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6.2 Chronic Aggregate Risk 24

7.0 Cumulative Risk Characterization/Assessment 24

8.0 Occupational Exposure/Risk Pathway 24

8.1 Short- and Intermediate-Term Handler Risk 24

8.2 Short-Term Post-application Risk 27

8.2.1 Dermal Post-application Risk 27

8.2.2 Inhalation Post-application Risk 28

9.0 Data Needs and Label Recommendations 28

9.1 Toxicology 28

9.2 Residue Chemistry 28

9.3 Occupational Exposure 28

Appendix A. Toxicology Assessment 29

Appendix B. Tolerance Calculations 35

Appendix C. Review of Human Research 36
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1.0 Executive Summary

The Florida Department of Agriculture and Consumer Services and the Tennessee Department of 

Agriculture have proposed to amend the 2 lb a.i./gal suspension concentration (SC) formulation 

of spirotetramat (Movento®; EPA Reg. No. 264-1050) to add Section 18 emergency exemption 

uses on watercress. 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 a variety of crops (40 CFR 

§180.641). The most recent human-health risk assessment for spirotetramat was completed on 

22-DEC-2010 (Memo, J. Van Alstine, et al.; D368785). There are currently no registered or 

proposed residential uses for spirotetramat.

Hazard Assessment: Spirotetramat technical demonstrated moderate to low acute toxicity 

(Toxicity Category III or IV) via the oral, dermal, and inhalation routes. It was non-irritating to 

the skin (Toxicity Category IV), but irritating to the eye (Toxicity Category II) and exhibited 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 testes-epididymides 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 noted in a two-generation rat 

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. Testicular toxicity was seen at the relatively high dose of 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.

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

of a recently submitted and reviewed immunotoxicity study in rats does not indicate any 

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

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

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

system. 
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Dose-Response Assessment and Food Quality Protection Act (FQPA) Decision: Consistent with 

previous risk assessments for spirotetramat (Memo, J. Tyler, et al., 14-MAY-2008, D333437; 

Memo, J. Van Alstine, et al., D368785), 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 (limit dose) as maternal toxicity. 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. 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 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 with respect to the exposure database that will result 

in underestimation of exposure. The dietary food exposure assessment utilizes 

recommended tolerance-level residues and 100% crop treated (CT) information for all 

proposed commodities. By using this screening-level assessment, the acute and chronic 

exposures/risks will not be underestimated. 

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

model and associated modeling parameters that 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.
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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.

Food Residue Profile

The nature of the residue in plants and livestock is adequately understood. There is an adequate 

residue analytical method for the purposes of tolerance enforcement. The submitted field trial 

residue data are adequate for establishing a time-limited tolerance for residues of spirotetramat 

and its metabolites in/on watercress. The available field trial data reflect use rates that are higher 

than the proposed Section 18 use rates; therefore, HED expects residues in watercress due to the 

proposed Section 18 uses to be less than the recommended tolerance. Use of the Organization 

for Economic Co-operation and Development (OECD) tolerance-calculation procedures and the 

submitted residue data sets indicates that requested tolerance level is not appropriate (Table 1.0). 

There are no residue chemistry issues that would preclude granting time-limited tolerance for the 

requested emergency exemption use of spirotetramat on watercress in FL and TN. 

Exposure/Risk Assessment Characterization

Acute and chronic risk assessments were conducted for dietary exposure based on the existing 

and proposed uses. The acute and chronic assessments directly incorporated drinking water 

estimates. Assumptions for the acute and chronic assessments included tolerance-level residues 

for all commodities and 100% CT. Empirical processing factors were used for apple, orange, 

grape, and tomato juice, applesauce, and dried apples, and Dietary Exposure Evaluation Model 

software with the Food Commodity Intake Database (DEEM-FCIDTM) 7.81 default processing 

factors were used for the remaining processed commodities (where provided). All exposure and 

risk estimates were not of concern. A cancer dietary assessment was not conducted because 

sulfentrazone is classified as “not likely to be carcinogenic to humans.”

There are no registered or proposed residential uses for spirotetramat; therefore, a residential 

exposure assessment was not conducted.

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

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

chronic aggregate exposure, respectively. Short- and intermediate-term assessments, which are 

used to evaluate aggregate dietary and residential exposures, were not performed because there 

are no registered or proposed residential non-food uses. Spirotetramat is classified as “Not 

Likely to be Carcinogenic to Humans”; therefore, cancer aggregate risk assessments were not 

performed.

