 
                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                      OFFICE OF
                                                            CHEMICAL SAFETY AND
                                                           POLLUTION PREVENTION

MEMORANDUM


DATE:	27-MAR-2013

SUBJECT:	Spirotetramat.  Human-Health Risk Assessment for the Proposed Uses in/on Taro, Leaves; Watercress; Pomegranate; Banana; Vegetable, Bulb, Group 3-07; Low growing Berry Subgroup 13-07H, Except Strawberry and Lowbush Blueberry; Bushberry Subgroup 13-07B; Artichoke, Globe; Vegetable, Fruiting, Group 8-10; Fruit, Pome, Group 11-10; Fruit, Citrus, Group 10-10; Pineapple; and Coffee; and Tolerances without U.S. Registration in/on Corn, Sweet, Kernel Plus Cob with Husks Removed as Part of the U.S.-Canada Regulatory Cooperation Council (RCC) Pilot Project.

PC Code:  392201
DP Barcode:  D398509
Decision Nos.:  459092; 459087
Registration Nos.:  264-1050, 264-1065, 264-1051
Petition No.:  1E7958
Regulatory Action:  Section 3 Registration
Risk Assessment Type:  Single Chemical/Aggregate
Case No.:  7452
TXR No.:  NA
CAS No.:  203313-25-1
MRID No.:  None 
40 CFR:  §180.641

FROM:	Julie L. Van Alstine, MPH, Environmental Health Scientist 
		George F. Kramer, Ph.D., Senior Chemist 
      Kelly M. Lowe, Environmental Scientist
      Chester E. Rodriguez, Ph.D., Pharmacologist
      Risk Assessment Branch 1 (RAB1)
		Health Effects Division (HED; 7509P)

THROUGH:	Dana M. Vogel, Deputy Director 
	RAB1/HED (7509P)

TO:		Barbara Madden/Laura Nollen, RM 05
      Registration Division (RD; 7505P)


The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides.  The RD of OPP has requested that HED evaluate hazard and exposure data and conduct dietary, occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from the proposed Section 3 registration uses of the active ingredient (ai) spirotetramat (cis-3-(2,5-dimethlyphenyl)-8-methoxy-2-oxo-1-azaspiro[4.5]dec-3-en-4-yl-ethyl carbonate]) on taro, watercress, pomegranates, bananas, bulb vegetables, low-growing berries (except strawberries), bushberries, globe artichokes, fruiting vegetables, pome fruit, citrus fruit, pineapples, and coffee and, as part of the U.S.-Canada RCC pilot project, the establishment of a tolerance without U.S. registration for residues of spirotetramat in/on corn, sweet, kernel plus cob with husks removed.
A summary of the findings and an assessment of human-health risk resulting from the proposed and registered uses of spirotetramat are provided in this document.  The risk assessment and dietary exposure assessment were provided by Julie Van Alstine (RAB1); the residue chemistry assessment by George Kramer (RAB1); the hazard characterization and endpoint selection by Chester Rodriguez (RAB1); the occupational exposure and residential assessment by Kelly Lowe (RAB1); and the drinking water exposure assessment by José Meléndez of the Environmental Fate and Effects Division (EFED).  

The most recent human-health risk assessment for spirotetramat was for a Section 18 emergency exemption registration request for use on watercress in Florida and Tennessee, and was completed on 02-AUG-2012 (Memo, J. Van Alstine, et al.; D399022).  The most recent Section 3 human-health risk assessment for spirotetramat was for cotton, legume vegetables including soybean (crop groups 6 and 7a), and tropical fruit, and was completed on 22-DEC-2010 (Memo, J. Van Alstine, et al.; D368785).

                               Table of Contents
1.0	Executive Summary	5
2.0	HED Recommendations	7
2.1	Data Deficiencies	8
2.2	Tolerance Considerations	8
2.2.1	Enforcement Analytical Method	8
2.2.2	Recommended Tolerances	9
2.2.3	Revisions to Petitioned-For Tolerances	10
2.2.4	International Harmonization	10
2.3	Label Recommendations	10
3.0	Introduction	11
3.1	Chemical Identity	11
3.2	Physical/Chemical Characteristics	12
3.3	Pesticide Use Pattern	13
3.4	Anticipated Exposure Pathways	15
3.5	Consideration of Environmental Justice	15
4.0	Hazard Characterization and Dose-Response Assessment	16
4.1	Toxicology Studies Available for Analysis	16
4.2	Absorption, Distribution, Metabolism, and Excretion (ADME)	16
4.2.1	Dermal Absorption	16
4.3	Toxicological Effects	17
4.3.1	Summary of Toxicological Effects	17
4.4	Safety Factor for Infants and Children (FQPA SF)	19
4.4.1	Completeness of the Toxicology Database	19
4.4.2	Evidence of Neurotoxicity	19
4.4.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal	19
4.4.4	Residual Uncertainty in the Exposure Database	19
4.5	Toxicity Endpoint and Point of Departure Selections	20
4.5.1	Dose-Response Assessment	20
4.5.2	Recommendation for Combining Routes of Exposures for Risk Assessment	21
4.5.3	Cancer Classification and Risk Assessment Recommendation	21
4.5.4	Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment	21
5.0	Dietary Exposure and Risk Assessment	22
5.1	Residues of Concern Summary and Rationale	22
5.2	Food Residue Profile	23
5.3	Water Residue Profile	24
5.4	Dietary Risk Assessment	25
5.4.1	Description of Residue Data Used in Dietary Assessment	25
5.4.2	Percent Crop Treated Used in Dietary Assessment	25
5.4.3	Acute Dietary Risk Assessment	25
5.4.4	Chronic Dietary Risk Assessment	25
5.4.5	Cancer Dietary Risk Assessment	26
6.0	Residential (Non-Occupational) Exposure/Risk Characterization	26
6.1	Residential Bystander Post-Application Inhalation Exposure	26
6.2	Spray Drift	27
7.0	Aggregate Exposure/Risk Characterization	27
7.1	Acute Aggregate Risk	27
7.2	Chronic Aggregate Risk	27
8.0	Cumulative Exposure/Risk Characterization	28
9.0	Occupational Exposure/Risk Characterization	28
9.1	Short- and Intermediate-Term Handler Risk	28
9.2	Short- and Intermediate-Term Post-Application Risk	33
9.2.1	Dermal Post-Application Risk	33
9.2.2	Inhalation Post-Application Risk	35
10.0	References	36
Appendix A.  Toxicology Profile and Executive Summaries	37
A.1	Toxicology Data Requirements	37
A.2	Toxicity Profiles	38
Appendix B.  Physical/Chemical Properties	44
Appendix C.  Review of Human Research	44

	
1.0	Executive Summary

Background:  Spirotetramat is a tetramic acid derivative (ketoenole) and is active against sucking insects in a variety of plants.  It is systemic (xylem and phloem mobile) and can control hidden pests and protect new shoots.

Permanent tolerances for the combined residues of spirotetramat and its metabolites BYI 08330-enol, BYI 08330-ketohydroxy, BYI 08330-enol-Glc, and BYI 08330-mono-hydroxy, calculated as spirotetramat equivalents, are currently established in/on a variety of crops (40 CFR §180.641).  There are no registered residential uses for spirotetramat.

The Interregional Research Project Number 4 (IR-4) has submitted a Section 3 request to register a 2 lb ai/gal suspension-concentrate (SC) formulation (Movento[(R)]; EPA Reg. No. 264-1050), a 1.25 lb ai/gal SC formulation (Ultor[(R)]; EPA Reg. No. 264-1065), and a 1.25 lb ai/gal oil-dispersion (OD) formulation (BYI 8330 OD; EPA Reg. No. 264-1051) for use on taro, watercress, pomegranates, bananas, bulb vegetables, low-growing berries (except strawberries), bushberries, globe artichokes, fruiting vegetables, pome fruit, citrus fruit, pineapples, and coffee.  The end-use products are proposed for 2 to 5 foliar spray applications at 0.05-0.25 lb ai/A/application with minimum retreatment intervals (RTIs) of 7-30 days, for maximum seasonal rates of 0.16-1.25 lb ai/A.  The proposed labels allow for applications via aerial, groundboom, chemigation, and/or airblast equipment, depending on the crop.  Preharvest intervals (PHIs) of 1-14 days are proposed.  The rotational crop plantback intervals (PBIs) are 30 days for all non-labeled crops.  In conjunction with this petition, IR-4 has requested the establishment of permanent tolerances for the residues of the insecticide spirotetramat, including its metabolites and degradates, in or on the commodities summarized in Table 2.2.2.

Additionally, Canada's Pest Management Regulatory Agency (PMRA) has received a petition for the use of spirotetramat on sweet corn in Canada.  The Agency has not received a similar petition; however, as part of the RCC pilot project, HED has recommended a tolerance without U.S. registration for residues of spirotetramat and its metabolites and degradates in/on corn, sweet, kernel plus cob with husks removed based on the PMRA's evaluation of the Canadian sweet corn residue data.  For more information about the RCC pilot project, please refer to http://www.epa.gov/oppfead1/international/naftatwg/us-canada-rcc.html.  

Hazard Assessment:  The target organs of toxicity following subchronic and chronic oral exposures to spirotetramat were different in rats and dogs.  The thyroid and thymus glands were the target organs identified in subchronic and chronic toxicity studies in dogs while the testes were the target organs identified in rats.  The dog was the most sensitive species, and in both species, males were more sensitive than females.  The thyroid effects in the dog consisted of lower circulating levels of thyroid hormones (T3 and/or T4) along with a reduction in follicle size, a possible indication of reduced amount of colloid.  The effects in the dog thymus were described microscopically as involution, which also resulted in decreased organ weight.

In rats, reported testicular effects consisted of abnormal spermatozoa and hypospermia in the epididymis, decreased testicular weights, and testicular degenerative vacuolation.  An investigative subchronic study where rats were dosed with the primary enol metabolite of spirotetramat reproduced the same testicular effects as the parent chemical, suggesting that this metabolite is at minimum a primary contributor to the observed male reproductive toxicity.  Consistent with this notion, spirotetramat orally administered to rats was demonstrated to be extensively metabolized and males were noted to achieve much higher systemic exposures than their female counterparts, which helps explain the gender dependent differences.  Other effects reported in a rat chronic toxicity study were associated with kidney effects consisting of decreased organ weight and tubular dilatation.

There is no evidence of increased pre- or postnatal susceptibility.  Developmental toxicity in the rat occurred only in the presence of maternal toxicity at the limit dose.  Reduced fetal weight and an increased incidence of maltransformations and skeletal variations were reported in the presence of impaired food consumption and decreased body weight and body-weight gain.  No developmental effects were reported in the rabbit study, while similar maternal effects as the rat were reported.

In one- and two-generation rat reproductive toxicity studies, male reproductive toxicity (abnormal sperm cells and reproductive performance) similar to that reported in subchronic toxicity studies with adult rats was reported in the first generation (F1) males.  The effects were reported at relatively high dose levels:  sperm abnormalities and testicular toxicity were seen at 419 and 616 mg/kg/day, respectively in the two-generation reproduction study and at 1000 mg/kg/day (limit dose) in a special male reproductive toxicity study to determine the onset of testicular toxicity.  In all cases, a well-defined no-observed adverse-effect level (NOAEL) was established.

No evidence of tumor formation was found in long-term carcinogenicity studies in mice and rats.  Spirotetramat was also negative for mutagenicity and clastogenicity in several standard in vivo and in vitro assays.

Although the toxicology database for spirotetramat shows effects in the thymus gland in dog studies, the results of a recently submitted and reviewed immunotoxicity study in rats does not indicate any functional deficits in immune function.  Thymus involution has been demonstrated to occur when hypothyroidism is induced in animals, so it is reasonable to conclude that the thymus involution in dogs was secondary to the thyroid effects, rather than a direct effect on the immune system.

Consistent with previous risk assessments for spirotetramat (Memo, J. Tyler, et al., 14-MAY-2008, D333437; Memo, J. Van Alstine, et al., 22-DEC-2010, D368785; Memo, J. Van Alstine, et al., 02-AUG-2012, D399022), the spirotetramat risk assessment team recommends that the 10X Food Quality Protection Act Safety Factor (FQPA SF) be reduced to 1X for all exposure scenarios, as discussed in Section 4.4.

Food Residue Profile:  The nature of the residue in plants and livestock is adequately understood.  Organization for Economic Co-operation and Development (OECD) tolerance-calculation procedures and the submitted residue data sets were used to calculate the HED-recommended tolerances.  Additionally, as part of the RCC pilot project, HED has recommended a tolerance without U.S. registration for residues of spirotetramat and its metabolites in/on corn, sweet, kernel plus cob with husks removed based on PMRA's evaluation of the Canadian residue data for sweet corn.  There is an adequate residue analytical method for the purposes of tolerance enforcement.  The submitted field trial residue data are adequate and, provided that the data deficiencies identified in Section 2.1 are addressed, there are no residue chemistry issues that would preclude establishing unconditional tolerances for residues of spirotetramat and its metabolites, as outlined in Table 2.2.2.

Exposure/Risk Assessment Characterization:  Acute and chronic risk assessments were conducted for dietary exposure based on the existing and proposed uses.  The acute and chronic assessments directly incorporated drinking water estimates.  Assumptions for the acute assessment included tolerance-level residues for all foods, Dietary Exposure Evaluation Model (DEEM) 7.81 default processing factors (where provided), and 100% crop-treated (CT).  Assumptions for the chronic dietary assessment included average field trial residues for some commodities, tolerance-level residues for the remaining commodities, and 100% CT.  Some empirical processing factors were used in the chronic assessment along with DEEM 7.81 default processing factors (where provided).  All exposure and risk estimates were not of concern.  A cancer dietary assessment was not conducted because spirotetramat is classified as "not likely to be carcinogenic to humans."

