Spirotetramat Human

- Health Risk Assessment DP# : 399022

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### Page 3 of 36 6.2 Chronic Aggregate Risk 24 7.0 Cu mulative 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 Chemis try 28 9.3 Occupational Exposure 28 Appendix A. Toxicology Assessment 29 Appendix B. Tolerance Calculations 35 Appendix C. Review of Human Research 36Spirotetramat Human

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### Page 4 of 36 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 concen tration (SC) formulation of spirotetramat (Movento ® 

### ; EPA Reg. No. 264

- 1050) to add Section 18 emergency exemption

use s 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, B YI 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 complete d 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 exhibit ed 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 spirotetra mat 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

- ter m 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 addit ion 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, d evelopment of the sexual organs of offspring (balano

preputial 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 ob served 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 m g/kg/day ( l imit d ose) 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 de monstrated 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.Spirotetramat Human

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### Page 5 of 36 Dose

- Response Assessment and Food Q uality 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 S afety Factor (SF) be reduced to 1X based on the following:

There was no evidence of increased susceptibility of offspring following pre

- or post

natal exposure in any study. In the rat developmental toxicity study, toxicity to offspring was observed at t he same dose ( l imit d ose) 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 d ose 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 li kely a congenital anomaly that was not observed i n 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 ch ronic 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 estima tes 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 refer ence 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, P AD, 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 Intermediate

term 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.Spirotetramat Human

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### Page 6 of 36 Short

- and Intermediate

term 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 o f 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 requ ested tolerance level is not appropriate (Table 1.0). There are no residue chemistry issues that would preclude granting time

- limited tolerance for the requested e mergency e xemption use of spirotetramat on watercress in FL and TN.

Exposure/Risk Assessm ent 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 a ssessments 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 Com modity Intake Database (DEEM

- FCID TM 

### ) 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 sulfentrazo ne 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 intermediat e

- 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 chemigatio n equipment. Based on the proposed use pattern, the exposure is expected to be short

or 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 wereSpirotetramat Human

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### Page 7 of 36 intentionally exposed to a pesticid e 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, i n accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations,” ( http://www.hss.ener gy.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 compil ed 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 yea r, 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 exposure s 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

c ommitted 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 registration s for the requested use s of spirotetramat on watercress.

The proposed Section 18 emergency exem ption use s 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 bel ow 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,

c is

- 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, ca lculated 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 petitioner s have proposed a tolerance of 9 ppm. HED recommends a tolerance of 1.5 ppm based on the submitted field trial data and t he OECD tolerance calculation procedures.Spirotetramat Human

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### Page 8 of 36 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 p pm 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 prote ct new shoots. S pirotetramat 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 F L and TN . A summary of the proposed use patterns on watercress in F L 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 i nterval 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 ground boom or chemigation equipment only. The registered label has a PPE requirement that applicators andSpirotetramat Human

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### Page 9 of 36 other handlers wear a long

- slee ved 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 providedSpirotetramat Human

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### Page 10 of 36 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

- D

glucopyranoside CAS # None provided

Compound: BYI 08330

- mono

hydroxy 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

- enol

GA 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 providedSpirotetramat Human

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### Page 11 of 36 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 D 4 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, pK a 10.7 Included in MRID 47648203 Octanol/water partition coefficient, Log(K OW ) 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 cm 2 / mol) 211 22.0 x 10 3 276 0.8 x 10 3



### 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 exhibit ed 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 subchron ic 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

- gener ation rat reproductive toxicity study. However, d evelopment of the sexual organs of offspring (balano

preputial separation, vaginal opening) was unaffected. In an investigative study designed to explore the time of onset of testicular toxicity in rats, d ecreased epididymal sperm counts wereSpirotetramat Human

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### Page 12 of 36 noted after 10 days of exposure. Similar effects were observed after repeated dosing with the

eno l 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
tox icity 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 reasonabl e 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 assessment s for spirotetramat (Memo, J. Tyler, et al., 1 4

