Azoxystrobin Human Heal th Risk Assessment DP No. 402285

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

MEMORANDUM

Date: 03/21/20 13 OFFICE OF
CHEMICAL S AFETY AND POLLUTION PREVENTION

SUBJECT: Azoxystrobin: Revised Human Health Risk Assessment for Use on Ginseng (Import), Rye, and Oats, and Section 3 Amendments to Revise the Established
Tolerances on Cereal Grains (Barley and Wheat) Due to Changes ofPre

- Harvest
Intervals.

PC Code: 1288IO
Decision Nos.: 458947, 45965I, 460759 Petition Nos.: IE7945, 2F7976, 2 F 7984 Risk Assessment Type: Single ChemicaVAggregate
TXRNo.: NA
MRIDNo.: NA DP Barcodes: D402285, D402289 Registration Nos.: I 00

- 1 09 8, 100-1I 78, I OO-I3 24 Regulatory Action: Section 3 Registration
Case No.: 7020

CAS No.: 13I860

- 33

- 8

40 CFR: §I80.507

FROM: Meheret Negussie, Risk Assessor/Chemist 

## /tcl.erd- ;Jep(: Whang Phang, Senior**Toxi cologis** **~ ~~**  Nancy Tsaur, Chemist**(}{w~** 

## U

Risk Assessment Branch III
Health Effects Division (7509P)

THROUGH: Christine Olinger, Branch

### Chief**t% ~**  /



## . ff '

Risk Assessment Branch Ill ·

### ~**'l~** Health Effects Division (7509P)

TO: Erin Malone/Marcel Howard, RM# 20 Fungicide Branch Registration Division (7505P)

This document and attachments provide an assessment of the human health risk resulting from
the proposed and registered uses of azoxystrobin. The toxicology reevaluation was performed by Whang Phang, t he drinking water assessment was conducted by Ibrahim Abdel-Saheb (EPA
Environmental Fate and Effects Division (EFED)), the occupational and residential exposure

assessment was conducted by Nancy Tsaur and t he review of the residue chemistry data, the dietary expo s ure assessment, and the overall human health risk assessment were conducted by
Meheret Negussie. This document reflects revisions to a previous version (Oct-11-2012) to the
tolerance recommendations

.

Page 1 of37Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 2 of 37 1.0 Executive Summary ........................................................................................................... 4
2.0 HED Recommendations .................................................................................................... 7
2.1 Data Deficiencies ............................................................................................................ 7
2.2.1 Enforcement Analytical Method ............................................................................... 7
2.2.2 International Harmonization ..................................................................................... 7
2.2.3 Recommended Tolerances ......................................................................................... 8
2.2.4 Revisions to Petitioned-For Tolerances .................................................................... 9
2.3 Label Recommendations ................................................................................................ 9
3.0 Introduction ........................................................................................................................ 9
3.1 Chemical Identity ......................................................................................................... 10
3.2 Physical/Chemical Characteristics ............................................................................. 11
3.3 Pesticide Use Pattern .................................................................................................... 11
3.4 Anticipated Exposure Pathways ................................................................................. 13
3.5 Consideration of Environmental Justice .................................................................... 13
4.0 Hazard Characterization and Dose-Response Assessment .......................................... 14
4.1 Toxicological Effects .................................................................................................... 14
4.2 Safety Factor for Infants and Children (FQPA Safety Factor) ............................... 15
4.2.1 Completeness of the Toxicology Database .............................................................. 15
4.2.2 Evidence of Neurotoxicity ........................................................................................ 16
4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ........ 16
4.2.4 Residual Uncertainty in the Exposure Database ................................................... 16
4.3 Toxicity Endpoint and Point of Departure Selections .............................................. 16
4.3.1 Summary of Points of Departure and Toxi city Endpoints Used in Human Health
Risk Assessment ...................................................................................................................... 17
5.0 Dietary Exposure and Risk Assessment ......................................................................... 18
5.1 Metabolite/Degradate Residue Profile ....................................................................... 18
5.1.1. Summary of Metabolism Studies, Enviro nmental Degradation, and Metabolic Pathway Comparison .............................................................................................................. 18
5.1.2 Residues of Concern Summary ............................................................................... 18
5.2 Food Residue Profile .................................................................................................... 19
5.3 Water Residue Profile .................................................................................................. 19
5.4 Dietary Risk Assessment .............................................................................................. 19
5.4.1 Description of Residue Data & Percent Crop Treated Used in Dietary
Assessment

.............................................................................................................................. . 19
5.4.2 Acute Dietary Risk Assessment ............................................................................... 20
5.4.3 Chronic Dietary Risk Assessment ........................................................................... 20
5.4.4 Summary Table ......................................................................................................... 21
6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 21
6.1 Residential Handler Exposure .................................................................................... 21
6.2 Post-Application Exposure .......................................................................................... 23
6.3 Combined Exposure ..................................................................................................... 24
6.4 Residential Bystander Post-Application Inhalation Exposure ................................ 24
6.5 Spray Drift .................................................................................................................... 24
7.0 Aggregate Exposure/Risk Characterization .................................................................. 24
7.1 Acute Aggregate Risk ................................................................................................... 25Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 3 of 37 7.2 Short-Term Aggregate Risk ........................................................................................ 25
7.3 Intermediate-Term Aggregate Risk ........................................................................... 26
7.4 Chronic Aggregate Risk ............................................................................................... 26
7.5 Cancer Aggregate Risk ................................................................................................ 26
8.0 Cumulative Exposure/Risk Characterization ............................................................... 26
9.0 Occupational Exposure/Risk Characterization ............................................................ 26
9.1 Short-/Intermediate-Term Handler Risk ................................................................... 26
9.2 Short-/Intermediate-Term Post-Application Risk .................................................... 28
9.2.1 Dermal Post-Application Risk ................................................................................. 28
10.0 References ......................................................................................................................... 30 Appendix A. Toxicology Profile ................................................................................................ 31
A.1 Toxicology Data Requirements ................................................................................... 31
A.2 Toxicity Profiles ............................................................................................................ 32 Appendix B. Physical/Chemical Properties ............................................................................. 35 Appendix C. International Residue Limit Status Sheet. ........................................................ 36 Appendix D. Review of Human Research ................................................................................ 37Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 4 of 37 1.0 Executive Summary

Azoxystrobin [methyl (2 E )-2-{2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3- methoxyacrylate] is a broad spect rum fungicide used to control plant diseases on agricultural crops, turf and ornamentals, and to control molds and fungi on indoor surfaces. Azoxystrobin belongs to a class of pe sticidal compounds called β -methoxyacrylates, which are derived from the naturally occurring strobiluri ns. Its biochemical mode of action is inhibition of electron transport.

Syngenta Crop Protection, Inc. (Syngenta) has proposed azoxystrobin uses on ginseng (import), oats, and rye. Concurrently, S yngenta is requesting to amend the pre-harvest interv als (PHIs) of the registered labels for cereals (wheat, barley, a nd triticale) from 14-30 days to 7 days for forage and hay and to remove the 45-day PHI for grain and straw and replace it with a growth stage restriction for the last applica tion. The limitation is to apply th e last applicati on no later than Feekes Growth Stage 10.54. The most recent hu man health risk assessment was conducted to evaluate azoxystrobin use on sugarcane (K. Ru ry, D389702, 01/18/2012). Since the last risk assessment, no additional hazard data have been submitted. In accordance with the 2007 revised 40 CFR Part 158 Toxicology data requirements, a subchronic inhalation toxicity study and an immunotoxicity study were require d for azoxystrobin. The Agency has waived the inhalation toxicity study data requirement for az oxystrobin at this time (TXR# 0056307). An immunotoxicity study remains re quired for azoxystrobin.

Use Profile For ginseng, azoxystrobin SC (suspension conc entrate) Ortiva is proposed for four foliar applications at 10 mL formulated product/20 mL water with a 7-day pre-harvest interval (PHI). The maximum application rate is 1519 g ai/ha (1.36 lb ai/A). Add itional information was received: azoxystrobin conten t changed from 20% to 21.7%; application spray volume (3500 L/ha); product rate (1750 g (ml)/ha); a nd single application ra te (379.75 g/ha) (email communication Erin Malone, 10/09/12). Based on these information, the maximum seasonal application rate is 1519 g ai/ha (1.36 lb ai/A).

Azoxystrobin is proposed for use as a foliar ap plication on cereal gr ain crops using ground, aerial, and chemigation equipment. The use pr ofile is summarized in Table 3.3. The proposed application rates on cereals (wheat , triticale, barley, oats, and ry e) range from 0.07-0.20 lb ai/A or (4-12.0 fl oz product/A) with a maximum se asonal application rate of 0.40 lb ai/A for
Abound® Flowable Concentrate and 0.03-0.13 lb ai/A or (7-14 fl oz product/A) with a maximum seasonal application rate of 0.13-0.26 lb ai/A for Quilt Xcel® and Quilt®. The Abound®, Quilt Xcel®, and Quilt® labels specify that no more than 0.40 lb ai/A of any azoxystrobin containing products should be a pplied per season and no more than 2 foliar applications should be applied pe r season. All labels require a 7-day PHI for forage and hay. There is a growth stage restricti on for the last application to not apply later than Feekes Growth Stage 10.54 (BBCH 71).

In addition, Syngenta is requesting to add oats and rye use on three azoxystrobin manufacturing products: Azoxystrobin Manufact uring Use Concentrate (MUC ) (EPA Reg. No. 100-1119), Azoxystrobin Dry Technical Manuf acturing Use Concentrate (MUC ) (EPA Reg. No. 100-1120),Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 5 of 37 and Azoxystrobin Millbase Manufacturing Us e Product (MUP) (EPA Reg. No. 100-1220).

Toxicity/Hazard The risk assessment for azoxystrobin is based on a well-characterized and nearly complete toxicology database, with the exception of an immunotoxicity study and an inhalation toxicity study; however, the Agency has waived the inhala tion toxicity study data requirement at this time (TXR# 0056307). In a 21-day repeated dose derm al study in the rat, no dermal or systemic toxicity was seen at the limit dose. In repeat- dose oral studies, the live r and bile ducts were consistently the target organs of azoxystrobin toxicity. No deve lopmental effects were seen in rabbit or rat developmental toxicity studies and no reproductive or offspring effects were seen in the 2-generation rat reproduction study. Alt hough azoxystrobin induced a weak mutagenic response in the mouse lymphoma assay, the activity expressed in vitro is not expected to be expressed in whole animals ( in vivo ). Azoxystrobin is classified as “not likely to be carcinogenic
to humans.”

Azoxystrobin has a low order of acute toxicity via oral, dermal and inhalation routes of exposure as demonstrated by the toxicity cat egories (III & IV). Azoxystrobin is not an eye or skin irritant
and is not a skin sensitizer.

To account for the use of a lowest observed adverse effect level (LOAEL) from the acute neurotoxicity study in rats, the Agency believes that a 3X FQPA SF (Food Quality Protection Act (FQPA) Safety Factor (SF) (as opposed to a 10X) will be adequate to extrapolate a no observed adverse effect level (NOA EL) in assessing acute risk. No additional safety factor is needed for short-term, intermediate-term, and chronic risk assessment. Although an immunotoxicity study is needed to complete the t oxicological database, there are no concerns for immunotoxicity based on the resu lts of the existing studies. Th ere are no indications in the available studies that organs associated with i mmune function, such as the thymus and spleen, are affected by azoxystrobin, and azoxystrobin does not belong to a class of chemicals that would be expected to be imm unotoxic. The selected toxicity endpoints and PODs for risk
assessment are based on the most sensitive and relevant data.