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

Since there are no residential uses, the acute and chronic aggregate risks are made up only of dietary sources (food and drinking water) and the dietary exposure analyses represent acute and chronic aggregate exposure, respectively.  Short- and intermediate-term assessments, which are used to evaluate aggregate dietary and residential exposures, were not performed because there are no registered or proposed residential non-food uses.  Spirotetramat is classified as "not likely to be carcinogenic to humans"; therefore, cancer aggregate risk assessments were not performed.

The occupational handler and post-application assessments were completed assuming the maximum label application rate.  Based on the proposed use patterns, there is potential for short- and intermediate-term occupational exposure to spirotetramat during mixing, loading, applying, and other handling tasks; and during post-application activities.  Additionally, since the same endpoint and point of departure (POD) were selected for short- and intermediate-term durations, short-term exposure and risk estimates are considered to be protective of potential longer-term exposure and risk.  Chronic exposure is not expected for the proposed agricultural uses.  The level of concern (LOC) for occupational dermal and inhalation exposures are for margins of exposure (MOEs) <100.  For the proposed uses, all occupational short- and intermediate-term handler (with baseline attire) and post-application (on Day 0) MOEs were >100.  The spirotetramat label includes a personal-protective equipment (PPE) requirement that applicators and other handlers wear long-sleeved shirts, long pants, chemical-resistant gloves, shoes plus socks, and protective eyewear.

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  Please refer to Appendix C for a discussion of the human study data used in this risk assessment.  

2.0	HED Recommendations

Pending resolution of the deficiencies outlined below, there are no other residue chemistry, occupational, or toxicology data deficiencies that would preclude the establishment of permanent tolerances for residues of spirotetramat and it metabolites and degradates as outlined in Table 2.2.2.   

2.1	Data Deficiencies

860.1200 Directions for Use

   * Currently the label specifies a 30-day PBI for all crops; however, a 260-day PBI for rotational crops is required to support the proposed use on watercress.  
   * As no residue data were submitted for an OD or equivalent formulation, the use directions for the subject crops should be removed from the BYI 8330 OD label.
   * Since all of the banana field trials were performed in HI, the registration for use on this crop should be limited to the state of HI.

860.1550 Proposed Tolerances

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

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

860.1650 Submittal of Analytical Reference Standards

   * The analytical reference standard for BYI 08330-ketohydroxy has expired and the standards for the isotopically labeled internal standards of BYI 08330-enol and BYI 08330-ketohydroxy will soon expire (7/11/2013).  The registrant should either recertify the lot in the repository and send an updated certificate of analysis (COA), or submit new standards (different lot #) if the previous lots will not be recertified.  If new standards are being submitted, then they should be sent to the Analytical Chemistry Lab, which is located at Fort Meade, to the attention of either Theresa Cole or Thuy Nygen at the following address:
                 USEPA
                 National Pesticide Standards Repository/Analytical Chemistry Branch/OPP
                 701 Mapes Road
                 Fort George G. Meade, MD  20755-5350
 
2.2	Tolerance Considerations

2.2.1	Enforcement Analytical Method

Several high-performance liquid chromatography with tandem mass spectrometry (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 determination of residues of spirotetramat and the metabolites BYI 08330-enol and BYI 08330-enol-GA in livestock matrices by HPLC-MS/MS.  Each method has been adequately validated by the petitioner as well as by independent laboratories.  Methods 00857 and 00966 were also adequately radiovalidated using weathered samples obtained from metabolism studies.  

There is an adequate residue analytical method for the purposes of tolerance enforcement.  For the current petition, samples were analyzed for residues of spirotetramat and its metabolites BYI 08330-enol, BYI 08330-ketohydroxy, BYI 08330-mono-hydroxy, and BYI 08330-enol-glucoside using a HPLC-MS/MS method, Method 00857, which is the current enforcement method for crop commodities.  Residues of each metabolite were reported in parent equivalents.  Analytical method 00857 was developed for the determination of residues of spirotetramat, the metabolites BYI 08330-enol, BYI 08330-ketohydroxy, BYI 08330-mono-hydroxy, and BYI 08330-enol-Glc in plant matrices by HPLC-MS/MS using isotopically labeled internal standards.  Spirotetramat, BYI 08330-enol, BYI 08330-ketohydroxy, BYI 08330-mono-hydroxy, and BYI 08330-enol-Glc were extracted from the plant commodity using a blender with acidic acetonitrile/water (4/1, v/v).  After subsequent clean-up of the extract through a Bond Elut clean polyethylene frit, the corresponding internal standards were added.  The solution was made up to volume, diluted, and subjected to HPLC-MS/MS with multiple-reaction monitoring of two transitions for each matrix and analyte for quantitation and confirmation purposes.  The limit of quantitation (LOQ) was 0.01 ppm for each analyte on all tested plant commodities with the exception of roasted coffee bean (BYI 08830-glucoside had an LOQ of 0.05 ppm) and freeze-dried coffee (the LOQ was 0.1 ppm for each analyte).  The method was adequate for data collection based on acceptable concurrent method recovery data.  

2.2.2	Recommended Tolerances

The proposed uses and the submitted data support the following permanent tolerances for residues of the insecticide spirotetramat, including its metabolites and degradates, in or on the commodities in the table below.  Compliance with the tolerance levels specified below is to be determined by measuring only the sum of spirotetramat (cis-3-(2,5-dimethlyphenyl)-8-methoxy-2-oxo-1-azaspiro[4.5]dec-3-en-4-yl-ethyl carbonate]) and its metabolites cis-3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]dec-3-en-2-one, cis-3-(2,5-dimethylphenyl)-3-hydroxy-8-methoxy-1-azaspiro[4.5]decane-2,4-dione, cis-3-(2,5-dimethylphenyl)-8-methoxy-2-oxo-1-azaspiro[4.5]dec-3-en-4-yl beta-D-glucopyranoside, and cis-3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]decan-2-one, calculated as the stoichiometric equivalent of spirotetramat, in or on the following commodities summarized in Table 2.2.2.

Table 2.2.2.  Tolerance Summary for Spirotetramat.
                                   Commodity
                           Proposed Tolerance (ppm)
                          Recommended Tolerance (ppm)
                    Comments; Correct Commodity Definition
Taro, leaves
                                       9
                                      9.0

Watercress
                                      1.5
                                      2.0

Pomegranate
                                      0.5
                                     0.50

Banana[1]
                                       4
                                      4.0

Vegetable, bulb, group 3-07 
                                      0.6
                                     0.80

Low growing berry subgroup 13-07H, except strawberry
                                      0.3
                                     0.30
Low growing berry subgroup 13-07H, except strawberry and lowbush blueberry
Bushberry subgroup 13-07B 
                                       3
                                      3.0

Artichoke, globe
                                       2
                                      1.5

Vegetable, fruiting, crop group 8-10
                                      2.5
                                      2.5
Vegetable, fruiting, group 8-10
Fruit, pome, crop group 11-10 
                                      0.7
                                     0.70
Fruit, pome, group 11-10 
Fruit, citrus, crop group 10-10
                                      0.6
                                     0.60
Fruit, citrus, group 10-10
Pineapple
                                      0.3
                                     0.30

Pineapple, process residue
                                     0.36
                                       -

Coffee, green bean
                                      0.2
                                     0.20

Coffee, instant
                                       -
                                     0.50

Coffee, roasted bean
                                     0.32
                                       -

Corn, sweet, kernel plus cob with husks removed[2]
                                       -
                                      1.5

[1] This tolerance should be established under 40 CFR §180.641(c) Tolerances with regional registrations.
[2] There are no U.S. registrations as of [date] for use on corn, sweet.

2.2.3	Revisions to Petitioned-For Tolerances

The OECD tolerance calculation procedures were utilized to determine appropriate tolerance levels.  Based on these procedures, HED has recommended tolerances for residues of spirotetramat and its metabolites that are different than the IR-4-proposed tolerances in/on watercress, vegetable, bulb, group 3-07, and artichoke, globe.  

IR-4 has proposed tolerances for residues of spirotetramat and its metabolites in/on pineapple, process residue and coffee, roasted bean.  Since the HED-calculated tolerance values for these processed commodities are less than the HED-recommended tolerances for residues of spirotetramat in/on pineapple and coffee, green bean, separate tolerances for these processed commodities are not required.  

Although IR-4 has not requested a tolerance for coffee, instant, based on the available processing data, an LOQ-level tolerance of 0.50 ppm is required for this commodity.  HED has also recommended a tolerance for residues of spirotetramat in/on corn, sweet, kernel plus cob with husks removed as part of the U.S.-Canada RCC pilot project.

Note to RD:  With the establishment of these tolerances, the tolerances for the following commodities should be deleted from 40 CFR §180.641(a)(1):  onion, bulb, subgroup 3A-07; vegetable, fruiting group 8; fruit, citrus, group 10; fruit, pome, group 11; and okra.  HED also notes that the established tolerances for residues in/on feijoa, papaya, and Spanish lime in 40 CFR §180.641(a)(1) are incorrect and the previously recommended tolerance for residues in/on persimmon is missing.  The correct tolerances are:  2.5 ppm for residues in/on feijoa, 0.35 ppm for residues in/on papaya, 13 ppm for residues in/on Spanish lime, and 2.5 ppm for residues in/on persimmon (Memo, J. Van Alstine et al., 22-DEC-2010; D368785).  40 CFR §180.641(a)(1) should be updated to reflect the recommended tolerances.

2.2.4	International Harmonization

The Codex tolerances/maximum residue limits (MRLs) for residues of spirotetramat in/on bulb vegetables, fruiting vegetables, and citrus and pome fruits cannot be harmonized as the U.S./Canadian residue definition includes metabolites not included in the Codex residue definition.  The U.S. and Canadian tolerance/MRL levels for the subject crops are being harmonized as part of the RCC pilot project.

2.3	Label Recommendations

The submitted use directions for Movento[(R)] and Ultor[(R)] are adequate to allow evaluation of the residue data relative to the proposed uses except that a 260-day PBI is required to support the proposed use on watercress.  Since all of the banana field trials were performed in HI, the registration for use on this crop should be limited to the state of HI.  In addition, as no residue data were submitted for an OD or equivalent formulation, the use directions for the subject crops should be removed from the BYI 8330 OD label.  Revised labels are required.

3.0	Introduction

3.1	Chemical Identity

Table 3.1.  Test Compound Nomenclature.
Compound
Chemical Structure

Common name
Spirotetramat
Company experimental name
BYI 08330
IUPAC name
cis-4-(ethoxycarbonyloxy)-8-methoxy-3-(2,5-xylyl)-1-azaspiro[4.5]dec-3-en-2-one
CAS name
cis-3-(2,5-dimethylphenyl)-8-methoxy-2-oxo-1-azaspiro[4.5]dec-3-en-4-yl ethyl carbonate
CAS #
203313-25-1
End-use product/EP
Movento[(R)], Ultor[(R)], BYI 8330 OD
Compound:  BYI08330-enol
Chemical Structure

Common name
BYI 08330-enol
Company experimental name
BYI 08330-enol
IUPAC name
None provided
CAS name
cis-3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]dec-3-en-2-one
CAS #
None provided
Compound:  BYI08830-ketohydroxy
Chemical Structure

Common name
BYI 08830-ketohydroxy
Company experimental name
BYI 08830-ketohydroxy
IUPAC name
None provided
CAS name
cis-3-(2,5-dimethylphenyl)-3-hydroxy-8-methoxy-1-azaspiro[4.5]decane-2,4-dione
CAS #
None provided
Compound:  BYI08330-enol-Glc
Chemical Structure

Common name
BYI 08330-enol-Glc
Company experimental name
BYI 08330-enol-Glc
IUPAC name
None provided
CAS name
cis-3-(2,5-dimethylphenyl)-8-methoxy-2-oxo-1-azaspiro[4.5]dec-3-en-4-yl beta-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 provided

3.2	Physical/Chemical Characteristics
SPIROTETRAMAT IS A SYSTEMIC BROAD-SPECTRUM TETRAMIC ACID INSECTICIDE (KETOENOL CLASS) THAT IS APPLIED AS A PREVENTATIVE TREATMENT DURING AN EARLY THRESHOLD OF DEVELOPING CHEWING INSECT POPULATION WHEN SUFFICIENT LEAF TISSUE IS PRESENT FOR UPTAKE AND TRANSLOCATION TO OCCUR WITHIN AGRICULTURAL CROPS.  IT IS SYSTEMIC (XYLEM AND PHLOEM MOBILE) AND CAN CONTROL HIDDEN PESTS AND PROTECT NEW SHOOTS.  ITS VAPOR PRESSURE IS 5.6 X 10[-9] Pa at 20 ºC.  The mobility of spirotetramat is moderately high [partition coefficient (Kd) range 3.58-5.52 L/Kg, soil organic carbon partition coefficient (KOC) range 184-437 L/KgOC, moderately mobile, FAO 2000].  Spirotetramat is labile, especially under aerobic soil metabolism conditions.  Nonetheless, its total residues are relatively persistent.  A table of the physicochemical properties can be found in Appendix B.  

3.3	Pesticide Use Pattern

The petitioner has submitted draft labels for the 2 lb ai/gal SC formulation (Movento[(R)]; EPA Reg. No. 264-1050), for the 1.25 lb ai/gal SC formulation (Ultor[(R)]; EPA Reg. No. 264-1065), and the 1.25 lb ai/gal OD formulation (BYI 8330 OD; EPA Reg. No. 264-1051).  Information pertaining to the proposed end-use product is listed in Table 3.3.1.  A summary of the proposed use patterns on taro, watercress, pomegranates, bananas, bulb vegetables, low-growing berries (except strawberries), bushberries; globe artichokes, fruiting vegetables, pome fruit, citrus fruit, pineapples, and coffee is detailed in Table 3.3.2.  A summary of the recommended label changes can be found in Section 2.3.  

