### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 3 of 52 5.1.4 Residues of Concern Summary

................................ ................................ ............ 23

5.2 Food Residue Profile

................................ ................................ ................................ .... 24
5.3 Water Residue Profile

................................ ................................ ................................ .. 26
5.4 Dietary Risk Assessment

................................ ................................ .............................. 27
5.4. 1 Description of Residue Data & Percent Crop Treated Used in Dietary
Assessment

................................ ................................ ................................ ........................... 27

5.4.2 Acute Dietary Risk Assessment

................................ ................................ ........... 27

5.4.3 Chronic Dietary Risk Assessment

................................ ................................ ....... 27

5.4.4 Summary Table

................................ ................................ ................................ ..... 28

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

............................. 28
6.1 Residential Handler Exposure

................................ ................................ .................... 28
6.2 Post

- Application Exposure

................................ ................................ .......................... 29
6. 3 Combined Exposure

................................ ................................ ................................ ..... 30
6.4 Residential Bystander Post

- application Inhalation Exposure

................................ . 30
6.5 Spray Drift

................................ ................................ ................................ .................... 31
7.0 Aggregate Ex posure/Risk Characterization

................................ ................................ .. 31
7.1 Acute Aggregate Risk

................................ ................................ ................................ ... 31
7.2 Short

- Term Aggregate Risk

................................ ................................ ........................ 32
7.3 Intermediate

- Term Aggregate Risk

................................ ................................ ........... 32
7.4 Chronic Aggregate Risk

................................ ................................ .............................. 33
7.5 Cancer Aggregate Risk

................................ ................................ ................................ 33
8.0 Cumulative Exposure/Risk Characterization

................................ ............................... 33
9.0 Occupational Exposure/Risk Characterization

................................ ............................ 33
9.1 Short

- /Intermediate

- Term Handler Risk

................................ ................................ ... 34
9.2 Short

- /Intermediate

- Term Post

- Application Risk

................................ .................... 35
9.2.1 Dermal Post

- Application Risk

................................ ................................ ............. 35

10.0 References

................................ ................................ ................................ ......................... 36 Appendix A. Toxicology Profile

................................ ................................ ................................ 37
A.1 Toxicology Data Requirements

................................ ................................ ................... 37
A.2 Toxicity Profiles

................................ ................................ ................................ ............ 38 Appendix B. Physical/Chemical Properties

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

................................ ........................ 42 Appendix D. Azoxystrobin Metabolites

................................ ................................ ................... 44 Appendix E. Review of Human Research

................................ ................................ ................ 50

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 4 of 52 1.0 Executive Summary

Azoxystrobin [methyl ( E )

- 2

- (2

- (6

- (2

- cyanophenoxy)

- pyrimidin

- 4

- yloxy)

- phenyl)

- 3

- methoxyacrylate] is a broad spectrum fungicide that controls plant diseases on agricultural crops, turf and ornamentals, and controls molds and fungi on indoor surfaces. Azoxystrobin belongs to a class of pesticidal compounds called β

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

The Rutger’s University Interregional Research Project No. 4 (IR

- 4) has proposed azoxystrobin for use on post

- harvest tuberou s and corm vegetables (subgroup 1C) , and as a field application to dragon fruit and wasabi. IR

- 4 also requested the use profile of azoxystrobin be updated to incorporate the recent revisions to various crop groups: onion subgroups 3

- 07 A

, B; fruiting

vege table subgroups 8

- 10 A

, B; small fruit and berry subgroups 13

- 07 A, B, F, G; oilseeds subgroups A, B, C ; and citrus fruit group 10

- 10. The most recent human health risk assessment was conducted for a Special Local Need (Section 24c) use on tobacco in gree nhouses (W. Cutchin, D368146, 09/14/2009). Since the last risk assessment, no additional hazard data have
been submitted. HED also recently conducted a human health assessment scoping document in support of Registration Review (B. O’Keefe, D365660, 12/07 /2009). An immunotoxicity study is required for azoxystrobin under 40 CFR § 158. 500.

Use Profile Azoxystrobin is proposed for use as a foliar application on wasabi using ground and chemigation equipment. Wasabi is typically grown in greenhouses in the United States. Azoxystrobin is also proposed for use as a foliar application to dragon fruit using ground, aerial and chemigation equipment. Azoxystrobin is also proposed for post

- harvest use using T

- jet, controlled droplet application (CDA) or similar a pplication methods. Applications to post

- harvest tuberous and corm vegetables (subgroup 1C) may be made by mixing 0.6 fl oz Abound® with 0.5 gallons water and applying to one ton of tubers (2,000 lbs). The full use profile for azoxystrobin is
shown in Se ction 3.3.

Toxicity/Hazard
The risk assessment for azoxystrobin is based on a well

- characterized and complete toxicology database, with the exception of an immunotoxicity stud y

. In repeat

- dos e oral studies, t he liver and bile ducts were consistently the target organs of azoxystrobin toxicity. No developmental effects were seen in rabbit or rat developmental toxicity studies and no reproductive or offspring
effects were seen in the 2

- generation rat reproduction study

. 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. Azoxystrobin is classified as ―not likely to be carcinogenic to humans.‖

Azoxystrobi n 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.

The Food Quality Protection Act ( FQPA ) safety factor (SF) for azoxystrobin was retained at 3 X to account for using a lowest observed adverse effect level (LOAEL) to extrapolate to a no

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 5 of 52 observed adverse effect level (NOAEL) for the acute dietary exposure point of departure (PoD).

NOAELs w ere used for short

- term, intermediate

- term, and chronic risk assessments. Although an immunotoxicity study is needed to complete the toxicological database, the selected toxicity endpoints and PoDs for risk assessment are based on the most sensitive and r elevant data. Currently

, there are no concerns for structural immunotoxicity based on the results of existing
studies.

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 exposure or risk. Estimated drinking water concentrations (EDWCs) were incorporated directly into the dietary exposure assessments. 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 Exposure Evaluation Model

– Food Commodity Intake Database ( DEEM

- FCIDTM ) default processing factors. The resu lts 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 (<100% of the acute population adjusted dose ( a PAD ) ) for all population subgroups and

were estimated at 18 % of the a PAD for the U.S. general population and 42 % of the a PAD for the most highly exposed population subgroup (children 1

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

- level residues , average % CT estimates and default DEEM

F CIDTM processing factors was also conducted

. The results of the chronic dietary analysis for food and drinking water indicate that the chronic dietary risk estimates are below the Agency’s level of concern (<100% of the chronic population adjusted dose ( c P AD)) for all population subgroups and w ere estimated at 7 % of the c PAD for the U.S. general population and 16 % of the

c PAD 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 not performed.

Residential Exposure Residential exposures were not assessed in this document because the proposed uses of azoxystrobin do not in volve applications by homeowners or commercial applicators to residential settings. However, azoxystrobin is currently registered for use on several
residential/non

- agricultural use sites. Residential exposure and risks from use on turf and indoor
surfac es were assessed in a previous document (S. Piper, D344389, 4/30/ 20 08)

.

Occupational Exposure
Short

- and intermediate

- term dermal and inhalation exposure is expected for occupational
handlers. HED the proposed uses and requested changes to the azoxystro bin crop group tolerances and determined that an occupational exposure assessment is needed only for the post

harvest tuberous and corm (subgroup 1C) use. The new uses, and the uses included in the revised crop groups have either been adequately assessed by HEd or are expected to result in lower exposures than uses previously assessed. The results of the occupational handler exposure
and risk assessment estimates indicate that total short

- and intermediate

- term margins of exposure ( MOEs ) are not of concer n to HED (i.e. MOE > 100) with baseline attire. Although occupational dermal exposure is expected following treatment of post

- harvest tuberous and corm vegetables (subgroup p1C) , no dermal hazard was identified for azoxystrobin. Therefore, a

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 6 of 52 quantitative post

- application dermal risk assessment was not conducted. HED assumes that post

application inhalation exposures are minimal following applications of an a ctive ingredient (ai) with low vapor pressure (< 1.0 x10 - 7 

### mm Hg). Since azoxystrobin has low acute inhalation toxicity (Toxicity Category III) and a low vapor pressure (8.2 x10 - 13 

### mm Hg) , post

- application inhalation exposures and risks were not quantitatively assessed.

Review of Human Research This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies (Appendix E ) have been determined to require a review of their ethical conduct, and one of these studies is also subject to review by the Huma n Studies Review Board. All of the listed studies have received the appropriate review.

2.0 HED Recommendations

HED recommends the registration request be conditionally granted for azoxystrobin use on post

harvest tuberous and corm vegetables (subgroup 1C)

, and as field applications to dragon fruit and wasabi. HED also recommends that the use profile of azoxystrobin be updated to incorporate the recent 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; oilseeds subgroups A, B, C ; and citrus fruit group 10

- 10, with the tolerance revisions requested in Section

2.2.3.

2.1 Data Deficiencies/ Prior Conditions of Registration

The following data are required as conditions of registration:

870.7800 Immunotoxicity Study

The registrant must submit an immunotoxicity study. Syngenta has estimated the immunotoxicity study will be completed in November 2011. The immunotoxicity study
remains a condition of registration for azoxystrobin under Registration Review and is due
in 2012.

The following data should be submitted with future uses:

875.2100 Foliar Dislodgable Residue Dissipation

T urf transferable residue (TTR), studies may be required in the future i f the use profile is expanded.

2. 2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 7 of 52 Adequate residue analytical methods are available for tolerance enforcement: a gas chromatography method with nitrogen

- phosphorus detection (GC/NPD), RAM 243/04 for the analysis of crop commodities with azoxystrobin and its Z

- isomer; and a GC

- NPD method, R AM 255/01, for analysis of livestock commodities for residues of azoxystrobin.

2.2.2 International Harmonization

There are Canadian and Codex Maximum Residue Limits (MRLs) for residues of azoxystrobin
and its Z

- isomer for most of the requested crops. The Codex MRLs (JMPR Report 2008) are based on US field trials, except for subgroup 8

- 10A and 8

- 10B which were conducted in Europe. Even though the Codex MRLs are based predominately on US field trials, there is a slight
difference between MRLs of Codex/U S due in part to the difference in residue definition. The US residue definition includes both the predominant E

- isomer and the minor Z

- isomer. The Codex residue definition includes only the E

- isomer. The difference in Codex and US MRL estimates, based on the same data set, is based on the JMPR rounding procedures and the tendency to increase the estimate for small data sets.

The US tolerances and Codex MRLs are harmonized for c aneberry subgroup 13

- 07A ; strawberries; and sunflower subgroup 20B . The U S and Codex MRLs are not harmonized for

l ow growing berry subgroup 13

- 07G; dragon

- fruit (mango); onion, bulb and green (subgroups 3

- 07A & B) ; vegetable , fruiting, subgroup 8

- 10A; tuberous and corm vegetables (subgroup 1C); and wasabi (herbs, fresh and dry)

.

