### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 3 of 42 7.3 Intermediate

- Term Aggregate Risk

................................ ................................ ........... 31

7.4 Chronic Aggregate Risk

................................ ................................ .............................. 31

7.5 Cancer Aggregate Risk

................................ ................................ ................................ 31

8.0 Cumulative Exposure/Risk Characterization

................................ ............................... 31

9.0 Occupational Exposure/Risk Characterization

................................ ............................ 32

9.1 Short

- /Intermediate

- Term Handler Risk

................................ ................................ ... 32

9.2 Short

- /Intermediate

- Term Post

- Application Risk

................................ .................... 33

9.2.1 Dermal Post

- Application Risk

................................ ................................ ................. 33

10.0 References

................................ ................................ ................................ ......................... 34 Appendix A. Toxicology Profile

................................ ................................ ................................ 36

A.1 Toxicology Data Requirements

................................ ................................ ................... 36

A.2 Toxicity Profiles

................................ ................................ ................................ ............ 37 Appendix B . Physical/Chemical Properties

................................ ................................ ............. 40 Appendix C. International Residue Limit Status Sheet.

................................ ........................ 41 Appendix D. Review of Human Research

................................ ................................ ................ 42

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 4 of 42 1.0 Executive Summar y

Azoxystrobin [methyl (2 E )

- 2

- {2

- [6

- (2

- cyanophenoxy)pyrimidin

- 4

- yloxy]phenyl}

- 3

- methoxyacrylate] is a broad spectrum 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 pesticidal compounds called β

- methoxyacrylates, which are derived from the naturally occurring strobilurins. Its biochemical mode of action is inhibition of electron

transport.

Syngenta Crop Protection, Inc. (Syngent a) has proposed azoxystrobin uses on ginseng (import), oats, and cereal grains. Concurrently, Syngenta is requesting to amend the pre

- harvest intervals (PHIs) of the registered labels for cereals (wheat, barley, and triticale) from 14

- 30 days to 7 days

fo r 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 application. The limitation is to apply the last application no later than Feekes Growth Stage 10.54

. The most recent human health risk assessment was conducted to evaluate azoxystrobin use on sugarcane (K. Rury, 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 required for azoxystrobin. The Agency has waived the inhalation toxicity study data requirement for azoxystrobin at this time (TXR# 0056307). An immunotoxicity study remains required for azoxystrobin.

Use Profile For ginseng, azoxystrobin SC (suspension concentrate) Ortiva is proposed for four foliar applications at 10 m L formulated product/20 m L water with a 7

- day pre

- harvest interval ( PHI )

. The maximum application rate is 1519 g ai/ha (1.36 lb ai/A). Additional information was received: azoxystrobin content changed from 20% to 21.7%; application spray volume (3500 L/ha); product rate (1750 g (ml)/ha); and single application rate (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 application on cereal grain crops using ground, aerial, an d chemigation equipment. The use profile is summarized in Table 3.3. The proposed application rates on cereals (wheat, triticale, barley, oats, and rye) range from 0.07

- 0.20 lb ai/A or (4

- 12.0 fl oz product/A) with a maximum seasonal 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 applied per season and no more than 2 foliar applications should be applied per season . All labels require a 7

- day PHI for forage and hay. There is a growth stage restriction for the last appl ication 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 Manufacturing Use Concentrate (MUC) (EPA Reg. No. 100

- 1119), Azoxy strobin Dry Technical Manufacturing Use Concentrate (MUC) (EPA Reg. No. 100

- 1120),

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 5 of 42 and Azoxystrobin Millbase Manufacturing Use 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 inhalation toxicity study data requirement at this time (TXR# 0056307). In a 21

- day repeated dose d ermal study in the rat, no dermal or systemic toxicity was seen at the limit dose. In repeat

- dose oral studies, the liver and bile ducts were consistently the target organs of azoxystrobin toxicity. No developmental effects were seen in

rabbit or rat dev elopmental toxicity studies and no reproductive or offspring effects were seen in

the 2

- generation rat reproduction study. Although 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 e gories (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 ( NOAEL ) in assessing acute risk. No additional safety factor is

needed for short

- term, intermediate

- term, and ch ronic risk assessment. Although an immunotoxicity study is needed to complete the toxicological database, there are no concerns for immunotoxicity based on the results of the existing studies. There are no indications 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. 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 exp osure or risk. The estimated drinking water concentrations (EDWCs) 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 were incorporated directly into the dietary assessment. A partially refined acute dietary assessment was conducted using 100%

crop treated (%CT) estimates, tolerance

- level residues (for all commodities except citrus fruit)

and empirical or Dietary Exposu re Evaluation Model

– Food Commodity Intake Database ( DEEM

- FCID ) default processing factors. The results of the acute dietary analysis for food and drinking water show that the acute dietary risk estimates are below the Agency’s level of concern (LOC) (<1 00% of the acute population adjusted dose (aPAD)) for all population subgroups and

were estimated at 17 % of the aPAD for the general U.S. population and 41 % of the aPAD for the most highly exposed population subgroup (children 1

- 2 years old). A partially refined chronic dietary assessment was conducted using tolerance

- level residue s, a verage % CT estimates and

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 6 of 42 empirical or default DEEM

- FCIDTM processing factors

. The res ults of the chronic dietary analysis for food and drinking water indicate that the chronic dietary risk estimates are below the Agency’s LOC (<100% of the chronic population adjusted dose (cPAD)) for all population subgroups and w ere estimated at 7 % of the cPAD for the general U.S. population and 1 7 % of the cPAD for the most highly exposed population subgroup (children 1

- 2 years old). Azoxystrobin is classified as “not likely to be carcinogenic to humans;” therefore

, a cancer dietary risk

assessment was no t performed.

Residential Exposure No new residential uses were requested in this petition. However, a zoxystrobin is currently registered for use on several residential/non

- agricultural use sites. Residential exposure and risks

from use on turf and ind oor surfaces were reassessed using the updated 201 2 HED Residential Standard Operating Procedures (SOPs). All assessed residential risk estimates resulted in margins of exposure ( MOEs ) > 100; and therefore, are not of concern to HED.

Occupational Expo sure

Based on the proposed use pattern of azoxystrobin on cereal grains, t here is a potential for short

and intermediate

- term occupational exposure during handling (mixing

, loading , and applying ) and post

- application activities. Chronic exposure is not expected for the proposed 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., MOE s > 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 dermal exposure is expected following treatment of cereal grai n crops, dermal hazard was not identified for azoxystrobin. Therefore, a quantitative post

- application dermal risk assessment was not conducted. Based on the Agency's current practices, a quantitative non

- cancer occupational post

- application inhalation e xposure assessment was not performed for azoxystrobin at this time. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post

- application inhalation exposure assessment for azoxystrobin

. A c hem ical

- specific dislodgeable foliar residue (DFR) stud y 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 Rese arch This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data

, including studies from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), th e Agricultural Handler Exposure Task Force (AHETF) database, the Outdoor Residential Exposure Task Force (ORETF) database, and the Agricultural Re

- entry Task Force (ARTF) database, are subject to ethics review pursuant to 40 CFR 26, have received that revi ew, and are compliant with applicable ethics requirements. For certain studies

, that review may have included review by the Human Studies Review Board. Descriptions of data sources as well as guidance on their use can

be found at http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

.

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 7 of 42 2.0 HED Recommendations

HED recommends that the registration request be conditionally granted for azoxystrobin use on ginseng (import), oat, and rye.

2.1 Data Deficiencies

The following data are required:

870.7800 Imm unotoxicity 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 study is required for azoxystrobin under Regis tration Review and is due in 2012. A waiver request has been submitted and is pending review.