Permanent tolerances for the combined residues of spirotetramat and its metabolites BYI 08330-enol, BYI 08330-ketohydroxy, BYI08330-enol-Glc, and BYI 08330-mono-hydroxy, calculated as spirotetramat equivalents, are currently established in/on a wide variety of crops and crop groups in 40 CFR §180.641(a)(1), ranging from 0.25 ppm in tree nut crop group 14 to 16 ppm in soybean hay.  Tolerances are established in 40 CFR §180.641(a)(2) for the combined residues of spirotetramat and its BYI 08330-enol metabolite, calculated as spirotetramat equivalents, in/on the fat, meat, and meat byproducts of cattle, goat, horse, and sheep; the meat byproducts of hog and poultry; milk; and eggs.  Additionally, time-limited tolerances are established in 40 CFR §180.641(b) for the combined residues of spirotetramat and its metabolites BYI 08330-enol, BYI 08330-ketohydroxy, BYI08330-enol-Glc, and BYI 08330-mono-hydroxy, calculated as spirotetramat equivalents, in/on onion, dry bulb and watercress that expire on 31-DEC-2014 and 31-DEC-2015, respectively.  
TABLE 3.3.1.  SUMMARY OF PROPOSED END-USE PRODUCTS.
                                  Trade Name
                                   Reg. No.
                             ai (% of formulation)
                               Formulation Type
                                 Target Crops
                                 Target Pests
                                  Label Date
Movento[(R)]
                                   264-1050
                                     22.4
                                      SC
taro, watercress, pomegranates, bananas, bulb vegetables, low-growing berries (except strawberries), bushberries, globe artichokes, fruiting vegetables, pome fruit, citrus fruit, pineapples, and coffee.
sucking insects
Draft labels submitted 7/24/12
Ultor[(R)]
                                   264-1065
                                     14.5
                                      SC



BYI 8330 OD
                                   264-1051
                                     15.3
                                      OD



TABLE 3.3.2.  SUMMARY OF DIRECTIONS FOR USE OF SPIROTETRAMAT.
                    Application Timing, Type, and Equipment
                          Formulation [EPA Reg. No.]
                          Application Rate (lb ai/A)
                        Max. No. Applic. per Season[1]
                  Maximum Seasonal Application Rate (lb ai/A)
                                  PHI (days)
                        Use Directions and Limitations
                              Banana and Plantain
                              Aerial and Airblast
                        SC liquid [264-1050; 264-1065]
                                       
                             OD liquid [264-1051]
                                 0.16  -  0.25
Not specified on label:  assume maximum of 5 apps/crop season at maximum rate and maximum of 7 apps/crop season at minimum rate
                                     1.25
                                       1
                                 RTI = 14 days
                                       
                                 REI = 24 hrs
                                       
    Minimum spray volume:  50 gallons per acre (GPA) ground, 10 GPA aerial
                     Bushberry subgroups 13-07B and 13-07H
                             Aerial and Groundboom
                        SC liquid [264-1050; 264-1065]
                                       
                             OD liquid [264-1051]
                                   0.13-0.16
Not specified on label:  assume maximum of 2 apps/crop season at maximum rate and maximum of 3 apps/crop season at minimum rate 
                                     0.47
                                       7
                     Do not apply until after petal fall.
                                       
                                 RTI = 7 days
                                       
                                 REI = 24 hrs
                                       
              Minimum spray volume:  30 GPA ground, 10 GPA aerial
                                    Coffee
                              Aerial and Airblast
                        SC liquid [264-1050; 264-1065]
                                       
                             OD liquid [264-1051]
                                   0.13-0.16
Not specified on label:  assume maximum of 2 apps/crop season at maximum rate and maximum of 3 apps/crop season at minimum rate
                                     0.47
                                      14
                     Do not apply until after petal fall.
                                       
                                 RTI = 21 days
                                       
                                REI = 24 hours
                                       
              Minimum spray volume:  30 GPA ground, 10 GPA aerial
                                   Pineapple
                             Aerial and Groundboom
                        SC liquid [264-1050; 264-1065]
                                       
                             OD liquid [264-1051]
                                     0.16
Not specified on label:  assume maximum of 2 apps/crop season at maximum rate 
                                       
                                     0.32
                                       1
                                 RTI = 14 days
                                       
                                REI = 24 hours
                                       
              Minimum spray volume:  30 GPA ground, 10 GPA aerial
                                  Pomegranate
                              Aerial and Airblast
                        SC liquid [264-1050; 264-1065]
                                       
                             OD liquid [264-1051]
                                   0.13-0.16
Not specified on label:  assume maximum of 2 apps/crop season at maximum and minimum rate
                                     0.32
                                       1
                                 RTI = 14 days
                                       
                                REI = 24 hours
                                       
    Minimum spray volume:  50 gallons per acre (GPA) ground, 10 GPA aerial
                   Bulb vegetables subgroups 3-07A and 3-07B
                        Aerial, Groundboom, Chemigation
                        SC liquid [264-1050; 264-1065]
                                       
                             OD liquid [264-1051]
                                     0.08
 Not specified on label:  assume maximum of 2 apps/crop season at maximum rate
                                       
                                     0.16
                                   3-07A:  3
                                       
                                   3-07B: 7 
                                 RTI = 7 days
                                       
                                REI = 24 hours
                                       
              Minimum spray volume:  15 GPA ground, 5 GPA aerial
                                Globe artichoke
                        Aerial, Groundboom, Chemigation
                        SC liquid [264-1050; 264-1065]
                                       
                             OD liquid [264-1051]
                                   0.08-0.13
Not specified on label:  assume maximum of 3 apps/crop season at maximum rate and maximum of 6 apps/crop season at minimum rate 
                                      0.5
                                       3
                                 RTI = 7 days
                                       
                                REI = 24 hours
                                       
              Minimum spray volume:  15 GPA ground, 5 GPA aerial
                                  Watercress
                        Aerial, Groundboom, Chemigation
                        SC liquid [264-1050; 264-1065]
                                       
                             OD liquid [264-1051]
                                   0.06-0.2
Not specified on label:  assume maximum of 2 apps/crop season at maximum rate and maximum of 6 apps/crop season at minimum rate 
                                      0.4
                                       3
                                 RTI = 7 days
                                       
                                REI = 24 hours
                                       
              Minimum spray volume:  15 GPA ground, 5 GPA aerial
                    Additional Restrictions for all Crops:
Movento[(R)] and Ultor[(R)] must be tank-mixed with a spray adjuvant/additive.  BYI 8330 OD may not be tank-mixed with a spray adjuvant/additive having sticking properties.  
Use in enclosed structures, such as greenhouses or planthouses, is not permitted.
Rotational crop PBIs:  30 days for all non-labeled crops.
[1] The submitted labels did not include a maximum number of applications per season.  The maximum number of applications was calculated by dividing the maximum seasonal application rate by the individual application rates. 

3.4	Anticipated Exposure Pathways
RD HAS REQUESTED AN ASSESSMENT OF HUMAN-HEALTH RISK TO SUPPORT THE IR-4 PROPOSED NEW USES OF SPIROTETRAMAT ON WATERCRESS, POMEGRANATES, BANANAS, BULB VEGETABLES, LOW-GROWING BERRIES (EXCEPT STRAWBERRIES), BUSHBERRIES, GLOBE ARTICHOKES, FRUITING VEGETABLES, POME FRUIT, CITRUS FRUIT, PINEAPPLES, AND COFFEE AND THE RCC PILOT PROJECT TOLERANCE WITHOUT U.S. REGISTRATION FOR RESIDUES OF SPIROTETRAMAT AND ITS METABOLITES IN/ON CORN, SWEET, KERNEL PLUS COB WITH HUSKS REMOVED.  HUMANS MAY BE EXPOSED TO SPIROTETRAMAT IN FOOD AND DRINKING WATER, SINCE SPIROTETRAMAT MAY BE APPLIED DIRECTLY TO GROWING CROPS AND APPLICATION MAY RESULT IN SPIROTETRAMAT REACHING SURFACE AND GROUND WATER SOURCES OF DRINKING WATER.  THERE ARE NO RESIDENTIAL USES OF SPIROTETRAMAT, SO EXPOSURE IN RESIDENTIAL OR NON-OCCUPATIONAL SETTINGS IS NOT LIKELY.  IN AN OCCUPATIONAL SETTING, APPLICATORS MAY BE EXPOSED WHILE HANDLING THE PESTICIDE PRIOR TO APPLICATION, AS WELL AS DURING APPLICATION.  THERE IS ALSO A POTENTIAL FOR POST-APPLICATION EXPOSURE FOR WORKERS RE-ENTERING TREATED FIELDS.  

THIS RISK ASSESSMENT CONSIDERS ALL OF THE AFOREMENTIONED EXPOSURE PATHWAYS BASED ON THE PROPOSED NEW USES OF SPIROTETRAMAT, BUT ALSO CONSIDERS THE EXISTING REGISTERED USES AS WELL, PARTICULARLY FOR THE DIETARY EXPOSURE ASSESSMENT.  

3.5	Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," (http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf).  As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture (USDA) under the National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA; 2003-2008) and are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated.  Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0	Hazard Characterization and Dose-Response Assessment

Spirotetramat belongs to the class of cyclic ketoenol insecticides.  The proposed insecticidal mode of action for these agents is based on inhibition of acetyl-CoA carboxylase, a key enzyme in fatty acid biosynthesis in eukaryotes and prokaryotes.  Inhibition of lipogenesis, resulting in decreased lipid content (notably triglycerides and free fatty acids) in treated insects, hinders the ability of younger insects to develop and ultimately their ability to reproduce as adults.  The mammalian toxicity database for spirotetramat does not indicate changes in plasma lipid parameters such as plasma levels of triglycerides and cholesterol; therefore, it is unclear if a lipogenesis-inhibiting mode of action also operates in mammals.

4.1	Toxicology Studies Available for Analysis

The toxicology database for spirotetramat is adequate for characterization of its hazard, toxicity endpoint selection, and FQPA SF consideration.  In the last Section 3 risk assessment (J. Van Alstine et al., 22-DEC-2010; D368785), immunotoxicity and subchronic neurotoxicity studies were reported as data gaps.  Since then, an immunotoxicity study (MRID# 48525901) has been submitted and reviewed by the Agency.  The results of the study are included in this hazard characterization.  The Hazard and Science Policy Council (HASPOC) met on 04-OCT-2012 (TXR# 0056480) and concluded that repeated exposure inhalation toxicity and subchronic neurotoxicity (SCN) studies are not required for spirotetramat at this time.  

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

Absorption of orally-administered spirotetramat in rats was rapid and nearly complete.  In females, the time to maximum plasma levels (tmax) at the low dose tested of 2 mg/kg bw was estimated to be about 10 minutes, while at the high dose of 100 mg/kg bw, tmax was prolonged to 42 minutes.  In males, tmax was between 0.7 and 1 hour at both dose levels.  The extent of absorption was 89-98% by 48 hours following single low (2 mg/kg bw) and higher (100 mg/kg bw) gavage doses, as well as repeated low doses (2 mg/kg bw).  Systemic exposure estimated by the area under the plasma concentration-time curve (AUC0-infinity) was higher for male than female rats.  At 2 mg/kg bw (single or repeated dosing), the AUC for males was about 60% higher than females, and much greater at the high dose.  Less than 0.2% of the administered dose was detected in the body at 48 hours after sacrifice, and the highest concentrations were detected at similar levels in the liver and kidney.  Spirotetramat was completely metabolized in the rat, since no parent compound was detected in the excreta.  The main metabolic reaction was cleavage of the ester group, which resulted in formation of the major metabolite BYI 08330-enol (53-87% of administered dose).  All other identified metabolites could be derived from the primary enol metabolite.  Male rats exhibited much higher rates of demethylation of BYI 08330-enol to BYI 08330-desmethyl-enol (25-37%) when compared to female rats (5-10 %).  Excretion of radioactivity was relatively rapid with 88-95% of the administered dose eliminated via urine and 2-11% via feces by 48 hours of exposure.

4.2.1	Dermal Absorption

An in vivo dermal-penetration study in the rat was performed using the formulation OD150.  A dermal-absorption factor (DAF) of 10% was estimated based on the fraction absorbed and the fraction remaining at the application site (including stratum corneum) at 168 hours following a 10-hour exposure.  The fraction retained in the stratum corneum was included because radioactivity in the feces increased over the 168-hour time period, indicating that absorption continued after the 10-hour exposure.

4.3	Toxicological Effects

4.3.1	Summary of Toxicological Effects

The targets of toxicity following spirotetramat exposure were different for rats and dogs.  The thyroid and thymus glands were target organs in oral subchronic and chronic toxicity studies in the dog.  In a 28-day study, male dogs exhibited lower circulating levels of the thyroid hormones T3 and T4 at a lower dose level than females.  In a 90-day study, circulating levels of T4 were decreased in both sexes at a lower dose than were T3 levels.  Decreases in T4 were also observed at a lower dose as compared to subchronic exposures (above) in male and female dogs in a one-year study.  The only histopathological change in the thyroid was a reduction in follicle size in the high-dose group, a possible indication of reduced amount of colloid.  There were no correlative changes in thyroid weight, thyroid histopathology, or thyroid-stimulating hormone (TSH) in either sex.  In all three dog studies (28-day, 90-day, and 1-year), there were decreases in thymus weights described microscopically as involution.  In the one-year chronic study, the thymus involution was only observed in males.