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

maximum label application rate. The proposed labels allow for application via groundboom or 

chemigation equipment. Based on the proposed use pattern, the exposure is expected to be shortor intermediate-term duration. 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 (>6 months) are not anticipated 

based on the proposed use pattern. The spirotetramat label includes a personal-protective 

equipment (PPE) requirement that applicators and other handlers wear a long-sleeved shirt, long 

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

This risk assessment relies in part on data from studies in which adult human subjects were 
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intentionally exposed to a pesticide or other chemical. Additional details regarding this can be 

found in Appendix C. 

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 the Continuing Surveys of Food Intakes by Individuals (CSFII) and are used 

in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed 

and categorized by subgroups based on age, season of the year, ethnic group, and region of the 

country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups 

and exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, non-dietary exposures based on home use of pesticide products and associated risks 

for adult applicators and for toddlers, youths, and adults entering or playing on treated areas 

post-application are evaluated. Further considerations are currently in development as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary 

patterns among specific subgroups.

Recommendations for Tolerances: There are currently no residue chemistry, toxicology, or 

occupational exposure issues that would preclude granting Section 18 emergency exemption 

registrations for the requested uses of spirotetramat on watercress. 

The proposed Section 18 emergency exemption uses and the submitted data support the 

following time-limited tolerance for residues of the insecticide spirotetramat, including its 

metabolites and degradates, in or on the commodity listed 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-methoxy-2-oxo-1-azaspiro[4.5]dec-3-en-4-yl-ethyl carbonate]) and its 

metabolites cis-3-(2,5-dimethylphenyl)-4-hydroxy-8-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 commodity:

Table 1.0. Tolerance Summary for Spirotetramat.

Commodity Established/Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments

Correct Commodity Definition

Watercress 9 1.5 -

The petitioners have proposed a tolerance of 9 ppm. HED recommends a tolerance of 1.5 ppm 

based on the submitted field trial data and the OECD tolerance calculation procedures.
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Note to RD: The tolerances for feijoa, papaya, and Spanish lime in 40 CFR §180.641 are 

incorrect. Additionally, the recommended persimmon tolerance is missing. The correct 

tolerances are: 2.5 ppm for feijoa, 0.35 ppm for papaya, 13 ppm for Spanish lime, and 2.5 ppm 

for persimmon (Memo, J. Van Alstine et al., 22-DEC-2010; D368785). 40 CFR §180.641 

should be updated to reflect the recommended tolerances. 

Data Needs/Deficiencies

Toxicology

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

Chemistry

860.1550 Proposed Tolerances

- The tolerance level should be revised to reflect the HED-recommended tolerance of 

1.5 ppm (Table 1.0).

Occupational Exposure

None.

2.0 Ingredient Profile

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

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

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

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

§180.641. 

The Florida Department of Agriculture and Consumer Services and the Tennessee Department of 

Agriculture have submitted draft labels for the Section 18 request to register a 2 lb a.i./gal SC 

formulation (Movento®; EPA Reg. No. 264-1050) of spirotetramat for use on watercress in FL 

and TN. A summary of the proposed use patterns on watercress in FL and TN is detailed in 

Table 2.1.

2.1 Summary of Proposed Uses

Table 2.1. Summary of Proposed Use Pattern.

Formulation Method of 

Application Use Sites Application Rate Timing of Application

Movento®

Suspension 

concentrate

(22.4% a.i.)

EPA Reg #264-

1050

(2 lb ai/gal)

Groundboom 

or 

Chemigation

Watercress 5 fl oz/A 

OR

0.078 lb ai/A

2 apps per crop cycle.

24-hour restricted-entry interval (REI).

7-day interval between applications

PHI: 3 days

HED Conclusions: The submitted use directions for Movento®are adequate to allow evaluation 

of the residue data relative to the proposed use. Applications are to be made with groundboom

or chemigation equipment only. The registered label has a PPE requirement that applicators and 
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other handlers wear a long-sleeved shirt, long pants, protective eyewear, chemical-resistant 

gloves, and shoes plus socks.