2. 2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate residue analytical methods are available for tolerance enforcement: a gas

chromato graphy 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 commodities for residues of azoxystrobin.

2.2.2 International Harmonization

Codex Maximum Residue Limits (MRLs) have been proposed for azoxystrobin i n ginseng at 0.1

ppm and dried ginseng including red ginseng at 0.5 ppm . A proposed MRL ginseng, processed products at 0.5 ppm has been returned to JMPR for further consideration of the processing study

. A Canadian MRL has been established for residues of azoxystrobin including the ( Z )

- isomer in ginseng roots at 0.5 ppm and at 0.03 ppm for barley, oats, rye, and wheat. Mexico adopts US

tolerances and/or Codex MRLs for its export purposes. Residue definitions are not harmonized with Codex; t he US residue definition includes both the predominant E isomer and the minor Z

isomer whereas t he Codex includes only the E isomer. The Codex MRL s on b arley grain a nd 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 and Codex MRLs are not in harmony for all proposed crops

. The US tolerances on oat grain (1. 5 ppm) and barley grain (3 ppm) could not be harmonized since the Codex MRLs are lower. HED recommends increasing

the US tolerances of ginseng to 0.5 ppm and to 0.2 ppm for rye and wheat grain to harmonize the numerical portion of the tolerance with the Codex MRL

. The Canadian MRL was harmonized only in ginseng roots.

2.2.3 Recommended Tolerances

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 8 of 42 Pending submission of a revised Section F, HED can recommend for establish ment of permanent
tolerance s for azoxystrobin in/ on ginseng and cereal grains. Th e tolerance values proposed by the petitioner need to be revised for all commodities as listed in the table below. The Organization for Economic Cooperation and Development (OECD) tolerance calculation procedures (March 2011 version) were utilized in dete rmining 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

-- 0.5 Based on data for dried ginseng root,

to harmonize with Codex.

Oat, forage 4 5

Oat , hay 7 10

Oat , straw 3 3

Oat

, grain 1 1.5

Rye, forage 4 7

Rye, straw 0.8 1.5

Rye, grain 0.07 0.2 To harmonize with Codex.

Barley, hay 7 10

Barley, straw 8 15

Barley, grain 2 3

Wheat, forage 10 15

Wheat, straw 6 10

Wheat, hay 20 30

Wheat, grain Not proposed (Established at 0.10) 0.2 Based on data/to harmonize with

Codex.

Grain, aspirated fractions 460 (Established at 420) 420 The established tolerance of 420 ppm

is sufficient. Grain, aspirated grain fractions

Livestock Commodities Requested To be Revised

Cattle, fat 0.3 Not Needed

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 9 of 42 Hog, fat 0.1

Hog, meat 0.02

Livestock Commodities Requested to be Established

Poultry, meat 0.01

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 P M: In conjunction with establishment of wheat grain tolerance at 0.2 ppm, the existing tolerance on wheat bran need to be removed from 40 CFR §180.507( a ) (1).

Note to P M : The tolerance expression in 40 CFR §180.507(a)(2) is incorrect. Therefore, the 40 CFR §180.507(a)(2) should be revised to specify the following tolerance expression : Tolerances are established for residues of the fungicide, azoxystrobin, including its metabolites and degradates, in or on the commodities in the following table. Compliance with the tolerance levels specified in the table is to be determined 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

Based on the available data, the proposed tolerances for all commodities must be revised to reflect the appropriate tolerance levels estimated using adjusted residue values to reflect the higher application rate of the Abound ® label. The proposed t olerances are based on residue data

submitted using lower application 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.

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, late blight in pistachios, brown rot blossom blight, and fruit rot in

stone fr uits; and leaf and fruit spot in tree nuts . It has the same biochemical mode of action as the naturally occurring strobilurins and is structurally related. Azoxystrobin is a

- methoxyacrylate, and acts by inhibiting 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

c ommodit ies due to amendments of PHIs. Azoxystrobin is currently registe red for use on a variety of vegetable, fruit, cereal, and nut crops, as well as on ornamental plants and turf.

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 10 of 42 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 exposure is expected from the proposed uses of azoxystrobin. Only short

- and intermediate

- term 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 active ingredient (MAI) product formulations containing both azoxystrobin and propiconazole (11.7% for both). In addition, Syngenta i s requesting to add oats and rye use on three azoxystrobin manufacturing products: Azoxystrobin Manufacturing Use Concentrate (MUC) (EPA Reg. No. 100

- 1119), Azoxystrobin Dry Technical Manufacturing Use Concentrate (MUC) (EPA Reg. No. 100

- 1120), and Azoxyst robin Millbase Manufacturing Use Product (MUP) (EPA Reg. No. 100

- 1220).

Azoxystrobin (20% SC formulation; Ortiva) is proposed for use on ginseng as four foliar applications at 10 m L formulated product/20 m L water with a 7

- day 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 application rate of 1519 g ai/ha (1.36 lb ai/A)

.

Azoxystrobin is proposed for use as a foliar application on oats and ry e using ground, aerial, and chemigation equipment. The use profile is summarized in Table 3.3. The p roposed single application rates on cereals (wheat, triticale, barley, oats, and rye) range from 0.07

- 0.20 lb ai/A (4

- 12.0 fl oz product/A) for Abound® Fl owable Concentrate and 0.03

- 0.13 lb ai/A (7

- 14 fl oz product/A) for Quilt Xcel® and Quilt. The Abound®, Quilt Xcel®, and Quilt® labels specifiy that no more than 0.40 lb ai/A of any azoxystrobin containing products should be applied per

season, and no mor e than 2 foliar applications should be applied per season . 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 presented in Table 3.1.

Table 3.1. Azoxystrobin Nomenclature.

Compound

Common name Azoxystrobin

Company experimental name ICIA5504 (Zeneca), R215504 (Syngenta)

IUPAC name methyl ( 2 E )

- 2

- {2

- [6

- (2

- cyanophenoxy)pyr i midin

- 4

- yloxy]phenyl}

- 3

- methoxyacrylate

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 11 of 42 Table 3.1. Azoxystrobin Nomenclature.

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, Z

isomer

Common name Azoxystrobin, Z

- isomer

Chemical name methyl ( Z )

- 2

- {2

- [6

- (2

- cyanophenoxy)pyr i midin

- 4

- yloxy]phenyl}

- 3

- methoxyacrylate



### 3.2 Physical/Chemical Characteristics

Azoxystrobin has a log octanol/water partition coefficient (log P ) of 2.5 and is considered relatively insoluble in water. However, azoxystrobin has a molecular weight of 403 g/mol; therefore, the potential to cross biological barriers is somewhat limited, as indicated by the low dermal absorption in the rat dermal pene tration study. In the cattle feeding study, azoxystrobin concentrated in cream. No quantifiable azoxystrobin residues were found in cattle muscle even at the highest dosing level, whereas quantifiable residues were observed in fat. The physicochemical p roperties of azoxystrobin are summarized in Appendix B

.

3.3 Pesticide Use Pattern

Syngenta has submitted a draft label with English translations for the 20% SC formulation of azoxystrobin (Azoxystrobin SC; Ortiva) reflecting established use patterns in Korea i n support of the requested import tolerance on ginseng. Syngenta has also submitted draft supplemental amended labels adding uses on oats and rye for Abound® Flowable Fungicide (EPA Reg. N o. 100

- 1098), Quilt Xcel® (EPA Reg. No. 100

- 1324), and Qui lt ® Fungicide (EPA Reg. No. 100

- 1178)

. In addition, Syngenta is requesting to add oats and rye use on three azoxystrobin manufacturing products: Azoxystrobin Manufacturing Use Concentrate (MUC) (EPA Reg. No.

