 

soybean aspirated grain fractions (AGF). Based on the proposed new uses, tolerances on eggs, 

poultry meat byproducts, and hog meat byproducts should be established, and the tolerances for 

cattle, goat, horse, and sheep meat byproducts should be increased (see Appendix B). HED has 

determined that high-performance liquid chromatography with tandem mass spectrometry 
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(HPLC-MS/MS) Methods 00857 and 00966 are suitable enforcement methods for plant and 

livestock commodities, respectively, since the methods passed a successful petition method 

validation (PMV) by Agency chemists at the Analytical Chemistry Laboratory/Biological and 

Economics Analysis Division (ACL/BEAD; E-mail, C. Stafford to D. Vogel; 19-FEB-2008). 

The existing confined and field rotational crop data are adequate to support the proposed 

rotational crop restrictions. 

Drinking water monitoring data are not available for spirotetramat. The effects of water 

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

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

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

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

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

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

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

Ground Water (SCI-GROW) models, respectively. New drinking water numbers were not 

calculated for the new uses of spirotetramat because the new use rates are similar to or lower 

than the previously assessed use rates in the 22-JAN-2008 EFED memo (J. Meléndez; 

D345275). 

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

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

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

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

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

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

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

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

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

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

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

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

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

population (4.8% of the aPAD) and all other population subgroups. The most highly exposed 

population subgroup is children 1-2 years old at 11% of the aPAD. The chronic dietary exposure 

estimates are not of concern to HED (<100% of the cPAD) for the general U.S. population (34% 

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

children 1-2 years old at 93% of the cPAD. 

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

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

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

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

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

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

Carcinogenic to Humans.” All aggregate exposure and risk estimates are not of concern to 

HED for the scenarios listed above.
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Occupational Exposure Estimates: Handler exposure is expected to be short- or intermediateterm based on information provided on the proposed labels. In addition, the short- and 

intermediate-term toxicological endpoints are the same; therefore, the estimates of risk for shortterm duration exposures are protective of those for intermediate-term duration exposures. Longterm exposures are not expected, therefore, a long-term assessment was not conducted. No 

chemical-specific data were available with which to assess potential exposure to pesticide 

handlers. The scenarios assessed for occupational handlers include mixing/loading liquids for 

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

and groundboom equipment, and flagging for aerial applications. The estimates of exposure to 

pesticide handlers are based upon surrogate study data available in the Pesticide Handlers 

Exposure Database (PHED; August, 1998). For pesticide handlers, HED presents estimates of 

dermal exposure for “baseline” (i.e., workers wearing a single layer of work clothing consisting 

of a long-sleeved shirt, long pants, shoes plus socks, and no protective gloves), as well as for 

“baseline” and the use of protective gloves or other personal-protective equipment (PPE), as 

might be necessary. The spirotetramat product labels direct applicators and other handlers to 

wear a long-sleeved shirt, long pants, protective eyewear, chemical-resistant gloves and shoes 

plus socks. HED has determined that risks are not of concern (i.e., MOEs >100), provided 

workers wear protective gloves as recommended on the label. 

Post-application exposure is expected to be short-term based on information provided on the 

proposed labels. However, the short- and intermediate-term toxicological endpoints are the 

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

intermediate-term duration exposures. Since no post-application exposure data were submitted 

in support of this registration action, dermal exposures during post-application activities were 

estimated using dermal transfer coefficients (TCs) from the Science Advisory Council for 

Exposure (ExpoSAC) Policy Number 3.1: Agricultural TCs (August, 2000). All post-application 

scenarios resulted in MOEs greater than 100 on day 0 (12 hours after application) and, therefore, 

are not of concern to HED. 

The acute toxicity categories for this chemical require a 24-hour restricted-entry interval (REI) 

under the Worker Protection Standard (WPS). The 24-hour REI, which appears on the proposed 

label, is adequate for these proposed use patterns. 

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

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

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

Populations and Low-Income Populations,” 

(http://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 USDA under CSFII and are used in pesticide risk assessments for all registered food uses 

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

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

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

conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on 
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home use of pesticide products and associated risks for adult applicators and for toddlers, youths, 

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

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

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

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

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

adult human subjects were intentionally exposed to a pesticide to determine their dermal and 

inhalation exposure. Many such studies, involving exposure to many different pesticides, 

comprise generic pesticide exposure databases such as PHED, the Outdoor Residential Exposure 

Task Force (ORETF), and the Agricultural Reentry Task Force (ARTF) databases. EPA has 

reviewed all the studies in these multi-pesticide generic exposure databases, and on the basis of 

available evidence has found them to have been neither fundamentally unethical nor significantly 

deficient relative to standards of ethical research conduct prevailing when they were conducted. 

There is no regulatory barrier to continued reliance on these studies, and all applicable 

requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) 

have been satisfied. 

Recommendations for Tolerances: Pending submission of revised Sections B and F, there are no 

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

unconditional registration for the use of spirotetramat on the requested crops, except tropical 

fruit. The registration for tropical fruit should be made conditional pending submission of 

bridging residue studies. 

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: 

Cotton, undelinted seed 0.30 ppm Avocado 0.60 ppm 

Cotton gin byproducts 10 ppm Black sapote 0.60 ppm 

Soybean seed 5.0 ppm Canistel 0.60 ppm 

Soybean forage 8.0 ppm Mamey sapote 0.60 ppm 

Soybean hay 16 ppm Mango 0.60 ppm 

Aspirated Grain Fraction 10 ppm Sapodilla 0.60 ppm 

Vegetables, legume, group 06, except soybean 2.5 ppm Star apple 0.60 ppm 

Vegetables, foliage of legume, except soybean, 

subgroup 07A 7.0 ppm Papaya 0.35 ppm 

Okra 2.5 ppm Guava 2.5 ppm 

Pistachio 0.25 ppm Feijoa 2.5 ppm 

Lychee 13 ppm Jaboticaba 2.5 ppm 

Longan 13 ppm Wax jambu 2.5 ppm 

Spanish lime 13 ppm Starfruit 2.5 ppm 

Rambutan 13 ppm Passionfruit 2.5 ppm 
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Pulasan 13 ppm Acerola 2.5 ppm 

Persimmon 2.5 ppm White sapote 0.60 ppm 

The proposed uses and the submitted data also 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 metabolite cis-3-(2,5-

dimethylphenyl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]dec-3-en-2-one, calculated as the 

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

Cattle, meat byproducts 0.20 ppm Eggs 0.02 ppm 

Goat, meat byproducts 0.20 ppm Hog, meat byproducts 0.02 ppm 

Horse, meat byproducts 0.20 ppm Poultry, meat byproducts 0.02 ppm 

Sheep, meat byproducts 0.20 ppm 

Data Needs/Deficiencies

Toxicology 

• Immunotoxicity study (new requirement under 40 CFR Part 158). 

• Subchronic neurotoxicity study (new requirement under 40 CFR Part 158). 

Residue Chemistry 

860.1200 Directions for Use

• Field trial data are required for sugar apple (the representative crop for atemoya, custard 

apple, cherimoya, ilama, soursop, and birida). As these data have not been submitted, the 

spirotetramat labels should be revised to delete instructions for use on sugar apple, 

atemoya, custard apple, cherimoya, ilama, soursop, and birida. 

860.1500 Crop Field Trials

• The submitted residue data for tropical fruit will not support the proposed use pattern as 

the trials were conducted at a ~2X use rate. HED thus requests that the petitioner 

conduct bridging studies with lychee and guava (1 trial each with four samples per 

treatment regimen) in order to determine the relationship between residues resulting from 

the labeled use pattern and that used in the submitted field trials (MRID# 47648205). 

Based on this relationship, the submitted residue data will be adjusted and the appropriate 

tolerances determined. 

860.1550 Proposed Tolerances

• The petitioner is requested to submit a revised Section F specifying revised tolerance 

levels and commodity definitions in Appendix B (summarized above). 

Occupational and Residential Exposure 

• None.

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

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

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

hidden pests and protect new shoots. Spirotetramat tolerances are published in 40 CFR§180.641. 

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

The petitioner has submitted draft labels for a Section 3 request to register a 2 lb a.i./gal SC 

formulation (MoventoTM; EPA Reg. No. 264-1050), a 1.25 lb a.i./gal SC formulation (UltorTM; 

EPA Reg. No. 264-1065), and a 1.25 lb a.i./gal OD formulation (BYI 8330 OD; EPA Reg. No. 

264-1051) of spirotetramat for use on cotton, legume vegetables including soybean (crop groups 

6 and 7a), and tropical fruit. A summary of the proposed use patterns on cotton, legume 

vegetables including soybean (crop groups 6 and 7a), and tropical fruit is detailed in Table 2.1. 