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 Movento®, Ultor®, 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 10-9Pa (20 oC)

1.5 x 10-8Pa (25 oC)

1.5 x 10-6Pa (50 oC)

Dissociation constant, pKa 10.7 Included in MRID 

47648203

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

pH 7: 2.51

pH 9: 2.50

EPA Chemical Fact Sheet 

for Spirotetramat, June 

2008

UV/visible absorption spectrum Peak Maxima Molar Absorptivity 

 (nm) (1000 cm2/ mol)

 211 22.0 x 103 

 276 0.8 x 103

3.0 Hazard Characterization/Assessment

3.1 Hazard and Dose-Response Characterization

Spirotetramat technical demonstrated moderate to low acute toxicity (Toxicity Category III or 

IV) via the oral, dermal, and inhalation routes. It was non-irritating to the skin (Toxicity 

Category IV), but irritating to the eye (Toxicity Category II) and exhibited 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 testes-epididymides 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 oneyear 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 noted in a two-generation rat 

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

enol metabolite of spirotetramat. Testicular toxicity was seen at the relatively high dose of 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.

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

of a recently submitted and reviewed immunotoxicity study in rats does not indicate any 

functional deficits in immune function. Furthermore, 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 dogs was secondary to the thyroid effects, 

rather than a direct effect on the immune system.

3.2 FQPA Considerations

Consistent with the most recent risk assessments for spirotetramat (Memo, J. Tyler, et al., 14-

MAY-2008, D333437; J. Van Alstine, et al., 22-DEC-2010, D368785), 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.

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 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 
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anomaly 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 residues.

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

model and associated modeling parameters that 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.

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)

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 intermediate-
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term 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/day

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.
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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.

4.0 Dietary Exposure/Risk Characterization

The acute and chronic dietary exposure assessments were completed by J. Van Alstine (01-

AUG-2012; D404051). The drinking water assessment was provided by EFED (D399575, J. 

Meléndez, 05-APR-2012). 

4.1 Pesticide Metabolism and Environmental Degradation

4.1.1 Metabolism in Primary Crops

Adequate metabolism data for apple, lettuce, cotton, and potato are available 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. 
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4.1.2 Metabolism in Rotational Crops

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

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

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

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

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

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

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

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

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

4.1.3 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.

4.1.4 Analytical Methodology

Several high-performance liquid chromatography with tandem mass spectrometry (HPLCMS/MS) residue analytical methods have been submitted for the determination of residues of the 

parent and its metabolites in/on plant and livestock commodities. Analytical method 00857 was 

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

BYI 08330-ketohydroxy, BYI 08330-mono-hydroxy, and BYI 08330-enol-Glc in plant matrices 

by HPLC-MS/MS. Analytical method 00966 was developed for the determination of residues of 

spirotetramat and the metabolites BYI 08330-enol and BYI 08330-enol-GA in livestock matrices 

by HPLC-MS/MS. Method 00857 was used, with minor modifications, as the data-collection 

methods in the analysis of samples for residues of concern from the various studies associated 

with the current petitions. 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 these 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; 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 
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or its metabolites. The MRM testing data were forwarded to the FDA for further evaluation and 

inclusion of results in PAM Vol. I. 

4.1.5 Environmental Degradation

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

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

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

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

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

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

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

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

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

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

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

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

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

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

dimethyl-benzoic acid.

Spirotetramat degraded quickly, with calculated half-lives (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 
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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.

4.1.6 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 that resulted in the formation of the primary and most predominant metabolite 

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

derived from the enol intermediate. The second prominent metabolic transformation was 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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). 

4.1.7 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.
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4.1.8 Pesticide Metabolites and Degradates of Concern

Table 4.1.8. 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-enolGA2Spirotetramat and BYI 08330-enol2

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

ketohydroxy

Not Applicable

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

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

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

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

setting.

2

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

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

commodities.

Plants (Primary Crops): The residues of concern for both tolerance and risk assessment 

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

BYI08330-enol-Glc, and BYI 08330-mono-hydroxy (Memo, J. Tyler, et al., 14-MAY-2008; 

D333437). 

Plants (Rotational Crops): The residues of concern are spirotetramat and its metabolites BYI 

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

desmethyl-di-hydroxy, and BYI 08330-ketohydroxy-alcohol (Memo, J. Tyler, et al., 14-MAY2008; D333437). 