In rats, the testes were the target organ following subchronic and chronic studies.  Abnormal spermatozoa and hypospermia in the epididymis, decreased testicular weight, and testicular degeneration and vacuolation were observed in males after 90 days of exposure at 10,000 ppm (616 mg/kg bw/day).  These effects proved to be reversible in most animals after cessation of treatment.  Abnormal sperm or spermatid degeneration in the testes and germ cell exfoliated debris in the epididymis were observed in male rats at the high dose only (7500 ppm; 414 or 373 mg/kg bw/day) following 12 (not statistically significant) or 24 months of oral exposure.  Other target organs in rats following exposure for 2 years were the kidney (both sexes) at mid and high doses and the liver (females) at the highest dose only, which may be related to the excretory and/or detoxification roles of the kidney and liver.  Kidney toxicity consisted of decreased organ weight and tubular dilation.  Similar kidney toxicity (decreased weight and histopathology) was also observed at higher doses (419.3 or 484.7 mg/kg bw/day) in parental animals of the F1 generation in the two-generation reproductive toxicity study in rats.

It should be noted that the thyroid and thymus were unaffected in rats at any dose tested, while testicular histopathology was unobserved in dogs.

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

Developmental toxicity only occurred in the presence of maternal toxicity in both rats and rabbits.  Reduced fetal weight and increased incidences of malformations and skeletal deviations were observed along with decreased maternal body weight and food consumption at the limit dose in a rat developmental toxicity study.  In the rabbit, maternal toxicity included a dose-dependent increase in late abortions and other clinical signs of systemic toxicity such as increased weight loss and impaired food and water consumption.

The two-generation reproductive toxicity study showed evidence of male reproductive toxicity similar to chronic and subchronic studies with adult rats.  Abnormal sperm cells were reported in F1-generation male rats treated with 6000-ppm (419 mg/kg bw/day) spirotetramat in the diet, and decreased reproductive performance was also observed in one of these males.  Similar results were obtained in the one-generation reproductive toxicity range-finding study, in which decreased sperm motility and progression and increased abnormal sperm cells in the epididymides were observed in F1 males at >=6000 ppm (320 mg/kg bw/day).  Development of the sexual organs of offspring (balano-preputial separation, vaginal opening) was unaffected in either study, and no treatment-related effects were observed at lower doses.

In an investigative study designed to explore the time of onset of testicular toxicity in rats, decreased epididymal sperm counts were observed after 10 days or more of treatment with 1000 mg/kg bw/day spirotetramat by oral gavage.  Although the data demonstrate that the decreased sperm counts were the result of repeated dosing with spirotetramat, it is noted that since sperm development is a lengthy process (approximately 8 weeks in rats and 10 weeks in humans), the decreased sperm counts may have resulted from single-dose toxicity to an immature precursor that did not manifest until 10 days later.  However, while plausible, this hypothesis is unproven in the absence of additional mechanistic data.

In a second investigative study, male rats were treated by gavage with the enol metabolite of spirotetramat for 21 days at a dose of 800 mg/kg bw/day.  Spermatotoxicity, abnormal sperm, and Sertoli cell vacuolation were observed in the testes-epididymides of treated animals.  In conjunction with the ADME data, which indicates that the parent chemical is completely metabolized to the enol metabolite, these data support the conclusion that male reproductive toxicity in rats is likely due to the enol metabolite of spirotetramat.

In a 28-day dermal toxicity study in rats, there were no effects (local or systemic) reported at the limit dose.  Spirotetramat tested positive for dermal sensitization, which was supported by two cases of Type IV hypersensitivity that were reported in spirotetramat manufacturing plant personnel.

An inhalation toxicity study based on repeated exposures to spirotetramat is not available.  Based on an acute inhalation toxicity study in rats, spirotetramat was classified as Toxicity Category IV, the lowest category for acute toxicity.  The HASPOC concluded that a 28-day inhalation toxicity study is not required as a condition of registration for spirotetramat at this time (TXR# 0056480).  

In the available acute neurotoxicity study, the only evidence of neurotoxicity was based on decreased motor and locomotor activity which occurred only at relatively high-dose levels (200 mg/kg bw).  As a result of the low concern for neurotoxicity in the available toxicity database, the HASPOC also concluded that an SCN study was not required as condition of registration (TXR# 0056480).  Consistent with a low LOC for neurotoxicity, a preliminary review of a recently submitted SCN study where spirotetramat was administered to rats via the diet does not indicate neurotoxicity even at the highest doses tested of 585 and 707 mg/kg bw/day for males and females, respectively.

Although the toxicology database for spirotetramat shows effects in the thymus gland in dogs, the results of a recently submitted and reviewed immunotoxicity study in rats do not indicate any functional deficits in immune function.  Thymus involution has been demonstrated to occur when hypothyroidism is induced in animals, so it is reasonable to conclude that the thymus involution in dogs was secondary to the thyroid effects, rather than a direct effect on the immune system.

There is no evidence of carcinogenicity; treatment-related increases in tumor incidence were not observed in either sex in rats or mice.  Spirotetramat was also negative for mutagenicity and clastogenicity in several standard in vivo and in vitro assays.

4.4	Safety Factor for Infants and Children (FQPA SF)

The RAB1 risk assessment team recommends that the FQPA SF be reduced to 1X for all exposure scenarios.  The rationale is provided below.

4.4.1	Completeness of the Toxicology Database

The existing toxicology database for spirotetramat is complete for FQPA SF evaluation.  The following acceptable studies are available:  developmental toxicity studies in rats and rabbits, a one- and two-generation reproductive toxicity studies in rats, and an acute neurotoxicity study in rats.

4.4.2	Evidence of Neurotoxicity

There is evidence of neurotoxicity from the acute neurotoxicity study at high dose levels (200 mg/kg bw) based on decreased motor and locomotor activity in both sexes, with males being more sensitive than females.  However, the existing toxicological database indicates that spirotetramat is not a neurotoxic chemical in mammals.  The decreased motor activity observed is not considered evidence of direct neurotoxicity because there were no effects on movement or gait and there were no confirmatory findings of neurological pathology observed at relatively high doses [lowest-observed adverse-effect level (LOAEL) of 200 mg/kg bw].  In addition, a preliminary review of the recently submitted SCN does not indicate a concern for neurotoxicity even at very high dose levels administered to rats through the diet.  Finally, the conclusion that spirotetramat is not a neurotoxic chemical is supported by the fact that the acute, subchronic, and developmental neurotoxicity studies available for structurally-related compounds (spirodiclofen and spiromesifen) do not show evidence of neurotoxicity in adults or the young.

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

There was no evidence of increased susceptibility of offspring following pre- or postnatal exposure in any study.  In the rat developmental toxicity study, toxicity to offspring was observed at the same dose as maternal toxicity, which was also the limit dose.  In the developmental toxicity study in the rabbit, only maternal toxicity was observed.  In both reproductive toxicity studies, toxicity to offspring (decreased body weight) was observed at the same dose as parental toxicity.  Therefore, no evidence of increased susceptibility of offspring was found across four relevant toxicity studies with spirotetramat.

4.4.4	Residual Uncertainty in the Exposure Database

The acute dietary food exposure assessment utilizes existing and proposed tolerance-level residues, DEEM 7.81 default processing factors (where provided), and 100% CT information for all commodities.  By using these screening-level assessments, actual exposures/risks will not be underestimated.
The chronic dietary food exposure assessment utilizes average field trial residues for some commodities, tolerance-level residues for the remaining commodities, and 100% CT.  Some empirical processing factors were used in the chronic assessment along with DEEM 7.81 default processing factors (where provided).  The chronic assessment is somewhat refined; however, since it is based on reliable data, it will not underestimate exposure/risk.

The dietary drinking water assessments utilize water concentration values generated by the Tier 1 Rice Model v.1.0.  The resulting screening-level estimated drinking water concentrations (EDWCs) provide conservative, health-protective, high-end estimates of water concentrations that will not likely be exceeded.

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

4.5	Toxicity Endpoint and Point of Departure Selections

4.5.1	Dose-Response Assessment

Tables 4.5.4.1 and 4.5.4.2 summarize the toxicological doses and endpoints selected for human-health risk assessment.  Acute and chronic dietary and short- and intermediate-term inhalation and dermal exposure scenarios were assessed.  There are no registered residential uses of spirotetramat.

Acute Dietary Endpoint (General Population):  This dietary endpoint was based on clinical signs and decreased motor activity observed in the acute neurotoxicity study at the LOAEL of 200 mg/kg bw (NOAEL = 100 mg/kg bw).  The standard combined uncertainty factor (UF) of 100X is being applied to account for interspecies (10X) and intraspecies (10X) extrapolation.  The FQPA SF was reduced to 1X for this exposure scenario since the toxicology database is complete and there were no residual uncertainties for pre- and/or postnatal susceptibility.  Thus, the acute reference dose (aRfD) and population-adjusted dose (aPAD) are equivalent at 1.0 mg/kg bw. 

Chronic Dietary (All Populations):  This dietary endpoint was based on the thymus involution in males in the dog chronic study at the LOAEL of 20 mg/kg bw/day (NOAEL = 5 mg/kg bw/day).  The standard combined UF of 100X is being applied to account for interspecies (10X) and intraspecies (10X) extrapolation.  The FQPA SF was reduced to 1X for this exposure scenario since the toxicology database is complete and there were no residual uncertainties for pre-and or postnatal susceptibility.  Thus, the chronic reference dose (cRfD) and population-adjusted dose (cPAD) are equivalent at 0.05 mg/kg bw. 

Dermal [Short- (1-30 days) and Intermediate- (1-6 months) Term]- Occupational:  This endpoint was based on late abortions (>=GD 22), clinical signs, impaired food and water consumption, and body-weight loss in the rabbit prenatal developmental toxicity study at the LOAEL of 40 mg/kg bw/day (NOAEL = 10 mg/kg bw/day).  Although a 21-day rabbit dermal toxicity study was performed and no toxic effects were observed, such studies are based on non-pregnant adult animals and thus do not account for potential developmental effects.

A DAF of 10% was previously estimated based on an in vivo rat dermal-penetration study with an OD formulation containing spirotetramat.  A LOC for MOEs <100, based on interspecies (10X) and intraspecies (10X) extrapolation, is adequate for this scenario. 
Inhalation [Short- (1-30 days) and Intermediate- (1-6 months) Term]- Occupational:  This endpoint was also based on late abortions (>=GD 22), clinical signs, impaired food and water consumption, and body-weight loss in the rabbit prenatal developmental toxicity study at the LOAEL of 40 mg/kg bw/day (NOAEL = 10 mg/kg bw/day).  A LOC for MOEs <100, based on interspecies (10X) and intraspecies (10X) extrapolation, is adequate for this scenario. 

4.5.2	Recommendation for Combining Routes of Exposures for Risk Assessment

For occupational exposure, dermal and inhalation exposures can be combined since the toxicological effects of concern are the same and were identified from the same study.  Currently there are no registered residential uses of spirotetramat.

4.5.3	Cancer Classification and Risk Assessment Recommendation

There is no evidence of carcinogenicity in chronic toxicity/carcinogenicity studies performed in rats and mice.  Spirotetramat has been classified as "not likely to be carcinogenic to humans" based on lack of evidence for carcinogenicity in rodent studies.  

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

Table 4.5.4.1.  Summary of Toxicological Doses and Endpoints for Spirotetramat for Use in Dietary Human-Health Risk Assessments. 
                               Exposure Scenario
                                      POD
                        Uncertainty/FQPA Safety Factors
                       RfD, PAD, LOC for Risk Assessment
                   Study and Relevant Toxicological Effects
Acute Dietary (General Population, including Infants and Children)
NOAEL = 100
mg/kg/day
UFA = 10X
UFH = 10X
UFFQPA = 1X
aRfD = aPAD = 1.0 mg/kg/day
Acute neurotoxicity (rat; oral gavage)
LOAEL = 200 mg/kg based on clinical signs and decreased motor activity.
Chronic Dietary (All Populations)
NOAEL = 5
mg/kg/day
UFA = 10X
UFH = 10X
UFFQPA = 1X
cRfD = cPAD = 0.05 mg/kg/day[1]
Chronic toxicity (dog; dietary)
LOAEL = 20 mg/kg/day based on thymus involution in males.
Cancer (Oral, Dermal, Inhalation)
Classification:  "not likely to be carcinogenic to humans" based on lack of evidence of carcinogenicity in two oral rodent carcinogenicity studies.
Abbreviations:  UF = uncertainty factor, UFA = extrapolation from animal to human (interspecies), UFH = potential variation in sensitivity among members of the human population (intraspecies), UFFQPA = FQPA Safety Factor, NOAEL = no-observed adverse-effect level, LOAEL = lowest-observed adverse-effect level, RfD = reference dose (a = acute, c = chronic), PAD = population-adjusted dose, LOC = level of concern.
[1] The cRfD has been harmonized across American (USEPA), Canadian (PMRA), and Austrian (AGES) regulatory agencies.  However, it is noted that USEPA considered a NOAEL = 6 mg/kg/day in males and a NOAEL = 19 mg/kg/day in females to more accurately reflect the toxicological data.  The difference between 5 mg/kg/day (NOAEL in females for PMRA and AGES) and 6 mg/kg/day was considered negligible for risk assessment.