2.1 Summary of Proposed Uses

Table 2.1. Summary of Directions for Use of Spirotetramat. 

Trade 

Names 

Application 

Timing, 

Type, and 

Equipment 

Application 

Rate 

(lb a.i./A) 

Maximum 

Number 

Applications 

per Season 

Maximum 

Seasonal 

Application 

Rate 

(lb a.i./A) 

PHI 

(days) Use Directions and Limitations 

Cotton 

BYI 8330 

OD 

MoventoTM 

UltorTM

Ground & 

aerial 0.04-0.08 4 0.16 21 

Minimum RTI: 7 days 

Minimum spray volume: 10 gallons per acre 

(GPA) ground, 5 GPA aerial 

REI: 24 hours 

Soybean 

BYI 8330 

OD 

MoventoTM 

UltorTM

Ground & 

aerial 0.04-0.08 4 0.16 21 

Minimum RTI: 7 days 

Minimum spray volume: 10 GPA ground, 5 

GPA aerial 

REI: 24 hours 

Legume Vegetables (excluding soybean, dry) 

BYI 8330 

OD 

MoventoTM 

UltorTM

Ground & 

aerial 0.04-0.08 4 0.16 

1 (ediblepodded, 

succulent) 

7 (dry 

shelled) 

Minimum RTI: 7 days 

Minimum spray volume: 15 GPA ground, 5 

GPA aerial 

REI: 24 hours 

Tropical Fruit (Acerola, Atemoya, Avocado, Birida, Black sapote, Canistel, Cherimoya, Custard Apple, Feijoa, 

Jaboticaba, Guava, Llama (sic), Longan, Lychee, Mamey sapote, Mango, Papaya, Passionfruit, Persimmon, 

Pulasan, Rambutan, Sapodilla, Soursop, Spanish lime, Star apple, Starfruit, Sugar apple, Wax jambu, White sapote) 

BYI 8330 

OD 

MoventoTM 

UltorTM

Ground & 

aerial 0.13-0.16 3 0.40 1 

Minimum RTI: 14 days 

Minimum spray volume: 30 GPA ground, 10 

GPA aerial 

REI: 24 hours 

Additional Restrictions for all Crops: 

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

adjuvant/additive. 

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

supplemental labeling. 

Rotational crop plantback intervals (PBIs): 30 days for all non-labeled crops. 

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

adequate to allow evaluation of the residue data relative to the proposed use. Field trial data are 

required for sugar apple (the representative crop for atemoya, custard apple, cherimoya, ilama, 

soursop, and birida). As these data have not been submitted, the spirotetramat labels should be 

revised to delete instructions for use on sugar apple, atemoya, custard apple, cherimoya, ilama, 

soursop, and birida. 
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2.2 Structure and Nomenclature 

Table 2.2. Test Compound Nomenclature.

Compound 

Chemical Structure 

Common name Spirotetramat 

Company experimental name BYI 08330 

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

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

carbonate 

CAS # 203313-25-1 

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

Compound: BYI08330-enol 

Chemical Structure 

Common name BYI08330-enol 

Company experimental name BYI08330-enol 

IUPAC name None provided 

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

CAS # None provided 

Compound: BYI08830-

ketohydroxy 

Chemical Structure 

Common name BYI08830-ketohydroxy 

Company experimental name BYI08830-ketohydroxy 

IUPAC name None provided 

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

CAS # None provided 
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Compound: BYI08330-enol-Glc 

Chemical Structure 

Common name BYI08330-enol-Glc 

Company experimental name BYI08330-enol-Glc 

IUPAC name None provided 

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

CAS # None provided 

Compound: BYI 08330-monohydroxy 

Chemical Structure 

Common name BYI 08330-mono-hydroxy 

Company experimental name BYI 08330-mono-hydroxy 

IUPAC name None provided 

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

CAS # None provided 

Compound: BYI 08330-enolGA 

Chemical Structure 

Common name BYI 08330-enol-GA 

Company experimental name BYI 08330-enol-GA 

IUPAC name None provided 

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

en-2-one 

CAS # None provided 
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2.3 Physical and Chemical Properties

Table 2.3. Physicochemical Properties of the Technical Grade 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 10-9 Pa (20 oC) 

1.5 x 10-8 Pa (25 oC) 

1.5 x 10-6 Pa (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

3.0 Hazard Characterization/Assessment

3.1 Hazard and Dose-Response Characterization

3.1.1 Database Summary

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

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

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

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

studies. 

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

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

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

one in vivo dermal penetration study (rat). 

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

potential, and data quality is acceptable. 
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3.1.2 Mammalian Toxicology

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

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

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

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

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

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

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

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

toxicology database for spirotetramat. 

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

89-98% at 48 hours following single low (2 mg/kg bw) and higher (100 mg/kg bw) doses, as 

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

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

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

liver and kidney. Spirotetramat was completely metabolized by the rat, since no parent 

compound was detected in the excreta. The main metabolic reaction was cleavage of the ester 

group, which resulted in formation of the major metabolite BYI 08330-enol (53-87% of 

administered dose). All other identified metabolites could be derived from enol. Male rats 

exhibited much higher rates of demethylation of BYI 08330-enol to BYI 08330-desmethyl-enol 

(25-37%) when compared to female rats (5-10 %). Spirotetramat was excreted quickly with 88-

95% of the administered dose eliminated via urine and 2-11% via feces within 48 hours of 

exposure. 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

spirotetramat manufacturing plant personnel. 

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

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

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

dogs to spirotetramat was characterized by statistically significant declines in circulating thyroid 

hormones (T4) at ≥1200 ppm (32 mg/kg bw/day); decreased T3 was observed at the highest dose 
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tested only (2500 ppm; 72 mg kg bw/day). However, correlative changes in thyroid weight, 

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

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

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

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

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

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

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

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

route yielded no evidence of systemic toxicity. 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

the limit dose following long-term treatment with spirotetramat. 

 

Carcinogenicity and Genotoxicity: Treatment-related increases in tumor incidence were not 

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

clastogenicity in several standard in vivo and in vitro assays. 

Developmental Toxicity: Developmental toxicity in the absence of maternal toxicity was not 

observed in either the rat or rabbit. In the rat, decreased body weight and food consumption 

were observed in dams at the limit dose in a developmental toxicity study. Developmental 

toxicity (reduced fetal weight and increased incidences of malformations and skeletal deviations) 

was also observed at the limit dose. The NOAEL was established at the next lower dose (140 

mg/kg bw/day) in both dams and offspring. In the rabbit, developmental toxicity was not 

observed up to the highest dose tested (160 mg/kg bw/day). However, maternal toxicity was 
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observed at ≥40 mg/kg bw/day, including a dose-dependent increase in abortion and other 

clinical signs of systemic toxicity in affected animals. 

Reproductive Toxicity: In addition to testicular histopathology observed following subchronic 

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

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

F1-generation male rats treated with 6000 ppm (419 mg/kg bw/day) spirotetramat in the diet, and 

decreased reproductive performance was also observed in one of these males. Similar results 

were obtained in the 1-generation reproductive toxicity range-finding study, in which decreased 

sperm motility and progression and increased abnormal sperm cells in the epididymides were 

observed in F1 males at ≥6000 ppm (320 mg/kg bw/day). Development of the sexual organs of 

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

treatment-related effects were observed at lower doses. 

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

decreased epididymal sperm counts were observed after 10 days or more of treatment with 1000 

mg/kg bw/day by gavage. 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 testesepididymides of treated animals. Therefore, male reproductive toxicity in rats is likely due to the 

enol metabolite of spirotetramat. 

Although reproductive effects manifested as testicular toxicity and sperm abnormalities in a 90-

day rat study, in a two-generation reproductive toxicity study and in a special reproductive 

toxicity, the reproductive effects were seen at very high doses. Testicular toxicity was seen at 

616 mg/kg/day and the sperm abnormalities were seen at 419 mg/kg/day in the two generation 

reproduction study and at 1000 mg/kg/day (Limit Dose) in the special male reproductive toxicity 

study. 