Dietary Exposure (Food and Water) The residue chemistry data and environmental fate data are adequate to assess human exposure.
The assessments are based on reliable data and will not underestimate expo sure or risk. The estimated drinking water concentrations (EDW Cs) have not changed since the last risk assessment (K. Rury, D389702, 01/18/2012) from the turf application scenario (currently registered). The highest EDWCs for all proposed and registered we re incorporated directly into the dietary assessment. A partially refined acu te dietary assessment was conducted using 100% crop treated (%CT) estimates, tolerance-level resi dues (for all commodities except citrus fruit) and empirical or Dietary Exposure Evaluati on Model – Food Commodity Intake Database (DEEM-FCID) default processing factors. The resu lts of the acute dietar y analysis for food and drinking water show that the acute dietary risk estimates are belo w the Agency’s level of concern (LOC) (<100% of the acute population adjusted dose (aPAD)) for all pop ulation subgroups and were estimated at 17% of the aPAD for the gene ral U.S. population and 41% of the aPAD for the most highly exposed population s ubgroup (children 1-2 years old). A partially refined chronic dietary assessment was conducted using toleranc e-level residues, averag e % CT estimates andAzoxystrobin Human Health Risk Assessment DP No. 402285

Page 6 of 37 empirical or default DEEM-FCIDTM processing f actors. The results of the chronic dietary analysis for food and drinking wate r indicate that the ch ronic dietary risk estimates are below the Agency’s LOC (<100% of the chronic populatio n adjusted dose (cPAD)) for all population subgroups and were estimated at 7% of the cPAD for the general U.S. population and 17% of the cPAD for the most highly exposed population su bgroup (children 1-2 years old). Azoxystrobin is classified as “not likely to be carcinogenic to humans;” th erefore, a cancer dietary risk assessment was not performed.

Residential Exposure No new residential uses were requested in this petition. However, az oxystrobin is currently registered for use on several resi dential/non-agricultural use sites. Residential exposure and risks
from use on turf and indoor surfaces were r eassessed using the updated 2012 HED Residential Standard Operating Procedures (SOPs). All asse ssed residential risk estimates resulted in margins of exposure (MOEs) > 100; and theref ore, are not of concern to HED.

Occupational Exposure Based on the proposed use pattern of azoxystrobin on cereal grains, there is a potential for shortand intermediate-term occupational exposure du ring handling (mixing, lo ading, and applying) and post-application activities. Chronic exposure is not expected for the propos ed use patterns. The results of the occupational handler exposure and risk assessment estimates indicate that
short- and intermediate-term inhalation MOEs are not of concern to HED (i.e., MOEs > 100) with baseline mitigation. The short-term inhalation MOEs range from 38,000 to 570,000 for occupational handlers. The intermediate-term MOEs range from 30,000 to 460,000 for occupational handlers. Although occupational derm al exposure is expected following treatment of cereal grain crops, dermal hazard was not identified for azoxystrobin. Therefore, a quantitative post-application derm al risk assessment was not conducted. Based on the Agency's current practices, a quantitative non-cancer oc cupational post-applica tion inhalation exposure assessment was not performed for azoxystrobin at this time. If new po licies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for azoxystrobin . A chemical-specific dislodgeable foliar residue (DFR) study is available for the use of azoxystrobin on grapes, but has not been employed in this or previous risk assessments because HED determined there is no hazard via
the dermal route.

Review of Human Research This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pest icide or other chemical. Thes e data, including studies from the Pesticide Handlers Exposure Database Versi on 1.1 (PHED 1.1), the Agricultural Handler Exposure Task Force (AHETF) database, the Outdoor Residential Exposure Task Force (ORETF) database, and the Agricultural Re-entry Task Force (ARTF) da tabase, are subject to ethics review pursuant to 40 CFR 26, have re ceived that review, and are compliant with applicable ethics requirements. For certain studi es, that review may have included review by the
Human Studies Review Boar d. Descriptions of data sources as well as guidance on their use can
be found at http://www.epa.gov/pesticides/scien ce/handler-exposure-data.html and http://www.epa.gov/pesticides/sci ence/post-app-exposure-data.html

.Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 7 of 37 2.0 HED Recommendations

Pending submission of a revised Section F, ther e are no residue chemistry issues that would preclude granting tolerances for combin ed residues of azoxystrobin and the Z -isomer in/on ginseng (import), oat, and rye. HED also re commends revising the established tolerances on wheat and barley as li sted in Section 2.2.3.

2.1 Data Deficiencies

The following data are required:

870.7800 Immunotoxicity Study

 In 2007, the Agency revised 40 CFR Part 158.500 Toxicology data requirements to include functional immunotoxicity testing and granted a 2-year grace period to allow time for registrants to develop the required data . Syngenta estimated that the immunotoxicity study would be completed in November 2011. The immunotoxicity stud y is required for azoxystrobin under Registration Review and is due in 2012. A waiver request has been submitted and is currently under review.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate residue analytical methods are available for tolerance enforcement: a gas chromatography method with nitrogen-phosphorus detection (GC/NPD), RAM 243/04, for the analysis of crop commodities with azoxystrobin and its Z- isomer; and a GC-NPD method, RAM 255/01, for analysis of livestock commod ities for residues of azoxystrobin.

2.2.2 International Harmonization

The residue definitions for plants and livestock are not harmonized with Codex; the US and the
Canadian residue definitions include both the predominant E isomer and the minor Z isomer
whereas the Codex includes only the E isomer.

Codex maximum residue limits (MRLs) are esta blished for azoxystrobin on ginseng at 0.1 ppm and dry ginseng including red ginseng at 0.5 ppm. A proposed MRL ginseng, processed products at 0.5 ppm has been returned to JMPR fo r further consideration of the processing study (Report of the 44 th Session of the CCPR, April 2012, paragraph 59 and Appendix III). Canadian
MRLs have been established for re sidues of azoxystrobin including the ( Z )-isomer on ginseng roots at 0.5 ppm and at 0.03 ppm for barley, oats, rye, and wheat which are not in agreement with the US tolerances, except for ginseng roots. Mexico adopts US tolerances and/or Codex MRLs for its export purposes.Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 8 of 37 The Codex MRLs on barley grain and wheat grain are estimated at 0.5 and 0.2 ppm, respectively, and MRLs for oats and rye are extrapolated from the data on barley and wheat, respectively. The US tolerances on oat grain (1.5 ppm) and barley gr ain (3 ppm) could not be harmonized since the Codex MRLs are lower. Setting th e US tolerance to be consiste nt with the Codex MRLs might lead to residues in excess of the tolerance, de spite legal use of the pesticide in accordance with the registered label. HED recommends increasing the US tolerances of ginseng to 0.5 ppm, and rye grain and wheat grain to 0.2 ppm to harmoni ze with the numerical portion of the Codex MRL. The US is not establishing a tolerance on ginseng (fresh roots) since the dried ginseng
covers the fresh roots.

2.2.3 Recommended Tolerances

Pending submission of a revised Section F, HED can recommend for establishment of permanent tolerances for azoxystrobin in/on ginseng and cer eal grains. The tolera nce values proposed by the petitioner need to be revised for all co mmodities as listed in the table below. The Organization for Economic Cooperation and De velopment (OECD) tolerance calculation procedures (March 2011 version) we re utilized in determining the appropriate tolerance level.

Table 2.2.3. Tolerance Summary for Azoxystrobin.
Commodity Proposed Tolerance (ppm) Recommended Tolerance (ppm) Comments; Correct Commodity Definition
Ginseng Extract (Red Ginseng Extract and Ginseng Extract) 0.5 -- The US does not currently regulate any processed commodity of ginseng; therefore, this tolerance is not
needed.
Ginseng -- 0.50 Based on data for dried ginseng root/
to harmonize with Codex.
Oat, forage 4 5.0
Oat, hay 7 10.0
Oat, straw 3 3.0
Oat, grain 1 1.50
Rye, forage 4 7.0
Rye, straw 0.8 1.50
Rye, grain 0.07 0.20 To harmonize with Codex.
Barley, hay 7 10.0
Barley, straw 8 15.0
Barley, grain 2 3.0
Wheat, forage 10 15.0
Wheat, straw 6 10.0
Wheat, hay 20 30.0
Grain, aspirated fractions 460 (Established at 420) 420 The established tolerance of 420 ppm
is sufficient. Grain, aspirated grain fractions

Tolerance That Need To be Revised
Wheat, grain Not proposed (Established at 0.10) 0.20 Based on data/to harmonize with
Codex.Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 9 of 37 Livestock Commodities Requested To be Revised
Cattle, fat 0.3 Not Needed
Hog, fat 0.1
Hog, meat 0.02
Livestock Commodities Requested to be Established
Poultry, meat 0.01 Not Needed
Poultry, liver 0.2
Poultry, fat 0.01
Egg 0.1
Cattle, liver 0.5
Cattle, kidney 0.1
Hog, liver 0.2
Hog, kidney 0.03

Note to PM: In conjunction with establishment of wheat grain tolerance at 0.20 ppm, the existing tolerance on wheat bran need to be removed from 40 CFR §180.507(a)(1).

Note to PM : The tolerance expression in 40 CFR §180.507( a)(2) is incorrect. Therefore, the 40 CFR §180.507(a)(2) should be revise d to specify the following tole rance expression: Tolerances are established for residues of the fungici de, azoxystrobin, includi ng its metabolites and degradates, in or on the commodities in the fo llowing table. Compliance with the tolerance levels specified in the table is to be de termined by measuring only azoxystrobin, [methyl( E )-2- (2-(6-(2-cyanophenoxy) pyrimidin-4-yloxy)phenyl)-3 -methoxyacrylate] in or on the commodity.

2.2.4 Revisions to Petitioned-For Tolerances

For the cereal grains, based on the available da ta, the proposed tolerances for all commodities must be revised to reflect the appropriate toleranc e levels estimated using adjusted residue values to reflect the higher application rate of the A bound® label. The proposed tolerances are based on residue data submitted using lower applicatio n rates which do not cover the highest proposed
rate. A revised Section F needs to be submitted to reflect the recommended tolerances as listed in Table 2.2.3. The petitioner needs to submit a revised section F to revise the established tolerance on wheat grain to 0.20 ppm.

For ginseng, the recommended tolerance for gi nseng at 0.5 ppm is sufficient to cover the expected residues in the processed commodities. The petitioner needs to submit a revised section F to propose a tolera nce on ginseng at 0.5 ppm.

2.3 Label Recommendations

None

3.0 Introduction

Azoxystrobin is a broad spectrum fungicide used to control many plant diseases, such as early and late leaf spot in peanuts, la te blight in pistachios, brown ro t blossom blight, and fruit rot inAzoxystrobin Human Health Risk Assessment DP No. 402285

Page 10 of 37 stone fruits; and leaf and fruit s pot in tree nuts. It has the same biochemical mode of action as the naturally occurring strob ilurins and is structurally related. Azoxystrobin is a 

- methoxyacrylate, and acts by inhi biting electron transport.