HED recommends increasing the US MRLs for bushberry, subgroup 13

- 07B; cottonseed, subgroup 20C; fruit, citrus, group 10

- 10 ; small fru it vine climbing 13

- 07F [grape]; and vegetable, fruiting, subgroup 8

- 10B to harmonize with Codex.

The US tolerances and Canadian MRLs are in harmony on all proposed crops, except subgroup

13

- 07F, 13

- 07G, cot ton seed

, and for the proposed tuberous and corm vegetables subgroup 1C

. There are no Canadian MRLs on cotton seed. Canadian MRLs were not established as subgroups for 13

- 07F and 13

- 07G and were established on grapes (3 ppm) and lowbush
blueberries and li n gonberries (subgroup 13

- 07B) at 3ppm; US MRLs were established at 1ppm
for 13

- 07F and at 10 ppm for 13

- 07G. Based on the Organization for Economic Cooperation and

Dev elopment (OECD) calculation procedures for the current post

- harvest potato data, HED recommends increasing the US tolerances for vegetable tuberous and corm, subgroup 1C to 8

ppm , which is in agreement with the proposed Canadian MRL

.

2.2.3 Recommended T olerances

Pending submission of a revised Section F , there are no residue chemistry issues that will preclude establish ment of permanent tolerance s for azoxystrobin in/ on the following crops or crop groups/subgroups:

Table 2.2.3. Tolerance Summary for Azoxystrobin

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 8 of 52 Commodity Established Tolerance (ppm) Proposed

Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct

Commodity Definition

Onion, bulb, subgroup 3

- 07A Onion, bulb 1.0 1.0 1.0

Onion, green, subgroup 3

- 07B Onion, green 7.5 7.5 7.5

Vegetable, fruiting, subgroup 8

- 10A Tomato 0.2 0.2 0.2 Tomato subgroup 8

- 10A

Vegetable, fruiting, subgroup 8

- 10B Vegetable, fruiting, group 8, except tomato 2.0 2.0 3.0 Pepper/eggplant subgoup 8

- 10B

Tolerance increase to
harmonize with Codex.

Fruit, citrus, group 10

- 10 Fruit, citrus, group 10

10.0 10.0 15.0 Tolerance increase to
harmonize with Codex.

Caneberry subgroup 13

- 07A Caneberry subgroup 13A

5.0 5.0 5.0

Bushberry subgroup 13

- 07B Bushberry subgroup 13B, Juneberry, Lingonberry, and
Salal at 3.0 3.0 5.0 Tolerance increase to
harmonize with Codex.

Small fruit vine climbing, except fuzzy kiwifruit subgroup 13

- 07F Grape 1.0 1.0 2.0 Fruit, small vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F

Tolerance increase to
harmonize with Codex.
Low growing berry subgroup 13

- 07G, except cranberry Strawberry 10.0 10.0 10.0 Berry, low growing, subgroup

13

- 07G, except cranberry
Rapeseed subgroup 20A Canola, seed 1.0 1.0 1.0

Sunflower subgroup 20B Safflower, seed and sunflower,
seed 0.5 0.5 0.5

Cottonseed subgroup 20C Cotton,
undelinted seed

0.6 0.6 0.7 Tolerance increase to
harmonize with Codex.

Wasabi Herb subgroup 19A, fresh leaves

50 50 50 Wasabi, fresh

Wasabi , dry Herb subgroup 19A, dried leaves

260 Not proposed 260 Wasabi, dry

Dragon

- fruit Mango 2.0 2.0 2.0
Vegetable, tuberous and corm, subgroup 1C 0.03 6.0 8.0



### Note to P M : In conjunction with establishment of the above tolerances, the existing tolerances for potato; onion, bulb; onion, green; vegetable, fruiting, group 8, except tomato; okra; tomato;

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 9 of 52 fruit, citrus, group 10; caneberry subgroup 13A; bushberry subgroup 13B; gr ape; strawberry; juneberry; lingonberry; salal; cotton, undelinted seed; canola, seed; sunflower, seed; crambe, seed; flax, seed; rapeseed, seed; rapeseed, Indian; mustard, field, seed; mustard, Indian, seed; mustard, seed; and safflower, seed need to be r emoved from 40 CFR §180.507(a).

Note to P M: The e

- CFR includes the Z

- isomer in the tolerance expression for livestock. The Z

isomer should be removed from the tolerance expression for livestock.

Note to PM: The existing separate tolerance on potato should be removed and the established vegetable, tuberous and corm, subgroup 1C needs to be revised.

2.2.4 Revisions to Petitioned

- For Tolerances

HED recommends increasing the proposed US crop group tolerances for bushberry, subgroup

13

- 07B, cottonseed, citrus fruit, 10

- 10, fruit vine climbing 13

- 07F [grape], and pepper/eggplant

8

- 10B to harmonize with Codex. Based on the OECD calculation procedures for the current post

- harvest potato data, HED recommends increa sing the US tolerances for vegetable tuberous and corm, subgroup 1C to 8 ppm

. See Table 2.2.3 for required revisions to the petitioned
tolerances.

2.3 Petition Recommendations

860.1550 Proposed Tolerances

A revised Section B must be submitted to reflect the use on the entire vegetable, tuberous and corm, subgroup 1C, instead of post

- harvest potatoes only. A revised Section F must be submitted to propose a tolerance for wasabi, dry at 260 ppm.

2. 4 Label Recommendations

2. 4 .1 Recommendations from Residue Reviews

A revised label must be submitted to reflect the use on the entire vegetable, tuberous and corm, subgroup 1C, instead of post

- harvest potatoes only.

2. 4 .2 Recommendations from Occupational Assessment

Based on email correspondence with Syngenta (dated 11/04/2011), 0.6 gallons of Abound ® 

### (EPA Reg. No. 100

- 1098) should be mixed with 0.5 gallons of water and applied to 2,000 lbs of tuberous vegetables in the packing facility. T hese specific mixing and use instr uctions should be provided on the Abound ® 

### label for the post

- harvest use.

3.0 In troduction

Azoxystrobin is a broad spectrum fungicide for control of 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 fruits, and leaf and fruit spot in tree nuts . It has the same biochemical mode of action as the

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 10 of 52 naturally occurring strobilurins and is structurally related. Azoxystrobin is a

- methoxyacrylate. Azoxystrobin acts by inhibiting electron transport.

The proposed uses of azoxystrobin are for use on post

- harvest tuberous and corm vegetables (subgroup 1C) , and as field applications to dragon fruit and wasabi. IR

- 4 has also requested that the use profile of azoxystrob in be updated to incorporate the recent 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; oilseeds subgroups A, B, C ; and citrus fruit group 10

- 10. Azoxys trobin is currently registered for use on a variety of field, vegetable, fruit, and nut crops as well as on ornamental plants and turf. The propose d uses of azoxystrobin are expected to result in occupational exposure only; no residential exposure is expe cted from the proposed uses of azoxystrobin. Only s hort

- and intermediate

- term occupational exposure s w ere assessed for the proposed uses of azoxystrobin . The formulated end use products (EPs) evaluated in this assessment are Abound® Flowable Fungicide ( 22.9% ai), Graduate A+ (20.6% ai), Quadris Top (18.2% ai), Quilt® (7.0% ai) and Quilt XcelTM (13.5% ai).

Azoxystrobin is proposed for use as a foliar application on wasabi using ground and chemigation equipment. Proposed application rates on wasabi rang e from 6.2

- 15.4 fl oz (0.10

- 0.25 lb ai)/A, with a maximum seasonal application rate of 1.5 lb ai/A. Applications should be made on a 7 day schedule, with no more than 2 sequential applications before alternation with another type of fungicide. Wasabi is typically grown in greenhouses in the United States.

Azoxystrobin is also proposed for use as a foliar application to dragon fruit using ground, aerial and chemigation equipment. Proposed application rates range from 6.2

- 15.5 fl oz or from 0.40

- 0.8 f l oz/1,000 row feet (0.10

- 0.32 lb ai/A) on dragon fruit. Applications should be made on a

10

- 14 day schedule, with no more than 2 sequential applications before alternation with another type of fungicide.

Azoxystrobin is also proposed for use on post

- h arvest tuberous and corm vegetables (subgroup 1C) using T

-

jet, controlled droplet application (CDA) or similar application methods. Applications to post

- harvest tuberous and corm vegetables (subgroup 1C) may be made by mixing 0.6 fl oz Abound® with 0.5 ga llons water and applying to one ton of tubers (2,000 lbs).

3.1 Chemical Identity

The chemical structure and nomenclature of azoxystrobin are presented in Table 3.1.

Table 3.1. Azoxystrobin Nomenclature.
Compound

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 11 of 52 Table 3.1. Azoxystrobin Nomenclature.

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

CAS name methyl ( α E )

- 2

- [[6

- (2

- cyanophenoxy)

- 4

- pyrimidinyl]oxy]

- α

- (methoxymethylene)

- benzeneacetate
CAS reg istry number 131860

- 33

- 8

End

- use products (EP) Abound® Flowable Fungicide (EPA Reg. No. 100

- 1098); Quilt® (EPA Reg. No. 100

- 1178) ; Graduate A+TM (EPA Reg. No. 100

- 1308) ; Quadris TopTM (EPA Reg. No. 100

- 1313) ; and Quilt XcelTM (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
ow 

### ) of 2.5, a molecular weight of 403 g/mol, and is considered relatively insoluble in water. For these reasons, the potential for azoxystrobin to cross biological barriers of the skin is so mewhat limited

. 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. Although azoxystrobi n represents a borderline case of fat solubility, HED considers azoxystrobin residues fat

- soluble. The physi c ochemical properties of azoxystrobin are summarized in Appendix B

.

3.3 Pesticide Use Pattern

In Section B of the petition, IR

- 4 submitted amended labels for Abound® Flowable Fungicide (EPA Reg. N o. 100

- 1098), to add new use s on tuberous and corm vegetables (subgroup 1C) (post

- harvest) , dragon fruit, wasabi, and crop group expansions. T he petiti oner has also requested amendment of the label s for Quilt® (EPA Reg. No. 100

- 1178 )

, Graduate A+ TM (EPA Reg. No. 100

- 1308) , Quadris TopTM (EPA Reg. No. 100

- 1313 ) , and Quilt XcelTM (EPA Reg. No.

100

- 1324 ) to reflect the revision/expansion of the crop groups. Table 3.3 .1 provides a summary of the proposed use sites of azoxystrobin. Table 3.3. 2 provides a summary of the use pattern for the crop group conversions.