Livestock: The residues of concern for the tolerance expression for livestock commodities are 

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

assessment for livestock commodities are spirotetramat and its metabolites BYI 08330-enol and 

BYI 08330-enol-GA (Memo, J. Tyler, et al., 14-MAY-2008; D333437). 

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

spirotetramat, BYI 08330-enol, and BYI 08330-ketohydroxy (Memo, J. Tyler, et al., 14-MAY2008; D333437). BYI 08330-enol and BYI 08330-ketohydroxy were the major metabolites in 

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

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

4.1.9 Drinking Water Residue Profile

EFED provided Tier 1 ground and surface water estimated drinking-water concentrations 

(EDWCs) for spirotetramat and the major transformation products, spirotetramat-enol and 

spirotetramat-ketohydroxy (D399575, J. Meléndez, 05-APR-2012 and D403322, J. Meléndez, 

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

applications to pome fruits) and the Rice Model v.1.0 (surface water). The use of spirotetramat 

on pome fruits at 0.4 lb a.i./A/season (groundwater) and watercress at an application rate of 0.16 

lb a.i./A/season (surface water) are the uses that result in the highest exposure. Since the highest 

seasonal application rate (pome fruit) has not changed, the groundwater results are the same as 
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what was previously reported (Memo, J. Meléndez, 22-JAN-2008; D345275). The screeninglevel surface water EDWCs, however, have increased due to the proposed watercress uses. The 

Rice Model (v.1.0) resulted in the highest EDWC for use in the acute and chronic assessments;

therefore, the surface water EDWC value of 0.158 ppm was incorporated in DEEM-FCIDTM into 

the food categories “water, direct, all sources” and “water, indirect, all sources” for both the 

acute and chronic assessments. 

Table 4.1.9. Maximum Tier I Estimated Drinking Water Concentrations (EDWCs) for Drinking 

Water Risk Assessment Based on Aerial Application of Spirotetramat on Pome Fruits (for 

Groundwater) at 0.4 lb ai/A/Season, and Ground or Chemigation Applications on Watercress (in FL 

and TN Only) (for Surface Water) at 0.16 lb ai/A/Season.

Drinking 

Water Source 

(MODEL)

Chemical:

Estimated Drinking Water Concentration (EDWC)

Parent

Spirotetramat

SpirotetramatenolSpirotetramatketohydroxyTotal Toxic 

Residues (TTR)1

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

Ground-water 

(SCI-GROW)

Acute & 

Chronic 2 2.25x10-5

1.64x10-53.57x10-43.96x10-4

Surface Water 

(Tier 1 Rice 

Model v.1.0)

Acute & 

Chronic 2 N/A N/A N/A 158

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

2

Surface-water concentrations calculated by the Tier I Rice Model v1.0 and ground water concentrations calculated 

by SCI-GROW do not distinguish between peak and chronic concentrations.

4.1.10 Food Residue Profile

Crop field trials were conducted on watercress at two field trial locations in FL and one location 

in MD. All field trials had one control plot and one plot treated with a broadcast spray (two 

applications ranging from 0.189 to 0.199 lb ai/A), except for one of the locations in FL, where an 

additional plot was treated using chemigation (two applications of 0.196 lb ai/A). The 

retreatment interval (RTI) was 7-8 days and the preharvest interval (PHI) was 3 days. An 

organo-silicone surfactant (Dyne-Amic) was used for all applications. Although the field trials 

were conducted at a higher rate than the proposed Section 18 labels (0.379-0.395 lb ai/A as 

opposed to 0.16 lb ai/A), the field trials are considered to be acceptable. HED anticipates that 

the lower Section 18 application rate will result in watercress residues that are below the 

recommended tolerance. 

Residues were similar for the chemigation and broadcast field trials. For all trials, total residues 

of spirotetramat and its metabolites ranged from 0.243 to 0.586 ppm, with residues of parent 

ranging from <0.01 ppm to 0.054 ppm. Samples were stored for 284 to 472 days. Storage 

stability data were not submitted with the petition, however storage stability data are available 

for residues of spirotetramat and its metabolites in/on tomato fruit, potato tubers, lettuce heads, 

climbing French bean, and almond nutmeat during frozen storage for up to 714 days and in 

orange juice for at least 150 days (47244601.der.doc). 