- 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 p re

- or post

natal 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 l imit d ose. In the developmental toxicity study in the rabbit, only maternal to xicity 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 t oxicity 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 acu te 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 we re 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 th ere 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

- rel ated 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 m ost likely a congenitalSpirotetramat Human

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### Page 13 of 36 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 uncerta inties 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 mod eling 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 base d 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 Inciden tal 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 stra tum 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

-Spirotetramat Human

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### Page 14 of 36 term dermal occu pational 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

consu mption, 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 pot ential 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 relat ed 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

rece ived 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 condu cting 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 s cenario. 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.Spirotetramat Human

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### Page 15 of 36 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 th e 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 Toxicolog ical 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/non

occupational risk assessments and occupational risk assessment are listed below in Tables 3.3.12a and 3.3.12b, respectively.

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

Health Risk Assessments.
Exposure Scenario Point of Departure Uncertainty/FQPA

Safety Factors RfD, PAD, LOC for

Risk Assessment Study and Relevant Toxicological Effects Acute Dietary (General Population, including Infants and Children) NOAEL = 100 mg/kg/day UF A = 10X

UF H = 10X UF FQPA = 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 UF A = 10X

UF H = 10X UF FQPA = 1X cRfD = cPAD = 0.05

mg/kg/day Chronic toxicity (dog; dietary) LOAEL = 20 mg/kg/day (M) b ased 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, UF A = extrapolation from animal to human (interspecies), UF H = potential variation in sensitivity among members of the human population (intraspecies), UF FQPA = FQPA Safety Factor, NOAEL = no

- observed adverse

- effect level, LOAEL = lowest

observed adverse

- effe ct level, RfD = reference dose (a = acute, c = chronic), PAD = population

- adjusted dose, LOC = level of concern.Spirotetramat Human

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### Page 16 of 36 Table 3.3.12b. Summary of Toxicological Doses and Endpoints for Spirotetramat for Use in Occupational Human

- Health Risk Assessments. Exposu re Scenario Point of

Departure Uncertainty Factors LOC for Risk Assessment Study and Toxicological Effects Dermal Short

- and Intermediate

Term (1

- 30 days and 1

- 6 months) NOAEL = 10

mg/kg/day

Dermal

absorption factor = 10% UF A = 10X

UF H = 10X Occupational LOC for MOE <100 Prenatal developmental toxicity (rabbit) Maternal LOAEL = 40 mg/kg/day based on late abortion (≥GD 22)

, clinical signs , impaired food and water consumption, and body

- weight loss. Dermal Long

- Term (>6 months) NOAEL = 5

mg/kg/day

Dermal

absorption factor = 10% UF A = 10X

UF H = 10X Occupational LOC for MOE <100 Chronic toxicity (dog; dietary) LOAEL = 20 mg/kg/day (M) based on thymus involution.

Inhalation Short

- and Intermediate

Term (1

- 30 days and 1

- 6 months) NOAEL = 10

mg/kg/day

100% inhalation assumed UF A = 10X

UF H = 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 UF A = 10X

UF H = 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, UF A = extrapolation from animal to human (interspecies), UF H = potential variation in sensitivity among members of the human population (intraspecies), UF FQPA = FQPA Safety Factor, NOAEL = no

- observed adverse

- effect level, LOAEL = lowest

observed adverse

- effe ct 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; D 40405 1 ). 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 a cid 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 intermedia te (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.Spirotetramat Human

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### Page 17 of 36 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 resultin g 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

- desmethy l

- enol

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

- ketohydroxy

alcohol. 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 sp irotetramat 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 m oiety 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

S evera l high

- performance liquid chromatography with tandem mass spectrometry ( HPLC

MS/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 d etermination of residues of spirotetramat and the metabolites BYI 08330

- enol and BYI 08330

- enol

- GA in livestock matrices by HPLC

- MS/MS. M ethod 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 petition s . 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 sa mples obtained from metabolism studies.