Table 4.5.4.2.  Summary of Toxicological Doses and Endpoints for Spirotetramat for Use in Occupational Human-Health Risk Assessments.
                               Exposure Scenario
                                      POD
                              Uncertainty Factors
                            LOC for Risk Assessment
                        Study and Toxicological Effects
Dermal
Short- and Intermediate- Term (1-30 days and 1-6 months)
NOAEL = 10
mg/kg/day 

Dermal-absorption factor = 10%
UFA = 10X
UFH = 10X


Occupational LOC for MOE <100
Prenatal developmental toxicity (rabbit) Maternal LOAEL = 40 mg/kg/day based on late abortion (>=GD 22), clinical signs, impaired food and water consumption, and body-weight loss.
Inhalation
Short- and Intermediate- Term (1-30 days and 1-6 months)
NOAEL = 10
mg/kg/day 

100% absorption assumed
UFA = 10X
UFH = 10X
Occupational LOC for MOE <100
Prenatal developmental toxicity (rabbit) Maternal LOAEL = 40 mg/kg/day based on late abortion (>=GD 22), clinical signs, impaired food and water consumption and body-weight loss.
Cancer (oral, dermal, inhalation)
Classification:  "not likely to be carcinogenic to humans" based on lack of evidence of carcinogenicity in two oral rodent carcinogenicity studies.
Abbreviations:  UF = uncertainty factor, UFA = extrapolation from animal to human (interspecies), UFH = potential variation in sensitivity among members of the human population (intraspecies), NOAEL = no-observed adverse-effect level, LOAEL = lowest-observed adverse-effect level, MOE = margin of exposure, LOC = level of concern.

5.0	Dietary Exposure and Risk Assessment 

An overview of the metabolism and environmental degradation of spirotetramat can be found in the August 2012 human-health risk assessment (Memo, J. Van Alstine, et al.; D399022).

5.1	Residues of Concern Summary and Rationale

The nature of the residue in plants, rotational crops, and livestock is adequately understood based on acceptable metabolism studies conducted with apple, lettuce, cotton, potato, rotational crops, lactating goats, and laying hens.

Plants (Primary Crops):  The residues of concern for both tolerance and risk assessment purposes are spirotetramat and its metabolites BYI 08330-enol, BYI 08330-ketohydroxy, BYI08330-enol-Glc, and BYI 08330-mono-hydroxy (Memo, J. Tyler, et al., 14-MAY-2008; D333437).

Plants (Rotational Crops):  The residues of concern are spirotetramat and its metabolites BYI 08330-ketohydroxy and free and conjugated BYI 08330-desmethyl-ketohydroxy, BYI 08330-desmethyl-di-hydroxy, and BYI 08330-ketohydroxy-alcohol (Memo, J. Tyler, et al., 14-MAY-2008; D333437).

Livestock:  The residues of concern for the tolerance expression for livestock commodities are spirotetramat and its metabolite BYI 08330-enol and the residues of concern for the risk assessment for livestock commodities are spirotetramat and its metabolites BYI 08330-enol and BYI 08330-enol-GA (Memo, J. Tyler, et al., 14-MAY-2008; D333437). 

Drinking Water:  The residues of concern in drinking water for risk assessment purposes are spirotetramat, BYI 08330-enol, and BYI 08330-ketohydroxy (Memo, J. Tyler, et al., 14-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.

Table 5.1.  Summary of Metabolites and Degradates to be included in Risk Assessment and Tolerance Expression[1].
                                    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[2]
Not Applicable[2]
Livestock (Ruminant and Poultry)
Spirotetramat, BYI 08330-enol, and BYI 08330-enol-GA[2]
Spirotetramat and BYI 08330-enol[3]
Drinking Water
Spirotetramat, BYI 08330-enol, and BYI 08330-ketohydroxy
Not Applicable
[1] Memo, J. Tyler, et al., 14-MAY-2008; D333437.
[2] The following potential residues of concern were identified in the confined rotational crop study:  Spirotetramat, BYI 08330-ketohydroxy and free and conjugated BYI 08330-desmethyl-ketohydroxy, BYI 08330-desmethyl-di-hydroxy and BYI 08330-ketohydroxy-alcohol.  None of these residues were found in the limited rotational crop field trials at a 30-day PBI.  Provided a 30-day PBI is specified on the spirotetramat labels and use rates in are below 0.16 lb ai/A for annual crops, residues in rotational crops are not currently of concern for the risk assessment or for tolerance setting.
[3] If future proposed uses result in significant exposure of livestock to the plant metabolites BYI 08330-ketohydroxy, BYI08330-enol-Glc, and BYI 08330-mono-hydroxy, then these metabolites may need to be included as additional residues of concern for livestock commodities.

5.2	Food Residue Profile

Spirotetramat is systemic (xylem and phloem mobile).  The submitted magnitude of the residue data for the raw agricultural commodities (RACs) of watercress, pomegranates, bananas, bulb vegetables, low-growing berries (except strawberries), bushberries, globe artichokes, pineapples, and coffee will support the proposed use patterns.  As no residue data were submitted for an OD or equivalent formulation and higher residues result from this formulation type (Memo, G. Kramer, 17-APR-2008; D339694), the use directions for the subject crops should be removed from the BYI 8330 OD label.  In addition, as all of the banana field trials were performed in HI, the registration for use on this crop should be limited to the state of HI.  

Residue-decline data show that residues of concern decreased in blueberries, cranberries, pomegranate, globe artichoke, green onions, pineapple, and sweet corn forage with increasing PHIs.  The residue-decline data indicate that the residues of concern increased with increasing PHIs for coffee, and remained fairly stable for dry bulb onion and sweet corn stover.  For pomegranate and pineapple, residues of the metabolites BYI 08330-enol, BYI 08330-ketohydroxy, BYI 08330-monohydroxy, and BYI 08330-glucoside were <LOQ at each sampling interval; therefore, residue decline could not be assessed for these metabolites in these commodities.  Average combined residues of spirotetramat and its metabolites in banana were <1.5 ppm at the 1-day PHI, decreased to <0.49 ppm at the 7-day PHI, and increased to <0.63 ppm at the 14-day PHI.  

Acceptable coffee and pineapple processing studies are available.  The processing studies show that following processing of RAC samples bearing quantifiable residues, total residues of spirotetramat and its metabolites concentrated in roasted coffee bean (<1.9X), instant coffee (<10X), and pineapple process residue (1.2X).  

Freezer storage stability data are available for five diverse crops (i.e., a fruiting vegetable-tomato; a root crop-potato, a leafy vegetable-head lettuce; a nut-almond nutmeat; and a legume-bean with pod) which demonstrate stability of residues of spirotetramat, BYI 08330-enol, BYI 08330-enol-Glc, BYI 08330-ketohydroxy, and BYI 08330-mono-hydroxy for up to 718 days of frozen storage.  These data support the storage conditions and intervals of samples collected from the various crop field trials.  There are no unresolved storage stability issues, and no corrections need to be applied to the various residue crop studies.  

The only feedstuff associated with the proposed new uses is pineapple process residue, a minor feed item.  As the calculated maximum residue calculated for pineapple process residue (0.14 ppm) is very low relative to the reasonably balanced dietary burdens (RBDBs) for spirotetramat and its metabolites, addition of this feed item to the livestock diets would not have a significant effect on the estimated residue levels in livestock.  The established tolerances for residues of spirotetramat and its metabolite in livestock commodities are thus adequate to support the proposed new uses.

The metabolism of spirotetramat in rotational crops appears to be consistent with the pathway observed in the plant metabolism studies.  The available field accumulation data indicate that residues of the parent and its metabolites (BYI 08330-ketohydroxy, BYI 08330-desmethyl-ketohydroxy, BYI 08330-desmethyl-di-hydroxy and BYI 08330-ketohydroxy-alcohol) were each <0.020 ppm in/on all rotational crop matrices at a 30-day PBI.  Unless the petitioner requests PBIs shorter than 30 days or use rates in excess of 0.16 lb ai/A for annual crops, no additional data are required, and tolerances for inadvertent residues in/on rotational crops need not be established in conjunction with the currently proposed uses.  The proposed use rate for watercress is 0.4 lb ai/A; therefore, based on the results of the confined rotational crop study (conducted at an application rate of 0.36 lbs. ai/A), a 260-day PBI is required to support the proposed use on watercress. 

5.3	Water Residue Profile

EFED provided Tier 1 ground and surface EDWCs for spirotetramat and the major transformation products, spirotetramat-enol and spirotetramat-ketohydroxy (Memo, J. Meléndez, 19-JUL-2012; D398507).  The EDWCs were calculated using SCI-GROW v.2.3 (groundwater, applications to bananas and plantains) and the Tier 1 Rice Model v.1.0 (surface water, as a surrogate for applications to watercress).  The Tier 1 Rice Model v.1.0 resulted in the highest EDWC for use in the acute and chronic assessments.  Therefore, the surface water EDWC value of 0.395 ppm was incorporated in DEEM-FCID, Version 3.16, into the food categories "water, direct, all sources" and "water, indirect, all sources" for both the acute and chronic assessments.  

The Tier 1 Rice Model v.1.0 provides a conservative, screening-level estimate.  Crop interception, pesticide degradation, stream flow, and runoff dilution from the areas in the watershed which are not treated all have the potential to reduce the conservative EDWCs generated by the Tier 1 Rice Model.  

Table 5.3.  Maximum Tier I EDWCs Based on Ground or Aerial Application of Spirotetramat on Plantains and Bananas (for Groundwater) at 1.25 lb ai/A/Season, and Ground, Aerial, or Chemigation Applications on Watercress (for Surface Water) at 0.4 lb ai/A/Season.
Drinking Water Source (MODEL)
                 Estimated Drinking Water Concentration (EDWC)

                                   Chemical:
                                    Parent
                                 Spirotetramat
                              Spirotetramat-enol
                           Spirotetramat-ketohydroxy
                         Total Toxic Residues (TTR)[1]

                                 Risk \ Units
                                     (ppb)
                                     (ppb)
                                     (ppb)
                                     (ppb)
Ground-water (SCI-GROW)
Acute and Chronic [2]
                                 7.06 x 10[-5]
                                 5.15 x 10[-5]
                                 1.12 x 10[-3]
                                 1.24 x 10[-3]
Surface Water (Tier 1 Rice Model v.1.0)
Acute and Chronic [2]
                                      N/A
                                      N/A
                                      N/A
                                      395
 TTR = total toxic residue (sum of spirotetramat + spirotetramat-enol + spirotetramat-ketohydroxy).
[2] Surface-water concentrations calculated by the Tier I Rice Model v1.0 and ground water concentrations calculated by SCI-GROW do not distinguish between peak and chronic concentrations.

5.4	Dietary Risk Assessment

5.4.1	Description of Residue Data Used in Dietary Assessment

Acute and chronic dietary-exposure (food plus water) and risk assessments were conducted using DEEM-FCID, Version 3.16, which uses food consumption data from the USDA's NHANES/WWEIA survey from 2003 through 2008.  The assessments were performed for the general U.S. population and all population subgroups.  Assumptions for the acute assessment included tolerance-level residues for all foods, DEEM 7.81 default processing factors (where provided), and 100% CT.  Assumptions for the chronic dietary assessment included average field trial residues for some commodities, tolerance-level residues for the remaining commodities, and 100% CT.  Some empirical processing factors were used in the chronic assessment along with DEEM 7.81 default processing factors (where provided).  Drinking water estimates were provided by EFED.  The EDWC values were generated using the watercress use pattern and the Tier 1 Rice Model v.1.0.  The resulting screening-level EDWC estimate of 0.395 ppm was used for both the acute and chronic assessments.  

5.4.2	Percent Crop Treated Used in Dietary Assessment

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

5.4.3	Acute Dietary Risk Assessment

Acute dietary risk estimates (food and drinking water) are not of concern for the general population or any other population subgroup.  The assessment was unrefined and the highest exposure estimate was for the population subgroup children 1-2 years old, which utilized 16% of the aPAD for spirotetramat.  The acute exposure estimate for the general U.S. population utilized 7% of the aPAD.  A summary table of dietary exposure and risk for spirotetramat can be found in Section 5.4.6.  

5.4.4	Chronic Dietary Risk Assessment

Chronic dietary risk estimates (food and drinking water) are not of concern for the general population or any other population subgroup.  The assessment was somewhat refined and the highest exposure and risk estimates were for the population subgroup children 1-2 years old, which utilized 76% of the cPAD for spirotetramat.  The chronic exposure estimate for the general U.S. population utilized 36% of the cPAD.  A summary table of dietary exposure and risk for spirotetramat can be found in Section 5.4.6.  Although further refinement to the analysis is not required at this time, future assessments could be refined through the use of additional average field trial values and translation of average field trial residues to other commodities using HED SOP 2000.1, additional empirical processing factors, incorporation of % CT data, or monitoring data.  

5.4.5	Cancer Dietary Risk Assessment

A cancer dietary assessment was not performed because spirotetramat was classified as "not likely to be carcinogenic to humans."

5.4.6	Summary Table

 Table 5.4.6.  Summary of Dietary (Food and Drinking Water) Exposure Risk for 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
                                    0.066115
                                       7
                                    0.017785
                                      36
 All Infants (<1 year old)
                                    0.137642
                                      14
                                    0.036886
                                      74
 Children 1-2 years old
                                    0.155241
                                      16
                                    0.038038
                                      76
 Children 3-5 years old
                                    0.125606
                                      13
                                    0.030925
                                      62
 Children 6-12 years old
                                    0.075624
                                       8
                                    0.019418
                                      39
 Youth 13-19 years old
                                    0.046354
                                       5
                                    0.013149
                                      26
 Adults 20-49 years old
                                    0.053000
                                       5
                                    0.016159
                                      32
 Adults 50-99 years old
                                    0.050326
                                       5
                                    0.016494
                                      33
 Females 13-49 years old
                                    0.052999
                                       5
                                    0.015902
                                      32
 [1] The values for the highest exposed population for each type of risk assessment are bolded.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

The proposed uses are not expected to result in residential exposure, and there are no currently registered residential uses of spirotetramat; therefore, a quantitative residential exposure assessment was not conducted.