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 12 of 52 Table 3.3.1. Proposed Uses of Azoxystrobin

Product (EPA Registration No.) Use Site Application

Method Application

Rate Range (lb ai/A) Maximum

Seasonal Application Rate (lb ai/A) Comments

Abound® (100

- 1098) 22.90% 2.08 lbs ai/gal Wasabi Ground and Chemigation 0.10

- 0.25 1.49 Application should be made on a 7 day schedule, no more than 2 sequential applications before alternation with another type of fungicide, 0 day PHI

Dragon Fruit Ground,

Aerial, Chemigation 0.10

- 0.32

(soil borne disease) 1.49 10

- 14 day application schedule, no more than 2 sequential applications before alternation with another type of

fungicide, 0 day PHI

Post

- Harvest

Potatoes T

-

jet, CDA or

similar 0.6 fl oz/ton

of tubers Do not make more than one post

- harvest application. In response to the question concerning post harvest use on potatoes for azoxystrobin, the potatoes will not be treated in

the field

- only at the potato storage facility as they are being placed into storage. The treatment is a non

- recovery

spray with no waste or run

- off.

Table 3.3. 2 Azoxystrobin Use Pattern for Crop Group Conversions

Product (EPA Registration No.) Use Site Application

Method Application Rate

Range (lb ai/A) Maximum
Seasonal Application Rate (lb ai/A) Comments

Abound ® (100

- 1098)
22.9% 2.08 lbs ai/gal Onion, Subgroups 13

- 07 A
& B Ground,

Aerial, Chemigation 0.10

- 0.32 (soil borne disease) 1.49 Do not apply more than one application before alternation with another type of fungicide

.

Vegetable, Fruiting, Subgroup 8

- 10 A Ground, Aerial, Chemigation 0.08

- 0.10 0. 6 Applications should be made on a 5

- 7 schedule for late blight, 7

- 21 day schedule for other diseases, with no more than 2 sequential applications before alternation with another fungicide not in group 11. 0 day PHI

Vegetable, Fruiting, Subgroup 8

- 10B Ground, Aerial, Chemigation 0.10

- 0.32 (soil borne disease) 1 Applications should be made on a 7

- 14 day schedule

. 0 day PHI Do not apply more than 2 sequential applications before alternation with another fungicide not in group 11

.

Bushberry Subgroup 13

- 07

B Ground,

Aerial, Chemigation 0.10

- 0.25 0.74 Applications should be made on a 7

- 14 day schedule, with no more than 2 sequential applications before alternation with another fungicide not in group 11. 0 day PHI

Caneberry Subgroup 13

-

07A Ground,

Aerial, Chemigation 0.10

- 0.25 1.49 Applications should be made on a 7

- 14 day schedule, with no more than 2 sequential applications before alternation with another fungicide not in group 11. 0 day PHI

Small Fruit Vine Climbing, except fuzzy
kiwi fruit Subgroup 13

- 07F Ground,

Aerial, Chemigation 0.16

- 0.25 1.49 Applications should be made on a 10

- 14 day schedule, with no more than 2 sequential applications before alternation with another fungicide not in group 11. 14 day PHI.

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 13 of 52 Table 3.3. 2 Azoxystrobin Use Pattern for Crop Group Conversions

Product (EPA Registration No.) Use Site Application

Method Application Rate

Range (lb ai/A) Maximum
Seasonal Application Rate (lb ai/A) Comments

Low Growing Berry Subgroup 13

- 07G (except cranberry) Ground, Aerial, Chemigation 0.10

- 0.32 (soil borne disease) 1 Applications should be made on a 7

- 10 day schedule, with no more than 2 sequential applications before alternation with another fungicide not in group 11.

For dip applications at transplanting

, mix up to 8 fl oz product per 100 gals water

, dip plants for 2

- 5 minutes, and plant treated plants as quickly as possible

. 0 day PHI

Oilseeds Subgroups A, B,

C Ground,

Aerial, Chemigation 0.10

- 0.25 0.44 Do not apply more than one application before alternation with another type of fungicide

. 30 day PHI

Fruit, Citrus Group 10

- 10 Ground, Aerial, Chemigation 0.20

- 0.32 (soil borne disease) 1.49 Applications should be made on a 7

- 21 day schedule, with no more than 2 sequential applications before alternation with another fungicide not in group 11. 0 day PHI

Graduate A+ TM (100

- 1308)
20.6% 1.99 lb ai/gal Post Harvest Citrus 32

- 64 fl oz/100 gal (in

line dip/drench) or 32

- 64 fl oz/250,000 lb of fruit (in line aqueous or fruit coating spray application) Do not make more than 2 applications to
citrus fruit

.

Quadris Top TM (100

- 1313)
18.2% 1.67 lb ai/gal Fruit, Citrus Group 10

- 10 Ground or

Aerial 0.13

- 0.2

Quilt ®
(100

- 1178)
7.0% 0.62 lb ai/gal Bushberry Subgroup 13

- 07

B Ground or

Aerial 0.07

- 0.10 0.96 Applications should be made on a 7

- 10 day schedule, with no more than 2 consecutive applications for mummy berry; other diseases require a 14 day application interval

. Make no more than 2 consecutive applications, and no more than 3 applications per crop

. 30 day PHI

Caneberry Subgroup 13

-

07A Ground or

Aerial 0.07

- 0.10 0.96 Applications should be made on a 7

- 14 day schedule with no more than 2 sequential applications before alternation with another type of fungicide

. 30 day PHI

Onion, Subgroups 13

- 07 A

& B Ground or

Aerial 0.07

- 0.13 0.51 Applications should be made on a 7

- 10 day schedule with no more than 2 sequential applications before alternation with another type of fungicide

. 14 day PHI for dry bulb, 0 day PHI for green onion types

.

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 14 of 52 Table 3.3. 2 Azoxystrobin Use Pattern for Crop Group Conversions

Product (EPA Registration No.) Use Site Application

Method Application Rate

Range (lb ai/A) Maximum
Seasonal Application Rate (lb ai/A) Comments

Quilt XcelTM (100

- 1324)
13.5% 1.18 lb ai/gal Berries Bushberry

Subgroup 13

- 07B Ground or
Aerial 0.13

- 0.19 0.76 For mummyberry, apply first at the green tip stage and repeat every 7

- 10 days and do not apply more than 2 consecutive applications.

For other diseases

, applications should be
made on a 7

- 14 day schedule with no more than 2 consecutive applications

. Mak e no more than 3 applications of Quilt XL (or other group 11 fungicides)

per crop 30 day PHI

Berries Caneberry Subgroup 13

- 07A Ground or
Aerial 0.13

- 0.19 0.98 Applications should be made on a 14 day
schedule with no more than 2 consecutive

sprays

. Make no more than 3 applications of QuiltXcel or other group 11 fungicide

. 30 day PHI

Onion, Subgroups 13

- 07 A

& B Ground or

Aerial 0.13

- 0.19 (purple blotch,

rust, cladoporium leaf blotch), 0.16

- 0.24 (white rot, downy mildew, leaf blight) 0.52 Applications should be made on a 7

- 10 day schedule Apply only once before alternating to another group 11 fungicide 14 day PHI for bulb onions, 0 day PHI green onions

Low Growing Berry Subgroup 13

- 07G (except cranberry) Ground or
Aerial 0.13 0.52 Applications should be made on a 10

- 14 day schedule with no more than 2 consecutive applications

. Make no more than 4 applications of Quilt or similar fungicide

. 0 day PHI



### 3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed new use s of azoxystrobin on tuberous and corm vegetables, subgroup 1C , wasabi and dragon fruit, and the revisions to various crop groups. Humans may be exposed to azoxystrobin in drinking water, sin ce 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 application. There is also a potential for post

- application expo sure for workers re

- entering
treated sites.

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

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 15 of 52 3.5 Consideration of Environmental Justice

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

- Income Populations," ( http://www. 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 home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic gr oup 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 ho me use of pesticide products and associated risks for adult applicators and
for children 3 to < 6 years old , 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 consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization a nd Dose

- Response Assessment

4.1 Toxicology Studies Available for Analysis

The toxicology data for azoxystrobin are sufficient and are of good quality for selecting toxicity endpoints and points of departure for risk assessment. The available toxicology studies include (1) subchronic oral toxicity studies in rats and dogs; (2) a 21 day dermal toxicity study in rats; (3) developmental toxicity studies in rats and rabbits; (4) a 2

- generation reproduction study in rats; (5) a chronic toxicity study in dogs; (6) a carcinogenicity study in mice and a combined chronic toxicity/carcinogenicity study in rats; (7) a battery of the required genotoxicity studies; (8) a metabolism study in rats; (9) acute and subchronic neurotoxicity studies; and (10) a dermal
penetra tion study in rats.

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

Pharmacokinetics and metabolism studies in rats showed that azoxystrobin was absorbed and distributed broadly following oral administration. Based upon the results of th e various experiments, absorption of azoxystrobin was difficult to accurately assess. For the single high

- dose group, assessment of biliary excretion suggested approximately 70% absorption with approximately 32% of administered radioactivity remaining as parent compound in the gastrointestinal tract. The greatest amounts of absorbed azoxystrobin were distributed to organs associated with either metabolism or excretory function, especially the liver and kidneys. Less than 0.5% of the
administered dose was detected in the tissues examined on the 7 th 

### day after dosing which

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 16 of 52 sugges ts minimal potential for bioaccumulation. There were no apparent sex

- related differences
in distribution. The absorbed a zoxystrobin appeared to be extensively metabolized. A metabo lic pathway, consistent with the data on metabolite identification and quantitation, was proposed showing hydrolysis and subsequent glucuronide conjugation as the major biotransformation

process. A total of 15 metabolites were detected in the excreta and subsequently identified.
Seven additional metabolites were detected but not identified. None of the unidentified metabolites represented more than 4.9% of the administered dose. The glucuronide conjugate (metabolite V) was the most prevalent biliary met abolite in both males and females. The parent compound was not detected in the bile , w ith the exception of metabolite V

, ( which represented 29.3% (males) and 27.4% (females) of the administered dose ) ; the other biliary metabolites represented less than 10% of the administered dose. Minor qualitiative and quantitative differences in biliary metabolites were observed in males and females. The primary route of elimination was via the feces ( 73

- 89% of the adminis tered dose) followed by the urine ( 9

- 18%). The fecal vs. urinary route of excretion did not vary considerably with dose. There were
no apparent sex

- or dose

- related differences in the pattern of excretion.