Syngenta has requested azoxystrobin be registered for use on ginseng (import), oats, and rye. Concurrently, Syngenta is requesting revision of the established tolerances on wheat and barley commodities due to amendments of PHIs. Azoxys trobin is currently registered for use on a variety of vegetable, fruit, cereal, and nut cr ops, as well as on ornamental plants and turf. Tolerances are currently established for barley bran (6.0 ppm), forage ( 25 ppm), grain (3.0 ppm), hay (15 ppm), and straw (7 ppm); wheat bran ( 0.20 ppm), forage (25 ppm), grain (0.10 ppm), hay (15 ppm), and straw (4 ppm). The proposed uses of azoxystrobin are expected to result in occupational exposure only; no residential exposur e is expected from the proposed uses of azoxystrobin. Only short- and intermediate-ter m occupational exposures were assessed for the proposed uses of azoxystrobin. The formulated end use products (EPs) evaluated in this assessment are Abound® Flowable Fungicide (22.9% ai) (EPA Reg. No. 100-1098), Quilt Xcel® (13.5% ai) (EPA Reg. No. 100-1324), and Quilt® Fungicide (0.62 lb ai) (EPA Reg. No. 100-1178). Quilt Xcel® and Quilt® are multiple ac tive ingredient (MAI) product formulations containing both azoxystrobin and propiconazole (11.7% for both). In addition, Syngenta is requesting to add oats and rye use on three azoxystrobin manufacturing products: Azoxystrobin Manufacturing Use Concentrat e (MUC) (EPA Reg. No. 100-1119) , Azoxystrobin Dry Technical Manufacturing Use Concentrat e (MUC) (EPA Reg. No. 100-1120), and Azoxystrobin Millbase Manufacturing Use Product (MUP) (EPA Reg. No. 100-1220).

Azoxystrobin (20% SC formulati on; Ortiva) is proposed for us e on ginseng as four foliar applications at 10 mL formulated product/20 mL water with a 7-da y pre-harvest interval (PHI). Based on the additional use pattern information submitted, the single application rate is 379.75 g ai/ha (0.34 lb ai/A) with maximum applicati on rate of 1519 g ai/ha (1.36 lb ai/A).

Azoxystrobin is proposed for use as a foliar appl ication on oats and rye using ground, aerial, and chemigation equipment. The use profile is summarized in Table 3.3. The proposed single application rates on cereals (wheat , triticale, barley, oats, and ry e) range from 0.07-0.20 lb ai/A (4-12.0 fl oz product/A) for A bound® Flowable Concentrate and 0.03-0.13 lb ai/A (7-14 fl oz product/A) for Quilt Xcel® and Quilt. The A bound®, Quilt Xcel®, and Quilt® labels specifiy that no more than 0.40 lb ai/A of any azoxystrob in containing products should be applied per season, and no more than 2 foliar applications sh ould be applied per seas on. All labels require a 7-day PHI for forage and hay. There is a growth stage restriction for the last application to not apply later than Feekes Growth Stage 10.54 (BBCH 71).

3.1 Chemical Identity

The chemical structure and nomenclature of azoxystrobin are pres ented in Table 3.1.Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 11 of 37 Table 3.1. Azoxystrobin Nomenclature.
Compound

Common name Azoxystrobin
Company experimental name ICIA 5504 (Zeneca), R 215504 (Syngenta)
IUPAC name methyl (2 E )-2-{2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3- methoxyacrylate
CAS name methyl ( α E )-2-[[6-(2-cyanophenoxy)-4-pyrimidinyl]oxy]- α -(methoxymethylene)-
benzeneacetate
CAS registry number 131860-33-8
End-use products (EP) 20% SC formulation (Azoxystrobin SC; Ortiva); Abound® Flowable Fungicide (EPA Reg. No. 100-1098); Quilt® Fungicide (EPA Reg. No. 100-1178); and Quilt Xcel ® Fungicide (EPA Reg. No. 100-1324).
Regulated metabolite, Zisomer

Common name Azoxystrobin, Z-isomer
Chemical name methyl ( Z )-2-{2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3- methoxyacrylate

3.2 Physical/Chemical Characteristics

Azoxystrobin has a log octanol/water partition coe fficient (log P) of 2.5 and is considered relatively insoluble in water. However, az oxystrobin has a molecular weight of 403 g/mol; therefore, the potential to cross biological barrie rs is somewhat limited, as indicated by the low dermal absorption in the rat dermal penetrati on study. In the cattle f eeding study, azoxystrobin concentrated in cream. No qua ntifiable azoxystrobin residues were found in cattle muscle even at the highest dosing level, whereas quantif iable residues were observed in fat. The physicochemical properties of azoxystrobi n are summarized in Appendix B.

3.3 Pesticide Use Pattern

Syngenta has submitted a draft labe l with English translations fo r the 20% SC formulation of azoxystrobin (Azoxystrobin SC; Ortiva) reflecting es tablished use patterns in Korea in support of the requested import tolerance on ginseng. Syngenta has also submitted draft supplemental N N

O O

CN OCH 3

O H 3 CO

N N

O O

CN

OCH 3 O H

3 COAzoxystrobin Human Health Risk Assessment DP No. 402285

Page 12 of 37 amended labels adding uses on oats and rye for Abound® Flowable Fungicide (EPA Reg. No. 100-1098), Quilt Xcel® (EPA Reg. No. 100-1324), and Quilt® Fungicide (EPA Reg. No. 100- 1178). In addition, Syngenta is requesting to add oats and rye use on three azoxystrobin manufacturing products: Azoxystr obin Manufacturing Use Concen trate (MUC) (EPA Reg. No. 100-1119), Azoxystrobin Dry Techni cal Manufacturing Use Concen trate (MUC) (EPA Reg. No. 100-1120), and Azoxystrobin Millbase Manufactur ing Use Product (MUP) (EPA Reg. No. 100- 1220). Table 3.3 provides a summary of th e proposed use sites of azoxystrobin.

Table 3.3.1 Summary of Directions for Use of Azoxystrobin on Ginseng.
Applic. Timing; Type; and Equip. Formulation Applic.
Rate 1 Max. No. Applic. per

Season Max. Seasonal Applic. Rate PHI (days) Use Directions and
Limitations

Ginseng
Foliar; Broadcast; Equipment not specified 20% SC 10 mL
formulated

product/
20 L water 4 Not specified:
Run-off spraying is
recommended 7 Applications are to be made at the beginning of
infestation after leaves are fully opened with a 10-day retreatment interval (RTI).
Use of surfactants or penetration stimulators is prohibited.

Table 3.3.2 Summary of Directions fo r Use of Azoxystrobin on Cereals.

Applic. Timing, Type, and Equip. Formulation [EPA Reg. No.] Applic. Rate
fl oz/A (lb ai/A) Max.
No. Applic.

per Season Max.
Seasonal Applic.

Rate
fl oz/A (lb ai/A) PHI (days) Use Directions and Limitations 2

Cereals (Wheat, Triticale)

Foliar Ground, aerial or chemigation 2.08 lb ai/gal SC [100-1098] 4.0-12 (0.07-0.20) 2 1 0.40 7-forage and hay Applications are to be made prior to disease development. A crop oil concentrate adjuvant may be added at 1.0% v/v to optimize efficacy.

Foliar Ground, aerial or chemigation SE/MAI (0.62 lb ai/gal) [100-1178] 7-14 (0.03-0.07) 2 1 28 (0.14) 7-forage and hay Apply Quilt in the spring for suppression of early season diseases. Follow up with a second application for full season control. For high yields apply Quilt when flag leaf is 50% to full head emergence (Feekes 10.5). Applications may be made no closer than a 14-day interval. Foliar Ground, aerial or chemigation SE/MAI (1.18 lb ai/gal) [100-1324] 7-14 (0.06-0.13) 2 1 28 (0.26) 7-forage and hay

Cereals (Barley, Oat and Rye) 100-11 78, 100-1324 in cludes Triticale

Foliar Ground, aerial or chemigation 2.08 lb ai/gal SC [100-1098] 6-12 (0.10-0.20) 2 1 0.40 7-forage and hay Applications are to be made prior to disease development.
Minimum volume for aerial applications is 5 gal/A.Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 13 of 37 Table 3.3.2 Summary of Directions fo r Use of Azoxystrobin on Cereals.

Applic. Timing, Type, and Equip. Formulation [EPA Reg. No.] Applic. Rate
fl oz/A (lb ai/A) Max.
No. Applic.

per Season Max.
Seasonal Applic.

Rate
fl oz/A (lb ai/A) PHI (days) Use Directions and Limitations 2

Foliar Ground, aerial or chemigation SE/MAI (0.62 lb ai/gal) [100-1178] 7-14 (0.03-0.07) 2 1 28 (0.14) 7-forage
and hay Apply Quilt in the spring for suppression of early season diseases. Follow up with a second application for full season control. For high yields apply Quilt when flag leaf is 50% to full head emergence (Feekes 10.5). Applications may be made no closer than a 14-day interval. An adjuvant may be added at
recommended rates. Foliar Ground, aerial or chemigation SE/MAI (1.18 lb ai/gal) [100-1324] 7-14 (0.06-0.13) 2 1 28 (0.26) 7-forage and hay

1 For resistance management, no more than two sequential applications of Abound Flowable Fungicide or other

Group 11 fungicides should be made before alternating with a fungicide having a different mode of action (not in Group 11). Do not make more than two foliar applications of Abound Flowable Fungicide or other Group 11 fungicide per season. 2 Applications may be made no closer than a 14-day interval (For Quilt and Quilt Xcel). Do not apply after Feekes 10.54. Do not apply more than 0.40 lb ai/A per season of azoxystrobin-containing products.

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assess ment of human health risk to support the proposed new use of azoxystrobin on ginseng, oa t, and rye. Humans may be exposed to azoxystrobin in drinking water, since applicatio n may result in azoxystrobin reaching surface and ground water sources of drinking water. Humans may also be exposed through their diet from applications to agricultural commodities. Ther e are residential uses of azoxystrobin, so exposure to azoxystrobin may occur in residential or non-o ccupational settings. In an occupational setting, handlers may be exposed while handling the pes ticide prior to applica tion, as well as during application. There is also a potential for pos t-application exposure for workers re-entering
treated sites.

Risk assessments have been completed for th e existing uses of azoxystrobin. This risk
assessment considers all of the aforementioned exposure pathways based on the proposed new uses of azoxystrobin, but also cons iders existing uses of azoxystrobi n, particularly in the dietary exposure assessment.

3.5 Consideration of Environmental Justice

Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human health risk assessment, in accordance w ith U.S. Executive Order 12898, "Federal Actions
to Address Environmental Just ice in Minority Populations an d Low-Income Populations," ( http://www.eh.doe.gov/oepa/ guidance/justice/eo12898.pdf . As a part of every pesticide riskAzoxystrobin Human Health Risk Assessment DP No. 402285

Page 14 of 37 assessment, OPP considers a large variety of c onsumer subgroups according to well-established procedures. In line with O PP policy, HED estimates risks to population subgroups from pesticide exposures that are ba sed on patterns of that subgrou p’s food and water consumption,
and activities in and around th e home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture’s National Health and Nutrition Ex amination Survey, What We Eat in America (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categ orized by subgroups based on age, season of the year, ethnic group and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when
conditions or circumstances warrant. Whenever appropriate, non-diet ary exposures based on home use of pesticide products and associated ri sks for adult applicators and for toddlers, youths and adults entering or playing on treated ar eas post-application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditi onal dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

- Azoxystrobin: Human Health Risk Assessment for Proposed Uses on Dragon Fruit, Wasabi, and Tuberous and Corm Vegetables (Subgroup 1C), and from the Revisions to Various Crop Groups (Onion Subgroups 3-07 A, B; Fruiting Vegetable Subgroups 8-10 A, B; Small Fruit and Berry Subgroup s 13-07 A, B, F, G, Oilseeds Subgroups A, B, C; and Citrus Fruit Group 10-10). K. Rury, DP# 389702, 01/18/2012.