100

- 1119), Azoxystrobin Dry Technical Manufacturing Use Concentrate (MUC) (EPA Reg. No.

100

- 1120), and Azoxystrobin Millbase Manufacturing Use Product (MUP) (EPA Reg. No. 100

- 1220). Table 3.3 provides a summary of the proposed use sites of azoxystrobin.

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 12 of 42 Table 3

. 3.1 Summar y of Directions for Use of Azoxystrobin on Ginseng

. Applic. Timing ; Type ; and Equip. Formu

lation Applic.

Rate 1 Max. No.

Applic. per

Season Max. Seasonal

Applic. Rate PHI

(days) Use Directions and

Limitations

Ginseng

Foliar; Broadcast; Equipment not specified 2 0% 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 for 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

- 1178, 100

- 1324 includes Triticale

Foliar Ground, aerial or chemigation 2.08 lb

ai/gal SC [100

- 1098] 6

- 12

( 0. 10

- 0.20 ) 2 1 0. 4 0 7

- forage

and hay Applications are to be made prior

to disease development

. Minimum volume for aerial applications is 5 gal/A.

Foliar Ground, aerial or chemigation SE/ MAI

( 0.62 lb ai/gal) [100

- 1 178 ] 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 a ppl y

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 13 of 42 Table 3.3

. 2 Summary of Directions for 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

( 1.18 lb ai/gal) [100

- 1 324 ] 7

- 14

( 0. 06

- 0. 13) 2 1 28 ( 0. 26) 7

- forage

and hay Quilt when flag leaf is 50% to

full head emergence (Feekes 10.5). Applicatio ns may be made no

closer than a 14

- day interval. An adjuvant may be added at

recommended rates.

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 mor e than 0.40 lb ai/A per season of azoxystrobin

- containing products.



### 3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed new use of azoxystrobin on ginseng, oat, and rye. Hu mans may be exposed to azoxystrobin in drinking water, since application 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. There are residential uses of azoxystrobin, so exposure to azoxystrobin may occur in residential or non

- occupational settings. In an occupational setting, handlers may be exposed while handling the pesticide prior to application, as well as during applica tion. There is also a potential for post

- application exposure for workers re

- entering

treated sites.

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

exposure assessment.

3.5 Consideration of Environ mental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Po pulations and Low

- Income Populations," ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption,

and activities in and around the ho me that involve pesticide use in a residential setting.

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 14 of 42 Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture’s National Health and Nutrition Examination 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 categorized by subgroups based on age, season of the year, ethnic group and region of the country. Additionally, OPP is able to assess dietary

exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for todd lers , youths and adults entering or playing on treated areas post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consid er exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

- 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 Subgroups 13

- 07 A, B, F, G, Oilsee ds 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 risk assessment (K. Rury, D389702, 01/18/2 012). The submitted studies are of good quality and provide sufficient information to determine whether azoxystrobin poses a human health hazard . In addition, the registrant, Syngenta, has committed to submitting an adequate functional immunotoxicity stu dy that is currently underway and expected to be submitted to the Agency in 2012. A waiver request has been submitted and is pending review.

4.1 Toxicological Effects

Azoxystrobin has a low acute toxicity via the oral, dermal and inhalation routes of e xposure. It produced light irritation to eye and skin, but the effects were cleared by 48 hours for the eye and three days for the skin. Dietary administration of azoxystrobin to rats resulted in decreased body weights, decreased food intake and utilizat ion, increased diarrhea

, and other clinical toxicity observations (increased urinary incontinence, hunched postures

, and distended abdomens). In addition, liver effects

, characterized by increased liver weights, increases in alkaline phosphatase and ga m ma glutamyltransferase, decreases in albumin

, 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, in creased incidence of diarrhea was observed at all dose levels tested including the LOAEL. Decreased body weight , decreased body weight gain, and food utilization was noted in the rat subchronic neurotoxicity study

. T here were no indications

of treatment

- related neurotoxicity in either the acute or subchronic neurotoxicity studies.

In the rat developmental toxicity study, diarrhea, urinary incontinence

, and salivation were observed in maternal animals; in the rabbit developmental toxicity study, materna l animals exhibited decreased body weight gain. No adverse treatment

- related developmental effects were

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 15 of 42 seen in either study. In the rat reproduction study, offspring and parental effects (decreased body weights and increased adjusted liver weights) 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 lymphoma assay, but the activity expressed in vitro is not expected to be expressed in whole animals.

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

EPA has retained the FQPA SF, reduced to 3X, in assessing acute dietary risk. An additional safety factor is needed for acute risk assessment to account for the use of a LOAEL from the acute neurotoxicity study in rats in deriving the acute reference dose used for assessing acute dietary exposure for all populations including infants and children. To a ccount 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 extrapolate a NOAEL in assessing acute risk and that no additional safety factor is needed for short

- t erm, 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 involving gavage dosing in the rat but not in repeat dosing through dietary administration 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 determinatio n is based on the following considerations:

4.2.1 Completeness o f the Toxicology Database

The toxicity database for azoxystrobin is complete except for immunotoxicity and subchronic inhalation toxicity testing. Changes to 40 CFR part 158 make immunotox icity testing (OPPTS Guideline 870.7800) required for pesticide registration; however, the existing data are sufficient for endpoint selection for exposure/risk assessment scenarios, and for evaluation of the requirements under the FQPA. There are no indic ations 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 c onsiderations, EPA does not believe that conducting the immunotoxicity study will result in a dose less than the point of departure already used in this risk assessment, and an additional database uncertainty factor for potential immunotoxicity does

not ne ed to be applied

.

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

4.2.2 Evidence of N eurotoxicity

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 16 of 42 Clinical signs , including transient diarrhea and decreased body weight, body weight gain, and food utilization, were no ted in the acute and subchronic neurotoxicity studies , but were not
considered indicative of neurotoxicity. There is no need for a developmental neurotoxicity study or additional UFs to account for neurotoxicity.

4.2.3 Evidence o f Sensitivity/Su sceptibil ity in the Developing o r Young Animal

There is no evidence that azoxystrobin results 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 Datab ase

There are no residual uncertainties in the azoxystrobin exposure database. While some refinements were incorporated into the dietary exposure calculations, EPA is confident that the aggregate risk from exposure to azo xystrobin in food, drinking water

, and residential pathways

will not be underestimated. The acute dietary (food) exposure assessment utilized conservative

upper

- bound inputs including 100% of the proposed and registered crops treated, and tolerance

level residues for all existing and proposed commodities, except citrus 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 a nd % CT estimates when available (Screening Level Usage Analysis (SLUA), 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 and associated modeling parameters which are designed to produce conservative, 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 potential exposure for infants, children

, or women of child bearing age. In addition, the residential exposure assessment is base d on the updated 2012 Residential SOPs employing surrogate study data, including conservative exposure assumptions based on Day 0 dermal/oral contact to turf and surfaces treated at the maximum application rate. These data are reliable and are not expecte d to underestimate risks to adults or children. The Residential SOPs are based upon reasonable “worst

- case” assumptions are not expected to underestimate risk.

4.3 Toxicity Endpoint and Point of D eparture Selections

4.3.1 Summary of Points of Departure and Toxicity Endpoints Used in Human Health

Risk Assessment

The toxicological doses and endpoints supporting this petition remain unchanged and have been summarized in the previous human health risk assessment (K. Rury, D389702, 01/18/2012). T he toxicity endpoints and PODs are presented in Table 4. 3.1.

