Page 1 of 44 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460 **OFFICE OF CHEMICA** **L SA FETY**  **AND POLLUTION PREVENTION**  **MEMORANDUM D**  **ATE :**  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; Ve getable, 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 No s**  **.:** 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 **T XR 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 aggre gate 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 - dimethly phenyl ) - 8 - methoxy- 2 - oxo - 1 - azaspiro[4.5]dec - 3 - en - 4 - yl - e thyl 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 RC C 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.Spirotetramat Human - Health Risk Assessment DP# 398509

Page 2 of 44 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 b y 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 L owe (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 soy bean (crop groups 6 and 7a), and tropical fruit, and was completed on 22 - DEC - 2010 (Memo, J. Van Alstine, et al. ; D368785).Spirotetramat Human - Health Risk Assessment DP# 398509

Page 3 of 44 **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 To**  **lerances ................................**  **................................ ..**  **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 ................................**  **................................ ....**  **1 5**  **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**Spirotetramat Human - Health Risk Assessment DP# 398509

Page 4 of 44 **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**Spirotetramat Human - Health Risk Assessment DP# 398509

Page 5 of 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 s ys temic (x yl em and phloem mobile) and can control hidden pests and protect new shoots. Permanent tolerances for the combined re sidues of spirotetramat and its metabolites BYI 08330 - enol, BYI 08330 - ketohydrox y, BYI 08330 - enol - Glc, and BYI 08330 - mono - hydroxy , calculated as spirotetramat equivalents, are currentl y established in/on a variety of crops (40 CFR §180.641). There are no registered residential uses for spirotetramat. The Interregional Research Project Number 4 (IR- 4) has submitted a Section 3 request to register a 2 lb ai/gal suspension - concentrate (SC) formulation (Movento ® ; EPA Reg. No. 264 - 1050), a 1.25 lb ai/gal SC fo rmulation (Ultor® ; 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 (RTI s) of 7 - 30 day s, 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 day s are proposed. The rotational crop plantback intervals (PBIs) are 30 day s 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 par

t 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 swee t 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 A ssessment** **:** The target organs of toxicity following subchronic and chronic oral exposures to spirotetramat were di fferent in rats and dogs. The thyr oid and thy mus 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 thy roid effects in the dog consisted of lower circulating levels of thy roid 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 hy pospermia in the epididy mis, 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 orall y administered to rats was demo nstrated to be extensively

metabolized and males were noted to achieve much higher s ys temic exposures thanSpirotetramat Human - Health Risk Assessment DP# 398509

Page 6 of 44 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 onl y in the presence of maternal toxicity at the limit dos e. 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 rabb it 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 (F 1 ) males. The effects were reported at relativel y high dose levels: sperm abnormalities and testicular toxicity were seen at 419 and 616 mg/kg/day , respectivel y in the two - generation reprodu ction 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 assay s. 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 thy mus involution in dogs was secondary to the thy

roid effects, rather than a direct effect on the immune sy stem. 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 fo r all exposure scenarios, as discussed in Section 4.4. **Food Residue Profile:** The nature of the residue in plants and livestock is adequatel y 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 tol erances. 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 anal ytical 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 addre ssed, there are no resi due 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 assessm ents wereSpirotetramat Human - Health Risk Assessment DP# 398509

Page 7 of 44 conducted for dietary

exposure based on the existing and proposed uses. The acute and chronic assessments directl y incorporated drinking water estimates. Assumptions for the acute assessment included tolerance - level residues for all foods, Diet ary 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 likel y 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 onl y of dietary sources (food and drinking water) and the dietary exposure anal ys es represent acute and chronic aggregate exposure, respectivel y. 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 likel y 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 pattern s, there is potential for short and intermediate - term occupational exposure to spirotetramat during mixing, loading, appl ying, 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 exp osure 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 >1 00 . 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 rel ies 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.Spirotetramat Human - Health Risk Assessment DP# 398509

Page 8 of 44 **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 res idue 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 Analy tical Reference Standards

 The anal ytical reference standard for BYI 08330 - ketohydroxy has expired and the standards for the isotopically labeled internal standards of BYI 08330 - enol and BYI 08330 - ketohydrox y will soon expire (7/11/2013). The registrant should either recertify the lot in the repository

and send an updated certificate of anal ys is (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 Analy tical Chemistry

L ab, 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 /Anal ytical Chemistry

Branch/OPP 701 Mapes Road Fort George G. Me ade, MD 20755 - 5350 **2.2 Tolerance Considerations**  **2.2.1 Enforcement Analytical Method**  Several high - performance liquid chromatography with tandem mass spectrometry ( HPL C MS/MS) residue anal ytical methods have been submitted for the determination of resid ues of the parent and its metabolites in/on plant and livestock commodities. Analy tical method 00857 was developed for the determination of residues of spirotetramat, the metabolites BYI 08330 - enol, BYI 08330 - ketohydrox y, BYI 08330 - mono - hydroxy, and BYI 0 8330 - enol - Glc in plant matrices by HPLC - MS/MS. Analy

tical 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 ade quately validated by

the petitioner as well as b y independent laboratories. Methods 00857 and 00966 were also adequatel y radiovalidated using weathered samples obtained from metabolism studies. There is an adequate residue anal ytical method for the pur poses of tolerance enforcement. For the current petition, samples were anal yz ed for residues of spirotetramat and its metabolites BYISpirotetramat Human - Health Risk Assessment DP# 398509