The OECD tolerance calculation procedures were used to determine the appropriate tolerance 

level for residues of spirotetramat and its metabolites in/on watercress (1.5 ppm; Appendix B). 
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4.2 Dietary Exposure and Risk

4.2.1 Description of Residue Data Used in Dietary Assessment

Acute and chronic dietary-exposure and risk assessments were conducted using DEEM-FCIDTM, 

Version 2.03, which uses food consumption data from the USDA’s CSFII from 1994-1996 and 

1998. The assessments were performed for the general U.S. population and all population 

subgroups. Assumptions for the acute and chronic assessments included tolerance-level residues 

for all commodities and 100% CT. Empirical processing factors were used for apple, orange, 

grape, and tomato juice, applesauce, and dried apples, and DEEMTM 7.81 default processing 

factors were used for the remaining processed commodities (where provided). Drinking water 

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

pattern and the Tier 1 Rice Model v.1.0. The resulting screening-level EDWC estimate of 0.158 

ppm was used for both the acute and chronic assessments. 

4.2.2 Percent Crop Treated Used in Dietary Assessment

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

4.2.3 Acute Dietary Exposure/Risk

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

population or any other population subgroup. The highest exposure estimate was for the 

population subgroup children 1-2 years old, which utilized 10% of the aPAD for spirotetramat. 

The acute exposure estimate for the general U.S. population utilized 5% of the aPAD. A 

summary table of dietary exposure and risk for spirotetramat can be found in Section 4.2.6. 

4.2.4 Chronic Dietary Exposure/Risk

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

population or any other population subgroup. The highest exposure and risk estimates were for 

the population subgroup children 1-2 years old, which utilized 83% of the cPAD for 

spirotetramat. The chronic exposure estimate for the general U.S. population utilized 37% of the 

cPAD. A summary table of dietary exposure and risk for spirotetramat can be found in Section 

4.4.6. 

4.2.5 Cancer Dietary Risk Assessment

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

Likely to be Carcinogenic to Humans.”
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4.2.6 Dietary Summary Table

Table 4.2.6. Summary of Dietary (Food and Drinking Water) Exposure Risk for Spirotetramat1.

Population Subgroup

Acute Dietary (95th Percentile) Chronic Dietary

Dietary Exposure 

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

General U.S. Population 0.047739 5 0.018597 37

All Infants (<1 year old) 0.091555 9 0.034463 69

Children 1-2 years old 0.099385 10 0.041412 83

Children 3-5 years old 0.082236 8 0.034878 70

Children 6-12 years old 0.056485 6 0.023005 46

Youth 13-19 years old 0.039235 4 0.015553 31

Adults 20-49 years old 0.038985 4 0.015961 32

Adults 50+ years old 0.038672 4 0.015924 32

Females 13-49 years old 0.038682 4 0.015729 32

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

5.0 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.

5.1 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-driftmanagement 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 database submitted by the Spray Drift Task Force, a membership of U.S. 

pesticide registrants, and is developing a policy on how to appropriately apply the data and the 

AgDRIFT®computer model to its risk assessments for pesticides applied by air, orchard airblast, 

and ground hydraulic methods. After the policy is in place, the Agency may impose further 

refinements in spray-drift-management practices to reduce off-target drift and risks associated 

with aerial as well as other application types where appropriate. 

6.0 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.

6.1 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 4.2.6). The dietary exposure 

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

uses, some empirical processing factors, and a Tier 1 surface water EDWC generated by the Tier 

1 Rice Model v.1.0. 

6.2 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 4.2.6). The dietary exposure assessment was a conservative 

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

uses, some empirical processing factors, and a Tier 1 chronic surface water EDWC generated by 

the Tier 1 Rice Model v.1.0. 

7.0 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/.

8.0 Occupational Exposure/Risk Pathway

An occupational exposure assessment was provided in a HED memorandum dated 01-AUG2012 (K. Lowe; D399022). It is anticipated that there will be occupational handler and postapplication exposure from the proposed Section 18 uses of spirotetramat on watercress. Based 

on label information, exposure is expected to occur for short- and intermediate-term durations.