6.1	Residential Bystander Post-Application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for spirotetramat at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure (5.6 x 10[-9] Pa at 20 ºC), and the low proposed use rate (0.25 lb ai/A).  However, volatilization of pesticides may be a source of post-application inhalation exposure to individuals nearby pesticide applications.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010.  The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are developed, then the Agency may revisit the need for a quantitative post-application inhalation exposure assessment for spirotetramat.

6.2	Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations.  This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for spirotetramat.  The Agency has been working with the Spray Drift Task Force, EPA Regional Offices, and State Lead Agencies for pesticide regulation and other parties to develop the best spray-drift-management practices (see the Agency's Spray Drift website for more information.  The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT[(R)] computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods.  After the policy is in place, the Agency may impose further refinements in spray-drift-management practices to reduce off-target drift with specific products with significant risk estimates associated with drift.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential exposures.  In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated.  When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

For spirotetramat, aggregate exposure risk assessments were performed for the following scenarios:  acute aggregate exposure (food and drinking water) and chronic aggregate exposure (food and drinking water).  Short- and intermediate-term assessments, which are used to evaluate aggregate dietary and residential exposures, were not performed because there are no registered or proposed residential non-food uses.  Spirotetramat is classified as "not likely to be carcinogenic to humans"; therefore, cancer aggregate risk assessments were not performed.

7.1	Acute Aggregate Risk

The acute aggregate risk assessment takes into account exposure estimates from dietary consumption of spirotetramat (food and drinking water).  The acute dietary exposure estimates are not of concern to HED (<100% aPAD) at the 95[th] exposure percentile for the general U.S. population and all other population subgroups (see Table 5.4.6).  The dietary exposure assessment utilized tolerance-level residues, 100% CT information for all proposed agricultural uses, DEEM 7.81 default processing factors (where provided), and a Tier 1 surface water EDWC generated by the Tier 1 Rice Model v.1.0.  

7.2	Chronic Aggregate Risk

The chronic aggregate risk assessment takes into account average exposure estimates from dietary consumption of spirotetramat (food and drinking water).  The chronic dietary exposure estimates are not of concern to HED (<100% cPAD) for the general U.S. population and all population subgroups (see Table 5.4.6).  The dietary exposure assessment utilized average field trial residues for some commodities, tolerance-level residues for the remaining commodities, 100% CT, some empirical processing factors, DEEM 7.81 default processing factors (where provided), and a Tier 1 chronic surface water EDWC generated by the Tier 1 Rice Model v.1.0.  

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to spirotetramat and any other substances and spirotetramat does not appear to produce a toxic metabolite produced by other substances.  For the purposes of this tolerance action, therefore, EPA has not assumed that spirotetramat has a common mechanism of toxicity with other substances.  For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

An occupational exposure assessment of the proposed uses was provided in a HED memorandum dated 26-MAR-2013 (K. Lowe; D398857).  For the proposed use sites, there is a potential for short- and intermediate-term occupational exposure to spirotetramat during mixing, loading, applying, and other handling tasks; and during post-application activities.  Additionally, since the same endpoint and POD were selected for short- and intermediate-term durations, short-term exposure and risk estimates are considered to be protective of potential longer-term exposure and risk.  Chronic exposure is not expected for the proposed agricultural uses.  

9.1	Short- and Intermediate-Term Handler Risk

The scenarios assessed for occupational handlers include mixing/loading liquids to support aerial, airblast, groundboom, and chemigation applications, applying sprays with aerial, airblast, and groundboom equipment, and flagging for liquid aerial applications.  

It is the policy of HED to use the best available data to assess handler exposure.  Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, include the Pesticide Handlers Exposure Database (PHED) 1.1, the Agricultural Handler Exposure Task Force (AHETF) database, the Outdoor Residential Exposure Task Force (ORETF) database, or other registrant-submitted occupational exposure studies.  Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA.  The standard values recommended for use in predicting handler exposure that are used in this assessment, known as "unit exposures," are outlined in the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table," which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website. 

Estimates of dermal and inhalation exposure were calculated for various levels of PPE.  Results are presented for "baseline," defined as a single layer of clothing consisting of a long-sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator, as well as baseline with various levels of PPE as necessary (e.g., gloves, respirator, etc.).  The spirotetramat product labels direct mixers, loaders, applicators and other handlers to wear long-sleeved shirts, long pants, chemical-resistant gloves, shoes plus socks, and protective eyewear. 

The occupational handler exposure and risk estimates indicate that short- and intermediate-term dermal and inhalation combined MOEs are not of concern to HED (i.e., MOEs > 100) with baseline attire.  With baseline attire, the dermal plus inhalation MOEs range from 360 to 43,000 (see Table 9.1.1).  HED has no data to assess exposures to pilots using open cockpits.  The only data available is for exposure to pilots in enclosed cockpits.  Therefore, risks to pilots are assessed using the engineering control (enclosed cockpits) and baseline attire (long-sleeved shirt, long pants, shoes, and socks); pilots are not required to wear protective gloves.  With this level of protection, there are no risk estimates of concern for applicators.

The Agency matches quantitative occupational exposure assessment with appropriate characterization of exposure potential.  While HED presents quantitative risk estimates for human flaggers where appropriate, agricultural aviation has changed dramatically over the past two decades.  According the 2012 National Agricultural Aviation Association (NAAA) survey of their membership, the use of the Global Positioning System (GPS) for swath guidance in agricultural aviation has grown steadily from the mid 1990s.  Over the same time period, the use of human flaggers for aerial pesticide applications has decreased steadily from ~15% in the late 1990s to only 1% in the most recent (2012) NAAA survey.  The Agency will continue to monitor all available information sources to best assess and characterize the exposure potential for human flaggers in agricultural aerial applications.

Table 9.1.1.  Short-/Intermediate-Term Occupational Exposure and Risk Estimates for Spirotetramat.  
                               Exposure Scenario
                                Crop or Target
                      Dermal Unit Exposure (ug/lb ai)[1]
                    Inhalation Unit Exposure (ug/lb ai)[1]
                           Maximum Application Rate 
                                 (lb ai/A)[2]
                              Area Treated Daily
                                  (acres)[3]
                                    Dermal
                                  Inhalation
                                     Total


                               Mitigation Level
                               Mitigation Level


                              Dose (mg/kg/day)[4]
                                    MOE[5]
                              Dose (mg/kg/day)[6]
                                    MOE[7]
                                    MOE[8]
                                 Mixer/Loader
                  Aerial Applications of Liquid Formulations
                               Banana, Plantain
                                220 (baseline)
                               0.219 (baseline)
                                     0.25
                                      350
                                     0.028
                                      360
                                   0.000278
                                    36,000
                                      360

                                  Watercress


                                      0.2

                                    0.0223
                                      450
                                   0.000222
                                    45,000
                                      450

    Bushberry subgroups 13-07B and 13-07H, Coffee, Pineapple, Pomegranate, 


                                     0.16

                                    0.0178
                                      560
                                   0.000178
                                    56,000
                                      550

                                Globe artichoke


                                     0.13

                                    0.0145
                                      690
                                   0.000144
                                    69,000
                                      680

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


                                     0.08

                                    0.00893
                                     1,100
                                   0.0000888
                                    110,000
                                     1,100
                 Airblast Applications of Liquid Formulations
                               Banana, Plantain
                                220 (baseline)
                               0.219 (baseline)
                                     0.25
                                      40
                                    0.00319
                                     3,100
                                   0.0000317
                                    320,000
                                     3,100

          Bushberry subgroups 13-07B and 13-07H, Coffee, Pomegranate


                                     0.16

                                    0.00204
                                     4,900
                                   0.0000203
                                    490,000
                                     4,900
                Chemigation Applications of Liquid Formulations
                                  Watercress
                                220 (baseline)
                               0.219 (baseline)
                                      0.2
                                      350
                                    0.0223
                                      450
                                   0.000222
                                    45,000
                                      450

                                Globe artichoke


                                     0.13

                                    0.0145
                                      690
                                   0.000144
                                    69,000
                                      680

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


                                     0.08

                                    0.00893
                                     1,100
                                   0.0000888
                                    110,000
                                     1,100
                 Groundboom Application of Liquid Formulations
                                  Watercress
                                220 (baseline)
                               0.219 (baseline)
                                      0.2
                                      80
                                    0.0051
                                     2,000
                                   0.0000507
                                    200,000
                                     2,000

               Bushberry subgroups 13-07B and 13-07H, Pineapple


                                     0.16

                                    0.00409
                                     2,400
                                   0.0000406
                                    250,000
                                     2,400

                                Globe artichoke


                                     0.13

                                    0.00332
                                     3,000
                                   0.000033
                                    300,000
                                     3,000

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


                                     0.08

                                    0.00204
                                     4,900
                                   0.0000203
                                    490,000
                                     4,900
                                  Applicator
                  Aerial Applications of Liquid Formulations
                               Banana, Plantain
                            5 (engineering control)
                          0.068 (engineering control)
                                     0.25
                                      350
                                   0.000635
                                    16,000
                                   0.0000862
                                    120,000
                                    14,000

                                  Watercress


                                      0.2

                                   0.000507
                                    20,000
                                   0.000069
                                    140,000
                                    18,000

    Bushberry subgroups 13-07B and 13-07H, Coffee, Pineapple, Pomegranate, 


                                     0.16

                                   0.000406
                                    25,000
                                   0.0000552
                                    180,000
                                    22,000

                                Globe artichoke


                                     0.13

                                    0.00033
                                    30,000
                                   0.0000448
                                    220,000
                                    26,000

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


                                     0.08

                                   0.000203
                                    49,000
                                   0.0000275
                                    360,000
                                    43,000
                 Airblast Applications of Liquid Formulations
                               Banana, Plantain
                                1770 (baseline)
                                4.71 (baseline)
                                     0.25
                                      40
                                    0.0257
                                      390
                                   0.000683
                                    15,000
                                      380

          Bushberry subgroups 13-07B and 13-07H, Coffee, Pomegranate


                                     0.16

                                    0.0164
                                      610
                                   0.000436
                                    23,000
                                      590
                 Groundboom Application of Liquid Formulations
                                  Watercress
                                78.6 (baseline)
                                0.34 (baseline)
                                      0.2
                                      80
                                    0.00183
                                     5,500
                                   0.0000788
                                    130,000
                                     5,300

               Bushberry subgroups 13-07B and 13-07H, Pineapple


                                     0.16

                                    0.00146
                                     6,800
                                   0.000063
                                    160,000
                                     6,500

                                Globe artichoke


                                     0.13

                                    0.00118
                                     8,500
                                   0.0000513
                                    190,000
                                     8,100

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


                                     0.08

                                   0.000729
                                    14,000
                                   0.0000316
                                    320,000
                                    13,000
                                    Flagger
                       Flagging for Aerial Applications
                               Banana, Plantain
                                 11 (baseline)
                                0.35 (baseline)
                                     0.25
                                      350
                                    0.0014
                                     7,100
                                   0.000443
                                    23,000
                                     5,400

                                  Watercress


                                      0.2

                                    0.00112
                                     8,900
                                   0.000355
                                    28,000
                                     6,800

    Bushberry subgroups 13-07B and 13-07H, Coffee, Pineapple, Pomegranate, 


                                     0.16

                                   0.000893
                                    11,000
                                   0.000284
                                    35,000
                                     8,400

                                Globe artichoke


                                     0.13

                                   0.000726
                                    14,000
                                    0.00023
                                    43,000
                                    11,000

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


                                     0.08

                                   0.000446
                                    22,000
                                   0.000142
                                    70,000
                                    17,000
[1] Based on "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (March 2012); includes data from PHED/ORETF/AHETF (level of mitigation:  Baseline for all scenarios except for aerial applicators which is assessed using eng. controls).
[2] Based on proposed labels (Reg. Nos. 264-1050, 264-1065, 264-1051).
[3] Exposure Science Advisory Council (ExpoSAC) Policy #9.1.
[4] Dermal Dose = Dermal Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre) x Area Treated (A/day) x DAF (10%) / BW (69 kg).
[5] Dermal MOE = Dermal NOAEL (10 mg/kg/day)/Dermal Dose (mg/kg/day).
[6] Inhalation Dose = Inhalation Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre) x Area Treated (A/day) / BW (69 kg).
[7] Inhalation MOE = Inhalation NOAEL (10 mg/kg/day)/Inhalation Dose (mg/kg/day).
[8] Total MOE = NOAEL (10 mg/kg/day)/Dermal Dose + Inhalation Dose.


9.2	Short- and Intermediate-Term Post-Application Risk

9.2.1	Dermal Post-Application Risk

HED expects that post-application exposure will occur since spirotetramat is applied as a foliar spray.  For spirotetramat, based on the proposed uses, short- and intermediate-term exposures are expected since there is the potential for multiple applications at the maximum application rate for most crops (range of 2 to 7 applications with RTIs ranging from 7 to 21 days).  In addition, both the short-term and intermediate-term endpoints are the same; therefore, estimates of short-term exposure/risk are protective of any potential longer-term exposures.  

No post-application exposure data were submitted in support of this registration action.  It is the policy of HED to use the best available data to assess post-application exposure.  Sources of generic post-application data, used as surrogate data in the absence of chemical-specific data, are derived from ARTF exposure monitoring studies, and, as proprietary data, are subject to the data protection provisions of FIFRA.  The standard values recommended for use in predicting post-application exposure that are used in this assessment, known as "transfer coefficients," are presented in the "Science Advisory Council for Exposure (ExpoSAC) Policy 3" (http://www.epa.gov/pesticides/science/exposac_policy3.pdf), which, along with additional information about the ARTF data, can be found at http://www.epa.gov/pesticides/science/post-app-exposure-data.html.  