HED has determined that Methods 00857 and 00966 are suitable enforcement methods for plant and livestock commodities, respectively, since th ese 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

- mono

hydroxy, BYI 08330

- en ol

- 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 spirotetramatSpirotetramat Human

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### Page 18 of 36 or its metabo lites. 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 a ppeared 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, respectivel y, 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 1 0 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 day s. 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 t he 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, th e 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 degrada tes 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 verySpirotetramat Human

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### Page 19 of 36 low. Non

- extractable residues were a maximum of 17.5% at 0.6 days. In an anaerobic aqua tic 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 Comparati ve 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 metabo lites 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 0833 0

- 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 metaboli te 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 08 330

- 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 BY I 08330

- desmethyl

- enol (animals and plants). Further reduction of the double bond in the te t ramic 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 signif icant 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), oxida tion 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.Spirotetramat Human

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### Page 20 of 36 4 .1.8 Pesticide Metabolites and Degradates of Concern

Table 4 .1.8. Summary of Metabolites and Degradates to be included in Risk Asse ssment 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 Applicable 1 Not Applicable 1 Livestock (Ruminant and Poultry) Spirotetramat, BYI 08330

- enol, and BYI 08330

- enol

GA 2 Spirotetramat and BYI 08330

- enol 2

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 o r for tolerance setting.
2 If future proposed uses result in significant exposure of livestock to the plant metabolites BYI 08 330

- 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 asses sment 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 spirotetram at 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

- MAY

2008; D333437)

.

Livestock: The residues of concern f or 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

- MAY

2008; 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 Wate r 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 an d 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 w atercress 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 asSpirotetramat Human

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### Page 21 of 36 what was previous ly reported (Memo, J. Meléndez, 22

- JAN

- 2008; D345275) . The screening

level surface water EDWCs, however, have increased due to the proposed watercress use s

. The Rice Model (v.1.0) resulted in the highest EDWC for use in the a cute and chronic assessments;
t herefore, the surface water EDWC value of 0.158 ppm was incorporated in DEEM

- FCID TM 

### 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 Wa ter Concentrations (EDWCs) for Drinking Water Risk Assessment B ased on Aerial Application of Spirotetramat on Pome Fruits (for Groundwater) at 0.4 lb ai/A/Season, and G round or Chemigation Applications on W atercress (i n FL and TN O nly ) (for Surface Water) at 0.16 lb ai/A/S eason.

Drinking Water Source (MODEL) Chemical: Estimated Drinking Water Concentration (EDWC) Parent Spirotetramat Spirotetramat

enol Spirotetramat

ketohydroxy Total Toxic

Residues (TTR) 1
Risk \ Units (ppb) (ppb) (ppb) (ppb) Ground

- water (SCI

- GROW) Acute &

Chronic 2 2.25x10 - 5 1.64x10 - 5 3.57x10 - 4 3.96x10 - 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 broad cast spray (two applications ranging from 0.189 to 0.199 lb ai/A), e xcept for one of the locations in FL

, where an additional plot was treated using chemig ation (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 (Dyn e

- Amic) was used for all applications. Although the field trials were conducted at a higher rate than the proposed Section 18 label s (0.3 79

- 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 w ith 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

oran ge 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 )

.Spirotetramat Human

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### Page 22 of 36 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

- FCID TM



### , 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 tolera nce

- 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 DEEM TM 

### 7.81 default processing factors were used for the remaining processed commoditie s (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 s pirotetramat was classified as “Not Likely to be Carcinogenic to Humans .”Spirotetramat Human

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### Page 23 of 36 4 .2.6 Dietary Summary Table

Table 4 .2

. 6. Summary of Dietary (Food and Drinking Water) Exposure Risk for Spirotetramat 1

.
Population Subgroup Acute Dietary (95 th 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 so urce 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 database submitted by the Spray Drift Task For ce, 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 Ri sk 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 adde d 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 spirotetr amat, 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 t o evaluate aggregate dietary and residential exposures, were not performed because there are no registeredSpirotetramat Human