4.2.1 Dermal Absorption

No adverse effects were seen up to the limit dose (1,000 mg/kg/day) in a 21

- day dermal repeated dose study in rats

. In a n acceptable dermal absorption study with 24 male rats , percutaneous absorption was minimal ( < 4.2%) and did not appear to exhibit a do se

- response relationship.
Time

- course data indicated that most absorption occurred during the first 0.5 hours and that this represented approximately 0.9% of the administered dose. Limited absorption precluded accurate
assessment of distribution and met abolite characterization. Both fecal and urinary excretion were quantified, the former representing about 6% or less of total absorption and the latter accounting for <0.1% of the absorbed dose over a 24

- hr period. Overall recovery of
administered radioa ctivity was 95

- 105%.

4.3 Toxicological Effects

With repeated dosing by the oral route, the liver and bile ducts were consistently the target organs of azoxystrobin toxicity. Liver and biliary effects were seen in rats (increased liver weights, gross and histopathological lesions of the bile duct and liver), and in dogs ( increased liver weights, clinical observations (including fluid feces and salivation ) and clinical chemistry alterations ( including increased levels of alkaline phosphatase, serum, and se rum gamma

glutamyl transferase; and decreases in albumin) . These effects seen are indicative of changes to liver/biliary function. Decreased body weight (rats and mice) and decreased body weight gain (rats and rabbits) were also consistent findings acros s studies and species. Other effects including decreased food intake/utilization, increased diarrhea and other clinical toxicity observations such as urinary incontinence, salivation

, hunched postures and distended abdomens
were also seen in various studi es (developmental toxicity, reproduction, and 90 day oral toxicity) in rats. All these effects do not suggest immunotoxic or neurotoxic potential for azoxystrobin.

No developmental effects were seen in the rabbit and rat developmental toxicity studies a nd no reproductive or offspring effects were seen in the 2

- generation rat reproduction study. In the reproduction study, decreased body weights and increased adjusted liver weights were observed

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 17 of 52 at the same dose in both offspring and parental animals. Th erefore, the toxicity data showed no increased susceptibility in the young.

In the acute and subchronic neurotoxicity studies, there were no consistent indications of

treatment

- related neurotoxicity. There was no evidence of neurotoxicity seen in the a cute neurotoxicity study in rats from a single gavage dose up to 2,000 mg/kg. There was also no evidence of neurotoxicity seen in the subchronic neurotoxicity study in rats up to the highest dose tested (201 mg/kg/day). Based on the toxicity profile of a zoxystrobin, a developmental neurotoxicity study in rats is not required (B. Tarplee and J. Rowland, HED Doc. No. 012844, 09/03/1998).

Although azoxystrobin induced a weak mutagenic response in the mouse lymphoma assay (non linear, slight but significant increases in the mutation frequency of mouse lymphoma cells), the activity expressed in vitro is not expected to be expressed in whole a nimals , for the following

reasons: (1) although colony sizing was not performed in the mouse lymphoma assay, it is likely that the increased mutation frequencies seen in this study were associated with a chromosomal rather than point mutational event. Thi s interpretation is based on the similarity of the response uncovered in the mouse lymphoma assay to the clastogenic response seen with and without S9 activation in human lymphocytes ; and (2) the negative findings of the UDS assay, the lack of an oncogenic effect in rat or mouse long

- term feeding studies and the absence of significant reproductive or developmental toxicity attributable to a mutagenic mode of action (i.e. decreased total implants, increased resorptions). Hence, it can be concluded that azox ystrobin is active in

vitro but this genotoxicity is not expressed in whole animals (G. Dannan, HIARC, 09/25/2000). There was no evidence of carcinogenicity in rats and mice at acceptable dose levels; azoxystrobin is classified as ―not likely to be carcin ogenic to human s

. ‖

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.

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

The HED azoxystrobin risk assessment team evaluated the quality of the toxicity and exposure data and recommends that the FQPA SF be retained at 3X to account for using a LOAEL to extrapolate to a NOAEL for the acute dietary exposure POD. The FQPA SF should be retained, despite the data showing no increased susceptibility in rats and rabbits exposed in utero and/or postnatally to azoxystrobin. HED selected the acute neurotoxicity study in rats, where diarrhea was seen two hours post dosing at all dose levels (up to and including the LOAEL) to represent the acute dietary exposure scenario. HED is confident that a SF of 3X (as opposed to 10X) is adequately protective due to (1) the relatively insi gnificant nature of the effect (transient diarrhea seen in the rat), (2) the fact that diarrhea was only seen in studies involving gavage dosing in the rat but not in repeat dosing through dietary administration in rats, mice, rabbits and dogs, (3) the

ver y high dose level needed to reach the acute oral lethal dose (LD) 50 

### (>5,000 mg/kg), and (4) the overall low toxicity of azoxystrobin. NOAELs were used for short

- term, intermediate

- term,
and chronic risk assessments. The FQPA SF was reduced to 1X for all exposure scenarios other than acute dietary because azoxystrobin showed no evidence of increased susceptibility in the

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 18 of 52 young. Although an immunotoxicity stud y is needed to complete the database, the selected toxicity endpoints and points of departure for risk assessment are based on the most sensitive and
relevant data. Currently, there are no concerns for structural immunotoxicity based on the results
of existin g studies.

4.4.1 Completeness o f the Toxicology Database

The toxicity database for azoxystrobin is considered adequate for selecting toxicity endpoints and points of departure for risk assessment, with the exception of an immunotoxicity study. Althoug h 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 functio n, 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. Therefore, EPA does not believe that conducting an 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 need to be applied.

4.4.2 Evidence of N eurotoxicity

Clinical signs noted in the acute and subchronic neurotoxicity studies were not considered
treatment related because of lack of dose

- response, inconsistency of observations at different time points and/or small magnitude of response. There is no need for a developmental neurotoxicity study or additional uncertainty factors ( UFs ) to account for neurotoxicity.

4.4.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

There is no evidence that azoxystrobin results in increased suscept ibility to in utero rats or rabbits in the prenatal developmental studies or in young rats in the 2

- generation reproduction study.

4.4.4 Residual Uncertainty in the Exposure Datab ase

While some refinements were incorporated into the dietary exposure ca lculations, EPA is confident that the aggregate risk from exposure to azoxystrobin in food, drinking water and residential pathways will not be underestimated. The acute dietary (food) exposure assessment
assumed 100% of the proposed and registered crops were treated, and utilized tolerance level
residues for all existing and proposed commodities, except citrus fruits where the highest field
trial residue was used. The chronic dietary exposure assessment used tolerance level residues for
all commodities and % crop treated (% CT ) estimates when available (Screening Level Usage Analysis (SLUA), 07/13/11) . The drinking water assessment utilized water concentration values generated by models and associated mod eling 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.

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 19 of 52 In addition, the previous residential exposure assessment incorporates similarly conservative assumptions in the assessment of post

- application exposure of children and in the incidental o ral exposure assessment for children . These assessments will not underestimate the exposures and risks posed by azoxystrobin.

4.5 Toxicity Endpoint and Point of D eparture Selections

4.5.1 Dose

- Response Assessment

The toxicity endpoints and points of departure are presented in Table 4.5.4

.

For azoxystrobin, HED has selected the most sensitive and protective endpoints from the available database to establish points of departure for the risk assessment. For acute oral exposure, an acute neurotoxicity s tudy in rats was used to select the dose and endpoint for establishing the aRfD (0.67 mg/kg/day) for the general population. The LOAEL of 200 mg/kg is based on diarrhea seen at two hours post

- dosing at all dose levels up to and including the

LOAEL. For c hronic oral exposure, a combined chronic toxicity/carcinogenicity study in rats was used to select the dose and endpoint for establishing the cRfD (0.18 mg/kg/day) for the general population. The LOAELs (82.4/117 mg/kg/day for males and females, respectiv ely) are based on reduced body weights in both sexes and bile duct lesions in males. A prenatal developmental oral toxicity study in rats (NOAEL=25 mg/kg/day) was used to assess short

- term
incidental oral and short

- term inhalation exposure based on increa sed maternal diarrhea, urinary incontinence, and salivation seen at the LOAEL (100 mg/kg/day). A 90

- day feeding study in rats (NOAEL=20 mg/kg/day) was used to assess intermediate

- term incidental oral and inhalation exposure based on decreased body weight gains in both sexes, and clinical signs indicative of reduced nutrition seen at the LOAEL (211/223 mg/kg/day in males/females). No dermal or systemic toxicity was seen at the limit dose (1,000 mg/kg/day) in a 21

- day repeated dose dermal study in rats. Th erefore, short

- and intermediate

- term dermal risk of azoxystrobin was not
assessed. Since no inhalation absorption data are available, toxicity by the inhalation route is considered to be equivalent to the estimated toxicity by the oral route of exposure (i.e. there is no inhalation absorption factor).

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

No dermal hazard was identified and dermal exposure to azoxystrobin was not assessed. Therefore, dermal and inhalation routes of exposure are not combined.

4.5.3 Cancer Classification and Increased Tumor Incidence Risk Assessment
Recommendation

Azoxystrobin is classified as ―Not likely to be Carcinogenic to Humans.‖ Canc er risk
assessments do not need to be conducted.

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

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 20 of 52 Table 4.5.4

. 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 up to and including to 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 Repeat ed 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.

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 en vironmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.



### Based on the available toxicity database and the Agency's current practices, the inhalation risk for azoxystrobin was assessed using an oral toxicity study. The Agency sought expert advice and input on issues related to this route to route extrapolation a pproach (i.e. the use of oral

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 21 of 52 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 a nd Risk Assessment

References:

- Azoxystrobin: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk
Assessments for Section 3 Petition For Use On Tuberous and Corm Vegetables Subgroup 1C (Post

harvest); Dragon Fruit; Wasabi; and Crop Group/Subgroup Expansions for Bulb Vegetables 3

- 07A and 3

- 07B; Caneberries 13

- 07A; Bushberries 13

- 07B; Small Fruit Vine Climbing 13

- 07F, Except Fuzzy Kiwifruit; Low growing Berry 13

- 07G, Except Cranberry; Low Growing Berry 13

- 07H, Except Strawberry; Citrus Crop Group 10

- 10; Fruiting Vegetable Crop Group 8

- 10; and Oilseed Crop Group 20

, M

. Negussie

, DP # 390838

, 11/29/11

.

- Drinking Water Exposure Assessment for New Uses of Azoxystrobin on Wasabi, Dragon

- fruit and Sugarcane, and the Proposed Tolerances for Residues of Azoxystrobin for Use on Onion subgroups, Fruiting Vegetables Subgroups, Small Fruit & Berry Subgroups, Oilseed Subgroups; and the Proposed Increased Tolerance for Tuberous & Corm Vegetables Subgroup

, R

. Baris

, DP# 389703 / 394475 , 1 1 / 28 / 11

.