Coffee is not currently assigned a crop group and/or transfer coefficients in ExpoSAC Policy 3.  According to USDA's Crop Profiles for coffee, this crop is described as a small evergreen tree.  Therefore, the activities and transfer coefficients assigned to trees, "fruit," evergreen/Christmas trees were used as a surrogate for the occupational post-application exposure assessment for coffee.

The fraction of ai retained on foliage surfaces is assumed to be 25% (0.25) of the application rate on the day of initial treatment.  This fraction is assumed to further dissipate at the rate of 10% (0.1) per day.  These are standard values established by HED ExpoSAC when no information is known about possible bonding to foliar surfaces and dissipation of the ai over time.

In accordance with the updated Part 158 data requirements (2007), one or more dislodgeable-foliar residue (DFR) studies are required when a pesticide has residential or occupational uses that could result in post-application dermal exposure.  As part of the recent revision to the Health Effects Division's 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment, HED analyzed a number of DFR studies and selected a new default value for the fraction of the application rate available to be dislodged after a foliar application (FAR).  This default value is 25% and is based on an analysis of 19 DFR studies where the FAR value ranged from 2% to 89%.  This value is recommended for use in both residential and occupational post-application assessments.  Of the analyzed DFR studies, the maximum FAR value seen was 89% or 3.6 times higher than the default residue transfer value.  Therefore, the HED has decided that a calculated MOE of approximately 4 times higher than the LOC (e.g., an MOE > 400 if the LOC = 100) using the default dislodged residue values would provide an adequate margin of safety for any potentially higher residues seen in a chemical-specific DFR study (Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar Residue (DFR) Studies.  Memo, J. Housenger, 12/12/12).  A DFR study is not required for spirotetramat at this time since the dermal MOEs are greater than 400 on Day 0 based on default values for the fraction of application rate available for transfer after a foliar application.

Table 9.2.1.  Summary of Short- and Intermediate-term Occupational/Commercial Post-application Risk Estimates for Spirotetramat.
                                   Crop/Site
                                  Activities
                        Transfer Coefficient (cm[2]/hr)
                                  DFR/TTR[1]
                                 Dermal Dose 
                                (mg/kg/day)[2]
                                    MOE[3]
                                Banana/Plantain
                                 Hand weeding
                                      100
                                     0.701
                                   0.000813
                                    12,000
                                       
                                Hand harvesting
                                     1,400
                                       
                                    0.0114
                                      880
                     Bushberry subgroups 13-07B and 13-07H
                     Hand weeding, Pruning, Hand (shears)
                                      70
                                     0.449
                                   0.000364
                                    27,000
                                       
                                 Transplanting
                                      230
                                       
                                    0.0012
                                     8,300
                                       
       Scouting, Hand pruning, Hand weeding, Bird control, Frost control
                                      640
                                       
                                    0.00333
                                     3,000
                                       
                           Hand harvesting, Scouting
                                     1,100
                                       
                                    0.00573
                                     1,700
                                       
                                Hand harvesting
                                     1,400
                                       
                                    0.00729
                                     1,400
                                       
                              Handset irrigation
                                     1,900
                                       
                                    0.00989
                                     1,000
                                    Coffee
                                 Hand weeding
                                      100
                                     0.449
                                   0.000521
                                    19,000
                                       
                                 Transplanting
                                      230
                                       
                                    0.0012
                                     8,300
                                       
                                   Scouting
                                      580
                                       
                                    0.00302
                                     3,300
                                       
                                Hand harvesting
                                     1,400
                                       
                                    0.00729
                                     1,400
                                       
                              Handset irrigation
                                     1,900
                                       
                                    0.00989
                                     1,000
                       Pineapple and Globe Artichoke[4]
 Hand weeding, Hand pruning (artichoke only), Thinning plants (artichoke only)
                                      70
                               0.365 (artichoke)
                                       
                               0.449 (pineapple)
                                   0.000364
                                    27,000
                                       
                                   Scouting
                                      210
                                       
                                    0.00109
                                     9,200
                                       
                        Transplanting (artichoke only)
                                      230
                                       
                                   0.000973
                                    10,000
                                       
                                Hand harvesting
                                     1,100
                                       
                                    0.00573
                                     1,700
                                       
                      Handset irrigation (artichoke only)
                                     1,900
                                       
                                    0.00804
                                     1,200
                                  Pomegranate
                              Orchard maintenance
                                      100
                                     0.449
                                   0.000521
                                    19,000
                                       
                                 Transplanting
                                      230
                                       
                                    0.0012
                                     8,300
                                       
                            Scouting, Hand pruning
                                      580
                                       
                                    0.00302
                                     3,300
                                       
                                Hand harvesting
                                     1,400
                                       
                                    0.00729
                                     1,400
                   Bulb Vegetables subgroups 3-07A and 3-07B
                           Scouting, Thinning plants
                                      330
                                     0.224
                                   0.000857
                                    12,000
                                       
                    Scouting, Hand weeding, Hand harvesting
                                     1,400
                                       
                                    0.00364
                                     2,700
                                       
                              Hand set irrigation
                                     1,900
                                       
                                    0.00493
                                     2,000
                                       
                                 Hand weeding
                                     4,200
                                       
                                    0.0109
                                      920
                                  Watercress
                         Thinning plants, Hand weeding
                                      70
                                     0.561
                                   0.000455
                                    22,000
                                       
                                   Scouting
                                      210
                                       
                                    0.00137
                                     7,300
                                       
                                 Transplanting
                                      230
                                       
                                    0.0015
                                     6,700
                                       
                                Hand harvesting
                                     1,100
                                       
                                    0.00715
                                     1,400
                                       
                              Hand set irrigation
                                     1,900
                                       
                                    0.0124
                                      810
[1] DFR = Application Rate x F x (1-D)[t] x 4.54E8 ug/lb x 2.47E-8 acre/cm[2]; where F = 0.25 and D = 0.10 per day.  
[2] Daily Dermal Dose = [DFR (ug/cm[2]) x Transfer Coefficient x 0.001 mg/ug x 8 hrs/day x dermal absorption (%)]  BW (kg).
[3] MOE = POD (mg/kg/day) / Daily Dermal Dose.  Daily Dermal Dose = [DFR/TTR (ug/cm[2]) x TC x 0.001 mg/ug x 8 hrs/day x dermal absorption]  BW (kg).
[4] For activities common to both pineapple and globe artichoke, only doses and MOE for the higher pineapple rate are shown.  

All scenarios resulted in MOEs greater than the LOC of 100 (ranging from 810 to 27,000) on day 0 (12 hours after application) and, therefore, are not of concern to HED.  Under 40 CFR 156.208 (c) (2) (iii), active ingredients classified as Toxicity Category II for acute dermal, eye irritation or primary skin irrigation are assigned a 24-hour REI.  Therefore, the [156 subpart K] Worker Protection Statement interim REI of 24 hours is adequate to protect agricultural workers from post-application exposures to spirotetramat.  The proposed labels for spirotetramat include an REI of 24 hours.

9.2.2	Inhalation Post-Application Risk

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for spirotetramat at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure (5.6 x 10[-9] Pa at 20 ºC), and the low proposed use rate (0.25 lb ai/A).  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, and received the SAP's final report on March 2, 2010.  The Agency is in the process of evaluating the SAP report as well as available post-application inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, then the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for spirotetramat.

Although a quantitative occupational post-application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers.  Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post-application exposure.  Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post-application inhalation exposure scenarios.


10.0	References

Previous Risk Assessments:  J. Tyler, et al., 14-MAY-2008, D333437; J. Van Alstine, et al. 22-DEC-2010, D368785; J. Van Alstine, et al. 02-AUG-2012, D399022

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

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

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

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

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


List of Appendices:
Appendix A.  Toxicology Profile and Executive Summaries
Appendix B.  Physical/Chemical Properties
Appendix C.  Review of Human Research






















cc:  J. Van Alstine, G. Kramer, K. Lowe, C. Rodriguez
RDI:  RAB1 (30-JAN-2013), C. Smith (30-JAN-2013)
J. Van Alstine: S-10951: Potomac Yard 1 (PY1): (703)603-8866: 7509P: RAB1
Appendix A.  Toxicology Profile and Executive Summaries

A.1	Toxicology Data Requirements

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

                                     Test 
                                   Technical

                                   Required
                                   Satisfied
870.1100	Acute Oral Toxicity
870.1200	Acute Dermal Toxicity
870.1300	Acute Inhalation Toxicity
870.2400	Primary Eye Irritation
870.2500	Primary Dermal Irritation
870.2600	Dermal Sensitization
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.3100	Oral Subchronic (rodent)
870.3150	Oral Subchronic (nonrodent)
870.3200	21-Day Dermal
870.3250	90-Day Dermal
870.3465	90-Day Inhalation
                                      yes
                                      yes
                                      yes
                                      no
                                      no
                                      yes
                                      yes
                                      yes
                                       -
                                     no[1]
870.3700a	Developmental Toxicity (rodent)
870.3700b	Developmental Toxicity (nonrodent)
870.3800	Reproduction
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.4100a	Chronic Toxicity (rodent)
870.4100b	Chronic Toxicity (nonrodent)
870.4200a	Oncogenicity (rat)
870.4200b	Oncogenicity (mouse)
870.4300	Chronic/Oncogenicity
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.5100	Mutagenicity -- Gene Mutation - bacterial
870.5300	Mutagenicity -- Gene Mutation - mammalian
870.5400	Mutagenicity -- Structural Chromosomal Aberrations
870.5500	Mutagenicity -- Other Genotoxic Effects
                                      yes
                                      yes
                                      yes
                                      no
                                      yes
                                      yes
                                      yes
                                       -
870.6100a	Acute Delayed Neurotox. (hen)
870.6100b	90-Day Neurotoxicity (hen)
870.6200a	Acute Neurotox. Screening Battery (rat)
870.6200b	90-Day Neuro. Screening Battery (rat)
870.6300	Develop. Neurotoxicity
                                      no
                                      no
                                      yes
                                      no
                                      no
                                       -
                                       -
                                      yes
                                      yes
                                       -
870.7485	General Metabolism
870.7600	Dermal Penetration
                                      yes
                                      yes
                                      yes
                                      yes
Special Studies for Ocular Effects
         Acute Oral (rat)	
         Subchronic Oral (rat)	
         Six-month Oral (dog)	
                                       
                                      no
                                      no
                                      no
                                       
                                       -
                                       -
                                       -
[1] The Hazard and Science Policy Council (HASPOC) met on 04-OCT-2012 (TXR# 0056480) and concluded that a repeated exposure inhalation toxicity study is not required for spirotetramat at this time.  
A.2	Toxicity Profiles

Table A.2.1.  Acute Toxicity Profile  -  Spirotetramat Technical. 
                                 Guideline No.
                                  Study Type
                                    MRID(s)
                                    Results
                               Toxicity Category
                                   870.1100
Acute oral (rat)
                                   46904527
LD50 >2000 mg/kg (F)
                                      III
                                   870.1200
Acute dermal (rat)
                                   46904529
LD50 >2000 mg/kg (M&F)
                                      III
                                   870.1300
Acute inhalation (rat)
                                   46904530
LC50 >4.183 mg/L (M&F)
                                      IV
                                   870.2400
Primary eye irritation (rabbit)
                                   46904531
Corneal opacity and iritis (grade 1); cleared by day 8
                                      II
                                   870.2500
Primary dermal irritation (rabbit)
                                   46904532
Negative
                                      IV
                                   870.2600
Dermal sensitization (mouse)
                                   46904565
Positive (LLNA)
                                      N/A

Table A.2.2.  Subchronic and Chronic Toxicity and Genotoxicity Profile  -  Spirotetramat Technical.
                                 Guideline No.
                                  Study Type
                     MRID No. (year)/ Classification/Doses
                                    Results
870.3100
28-Day oral toxicity (mouse)
46904536 (2001) Acceptable/non-guideline
0, 500, or 5000 ppm (equivalent to 0, 136.5 or 1415 mg/kg bw/day [M])
NOAEL = 5000 ppm (1415 mg/kg/day [M]).
LOAEL not observed.
870.3100

90-Day oral toxicity (mouse)
46904539 (2005) Acceptable/guideline
0, 70, 350, 1700, or 7000 ppm (equivalent to 0/0, 12.8/16, 59.6/72.4, 300/389, or 1305/1515 mg/kg bw/day [M/F])
NOAEL = 7000 ppm (1305/1515 mg/kg/day [M/F]).
LOAEL not observed.
870.3100
28-Day oral toxicity (rat)
46904537 (1998) Acceptable/non-guideline
0, 500 or 5000 ppm (equivalent to 0, 47.3, or 501.8 mg/kg bw/day [F])
NOAEL = 5000 ppm (501.8 mg/kg/day [F]).
LOAEL not observed.
870.3100

90-Day oral toxicity (rat)
46904538 (2005) Acceptable/guideline
0, 150, 600, 2500, or 10000 ppm (equivalent to 0/0, 9/11, 26/46, 148/188, or 616/752 mg/kg bw/day [M/F])
NOAEL = 2500 ppm (148/188 mg/kg/day [M/F]).
LOAEL = 10000 ppm (616/752 mg/kg/day [M/F]), based on decreased body weight, abnormal spermatozoa and hypospermia in the epididymis, decreased testicular weight, and testicular degeneration and vacuolation in males, and alveolar macrophages in both sexes.
870.3150

28-Day oral toxicity (dog)
46904572 (2004)
Acceptable/non-guideline
0, 100, 400, 1600, or 6400 ppm (equivalent to 0/0, 3/3, 13/12, 42/70, or 104/127 mg/kg/day [M/F])
NOAEL = 1600 ppm (42/70 mg/kg/day [M/F]).
LOAEL = 6400 ppm (104/127 mg/kg/day [M/F]) based on decreased thymus size and weight as well as decreased body weight and food consumption, which resulted in emaciation.
870.3150