Page 9 of 44 08330 - enol, BYI 08330 - ketohydroxy , BY I 08330 - mono - hydroxy , and BYI 08330 - enol glucoside using a HPL C - MS/MS method, Method 00857, which is the current enforcement method for crop commodities. Residues of each metabolite were reported in parent equivalents. Analy tical method 00857 was developed for the determination of residues of spirotetramat, the metabolites BYI 08330 - eno l, BYI 08330 - ketohydroxy, BYI 08330 - mono - hydroxy , and BYI 08330 - enol - Glc in plant matrices by HPL C - 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 polyethyl ene frit, the corresponding internal standards were added. The solution was made up to volume, diluted, and subjected to HPL C - MS/MS with multiple - reaction monitoring of two transitions for each matrix and analy te for quantitation and confirmation purposes. The limit of quantitation (L OQ) was 0.01 ppm for each anal yt e 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 belo w. Compliance with the tolerance levels specified below is to be determined b y measuring only the sum of spirotetramat ( cis - 3 - (2,5 - dimethly phenyl) - 8 - methoxy2 - oxo - 1 - azaspiro[4.5]dec - 3 - en - 4 - yl - ethylcarbonate]) 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 - ylbeta - D - glucopy ranoside, and cis - 3 - (2,5 - dimethylphenyl) - 4 - hydrox y- 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 Spirotetram at.**  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 Lo w growing berry subgroup 13 - 07H, except straw

berry 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 -Spirotetramat Human - Health Risk Assessment DP# 398509

Page 10 of 44 **Table 2.2.2. Tolerance Summary for Spirotetram at.**  Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity Definition Coffee, green bean 0.2 0.20 Coffee, instant - 0.50 Coffee, roasted bean 0.32 - Corn, sweet, kernel plus cob with husks removed2 - 1.5 1 This tolerance should be established under 40 CFR §180.641(c) Tolerances with regional registrations. 2 There are no U.S. registrations as of [date] for use on corn, sweet. **2.2.3 Revisions to Petitioned**  **- For Tolerances**  The OECD tolerance calculation procedures were utilized to determine appropriate tolerance levels. Based on these procedures, HED has recommended tolerances for residues of spirotetramat and its metabolites that are different than the IR - 4 - proposed tolerances in/on watercress, vegetable, bulb, group 3 - 07, and artichoke, globe. IR - 4 has proposed tolerances for residues of spirotetramat and its metabolites in/on pineapple, process residue and coffee, roasted bean. Since the HED - calculated tolerance value s 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 remo ved 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; D36878 5). 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 (MRL s) for residues of spirotetramat in/on bulb vegetable s, fruiting vegetables, and citrus and pome fruits cannot be harmonized as the U.S./Canadian residue definition includes metabolites not included in the Codex residue definition. The U.S. and Canadian tolerance/MRL levels for the subject crops are being harmonized as part of the RCC pilot project. **2.3 Label Recommendations**  The submitted use directions for Movento ® and Ultor® are adequate to allow evaluation of the residue data relative to the proposed uses except that a 260 - day PBI is required to support theSpirotetramat Human - Health Risk Assessment DP# 398509

Page 11 of 44 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 Com** **pound Nom enclature.**  Compound Chemical Structure

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

Compound: BYI08330 - enol Chemical Structure

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

Compound: BYI08830 - ketohydroxy Chemical Structure

Common name BYI 08830 - ketohydroxy Company experimental name BYI 08830 - ketohydroxy IUPAC name None provided CAS name cis - 3 - (2,5 - dimethylphenyl) - 3 - hydroxy- 8 - methoxy- 1 - azaspiro[4.5]decane - 2,4 - dione CAS # None providedSpirotetramat Human - Health Risk Assessment DP# 398509

Page 12 of 44 **Table 3.1. Test Com pound Nom** **enclature.**

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 sy stemic 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 wi thin agricultural crops. It is systemic (xyl em 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 moderatel y high [partition coefficient (K d

### ) range 3.58 - 5.52 L /Kg, soil organic carbon partition coefficient (K OC ) range 184 - 437 L /Kg OC , moderately

mobile, FAO 2000]. Spirotetramat isSpirotetramat Human - Health Risk Assessment DP# 398509

Page 13 of 44 labile, especiall y under aerobic soil metabolism conditions. Nonetheless, its total residues are relativel y persistent. A tab le of the phys icochemical properties can be found in Appendix B. **3.3 Pesticide Use Pattern**  The petitioner has submitted draft labels for the 2 lb ai/gal SC formulation (Movento ® ; EPA Reg. No. 264 - 1050), for the 1.25 lb ai/gal SC formulation (Ultor® ; EP A 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, b ananas, 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 - ketohydrox y, BYI08330 - enol - Glc, and BYI 08330 - mono - hydroxy , calculated as spirotetramat equivalents, are currentl y 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 soy bean hay . Tolerances are established in 40 CFR §180.641(a)(2) for the combined residues of spirotetramat and its BYI 0833 0 - enol metabolite, calculated as spirotetramat equivalents, in/on the fat, meat, and meat by products of cattle, goat, horse, and sheep; the meat by products 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 - ketohydrox y, BYI08330 - enol - Glc, and BYI 08330 - mono - hydrox y, calculated as spirotetramat equivalents, in/on onion, dry bulb and watercress that expire on 3 1 - DEC - 2014 and 31 - DEC - 2015, respectively . **Table 3.3.1. Summary of Proposed End -**  **Use Products.** Trade Name Reg.