3.2 FQPA Considerations

Consistent with the last risk assessment for spirotetramat (Memo, J. Tyler, et al., 14-MAY-2008; 

D333437), the spirotetramat risk assessment team recommends that the FQPA SF be reduced to 

1X for the following reasons: 

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

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

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

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

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

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

• Spirotetramat does not operate by way of a neurotoxic mechanism and there is no need 

for a developmental neurotoxicity study or additional UFs to account for neurotoxicity. 
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• Although a subchronic neurotoxicity study is now required as part of the revisions to 40 

CFR Part 158, the existing toxicological database indicates that spirotetramat is not a 

neurotoxic chemical in mammals. The only clinical signs at any dose in the acute 

neurotoxicity study were staining of the fur or perianal region with urine and decreased 

motor activity. The urine staining that was identified is not considered a neurotoxic 

effect and was likely due to a colored metabolite that was excreted into the urine or feces 

or to a change in the pH of the urine due to an excreted metabolite. The decreased motor 

activity observed is not considered evidence of neurotoxicity because there were no 

effects on movement or gait or and there were no confirmatory findings of neurological 

pathology. Thus, both of these effects of are considered signs of general toxicity 

(malaise). Further, the effects seen in the acute neurotoxicity study are not corroborated 

by any other study in the database. Although brain dilation was found in one dog in the 

one-year dog study, EPA concluded that this effect was most likely not caused by 

administration of spirotetramat given evidence showing this to be a congenital anomaly 

in the test species, and because there is no other evidence of brain pathology in the 

database. 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 young. 

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

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

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

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

not neurotoxic in adults or young animals. 

• There are no residual uncertainties identified in the exposure databases. The dietary food 

exposure assessments were performed based on 100% CT and tolerance-level or average 

field-trial residues. The submitted residue data for tropical fruit is not appropriate for the 

proposed use pattern as the trials were conducted at a ~2X use rate. The Agency is thus 

requesting that the petitioner conduct bridging studies with lychee and guava (1 trial each 

with four samples per treatment regimen) in order to determine the relationship between 

residues resulting from the labeled use pattern and that used in the submitted field trials. 

Based on this relationship, the submitted residue data will be adjusted and the appropriate 

tolerances determined. As the recommended tolerances are based on exaggerated-rate 

field trial data, it is likely that any future adjustment of these tolerances will be to a lower 

level. This risk assessment is thus likely to over-estimate the dietary risk from 

spirotetramat residues in/on tropical fruit. Use of tolerance levels based on exaggerated 

application rates in a risk assessment will tend to overstate exposure even more than the 

overestimate usually supplied by use of the assumption of tolerance-level residues. 

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

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

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

• The registered and/or proposed uses of spirotetramat are not expected to result in 

residential exposures. 

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

of the immune system, this finding does not raise uncertainty given the lack of an 

immunotoxicity study. The endpoint selected for risk assessment was based on accelerated 

thymus involution and hypothyroid effects in the dog. Thymus involution has been 
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demonstrated to occur when hypothyroidism is induced in animals, so it is reasonable to 

conclude that the thymus involution in these dogs was secondary to the thyroid effects, rather 

than a direct effect on the immune system. The dose at which these effects were observed is 

considered a LOAEL because there was some consistency of dose and effect seen across the 

subchronic and chronic toxicity studies. However, the effects occurred in relatively few animals 

and thus selection of this endpoint is considered a very protective POD; it is at least 10-fold 

lower than any other potential POD. With respect to immunotoxicity, no immunotoxic effects 

were seen in rats or mice, the species in which immunotoxicity studies are conducted. Thus, 

HED does not believe that conducting a functional immunotoxicity study in any rodent species 

will result in a lower POD than that currently used for overall risk assessment. For this reason 

and because the current POD is considered extremely protective, a UFDB is not needed to account 

for the lack of this study. 

3.3 Hazard Identification and Toxicity Endpoint Selection

3.3.1 Acute Reference Dose (aRfD)

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

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

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

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

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

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

3.3.2 Chronic Reference Dose (cRfD) 

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

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

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

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

1X. 

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

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

exposure was not chosen. 

3.3.4 Dermal Absorption

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

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

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

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

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

compound measured in the stratum corneum immediately after the 10-hour exposure continued 

to be absorbed. 

3.3.5 Dermal Exposure (Short- and Intermediate-Term)
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There are no registered or proposed residential uses for spirotetramat. The oral developmental 

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

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

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

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

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

systemic toxicity in pregnant workers. 

3.3.6 Dermal Exposure (Long-Term) 

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

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

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

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

duration of exposure. 

3.3.7 Inhalation Exposure (Short- and Intermediate-Term)

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

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

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

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

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

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

toxicity to pregnant workers. 

Based on the available toxicity database and the Agency's current practices, the inhalation risk 

for spirotetramat was assessed using an oral toxicity study. The Agency sought expert advice 

and input on issues related to this route-to-route extrapolation approach (i.e., the use of oral 

toxicity studies for inhalation risk assessment) from its Federal Insecticide, Fungicide, and 

Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009. The Agency 

received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report and may, as appropriate, re-examine and develop new 

policies and procedures for conducting inhalation risk assessments, including route to route 

extrapolation of toxicity data. If any new policies or procedures are developed, then the Agency 

may revisit the need for an inhalation toxicity study for spirotetramat and/or a re-examination of 

the inhalation toxicity risk assessment. 

3.3.8 Inhalation Exposure (Long-Term) 

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

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

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

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

duration of exposure. See section 3.3.7 for a discussion of the use of oral toxicity studies to 

assess inhalation risk. 
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3.3.9 Level of Concern for Margins of Exposure

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

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

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

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

Dermal 100 100 100 

Inhalation 100 100 100 

3.3.10 Recommendation for Aggregate Exposure Risk Assessments

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

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

concern are the same and identified from the same study. 

3.3.11 Classification of Carcinogenic Potential

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

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

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

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

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

Human-Health Risk Assessments

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

3.3.12a and 3.3.12b, respectively. 

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

Exposure Scenario Point of 

Departure 

Uncertainty/FQPA 

Safety Factors 

RfD, PAD, LOC for 

Risk Assessment 

Study and Relevant 

Toxicological Effects 

Acute Dietary (General 

Population, including 

Infants and Children) 

NOAEL = 

100 

mg/kg/day 

UFA = 10X 

UFH = 10X 

UFFQPA = 1X 

aRfD = aPAD = 1.0 

mg/kg/day 

Acute neurotoxicity (rat; 

gavage)

LOAEL = 200 mg/kg based on 

clinical signs (M&F) and 

decreased motor activity (M). 

Chronic Dietary (All 

Populations) 

NOAEL = 5 

mg/kg/day 

UFA = 10X 

UFH = 10X 

UFFQPA = 1X 

cRfD = cPAD = 0.05 

mg/kg/day1 

Chronic toxicity (dog; dietary)

LOAEL = 20 mg/kg/day (M) 

based on thymus involution.

Cancer (Oral, Dermal, 

Inhalation) 

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

carcinogenicity in two oral rodent carcinogenicity studies.

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

members of the human population (intraspecies), UFFQPA = FQPA Safety Factor, NOAEL = no-observed adverse-effect level, LOAEL = lowestobserved adverse-effect level, RfD = reference dose (a = acute, c = chronic), PAD = population-adjusted dose, 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 3.3.12b. Summary of Toxicological Doses and Endpoints for Spirotetramat for Use in Occupational 

Human-Health Risk Assessments. 

Exposure 

Scenario 

Point of 

Departure Uncertainty Factors 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.

Dermal 

Long-Term (>6 

months) 

NOAEL = 5 

mg/kg/day 

Dermalabsorption 

factor = 10% 

UFA = 10X 

UFH = 10X 

Occupational LOC for MOE 

<100 

Chronic toxicity (dog; 

dietary) LOAEL = 20 

mg/kg/day (M) based on 

thymus involution.

Inhalation 

Short- and 

IntermediateTerm (1-30 

days and 1-6 

months) 

NOAEL = 10 

mg/kg/day 

100% 

inhalation 

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. 

Inhalation 

Long-Term (>6 

months) 

NOAEL = 5 

mg/kg/day 

100% 

inhalation 

assumed 

UFA = 10X 

UFH = 10X 

Occupational LOC for MOE 

<100 

Chronic toxicity (dog; 

dietary) LOAEL = 20 

mg/kg/day (M) based on 

thymus involution.

Cancer (oral, 

dermal, 

inhalation) 

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

oral rodent carcinogenicity studies.

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

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

3.4 Endocrine Disruption 

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor 

Screening Program (EDSP) to determine whether certain substances (including pesticide active 

and other ingredients) may have an effect in humans or wildlife similar to an effect produced by 

a “naturally occurring estrogen, or other such endocrine effects as the Administrator may 

designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect. 

Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first 

group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. 

This list of chemicals was selected based on the potential for human exposure through pathways 

such as food and water, residential activity, and certain post-application agricultural scenarios. 

This list should not be construed as a list of known or likely endocrine disruptors. 
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Spirotetramat is not among the group of 58 pesticide active ingredients on the initial list to be 

screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide 

chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all 

pesticide active ingredients. 

For further information on the status of the EDSP, the policies and procedures, the list of 67 

chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: 

http://www.epa.gov/endo/. 