8.1 Short- and Intermediate-Term Handler Risk

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

chemigation applications, mixing/loading liquids to support groundboom applications, and 

applying sprays with groundboom equipment.
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It is the policy of HED to use the best available data to assess handler exposure. Sources of 

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

PHED 1.1, the AHETF database, the ORETF database, or other registrant-submitted 

occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and 

subject to the data protection provisions of FIFRA. The baseline clothing level was used as a 

starting point to calculate handler exposures, even though the proposed label recommends the 

use of baseline clothing plus chemical-resistant gloves. Depending upon the need for additional 

dermal and inhalation protection, additional PPE is added to obtain an MOE higher than the 

LOC. The baseline clothing level for occupational exposure scenarios generally represents an 

individual wearing long pants, a long-sleeved shirt, shoes, socks, no chemical-resistant gloves, 

and no respirator. PPE may involve the addition of chemical-resistant gloves or a respirator. 

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 8.1 presents the short- and intermediate-term estimated risks for occupational handlers. 

The results indicate that dermal and inhalation risk estimates do not exceed HED’s LOC, with 

MOEs greater than 100, at the baseline clothing scenario.
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Table 8.1. Short-/Intermediate-Term Occupational Exposure and Risk Estimates for Spirotetramat.

Exposure Scenario

Application 

Rate (lb 

ai/gallon)2

Amount 

Handled 

Daily 

(gallons)3

Baseline Unit 

Exposures (ug/lb ai)1 Dose (mg/kg/day) MOE Total MOE8

Dermal Inhalation Dermal4Inhalation5 Dermal6Inhalation7

Dermal + 

Inhalation

Single 

layer, no 

gloves

No 

Respirator

Single layer, 

no gloves No Respirator Single layer, no gloves

No 

Respirator

Mixer/Loaders

Mixing/Loading Liquids 

for Chemigation 

Applications

0.078 350 220 0.219 0.0087 0.000087 1,100 115,000 1,100

Mixing/Loading Liquids 

for Groundboom 

Applications

0.078 80 220 0.219 0.002 0.00002 5,000 500,000 5,000

Applicators

Applying Liquids via 

Groundboom 0.078 80 78.6 0.34 0.00071 0.000031 14,000 330,000 13,000

1 Based on “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2012); includes data from PHED/ORETF/AHETF.

2 Based on registered label (Reg. No. #264-1050).

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

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

5 Inhalation Dose = Inhalation Unit Exposure (mg/kg) x Application Rate (lb ai/A) x Area Treated (A/day) /BW (69 kg).

6 Dermal MOE = Dermal NOAEL (10 mg/kg/day)/Dermal Dose (mg/kg/day). Level of concern = 100.

7 Inhalation MOE = Inhalation NOAEL (10 mg/kg/day)/ Inhalation Dose (mg/kg/day). Level of concern = 100.

8 Total MOE = NOAEL (mg/kg/day)/(Dermal Dose + Inhalation Dose).
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8.2 Short-Term Post-application Risk

8.2.1 Dermal 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. 

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

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

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

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

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

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

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

information about the ARTF data, can be found at http://www.epa.gov/pesticides/science/postapp-exposure-data.html. Table 8.2.1.1 provides a summary of the transfer coefficients and 

activities associated with watercress.

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

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

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

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

Table 8.2.1.1. Anticipated Post-application Activities and Dermal Transfer Coefficients.

Proposed Crops Policy Crop/Group 

Category

Transfer Coefficients 

(cm2/hr) Activity

Watercress Leafy Vegetables

70 thinning plants, hand weeding

210 scouting

230 transplanting

1100 hand harvesting

1900 irrigation

A summary of the post-application MOEs and respective reentry intervals is provided in Table 

8.2.1.2. The short- and intermediate-term post-application assessments for watercress resulted in 

MOEs of 100 or greater on “day 0” (immediately after application) for all exposure activities, 

and are not of concern. 

Table 8.2.1.2. Summary of Short- and Intermediate-term Occupational Post-application Risks.

Crop/Site Transfer Coefficient 

(cm2/hr)

Application Rate 

(lb ai/A)

DFR on Day 

0 (ug/cm2)

1

Day 0 MOE2 Day X at which 

MOE ≥ LOC

ST and IT ST and IT

Watercress

70

0.078 0.219

56,000 0

210 19,000 0

230 17,000 0

1100 3,600 0

1900 2,100 0
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1 DFR = AR x F x (1-D)t

x 4.54E8 μg/lb x 2.47E-8 acre/cm2.

2 MOE = POD (NOAEL, 10 mg/kg/day) / Daily Dermal Dose. Daily Dermal Dose = [DFR (μg/cm2

) x TC x 0.001 mg/μg x 8 hrs/day x 10% 

dermal absorption] body weight 69 kg adult). 