- A zoxystrobin. Section 3 Petition For Use On Potatoes (Post

- harvest); Dragon Fruit; Wasabi; and Crop Group Expansions for Bulb Vegetables 3

- 07A and 3

- 07B; Caneberries 13

- 07A; Bushberries 13

- 07B; Small Fruit Vine Climbing 13

- 07F, Except Fuzzy Kiwifruit; Low growing Berry 13

- 07G, Except Cranberry; Low Growing Berry 13

- 07H, Except Strawberry; Citrus Crop Group 10

- 10; Fruiting Vegetable Crop Group 8

- 10; and Oilseed Crop Group 20. Summary of Analytical Chemistry and Residue Data

, M

. Negussie

, DP# 390152 , 11/ 16 / 11

.

- Drinking Water Assessment for amended label Quadris TopTM fungicide (EPA Reg. No. 100

- 1313) Azoxystrobin for use on golf course turf (only) , J. Wolf, DP#371383, 01/16/10.



### 5.1 Metabolite/Degradate Residue Profile

5.1.1. Summary of Plant and Animal Metabolism Studies

The nature of the residue in plants and livestock are adequately understood for the purposes of
th e IR

- 4 petition. Metabolism studies in grapes, peanuts, and wheat were submitted in conjunction with earlier azoxystrobin petitions, PP# s 5F4541 and 6F4762 . The database is adequate for determining azoxystrobin residues of concern

. A listing of the azoxystrobin metabolites is provided in Appendix D.

Primary Crops Azoxystrobin is systemic. Azoxystrobin undergoes photochemical isomerization to produce the

Z

- isomer and is extensively metabolized in plants. The parent compound undergoes cleavage of the ether linkages between the phenylacrylate and pyrimidinyl rings and the cyanophenyl and

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 22 of 52 pyri midinyl rings, with subsequent oxidation, hydrolysis, and/or reduction of the primary metabolites to form numerous secondary metabolites. HED has determined that the residues of concern in/on plants for tolerance expression and risk assessment purposes ar e azoxystrobin and
its Z

- isomer.

Rotational Crops Adequate confined rotational crop metabolism studies have previously been presented in
PP#6F4762 and re

- evaluated in PP#9F6058. Total radioactive residues (TRR), expressed as [ 14 

### C]azoxystrobin equivalents, accumulated at >0.01 ppm in the raw agricultural commodities of lettuce, radishes, and wheat planted in sandy loam soil 30, 200, and 365 days after treatment of the soil with [ 14 

### C]azoxystrobin at 1.8 lb ai/A. Residues were high est in rotated crop
commodities from the 30

- day plantback intervals (PBIs) and declined at subsequent PBIs.

Azoxystrobin is more extensively metabolized in rotational crops than in primary crops. The residues of concern in rotational crops are parent a nd the Z

- isomer.

Livestock The nature of the residue in livestock is adequately understood based on acceptable metabolism studies conducted on goats and laying hens. HED has determined that the residue of concern in livestock is parent azoxystrobin only

.

In the goat metabolism study, azoxystrobin and compounds 2, 20, 23, and 28 were identified in kidney , and azoxystrobin and compounds 2, 3, 10, 13, 20, and 28 were identified in liver. Although azoxystrobin is highly metabolized in livestock kidney and liver , these organs are minor components of the human diet and all residues were present at low levels/low percentages
of the total radioactive residue.

In poultry, azoxystrobin and compound 28 were identified in egg yolk and co mpound 28 was identified in liver. Residues in extracts of egg whites, muscle, skin with underlying fat, or peritoneal fat were <0.01

ppm.

5.1.2 Summary of Environmental Degradation

Azoxystrobin is relatively persistent, but no t highly mobile. Azoxystrobin is stable to hydrolysis at pH 5, 7, and 9 at 25 C. Azoxystrobin degrades through photolysis in water and soil and to a lesser extent by microbial

- mediated degradation. The dissipation half

- life (T 1⁄2 

### ) of azoxystrobin by phot olysis on soil ranges between 17.6 to 28.4 days (DT 50 

### =11 days). The dissipation of azoxystrobin by photodegradation half

- life in surface water ranges between 11.1 to 17 days

. Azoxystrobin will slowly biotransform in aerobic and anaerobic soils. The aero bic soil
metabolism half

- lives range from 72 to 164 days. Three major degradates were detected. HED has previously determined that the only residue of concern for dietary exposure is parent azoxystrobin. Thus, only the parent was considered in the drinki ng water assessment.

The soil/water partitioning coefficients (Freundlich K f 

### ) for azoxystrobin range from 1.5 to 23 mL/g in seven soils. K
oc 

### s range from 210 to 1690 mL/g
oc 

### . Azoxystrobin exhibits a low to

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 23 of 52 moderate mobility in all soils tested in the mobility studies. The relatively low mobility was confirmed in the field studies where azoxystrobin dissipated slowly on the surface (0

- 6 inch) of

non

- flooded soils. No azoxystrobin residue was found in soil l ayers deeper than 6 inches. The data suggest that azoxystrobin may be transported to surface and ground waters under some use
conditions.

B ased on environmental fate data, the dissipation of azoxystrobin appears to be predominately dependent on photodegr adation and to a lesser extent on microbial

- mediated degradation, and possible transport to surface and ground waters. Azoxystrobin is expected to have a high to moderate mobility in runoff and low to moderate potential to leach. The data suggest that

az oxystrobin may be transported to surface and ground waters under some use conditions

.

Since photodegradation is a major route of degradation for azoxystrobin, the dissipation of azoxystrobin is expected to be dependent on condition s of the water (e.g. sed iment loading, depth, etc.) affecting sunlight penetration. For example, azoxystrobin should not persist in clear shallow water bodies, but will be more persistent in turbid and/or deeper waters, particularly those with long hydrological residence times

.

5.1.3 Comparison of Metabolic Pathways

Azoxystrobin is metabolized in rats by undergoing hydrolysis and is biotransform ed during a subsequent glucuronide conju g ation process. Fifteen metabolites were detected in the excreta of rats studied, and seven ad ditional metabolites were detected but not identified. None of the unidentified metabolites represented more than 4.9% of the administered dose. The glucuronide conjugate (metabolite V) was the most prevalent biliary metabolite in both males and females.

Azoxystrobin undergoes photochemical isomerization to produce the Z

- isomer and is extensively metabolized in plants. The parent compound undergoes cleavage of the ether linkages between the phenylacrylate and pyrimidinyl rings and the cyanophenyl and pyrimidinyl rings, with subsequent oxidation, hydrolysis, and/or reduct ion of the primary metabolites to form numerous secondary metabolites. HED has determined that the residues of concern in/on plants for tolerance expression and risk assessment purposes are azoxystrobin and its Z

- isomer.

The metabolic pathway in plants a nd animals is qualitatively similar, although the Z

- isomer was not identified in animals; the major biotransformation process is hydrolysis.

5.1.4 Residues of Concern Summary

Table 5.1.4. Summary of Metabolites and Degradates included in the Azoxystr obin 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

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 24 of 52 Table 5.1.4. Summary of Metabolites and Degradates included in the Azoxystr obin Risk Assessment and Tolerance Expression

Matrix Residues included in

Risk Assessment Residues included in
Tolerance Expression

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/expansions of crop groups/subgroups of the fungicide azoxystrobin in/on d ragon fruit; wasabi; tuberous and corm vegetables subgroup 1C; onion, bulb and green subgroups 3

- 07A and B; caneberry subgro up 13

- 07A; bushberry subgroup 13

- 07B; small fruit vine climbing 13

- 07F, except fuzzy kiwifruit; low growing berry 13

- 07G, except cranberry; fruit, citrus group 10

- 10; fruiting vegetable group 8

- 10 A and B; and oilseed crop group 20.

Residues are quantifia ble 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, tom ato paste, and wheat bran. 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.

Residue chemistry studies are supported by adequate storage stability data which demonstrate that azoxystrobin and its Z

- isomer are stable for at least 24 months in water

- starch

- , protein

- , oil

- , and acid containing materials under frozen conditions.

Proposed Uses

Other than the post

- harvest potato field trial data (MRID 48437101)

, no new residue field trial data were submitted to support the proposed tolerances. The changes are a result of revised crop groups and are conversions from existing groups/subgroups or representative commodi ties , and have been adequately assessed previously

. The proposed tolerances for the dragon fruit and wasabi are extrapolated from existing azoxystrobin tolerances on mango (2.0 ppm) and herb subgroup 19A, fresh (50 ppm), respectively.

Table 5.2a. Sum mary of Residue Data from Potato Crop Field Trials with Azoxystrobin.

Commodity Analyte Total App.

Rate DAA Residue Levels (ppm) 1

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 25 of 52 g a.i./
2000 lb lb a.i./

2000 lb [g
a.i./100 kg n Sample

Min. Sample

Max. LAFT 3 HAFT 3 Median Mean Std. Dev. 4

TRT 02 (Conveyor Belt or Roller Table)

Potato tubers Azoxystrobin 4.0473

- 4.5105 0.0089

-

0.0099 [0.45

- 0.50] 0 10 0.992 4.15 0.994 3.79 2.22 2.40 1.20

R230310 10 <0.01 <0.01 0.01 0.01 0.01 0.01 N/A

Total Residues 10 <1.002 <4.16 1.004 3.80 2.23 2.41 1.20

TRT 0 3 ( Surface ) /Stationary

Potato tubers Azoxystrobin 4.0997 0.0090 [0.45] 0 2 1.05 1.22 1.14 1.14 N/A N/A N/A

R230310 2 <0.01 <0.01 0.01 0.01 N/A N/A N/A

Total Residues 2 <1.06 <1.23 1.15 1.15 N/A N/A N/A

TRT 0 4 ( Spray Chamber )

Potato tubers Azoxystrobin 4.0309 0.0089 [0.44] 0 2 3.50 3.57 3.54 3.54 N/A N/A N/A

R230310 2 <0.01 <0.01 0.01 0.01 N/A N/A N/A

Total Residues 2 <3.51 <3.58 3.55 3.55 N/A N/A N/A

TRT 0 5 ( Brush Table )

Potato tubers Azoxystrobin 4.0850 0.0090 [0.45] 0 2 2.23 2.31 2.27 2.27 N/A N/A N/A

R230310 2 <0.01 <0.01 0.01 0.01 N/A N/A N/A

Total Residues 2 <2.24 <2.32 2.28 2.28 N/A N/A N/A

Combined Treatments

Potato tubers Azoxystrobin 4.0309

- 4.5105 0.0089

-

0.0099 [0.44

- 0.50] 0 16 1 0.992 4.15

-- -- 2.25 2.37 1.12

8 2

-- -- 0.994 3.79 2.25 2.37 1.15

R230310 16 1 <0.01 <0.01

-- -- 0.01 0.01 N/A

8 2

-- -- 0.01 0.01 0.01 0.01 N/A

Total Residues 16 1 <1.002 <4.16

-- -- 2.26 2.38 1.12

8 2

-- -- 1.004 3.80 2.25 2.37 1.15

1 n = no. of samples. For calculation of median, mean, and standard deviation, the LOQ (0.01 ppm) was used for any results reported as <LOQ in Table C.3.