A detailed hazard characterization with a list of available toxicity studies for azoxystrobin is presented in the previous ri sk assessment (K. Rury, D 389702, 01/18/2012). The submitted studies are of good quality and pr ovide sufficient information to determine whether azoxystrobin poses a human health hazard. In addition, the registrant, Syngenta, has committed to submitting an adequate functional immunotoxi city study that is currently underway a nd expected to be submitted to the Agency in 2012. A waiver request has been submitted and is currently under
review.

4.1 Toxicological Effects

Azoxystrobin has a low acute toxicity via the oral, dermal and inhala tion routes of exposure. It produced light irritation to eye and skin, but th e effects were cleared by 48 hours for the eye and three days for the skin. Dietar y administration of azoxystrobin to rats resulted in decreased body weights, decreased food intake a nd utilization, in creased diarrhea, and ot her clinical toxicity observations (increased urinary incontinence, hun ched postures, and distended abdomens). In addition, liver effects, characteri zed by increased liver weights, increases in alkaline phosphatase and gamma glutamyltransferase, decreases in al bumin, and gross and histological lesions in the liver and bile ducts, were seen in rats. In dogs, effects on liver /biliary function were found after
oral administration.

In the acute neurotoxicity study in rats, increased incidence of diarrhea was observed at all dose levels tested including the L OAEL. Decreased body weight, de creased body weight gain, andAzoxystrobin Human Health Risk Assessment DP No. 402285

Page 15 of 37 food utilization was noted in the rat subchronic neurotoxicity study. There were no indications of treatment-related neurotoxicity in either the acute or subchronic neurotoxicity studies. In the rat developmental toxicity study, diarrh ea, urinary incontinence , and salivation were observed in maternal animals; in the rabbit de velopmental toxicity st udy, maternal animals exhibited decreased body weight gain. No advers e treatment-related developmental effects were seen in either study. In the rat reproduction st udy, offspring and parent al effects (decreased body weights and increased adjusted liver wei ghts) were observed at the same dose.

There was no evidence of carcinogenicity in rats and mice. As a result, EPA has classified azoxystrobin as “not likely to be carcinogenic to humans.” Azoxystrobin induced a weak mutagenic response in the mouse lympho ma assay, but the activity expressed in vitro is not expected to be expressed in whole animals.

4.2 Safety Factor for Infants and Children (FQPA Safety Factor)

EPA has retained the FQPA SF, reduced to 3X, in assessing acute dietar y risk. An additional safety factor is needed for acute risk assessm ent to account for the use of a LOAEL from the acute neurotoxicity study in rats in deriving th e acute reference dose used for assessing acute dietary exposure for all populati ons including infants and children. To account for the use of a LOAEL from the acute neurotoxicity study in rats, the Agency believes that a 3X FQPA SF (as opposed to a 10X) will be adequate to extrapolat e a NOAEL in assessing acute risk and that no additional safety factor is need ed for short-term, intermediate-term, and chronic risk assessment based on the following considerations:

a. the effect seen (transient diarrhea seen in the rat) is of a nature that is relatively insignificant;
b. the diarrhea was only seen in studies invol ving gavage dosing in the rat but not in repeat dosing through dietary administra tion in rats and mice, and not through gavage dosing in rabbits; and

c. the very high dose level needed to reach the acute oral lethal dose (LD) 50 (>5000 milligrams/kilogram (mg/kg)), and the ove rall low toxicity of azoxystrobin.

However, EPA has determined that reliable data show that it would be safe for infants and children to reduce the FQPA safety factor to 1X for short-term, intermediate-term, and chronic
risk assessment. This determination is based on the following considerations:

4.2.1 Completeness of the Toxicology Database

The toxicity database for azoxystrobin is co mplete except for immunotoxicity and subchronic inhalation toxicity tes ting. Changes to 40 CFR part 158 ma ke immunotoxicity testing (OPPTS Guideline 870.7800) required for pesticide registra tion; however, the existing data are sufficient for endpoint selection for exposure/risk asse ssment scenarios, and for evaluation of the requirements under the FQPA. There are no indicatio ns in the available studies that organs associated with immune function, such as the thymus and spleen, are affected by azoxystrobin and azoxystrobin does not belong to a class of chemicals that would be expected to be
immunotoxic. Based on the above consideratio ns, EPA does not believe that conducting the immunotoxicity study will result in a dose less than the point of departure already used in thisAzoxystrobin Human Health Risk Assessment DP No. 402285

Page 16 of 37 risk assessment, and an additional database uncer tainty factor for poten tial immunotoxicity does not need to be applied.

A subchronic inhalation toxi city study has been waived by HASPOC (TXR# 0056307).

4.2.2 Evidence of Neurotoxicity

Clinical signs, including transient diarrhea a nd decreased body weight, body weight gain, and food utilization, were noted in th e acute and subchronic neurotoxicity studies, but were not
considered indicative of neurotox icity. There is no need for a developmental neurotoxicity study or additional UFs to account for neurotoxicity.

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

There is no evidence that azoxystrobin re sults in increased susceptibility to in utero rats or rabbits in the prenatal developmental studies or in young rats in the 2-generation reproduction study.

4.2.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the azoxystrobin exposure database. While some refinements were incorporated in to the dietary exposur e calculations, EPA is confident that the aggregate risk from exposure to azoxystrobin in food, drinking water, an d residential pathways will not be underestimated. The acute dietary (f ood) exposure assessment utilized conservative upper-bound inputs including 100% of the proposed and registered crops treated, and tolerancelevel residues for all existing and proposed commodities, except ci trus fruits where the highest
field trial residue was used as a refinement . The chronic dietary exposure assessment was partially refined, and used tolerance-level residues for all commodities and % CT estimates when available (Screening Level Usage Analysis (SL UA), 07/13/11). Although the acute and chronic assessments included minor refinements, the use of field trial and % CT estimates ensures that actual exposures/risks from residues in food will not be underestimated. The drinking water
assessment utilized water concentration values generated by models a nd associated modeling parameters which are designed to produce conserva tive, health protective, high-end estimates of water concentrations which are not likely to be exceeded. The dietary (food and drinking water) exposure assessment does not underestimate the po tential exposure for infants, children, or women of child bearing age.

In addition, the residential exposure assessment is based on the updated 2012 Residential SOPs employing surrogate study data, including conser vative exposure assumptions based on Day 0
dermal/oral contact to turf and surfaces treated at the maximum a pplication rate. These data are reliable and are not expected to underestimate risks to adults or children. The Residential SOPs are based upon reasonable “worst-case” assumptions are not expected to u nderestimate risk.

4.3 Toxicity Endpoint and Point of Departure SelectionsAzoxystrobin Human Health Risk Assessment DP No. 402285

Page 17 of 37 4.3.1 Summary of Points of Departure and T oxicity Endpoints Used in Human Health
Risk Assessment

The toxicological doses and endpoi nts supporting this petition remain unchanged and have been summarized in the previous human health ri sk assessment (K. Rury, D389702, 01/18/2012). The toxicity endpoints and PODs are presented in Table 4.3.1.

Table 4.3.1. Summary of Toxicological Doses and Endpoints for Azoxystrobin for Use in Dietary, Non- Occupational and Occupational Human Health Risk Assessments. 1

Exposure/
Scenario Point of Departure Uncertainty/ FQPA Safety
Factors RfD, PAD, Level of
Concern for Risk
Assessment Study and Toxicological Effects

Acute Dietary (All Populations) LOAEL = 200 mg/kg/day UF A = 10X
UF H = 10X FQPA SF =
3X Acute RfD = 0.67mg/kg/day

aPAD = 0.67

mg/kg/day Acute Neurotoxicity - Rat. LOAEL = 200 mg/kg/day based on diarrhea at two-hours post dose at all dose levels including the LOAEL.

Chronic Dietary (All Populations) NOAEL = 18 mg/kg/day UF A = 10X
UF H = 10X FQPA SF =
1X Chronic RfD = 0.18 mg/kg/day

cPAD = 0.18

mg/kg/day Combined Chronic Toxicity/Carcinogenicity Feeding Study – Rat. LOAEL = 82.4/117 mg/kg/day (M/F) based on reduced body weights in both sexes and bile
duct lesions in males.
Incidental
Oral ShortTerm (1-30 days) NOAEL = 25 mg/kg/day UF A = 10X
UF H = 10X FQPA SF =
1X Residential LOC for
MOE = 100 Prenatal Developmental Oral Toxicity – Rat. LOAEL = 100 mg/kg/day based on increased maternal diarrhea, urinary incontinence, and salivation.
Incidental
Oral
IntermediateTerm (1-6 months) NOAEL = 20 mg/kg/day UF A = 10X
UF H = 10X FQPA SF =
1X Residential LOC for
MOE = 100 90-day Feeding Study – Rat. LOAEL = 211/223 mg/kg/day (M/F) based on decreased body weight gain in both sexes and clinical signs
indicative of reduced nutrition.
Dermal (All Durations) No hazard was identified for this exposure sc enario. 21-Day Repeated Dose Dermal Study – Rat. No dermal or systemic toxicity was seen at the limit dose (1,000 mg/kg/day).
Inhalation
Short-Term (1-30 days) Oral NOAEL
= 25 UF A = 10X
UF H = 10X FQPA SF =
1X Occupational &
Residential LOC for
MOE = 100 Prenatal Developmental Oral Toxicity – Rat. LOAEL = 100 mg/kg/day based on increased maternal diarrhea, urinary incontinence, and salivation.
Inhalation
IntermediateTerm (1-6 months) Oral NOAEL
= 20 UF A = 10X
UF H = 10X FQPA SF=1X Occupational &
Residential LOC for
MOE = 100 90-day Feeding Study – Rat. LOAEL = 211/223 mg/kg/day (M/F) based on decreased body weight gain in both sexes and clinical signs
indicative of reduced nutrition.
Cancer (oral, dermal, inhalation) Azoxystrobin is classified as "Not Likely" to be carcinogenic to humans.

1. Point of Departure (POD) = A data point or an estima ted point that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H =Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 18 of 37 potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute , c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.
2. Dermal penetration study showed low absorption factor (2-4%).

Based on the available toxicological database an d the Agency's current practices, the inhalation risk for azoxystrobin was assessed using an oral toxicity study. The Agency sought expert advice and input on issues related to this route to route extrapol ation approach (i.e., the use of oral toxicity studies for inhalati on risk assessment) from its Federal Insecticide, Fungicide, and
Rodenticide Act Scientific Advi sory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SA P/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, re-examine and develop new policies and procedures for conducting inhalati on risk assessments, in cluding route to route extrapolation of toxicity data. If any new polic ies or procedures are developed, the Agency may
revisit the need for an inhalation toxicity study for azoxystrobin and/or re-examine the inhalation toxicity risk assessment.

5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1. Summary of Metabolism Studies, Enviro nmental Degradation, and Metabolic Pathway Comparison

The nature of the residue in pl ants and livestock are adequately understood for the purposes of the Syngenta petition. Metabolism studies in grapes, peanuts, and wheat were submitted in conjunction with earlier azoxystr obin petitions, PP#s 5F4541 and 6F4762. No new plant or metabolism studies have been submitted for azoxystrobin since the last human health risk assessment; therefore, the metabolic pr ofile remains unchanged (K. Rury, D389702, 01/18/2012). A more detailed description of the plant and animal metabolism studies is presented in the previous risk assessment (K. Rury, D389702, 01/ 18/2012). The database is adequate for determining azoxystrobin residues of concern. The summary of environmental degradation of azoxystrobin also remains unchanged and has been summarized in the previous human health risk assessment (K. Rury, D 389702, 01/18/2012). A summary of the metabolites and degradates of azoxystrobin for human health risk assessment is summarized in Table 5.1.2.