No. ai (% of formulation) Form

ulation Ty pe Target Crops Target Pests Label Date Movento ® 264 -

1050 22.4 SC taro, watercress, pomegranates, bananas, bulb vegetables, low growing berries (except straw berries), bushberries, globe artichokes, fruiting vegetables, pome fruit, citrus fruit, pineapples, and coffee. sucking insects Draft labels

submitted 7/24/12 Ultor® 264 -

1065 14.5 SC BYI 8330 OD 264 -

1051 15.3 OD **Table 3.3.2. Summary of Directions for Use of Spirotetram at.**  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

Li mitations **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 aerialSpirotetramat Human - Health Risk Assessment DP# 398509

Page 14 of 44 **Table 3.3.2. Summary of Directions for Use of Spirotetram at.**  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

Li mitations **Bushberry subgroups 13 -**  **07B and 13 -**  **07H**

Aerial and Gr oundboom 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 Gr oundboom 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 **Pom egranate**  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, Gr oundboom, 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 artichok**

**e** Aerial, Gr oundboom, 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, Gr oundboom, 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 aerialSpirotetramat Human - Health Risk Assessment DP# 398509

Page 15 of 44 **Table 3.3.2. Summary of Directions for Use of Spirotetram at.**  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

Li mitations **Additional Restrictions for all Crops:** Movento ® and Ultor® must be tank - mixed with a spray adjuvant/additive. BYI 8330 OD may not be tank - mixed with a spray adjuvant/additive having sticking properties. Use in enclosed structures, such as greenhouses or planthouses, is not permitted. Rotational crop PBI s: 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 wa s 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 directl y 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 fo r 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, particularl y for the dietary expos ure 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 L ow - 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 subgr oups 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 th at 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; 200 3 - 2008) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized by subgroups based on age, season of the ye ar, ethnic group, and region of the country . Additionally , OPP is able to a ssess 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 andSpirotetramat Human - Health Risk Assessment DP# 398509

Page 16 of 44 expertise to the development of specialized software and models that consider exposure to by standers 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 ketoeno l insecticides. The proposed insecticidal mode of action for these agents is based on inhibition of acetyl - CoA carboxylase, a key enzy me in fatty acid biosy

nthesis in eukaryotes and prokaryotes. Inhibition of lipogenesis, resulting in decreased lipid content (notably trigl ycerides 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 pla sma lipid parameters such as plasma levels of trigl ycerides 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 repo rted 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 - 20 12 (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 orall y- 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). S ys temic exposure estimated by the area under the plasma concentration - time curve (AUC 0 - ∞ ) 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 completel y 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 demethyl ation 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 adm inistered dose eliminated via urine and 2 - 11% via feces b y 48 hours of exposure. **4.2.1 Dermal Absorption**  An in vivo dermal - penetration study in the rat was performed using the formulation OD150. ASpirotetramat Human - Health Risk Assessment DP# 398509

Page 17 of 44 dermal - absorption factor (DAF) of 10% was estimated base d 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 thy roid 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 thy roid 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 ye ar study . The onl y histopath ological change in the thy roid 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, thy roid histopathology , or thyroid - stimulating hormone (TSH) in either sex. In all three dog studies (28 - day , 90 - day , and 1 - ye ar), there were decreases in thy mus weights described microscopically as involution. In the one - year chronic study, the thy mus 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 epididym is, decreased testicular weight, and testicular degeneration and vacuolation were observed in males after 90 day s of exposure at 10,000 ppm (6 16 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 epididy

mis were observed in male rats at the high dose onl y (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 F 1 generation in the two - generation reproductive toxicity study in rats. It should be noted that the thy roid and thy

mus were unaffected in rats at any dose tested, while te sticular 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 ra bbits. 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 to xicity included a dose dependent increase in late abortions and other clinical signs of s ys temic toxicity such as increased weight loss and impaired food and water consumption.Spirotetramat Human - Health Risk Assessment DP# 398509

Page 18 of 44 The two - generation reproductive toxicity study showed evidence of male reprodu ctive toxicity similar to chronic and subchronic studies with adult rats. Abnormal sperm cells were reported in F 1 - generation m ale 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 an d increased abnormal sperm cells in the epididy mides were observed in F 1 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 epididy

mal sperm counts were observed after 10 day s 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 day s 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 day s at a dose of 800 mg/kg bw/day . Spermatotoxicity , abnormal sperm, and Sertoli cell vacuolation were observed in the testes - epididy mides 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 s ys temic) reported at the limit dose. Spirotetramat tested positive for dermal sensitization, which was supported by two cases of T yp e IV hyp ersensitivity that were report ed 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 onl y evidence of neurotoxicity was based on decreased motor and locomotor activity which occurred onl y at relativel y high - dose levels (200 mg/kg bw). A s 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 recentl y submitted SCN study where spirotetramat was administered to rats via the diet does not indicate neurot oxicity

even at the highest doses tested of 585 and 707 mg/kg bw/day for males and females, respectivel y. Although the toxicology

database for spirotetramat shows effects in the thymus gland in dogs, the results of a recentl y s ubmitted and reviewed immuno toxicity 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 thymusSpirotetramat Human - Health Risk Assessment DP# 398509

Page 19 of 44 involution in dogs was secondary to the thy roid effects, rather than a direct effect on the immune sy stem. 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 assay s. **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 provi ded 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 relativel y high doses [lowest - observed adverse - effect level (LOAEL) of 200 mg/kg bw] . In addition, a preliminary

review of the recentl y submitted SCN does not indicate a concern for neurotoxicity even at very

high dose levels administered to rats through the diet. Finall y, the conclusion that spirotetramat is not a neurotoxic chemical i s 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 Sensi** **tivity/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 s ame 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/ris ks will not be underestimated.Spirotetramat Human - Health Risk Assessment DP# 398509