2 n = no. of field trials ; statistical calculations are based on per

- trial average values

. 3 LAFT = lowest

- average

- field

- trial; HAFT = highest

- a verage

- f ield

- t rial.

4 N/A = Not applicable.



### Syngenta submitted an acceptable processing study for azoxystrobin on potato foll owing post

harvest treatment. Processing of the tuber RAC with quantifiable residues of azoxystrobin did not result in the concentration of residues in potato fractions (processing factors were all <1x). Residues of R230310 were below the LOQ in/on all samples of p otato RAC, flakes, chips, and wet peel. Therefore, processing factors were not calculated. The observed concentration factors
were less than the theoretical concentration factors. Acceptable methods were used for the determination of residues of azoxyst robin and the Z

- isomer metabolite. The sample storage conditions and durations for azoxystrobin analyses are supported by adequate storage stability
data. Results are provided in Table 5.2b.

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 26 of 52 Table 5.2b

. Residue Data from Potato Processing Studies wit h Azoxystrobin.

RAC Processed

Commodity Total Rate

DAA Residues (ppm) Processing Factor 1,2

g a.i./
2000

lb lb a.i./
2000 lb Azoxystrobin R230310 Total
Residues Azoxystrobin R230310 Total
Residues

Potato Tubers

(RAC) 4.1357 0.00 91 0 0.938 <0.01 <0.948

-- -- --

Flakes <0.01 <0.01 <0.02 <0.01x NC <0.02x Chips 0.0111 <0.01 <0.0211 0.01x NC <0.02x Wet peel 0.846 <0.01 < 0.856 0.90x NC <0.90x

1 NC = Not calculated; residues were below the LOQ (<0.01 ppm for all in analytes) in the RAC and processed fraction.

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



### Livestock

The livestock feedstuffs associated with this petition are potato culls and processed potato waste; in addition, there a re established tolerances for n umerous livestock feedstuffs. The previously
estimated livestock dietary burdens of azoxystrobin were revised to include the processed potato waste (dairy cattle only)

.

The existing azoxystrobin tolerances for milk and the fat, meat, and meat byproducts of cattle, goat, hog, horse, and sheep are adequate; no revision to the existing tolerances is needed to support the proposed uses of azoxystrobin. The proposed uses of azoxystrobin addressed in this
document do not alte r the Agency’s previous conclusion that there is no reasonable expectation of finite residues in poultry commodities [Category 3 of §180.6(a)]. No tolerances are needed for poultry tissues or eggs.

Rotational Crops Limited field 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 amended uses on do not result in increased maximum seasonal application rates of azoxystrobin, no changes to
the exist ing rotational crop restrictions are needed. The rotational crop restrictions on the label for EPA Reg. No. 100

- 1098 are adequate.

5. 3 Water Residue Profile

The drinking water inputs provided in the previous drinking water assessment (J. Wolf, DP371383, 01/6/ 20 10) were more conservative than the most recent drinking water assessment (R. Baris, DP389703/394475, 11/28/ 20 11). EFED estimates drinking water concentrations of a chemical based on the highest rate of application of the chemical on all registered and proposed crops. In the case of azoxystrobin, turf, a previously registered crop, has the highest application rate (0.55 lb ai/A, 9 applications per year with a 10

- day interval between applications). The

assessment was completed with the Ti er 1 screening model, FQPA Index Reservoir Screening Tool (FIRST). The model and its description is available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/

.

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 27 of 52 The proposed rates of application for wasabi and dragon fruit are lower than for turf. Therefore, the EDWCs reported for turf are representative of these current actions. EDWCs recommended for use in the human health risk assessment for all proposed/registered crops are li sted in Table

5.2.

Table 5.2 Summary of Estimated Surface Water Concentrations for Azoxystrobin.

Scenario Surface Water Conc., ppb

Acute 173

Chronic (non

- cancer) 33



### 5. 4 Dietary Risk Assessment

5. 4 .1 Description of Residue Data & Percent Crop Treated Used in Dietary Assessment

The acute dietary exposure assessment of azoxystrobi n is partially refined by using highest
residue values for citrus fruits and assumed 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 assessment was partially refined, based on toler ance level residues for all existing and proposed commodities. A SLUA was provided by the Biological and Economic Analysis Division (BEAD) ( 07/13/ 20 11). %CT estimates were used when available. For %CT estimates used in the dietary exposure assessment, s ee Appendix E.

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, adults 50+ and females 13

- 49 ). The acute dietary exposure estimate for food and drinking water utilized 18% of the aPAD for the general U.S. population. The acute dietary exposure estimate for the highest reported exposed population subgroup, chi ldren 1

- 2 years old , utilized 41.7% of the aPAD. The results are reported in Table 5 .4.4 . All population subgroups were
below the level of concern.

The acute dietary exposure assessment is partially refined, i.e. based on the assumption of
tolerance

- l evel 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 = 9.202 ppm]) , used 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 general U.S. population, and all population subgroups. The chronic dietary exposure for food and drinking water utilized 6.7 %
of the cPAD for the general U.S. population. The chronic dietary exposure for the highest

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 28 of 52 reported exposed population subgroup, children 1

- 2 years old , utilized 15.5 % of the cPAD. The
results are reported in table 5. 4.4 . All population subgroups were below the level of concern.

The chronic dietary exposure assessment is partially refined, i.e. based on the assumption of
tolerance

- level residues for all commodities , used default processing factors and % CT
information for some crops (Appendix E)

.

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 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 0.120415 17.97 0.012050 6.7

N/A N/A All Infants (< 1 year old) 0.146102 21.81 0.015196 8.4

Children 1

- 2 years old 0.279450 41.71 0.027847 15.5

Children 3

- 5 years old 0.218767 32.65 0.024065 13.4

Children 6

- 12 years old 0.144459 21.56 0.015268 8.5

Youth 13

- 19 years old 0.115468 17.23 0.011208 6.2

Adults 20

- 49 years old 0.100143 14.95 0.010190 5.7

Adults 50+ years old 0.094256 14.07 0.010004 5.6

Females 13

- 49 years old 0.102333 15.27 0.009822 5.5



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

Reference s :

- Azoxystrobin. Occupational and Residential Exposure Assessment to Evaluate the Risk from Proposed Uses on Dragon Fruit, Wasabi, and Post

- Harvest Potatoes, 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, Oilseeds Subgroups A, B, C, and Citrus Fruit Group 10

- 1 0), K. Rury,

D P 390837, 12/01/ 20 11

.

- Azoxystrobin. Human Health Risk Assessment for a Section 3 New/Amended Uses on Non

- grass Animal Feeds (Crop Group 18), Sorghum, Wheat, Cotton, and Wild Rice, S. Piper, D P 344389, 04/30/ 20 08.



### Residential exposure and risks from use on turf and indoor surfaces were described in a previous separate document ( S

. Piper

, D 344389

, 04 / 3 0/ 20 0 8 ). The residential uses for azoxystrobin have not changed.

6.1 Residential Handler Exposure

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 29 of 52 The proposed u ses of azoxystrobin do not involve applications by homeowners or commercial applicators to residential settings. However, azoxystrobin is currently registered for use on
several residential/non

- agricultural use sites; i.e. outdoor residential (lawns, orna mentals, flower gardens, vegetables, fruit and nut trees, berries and vines) and recreational (golf courses, parks and athletic fields) sites. Additionally, it is registered on indoor carpets/other surfaces by non

commercial applicators, and in treated pa ints (preservative incorporation). It is assumed that
most residential use will result in short

- term (1 to 30 days) handler exposures. Residential handlers are assumed to be wearing short

- sleeved shirts, short pants, shoes and socks during application of azoxystrobin

. Although PoD s 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. Because there was no dermal endpoint chosen for azoxyst robin, risk from exposure to azoxystrobin was assessed for the inhalation route only.

HED’s level of concern for the MOE is defined by the uncertainty factors that are applied to the assessment. HED applies a 10X factor to account for interspecies extr apolation and a 10X factor to account for intraspecies sensitivity. The total uncertainty factor that has been applied to the

non

- cancer risk assessment for azoxystrobin is 100X for residential exposure. Residential exposure and risk resulting in MOEs gr eater than or equal to 100 will not be of concern to HED.

The worst case residential handler scenario is summarized in Table 6.1. The MOE was 1,400 for residential handlers painting with an airless sprayer, and is not of concern to HED (i.e. an MOE

> 1 00).

Table 6.1. Summary of Worst

- Case Residential Handler Exposures and Risks.

Scenario Activity Application

Rate Area

Treated/Amount Applied (per day) Inhalation

UE (mg/lb ai) Dose

(mg/kg/day) MOE 1

Residential Handler Painting with

Airless Sprayer 1.0% ai by

weight 150 lb 0.83 0.078 1,400

1. MOE

- NOAEL/Dose where NOAEL is 25 mg ai/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. Because no dermal endpoint was chosen for azoxystrobin, and inhalation post

- application

exposures ar e considered negligible, post

- application residential exposure scenarios are not
combined. As a result, risk assessments have only been completed for post

- application scenarios in which incidental oral exposures are expected. The MOEs for worst

- case post

- application incidental oral exposures are summarized in Tables 6.2a and 6.2b. The MOEs ranged from 480 to 420,000 for incidental oral ingestion. All assessed residential exposures and risk estimates resulted in MOEs of >100; and therefore, are not of concern to HED.

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

- application inhalation exposure assessment was also not performed for azoxystrobin at this time primarily because it
has low vapor pressu re ( 8.2 x10 - 13 

### mm Hg ). However, volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 30 of 52 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 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the

pro cess of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

- application inhalation exposure into the Agency's risk assessments. If new policies or proce dures are developed, the Agency may revisit the need for a quantitative post

- application inhalation exposure assessment
for azoxystrobin

.

Table 6.2a. Short

- and Intermediate

- Term Incidental Oral Ingestion Exposure and Risk from Treated Indoor Surfaces.

Scenarios ISR (mg/cm 2 ) Short

- Term
PDR0

- norm (mg/kg/day) Intermediate

Term Potential Dose Rate ( 0

-

norm (mg/kg/day) ) Short

- Term

MOE Intermediate

Term MOE

Hand

- to

- Mouth (vinyl/hard surfaces) 1.70E

- 03 0.089 0.042 280 480

Hand

- to

- Mouth (carpet/textile surfaces) 8.34E

- 04 0.089 0.042 280 480

*Although the intermediate

- term MOEs are higher than the short

- term MOEs, one should not assume that it is safer to be exposed for a longer duration. It is an artifact of dose spacing in toxicity studies, and conservative exposure assumptions.