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 Worker Protection 

Standard. The 24-hour REI, which appears on the registered label, is adequate for the proposed 

Section 18 use pattern.

8.2.2 Inhalation Post-application Risk

Based on the Agency's current practices, a quantitative occupational post-application inhalation 

exposure assessment was not performed for spirotetramat at this time. However, there are 

multiple potential sources of post-application inhalation exposure to individuals performing postapplication activities in previously treated fields. These potential sources include volatilization 

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

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

SAP in December 2009. 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 as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate occupational 

post-application inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for spirotetramat.

9.0 Data Needs and Label Recommendations

9.1 Toxicology

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

9.2 Residue Chemistry

860.1550 Proposed Tolerances

- The tolerance level should be revised to reflect the HED-recommended tolerance of 

1.5 ppm (Table 1.0).

9.3 Occupational Exposure

None.

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

RDI: D. Hrdy (07-25-2012), G. Kramer (08-02-2012)

J. Van Alstine: S-10951: Potomac Yard 1 (PY1): (703)603-8866: 7509P: RAB1
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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

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.
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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

870.3150 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.

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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Table A.1.2. Subchronic and Chronic Toxicity and Genotoxicity Profile – Spirotetramat Technical.

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

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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Table A.1.2. Subchronic and Chronic Toxicity and Genotoxicity Profile – Spirotetramat Technical.

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

870.5100 Bacterial Gene 

Mutation

46904551 (2006)

Acceptable/guideline

0, 16, 50, 158, 500, 1581, 

or 5000 μg/plate +/- S9 

activation

Negative.

870.5100 Bacterial Gene 

Mutation

46904552 (2002)

Acceptable/guideline

0, 16, 50, 158, 500, 1581, 

or 5000 μg/plate +/- S9 

activation

Negative.

870.5300 Mammalian Gene 

Mutation

46904553 (2002)

Acceptable/guideline

0, 2.5, 5, 10, 20, 30, 40, 

50, 60, 70, or 80 g/mL (-

S9)

0, 20, 40, 60, 80, 92, 100, 

108, 116, 120, 124, 132, 

or 140 g/mL (+S9)

Negative.

870.5375 In vitro mammalian 

chromosome 

aberration

46904554 (2002)

Acceptable/guideline

0, 10, 12, 24, 30, 48, or 50 

μg/mL (-S9) 

0, 20, 40, or 80 μg/mL 

(+S9)

Weakly clastogenic at cytotoxic concentrations 

only.

870.5375 In vitro mammalian 

chromosome 

aberration

46904555 (2003)

Unacceptable/guideline

0, 30, 50, 70, 90, or 110 

μg/mL (-S9)

0, 40, 60, 80, 100, or 120 

μg/mL (+S9)

N/A

870.5395 In vivo erythrocyte 

micronucleus assay 

(mouse)

46904556 (2002)

Acceptable/guideline

0, 125, 250, or 500 mg/kg 

bw

Negative.

870.5385 In vivo bone 

marrow 

chromosomal 

aberration assay 

(mouse)

46904558 (2003)

Acceptable/guideline

0, 125, 250, or 500 mg/kg 

bw

Negative.

870.5550 In vivo/in vitro

UDS assay (rat 

hepatocytes)

46904557 (2003)

Acceptable/guideline

0, 1000, or 2000 mg/kg 

bw

Negative.

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).
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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

870.7485 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.

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.
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Table A.1.3. USEPA Toxicity Profile – Metabolites.

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

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.

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 Calculations

Residues (mg/kg) n

0.245 1

0.465 1

0.499 1

0.555 1

Spirotetramat

Water Cress

Sect 18 FL

Total number of data (n) 4

Percentage of censored data 0%

Number of non-censored data 4

Lowest residue 0.245

Highest residue 0.555

Median residue 0.482

Mean 0.441

Standard deviation (SD) 0.136

Correction factor for censoring (CF) 1.000

Proposed MRL estimate

- Highest residue 0.555

- Mean + 4 SD 0.984

- CF x 3 Mean 1.323

Unrounded MRL 1.323

Rounded MRL 1.5

High uncertainty of MRL estimate.

[Small dataset]
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Appendix C. Review of Human Research

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

intentionally exposed to a pesticide 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.