Page 20 of 44 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 th e 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 assessment s 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 spirote tramat. 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 unce rtainty 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 uncertaintie s for pre - and / or postnatal susceptibility . Thus, the acute reference dose (aRfD) and population - adjusted dose (aPAD) are e quivalent at 1.0 mg/kg bw. Chronic Dietary (All Populations ) : This dietary

endpoint was based on the thy mus 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 - ad justed dose (cPAD) are e quivalent 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 l oss 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.Spirotetramat Human - Health Risk Assessment DP# 398509

Page 21 of 44 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) extrapo lation, 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 perf ormed 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**  **Asses sm**  **ent Table 4.5.4.1. Summ**  **ary of Toxicological Doses and Endpoints for Spirotetram at**  **for Use in Dietary Hum an**  **** **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 UF A = 10X

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

UF H = 10X UF FQPA = 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, UF A = extrapolation from animal to human (interspecie s), UF H = potential variation in sensitivity among members of the human population (intraspecies), UF FQPA = FQPA Safety Factor, NOAEL = no - observed adverse - effect level, LOAEL = lowest observed adverse - effect level, RfD = reference dose (a = acute, c = chronic), PAD = population - adjusted dose, LOC = level of concern. 1 The cRfD has been harmoniz ed 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.Spirotetramat Human - Health Risk Assessment DP# 398509

Page 22 of 44 **Table 4.5.4.2. Summ ary of Toxicological Doses and Endpoints for Spirotetram**  **at for Use in Occupational**  **Hum an**  **- 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% UF A = 10X

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

mg/kg/day 100% absorption assumed UF A = 10X

UF H = 10X Occupational LOC for MOE <100 **Prenatal developmental toxicity (rabbit)**  Maternal LOAEL = 40 mg/kg/day based on late abortion ( ≥GD 22) , clinical signs , impaired food and water consumption and body- weight loss. Cancer (oral, dermal, inhalation) Classification: “not likely to be carcinog enic to humans” based on lack of evidence of carcinogenicity in two

oral rodent carcinogenicity studies. Abbreviations: UF = uncertainty factor, UF A = extrapolation from animal to human (interspecies), UF H = potential variation in sensitivity among members of the human population (intraspecies), 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 resid ues 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 Cr ops):**  The residues of concern are spirotetramat and its metabolites BYI 08330 - ketohydrox y and free and conjugated BYI 08330 - desmethyl - ketohydrox y, BYI 08330 - desmethyl - di - hydroxy , and BYI 08330 - ketohydrox y- alcohol (Memo, J. Tyler, et al. , 14 - MAY 2008; D333 437). **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 - ketohydrox y (Memo, J. Tyl er, 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 residueSpirotetramat Human - Health Risk Assessment DP# 398509

Page 23 of 44 of concern since it was never found at a level of >10% of the total residue. **Table 5.1. Summ ary 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 Pla nts 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 GA2 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 BY I 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 sy stemic (xylem and phloem mobile). The submitted magnitude of the residue data for the raw agri cultural 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 f or 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, glob e artichoke, green onions, pineapple, and sweet corn forage with increasing PHI s. The residue - decline data indicate that the residues of concern increased with increasing PHI s for coffee, and remained fairl y stable for dry bulb onion and sweet corn stover . For pomegranate and pineapple, residues of the metabolites BYI 08330 - enol, BYI 08330 - ketohydroxy , BY I 08330 - monohydrox y, 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 proces sing 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 pin eapple 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 -Spirotetramat Human - Health Risk Assessment DP# 398509

Page 24 of 44 bean with pod) which demonstrat e stability of residues of spirotetramat, BYI 08330 - enol, BYI 08330 - enol - Glc, BYI 08330 - ketohydrox y, and BYI 08330 - mono - hydrox y for up to 718 day s 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 reasonabl y 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 - ketohydrox y, BYI 08330 - desmethyl ketohydroxy , BY I 08330 - desmethyl - di - hydrox y and BYI 08330 - ketohydrox y- 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 currentl y proposed uses. The proposed use rate for watercress is 0.4 lb ai/A; th erefore, 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 surf ace EDWCs for spirotetramat and the major transformation products, spirotetramat - enol and spirotetramat - ketohydrox y (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 pp m 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 esti mate. 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 b y the Tier 1 Rice Model.Spirotetramat Human - Health Risk Assessment DP# 398509

Page 25 of 44 **Table 5.3. Maxim um** **Tier I EDWCs Based on Ground or Aerial Application of Spirotetram**  **at 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 1 TTR = t otal t oxic 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 i**  **n 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 process ing factors (where provided). Drinking water estimates were provided b y 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 analy ses 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 R** **isk 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 populatio n subgroup children 1 - 2 years old, which utilized 76% of the cPAD for spirotetramat. The chronic exposure estimate for theSpirotetramat Human - Health Risk Assessment DP# 398509

Page 26 of 44 general U.S. population utilized 36% of the cPAD. A summary table of dietary

exposure and risk for spirotetramat can be found in Se ction 5.4.6. Although further refinement to the anal ys is 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 carcin ogenic to humans.” **5.4.6 Summary Table**  **Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure Risk for Spirotetram at**  **1 .**  Population Subgroup Ac ute 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 -** **A pplication 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 nearb y 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 1 . 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, sub sequently , the way to incorporate post - application inhalation exposure into the Agency's risk assessments. If new policies or procedures are developed, then the Agency

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

1 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlSpirotetramat Human - Health Risk Assessment DP# 398509

Page 27 of 44 assessment for spirotetramat. **6. 2**  **Spray Drift** Spray drift is alway s 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 metho d 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 information2 . The Agency has completed its evaluation of the new database submitted by the Spray

Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriatel y apply

the data and the AgDRIFT ® computer model to its risk assessments for pesticides applied b y 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 - targ et 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. S pirotetramat 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 cons umption 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 diet ary 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 b y the Tier 1 Rice Model v.1.0. **7.2 Chron**  **ic Aggregate Risk** The chronic aggregate risk assessment takes into account average exposure estimates from dietary consumption of spirotetramat (food and drinking water). The chronic dietary exposure estimates are not of concern to HED (<100% cPAD) for the general U.S. population and all 2 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htmSpirotetramat Human - Health Risk Assessment DP# 398509

Page 28 of 44 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 b y other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that spirotetramat has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to de termine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by

EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for 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, appl ying, 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, ai rblast, groundboom, and chemigation applications, applying spray s 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 o f 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 e xposure that are used in this assessment, known as “unit exposures,” are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table 3 ,” which, along with additional information on HED policy on use of surrogate data, including d escriptions of the various sources, can be found at the Agency website 4

. 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 l ong - sleeved 3 Available: http://www.epa.gov/opp00001/science/handler - exposure - table.pdf 4 Available: http://www.epa.gov/pesticides/science/handler - exposure - data.htmlSpirotetramat Human - Health Risk Assessment DP# 398509

Page 29 of 44 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 onl y data available is for exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the engineering control (encl osed 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 de cades. According the 2012 National Agricultural Aviation Association (NAAA) survey of their membership, the use of the Global Positioning S ys tem (GPS) for swath guidance in agricultural aviation has grown steadil y from the mid 1990s. Over the same time p eriod, the use of human flaggers for aerial pesticide applications has decreased steadil y 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 an d characterize the exposure potential for human flaggers in agricultural aerial applications.Spirotetramat Human Health Risk Assessment DP# 398509

Page 30 of 44 **Table 9.1.1. Short**  **- /Interm**  **ediate -**  **Term Occupational Exposure and Risk Estimates for Spirotetram**  **at .**  Exposure Scenario Crop or Target Dermal Unit Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application Rate (lb ai/A) 2 Area

Treated Daily (acres) 3 Dermal Inhalation Total Mitigation Level Mitigation

Level Dose (mg/kg/day) 4 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 4,900Spirotetramat Human Health Risk Assessment DP# 398509

Page 31 of 44 **Table 9.1.1. Short**  **- /Interm**  **ediate -**  **Term Occupational Exposure and Risk Estimates for Spirotetram**  **at .**  Exposure Scenario Crop or Target Dermal Unit Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application Rate (lb ai/A) 2 Area

Treated Daily (acres) 3 Dermal Inhalation Total Mitigation Level Mitigation

Level Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8 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 13,000Spirotetramat Human Health Risk Assessment DP# 398509

Page 32 of 44 **Table 9.1.1. Short**  **- /Interm**  **ediate -**  **Term Occupational Exposure and Risk Estimates for Spirotetram**  **at .**  Exposure Scenario Crop or Target Dermal Unit Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application Rate (lb ai/A) 2 Area

Treated Daily (acres) 3 Dermal Inhalation Total Mitigation Level Mitigation

Level Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8 Flagger

Flagging for Aerial Applications Banana, Plantain 11 (baseline) 0.35 (baseline) 0.25

350 0.0014 7,100 0.000443 23,000 5,400

Watercress 0.2 0.00112 8,900 0.000355 28,000 6,800 Bushberry subgroups 13 - 07B and 13 - 07H, Coffee, Pineapple, Pomegranate, 0.16 0.000893 11,000 0.000284 35,000 8,400 Globe artichoke 0.13 0.000726 14,000 0.00023 43,000 11,000 Bulb vegetables subgroups 3 - 07A and 3 - 07B 0.08 0.000446 22,000 0.000142 70,000 17,000 1 Based on “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2012); includes data from PHED/ORETF/AHETF (level of mitigation: Baseline for all scenarios except for aerial applicators which is assessed using eng. controls). 2 Based on proposed labels (Reg. Nos. 264 - 1050, 264 - 1065, 264 - 1051). 3 Exposure Science Advisory Council (ExpoSAC) Policy #9.1. 4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre) x Area Treated (A/day) x DAF (10%) / BW (69 kg). 5 Dermal MOE = Dermal NOAEL (10 mg/kg/day)/Dermal Dose (mg/kg/day). 6 Inhalation Dose = I

nhalation Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre) x Are a Treated (A/day) / BW (69 kg). 7 Inhalation MOE = I

nhalation NOAEL (10 mg/kg/day)/I nhalation Dose (mg/kg/day). 8 Total MOE = NOAE L (10 mg/kg/day)/Dermal Dose + I nhalation Dose.Spirotetramat Human - Health Risk Assessment DP# 398509

Page 33 of 44 **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 RTI s 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 e xposure. 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 s tandard 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/sc ience/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 currentl y assigned a crop group and/or transfer coefficients in ExpoSAC Policy 3. According to USDA’s Crop Profiles for coffee, this crop is described as a small evergreen tree. 5 Therefore, the activities and transfer coefficients assigne d 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 anal yz ed 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 (F AR). This default value is 25% and is based on an analy sis of 19 DF R studies where the F AR value ranged from 2% to 89%. This value is recommended for use in both residential and occupational post application assessments. Of the anal yz ed DFR studies, the maximum F AR value seen was 89% or 3.6 times higher than the default residue transfer value. Therefore, the HED has decided that a calculated MOE of approximately 4 times higher than the LOC (e.g., an MOE > 400 if the LOC = 100) using the default dislodged residue values would provide an adequate margin of safety for 5 Available: http://www.ipmcenters.org/cropprofiles/docs/hicoffee.pdfSpirotetramat Human - Health Risk Assessment DP# 398509