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 17 of 42 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 = 10 X

UF H = 10 X FQPA SF =

3X Acute RfD =

0. 67 mg/kg/day

a PAD = 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 = 10 X

UF H = 10 X FQPA SF =

1 X 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 Short

Term (1

- 30 days) NOAEL = 25

mg/kg/day UF A = 10 X

UF H = 10 X FQPA SF =

1 X 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

Intermediate

Term (1

- 6 months) NOAEL = 20

mg/kg/day UF A = 10 X

UF H = 10 X FQPA SF =

1 X 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 scenario. 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 = 10 X

UF H = 10 X FQPA SF =

1 X 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

Intermediate

Term ( 1

- 6 months ) Oral NOAEL

= 20 UF A = 10 X

UF H = 10 X FQPA SF=1 X 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 estimated 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 f rom animal to human (interspecies). UF H = 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 = margi n 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 and the Agency's current practices, the inhalation risk for azoxystrobin was assesse d using an oral toxicity study. The Agency sought expert advice and input on issues related to this route to route extrapolation approach (i.e., the use of

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 18 of 42 oral toxicity studies for inhalation risk assessment) from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, re

- examine and develop new policies and procedures for conducting inhalation risk assessments, including route to route extrapolation of toxicity data. If any new policies or procedures are developed, 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, Environmental Degradation, and Metabolic Pathway Comparison

The nature of the residue in plants and livestock are adequately understood for the purposes of the Syngenta petition. Metabolism studies in grapes, peanuts, and wheat were submitted in conjunction with earli er azoxystrobin 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 profile remains unchanged (K. Rury, D389702, 01/18/2012). A m ore 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 degr adation of azoxystrobin also remains unchanged and has been summarized in the previous human health risk assessment (K. Rury, D389702, 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 Applicable



### 5.2 Food Residue Profile

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

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 19 of 42 Residues are quantifiable in all crops. Residues tend to be surface residues and generally decline with increasing pre

- harvest intervals (PHI). Processing studies indicate that residues concentrate in dried citrus pulp, citrus oil, dried basil, field corn oil, peanut oil, tomato paste, wheat bran , and

w heat germ . Livestock feeding studies indicate low transfer of residues to meat and milk with the highest transfer in liver. No quantifiable residues were found in any poultry commodity.

Proposed Uses Crop field trials were submitted to support the tole rances on ginseng (import), oat, and rye. In addition, crop field trials on barley and wheat were submitted to support the PHI revisions requested on the registered labels for cereals (wheat, barley, and triticale) and remove the 45

- day PHI for grain and straw and replace it with growth stage restriction for the last application on the proposed end use products. The established tolerances on barley and wheat commodities were revised due to these changes.

The submitted crop field trial data for ginseng c onducted in Korea are acceptable pending

submission of a revised Section F.

The submitted crop field trial data for oat, rye, barley, and wheat are acceptable pending

submission of Section F. Although the number of field trials is technically inadequate (oats and rye) , HED concludes that the available data are sufficient to support registration of azoxystrobin on oats and rye because the field trials c onducted cover all zones requested. The submitted wheat and barley data to change the PHIs of forage and hay from 14

- 30 days to 7

- days, and replace the 45

- day PHI with a growth stage restriction for grain and straw is acceptable.

The crop field trial data for oats, rye, barley, and wheat reflect the proposed use patterns of Quilt

® Fungicide (EPA Reg. No. 100

- 1178) and Quilt Xcel ® Fungicide (EPA Reg. No. 100

- 1324)

. The submitted crop field trials were conducted using Quilt Xcel ® with two foliar applications at 0.13 lb ai/A/application for a total seasonal application rate of 0.26 lb ai/A. The crop field trial data do not reflect the proposed use pattern of the Abound ® Flowable Fungicide (EPA Reg. No.

100

- 1098). The Abound ® can be applied in a miximum of two foliar applications at 0.20 l b ai/A/application for a total seasonal application rate of 0.40 lb ai/A. The existing wheat tolerances were established using the Abound ® according to the label rate

. The current tolerances on barley were established based on translation of residue data from wheat. The submitted crop field trials were conducted at lower application rates than the Abound ® label. Therefore, residue levels were adjusted using the proportionality rule before deriving a tolerance

level to reflect the proposed highest applic ation rate.

Syngenta submitted an acceptable processing study for azoxystrobin on wheat. Quantifiable total residues (azoxystrobin and Z

- isomer) concentrate in aspirated grain fractions (218x), bran (1.4x), and germ (1.2x), but not in flour, middlings, a nd shorts ( 0.3x, 0.4x, 0.5x, respectively ) following processing of the RAC (wheat grain) . All of the processing factors calculated in this study were less than the maximum theoretical concentration factors for wheat (7.7x for bran, 1.4x for flour, and 8.3 x for shorts).

Acceptable methods were used for the determination of residues of azoxystrobin and the Z

isomer metabolite. The sample storage conditions and durations are supported by adequate

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 20 of 42 storage stability data which demonstrate that azoxystrobin a nd its Z

- isomer are stable for at least

24 months in water

- starch

- , protein

- , oil

- , and acid containing materials under frozen conditions.

A summary of the residue data from the field trials including the wheat processing study are provided in Tables 5.2.a.

- 5.2. f.

Table 5.2a

. Summary of Residue Data from Ginseng Crop Field Trials with Azoxystrobin.

Commodity Plot 1 Total App.

Rate

lb ai/A (g ai/ha) PHI Residue Levels (ppm) 1

n Sample

Min. Sample

Max. LAFT 2 HAFT 2 Median Mean Std.

Dev.

Ginseng (proposed use = 10 mL formulated product/20 L water, 7

- day PHI)

MRID 48601203

Ginseng,

dried root 2008 trials 1.98 (2,222) 7 2 0.10 0.14 0.12 0.13 0.13 0.13 N/A

MRIDs 48601201 and 48601202

Ginseng,

dried root 1a

(2009 trials) 1.21

- 1.29

(1,355

- 1,450) 7 2 0.034 0.049 0.034 0.048 0.041 0.041 N/A

1b (2009

- 2010 trials) 2.43

- 2.58

(2,724

- 2,894) 7 2 0.060 0.179 0.063 0.177 0.120 0.120 N/A

The 2008 trials and Plot 1a received four foliar applications in year 1; plot 1b received four additional foliar applications in year 2 according to the same use pattern. The total seasonal application rate for Plot 2b was 1.221

- 1.288 lb ai/A (1,369

- 1,444 g ai/ha).

Table 5.2b

. Summary of Residue Data from Oat Crop Field Trials with Azoxystrobin.

Com

modity Analyte Total App.

Rate (lb ai/A) PHI Residue Levels (ppm) 1

n Sample

Min. Sample

Max. LAFT 2 HAFT 2 Median Mean Std.

Dev.

Forage Azoxystrobin 0.2494

- 0.2650 7 11 0.106 2.21 0.109 1.98 0.781 0.784 0.566

R230310 11 <0.01 0.124 <0.01 0.112 0.0312 0.0438 0.0345

Combined 11 <0.116 2.33 <0.119 2.09 0.815 0.826 0.597

Combined 3 11 0.179 3.59 0.183 3.22 1.26 1.27 0.92

Azoxystrobin 14 11 0.0417 1.02 0.0513 0.970 0.262 0.391 0.314

R230310 11 <0.01 0.0734 <0.01 0.0679 0.0126 0.0297 0.0249

Combined 11 <0.0517 1.09 <0.0613 1.04 0.272 0.421 0.338

Hay Azoxystrobin 7 11 0.147 3.38 0.200 3.16 1.06 1.48 1.19

R230310 11 <0.01 0.220 <0.0120 0.198 0.0577 0.0930 0.0724

Combined 11 <0.157 3.59 <0.212 3.36 1.19 1.58 1.26

Combined 3 11 0.242 5.53 0.326 5.17 1.83 2.43 1.94

Azoxystrobin 14 11 0.126 2.34 0.139 1.77 0.576 0.718 0.496

R230310 11 <0.01 0.181 <0.01 0.123 0.0435 0.0567 0.0402

Combined 11 <0.136 2.52 <0.149 1.89 0.619 0.774 0.534

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 21 of 42 Table 5.2b

. Summary of Residue Data from Oat Crop Field Trials with Azoxystrobin.