90-Day oral toxicity (dog)
46904541 (2005) Acceptable/guideline
0, 150, 300, 1200, or 4000/2500 ppm (equivalent to 0/0, 5/6, 9/10, 33/32, or 81/72 mg/kg bw/day)
NOAEL = 1200 (32 mg/kg/day) [F] & 2500 ppm (81 mg/kg/day) [M].
LOAEL = 2500 ppm (72 mg/kg/day) [F] based on decreased body-weight gain and food consumption, depressed RBC parameters (red blood cell count, hemoglobin level and hematocrit), and thymus atrophy.
870.3200

28-Day dermal toxicity (rat)
46904542 (2006)
Acceptable/guideline
0, 100, 300, or 1000 mg/kg bw/day (limit dose)
NOAEL = 1000 mg/kg/day.
LOAEL not established.
870.3700a

Prenatal developmental (rat)
46904543 (2004)
Acceptable/guideline
0, 20, 140, or 1000 mg/kg bw/day
Maternal NOAEL = 140 mg/kg/day.
LOAEL = 1000 mg/kg/day based on impaired food consumption, transient body weight loss, impaired body-weight gain, and reduced final body weight.
Developmental NOAEL = 140 mg/kg/day.
LOAEL = 1000 mg/kg/day based on reduced fetal weight and increased incidences of malformations and skeletal variations.
870.3700b

Prenatal developmental (rabbit)
46904544 (2004)
Acceptable/guideline
0, 10, 40, or 160 mg/kg bw/day
Maternal NOAEL = 10 mg/kg/day.
LOAEL = 40 mg/kg/day based on late abortion (>=GD 22), clinical signs, impaired food and water consumption, and body weight loss.
Developmental NOAEL = 160 mg/kg/day.
LOAEL not observed.
870.3800

1-gen. reproduction and fertility effects
(rat)  -  range finding
46904571 (2006)
Acceptable/non-guideline
0, 200, 500, 6000, or 10000 ppm (equivalent to 0/0, 10.5/12.8, 27.8/31.4, 320.1/384.1, or 537.9/645.7 mg/kg bw/day [M/F])
Parental/Systemic NOAEL = 500 ppm (27.8 and 31.4 mg/kg bw/day [M/F]).
LOAEL = 6,000 ppm (320.1 and 384.1 mg/kg bw/day [M/F]) based on decreased body-weight gain (P females) and terminal body weight (F1 males).
Reproductive NOAEL = 500 ppm (27.8 mg/kg bw/day [M]) and 10,000 ppm (645.7 mg/kg/day) [F].
LOAEL = 6,000 ppm (320.1 mg/kg bw/day [M]) based on decreased sperm motility and progression and increased abnormal sperm cells in the F1 males.
Offspring NOAEL = 500 ppm (27.8 and 31.4 mg/kg bw/day [M/F]).
LOAEL = 6,000 ppm (320.1 and 384.1 mg/kg bw/day [M/F]) based on decreased body weight and body-weight gain during lactation in F1 pups.
870.3800

2-gen. reproduction and fertility effects
(rat)
46904546 (2006)
Acceptable/guideline
0, 250, 1,000, or 6,000 ppm (equivalent to 0/0, 17.2/20, 70.7/82.5, or 419.3/484.7 mg/kg bw/day [M/F])
Parental/Systemic NOAEL = 1000 ppm (70.7/82.5 mg/kg/day [M/F]).
LOAEL = 6000 ppm (419.3/484.7 mg/kg/day [M/F]) based on decreases in body weight (F1 males and females), weight gain (P males, F1 males and females), and food consumption during lactation (P- and F1-generation females), and kidney histopathology and decreased kidney weights (F1 males and females).
Reproductive NOAEL = 1000 ppm (70.7 mg/kg/day) [M] & 6000 ppm (484.7 mg/kg/day) [F].
LOAEL = 6000 ppm (419.3 mg/kg/day) [M] based on abnormal sperm cells and decreased reproductive performance in the F1 males.
Offspring NOAEL = 1000 ppm (70.7/82.5 mg/kg/day [M/F]).
LOAEL = 6000 ppm (419.3/484.7 mg/kg/day [M/F]) based on decreased body weight and body-weight gain during lactation in both F1 and F2 generations.
870.4100

Chronic toxicity (1 year; dog)
46904548 (2006)
Acceptable/guideline
0, 200, 600, or 1800 ppm (equivalent to 0/0, 6/5, 20/19, or 55/48 mg/kg/day [M/F])
NOAEL = 200 ppm (6 mg/kg/day) [M] & 1800 ppm (48 mg/kg/day) [F].
LOAEL = 600 ppm (20 mg/kg/day) [M] based on thymus involution [M] and not observed [F].
870.4100

Chronic toxicity
(1 year; rat)
46904547 (2005)
Acceptable/guideline
0, 250, 3500, or 7500/12000 ppm (M/F) (equivalent to 0/0, 13.2/18, 189/255, or 414/890 mg/kg bw/day [M/F])
NOAEL = 250 ppm (13.2 mg/kg/day) [M] & 3500 ppm (255 mg/kg/day) [F].
LOAEL = 3500 ppm (189 mg/kg/day)[M] based on dose-dependent increase in alveolar macrophages; & 12000 ppm (890 mg/kg/day)[F] based on decreased body weight and body-weight gain, alveolar macrophages, discoloration of the lung, and yellow/brown staining of the perigenital area and tail.
870.4200

Carcinogenicity
(rat)
46904549 (2006)
Acceptable/guideline
0, 250, 3500, or 7500/12000 ppm (M/F) (equivalent to 0/0, 12.5/16.8, 169/229, or 373/823 mg/kg bw/day [M/F])
NOAEL = 250 ppm (12.5/16.8 mg/kg/day [M/F]).
LOAEL = 3500 ppm (169/229 mg/kg/day [M/F]) based on decreased kidney weight and renal tubular dilation.

No evidence of carcinogenicity.
870.4200

Carcinogenicity
(mouse)
46904550 (2006)
Acceptable/guideline
0, 70, 1700, or 7000/6000 ppm (M/F) (equivalent to 0/0, 10.9/13.7, 263/331, or 1022/1319 mg/kg/day [M/F])
NOAEL = 7000/6000 ppm (1022/1319 mg/kg/day [M/F]).
LOAEL not observed.

No evidence of carcinogenicity.
870.5100
Bacterial Gene Mutation
46904551 (2006)
Acceptable/guideline
0, 16, 50, 158, 500, 1581, or 5000 ug/plate +/- S9 activation
Negative.
870.5100
Bacterial Gene Mutation
46904552 (2002)
Acceptable/guideline
0, 16, 50, 158, 500, 1581, or 5000 ug/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 ug/mL (-S9)  
0, 20, 40, or 80 ug/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 ug/mL (-S9)
0, 40, 60, 80, 100, or 120 ug/mL (+S9)
N/A
870.5395
In vivo erythrocyte micronucleus assay (mouse)
46904556 (2002)
Acceptable/guideline
0, 125, 250, or 500 mg/kg bw
Negative.
870.5385
In vivo bone marrow chromosomal aberration assay (mouse)
46904558 (2003)
Acceptable/guideline
0, 125, 250, or 500 mg/kg bw
Negative.
870.5550
In vivo/in vitro UDS assay (rat hepatocytes)
46904557 (2003)
Acceptable/guideline
0, 1000, or 2000 mg/kg bw
Negative.
870.6200a

Acute neurotoxicity screening battery
46904560 (2005)
Acceptable/guideline
0, 50, 100, 200, 500, or 2000 mg/kg bw
NOAEL = 100 mg/kg/day.
LOAEL = 200 mg/kg/day based on clinical signs (males and females) and decreased motor activity (males).
870.6200b
Subchronic neurotoxicity  screening battery
48958802 (2012)
Pending formal review.
870.7485

Metabolism and pharmacokinetics
(rat)
46904504 (2006)
Acceptable/guideline
2 or 100 mg/kg bw (single)
2 mg/kg bw (repeat)
Absorption:  89-98% after 48 hrs (no significant differences among low dose, high dose, and repeated dose tests).
Distribution:  AUC0-infinity (measure of systemic exposure) slightly higher for males than females; <0.2% of administered dose detected in body 48 hrs after sacrifice; highest equivalent concentrations detected in liver and kidney.
Metabolism:  parent compound undetected in urine and feces of all tests; main metabolic reaction was cleavage of the ester group which resulted in formation of the primary metabolite BYI 08330-enol (53-87% of administered dose); all other identified metabolites could be derived from enol; male rats exhibited much higher rates of demethylation of BYI 08330-enol to BYI 08330-desmethyl-enol (25-37%) vs. females rats (5-10%).
Excretion:  88-95% of administered dose eliminated via urine and 2-11% via feces within 48 hrs.
870.7485

Metabolism and pharmacokinetics
(rat)
46904561 (2006)
Acceptable/guideline
2 or 1000 mg/kg bw (single)
At 1000 mg/kg bw:  Absorption and excretion less than low dose, with 27% of dose excreted in urine after 24 hours (18% in feces); plasma radioactivity slightly higher than in liver and kidney; these results are consistent with saturation of cellular transport mechanisms.  Tissue radioactivity decreased from 1 to 24 hours post dose.  Metabolism profile qualitatively similar to that of the low-dose group; BYI 08330-enol was most prominent metabolite; similar to low-dose group, BYI 08330-desmethyl-enol levels greater in urine than in plasma and organs.
870.7600
In vivo dermal penetration
(rat)
46904563 (2006)
Acceptable/guideline 
100, 15, or 5 ug ai/cm[2] (OD150 formulation)
Dermal absorption = 10%.
870.7800
Immunotoxicity
(rat)
48525901 (2011)
Acceptable/guideline
500, 2500, or 12,000 ppm (equivalent to 33, 164, or 795 mg/kg/day)

The functional immunotoxicity NOAEL is 12,000 ppm (equivalent to 795 mg/kg/day, the highest dose tested); the LOAEL was not established.
The systemic toxicity LOAEL for Spirotetramat in male rats is 12,000 ppm (equivalent to 795 mg/kg bw/day) based on decreased body weights, decreased body-weight gains, lowered food consumption, lower thymus weight, and observations of atrophic thymus.  The NOAEL for systemic toxicity is 2500 ppm (equivalent to 164 mg/kg bw/day)
Special study
Male reproductive toxicity 
46904569 (2005)
Acceptable/non-guideline
1000 mg/kg bw/day (3, 10, 21, or 41 days)
Primary testicular effects on or after day 10 were degeneration of round and elongating spermatids (stage 7-8 and 9-14, respectively), decreased sperm count, and increased numbers of aberrant/abnormal spermatozoa in the epididymis.


Table A.2.3.  USEPA Toxicity Profile  -  Metabolites.
                                 Guideline No.
                                  Study Type
                    MRID No. (year)/ Classification /Doses
                                    Results
Exploratory study
10-day gavage (enol metabolite)
46904601 (2006)
Acceptable/non-guideline
800 mg/kg bw/day
Decreased body-weight gain; histopathology not evaluated.
Special study
21-day gavage (enol metabolite)
47070901 (2006)
Acceptable/non-guideline
800 mg/kg bw/day
Clinical signs of toxicity, decreased body-weight gain, testicular/spermatotoxicity.
870.5100
Bacterial Gene Mutation
(ketohydroxy metabolite)
46904594 (2005)
Acceptable/guideline
0, 16, 50, 158, 500, 1581, or 5000 ug/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 tract, liver, and kidney; <0.2% of administered dose detected in body 48 hrs post dose.
Metabolism:  parent compound undetected in urine and trace amounts in feces; main metabolic reaction was oxidative demethylation of cyclohexyl-O-methyl group to form desmethyl-ketohydroxy metabolite (15% of administered dose); all other identified metabolites could be derived from 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 ug/plate +/- S9 activation
Negative.
870.5100
Bacterial Gene Mutation
(dihydroxy metabolite)
46904599 (2005)
Acceptable/guideline
0, 16, 50, 158, 500, 1581, or 5000 ug/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 ug/plate +/- S9 activation
Negative. 


Appendix B.  Physical/Chemical Properties

Table B.1.  Physicochemical Properties of the Spirotetramat.
                                   Parameter
                                     Value
                                   Reference
Melting point
142 °C
EPA Chemical Fact Sheet for Spirotetramat, June 2008
pH
6.3

Density
D4[20] = 1.22

Water solubility (20 ºC)
pH 4:  33.5 mg/L
pH 7:  29.9 mg/L
pH 9:  19.1 mg/L

Solvent solubility (20 ºC)
Solvent	g/L
n-hexane	0.055
Dichloromethane	>600
Dimethyl Sulfoxide	200-300
Toluene	60
Acetone	100-120
Ethyl acetate	67
Ethanol	44

Vapor pressure
Extrapolated Values:
5.6 x 10[-9] Pa (20 ºC)
1.5 x 10[-8] Pa (25 ºC)
1.5 x 10[-6] Pa (50 ºC)

Dissociation constant, pKa
10.7
Included in MRID 47648203
Octanol/water partition coefficient, Log(KOW)
pH 4:  2.51
pH 7:  2.51
pH 9:  2.50
EPA Chemical Fact Sheet for Spirotetramat, June 2008
UV/visible absorption spectrum
Peak Maxima    Molar Absorptivity 
        (nm)            (1000 cm[2]/ mol)
        211                22.0 x 10[3]        
        276                0.8 x 10[3]



Appendix C.  Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These data, which include studies from the PHED 1.1, the AHETF database, and the ARTF database are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements.  For certain studies, the ethics review may have included review by the Human Studies Review Board.  Descriptions of data sources, as well as guidance on their use, can be found at the Agency website.  