Page 34 of 44 any potentially

higher residues seen in a chemical - specific DFR study ( Guidance for Requiring/W

aiving 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 Interm ediate**  **- term** **Occupational/Commercial Post**  **- application Risk**  **Estimates for Spirotetram at.**  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 1,400Spirotetramat Human - Health Risk Assessment DP# 398509

Page 35 of 44 **Table 9.2.1. Summary of Short -**  **and Interm ediate**  **- term** **Occupational/Commercial Post**  **- application Risk**  **Estimates for Spirotetram at.**  Crop/Site Activities Transfer Coefficient (cm 2/hr) DFR/TTR 1 Dermal Dose

(mg/kg/day) 2 MOE 3 Hand set irrigation 1,900 0.0124 810 1 DFR = Application Rate × F × (1 - D) t × 4.54E8 μg/lb × 2.47E - 8 acre/cm2 ; where F = 0.25 and D = 0.10 per day. 2 Daily Dermal Dose = [DFR (μg/cm2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (%)]  BW (kg). 3 MOE = POD (mg/kg/day) / Daily Dermal Dose. Daily Dermal Dose = [DFR/TTR (μg/cm2 ) × TC × 0.001 mg/μg x 8 hrs/day × dermal absorption]  BW (kg). 4 For activities common to both pineapple and globe artichoke, only doses and MOE for the higher pineapple rat e 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 T oxicity 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 REIof 24 hours is adequate to protect agricultural workers from post - applicatio n exposures to spirotetramat . The proposed labels for spirotetramat include an REIof 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 source s 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 pesticide s. 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 6

. The Agency is in the process of evaluating the SAP report as well a s available post - application inhalation exposure data generated b y 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 expos ure than post - application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post - application inhalation exposure scenarios.

6 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlSpirotetramat Human - Health Risk Assessment DP# 398509

Page 36 of 44 **10.0 References**  Previous Risk Assessments: J. Tyle r, 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 W

ater 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. Phy sical/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 - JA N - 2013) J. Van Alstine: S - 10951: Potomac Yard 1 (PY1): (703)603 - 8866: 7509P: RAB1Spirotetramat Human - Health Risk Assessment DP# 398509

Page 37 of 44 **Appendix A. Toxic ology 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 Ac ute Oral Toxicity 870.1200 Ac ute Dermal Toxicity 870.1300 Ac ute 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 Ac ute Delayed Neurotox. (hen) 870.6100b 90 - Day

Neurotoxicity (hen) 870.6200a Ac ute 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

Ac ute Oral (rat) ................................ ........................... Subchronic Oral (rat) ................................ .................. Six - mo nth 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.Spirotetramat Human - Health Risk Assessment DP# 398509

Page 38 of 44 **A.2 Toxicity Profiles**  **Table A.2.1. Acute Toxicity Profile –**  **Spirotetram at Technical.**  Guideline No. Study T ype MRID(s) Results Toxicity Category 870.1100 Ac ute oral (rat) 46904527 LD 50 >2000 mg/kg (F) III 870.1200 Ac ute dermal (rat) 46904529 LD 50 >2000 mg/kg (M&F) III 870.1300 Ac ute inhalation (rat) 46904530 LC 50 >4.183 mg/L (M&F) IV 870.2400 Primary eye irritation (rabbit) 46904531 Corneal opacity and iritis (grade 1); cleared by day 8 II 870.2500 Primary dermal irritation (rabbit) 46904532 Negative IV 870.2600 Dermal sensitization (mouse) 46904565 Positive (LLNA) N/A **Table A.2.2. Subchronic and Chronic Toxicity and Genotoxicity Profile –**  **Spirotetramat Technical.** Guideline No. Study T ype 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 emaciati on. 870.3150 90 - Day

oral toxicity (dog) 46904541 (2005)

Acceptable/guideline NOAEL = 1200 (32 mg/kg/day) [F] & 2500 ppm (81 mg/kg/day) [M].Spirotetramat Human - Health Risk Assessment DP# 398509

Page 39 of 44 0, 150, 300, 1200, or 4000/2500 ppm (equivalent to 0/0, 5/6, 9/10, 33/32, or 81/72 mg/kg bw/day) LOAEL = 2500 ppm (72 mg/kg/day) [F] based on decreased body - weight gain and food consumption, depressed RBC parameters (red blood cell count, hemoglobin level and hematocrit), and thymus atrophy. 870.3200 28 - Day

dermal toxicity (rat) 46904542 (2006)

Acceptable/guideline 0, 100, 300, or 1000 mg/kg bw /day (limit dose) NOAEL = 1000 mg/kg/day. LOAEL not established. 870.3700a Prenatal

developmental (rat) 46904543 (2004)

Acceptable/guideline 0, 20, 140, or 1000 mg/kg bw /day **Maternal** NOAEL = 140 mg/kg/day. LOAEL = 1000 mg/kg/day based on im paired food consumption, transient body weight loss, impaired body- weight gain, and reduced final body weight. **Developm ental**  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 , im paired food and water consumption, and body weight loss. **Developm ental**  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/System ic**  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 fe males) and terminal body weight (F 1 males). **Reproductive** NOAEL = 500 ppm (27.8 mg/kg bw/day [M]) and 10,000 ppm (645.7 mg/kg/day) [F]. LOAEL = 6,000 ppm (320.1 mg/kg bw/day [M]) based on decreased sperm motility and progression and increased abnormal sperm cells in the F 1 males. **Offspring** NOAEL = 500 ppm (27.8 and 31.4 mg/kg bw/day [M/F]). LOAEL = 6,000 ppm (320.1 and 384.1 mg/kg bw/day [M/F]) based on decreased body weight and body - weight gain during lactation in F 1 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/System ic**  NOAEL = 1000 ppm (70.7/82.5 mg/kg/day [M/F]). LOAEL = 6000 ppm (419.3/484.7 mg/kg/day [M/F]) based on decreases in body weight (F 1 males and females), weight gain (P males, F 1 males and females), and food consumption during lactation (P - and F 1 - generation females), and kidney histopathology and decrea sed kidney weights (F 1 males and females) . **Reproductive** NOAEL = 1000 ppm (70.7Spirotetramat Human - Health Risk Assessment DP# 398509