Com

modity Analyte Total App.

Rate (lb ai/A) PHI Residue Levels (ppm) 1

n Sample

Min. Sample

Max. LAFT 2 HAFT 2 Median Mean Std.

Dev.

Grain Azoxystrobin 0.2532

- 0.2696 25

- 48 11 0.0115 0.636 0.0127 0.374 0.0521 0.120 0.134

R230310 11 <0.01 0.121 <0.01 0.0709 0.0106 0.0238 0.0229

Combined 11 <0.0215 0.751 <0.0227 0.444 0.0626 0.144 0.157

Combined 3 11 0.033 1.16 0.035 0.684 0.096 0.221 0.241

Straw Azoxystrobin 25

- 48 11 0.0429 0.934 0.0487 0.880 0.197 0.387 0.332

R230310 11 <0.01 0.146 <0.01 0.131 0.0189 0.0457 0.0438

Combined 11 <0.0529 1.08 <0.0587 1.01 0.215 0.432 0.373

Combined 3 11 0.082 1.66 0.129 1.56 0.564 0.721 0.556

Table 5.2c

. Summary of Residue Data from Rye Crop Field Trials with Azoxystrobin.

Com

modity Analyte Total App.

Rate (lb ai/A) PHI Residue Levels (ppm) 1

n Sample

Min. Sample

Max. LAFT 2 HAFT 2 Median Mean Std.

Dev.

Forage Azoxystrobin 0.2571

- 0.2617 6

- 8 4 1.03 1.54 1.05 1.52 1.25 1.27 0.227

R230310 4 0.0305 0.0955 0.0359 0.0955 0.0532 0.0595 0.0257

Combined 4 1.06 1.59 1.08 1.58 1.32 1.32 0.249

Combined 3 4 1.63 2.45 1.66 2.43 2.02 2.04 0.384

Azoxystrobin 13

- 15 4 0.396 0.628 0.418 0.590 0.486 0.495 0.0794

R230310 4 0.0176 0.0301 0.0183 0.0299 0.0245 0.0243 0.0063

Combined 4 0.414 0.658 0.437 0.619 0.510 0.519 0.0853

Grain Azoxystrobin 0.2563

- 0.2646 34

- 50 4 <0.01 0.0159 <0.01 0.0151 0.0100 0.0113 0.0026

R230310 4 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

Combined 4 <0.02 <0.0259 <0.02 <0.0251 0.0200 0.0213 0.0026

Combined 3 4 0.031 0.040 0.031 0.039 0.031 0.033 0.004

Straw Azoxystrobin 34

- 50 4 0.0911 0.495 0.0952 0.382 0.158 0.198 0.126

R230310 4 <0.01 0.0363 <0.01 0.0315 0.0198 0.0203 0.0091

Combined 4 <0.101 0.531 <0.105 0.414 0.178 0.219 0.135

Combined 3 4 0.156 0.818 0.162 0.638 0.273 0.336 0.208

Table 5.2d

. Summary of Residue Data from Barley Crop Field Trials with Azoxystrobin.

Com

modity Analyte Total App.

Rate (lb ai/A) PHI Residue Levels (ppm) 1

n Sample

Min. Sample

Max. LAFT 2 HAF

T 2 Median Mean Std.

Dev.

Hay Azoxystrobi

n 0.2532

-

0.2674 7 9 0.448 3.77 0.451 3.62 0.834 1.49 1.20

R230310 9 0.0139 0.391 0.0181 0.343 0.0702 0.0976 0.100

Combined 9 0.462 4.16 0.469 3.96 0.904 1.59 1.28

Combined 3 9 0.711 6.41 0.722 6.10 1.39 2.44 1.98

Azoxystrobi

n 14 9 0.145 2.93 0.150 2.73 0.337 0.856 0.878

R230310 9 <0.01 0.342 <0.0107 0.342 0.0343 0.0713 0.105

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 22 of 42 Table 5.2d

. Summary of Residue Data from Barley Crop Field Trials with Azoxystrobin.

Com

modity Analyte Total App.

Rate (lb ai/A) PHI Residue Levels (ppm) 1

n Sample

Min. Sample

Max. LAFT 2 HAF

T 2 Median Mean Std.

Dev.

Combined 9 0.156 3.27 0.160 3.07 0.371 0.926 0.973

Grain Azoxystrobi

n 0.2560

-

0.2649 16

- 49 9 <0.01 1.07 <0.01 0.974 0.0366 0.183 0.314

R230310 9 <0.01 0.116 <0.01 0.112 0.0100 0.0273 0.0341

Combined 9 <0.02 1.19 <0.02 1.09 0.0466 0.210 0.350

Combined 3 9 0.031 1.83 0.031 1.68 0.072 0.323 0.539

Straw Azoxystrobi

n 16

- 49 9 0.0835 3.83 0.0896 3.49 0.356 1.24 1.44

R230310 9 <0.01 0.463 <0.01 0.379 0.0295 0.131 0.157

Combined 9 0.0945 4.29 0.101 3.87 0.377 1.37 1.59

Combined 3 9 0.146 6.61 0.156 5.96 0.581 2.11 2.45

Table 5.2e

. Summary of Residue Data from Wheat Crop Field Trials with Azoxystrobin.

Com

modity Analyte Total App.

Rate (lb ai/A) PHI Residue Levels (ppm) 1

N Sample

Min. Sample

Max. LAFT 2 HAFT 2 Median Mean Std.

Dev.

Forage Azoxystrobin 0.2534

- 0.2668 7 15 0.0825 6.17 0.0898 5.91 0.799 1.67 1.85

R230310 15 <0.01 0.207 <0.01 0.175 0.0500 0.0597 0.0532

Combined 15 <0.0925 6.25 <0.0998 5.99 0.842 1.73 1.89

Combined 3 15 0.142 9.62 0.154 9.225 1.30 2.66 2.91

Azoxystrobin 14

- 20 15 0.0289 1.65 0.0307 1.62 0.258 0.457 0.495

R230310 15 <0.01 0.0962 <0.01 0.0870 0.0161 0.0266 0.0235

Combined 15 <0.0389 1.75 <0.0407 1.71 0.274 0.483 0.518

Hay Azoxystrobin 7 15 0.171 15.6 0.194 14.7 1.28 2.79 3.82

R230310 15 <0.01 0.333 <0.01 0.271 0.0835 0.103 0.0911

Combined 15 <0.181 15.8 <0.204 14.8 1.36 2.89 3.87

Combined 3 0.279 24.3 0.314 22.8 2.09 4.45 5.96

Azoxystrobin 14

- 20 15 0.0767 3.14 0.0816 2.73 0.534 0.858 0.888

R230310 15 <0.01 0.160 <0.01 0.138 0.0297 0.0519 0.0467

Combined 15 <0.0867 3.30 <0.0916 2.87 0.564 0.909 0.930

Grain Azoxystrobin 0.2475

- 0.2669 24

- 64 15 <0.01 0.0795 <0.01 0.0764 0.0107 0.0176 0.0170

R230310 15 <0.01 <0.01 < 0.01 <0.01 0.01 0.01 N/A

Combined 15 <0.02 <0.0895 <0.02 <0.0864 0.0207 0.0276 0.0170

Combined 3 15 0.031 0.138 0.031 0.133 0.032 0.042 0.026

Straw Azoxystrobin 24

- 64 15 0.0369 4.03 0.0377 4.00 0.546 0.991 1.14

R230310 15 <0.01 0.372 <0.01 0.358 0.0646 0.107 0.115

Combined 15 <0.0469 4.37 <0.0447 4.36 0.610 1.10 1.25

Combined 3 15 0.072 6.73 0.069 6.71 0.939 1.69 1.92

1 Except for sample min/max, values reflect per trial averages; n = no. of field trials. For calculation of median, mean, and standard deviation, the LOQ (0.01 ppm) was used for any results reported as <LOQ. N/A = Not applicable.