4.0 Public Health and Pesticide Epidemiology Data 

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

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

patch testing in spirotetramat manufacturing plant personnel in 2004. 

5.0 Dietary Exposure/Risk Characterization 

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

pending HED memorandum by G. Kramer (D362952). The drinking water assessment was 

provided by EFED in a memo dated 22-JAN-2008 (J. Meléndez; D345275). New drinking water 

numbers were not calculated for the new uses of spirotetramat because the new use rates are 

similar to or lower than the previously assessed use rates in the 22-JAN-2008 EFED memo. The 

acute and chronic dietary exposure assessments were completed in a HED memorandum by J. 

Van Alstine (22-DEC-2010; D368786). 

5.1 Pesticide Metabolism and Environmental Degradation

5.1.1 Metabolism in Primary Crops

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

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

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

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

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

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

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

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

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

glucose. 

5.1.2 Metabolism in Rotational Crops

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

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

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

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

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

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

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

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

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

5.1.3 Metabolism in Livestock 

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

degradation of spirotetramat in livestock can be characterized as cleavage of the carbonate ester 

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

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

BYI 08330-ketohydroxy and demethylation of the methoxy group to BYI 08330-desmethyl-enol 

were minor metabolic reactions in ruminants as well as reduction of the azaspirodecenyl moiety 

to BYI 08330-monohydroxy. 

5.1.4 Analytical Methodology 

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

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

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

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

08330-enol-Glc in plant matrices by HPLC-MS/MS. Analytical method 00966 was developed 

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

08330-enol-GA in livestock matrices by HPLC-MS/MS. These methods were used as the datacollection methods in the analysis of samples for residues of concern from the various studies 

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

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

adequately radiovalidated using weathered samples obtained from metabolism studies. 

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

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

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

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

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

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

or its metabolites. The MRM testing data were forwarded to the FDA for further evaluation and 

inclusion of results in PAM Vol. I. 

5.1.5 Environmental Degradation

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

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

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

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

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

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

correspond to 14.4 and 0.74 days, respectively, under environmental conditions (summer light in 
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Phoenix, AZ). In sterilized natural water, the major products observed were BYI 08330-enol 

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

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

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

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

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

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

dimethyl-benzoic acid. 

Spirotetramat degraded quickly, with DT50s of <1 day in four aerobic soils. Furthermore, 

spirotetramat-enol also degraded relatively quickly, with calculated DT50s of <1 day, in four 

aerobic soils. DT50s for BYI 08330-ketohydroxy (at a maximum of 24.0% of the applied, range 

of DT50s 1.5-16.7 days) and spirotetramat-amide (maximum 5.2% of the applied, range of 

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

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

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

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

spirotetramat degraded with calculated DT50s of 1.2 and 2.9 days. BYI 08330-enol was a 

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

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

compounds were also observed in the marginally supplemental soil photodegradation studies. 

In aquatic environments, under aerobic aquatic conditions, spirotetramat degraded with 

calculated half-lives (DT50s) of 0.7 and 0.9 days in the total system. Spirotetramat was initially 

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

at 14 days at 99.0%, and decreased to less than the limit of quantitation (<LOQ) to 21.0% at 120 

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

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

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

maximum of 13.5-24.0% at 120 days. 

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

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

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

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

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

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

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

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

to be 2.8 days in the total anaerobic system. 

5.1.6 Comparative Metabolic Profile

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

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

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

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

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

could be derived from the enol intermediate. The second prominent metabolic transformation 
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was oxidative demethylation of the 8-methoxy group to BYI 08330-desmethyl-enol (5-37% of 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

various metabolites bearing a hydroxy group (plants). 

5.1.7 Toxicity Profile of Major Metabolites and Degradates 

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

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

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

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

to the parent. 

5.1.8 Pesticide Metabolites and Degradates of Concern 

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

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression 

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 Applicable1 Not Applicable1

Livestock (Ruminant and 

Poultry) 

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

Spirotetramat and BYI 08330-enol2

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

ketohydroxy 

Not Applicable 
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1

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

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

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

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

setting. 

2

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

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

commodities. 

Plants (Primary Crops): The 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). This decision was based on the following: 

• BYI 08330-enol was a major metabolite in apple leaves, lettuce, cotton gin trash and 

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

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

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

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

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

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

to the parent. 

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

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

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

assumed to be of comparable toxicity to the parent. 

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

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

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

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

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

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

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

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

method. 

Plants (Rotational Crops): The 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). This decision was based on the following: 

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

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

of comparable toxicity to the parent. 

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

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

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

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

forage, and hay. Based on the structural similarity to the parent, BYI 08330-desmethyldi-hydroxy is assumed to be of comparable toxicity to the parent. 
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• BYI 08330-ketohydroxy-alcohol (conjugated) was a major metabolite in wheat straw, 

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

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

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

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

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

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

Livestock: The 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). This decision was 

based on the following: 

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

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

to be of comparable toxicity to the parent. 

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

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

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

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

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

enol-GA does not need to be included in the tolerance expression. 

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

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

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

commodities. 

Drinking Water: The 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 

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

5.1.9 Drinking Water Residue Profile

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

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

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

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

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

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

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

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

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

sediments, and water. The parent spirotetramat appears to be labile in most environments 

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

ketohydroxy) have a potential to contaminate surface waters for a period of weeks to months 
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post-treatment, and a potential to move subsurface and contaminate groundwater. There is also 

the chance that spirotetramat would be deposited off-target by spray drift [the chemical may be 

applied by ground (groundboom and airblast) and aerial methods]. In addition, given the 

relatively high solubility of BYI 08330-enol and BYI 08330-ketohydroxy and their relatively 

low level of binding, these particular transformation products could be released via plant washoff to soils in large rain events, especially if they occur shortly after application. It appears that 

the residues could reach adjacent bodies of water in runoff events both via dissolution or bound 

to the soils (high levels of bound residue were observed in most laboratory studies). 

Drinking water monitoring data are not available for spirotetramat. The effects of water 

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

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

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

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

the parent degrades relatively fast in most environments. 

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

transformation products spirotetramat-enol and spirotetramat-ketohydroxy (D345275, J. 

Meléndez, 22-JAN-2008). New drinking water numbers were not calculated for the new uses of 

spirotetramat because the new use rates are similar to or lower than the previously assessed use 

rates in the 22-JAN-2008 EFED memo. The ground and surface water EDWCs were generated 

using SCI-GROW and FIRST, respectively, and were based on the highest application rates. 

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

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

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

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

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

EDWCs for spirotetramat. 

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

Drinking Water 

Source (Model) 

Type of 

Risk 

EDWC (ppb) 

Spirotetramat Spirotetramatenol 

Spirotetramat -

ketohydroxy 

Maximum Total 

Residues3

Ground-water 

(SCI-GROW)1

Acute and 

Chronic 2.25x10-5 1.64x10-5

3.57x10-4 3.96x10-4 

Surface Water 

(FIRST)2 Acute 0.208 8.0x10-5

3.60x10-3 0.212

Chronic 1.1x10-3 1.7x10-5

2.50x10-4 1.37x10-3 

1

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

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

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

5.1.10 Food Residue Profile

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

cotton and legume vegetables including soybean (crop groups 6 and 7a) will support the 

proposed use patterns. There are adequate storage stability data to validate the storage 

conditions and intervals of samples collected from the field trials. The submitted residue data for 

tropical fruit will not support the proposed use pattern as the trials were conducted at a ~2X use 

rate. HED thus requests that the petitioner conduct bridging studies with lychee and guava (1 
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trial each with four samples per treatment regimen) in order to determine the relationship 

between residues resulting from the labeled use pattern and that used in the submitted field trials. 

Field trial data are also required for sugar apple (the representative crop for atemoya, custard 

apple, cherimoya, ilama, soursop, and birida). As these data have not been submitted, the 

spirotetramat labels should be revised to delete instructions for use on sugar apple, atemoya, 

custard apple, cherimoya, ilama, soursop, and birida. 

Acceptable cotton and soybean 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 cotton meal (1.2X) and hulls (1.1X) and 

soybean AGF (4.1X) and meal (1.4X). 

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

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

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

required for some livestock commodities. The required tolerances for residues in eggs and 

poultry meat byproducts are based on the hen metabolism study. A poultry feeding study will 

not be required to support the currently proposed new uses due to the dose level (1 ppm, 0.8X) 

and the duration (14 days) of the hen metabolism study. However, the petitioner is advised that 

any significant in7crease in the poultry dietary burden may trigger the requirement for a poultry 

feeding study. 

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

for determining appropriate tolerance levels listed in Appendix B. 

5.1.11 International Residue Limits

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

its metabolites in cotton, legume vegetables including soybean (crop groups 6 and 7a), and 

tropical fruit. 