5.1.2 Residues of Concern Summary

Table 5.1.2. Summary of Metabolites and Degradates included in the Azoxystrobin Risk Assessment and Tolerance Expression.

Matrix Residues included in
Risk Assessment Residues included in Tolerance Expression

Plants Primary Crop Azoxystrobin and Z-isomer Azoxystrobin and Z-isomer Rotational Crop Azoxystrobin and Z-isomer Azoxystrobin and Z-isomer

Livestock Ruminant Azoxystrobin Azoxystrobin Poultry Azoxystrobin Azoxystrobin Drinking Water Azoxystrobin Not ApplicableAzoxystrobin Human Health Risk Assessment DP No. 402285

Page 19 of 37 5.2 Food Residue Profile

Adequate residue data are avai lable to support dietary risk as sessment as well as the proposed tolerances of azoxystrobin on ginseng, oat, and rye.

Residues are quantifiable in all crops. Residues tend to be surface residue s and generally decline with increasing pre-harvest intervals (PHI). Pr ocessing studies indicate th at residues concentrate in dried citrus pulp, citrus oil, dried basil, field co rn oil, peanut oil, toma to paste, wheat bran, and wheat germ, and slightly in ginse ng extract. Livestock feeding st udies indicate low transfer of
residues to meat and milk with the highest transfer in liver. No quantifiable residues were found in any poultry commodity.

5.3 Water Residue Profile

The drinking water inputs provided in the prev ious drinking water assessment on turf (J. Wolf, D371383, 01/6/2010) were more conservative than the most recent drinking water assessment on rye and oat (I. Abdel-Saheb, D400772, 07/25/201 2). EFED estimates drinking water concentrations of a chemical based on the highe st rate of application of the chemical on all registered and proposed crops. In the case of azoxystrobi n, turf, a previously registered use, has the highest application ra te (0.55 lb ai/A, 9 applications per ye ar with a 10-day interval between applications). The assessment was completed with the Tier 1 screen ing model, FQPA Index Reservoir Screening Tool (FIRST). The model and its description is available at the EPA
internet site: http://www.epa.gov/oppefed1/models/water/

.

The proposed rates of application for oat and rye are lower than for turf. Therefore, the EDWCs reported for turf are used. EDWCs recommended fo r use in the human health risk assessment for all proposed/registered crops are listed in Table 5.3. For ground water, the EDWC is 3.1 ppb.

Table 5.3. Summary of Estimated Surface Water Concentrations for Azoxystrobin.

Scenario Surface Water Conc., ppb

Acute 173

Chronic (non-cancer) 33

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data & Percent Crop Treated Used in Dietary Assessment

The acute dietary exposure assessment of azoxystrobi n is partially refined by using highest field trial values for citrus fruits and assuming tole rance-level residues for all other existing and proposed commodities. 100% of the crops were assumed treated with azoxystrobin and DEEM version 7.81 default processing factors were used except where tolerances were established for processed commodities.Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 20 of 37 The chronic dietary exposure assessment was pa rtially refined, based on tolerance level residues for all existing and proposed commodities. A SLUA was provided by the Biological and Economic Analysis Division (BEAD) (07/13/2011).

HED utilized BEAD’s estimated % CT for the exis ting uses as follows: almonds, 25%; apricots, 10%; artichokes, 25%; asparagus, 2.5%; green beans, 10%; blac kberries, 5%; blueberries, 10%, broccoli, 5%; cabbage, 10%; cantaloupes, 10% ; carrots, 10%; cauliflow er, 2.5%; celery, 10%; cherries, 5%; corn, 2.5%; cotton, 5%; cucumber s, 20%; dry beans/peas, 1%; garlic, 60%; grapefruit, 20%; grapes, 5%; ha zelnuts (filberts), 5%; lettuce, 2.5%; onions, 10%; oranges, 5%; peaches, 5%; peanuts, 15%; green peas, 2.5%; pecans, 2.5%; peppers, 15%; pistachios, 15%; potatoes, 35%; prunes, 2.5%; pumpkins, 20%; raspberries, 5% ; rice, 35%; soybeans, 2.5%; spinach, 10%; squash, 15%; strawberries, 30%; sugar beets, 5%; sweet corn, 10%; tangerines, 15%; tomatoes, 15%; walnuts, 1%; watermelon, 20%; and wheat, 2.5%.

5.4.2 Acute Dietary Risk Assessment

An acute dietary exposure assessment was condu cted for the general U.S. population and all population subgroups (all infants, children 1-2, children 3-5, children 6-12, youth 13-19, adults 20-49, adults 50+ and females 13-49). The acute dietary exposure estimate for food and drinking water utilized 17% of the aPAD for the genera l U.S. population. The acute dietary exposure estimate for the highest reported exposed populati on subgroup, children 1-2 years old, utilized 41% of the aPAD. The results are reported in Table 5.4.4. All population subgroups were below
the LOC.

The acute dietary exposure assessment is partia lly refined, i.e., based on the assumption of tolerance-level residues for all commodities, except citrus (which used the highest residues from residue trials [Grapefruit = 5.447 ppm, Ora nge = 4.014 ppm, Orange, peel = 5.538 ppm, Lemon and Lime = 9.202 ppm]), used empirical or defa ult DEEM processing factors, and assumed 100 % CT for all crops.

5.4.3 Chronic Dietary Risk Assessment A chronic dietary exposure assessment was cond ucted for the general U.S. population and all population subgroups. The chronic dietary exposure for food and drinking water utilized 7% of the cPAD for the general U.S. population. The ch ronic dietary exposure for the highest reported exposed population subgroup, childr en 1-2 years old, utilized 17% of the cPAD. The results are reported in table 5.4.4. All population subgroups were below the LOC.

The chronic dietary exposure assessment is part ially refined, i.e., based on the assumption of tolerance-level residues for all commodities, used empirical or default processing factors and % CT information for the crops listed in Section 5.4.1.Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 21 of 37 5.4.4 Summary Table

Table 5.4.4. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Azoxystrobin.

Population Subgroup Acute Dietary (95th Percentile) Chronic Dietary Cancer

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

General U.S. Population 0.114142 17 0.012290 6.8

Not Applicable All Infants (< 1 year old) 0.140251 21 0.017162 9.5

Children 1-2 years old 0.276719 41 0.031142 17

Children 3-5 years old 0.230886 34 0.025217 14

Children 6-12 years old 0.133704 20 0.015693 8.7

Youth 13-19 years old 0.098862 15 0.009994 5.6

Adults 20-49 years old 0.099791 15 0.010809 6.0

Adults 50-99 0.091527 14 0.010301 5.7

Females 13-49 years old 0.101784 15 0.010307 5.7

1 Higher exposure values are bolded.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

This document addresses the proposed new agricultu ral uses of azoxystrobin on barley, oats, rye, wheat, and triticale; therefore, no new residential exposure is expected. However, there are currently registered uses of azoxystrobin by both commercial and resi dential handlers on residential use sites, including turf, ornamentals, indoor uses (carpet and hard surfaces), and in paints. Each of these existing residential use patterns has prev iously been assessed by HED and the resulting exposures and risk estimates do not exceed HED’s LOC. However, HED has recently updated the residential standard opera ting procedures (SOPs) and body weights to be
used in all human health assessments. Therefor e, all the existing residential use patterns have
been reassessed for residential handler a nd post-application exposures using these new procedures and data (K. Rury, D394287, 03/30/2012).

6.1 Residential Handler Exposure

The proposed uses of azoxystrobin do not invol ve applications by homeowners or commercial applicators to residential settings. However, azoxystrobin is currently registered for use by residential and commercial applicators on severa l residential/non-agricultural use sites; i.e., outdoor residential (lawns, ornament als, flower gardens, vegetables , fruit and nut trees, berries and vines) and recreational (gol f courses, parks and athletic fields) sites. Additionally, residential and commercial applicators may us e azoxystrobin on indoor carpets/other surfaces, and in treated paints (preservat ive incorporation). All existing residential exposures have beenAzoxystrobin Human Health Risk Assessment DP No. 402285

Page 22 of 37 reassessed to account for updates to HED’s 2012 Re sidential SOPs along with policy changes for body weight assumptions. It is assumed that most residential uses will resu lt in short-term (1 to 30 days) handler exposures. Residential handlers are assumed to be wearing short-sleeved shirts, short pants, shoes and socks during application of azoxystrobin. Because there was no dermal endpoint chosen for azoxystrobin, risk from e xposure to azoxystrobin was assessed for the inhalation route only. Although PODs from an oral study were used to assess residential handler inhalation risks for azoxystrobin, HED does not be lieve this assessment is under-protective of
adult handlers.

HED’s LOC for the MOE is defined by the uncertainty factors that are applie d to the assessment. HED applies a 10X factor to acc ount for interspecies extrapolation and a 10X factor to account for intraspecies sensitivity. The total uncertainty factor that has been applied to the non-cancer risk assessment for azoxystrobin is 100X for resi dential exposure. Residential exposure and risk resulting in MOEs greater than or equal to 100 will not be of concern to HED.

Table 6.1 lists the MOE of residential handler exposure and risk estimate using the updated residential SOPs (2012). The new exposure and risk estimates for all residential handler scenarios result in risk estimates that are greater than the LOC MOE of 100; therefore, they are
not of concern to HED. The MOEs for adul t handlers ranged from 2,400 (painting with an airless sprayer) to 1,000,000,000 (mixing/loadin g/applying [M/L/A] a wettable powder to gardens and trees using a hose-end sprayer).

Table 6.1. Short-Term Residentia l Handler Non-Cancer Expo sure and Risk Estimate for Azoxystrobin.

Exposure Scenario Level of
Concern Inhalation
Unit Exposure ( μ g/lb ai) Maximum Application
Rate 1 Area Treated or
Amount Handled Daily 2 Inhalation

Dose (mg/kg/day) 3 MOE 4

Applicator

Painting with Airless Sprayer 100 0.56 1.0% ai by weight 5 one-gallon

cans 0.0149 2,400

Painting with a Brush 100 0.2 1.0% ai by weight 2 one-gallon

cans 0.0005 50,000

Indoor Manually-Pressurized
Handwand Wettable Powder 100 1.1 0.0047 (lb ai/gal) 0.5 gallons 0.000032 770,000

Indoor Manually-Pressurized
Handwand Wettable Powder
in WSB 100 1.1 0.0047 (lb ai/gal) 0.5 gallons 0.000032 770,000

M/L/A Wettable Powders to

Turf [Hose End Sprayer] 100 0.022 0.95 (lb ai/A) 0.5 acres 0.00013 190,000

M/L/A Wettable Powder to Turf [Manually Pressurized

Handwand or Backpack Sprayer] 100 1.1 0.011 (lb ai/gal) 5 gallons 0.00076 33,000

M/L/A Wettable Powders in

WSB to Turf [Hose End Sprayer] 100 0.034 0.95 (lb ai/A) 0.5 acres 0.0002 120,000

M/L/A Wettable Powder in

WSB to Turf [Manually
Pressurized Handwand or 100 0.018 0.011 (lb ai/gal) 5 gallons 0.000012 2,000,000Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 23 of 37 Table 6.1. Short-Term Residentia l Handler Non-Cancer Expo sure and Risk Estimate for Azoxystrobin.