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 23 of 42 2 LAFT = lowest average f ield trial; HAFT = highest average field trial.

3 Adjusted combined residues.

Table 5.2f

. Residue Data from Wheat Processing Study with Azoxystrobin.

RAC Processed

Commodity Total

Rate (lb ai/A) PHI Residues (ppm) 1 [Average] Processing Factor 2

Azoxystrobi

n R230310 Combined Azoxystrobi

n R230310 Combined

Cheneyville, LA; 2009 (E17

- 9032)

Wheat Grain

(RAC) 1.283 30 0.129, 0.119 [0.124] 0.0136,

0.0109 [0.0123] 0.143,

0.130 [0.136] -- -- --

AGF 28.1 2.82 30.9 227x 230x 227x

Bran 0.129 0.0163 0.145 1.0x 1.3x 1.1x

Flour 0.0273 <0.01 <0.0373 0.22x <0.82x <0.27x

Middlings 0.0535 <0.01 <0.0635 0.43x <0.82x <0.47x

Shorts 0.0814 <0.01 <0.0914 0.66x <0.82x <0.67x

Germ 0.114 0.0134 0.127 0.92x 1.1x 0.94x

Carrington, ND; 2009 (C13

- 9038)

Wheat Grain

(RAC) 1.283 55 0.0524, 0.0523,

0.0529 [0.0525] <0.01,

<0.01,

<0.01 [<0.01] <0.0624,

<0.0623,

<0.0629 [<0.0625] -- -- --

AGF 12.1 0.942 13.0 230x >94x >209x

Bran 0.0887 0.0150 0.104 1.7x >1.5x >1.7x

Flour <0.01 ND <0.0200 <0.19x NC 3 <0.32x

Middlings 0.0115 <0.01 <0.0215 0.22x NC <0.34x

Shorts 0.0102 <0.01 <0.0202 0.19x NC <0.32x

Germ 0.0851 <0.01 <0.0951 1.6x NC <1.5x

Average 4

Wheat Grain

(RAC) 1.283 30

-

55 -- -- --

AGF 228x >162x >218x

Bran 1.4x > 1.4x >1.4x

Flour <0.21x <0.91x <0.30x

Middlings 0.33x <0.91x <0.40x

Shorts 0.43x <0.91x <0.50x

Germ 1.3x <1.1x <1.2x

1 The LOQ was 0.01 ppm for all analytes in all matrices. Per trial average residues were calculated by the study reviewer using the LOQ for all residues reported as <LOQ. ND = Not detected. Residues were not adjusted.

2 Processing Factor = [Measured residue for analyte in the processed fract ion] / [Measured residue for analyte in the grain RAC].

3 NC = Not calculated; residues were below the LOQ in both RAC and processed fraction.

4 In the calculation of the average processing factor, a value of 1.0 was used when a processing factor was not calculated due to residues <LOQ in the processed fraction.

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 24 of 42 Livestock

The additional livestock feedstuffs associated with this petition are gr ain, forage, hay, and straw of oats, and rye. The established tolerances for hay and straw of wheat and hay of barley will increase based on the submitted data, but were not included in the current dietary burden

estimate since these tolerances will not a ffect the total estimated dietary burden. H ED has recently revised its approach to calculating dietary burdens, replac ing tolerance values in the calculation with HAFT residues for most feedstuffs, median residues for blended feeds, and

median residues x processing factors for most processed commodities. This has generally resulted in appreciably lower dietary burdens for all species. The proposed commodities are fed to beef and dairy cattle, but are not fed to poultry or swine, except oat and rye grain which are fed to poultry. The previously estimated dietary burden ( D390152 , M. Negussie, 01/04/2012), will not be affected since the recommended tolerances and the percents of the diets are much lower for oat and rye commodities.

The existing azoxystrobi n tolerances for milk , milk fat

, meat, and the meat byproducts of goat

, hog

, horse

, and sheep are adequate . R evision s to the existing tolerances are not needed to support the proposed uses of azoxystrobin. The proposed uses of azoxystrobin addressed in t his document do not alter the Agency’s previous conclusion that there is no reasonable expectation of finite residues in poultry commodities [Category 3 of §180.6(a)]. T olerances are not needed for poultry tissues or eggs.

Rotational Crops

Limited fiel d rotational crop studies, reflecting applications made to the primary crop at a

seasonal rate of 0.8

- 2.0 lb ai/A, were previously reviewed. Because the proposed use s on oat and rye do not result in increased maximum seasonal application rates of azoxystr obin, no changes to the existing rotational crop restrictions are needed. Subsequent to the establishment of tolerances in/on oat and rye, t he rotational crop restrictions on the r egistered labels for the Abound ® and Quilt Xcel ® Fungicides should be revis ed to change the PBIs for oats and rye to 0

- days. HED assumes that the rotational crop restrictions specified on the Quilt labels are due to use of propioconazole.

5. 3 Water Residue Profile

The drinking water inputs provided in the previous 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, 07/25/2012). EFED estimates drinking water concentrations of a chemical based on the high est rate of application of the chemical on all registered and proposed crops. In the case of azoxystrobin, turf, a previously registered use, has the highest application rate (0.55 lb ai/A, 9 applications per year with a 10

- day interval between applicatio ns). The assessment was completed with the Tier 1 screening model, FQPA Index Reservoir Screening Tool (FIRST). The model and its description is available at the EPA

internet site: http://www.epa.go v/oppefed1/models/water/

.

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 25 of 42 The proposed rates of application for oat and rye are lower than for turf. Therefore, the EDWCs reported for turf are used. EDWCs recommended for use in the human health risk assessment for all proposed/registered crops are lis ted 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 azoxystrobin is partially refined by using highest residue values for citrus fruits and assuming tolerance

- 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.

The chronic dietary exposure asse ssment was partially 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). % CT estimates were used when available.

HED utilized BEAD’s estimated % CT for the existing uses as follows: a lmonds, 25%; apricots, 10%; artichokes, 25%; asparagus, 2.5%; green beans, 10%; blackberries, 5%; blueberries, 10%, broccoli, 5%; cabbage, 10%; cantaloupes, 10%; carrots, 10%; cauliflower, 2.5%; cele ry, 10%; cherries, 5%; corn, 2.5%; cotton, 5%; cucumbers, 20%; dry beans/peas, 1%; garlic, 60%; grapefruit, 20%; grapes, 5%; hazelnuts (filberts), 5%; lettuce, 2.5%; onions, 10%; oranges, 5%; peaches, 5%; peanuts, 15%; green peas, 2.5%; pecans, 2.5%; peppe rs, 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 conducted 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, adult s 50+ and females 13

- 49 ). The acute dietary exposure estimate for food and drinking

water utilized 17% of the aPAD for the general U.S. population. The acute dietary exposure estimate for the highest reported exposed population 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

th e LOC.