5.2 Dietary Exposure and Risk

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

and 1998. The 1994-96 and 1998 data are based on the reported consumption of more than 

20,000 individuals over two non-consecutive survey days. Foods “as consumed” (e.g., apple pie) 

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

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

files developed jointly by USDA/ARS and EPA. For chronic exposure assessment, consumption 

data are averaged for the entire U.S. population and within population subgroups, but for acute 

exposure assessment are retained as individual consumption events. Based on analysis of the 

1994-96 and 1998 CSFII consumption data, which took into account dietary patterns and survey 

respondents, HED concluded that it is most appropriate to report risk for the following 

population subgroups: the general U.S. population, all infants (<1 year old), children 1-2, 

children 3-5, children 6-12, youth 13-19, adults 20-49, females 13-49, and adults 50+ years old. 

For chronic dietary exposure assessment, an estimate of the residue level in each food or foodform (e.g., orange or orange juice) on the food commodity residue list is multiplied by the 
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average daily consumption estimate for that food/food form to produce a residue intake estimate. 

The resulting residue intake estimate for each food/food form is summed with the residue intake 

estimates for all other food/food forms on the commodity residue list to arrive at the total 

average estimated exposure. Exposure is expressed in mg/kg body weight/day and as a percent 

of the cPAD. This procedure is performed for each population subgroup. 

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

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

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

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

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

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

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

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

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

significant differences in user vs. per capita exposure and risk are specifically identified and 

noted in the risk assessment. 

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

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

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

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

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

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

5.2.1 Acute Dietary Exposure/Risk

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

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

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

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

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

aPAD) for the general U.S. population (4.8% of the aPAD) and all other populations subgroups. 

The most highly exposed population subgroup is children 1-2 years old at 11% of the aPAD. 

5.2.2 Chronic Dietary Exposure/Risk

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

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

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

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

chronic dietary exposure estimates are below HED’s LOC (<100% of the cPAD) for the general 

U.S. population (34% of the cPAD) and all population subgroups. The most highly exposed 

population subgroup is children 1-2 years old at 93% of the cPAD. 
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Table 5.2. Summary of Dietary (Food and Drinking Water) Exposure Risk for Spirotetramat. 

Population Subgroup Acute Dietary (95th Percentile) Chronic Dietary 

Dietary 

Exposure 

(mg/kg/day) 

% aPAD Dietary 

Exposure 

(mg/kg/day) 

% cPAD 

General U.S. Population 0.048149 4.8 0.017143 34 

All Infants (<1 year old) 0.092334 9.2 0.028378 57 

Children 1-2 years old 0.112462 11 0.046603 93 

Children 3-5 years old 0.090437 9.0 0.036756 74 

Children 6-12 years old 0.056308 5.6 0.022814 46 

Youth 13-19 years old 0.039450 3.9 0.014810 30 

Adults 20-49 years old 0.037239 3.7 0.013886 28 

Adults 50+ years old 0.036246 3.6 0.013593 27 

Females 13-49 years old 0.037049 3.7 0.013754 28 

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

6.0 Residential (Non-Occupational) Exposure/Risk Characterization 

As there are currently no registered or proposed residential uses for spirotetramat, a residential 

exposure assessment was not conducted. 

6.1 Spray Drift 

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for spirotetramat. 

The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State 

Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices. The Agency is now requiring interim mitigation measures for aerial 

applications that must be placed on product labels/labeling. The Agency has completed its 

evaluation of the new data base 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 and risks associated 

with aerial as well as other application types where appropriate. 

7.0 Aggregate Risk Assessments and Risk Characterization

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks 

from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure. 

For spirotetramat, aggregate exposure risk assessments were performed for the following 

scenarios: acute aggregate exposure (food and drinking water), and chronic aggregate exposure 

(food and drinking water). Short- and intermediate-term assessments, which are used to evaluate 

aggregate dietary and residential exposures, were not performed because there are no registered 
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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 5.2). The dietary exposure assessment 

was a screening-level assessment, utilizing tolerance-level residues and 100% CT information 

for all proposed agricultural uses and a Tier 1 acute surface water EDWCs generated by FIRST. 

Therefore, the acute aggregate risk associated with the proposed uses of spirotetramat is not of 

concern to HED for the general U.S. population or any population subgroups.

7.2 Chronic Aggregate Risk

The chronic aggregate risk assessment takes into account average exposure estimates from 

dietary consumption of spirotetramat (food and drinking water). The chronic dietary exposure 

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

population subgroups (see Table 5.2). The dietary exposure assessment was a conservative 

assessment, utilizing average field-trial residues and 100% CT information for all proposed 

agricultural uses and a Tier 1 chronic surface water EDWCs generated by FIRST. Therefore, the 

chronic aggregate risk associated with the proposed uses of spirotetramat is not of concern to 

HED for the general U.S. population or any population subgroups. 

8.0 Cumulative Risk Characterization/Assessment

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to spirotetramat and any other substances and spirotetramat does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 

EPA has not assumed that spirotetramat has a common mechanism of toxicity with other 

substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Pathway

An occupational exposure assessment was provided in a HED memorandum dated 12-NOV2009 (K. Lowe; D368787). It is anticipated that there will be occupational handler and postapplication exposure from the proposed uses of spirotetramat. Based on label information, 

exposure is expected to occur for short- and intermediate-term durations. 
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9.1 Short- and Intermediate-Term Handler Risk

The scenarios assessed for occupational handlers include mixing/loading liquids for aerial, 

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

groundboom equipment, and flagging for aerial applications. 

As no chemical-specific data were available with which to assess potential exposure of 

spirotetramat to pesticide handlers, the estimates of exposure to pesticide handlers are based 

upon surrogate study data available in the PHED Surrogate Exposure Guide (August 1998). For 

pesticide handlers, HED presents estimates of dermal exposure for “baseline” (i.e., workers 

wearing a single layer of work clothing consisting of a long-sleeved shirt, long pants, shoes plus 

socks, and no protective gloves), as well as for “baseline” and the use of protective gloves or 

other PPE, as might be necessary. The spirotetramat product labels direct applicators and other 

handlers to wear a long-sleeved shirt, long pants, protective eyewear, chemical-resistant gloves, 

and shoes plus socks. 

Handler exposure is expected to be short- or intermediate-term based on information provided on 

proposed labels. In addition, the short- and intermediate-term toxicological endpoints are the 

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

intermediate-term duration exposures. Long-term exposures are not expected, therefore, a longterm assessment was not conducted. 

Table 9.1 presents the short- and intermediate-term estimated risks for occupational handlers. 

HED has determined that risks are not of concern (i.e., MOEs >100), provided workers wear 

protective gloves as recommended on the label. 
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Table 9.1. Short- and Intermediate-Term Occupational Handler Exposure and Risk for Spirotetramat.

Exposure 

Scenario Crop 

App 

Ratea

(lb ai/A) 

Acres 

Treated 

Dailyb

Unit Exposurec Dose (mg/kg/day) 

Baseline 

Dermald

(mg/lb 

ai) 

PPE-G 

Dermale 

(mg/lb ai)

Baseline 

Inhalationf

(μg/lb ai) 

Baseline 

Dermalg

PPE-G 

Dermalg

Baseline 

Inhalationh

Baseline 

Dermali

PPE-G 

Dermali

Mixer/Loader

Mixing/Loadin

g Liquids for 

Aerial 

Applications 

Cotton, 

soybeans 0.078 1200 2.9 0.023 1.2 0.45 0.0036 0.0019 22 2,800 

Legume 

vegetables 0.078 350 2.9 0.023 1.2 0.13 0.001 0.00055 76 9,600 

Tropical 

fruits 0.16 350 2.9 0.023 1.2 0.27 0.0021 0.0011 37 4,700 

Mixing/Loadin

g Liquids for 

Chemigation 

Applications 

Legume 

vegetables 0.078 350 2.9 0.023 1.2 0.13 0.001 0.00055 76 9,600 

Mixing/Loadin

g Liquids for 

Groundboom 

Applications 

Cotton, 

soybeans 0.078 200 2.9 0.023 1.2 0.075 0.0006 0.00031 130 17,000 

Legume 

vegetables 0.078 80 2.9 0.023 1.2 0.03 0.00024 0.00012 330 42,000 

Mixing/Loadin

g Liquids for 

Airblast 

Applications 

Tropical 

fruits 0.16 40 2.9 0.023 1.2 0.031 0.00025 0.00013 320 41,000 

Applicator

Applying 

Sprays via 

Aerial 

Equipment 

Cotton, 

soybeans 0.078 1200 

0.005 

(eng. 

control

m) 

No Data 

0.068 

(eng. 

control) 

0.00078 

(eng. 

control) 

No Data 

0.00011 

(eng. 

control) 

13,000 

(eng. 

control) 

No 

Data 

Legume 

vegetables 0.078 350 

0.005 

(eng. 

control) 

No Data 

0.068 

(eng. 

control) 

0.00023 

(eng. 

control) 

No Data 

0.000031 

(eng. 

control) 

44,000 

(eng. 

control) 

No 

Data 

Tropical 

fruits 0.16 350 

0.005 

(eng. 

control) 

No Data 

0.068 

(eng. 

control) 

0.00047 

(eng. 

control) 

No Data 

0.000063 

(eng. 

control) 

21,000 

(eng. 

control) 

No 

Data 

Applying 

Sprays via 

Groundboom 

Equipment 

Cotton, 

soybeans 0.078 200 0.014 0.014 0.74 0.00036 0.00036 0.00019 27,000 27,000 

Legume 

vegetables 0.078 80 0.014 0.014 0.74 0.00015 0.00015 0.000077 69,000 69,000 
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Table 9.1. Short- and Intermediate-Term Occupational Handler Exposure and Risk for Spirotetramat.