Exposure Scenario Level of
Concern Inhalation
Unit Exposure ( μ g/lb ai) Maximum Application
Rate 1 Area Treated or
Amount Handled Daily 2 Inhalation

Dose (mg/kg/day) 3 MOE 4

Backpack Sprayer]

M/L/A Wettable Powder Azoxystrobin to Gardens and Trees [Manually-Pressurized

Handwand or Backpack Sprayer] 100 1.1 0.000125 (lb ai/gal) 5 gallons 0.0000086 2,900,000

M/L/A Wettable Powder Azoxystrobin to Gardens and

Trees [Hose-End Sprayer] 100 0.0014 0.000125 (lb ai/gal) 11 gallons 0.000000024 1,000,000,000

M/L/A Wettable Powder

Water Soluble Packets Azoxystrobin to Gardens and Trees [Manually-Pressurized

Handwand or Backpack Sprayer] 100 0.018 0.000125 (lb ai/gal) 5 gallons 0.00000014 180,000,000

M/L/A Wettable Powder

Water Soluble Packets Azoxystrobin to Gardens and

Trees [Hose-End Sprayer] 100 0.034 0.000125 (lb ai/gal) 11 gallons 0.00000059 43,000,000

1 Based on registered or proposed label (Reg. No. 100-1229). 2 Exposure Science Advisory Council Policy #9.1. 3 Inhalation Dose = Inhalation Unit Exposure ( μ g/lb ai) x Conversion Factor (0.001 mg/ μ g) x Application Rate (lb ai/acre or gal)

x Amount Handled (gallons/day) / BW (kg). 4 Inhalation MOE = Inhalation NOAEL (mg/kg/day) / Inhala tion Dose (mg/kg/day). Short-term Inhalation NOAEL = 25

mg/kg/day.

6.2 Post-Application Exposure

When determining the potential for residential ex posure, the Agency considers residues, leaf to skin/hand residue transfer, children’s hand-to-m outh residue transfer, and exposure time. No dermal endpoint was chosen for azoxystrobin; therefore, a dermal post-application risk assessment was not conducted. Residential pos t-application inhalati on exposure in outdoor settings is considered negligible; however, re sidential post-application inhalation exposure has been assessed. Post-application exposure in residential settings is expected to be short-term in duration only. Tables 6.2 lists the highest estim ate based on updated assessm ents of residential post-application exposures and risk estimat es. The MOEs ranged from 250 to 810,000 for incidental oral ingestion. The MOE for adults was 220,000,000, 000 and was 52,000,000,000 for children for indoor post-applicati on inhalation exposure. The ne w exposure and risk estimates for all residential post-application uses result in risk estimates that ar e greater than the LOC MOE of 100, and therefore are not of concern to HED.

A turf transferable residue (TTR) study may be required in the future if the use profile is expanded. However, the TTR study requirement is currently waived for azoxystrobin (TXR# 0056307).Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 24 of 37 Table 6.2. Highest Residential Post-Applicat ion Non-Cancer Exposure a nd Risk Estimates for Azoxystrobin. Lifestage Post-Application Exposure Scenario Dose MOEs

Adult Indoor Inhalation 0.00000000011 220,000,000,000

Child Inhalation 0.00000000087 52,000,000,000 Indoor Carpet - Broadcast Hand to Mouth 0.098 250

6.3 Combined Exposure

FQPA requires residential exposures that could r easonably be expected to occur on the same day to be combined and compared to the appropriate toxicity endpoint. In general, residential handler and post-application scenarios genera lly should not be combined. Additionally, no dermal endpoint was chosen for azoxystrobin an d outdoor inhalation post-a pplication exposure is considered negligible. Therefore, reside ntial post-application exposure scenarios for azoxystrobin were not combined.

6.4 Residential Bystander Post-Application Inhalation Exposure

Although a quantitative residential post-applic ation inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for residential handlers. This exposure scenario is representative of a worse case inhalation exposure an d should be considered protective of most post-applicati on inhalation exposu re scenarios.

6.5 Spray Drift

Spray drift is always a potential source of expos ure to residents nearby to spraying operations. This is particularly the case with aerial appl ication, but, to a lesser ex tent, could also be a potential source of exposure from the ground application method employed for azoxystrobin. The Agency has been working with the Spray Dr ift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and ot her parties to develop the best spray drift management practices (see the Agency’s Spra y Drift website for more information at http://www.epa.gov/opp00001/factsheets/ spraydrift.htm). On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has comp leted 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 appr opriately apply the data and th e AgDRIFT computer model to its risk assessments for pesticides applied by ai r, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drif t with specific products with significant risks
associated with drift.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking wate r and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitativeAzoxystrobin Human Health Risk Assessment DP No. 402285

Page 25 of 37 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 consider s both the route and duration of exposure. For azoxystrobin, pot ential exposures from f ood, drinking water and residential scenarios were aggregated.

This assessment has considered the changes in the new Residential Standard Operating Procedures (SOPs) implemented in January of 2012. HED confirms that there are no risks of concern resulting from the proposed uses, nor from utilizing the new Residential SOPs to estimate residential exposure and risk.

7.1 Acute Aggregate Risk

The aggregate acute risk estimates include e xposure to residues of azoxystrobin in food and water, and do not include dermal, inhalation, or incidental oral e xposure. The acute risk estimate for the U.S. population and all other population subgroups, resulting from aggregate exposure to azoxystrobin in food and drinking water, is be low the Agency’s LOC. The food and drinking water exposure estimates are 17% of the aPAD for the general U.S. population, and 41% for the most highly exposed subgroup, children 1-2 years old.

7.2 Short-Term Aggregate Risk

There is potential short-term exposure to az oxystrobin via dietary (w hich is considered background exposure) and residentia l (which is considered primary) exposure pathways. For adults, these pathways lead to exposure via or al (background) as well as dermal and inhalation (primary) routes. The most conservative scenar io was chosen for each population (e.g., hand-tomouth exposure from carpets and textiles for child ren 1-2 years old). Fo r a description of the residential exposure scenarios considered in the aggregate assessment, see Section 6.0.

The general US population (inhala tion) aggregate MOE is 920. Therefore, adult aggregate exposure and risk does not exceed HED’s LOC (MOE <100). The aggregate MOE for children 1-2 years old, including incident al oral exposures from treated carpets, is 190, which indicates that aggregate exposure and risk is greater than HED’s LOC (M OE<100). Further refinement using additional % CT estimates or more refined EDWCs may need to be incorporated in future

assessments.

Table 7.2. Short-Term Aggregate Risk Calculations.

Population & Activity NOAEL mg/kg/day LOC 1 Max
Allowable Exposure 2 mg/kg/day Average
Food and

Water Exposure mg/kg/day Residential Exposure mg/kg/day 3 Total Exposure mg/kg/day 4 Aggregate MOE (food,

water and residential) 5

General U.S. Population 25 100 1 0.012290 0.0149 0.02719 920

Children 1-2

years 25 100 1 0.031142 0.0982 0.129342 190

1. LOC includes standard inter- (10X) and intra- ( 10X) species uncertainty factors totaling 100.
2. Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOCAzoxystrobin Human Health Risk Assessment DP No. 402285

Page 26 of 37 3. Residential Exposure = [Oral exposure + Inhalation Expos ure]. Source of residential e xposure values used in aggregate assessment (Table 6.1 and Table 6.2). E xposure estimate for Children 1-2 years in cludes post-application inhalation exposure (0.00000000087 mg/kg/day)+ incidental oral ingestion from trea ting carpets (0.0982 mg/kg/da y) = 0.098 mg/kg/day.
4. Total Exposure = Avg Food & Water Exposur e + Residential Exposure)
5. Aggregate MOE = [NOAEL

 / (Avg Food & Water Exposure + Resident ial Exposure)], NOAEL=25 mg/kg/day.

7.3 Intermediate-Term Aggregate Risk

Intermediate-term exposure is not expected fo r the adult residential (inhalation) exposure pathway. Therefore, the intermediate-term aggreg ate risk would be equi valent to the chronic dietary exposure estimate. In the previous ri sk assessment, both short- and intermediate-term
incidental oral residential risk s were included in the aggregate risk assessment for azoxystrobin (K. Rury, D389702, 1/18/2012). Based on the azoxys trobin use pattern, and the 2012 Revised Residential SOPs (2012), only short-term reside ntial handler and post- application exposures should be included in the aggr egate risk assessment.

7.4 Chronic Aggregate Risk

Chronic exposure is not expected for the adul t residential (dermal and inhalation) exposure pathway. Therefore, the chronic aggregate risk would be equivalent to the chronic dietary exposure estimate. Refer to Section 5.4.3 for the chronic dietary (food and drinking water) exposure assessment.

7.5 Cancer Aggregate Risk

Azoxystrobin is considered “not likely to be ca rcinogenic to humans;” therefore, an aggregate
cancer risk assessment has not been conducted.

8.0 Cumulative Exposure/Risk Characterization

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

9.0 Occupational Exposure/Risk Characterization

References:

- Azoxystrobin. Occupational and Residential Exposure Assessment to Evaluate the Risk from Proposed Uses on Sugarcane, K. Rury, DP#394287, 03/30/2012.

9.1 Short-/Intermediate-Term Handler RiskAzoxystrobin Human Health Risk Assessment DP No. 402285

Page 27 of 37 Azoxystrobin is proposed for use as a foliar appli cation to cereal grains . Application methods, maximum application rates and use sites are summarized in Table 9.1. Based on the proposed use pattern of azoxystrobin, ther e is a potential for short- a nd intermediate-term occupational exposure during handling (mixing, loading, flagging, and applying) . Chronic exposure is not expected for the proposed use patterns. PPE was assessed at baseline (lon g pants, a long-sleeved shirt, shoes, socks, no chemical-resistant glove s, and no respirator). The Quilt Xcel®, Quilt® and Abound® require handlers to w ear long sleeved shirts, long pant s, chemical resistant gloves, shoes, and socks. Quilt Xcel® and Quilt® also require the use of protective eyewear.

The results of the occupational handler exposure and risk assessment estimates indicate that
short- and intermediate-term inhalation MOEs are not of concern to HED (i.e. MOEs > 100) with baseline mitigation (no respirator). The s hort-term inhalation MOEs range from 38,000 to 570,000 for occupational handlers. The intermediate-term MOEs range from 30,000 to 460,000 for occupational handlers (Table 9.1).

The Agency has evaluated scenarios that may be limited in nature such as flagging during aerial applications because engineering controls (i.e., Global Positioning Satellite technology) are now predominantly used as indicated by the 1998 National Agricultural Aviation Association (NAAA) survey of their membership. It appear s, however, that flagge rs are still used in approximately 10 to 15 percent of aerial application operati ons. In cases like these, the Agency strongly encourages the use of th e engineering control system but will continue to evaluate risks for flaggers and any other population where a cl ear exposure pathway exists until the potential for exposure is eliminated. The Agency is aware that NAAA is conducting another survey on exposure issues and will cons ider those results as they are timely and appropriate.

HED has no data to assess exposures to pilots using open cockpits. The only data available is for exposure to pilots in enclosed cockpits. Ther efore, risks to pilots are assessed using the engineering control (enclosed coc kpits) and baseline attire (long- sleeve shirt, long pants, shoes, and socks); pilots are not required to wear protec tive gloves. With this level of protection, there are no risk estimates of concern for applicators.

Table 9.1. Short- and Intermediate-Term Occupational Exposure and Risk Estimates for Proposed Use of Azoxystrobin on Cereal Grains (Barley, Oats, Rye, Wheat, and Triticale)

. All estimates are at baseline mitigation (single layer without glov es or respiratory protection).