The acute dietary exposure assessment is partially 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, Orange = 4.014 ppm, Orange, peel = 5.538 ppm, Lemon

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 26 of 42 and Lime = 9.202 ppm]), used empirical or default DEEM processing factors, and assumed 100

% CT for all crops.

5. 4

. 3 Chronic Dietary Risk Assessment

A chronic dietary exposure assessment was conducted for the genera l 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 chronic dietary exposure for the highest reported exposed population subgroup, children 1

- 2 years old , utilized 1 7 % 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 partially refined, i.e.

, based on the assumption of

tolerance

- level residues for all commodities , used empirical or default processing factors and %

CT information fo r the crops listed in Section 5.4.1.

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 agricultural use s 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 residential handlers on resi dential use sites, including turf, ornamentals, indoor uses (carpet and hard surfaces)

, and in paints. Each of these existing residential use patterns has previously been assessed by HED and

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 27 of 42 the resulting exposures and risk estimates do not exceed HED’s L OC . However, HED has recently updated the residential standard operating procedures (SOPs) and body weights to be used in all human health assessments. Therefore, all the existing residential use patterns have

been reassessed for residential handler and 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 involve applications by homeowners or commercial applicators to residential setting s. However, azoxystrobin is currently registered for use by residential and commercial applicators on several residential/non

- agricultural use sites; i.e., outdoor residential (lawns, ornamentals, flower gardens, vegetables, fruit and nut trees, berries

a nd vines) and recreational (golf courses, parks and athletic fields) sites. Additionally, residential and commercial applicators may use azoxystrobin on indoor carpets/other surfaces, and in treated paints (preservative incorporation). All existing r esid ential exposures have been reassessed to account for updates to HED’s 2012 Residential SOPs along with policy changes for body weight assumptions. It is assumed that most residential uses will result in short

- term (1 to 30 days) handler exposures. Reside ntial 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 exposure 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 believe this assessment is under

- protective of

adult handlers.

HED’s LOC for the MOE i s defined by the uncertainty factors that are applied to the assessment. HED applies a 10X factor to account for interspecies extrapolation and a 10X factor to account for intraspecies sensitivity. The total uncertainty factor that has been applied to th e non

- cancer risk assessment for azoxystrobin is 100X for residential 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 10 0; therefore, they are not of concern to HED. The MOEs for adult handlers ranged from 2,400 (painting with an airless sprayer) to 1,000,000,000 (mixing/loading/applying [M/L/A] a wettable powder to gardens and trees using a hose

- end sprayer).

Table 6 .1

. Short

- Term Residential Handler Non

- Cancer Exposure and Risk Estimate for Azoxystrobin.

Exposure Scenario Level of

Concern Inhalation

Unit Exposure (μg/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

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 28 of 42 Table 6 .1

. Short

- Term Residential Handler Non

- Cancer Exposure and Risk Estimate for Azoxystrobin.

Exposure Scenario Level of

Concern Inhalation

Unit Exposure (μg/lb ai) Maximum

Application

Rate 1 Area Treated or

Amount Handled Daily 2 Inhalation

Dose (mg/kg/day) 3 MOE 4

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 Backpack Sprayer] 100 0.018 0.011 (lb ai/gal) 5 gallons 0.000012 2,000,000

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 (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Amount Handled (gallons/day) / BW (kg).

4 Inhalation MOE = Inhalation NOAEL (mg/kg/day) / Inhalation Dose (mg/kg/day). Short

- term Inhalation NOAEL = 25 mg/kg/day

.



### 6.2 Post

- Application Exposure

When determining the potential for residential exposure, the Agency considers residues, leaf to skin/hand residue transfer, children’s hand

- to

- mouth residue transfer, and exposure time. No dermal endpoint was chosen for a zoxystrobin; therefore, a dermal post

- application risk

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 29 of 42 assessment was not conducted. Residential post

- application inhalation exposure in outdoor settings is considered negligible; however, residential post

- application inhalation exposure has

been assessed . Post

- application exposure in residential settings is expected to be short

- term in duration only. Table s 6.2 lists t he highest estimate based on updated assessments of residential

post

- application exposures and risk estimates. 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

- application inhalation exposure. The new exposure and risk estimates for all residential post

- application uses result in risk estimates that are greater than the LOC MOE of 100, and therefore are not of concern to HED.

A t urf transferable residue (TTR) stud y may be required in the future if the use profile is expanded. However, the TTR study requirement is currently waived for azoxystrobin (TXR# 0056307).

Table 6. 2

. Highest Residential Post

- Application Non

- Cancer Exposure and 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 reasonably 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 generally should not be combine d. Additionally, no dermal endpoint was chosen for azoxystrobin and outdoor inhalation post

- application exposure is considered negligible. Therefore, residential post

- application exposure scenarios for azoxystrobin were not combined.

6.4 Residential B ystander Post

- A pplication Inhalation Exposure Although a quantitative residential post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for residential handlers. This exposure scenario is repres entative of a worse case inhalation exposure and should be considered protective of most post

- application inhalation exposure scenarios.

6.5 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for azoxystrobin

. The Agency has been working with the Spray Drift Task Force, EPA Reg ional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information 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

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 30 of 42 on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task For ce, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods.

After th e policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off

- target drift with specific products with significant risks

associated with drift.

7.0 Aggregate Exposure/Risk Characterization

In accordance wit h the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quanti tative estimates of hazard (e.g. a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. For azoxystrobin, potential exposures from food , 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 exposure to residues of azoxystrobin in food and water, and do not include dermal, inhalation

, or incidental oral exposure. 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 below 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 azoxystrobi n via dietary (which is considered background exposure) and residential (which is considered primary) exposure pathways. For adults, these pathways lead to exposure via oral (background) as well as dermal and inhalation (primary) routes. The most conserv ative scenario was chosen for each population ( e.g

. , hand

- to

mouth exposure from carpets and textiles for children 1

- 2 years old ). For a description of the residential exposure scenarios considered in the aggregate assessment

, see Section 6.0.

The genera l US population (inhalation) aggregate MOE is 920

. Therefore, adult aggregate exposure and risk do es not exceed HED’s LOC (MOE < 100). The aggregate MOE for children

1

- 2 years old , including incidental oral exposures from treated carpets, is 190 , which in dicates

that aggregate exposure and risk is greater than HED’s LOC (MOE < 100). Further refinement

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 31 of 42 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/LOC

3. Residential Exposure = [Oral exposure + Inhalation Exposure]. Source of residential exposure values used in aggregate assessment (Table 6.1 and Table 6.2). Exposure estimate for Children 1

- 2 years includes post

- application inhalation exposure (0.00000000 087 mg/kg/day)+ incidental oral ingestion from treating carpets (0.0982 mg/kg/day) = 0.098 mg/kg/day.

4. Total Exposure = Avg Food & Water Exposure + Residential Exposure)

5. Aggregate MOE OAEL=25 mg/kg/day.



### 7.3 Intermediate

- Term Aggregate Risk

Intermediate

- term exposure is not expected for the adult residential (inhalation) exposure pathway. Therefore, the intermediate

- term aggregate risk would be equivalent to the chronic dietary exposu re estimate

. In the previous risk assessment, both short

- and intermediate

- term incidental oral residential risks were included in the aggregate risk assessment for azoxystrobin (K. Rury, D389702, 1/18/2012). Based on the azoxystrobin use pattern, and th e 2012 Revised Residential SOPs (2012), only short

- term residential handler and post

- application exposures should be included in the aggregate risk assessment.