Exposure 

Scenario Crop 

App 

Ratea

(lb ai/A) 

Acres 

Treated 

Dailyb

Unit Exposurec Dose (mg/kg/day) 

Baseline 

Dermald

(mg/lb 

ai) 

PPE-G 

Dermale 

(mg/lb ai)

Baseline 

Inhalationf

(μg/lb ai) 

Baseline 

Dermalg

PPE-G 

Dermalg

Baseline 

Inhalationh

Baseline 

Dermali

PPE-G 

Dermali

Applying 

Sprays via 

Airblast 

Equipment 

Tropical 

fruits 0.16 40 0.36 0.24 4.5 0.0038 0.0026 0.00048 2,600 3,900 

Flagger

Flagging for 

Aerial Sprays 

Applications 

Cotton, 

soybeans 0.078 350 0.011 NAn 0.35 0.0005 NA 0.00016 20,000 NA 

Legume 

vegetables 0.078 350 0.011 NA 0.35 0.0005 NA 0.00016 20,000 NA 

Tropical 

fruits 0.16 350 0.011 NA 0.35 0.001 NA 0.00033 9,700 NA 

a. Application Rates based on proposed uses on labels for spirotetramat products BYI 8330 150 OD Insecticide, UltorTM, and Movento

TM

. 

b. ExpoSAC Policy # 9.1. c. Unit Exposures based on PHED. d. Baseline Dermal: long-sleeved shirt, long pants, and no gloves. e. PPE-G Dermal: baseline dermal plus chemical-resistant gloves. f. Baseline Inhalation: no respirator. g. Dermal Dose (mg/kg/day) = unit exposure (mg/lb ai) * application rate (lb ai/acre) * acres treated * dermal-absorption factor (10%) / body weight (60 kg). 

h. Inhalation Dose (mg/kg/day) = unit exposure (ug/lb ai) * 1E-03 mg/ug * application rate (lb ai/acre) * acres treated * inhalation absorption (100%) / body weight (60 kg). 

i. Dermal MOE = NOAEL (10 mg/kg/day) / dermal dose (mg/kg/day). LOC = 100. j. Inhalation MOE = NOAEL (10 mg/kg/day) / inhalation dose (mg/kg/day). LOC = 100. k. Combined Baseline Dermal + Inhalation MOE = NOAEL (10 mg/kg/day) / (baseline dermal dose + baseline inhalation dose). 

l. Combined PPE-G + Baseline Inhalation MOE = NOAEL (10 mg/kg/day) / (PPE-G dermal dose + baseline inhalation dose). m. Eng. control = engineering control; enclosed cockpit. n. Not applicable. 
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9.2 Short-Term Post-application Risk

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

spray. Post-application exposure is expected to be short-term based on information provided on 

the proposed labels. However, the short- and intermediate-term toxicological endpoints are the 

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

intermediate-term duration exposures. 

Since no post-application exposure data were submitted in support of this registration action, 

dermal exposures during post-application activities were estimated using dermal TCs from the 

ExpoSAC Policy Number 3.1: Agricultural TCs (August, 2000). Table 9.2.1 summarizes the 

scenarios assessed. In addition, the following assumptions were used in the calculations: 

• Application Rate = 0.078 lb ai/A for foliar applications to cotton, soybean, and 

legume vegetables; 0.16 lb ai/A for foliar applications to 

tropical fruit crops; 

• Exposure Duration = 8 hours per day; 

• Body Weight = 60 kg; 

• Dermal Absorption = 10%; and 

• Fraction of ai retained on foliage is assumed to be 20% (0.2) on day zero (= % 

dislodgeable-foliar residue, DFR, after initial treatment) for agricultural crops. This 

fraction is assumed to further dissipate at the rate of 10% (0.1) per day on following days. 

These are default values established by HED’s ExpoSAC. 

Table 9.2.1. Anticipated Post-Application Activities and Dermal TCs.

Proposed 

Crops 

Policy Crop 

Group 

Category 

Application 

Rate (lb 

ai/acre) 

TCs (cm2/hr) Activities 

Cotton, 

soybean, 

legume 

vegetables 

Field/row 

crop, 

low/medium 

0.0078 

100 Irrigation, hand weeding and scouting 

(minimum foliage) 

1,500 Irrigation, hand weeding and scouting (full 

foliage) 

2,500 Hand harvesting 

Tropical 

fruit 

Tree, “fruit,” 

evergreen 

0.16 

1,500 Harvesting 

3,000 Thinning 

The following equations were used to calculate risks for workers performing postapplication 

activities: 

DFRt (μg/cm2) = AR (lb ai/acre) * F * (1-D)t * 4.54E8 μg/lb * 24.7E-9 acre/cm2

Where: 

DFRt = dislodgeable foliage residue on day "t" (μg/cm2

); 

AR = application rate (lb ai/acre); 

F = fraction of ai retained on foliage (unitless); and 
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D = fraction of residue that dissipates daily (unitless). 

and

Daily dermal dose t (mg/kg-day) = [DFRt (μg/cm2

) * 1E-3 mg/μg * TC (cm2/hr) * DA * ET (hrs)] / BW (kg) 

Where: 

DFRt = dislodgeable foliage residue on day "t" (μg/cm2

); 

t = number of days after application day (days); 

TC = transfer coefficient (cm2

/hr); 

DA = dermal-absorption factor (unitless); 

ET = exposure time (hr/day); and 

BW = body weight (kg). 

The post-application exposure associated with the proposed new uses in agricultural crops is 

summarized in Table 9.2.2. All scenarios resulted in MOEs greater than 100 on day 0 (12 hours 

after application) and, therefore, are not of concern to HED. 

Table 9.2.2. Postapplication Exposure and Risk for Spirotetramat. 

Crop Grouping 

(Crop) 

TC 

(cm2/hr) 

Days after 

Treatment DFRa

 (μg/cm2) 

Daily Dermal 

Doseb

(mg/kg/day) 

MOEc 

Field/row crop, low/medium 

(cotton, soybean, legume 

vegetables) 

100 

0 

(12 hours) 0.18 

0.00023 43,000 

1,500 0.0035 2,900 

2,500 0.0058 1,700 

Tree, “fruit,” evergreen 

(tropical fruit) 

1,500 0 

(12 hours) 0.36 

0.0072 1,400 

3,000 0.014 700 

a. DFR = Dislodgeable Foliar Residue = Application rate (lb ai/A) * Fraction of ai retained on foliage (20%) * (1- daily 

dissipation rate)t

 * 4.54E8 μg/lb * 24.7E-9 A/cm2. 

b. Daily Dermal Dose = [DFR (μg/cm2

) x*1E-03 mg/μg * TC (cm2/hr) * dermal absorption (10%) * 8 hrs/day] / body 

weight (60 kg). 

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

Since the post-application assessment is not a concern on Day 0 (12 hours following 

application), the REI is based on the acute toxicity of spirotetramat technical material. 

Spirotetramat is classified as Toxicity Category III for acute dermal; Toxicity Category II for 

primary eye irritation; and as Toxicity Category IV for primary dermal irritation. Therefore, the 

acute toxicity categories for this chemical require a 24 hour REI under the WPS. The 24-hour 

REI, which appears on the proposed label, is adequate for these proposed use patterns. 

10.0 Data Needs and Label Recommendations

10.1 Toxicology

• Immunotoxicity study (new requirement under 40 CFR Part 158). 

• Subchronic neurotoxicity study (new requirement under 40 CFR Part 158). 
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10.2 Residue Chemistry

860.1200 Directions for Use

• Field trial data are required for sugar apple (the representative crop for atemoya, custard 

apple, cherimoya, ilama, soursop, and birida). As these data have not been submitted, the 

spirotetramat labels should be revised to delete instructions for use on sugar apple, 

atemoya, custard apple, cherimoya, ilama, soursop, and birida. 