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### Page 24 of 36 or proposed residential non

- food uses. Spirotetramat is classified as “Not Likely to be Carcinogenic to Humans” ; therefore, cancer aggregate risk as sessments 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 concer n to HED (<100% aPAD) at the 95 th 

### exposure percentile for the general U.S. population and all other population subgroups (see Table 4 .2 .6 ). The dietary exposure assessment utiliz ed 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 co nservative 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 C haracterization/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 de termine 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 cum ulating 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 asses sment was provided in a HED memorandum dated 01

- AUG

2012 (K. Lowe; D399022 ). It is anticipated that there will be occupational handler and post

application exposure from the proposed Section 18 use s 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, mixi ng/loading liquids to support groundboom applications, and applying sprays with groundboom equipment.Spirotetramat Human

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### Page 25 of 36 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 absenc e 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 FIF RA. 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 inhalati on 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 g loves, 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 intermedi ate

- 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 long

term 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 sc enario.Spirotetramat Human

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### Page 26 of 36 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 MOE 8
Dermal Inhalation Dermal 4 Inhalation 5 Dermal 6 Inhalation 7 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 = D ermal 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).Spirotetramat Human

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### Page 27 of 36 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 base d 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 exp osures.

N o 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 dat a 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 post

application exposur e 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 abo ut the ARTF data, can be found at http://www.epa.gov/pesticides/science/post

app

- exposure

- data.html

. Table 8 .2.1 .1 provides a summary of the transfer coefficients and activiti es 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 (cm 2 /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

- an d Intermediate

- term Occupational Post

- application Risks.

Crop/Site Transfer Coefficient

(cm 2 /hr) Application Rate

(lb ai/A) DFR on Day

0 (ug/cm 2 ) 1 Day 0 MOE 2 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 0Spirotetramat Human

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### Page 28 of 36 1 DFR = AR x F x (1

- D) t x 4.54E8 μg/lb x 2.47E

- 8 acre/cm 2

. 2 MOE = POD (NOAEL, 10 mg/kg/day) / Daily Dermal Dose. Daily Dermal Dose = [DFR (μg/cm 2 ) 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 C ategory 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 spir otetramat at this time. However, there are multiple potential sources of post

- application inhalation exposure to individuals performing post

application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009. 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 A gency 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 ( 0 8

- 0 2

- 2012) J. Van Alstine: S

- 10951 : Potomac Yard 1 (PY1): (703)603

- 8866: 7509P: RAB1Spirotetramat Human

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### Page 29 of 36 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 LD 50 >2000 mg/kg (F) III

870.1200 Acute dermal (rat) 46904529 LD 50 >2000 mg/kg (M&F) III

870.1300 Acute inhalation (rat) 46904530 LC 50 >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 hypos permia 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
p pm (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.Spirotetramat Human

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### Page 30 of 36 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 (F 1 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 F 1 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 wei ght and body

- weight gain during lactation in F 1 pups.Spirotetramat Human

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### Page 31 of 36 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 (F 1 males and females), weight gain (P males, F 1 males and females), and food consumption during lactation (P

- and F 1 - generation females), and kidney histopathology and decreased kidney weights (F 1 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 F 1 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 F 1 and F 2 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

m acrophages; & 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)

Ac ceptable/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.Spirotetramat Human

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### Page 32 of 36 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).Spirotetramat Human

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### Page 33 of 36 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: AUC 0

- ∞ (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 metabo lites 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 withi n 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 th e 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/cm 2 (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.Spirotetramat Human

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### Page 34 of 36 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 desmethyl

ketohydroxy metabolite. Excretion: 54% of administered dose eliminated via urine and 44% via feces within 48 hrs. 870.5100 Bacterial Gene

Mutation (desmethyl

ketohydroxy 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/pla te +/

- S9 activation Negative.Spirotetramat Human

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### Page 35 of 36 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]Spirotetramat Human

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### Page 36 of 36 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, compris e 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 o n 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 re liance 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.