Exposure Scenario Crop(s) Baseline
Inhalation
Unit Exposure ( μ g/lb ai) 1 Maximum Applicatio n Rate (lb

ai/A) 2 Area
Treated or

Amount
Handled

Daily 3 Inhalation

Dose (mg/kg/day) 4 Short-Term
MOE 5 IntermediateTerm MOE 6

Mixer/Loader

Mixing/Loading Liquids
for Groundboom

Application Barley, Oats, Rye

0.219 0.20 80 0.000044 570,000 460,000

Wheat,
Triticale 200 0.00011 230,000 180,000

Mixing/Loading Liquids
for Aerial and Chemigation Application Barley, Oats, Rye 350 0.00019 130,000 100,000

Wheat,
Triticale 1200 0.00066 38,000 30,000Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 28 of 37 Table 9.1. Short- and Intermediate-Term Occupational Exposure and Risk Estimates for Proposed Use of Azoxystrobin on Cereal Grains (Barley, Oats, Rye, Wheat, and Triticale)

. All estimates are at baseline mitigation (single layer without glov es or respiratory protection).

Exposure Scenario Crop(s) Baseline
Inhalation
Unit Exposure ( μ g/lb ai) 1 Maximum Applicatio n Rate (lb

ai/A) 2 Area
Treated or

Amount
Handled

Daily 3 Inhalation

Dose (mg/kg/day) 4 Short-Term
MOE 5 IntermediateTerm MOE 6

Flagger

Flagging for Aerial Application Barley, Oats, Rye, Wheat,

Triticale 0.35 0.20 350 0.00031 82,000 65,000

Applicator

Applying Sprays via Groundboom Equipment Barley, Oats, Rye 0.34

0.20 80 0.000068 370,000 290,000

Wheat,
Triticale 200 0.00017 150,000 120,000

Applying Sprays via Aerial Equipment * Barley, Oats, Rye 0.068 350 0.000060 420,000 340,000

Wheat,
Triticale 1200 0.00020 120,000 98,000

1 Based on “Occupational Pesticide Handler Unit Exposure Surrogate Reference Ta ble” (March 2012); includes data from PHED /AHETF. Level of mitigation: Baseline. 2 Based on registered labels with proposed new uses (Reg. Nos. 100-1098, 100-1178, 100-1324). 3 Exposure Science Advisory Council Policy #9.1. 4 Inhalation Dose = Inhalation Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Ra te (lb ai/acre) ×

Area Treated Daily (A/day) ÷ BW (kg). Bodyweight = 80 kg. 5 Inhalation MOE = Inhalation NOAEL (m g/kg/day) ÷ Inhalation Dose (mg/kg/da y). Short-Term Inhalation NOAEL = 25

mg/kg/day. 6 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). Intermedia te-Term Inhalation NOAEL = 20 mg/kg/day.

9.2 Short-/Intermediate-Term Post-Application Risk

9.2.1 Dermal Post-Application Risk

The proposed occupational uses for azoxystrobin addressed in this document result in the potential for exposure to azoxystrobin duri ng scouting, hand weeding, and hand harvesting. However, no appropriate dermal endpoint was identified for azoxystrobin. Therefore, an assessment of occupational dermal post-application exposure to azoxystrobin was not conducted. A chemical-specific dislodgeable foliar resi due (DFR) study is available for the use of azoxystrobin on grapes, but has not been employed in this or previous risk assessments because
HED determined there is no hazard via the dermal route.

Based on the Agency's current practices, a quant itative post-application inhalation exposure assessment was not performed for azoxystrobin at this time primarily beca use of the low acute inhalation toxicity (Toxicity Cate gory III), low vapor pressure (8.2x10 -13 mm Hg at 20oC), and the low proposed use rate (0.20 lb ai/A). Howe ver, there are multiple po tential sources of postapplication inhalation exposure to individuals performing po st-application activities in previously treated fields. Th ese potential sources include vol atilization of pesticides and resuspension of dusts and/or pa rticulates that contain pesticid es. The Agency sought expertAzoxystrobin Human Health Risk Assessment DP No. 402285

Page 29 of 37 advice and input on issues related to volatilization of pe sticides from its Federal Insecticide, Fungicide, and Rodenticide Act 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 as well as available post-applic ation inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and procedures, to iden tify the need for and, subsequently, the way to incorporate occupational post-application inhala tion exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may
revisit the need for a quantitative occupational post-applic ation inhalation exposure assessment for azoxystrobin.

Although a quantitative occupational post-applic ation inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resultin g from application of pesticides outdoors is likely to result in higher exposure than post -application exposure. Therefore, it is expect ed that these handler inhalation exposure estimates would be protec tive of most occupatio nal post-application inhalation exposure scenarios.

Nevertheless, per the Worker Protection Standa rd (WPS), a 12-hour restricted entry interval (REI) is required for chemicals classified unde r Toxicity Category III or IV. Azoxystrobin is classified as Toxicity Category III for acute dermal and primary eye irritation and Toxicity Category IV for primary skin irritation. Even though a 12-hour REI usually is the shortest waiting period permitted under the WPS, REIs may be further reduced from 12 hours if certain
criteria are met for both the tec hnical material and the different end-use products in accordance with the Pesticide Registration (PR) Notice 95- 3 [Reduction of Worker protection Standard (WPS) Interim Restricted Entry Intervals (REIs) for Certain Low Risk Pesticides]. Previously,
HED determined that the criteria for the techni cal material had been met for azoxystrobin, and RD had determined the criteria for the end-use products Abound ® had been met, and therefore, the 4-hour REI, as listed on th e label, is acceptable for Abound ® . It should be noted that the REI of 12 hours listed on the multiple ai products Qu ilt Xcel® and Quilt ® with both azoxystrobin and propiconazole, is accep table under the WPS.

1 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlAzoxystrobin Human Health Risk Assessment DP No. 402285

Page 30 of 37 10.0 References

J. Wolf, 01/06/2010, DP#371383, Drinking Water Asse ssment for amended label Quadris TopTM fungicide (EPA Reg. No. 100-1313) Azoxystrobin for use on golf course turf (only). I. Abdel-Saheb, 07/25/2012, DP#400 772, Drinking Water Exposure Assessment for new use of azoxystrobin on oat and rye.

N. Tsaur, 10/09/2012, DP#402288, Occupati onal and Residential Exposure Assessment for a Proposed Use on Cereal Grains (Barley, Oats, Rye, Wheat, and Triticale).

M. Negussie, 09/25/2012, DP#402287, Acute an d Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for Section 3 Petit ions for the Establishment of Tolerances on Ginseng (import, PP#1E7945); Rye and Oats (PP#2F7976), and Section 3
Amendments to Revise the Established Tolerances on Cereal Grains (Barley and Wheat) Due to Changes of Pre-Harvest Intervals (PP# 2F7984).

M. Negussie, 03/21/2013, DP#397692, Section 3 Petiti ons for the Establishment of Tolerances on Ginseng (import, PP#1E7945), Rye, and Oats (PP#2F7976), and Section 3 Amendments to
Revise the Established Tolerances on Cereal Gr ains (Barley and Wheat) Due to Changes of PreHarvest Intervals (PP# 2F7984). Summary of Analytical Chemistry and Residue Data

Pesticide Residues in Food 2011: Summary Report 2011. Joint FAO/WHO Meeting on Pesticide Residues (JMPR) (http://www.fao.org)Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 31 of 37 Appendix A. Toxicology Profile

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.500) for non-food use for azoxystrobin are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity ....................................................... 870.1200 Acute Dermal Toxicity ..................................................
870.1300 Acute In halation Toxicity ..............................................
870.2400 Primar y Eye Irr itation

.................................................... 870.2500 Primar y Dermal Irr itation

.............................................. 870.2600 Derm al Sensiti zation...................................................... yes
yes
yes
yes
yes
yes yes
yes
yes
yes
yes
yes

870.3100 Oral Su bchronic (rodent) ...............................................
870.3150 Oral Su bchronic (nonr odent) ......................................... 870.3200 21-Day Dermal .............................................................. 870.3250 90-Day Dermal ..............................................................
870.3465 90-D ay Inhala tion .......................................................... yes
yes
yes

no CR 1 yes
yes
yes

no yes*

870.3700a Developmental Toxicity (rodent) ................................... 870.3700b Developmental Toxicity (nonrodent).............................
870.3800 Reproduc tion ................................................................. yes
yes
yes yes
yes
yes

870.4100a Chronic T oxicity (rodent) ..............................................
870.4100b Chronic Toxi city (nonrodent) ........................................ 870.4200a Oncoge nicity (ra t) .......................................................... 870.4200b Oncogenicity (mouse) ....................................................
870.4300 Chroni c/Oncogeni city .................................................... yes
yes
yes
yes
yes yes
yes
yes
yes

yes
870.5100 Mutagenicity—G ene Mutation - bacterial ..................... 870.5300 Mutagenicity—Gene Mutation - mammalian ................ 870.5375 Mutagenicity—Struc tural Chromosomal Aberrations ... 870.5385 Mutagenicity—O ther Genotoxic Effects ....................... yes
yes
yes
yes yes
yes
yes
yes

870.6100a Acute Delayed Neurotoxicity (hen) ............................... 870.6100b 90-Day Neurotoxicity (hen) ........................................... 870.6200a Acute Neurotoxicity Screening Battery (rat) ................. 870.6200b 90-Day Neurotoxicity Screening Battery (rat) ............... 870.6300 Develop. Neurotoxicity ................................................. no

no
yes
yes

no -

- yes
yes

no

870.7485 Gene ral Metabo lism ......................................................
870.7600 Derm al Penetr ation ........................................................
870.7800 Immunotoxicity ............................................................. yes

no

yes yes

yes
no*

Special Studies for Ocular Effects Acute Oral (rat) ...........................................................
Subchronic Oral (rat) .................................................. Six-month Oral (dog) .................................................. yes

no
yes -

-

-

1 CR = Conditionally Required * The requirement for a subchronic inhalation toxicity study has been waived (TXR#0056307) * A waiver request for an Immunotoxicity study ha s been submitted and is currently under review.Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 32 of 37 A.2 Toxicity Profiles

Table A.2.1. Acute Toxicity Data on Technical Azoxystrobin.

Guideline
No. Study Type MRID # Results Toxicity Category
870.1100 Acute Oral - Rat 43678122 LD 50 > 5000 mg/kg (Limit Test) in Males &
Females IV

870.1200 Acute Dermal -

Rat 43678124 LD 50 > 2000 mg/kg (Limit Test) in Males &
Females III

870.1300 Acute Inhalation -

Rat 43678126 LC 50 Males = 0.962 mg/L (95% C.I. = 0.674) Females = 0.698 mg/L (95% C.I. = 0.509, 2.425)
The combined LC50 was not calculated due to mortality pattern III

870.2400 Primary Eye
Irritation - Rabbit 43678128 Slight to moderate erythema and slight chemosis in all rabbits within one hour, but effects resolved
within 48 hours of treatment. III

870.2500 Primary Skin
Irritation - Rabbit 43678130 Very slight erythema and edema that persisted for three days on one rabbit and for one hour on
another. IV

870.2600 Dermal
Sensitization -

Guinea Pig 43678132 No erythema or edema were found 38 or 48 hrs after challenge with test material. Not a
dermal
sensitizer

Table A.2.2. Azoxystrobin Toxicity Results From Repeated Dosing and Other Studies.

Study Guideline/Study MRID Results
870.3100 90-Day oral toxicity in

rats 43678135 (1992) Acceptable/guideline 0, 200, 2000, 4000 ppm M: 0, 20.4, 211.0, 443.8 mg/kg/day F: 0, 22.4, 223.0, 448.6 mg/kg/day NOAEL = 20 mg/kg/day LOAEL = 211 mg/kg/day based on decreased weight gain in both sexes, clinical observations of distended abdomens and reduced body size, and clinical pathology findings attributable to reduced nutritional

status.