Page 40 of 44 mg/kg/day) [M] & 6000 ppm (484.7

mg/kg/day) [F]. LOAEL = 6000 ppm (419.3 mg/kg/day) [M] based on abnormal sperm cells and decreased reproductive performance in the F 1 males. **Offspring** NOAEL = 1000 ppm (70.7/82.5 mg/kg/day [M/F]). LOAEL = 6000 ppm (419.3/484.7 mg/kg/day [M/F]) based on decreased body weight and body- weight gain during lactation in both F 1 and F 2 generations . 870.4100 Chronic toxicity (1

year; dog) 46904548 (2 006)

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- we ight gain, alveolar macrophages, discoloration of the lung, and yellow/brown stainin g of the perigenital area and tail. 870.4200 Carcinogenicity

(rat) 46904549 (2006)

Acceptable/guideline 0, 250, 3500, or 7500/12000 ppm (M/F) (equivalent to 0/0, 12.5/16.8, 169/229, or 373/823 mg/kg bw/day [M/F]) NOAEL = 250 ppm (12.5/16.8 mg/kg/day [M/F]). LOAEL = 3500 ppm (169/229 mg/kg/day [M/F]) based on decreased kidney weight and renal tubular dilation. No evidence of carcinogenicity. 870.4200 Carcinogenicity

(mouse) 46904550 (2006)

Acceptable/guideline 0, 70, 1700, or 7000/6000 ppm (M/F) (equivalent to 0/0, 10.9/13.7, 263/331, or 1022/1319 mg/kg/day [M/F]) NOAEL = 7000/6000 ppm (1022/1319 mg/kg/day [M/F]). LOAEL not observed. No evidence of carcinogenicity. 870.5100 Bacterial Gene

Mutation 46904551 (2006)

Acceptable/guideline 0, 16, 50, 158, 500, 1581, or 5000 μg/plate +/ - S9 activation Negative.

870.5100 Bacterial Gene

Mutation 46904552 (2002)

Acceptable/guideline 0, 16, 50, 158, 500, 1581, or 5000 μg/plate +/ - S9 activation Negative.

870.5300 Mammalian Gene

Mutation 46904553 (2002)

Acceptable/guideline 0, 2.5, 5, 10, 20, 30, 40, 50, 60, 70, or 80  g/mL ( - S9) 0, 20, 40, 60, 80, 92, 100, 108, 116, 120, 124, 132, or 140 Negative.Spirotetramat Human - Health Risk Assessment DP# 398509

Page 41 of 44  g/mL (+S9) 870.5375 In vitro mammalian

chromosome aberration 46904554 (2002)

Acceptable/guideline 0, 10, 12, 24, 30, 48, or 50 μg/mL ( - S9) 0, 20, 40, or 80 μg/mL (+S9) Weakly clastogenic at cytotoxic concentrations only. 870.5375 In vitro mammalian

chromosome aberration 46904555 (2003)

Unacceptable/guideline 0, 30, 50, 70, 90, or 110 μg/mL ( - S9) 0, 40, 60, 80, 100, or 120 μg/mL (+S9) N/A

870.5395 In vivo erythrocyte

micronucleus assay (mouse) 46904556 (2002)

Acceptable/guideline 0, 125, 250, or 500 mg/kg bw Negative. 870.5385 In vivo bone

marrow chromosomal aberration assay (mouse) 46904558 (2003)

Acceptable/guideline 0, 125, 250, or 500 mg/kg bw Negative.

870.5550 In vivo / in vitro UDS

assay (rat hepatocytes) 46904557 (2003)

Acceptable/guideline 0, 1000, or 2000 mg/kg bw Negative. 870.6200a Ac ute 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 mo tor 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: AUC 0 - ∞ (measure of systemic exposure) slightly higher for males than females; <0.2% of administered dose detected in body 48 hrs after sacrifice; highest equivalent concentrations detected in liver and kidney. Metabolis m: 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 cou ld be derived from enol; male rats exhibited much higher rates of demethylation of BYI 08330 - enol to BYI 08330 - desmethyl - enol (25 - 37%) vs. females rats (5 - 10%). Excretion: 88 - 95% of administered dose eliminated via urine and 2 - 11% via feces within 48 hrs. 870.7485 Metabolism and

pharmacokinetics 46904561 (2006)

Acceptable/guideline At 1000 mg/kg bw: Absorption and excretion less than low dose, with 27% ofSpirotetramat Human - Health Risk Assessment DP# 398509

Page 42 of 44 **Table A.2.3. USEPA Toxicity Profile –**  **Metabolites.** Guideline No. Study T ype 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- we ight gain; histopathology not evaluated. Special study 21 - day gavage

(enol metabolite) 47070901 (2006)

Acceptable/non - guideline 800 mg/kg bw/day Clinical signs of toxicity, decreased bodyweight gain, testicular/spermatotoxicity. 870.5100 Bacterial Gene