860.1500 Crop Field Trials

• The submitted residue data for tropical fruit will not support the proposed use pattern as 

the trials were conducted at a ~2X use rate. HED thus requests that the petitioner 

conduct bridging studies with lychee and guava (1 trial each with four samples per 

treatment regimen) in order to determine the relationship between residues resulting from 

the labeled use pattern and that used in the submitted field trials (MRID# 47648205). 

860.1550 Proposed Tolerances

• The petitioner is requested to submit a revised Section F specifying the revised tolerance 

levels and commodity definitions summarized in Appendix B. 

10.3 Occupational Exposure

• None.

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

RDI: RAB1 Branch (10/28/09); D. Vogel (11/12/09) 

J. Van Alstine: S-10951: Potomac Yard 1 (PY1): (703)603-8866: 7509P: RAB1 
Spirotetramat Human-Health Risk Assessment DP#: D368785 

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Appendix A. Toxicology Assessment 

A.1. Toxicity Profiles

Table A.1.1. 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 
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Table A.1.2. Subchronic and Chronic Toxicity and Genotoxicity Profile – Spirotetramat Technical.

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

870.3100 28-Day oral 

toxicity (mouse) 

46904536 (2001) 

Acceptable/non-guideline 

0, 500, or 5000 ppm 

(equivalent to 0, 136.5 or 

1415 mg/kg bw/day [M]) 

NOAEL = 5000 ppm (1415 mg/kg/day [M]). 

LOAEL not observed. 

870.3100 90-Day oral 

toxicity (mouse) 

46904539 (2005) 

Acceptable/guideline 

0, 70, 350, 1700, or 7000 

ppm (equivalent to 0/0, 

12.8/16, 59.6/72.4, 

300/389, or 1305/1515 

mg/kg bw/day [M/F]) 

NOAEL = 7000 ppm (1305/1515 mg/kg/day

[M/F]). 

LOAEL not observed. 

870.3100 28-Day oral 

toxicity (rat) 

46904537 (1998) 

Acceptable/non-guideline 

0, 500 or 5000 ppm 

(equivalent to 0, 47.3, or 

501.8 mg/kg bw/day [F]) 

NOAEL = 5000 ppm (501.8 mg/kg/day [F]). 

LOAEL not observed. 

870.3100 90-Day oral 

toxicity (rat) 

46904538 (2005) 

Acceptable/guideline 

0, 150, 600, 2500, or 

10000 ppm (equivalent to 

0/0, 9/11, 26/46, 148/188, 

or 616/752 mg/kg bw/day 

[M/F]) 

NOAEL = 2500 ppm (148/188 mg/kg/day 

[M/F]). 

LOAEL = 10000 ppm (616/752 mg/kg/day 

[M/F]), based on decreased body weight, 

abnormal spermatozoa and hypospermia in the 

epididymis, decreased testicular weight, and 

testicular degeneration and vacuolation in 

males, and alveolar macrophages in both sexes. 

870.3150 28-Day oral 

toxicity (dog) 

46904572 (2004) 

Acceptable/non-guideline 

0, 100, 400, 1600, or 6400 

ppm (equivalent to 0/0, 

3/3, 13/12, 42/70, or 

104/127 mg/kg/day 

[M/F]) 

NOAEL = 1600 ppm (42/70 mg/kg/day [M/F]). 

LOAEL = 6400 ppm (104/127 mg/kg/day 

[M/F]) based on decreased thymus size and 

weight as well as decreased body weight and 

food consumption, which resulted in 

emaciation. 

870.3150 90-Day oral 

toxicity (dog) 

46904541 (2005) 

Acceptable/guideline 

0, 150, 300, 1200, or 

4000/2500 ppm 

(equivalent to 0/0, 5/6, 

9/10, 33/32, or 81/72 

mg/kg bw/day) 

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

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

LOAEL = 2500 ppm (72 mg/kg/day)[F] based 

on decreased body-weight gain and food 

consumption, depressed RBC parameters (red 

blood cell count, hemoglobin level and 

hematocrit), and thymus atrophy. 

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. 
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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. 
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870.3800 2-gen. reproduction 

and fertility effects 

(rat) 

46904546 (2006) 

Acceptable/guideline 

0, 250, 1,000, or 6,000 

ppm (equivalent to 0/0, 

17.2/20, 70.7/82.5, or 

419.3/484.7 mg/kg 

bw/day [M/F]) 

Parental/Systemic NOAEL = 1000 ppm 

(70.7/82.5 mg/kg/day [M/F]). 

LOAEL = 6000 ppm (419.3/484.7 mg/kg/day 

[M/F]) based on decreases in body weight (F1

males and females), weight gain (P males, F1

males and females), and food consumption 

during lactation (P- and F1-generation females), 

and kidney histopathology and decreased 

kidney weights (F1 males and females). 

Reproductive NOAEL = 1000 ppm (70.7 

mg/kg/day)[M] & 6000 ppm (484.7 

mg/kg/day)[F]. 

LOAEL = 6000 ppm (419.3 mg/kg/day)[M] 

based on abnormal sperm cells and decreased 

reproductive performance in the F1 males. 

Offspring NOAEL = 1000 ppm (70.7/82.5 

mg/kg/day [M/F]). 

LOAEL = 6000 ppm (419.3/484.7 mg/kg/day 

[M/F]) based on decreased body weight and 

body-weight gain during lactation in both F1

and F2 generations. 

870.4100 Chronic toxicity (1 

year; dog) 

46904548 (2006) 

Acceptable/guideline 

0, 200, 600, or 1800 ppm 

(equivalent to 0/0, 6/5, 

20/19, or 55/48 mg/kg/day 

[M/F]) 

NOAEL = 200 ppm (6 mg/kg/day)[M] & 1800 

ppm (48 mg/kg/day)[F]. 

LOAEL = 600 ppm (20 mg/kg/day)[M] based 

on thymus involution [M] and not observed [F]. 

870.4100 Chronic toxicity 

(1 year; rat) 

46904547 (2005) 

Acceptable/guideline 

0, 250, 3500, or 

7500/12000 ppm (M/F) 

(equivalent to 0/0, 

13.2/18, 189/255, or 

414/890 mg/kg bw/day 

[M/F]) 

NOAEL = 250 ppm (13.2 mg/kg/day)[M] & 

3500 ppm (255 mg/kg/day)[F]. 

LOAEL = 3500 ppm (189 mg/kg/day)[M] 

based on dose-dependent increase in alveolar 

macrophages; & 12000 ppm (890 

mg/kg/day)[F] based on decreased body weight 

and body-weight gain, alveolar macrophages, 

discoloration of the lung, and yellow/brown 

staining of the perigenital area and tail. 

870.4200 Carcinogenicity 

(rat) 

46904549 (2006) 

Acceptable/guideline 

0, 250, 3500, or 

7500/12000 ppm (M/F) 

(equivalent to 0/0, 

12.5/16.8, 169/229, or 

373/823 mg/kg bw/day 

[M/F]) 

NOAEL = 250 ppm (12.5/16.8 mg/kg/day 

[M/F]). 

LOAEL = 3500 ppm (169/229 mg/kg/day 

[M/F]) based on decreased kidney weight and 

renal tubular dilation. 

No evidence of carcinogenicity. 

870.4200 Carcinogenicity 

(mouse) 

46904550 (2006) 

Acceptable/guideline 

0, 70, 1700, or 7000/6000 

ppm (M/F) (equivalent to 

0/0, 10.9/13.7, 263/331, or 

1022/1319 mg/kg/day 

[M/F]) 

NOAEL = 7000/6000 ppm (1022/1319 

mg/kg/day [M/F]). 

LOAEL not observed. 

No evidence of carcinogenicity. 
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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 μg/mL (-

S9) 

0, 20, 40, 60, 80, 92, 100, 

108, 116, 120, 124, 132, 

or 140 μg/mL (+S9) 

Negative. 

870.5375 In vitro mammalian 

chromosome 

aberration 

46904554 (2002) 

Acceptable/guideline 

0, 10, 12, 24, 30, 48, or 50 

μg/mL (-S9) 

0, 20, 40, or 80 μg/mL 

(+S9) 

Weakly clastogenic at cytotoxic concentrations 

only. 

870.5375 In vitro mammalian 

chromosome 

aberration 

46904555 (2003) 

Unacceptable/guideline 

0, 30, 50, 70, 90, or 110 

μg/mL (-S9) 

0, 40, 60, 80, 100, or 120 

μg/mL (+S9) 

N/A 

870.5395 In vivo erythrocyte 

micronucleus assay 

(mouse) 

46904556 (2002) 

Acceptable/guideline 

0, 125, 250, or 500 mg/kg 

bw 

Negative. 