870.3150 90-Day oral toxicity in dogs 43678136 (1993) Acceptable/guideline M & F: 0, 10, 50, 250 mg/kg/day NOAEL = 50 mg/kg/day LOAEL = 250 mg/kg/day based on treatment-related clinical observations and clinical chemistry alterations indicative of effects on liver/biliary
function in both sexes.

870.3200 21-Day dermal toxicity in

rats 43678137 (1994) Acceptable/guideline M & F: 0, 200, 500, 1000 NOAEL = 1000 mg/kg/day (limit dose) LOAEL > 1000 mg/kg/day.

870.3700a Prenatal developmental in

rats 43678142 (1994) Acceptable/guideline 0, 25, 100, 300 mg/kg/day Maternal NOAEL = 25 mg/kg/day LOAEL = 100 mg/kg/day based on the maternal clinical signs of incr eased diarrhea, urinary incontinence, and salivation. Developmental NOAEL = 100 mg/kg/day LOAEL > 100 mg/kg/day.
870.3700b Prenatal developmental in
rabbits 44058701 (1995) Acceptable/guideline 0, 50, 150, 500 mg/kg/day Maternal NOAEL = 150 mg/kg/day LOAEL = 500 mg/kg/day based on decreased body weight gain. Developmental NOAEL = 500 mg/kg/day LOAEL > 500 mg/kg/day.

870.3800 Reproduction and fertility 43678144 (1994) Acceptable/guideline Parental/Systemic NOAEL = 32 mg/kg/day LOAEL = 165 mg/kg/day based on reduced bodyAzoxystrobin Human Health Risk Assessment DP No. 402285

Page 33 of 37 Table A.2.2. Azoxystrobin Toxicity Results From Repeated Dosing and Other Studies.

Study Guideline/Study MRID Results effects in rats 0, 60, 300, 1500 ppm M: 0, 6.4, 32.3, 165.4 mg/kg/day F: 0, 6.8, 33.8, 175.0 mg/kg/day weight, reduced food consumption, and increased adjusted liver weights in both sexes in addition to gross and histopathologic lesions of the bile duct and
liver in males. Reproductive NOAEL = 165 mg/kg/day LOAEL > 165 mg/kg/day. Offspring NOAEL = 32 mg/kg/day LOAEL = 165 mg/kg/day based on reduced pup body weight and increased adjusted liver weights.

870.4100 Chronic toxicity in dogs 43678140 (1994) Acceptable/guideline 0, 3, 25, 200 mg/kg/day NOAEL = 25 mg/kg/day LOAEL = 200 mg/kg/day based, in both sexes, on clinical observations, increased liver weight, and clinical chemistry changes indicative of effects on liver/biliary function.

870.4200 Carcinogenicity in mice 43678141 (1995) Acceptable/guideline 0, 50, 300, 2000 ppm M: 0, 6.2, 37.5, 272.4 mg/kg/day F: 0, 8.5, 51.3, 363.3 mg/kg/day NOAEL = 38 mg/kg/day LOAEL = 272 mg/kg/day based on reduced body weights in both sexes. There was no evidence of carcinogenicity.

870.4300
Combined Chronic toxicity/ Carcinogenicity
in rats 43678139 (1995) Acceptable/guideline 0, 60, 300, &1500/750 ppm for males (due to excessive death the high dose was reduced beginning at week 52-104) For females: 0, 60, 300,& 1500 ppm M: 0, 3.6, 18.2, 82.4 mg/kg/day F: 0, 4.5, 22.3, 117.1 mg/kg/day NOAEL = 18 mg/kg/day LOAEL = 82.4 mg/kg/day in males and 117 mg/kg/day in females based on reduced body weights in both sexes and bile duct lesions in males. There was no evidence of carcinogenicity.

870.5100 Bacterial reverse gene
mutation 43668146 (1992) Acceptable/guideline 100, 200, 500, 1000, 2500, 5000 μg/plate Negative in increasing revertant colonies up to 5000 μg/plate +/-S9 using both plate incorporation and preincubation protocols and Salmonella strains TA98, TA100, TA1535, and TA1537 as well as the E. Coli strains WP2P and WP2PuvrA. Cytotoxicity and compound precipitation were seen at the high
dose.

870.5300
Mammalian cell forward gene mutation (mouse lymphoma cells) 43678145 (1993) Acceptable/guideline 8 to 80 μg/mL in three

assays Nonlinear, slight but significant increases in the mutation frequency (MF) of mouse lymphoma
L5178Y TK +/- at 15-60 μg/mL +/-S9. Despite the absence of a dose response, increased MFs were reproducible; therefore, Azoxystrobin is considered positive in this test system. Colony sizing was not performed.

870.5375 Cytogenetics
chromosomal aberration 43678147 (1992) Acceptable/guideline0.5 to 50 μg/mL without S9 1 to 300 μg/mL with S-9 The in vitro test in human lymphocytes was positive
for the induction of chromosomal aberrations in both the presence and absence of S9 at doses (5-50 μg/mL -S9; 100-200 μg/mL +S9) that were moderately to severely cytotoxic (i.e. > 16-70% reductions inAzoxystrobin Human Health Risk Assessment DP No. 402285

Page 34 of 37 Table A.2.2. Azoxystrobin Toxicity Results From Repeated Dosing and Other Studies.

Study Guideline/Study MRID Results mitotic cells, respectively)

870.5385 Cytogenetics bone

marrow 43678148 (1992) Acceptable/guideline
5000 mg/kg The in vivo mouse bone marrow micronucleus assay

was negative at 5000 mg/kg when administered once by oral gavage. Overt toxicity and depression of erythropoiesis seen in addition to cytotoxic effects on the target cell in the males.

870.5550
Other: Unscheduled DNA synthesis 43678149 (1992) Acceptable/guideline 1250 and 2000 mg/kg The in vivo /in vitro unscheduled DNA synthesis test in rat hepatocytes was negative . No toxicity to the treated animals or cytotoxic effects on recovered hepatocytes up to the limit dose for acute testing (2000 mg/kg) when administered once by oral

gavage. 870.6200a Acute neurotoxicity screening battery in rats 43678134 (1994) Acceptable/guideline 0, 200, 600, 2000 mg/kg NOAEL < 200 mg/kg/day LOAEL = 200 mg/kg/day based on transient diarrhea
in both sexes.

870.6200b Subchronic neurotoxicity screening battery in rats 43678138 (1994) Acceptable/guideline 0, 100, 500, 2000 ppm M: 0, 8.0, 38.5, 161 mg/kg/day F: 0, 9.1, 47.9, 201.5 mg/kg/d NOAEL = 39 mg/kg/day. LOAEL = 161 mg/kg/day based on decreased body weight/weight gain and food utilization in both

sexes.

870.7485
Metabolism and pharmacokinetics 43678150
43678151
43678152
43678153
43678154 1 or 100 mg/kg (single gavage) or 1 mg/kg (14- day repeated) Following oral administration as a single gavage dose of 1 or 100 mg/kg or 15-day repeated doses of 1 mg/kg, azoxystrobin was widely distributed with the liver and kidneys having the highest concentrations; however, less than 0.5% of the administered dose was detected in the tissues at seven days postdosing. The primary route of excretion was via the feces ( ≈ 73-89%) followed by urine ( ≈ 9-18%). There were no apparent sex- or dose-related differences in distribution or in the pattern of excretion. In a bile duct cannulated single high-dose group, assessment of biliary excretion suggested approximately 70% absorption with ≈ 32% of the administered dose remaining as parent compound in the gastrointestinal tract. Absorbed azoxystrobin appeared to be extensively metabolized with minor sex-related qualitative and quantitative differences in biliary metabolites. A metabolic pathway was proposed showing hydrolysis and subsequent glucuronide conjugation as the major biotransformation process.

870.7600 Dermal penetration (rat) 43678155 (1994) Acceptable/guideline 0.01, 0.1, 0.9, 13.3 mg/kg 2 - 4 % Dermal AbsorptionAzoxystrobin Human Health Risk Assessment DP No. 402285

Page 35 of 37 Appendix B. Physical/Chemical Properties

Table B. Physicochemical Properties of Technical Grade Azoxystrobin.

Parameter Value Reference
Melting point/range 114-116oC DP#s 218318 and 218448, 3/19/96, J. Garbus pH 6.4
Density 1.25 g/cm 3

Water solubility (20°C) pH 5.2 6.7 mg/L pH 7.0 6.7 mg/L pH 9.2 5.9 mg/L
Solvent solubility (20°C) Hexane 0.057 mg/L Octanol 1.4 mg/L Methanol 20 mg/L Toluene 55 mg/L Acetone 86 mg/L Ethyl Acetate 130 mg/L Acetonitrile 340 mg/L Dichloromethane 400 mg/L
Vapor pressure (20°C) 1.1x10 -13 kPa (8.2x10 -13 mm Hg)
Dissociation constant, pK

a Not dissociable
Octanol/water partition coefficient, Log(K O W ) log P = 2.5

UV/visible absorption spectrum Not availableAzoxystrobin Human Health Risk Assessment DP No. 402285

Page 36 of 37 Appendix C. International Residue Limit Status Sheet.

Azoxystrobin (PC Code 128810; 08/22/12) Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 2 Codex 3

40 CFR 180.507: Plant: sum of azoxystrobin, [methyl( E )-2-(2-(6-(2- cyanophenoxy) pyrimidin-4- yloxy)phenyl)-3- methoxyacrylate], and the Z

isomer of azoxystrobin [methyl( Z )-2-(2-(6-(2- cyanophenoxy)pyrimidin-4- yloxy)phenyl)-3 methoxyacrylate] ( α E)-methyl 2-[[6-(2- cyanophenoxy)-4- pyrimidinyl]oxy]- α - methoxymethylene)benzene
acetate, including the isomer (Z)- methyl 2-[[6-(2- cyanophenoxy)-4- pyrimidinyl]oxy]-- (methoxymethylene)benzen

eacetate Azoxystrobin.
The residue is fat
soluble.

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)
US Canada Mexico 2 Codex 3

Ginseng 0.50 0.5 ginseng roots 0.1Ginseng 0.5 Ginseng, dried including red ginseng 0.5 ginseng, processed products (proposed) Oat, forage 5.0 Oat, hay 10.0 Oat, straw 3.0 15 straw and fodder of cereal grains Oat, grain 1.50 0.03 0.5 Rye, forage 7.0 Rye, straw 1.50 15 straw and fodder of cereal grains Rye, grain 0.20 0.03 0.2 Barley, hay 10.0 Barley, straw 15.0 15 straw and fodder of cereal grains Barley, grain 3.0 0.03 0.5 Wheat, forage 15.0 Wheat, straw 10.0 15 straw and fodder of cereal grains Wheat, hay 30.0 Wheat, grain 0.20 0.03 0.2 Grain, aspirated grain
fractions* 420

Completed: M. Negussie; 08/31/2012

1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant. *The established tolerance should remain at 420 ppm.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 37 of 37 3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated co mmodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.

Appendix D. Review of Human Research

Studies reviewed for ethical conduct:

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database , Version 1.1.
Electronic Database. Task Force members Heal th Canada, U. S. Environmental Protection Agency, and the National Agricultural Chem icals Association, released February, 1995.

The Agricultural Handler Exposur e Task Force (AHETF), 2011. The Occupational Handler Unit Exposure Surrogate Reference Table. U.S. Environmental Protection Agency. Released June 21, 2011.

Data from the Outdoor Residential Exposure Task Force (ORETF).