7.4 Chronic Aggregate Risk

Chronic exposure is not expected for the adult residential (derma l 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 carcinogenic 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 followed 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 toxicity with other

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 32 of 42 substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to ev aluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have

a common mechanism on E PA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

Reference s :

- Azoxystrobin. Occupational and Residential Exposure Assessment to Evaluate the Risk from Proposed Uses on Sugarcane , K. Rury, D P#394287

, 03/30/2012

.



### 9 .1 Short

- /Intermediate

- Term Handler Risk

Azoxystrobin is proposed for use as a foliar application 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, t here is a potential for short

- and 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 ( long pa nts, a long

- sleeved shirt, shoes, socks, no chemical

- resistant gloves, and no respirator ). The Quilt Xcel®, Quilt® and Abound® require handlers to wear long sleeved shirts, long pants, chemical resistant gloves, shoes, and socks. Quilt Xcel® and Quilt® a lso 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. MOE s > 100) with

baseline mitigation (no respirator) . The short

- term inhalation MOE s 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 appears, however, that flaggers are still used in approximately 10 to 15 percent of aerial application operations. In cases like these, the Agency strongly encourages the use of the engineering control system but will continue to evaluate risks

for flaggers and any other population where a clear 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 consider those results as they are timely and ap propriate.

HED has no data to assess exposures to pilots using open cockpits. The only data available is for exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the engineering control (enclosed cockpits) and baseline attire (long

- sleeve shirt, long pants, shoes, and socks); pilots are not required to wear protective gloves. With this level of protection, there are no risk estimates of concern for applicators.

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 33 of 42 Table 9 .1. Short

- and Intermediate

- Term Occupational Expo sure 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 gloves or respirator y protection ).

Exposure Scenario Crop(s) Baseline

In halation

Unit Exposure (μg/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 Intermediate

Term 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 30,000

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 Table” (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 (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre) × Area Treated Daily (A/day) ÷ BW (kg). Bodyweight = 80 kg.

5 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). Short

- Term Inhalation NOAEL = 2 5 mg/kg/day.

6 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). Intermediate

- 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 during scouting, hand weeding, and hand harvesting. However, no appropriate dermal endpoint was identified for azoxystrobin. T herefore, an assessment of occupational dermal post

- application exposure to azoxystrobin was not conducted.

A c hemical

- specific dislodgeable foliar residue (DFR) stud y is available for the use of

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 34 of 42 azoxystrobin on grapes, but has not been employed in this o r previous risk assessments because

HED determined there is no hazard via the dermal route.

Based on the Agency's current practices, a quantitative post

- application inhalation exposure

a ssessment was not performed for azoxystrobin at this time primarily because of the low acute inhalation toxicity (Toxicity Category III), low vapor pressure ( 8.2x10 - 13 

### mm Hg at 20oC ), and the low proposed use rate (0. 20 lb ai/A). However, there are multiple potential sources of post

application inhalation exposure to ind ividuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its 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

- application inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post

- application inh alation exposure assessment for azoxystrobin

.

Although a quantit ative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to res ult in higher exposure than post

- application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post

- application inhalation exposure scenarios.

Nevertheless, per the Worker Protec tion Standard (WPS), a 12

- hour restricted entry interval (REI) is required for chemicals classified un der 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 technical material and the different end

- use product s 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 technical mate rial 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 the label, is acceptable for Abound ®



### . It should be noted that the REI

of 12 hours listed on t he multiple ai products Quilt Xcel® and Quilt ® with both azoxystrobin and propiconazole, is acceptable under the WPS.

10.0 References

J. Wolf, 01/06/ 20 10, DP#371383, Drinking Water Assessment for amended label Quadris TopTM fungicide (EPA Reg. No. 100

- 1313) Azoxystrobin for use on golf course turf (only).

1 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 35 of 42 I. Abdel

- Saheb, 07/25/2012, DP# 400772

, Drinking Water Exposure Assessment for new use of azoxystrobin on oat and rye.

N. Tsaur

, 10/09/2012 , DP# 4 02288

, Occupa tional 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 and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for Sectio n 3 Petitions 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# 2F798 4).

M. Negussie, 10/11 /2012, DP#397692, Section 3 Petitions 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)

. Summary of Analytical Chemistry and Residue Data

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 36 of 42 A ppendix 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 Inhalation Toxicity

................................ .............. 870.2400 Primary Eye Irritation

................................ .................... 870.2500 Primary Dermal Irritation

................................ .............. 870.2600 Dermal Sensitization

................................ ...................... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

................................ ............... 870.3150 Oral Subchronic (nonrodent )

................................ ......... 870.3200 21

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 90

- Day Inhalation

................................ .......................... yes

yes

yes

no CR 1 yes

yes

yes

no yes*

870.3700a Developmental Toxicity (rodent)

................................ ... 870.3700b Developmental Toxicity (nonrodent)

............................. 870.3800 Reproduction

................................ ................................ . yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

................................ .............. 870.4100b Chronic Toxicity (nonrodent)

................................ ........ 870.4200a Oncogenicity (rat)

................................ .......................... 870.4200b Oncogenicity (mouse)

................................ .................... 870.4300 Chronic/Oncogenicity

................................ .................... yes

yes

yes

yes

yes yes

yes

yes

yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

..................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

................ 870.5375 Mutagenicity

— Structural Chromosomal Aberrations

... 870.5385 Mutagenicity

— Other 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 General Metabolism

................................ ...................... 870.7600 Dermal Penetration

................................ ........................ 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)

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 37 of 42 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

2 1

- 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 increased 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 body

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 38 of 42 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 t he 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 syste m. Colony sizing was not performed.

870.5375 Cytogenetics

chromosomal aberration 43678147 (1992) Acceptable/guideline 0.5 to 50 μg/mL without S

9 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 μ g/mL

- S9; 100

- 200 μ g/mL +S9) that were moderately to severely cytotoxic (i.e. > 16

- 70% reductions in

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 39 of 42 Table A

. 2 .2 . Azoxystrobin Toxicity Results From Repeated Dosing and Other Studies. Study Guideline/Study MRID Results mitotic cells, respectively)

870.5385 Cytogenetics bo ne

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 glucuronid e 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 Absorption

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 40 of 42 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 OW ) log P = 2.5

UV/visible absorption spectrum Not available

### Azoxystrobin Human Health Risk Assessment DP No. 402285

Page 41 of 42 Appendix C. International Residue Limit Status Sheet

.



## Azoxystrobin (PC Code 128810; 08/22 /1 2 )

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] (αE)

- 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. 5 0.5 ginseng roots 0.1 Ginseng 0.5 Ginseng, dried 0.5 ginseng, processed products (both proposed) Oat, forage 5 Oat, hay 10
Oat, straw 3 15 straw and fodder of cereal grains Oat, grain 1.5 0.03 0.5 Rye, forage 7 Rye, straw 1.5 15 straw and fodder of cereal grains Rye, grain 0.2 0.03 0.2 Barley, hay 10 Barley, straw 15 15 straw and fodder of cereal grains Barley, grain 3 0.03 0.5 Wheat, forage 15
Wheat, straw 10 15 straw and fodder of cereal grains Wheat, hay 30 Wheat, grain 0. 2 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

n o t 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 42 of 42 3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of tre ated 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 Health Canada, U. S. Environmental Protection Agency, and the National Agricultural Chemicals Association, released February, 1995.

The Agricultural Handler Exposure 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).