870.5385 In vivo bone 

marrow 

chromosomal 

aberration assay 

(mouse) 

46904558 (2003) 

Acceptable/guideline 

0, 125, 250, or 500 mg/kg 

bw 

Negative. 

870.5550 In vivo/in vitro

UDS assay (rat 

hepatocytes) 

46904557 (2003) 

Acceptable/guideline 

0, 1000, or 2000 mg/kg 

bw 

Negative. 
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870.6200a Acute neurotoxicity 

screening battery 

46904560 (2005) 

Acceptable/guideline 

0, 50, 100, 200, 500, or 

2000 mg/kg bw 

NOAEL = 100 mg/kg/day. 

LOAEL = 200 mg/kg/day based on clinical 

signs (males and females) and decreased motor 

activity (males). 

870.7485 Metabolism and 

pharmacokinetics 

(rat) 

46904504 (2006) 

Acceptable/guideline 

2 or 100 mg/kg bw 

(single) 

2 mg/kg bw (repeat) 

Absorption: 89-98% after 48 hrs (no 

significant differences among low dose, high 

dose, and repeated dose tests). 

Distribution: AUC0-∞ (measure of systemic 

exposure) slightly higher for males than 

females; <0.2% of administered dose detected 

in body 48 hrs after sacrifice; highest 

equivalent concentrations detected in liver and 

kidney. 

Metabolism: parent compound undetected in 

urine and feces of all tests; main metabolic 

reaction was cleavage of the ester group which 

resulted in formation of the primary metabolite 

BYI 08330-enol (53-87% of administered 

dose); all other identified metabolites could be 

derived from enol; male rats exhibited much 

higher rates of demethylation of BYI 08330-

enol to BYI 08330-desmethyl-enol (25-37%) 

vs. females rats (5-10%). 

Excretion: 88-95% of administered dose 

eliminated via urine and 2-11% via feces within 

48 hrs. 

870.7485 Metabolism and 

pharmacokinetics 

(rat) 

46904561 (2006) 

Acceptable/guideline 

2 or 1000 mg/kg bw 

(single) 

At 1000 mg/kg bw: Absorption and excretion 

less than low dose, with 27% of dose excreted 

in urine after 24 hours (18% in feces); plasma 

radioactivity slightly higher than in liver and 

kidney; these results are consistent with 

saturation of cellular transport mechanisms. 

Tissue radioactivity decreased from 1 h to 24 h 

post dose. Metabolism profile qualitatively 

similar to that of the low dose; BYI 08330-enol 

was most prominent metabolite; similar to low 

dose group, BYI 08330-desmethyl-enol levels 

greater in urine than in plasma and organs. 

870.7600 In vivo dermal 

penetration 

(rat) 

46904563 (2006) 

Acceptable/guideline 

100, 15, or 5 μg ai/cm2

(OD150 formulation) 

Dermal absorption = 10%. 

Special 

study 

Male reproductive 

toxicity 

46904569 (2005) 

Acceptable/non-guideline 

1000 mg/kg bw/day (3, 

10, 21, or 41 days) 

Primary testicular effects on or after day 10 

were degeneration of round and elongating 

spermatids (stage 7-8 and 9-14, respectively), 

decreased sperm count, and increased numbers 

of aberrant/abnormal spermatozoa in the 

epididymis. 
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Table A.1.3. USEPA Toxicity Profile – Metabolites.

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

Exploratory 

study

10-day gavage 

(enol metabolite) 46904601 (2006) 

Acceptable/non-guideline 

800 mg/kg bw/day 

Decreased BWG; histopathology not evaluated. 

Special 

study

21-day gavage 

(enol metabolite) 47070901 (2006) 

Acceptable/non-guideline 

800 mg/kg bw/day 

Clinical signs of toxicity, decreased BWG, 

testicular/spermatotoxicity. 

870.5100 Bacterial Gene 

Mutation 

(ketohydroxy 

metabolite) 

46904594 (2005) 

Acceptable/guideline 

0, 16, 50, 158, 500, 1581, 

or 5000 μg/plate +/- S9 

activation 

Negative. 

870.7485 Metabolism and 

Pharmacokinetics 

(rat) 

(ketohydroxy 

metabolite) 

46904595 (2006) 

Acceptable/guideline 

2 mg/kg bw (single) 

Absorption: ≥55% after 48 hrs. 

Distribution: highest concentrations detected in 

GI, liver, and kidney; <0.2% of administered 

dose detected in body 48 hrs post dose. 

Metabolism: parent compound undetected in 

urine and trace amounts in feces; main 

metabolic reaction was oxidative demethylation 

of cyclohexyl-O-methyl group to form 

desmethyl-ketohydroxy metabolite (15% of 

administered dose); all other identified 

metabolites could be derived from desmethylketohydroxy metabolite. 

Excretion: 54% of administered dose 

eliminated via urine and 44% via feces within 

48 hrs. 

870.5100 Bacterial Gene 

Mutation 

(desmethylketohydroxy 

metabolite) 

46904597 (2006) 

Acceptable/guideline 

0, 16, 50, 158, 500, 1581, 

or 5000 μg/plate +/- S9 

activation 

Negative. 

870.5100 Bacterial Gene 

Mutation 

(dihydroxy 

metabolite) 

46904599 (2005) 

Acceptable/guideline 

0, 16, 50, 158, 500, 1581, 

or 5000 μg/plate +/- S9 

activation 

Negative. 
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Table A.1.3. USEPA Toxicity Profile – Metabolites.

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.7485 Metabolism and 

Pharmacokinetics 

(rat) 

(enol glucoside 

metabolite) 

46904602 (2006) 

Acceptable/non-guideline 

0.1 mg/kg bw (single; 1 

rat) 

Absorption: 54% after 48 hrs. 

Distribution: plasma concentrations peaked 4 

hrs post dose; 1% of administered dose 

detected in body 48 hrs post dose. 

Metabolism: parent compound detected in 

feces (21%); main metabolite was enol (64% of 

administered dose). 

Excretion: 53% of administered dose 

eliminated via urine and 44% via feces within 

48 hrs. 

870.5100 Bacterial Gene 

Mutation 

(monohydroxy 

metabolite) 

46904604 (2005) 

Acceptable/guideline 

0, 16, 50, 158, 500, 1581, 

or 5000 μg/plate +/- S9 

activation 

Negative. 
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Appendix B. Tolerance Summary Table for Spirotetramat 

Commodity Proposed 

Tolerance (ppm) 

HED-Recommended 

Tolerance (ppm) 

Comments; Correct Commodity 

Definition

Cotton – undelinted seed 0.4 0.30 Cotton, undelinted seed 

Cotton gin byproducts 7.0 10 

Soybean seed 3 5.0 

Soybean forage 9 8.0 

Soybean hay 16 16 

Aspirated Grain Fraction 10 10 

Vegetables, legume, group 

06 (except soybean) 4.0 2.5 Vegetables, legume, group 06, except soybean 

Vegetables, foliage of 

legume, except soybean, 

subgroup 07A 

5.0 7.0 

Okra 2.5 2.5 Translated from fruiting 

vegetables

Pistachio 0.25 0.25 Translated from tree nuts 

Dried prunes 4.5 - Not required 

Tropical Fruit (except 

lychee) 1.5 - Not a recognized crop group 

Lychee 12 13 

Longan - 13 Translated from lychee 

Spanish lime - 13 Translated from lychee 

Rambutan - 13 Translated from lychee 

Pulasan - 13 Translated from lychee 

Avocado - 0.60 

Black sapote - 0.60 Translated from avocado 

Canistel - 0.60 Translated from avocado 

Mamey sapote - 0.60 Translated from avocado 

Mango - 0.60 Translated from avocado 

Sapodilla - 0.60 Translated from avocado 

Star apple - 0.60 Translated from avocado 

Papaya - 0.35 

Guava - 2.5 

Feijoa - 2.5 Translated from guava 

Jaboticaba - 2.5 Translated from guava 

Wax jambu - 2.5 Translated from guava 

Starfruit - 2.5 Translated from guava 

Passionfruit - 2.5 Translated from guava 

Persimmon - 2.5 Translated from guava 

Acerola - 2.5 Translated from guava 

White sapote - 0.60 Translated from citrus fruit 

Eggs - 0.02 

Hog meat byproducts - 0.02 

Poultry meat byproducts - 0.02 

Cattle, meat byproducts - 0.20 

Goat, meat byproducts - 0.20 

Horse, meat byproducts - 0.20 

Sheep, meat byproducts - 0.20