Mutation (ketohydroxy metabolite) 46904594 (2005)

Acceptable/guideline 0, 16, 50, 158, 500, 1581, or 5000 μg/plate +/ - S9 activation Negative. (rat) 2 or 1000 mg/kg bw (single) dose excreted in urine after 24 hours (18% in feces); plasma radioactivity slightly higher than in liver and kidney; these results are consistent with saturation of cellular transport mechanisms. Tissue radioactivity decreased from 1 to 24 hours post dose. Metabolism profile qualitatively similar to that of the lo w - dose group; BYI 08330 - enol wa s most prominent metabolite; similar to low - dose group, BYI 08330 - desmethyl - enol levels greater in urine than in plasma and organs. 870.7600 In vivo dermal

penetration (rat) 46904563 (2006)

Acceptable/guideline 100, 15, or 5 μg ai/cm 2 (OD150 formulation) Dermal absorption = 10%. 870.7800 Immunotoxicity

(rat) 48525901 (2011)

Acceptable/guideline 500, 2500, or 12,000 ppm (equivalent to 33, 164, or 795 mg/kg/day) The functional immunotoxicity NOAEL is 12,000 ppm (equivalent to 795 mg/kg/day, the highest dose tested); the LOAEL was not established. The systemic toxicity LOAEL for Spirotetramat in male rats is 12,000 ppm (equivalent to 795 mg/kg bw/day) based on decreased body weights, decreased bodyweight gains, lowered food consumption, lower thymus weight, and observations of atrophic thymus. The NOAEL for systemic toxicity is 2500 ppm (equivalent to 164 mg/kg bw/day) Special study Male reproductive

toxicity 46904569 (2005)

Acceptable/non - guideline 1000 mg/kg bw

/day (3, 10, 21, or 41 days) Primary testicular effects on or after day 10 were degeneration of round and elongating spermatids (stage 7 - 8 and 9 - 14, respectively), decreased sperm count, and increased numbers of aberrant/abnormal spermatozoa in the epididymis.Spirotetramat Human - Health Risk Assessment DP# 398509

Page 43 of 44 **Table A.2.3. USEPA Toxicity Profile –**  **Metabolites.** Guideline No. Study T ype MRID No. (year)/ Classification /Doses Results 870.7485 Metabolism and

Pharmacokinetics (rat) (ketohydroxy metabolite) 46904595 (2006)

Acceptable/guideline 2 mg/kg bw (single) Absorption: ≥55% after 48 hrs. Distribution: highest concentrations detected in GI tract, liver, and kidney; <0.2% of administered dose detected in body 48 hrs post dose. Metabolism: parent compound undetected in urine and trace amounts in feces; main metabolic reaction was oxidative demethylation of cyclohexyl - O - me thyl group to form desmethyl - ketohydroxy metabolite (15% of administered dose); all other identified metabolites could be derived from desmethyl ketohydroxy metabolite. Excr etion: 54% of administered dose eliminated via urine and 44% via feces within 48 hrs. 870.5100 Bacterial Gene

Mutation (desmethyl ketohydroxy metabolite) 46904597 (2006)

Acceptable/guideline 0, 16, 50, 158, 500, 1581, or 5000 μg/plate +/ - S9 activation Negative.

870.5100 Bacterial Gene

Mutation (dihydroxy metabolite) 46904599 (2005)

Acceptable/guideline 0, 16, 50, 158, 500, 1581, or 5000 μg/plate +/ - S9 activation Negative.

870.7485 Metabolism and

Pharmacokinetics (rat) (enol glucoside metabolite) 46904602 (2006)

Acceptable/non - guideline 0.1 mg/kg bw (single; 1 rat) Absorption: 54% after 48 hrs. Distribution: plasma concentrations peaked 4 hrs post dose; 1% of administered dose detected in body 48 hrs post dose. Metabolism: parent compound detected in feces (21%); main metabolite was enol (64% of administered dose). Excretion: 53% of administered dose eliminated via urine and 44% via feces within 48 hrs. 870.5100 Bacterial Gene

Mutation (monohydroxy metabolite) 46904604 (2005)

Acceptable/guideline 0, 16, 50, 158, 500, 1581, or 5000 μg/plate +/ - S9 activation Negative.Spirotetramat Human - Health Risk Assessment DP# 398509

Page 44 of 44 **Appendix B. Physical/Chemical Properties Table B.1.**  **Physicochem ical Properties of the Spirotetramat.** 

Parameter Value Reference Melting point 142 °C EPA Chemical Fact Sheet for Spirotetramat, June 2008 pH 6.3 Density D 4 20 = 1.22 Water solubility (20 oC) pH 4: 33.5 mg/L pH 7: 29.9 mg/L pH 9: 19.1 mg/L Solvent solubility (20 oC) Solvent g/L n - hexane 0.055 Dichloromethane >600 Dimethyl Sulfoxide 200 - 300 Toluene 60 Acetone 100 - 120 Ethyl acetate 67 Ethanol 44 Vapor pressure Extrapolated Values: 5.6 x 10 - 9 Pa (20 oC) 1.5 x 10 - 8 Pa (25 oC) 1.5 x 10 - 6 Pa (50 oC) Dissociation constant, pKa 10.7 Included in MRID 47648203 Octanol/water partition coefficient, Log(KOW) pH 4: 2.51 pH 7: 2.51 pH 9: 2.50 EPA Chemical Fact Sheet for Spirotetramat, June 2008 UV/visible absorption spectrum Peak Maxima Molar Absorptivity (nm) (1000 cm2/ mol) 211 22.0 x 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 b y the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 7

.

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