Table 6.2b. Short

- and Intermediate

- Term Incidental Oral Ingestion Exposure and Risk from Treated Turf.

Scenarios TTR/GR/SR0

(μg/cm 2 or g) Short

- Term PDR0

-

norm (mg/kg/day) Intermediate

- Term
PRD0

- norm (mg/kg/day) Short

- Term
MOE Intermediate

Term MOE

Hand

- to

- Mouth 0.53 0.014 0.0067 1,800 3,000

Mouthing Grass 2.13 0.0035 0.0035 7,000 5,600

Soil Ingestion 7.1 0.000048 0.000048 530,000 420,000

Combined N/A 0.018 0.01 1,400 1,900

*Although the intermediate

- term MOEs are higher than the short

- term MOEs, one should not assume that it is safer to be exposed for a longer duration. It is an artifact of dose spacing in toxicity studies, and conservative exposure assumptions.



### 6. 3 Combined Exposure

FQPA requires residential exposures that could reasonably be expected to occur on the same day be combined and compared to the appropriate toxicity endpoint. Because no dermal endpoint was chosen for azoxystrobin, and inhalation post

- application exposures are considered negligible, post

- application residential exposure scenarios are not combined. In addition, residential handler and post

- application scenarios generally should not be combined.

6. 4 Residential Bystander Post

- application Inhalation Exposu re

Although a quantitative residential post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for residential handlers. This

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 31 of 52 exposure scenario is representative of a worse case inhalation exposu re 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 app lication, 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 Regional Offices and State Lead Agencies for pes ticide 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 n ow requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrant s, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose f urther 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 with 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 c ompared to quantitative estimates of hazard (e.g. a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. For azoxystrobin , potential ex posures 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 finds no changes that would affect

t he aggregate safety finding and confirms that there are no risks of concern resulting from post

harvest use on tuberous and corm vegetables (subgroup 1C) dragon fruit, wasabi, the changes to the requested crop groups, 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 does not include dermal, inhalation or incidental oral exposure. The acute r isk 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 18 % of the aPAD for the U. S. general population, and 41.7% for the most highly exposed subgroup, children 1

- 2 years old.

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 32 of 52 7.2 Short

- Term Aggregate Risk

There is potential short

- term exposure to azoxystrobin 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 conservative scenario was chosen for each population (i.e. hand

- to

mouth exposure fro m 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 adult (inhalation) aggregate MOE (for males and females) is 280

, w hich indicates that exposure and risk do not exceed HED’s level of concern ( MOE < 100)

. The aggregate MOE for
children 1

- 2 years old , including incidental oral exposures from treated carpets and hard surfaces, is 210, which indicates that exposure and risk do not exceed HED’ s LOC (MOE < 100). Further refinement using additional % CT estimates or more refined EDWCs may need to be incorporated in future assessments.

Table 7.2

. Short

- Term Aggregate Risk Calculations.

Population & Activity NOAEL

mg/kg/day LOC 1 Max

Allowable Exposure 2
mg/kg/day Average

Food and

Water Exposure mg/kg/day Residential

Exposure mg/kg/day 3 Total

Exposure mg/kg/day 4 Aggregate

MOE (food,

water and residential) 5

Adult Males 25 100 1 0.012050 0.078 0.090 1 280

Females 13

- 49 25 100 1 0.011208 0.078 0.089 280

Children 1

- 2 25 100 1 0.027847 0.089 0.117 210

1 LOC includes standard inter

- (10 X ) and intra

- (10 X ) species uncertainty factors totaling 100

. 2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Residential Exposure = [Oral exposure + Inhalation Exposure]. S ource of residential exposure values used in aggregate assessment ( Table 6.1
and Table 6.2a ).

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

5 Aggregate MOE = [NOAE L (Avg Food & Water Exposure + Residential Exposure)] , NOAEL=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 exposure estimate

. However, intermediate

- term exposure could be expected for children via incidental oral exposure from treated surfaces. The aggregate MOE for children 1

- 2 years
old , including incidental oral exposures from treated carpets and hard surfaces, is 360 , which indicates that exposure and risk do not exceed HED’s LOC (MOE=100). Although intermediate

term MOEs are higher than the short

- term MOEs, one should not assume that it is safer to be exposed for a longer duration. It is an artifact of dose spacing in toxicity studies, and conservative exposure assumptions. Further refinement could be made using anticipated residues, monitoring data, and additional % CT estimate s , or more refined EDWCs may need to be incorporated in future assessments.

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 33 of 52 Table 7. 3. Intermediate

- 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

Children 1

- 2 20 100 1 0.027847 0.0 42 0. 070 360

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 asses sment (Table

6. 2a ).

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

5



### 7.4 Chronic Aggregate Risk

Chronic exposure is not expected for the adult residential (dermal and inhalation) exposure pathway. Therefore, the chronic aggregate risk would be equivalent to the chronic dietary exposure estimate. Refer to Section 5.4. 3 for the chronic dietary (food and drinking water)
exposure assessment.

7.5 Cancer Aggregate Risk

Azoxystrobin is considered ―not likely to be 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 substances. For information regarding EPA’s efforts to determ ine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulat ing effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

Reference s :

- Azoxystrobin. Occupational and Residential Exposure Assessment to Evaluat e the Risk from Proposed Uses on Dragon Fruit, Wasabi, and Post

- Harvest Potatoes, 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, Oilseeds Subgroups A, B, C, and Citrus Fruit Group 10

- 10), K. Rury,

D P 390837, 12/01/ 20 11

.

- Azoxystrobin. Human Health Assessment Scoping Document in Support of Registration Review, B. O’Keefe, D P 365660, 12/07/ 20 09.

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 34 of 52 9 .1 Short

- /Intermediate

- Term Handler Risk

Azoxystrobin is proposed for use as a foliar application to wasabi, dragon fruit and as a post

harvest treatment to tuberous and corm vegetables (subgroup 1C)

. Application methods, maximum application rates and use sites are summarized in Table 3.3 .1

. Ba sed on the proposed use pattern of azoxystrobin, t here is a potential for short

- and intermediate

- term occupational exposure during handling (mixing & loading) and post

- application activities (sorting, packing and culling) . Chronic exposure is not expecte d for the proposed use patterns. PPE was assessed at baseline ( long pants, a long

- sleeved shirt, shoes, socks, no chemical

- resistant gloves, and no respirator ). There are no requirements for personal protective equipment on either proposed label.

HE D evaluated the proposed uses and requested changes to the azoxystrobin crop group tolerances and determined that an ORE assessment is needed only for the post

- harvest tuberous and corm (subgroup 1C) use. These new uses, and the uses included in the revis ed crop groups, have either been adequately assessed by HED or are expected to result in lower exposures than uses previously assessed. For a summary of recent ORE assessments, refer to the 2009 azoxystrobin scoping document (B. O’Keefe, D365660, 12/07/20 09).

HED’s level of concern for the MOE is 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 un certainty factor that has been applied to the

non

- cancer risk assessment for azoxystrobin is 100X for occupational exposure. Occupational exposure and risk estimates resulting in MOEs greater than or equal to 100 will not be of concern

to HED.

Summaries of the short

- and intermediate

- term risks for occupational handlers applying azoxystrobin to post

- harvest tuberous and corm vegetables (subgroup 1C, represented by post

harvest potato) are include d in Table 9 .1. No dermal hazard was identified for azoxyst robin, therefore, only a quantitative inhalation exposure assessment was performed. The results of the occupational handler exposure and risk assessment indicate that total short

- and intermediate

term MOEs are not of concern to HED (i.e. an MOE > 100) wi th baseline attire. The short

- term inhalation MOE for occupational application of azoxystrobin to post

- harvest use sites was 1,100,000 . The intermediate

- term MOE for occupational application of azoxystrobin to post

harvest use sites was 910,000.

Table 9.1 . Occupational Handler Short

- and Intermediate

- Term Dermal and Inhalation Exposure and Risk Estimates for

Post

- Harvest Use

Activity/Exposure
Scenario Solution

Concentration 2
(lb ai/gal soln) Amount

Treated per Day 3
(1 gal/lbs of potatoes) Amou nt

Processed per Day 4
(lbs boxes/hr) Inhalation

UE 5 (mg/lb ai) ST & IT

Inhalation Daily

Dose 6 (mg ai/kg/day) ST MOE 7 IT
MOE 8

Open Mixing/Loading Liquids 0.0195 1/4000 180,000 0.000219 0.000022 1,100,000 910,000

1. Liquid Formulation

- Abound® Flowable Fungicide EPA Reg. No. 100

- 1098

2. Solution Concentration

- fl oz product/gal water x lb ai/gal x 1 gal/128 fl oz (e.g. 0.6 fl oz/0.5 gal water x 2.08 lb ai/gal x 1 gal/128 oz) 3. Amount Treated Per day

- gallons/lb of tubers (e.g. 0.5 gal treats 2,000 lb tubers = 1 gal/4,000 lb tubers) . Provided by the registrant, in an email

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 35 of 52 correspondence. 4. Amount Processed per day

- lbs boxes per hour. Assumed that a packing facility could potentially pack 2,000 boxes per hour, each weighing 90 lbs (2,000 boxes/hr x 90 lbs each = 180,000 lbs boxes/hr) 5. Unit Exposure Values

- Baseline (e.g. no respirator)

6. Short

- a nd Intermediate Term Inhalation Daily Dose

- [Amount Processed (lb boxes/hr) x Amount Treated daily (gal/lb) x soln concentration (lb ai/gal soln) x Unit Exposure x 8 (hr/day) x absorption factor (1.0)]/body weight
7. Short Term MOE

- NOAEL (25 mg/kg/day)/Daily Dose (mg ai/kg/day)

8. Intermediate Term MOE

- NOAEL (20 mg/kg/day)/Daily Dose (mg ai/kg/day)



### 9 .2 Short

- /Intermediate

- Te rm Post

- Application Risk

9 .2.1 Dermal Post

- A pplication Risk

The proposed occupational uses for azoxystrobin addressed in this document involve post

harvest applications, resulting in the potential for exposure to azoxystrobin during sorting, packing and culling treated vegetables . However, no appropriate dermal en dpoint was identified for azoxystrobin. Therefore, 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 on g rapes, but has not been employed in this or previous
risk assessments because HED determined there is no hazard via the dermal route.

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

- application inhalation exposure assessment was not perform ed for azoxystrobin primarily because of its low acute inhalation toxicity (Toxicity Category III), and low vapor pressure (8.2x10 - 13 

### mm Hg). Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from mixing/loading pesticides a fter harvest is likely to result in higher exposure than post

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

- application inhalation exposure scenarios. 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.

Nevertheless, per the Worker Protection 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 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 products. Previously, HED
determined that the criteria for th e technical material had been met for azoxystrobin, and RD had
determined the criteria for the end

- use products Abound ® 

### had been met, and therefore, the 4

- hour

REI , as listed on the label, is acceptable for Abound ®



### .

It should be noted, that the WPS doe s not apply to the post

- harvest use s on citrus & tuberous and corm vegetables (subgroup 1C) addressed in this document, as outlined in 4 0 CFR 170.103(i) and 170.203(h). W orkers should wai t for the solution on the fruit/tubers to dry before engaging in pos t

- application activities (such as packing, sorting and culling). Workers are assumed to be wearing baseline clothing while mixing/loading for post

- harvest uses.

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 36 of 52 10 .0 References

R. Baris, 11/28/11, DP#389703/394475, Drinking Water Exposure Assessment f or New Uses of Azoxystrobin on Wasabi, Dragon

- fruit and Sugarcane, and the Proposed Tolerances for Residues of Azoxystrobin for Use on Onion subgroups, Fruiting Vegetables Subgroups, Small Fruit & Berry Subgroups, Oilseed Subgroups; and the Proposed Increa sed Tolerance for Tuberous & Corm Vegetables Subgroup.

M. Negussie, 11/29/11, DP#390838, Azoxystrobin: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for Section 3 Petition For Use On
Tuberous and Corm Vegetables subgroup 1C ( p ost

- harvest); Dragon Fruit; Wasabi; and Crop Group/Subgroup Expansions for Bulb Vegetables 3

- 07A and 3

- 07B; Caneberries 13

- 07A;
Bushberries 13

- 07B; Small Fruit Vine Climbing 13

- 07F, Except Fuzzy Kiwifruit; Low growing Berry 13

- 07G, Except Cranberry; Low Growing Berry 13

- 07H, Except Strawberry; Citrus Crop Group 10

- 10; Fruiting Vegetable Crop Group 8

- 10; and Oilseed Crop Group 20

.

M. Negussie, 11/16/11, DP#390152, Azoxystrobin. Section 3 Petition For Use On Potatoes (Post

- harve st); Dragon Fruit; Wasabi; and Crop Group Expansions for Bulb Vegetables 3

- 07A
and 3

- 07B; Caneberries 13

- 07A; Bushberries 13

- 07B; Small Fruit Vine Climbing 13

- 07F, Except Fuzzy Kiwifruit; Low growing Berry 13

- 07G, Except Cranberry; Low Growing Berry

13

- 07H , Except Strawberry; Citrus Crop Group 10

- 10; Fruiting Vegetable Crop Group 8

- 10; and Oilseed Crop Group 20. Summary of Analytical Chemistry and Residue Data

.
B. O’Keefe, 12/07/09, DP#365660, Azoxystrobin. Human Health Assessment Scoping

Document in S upport of Registration Review.

S. Piper, 04/30/08, DP#344389, Azoxystrobin. Human Health Risk Assessment for a Section 3
New/Amended Uses on Non

- grass Animal Feeds (Crop Group 18), Sorghum, Wheat, Cotton,
and Wild Rice.

K. Rury, 12/01/11, DP#390837, A zoxystrobin. Occupational and Residential Exposure Assessment to Evaluate the Risk from Proposed Uses on Dragon Fruit, Wasabi, and Post

- Harvest Potatoes, and from the Revisions to Various Crop Groups (Onion Subgroups 3

- 07 A & B, Fruiting Vegetable Subgroup s 8

- 10 A & B, Small Fruit and Berry Subgroups 13

- 07 A, B, F, G, Oilseeds Subgroups A, B, C, and Citrus Fruit Group 10

- 10)

.

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

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

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 37 of 52 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

no

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 CR -

- 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

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 38 of 52 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. 389702

Page 39 of 52 Table A

. 2 .2

. Azoxystrobin Toxicity Results From Repeated Dosing and Other Studies. Study Guideline/Study MRID Results

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

. Offspring NOAEL = 32 mg/kg/ day LOAEL = 165 mg/kg/day based on reduced pup body weight and increased adjusted liver weights.

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

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

870.4300
Combined Chronic toxicity/ Carcinogenicity

in rats 43678139 (1995) Acceptable/guideline 0, 60, 300, &1500/750 ppm for males (due to excessive death the high dose was reduced beginning at week

52

- 104) For females: 0, 60, 300,& 1500 ppm M: 0, 3.6, 18.2, 82.4 mg/kg/day F: 0, 4.5, 22.3, 117.1 mg/kg/day NOAEL = 18 mg/kg/day LOAEL = 82.4 mg/kg/day in males and 117 mg/kg/day in females based on reduced body weights in both sexes and bile duct lesions in males. There was no evidence of carcinogenicity

.

870.5100 Bacterial reverse gene

mutation 43668146 (1992) Acceptable/guideline 100, 200, 500, 1000, 2500, 5000 μg/plate Negative in increasing revertant colonies up to 5000 μg/plate +/

- S9 using both plate incorporation and preincubation protocols and Salmonella strains TA98, TA100, TA1535, and TA1537 as well as the E. Coli strains WP2P and WP2PuvrA. Cytotoxicity and compound precipitation were seen at the high
dose.

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

assays Nonlinear, slight but significant increases in the mutation frequency (MF) of mouse lymphoma

L5178Y TK +/

- at 15

- 60 μg/mL +/

- S9 . Despite the absence of a dose response, increased MFs were reproducible; therefore, Azoxystrobin is considered positive in this test system. Colony sizing was not performed.

870.5375 Cytogenetics

chromosomal aberration 43678147 (1992) Acceptable/guid eline 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. 389702

Page 40 of 52 Table A

. 2 .2

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

870.5385 Cytogenetics bone

marrow 43678148 (1992) Acceptable/guideline

5000 mg/kg The in vivo mouse bone marrow micronucleus assay

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

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

- do se 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

- rel ated qualitative and quantitative differences in biliary metabolites. A metabolic pathway was proposed showing hydrolysis and subsequent glucuronide conjugation as the major biotransformation process.

870.7600 Dermal penetration (rat) 43678155 (1994) Acceptable/guideline 0.01, 0.1, 0.9, 13.3 mg/kg 2

- 4 % Dermal Absorption

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 41 of 52 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 OW = 2.5

UV/visible absorption spectrum Not available

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 42 of 52 Appendix C

. International Residue Limit Status Sheet

.

Tab le C. Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :

US Canada Mexico 2 Codex 3

40 CFR 180. 507
Plants: sum of azoxystrobin, [methyl( E )

- 2

- (2

- (6

- (2

- cyanophenoxy) pyrimidin

- 4

- yloxy)phenyl)

- 3

- methoxyacrylate], and the Z

isomer of azoxystrobin [methyl(

Z )

- 2

- (2

- (6

- (2

- cyanophenoxy)pyrimidin

- 4

- yloxy)phenyl)

- 3 methoxyacrylate] (α E )

- methyl 2

- [[6

- (2

- cyanophenoxy)

- 4

- pyrimidinyl]oxy]

- α

- (methoxymethylene) benzeneacetate, including the isomer ( Z )

- methyl 2

- [[6

- (2

- cyanophenoxy)

- 4

- pyrimidinyl] oxy]

- α

- (methoxymethylene)benzeneacetate Azoxystrobin. The
residue is fat soluble.



### Commodity 1 

### Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 2 

### Codex 3

Berry, low growing, subgroup 13

- 07G, except cranberry 10.0 3.0 lowbush blueberries

, lingonberries 5 berries and other small fruits, except

cr anberry, grapes and strawberry 10 strawberry

Bushberry subgroup 13

- 07B 5.0 3.0 bushberries (crop subgroup

13

- 07B) aronia berries, blueberries, buffalo currants, Chilean guava,

currant s , elderberries, European barberries, gooseberries, highbush blueberries, highbush cranberries, honeysuckle, huckleberries, jostaberri es, lingonberries, lowbush blueberries, native currants, salal

berries saskatoon berries (juneberries) , sea buckthorn 5 berries and other small fruits, except cranberry, grapes and strawberry

Caneberry subgroup 13

- 07A 5.0 5.0 caneberries (crop subgroup

13

- 07A) blackberries, loganberries, raspberries, wild raspberries 5 berries and other small fruits, except cranberry, grapes and strawberry Cottonseed subgroup 20C 0.7 0.7 cotton seed Dragon

- fruit 2.0 2 mangoes 0.7 mango

### Azoxystrobin Human Health Risk Assessment DP No. 389702

Page 43 of 52 Tab le C. Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :

US Canada Mexico 2 Codex 3

Fruit, citrus, group 10

- 10 15.0 10 citrus fruits ; Australian desert limes, Australian finger limes, Australian round limes, Brown River finger limes,

calamondin s , citrus citron s , citrus hybrids, grapefruits, Japanese summer grapefruits, kumquats, lemons, limes,

Mediterra nean mandarins, mount White limes, new Guinea wild limes, oranges, pummelos, Russell River limes, Satsuma
mandarins , sweet limes, tachibana oranges, Tahiti limes, tangelo s , tangerines

, tangor s , trifoliate oranges, uniq fruits 15 citrus fruits

Fruit small vine climbing, except fuzzy kiwifruit subgroup 13

- 07F 2.0 3 grapes 2 grapes

Onion, bulb, subgroup 3

- 07A 1.0 1.0 dry bulb onions 10 bulb vegetables Onion, green, subgroup 3

- 07B 7.5 7.5 green onions

Pepper/eggplant subgroup 8

- 10B 3.0 2.0 bell peppers, eggplants, non

bell peppers, pepinos, pepper hybrids, 3 fruiting vegetables

other than cucurbits except mushrooms and sweet corn; 30 peppers chili dried Rapeseed subgroup 20A 1.0 1.0 rapeseeds (canola) Sunflower subgroup 20B 0.5 0.5 sunflower seeds 0.5 sunflower seed Tomato subgroup 8

- 10A

0.2 2.0 ground cherries, tomatillos

0.2 tomatoes 0.6 tomato paste 3 fruiting vegetables
other than cucurbits except mushrooms
and sweet corn

Vegetable, tuberous and corm, subgroup 1C 8.0 8.0 ( vegetable, tuberous and corm, subgroup 1C ( proposed) 0.03 potatoes 1 root and tuber vegetables

Wasabi , fresh 50 50 Herbs (crop subgroup 19A; fresh leaves) 70 herbs

Wasabi, dry 260 260 Herbs (crop subgroup 19A; dried leaves) 300 dried herbs (except hops (dry))

Completed: M. Negussie; 10/31/ 2011

1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

3 * = absent at the limit of quantitation; Po = post

- harvest treatment, such as treatment of stored grains. PoP = processed post

- harvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.

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Page 50 of 52 Appendix E

. 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.

T he 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).

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