Azoxystrobin Human H ealth Ri sk Assessment DP Nos. D 423691, D418 374

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY



### MEMORANDUM

DATE: April 7, 2015 WASHIN GT ON, D

. C. 20460

OFFICE O F CHEMICAL SA FETY AND POLL U T I ON PREVENT ION



### SUBJECT: Azoxystrobin. Human H ealth Aggregate Ri sk Assessment for Permanent
Toleran ces on Imported Asian P ea r , Im po rt ed Tea, and Import ed Coffee;
Est abli s hm e nt of Permanent To lerances on Ti Palm and for Crop Grou p Conversions fo r Sto n e Fruit s Group 12 -1 2 and Tree Nut Group 14-1 2 Crop
Gro u ps.

PC Code: 1 2 8810
Deci s ion Nos

. : 495749, 486446
Petiti o n Nos.: 3E822 8 ; 4E83 I 9
Risk Asses s ment Type: Si n gle Chemica l/ Aggregate

TXR No.: NA

MRID No.: NA



### FROM: Kristin Rur y, Risk Assessor
Ste ve F unk

, Sen i o r Chemist DP Barcodes: 0423691

, 04 1 8374 Registration Nos.: NA Regulator y Action: Section 3 Registrat i on, Import Tolerances
Case No.: 7020
CAS No.: 1 31860-33 -8
40 CFR: § 180

. 507

Whang Phang, Senior T oxicologist
Risk Assessment Branch 3 (RA B 3)
Health Effects D iv i sion (7509P)



### THRO UGH : Christine O lin ger, Branch Chief 

## .f, r 

# /3.**~** 

## 'fl

0 

## p,, Ri sk Asse ss ment Branch 3 (RAB 3) r**~** Health Effects Division (7509P)



### TO: Rache l H o ll oman/Shaja J oyne r Fungicide Herb i cide B ranch Registration Div i sion (7505P)

And

Andrew Ertman/Bar bara Madden
Minor Us e B ra n ch Registra t io n Division (7505P)

P age 1 of 34Azoxystrobin Human Health Risk Assessμient DP Nos

. D423691, D418374

1.0 Executive Summary

..... .. ..... . .. .. .. . .. .. ...... . ............ . ......... . .. .. .. .. .. . .. .. ... . ................. .. ... .. . ... .. .. .. 4
2.0 HED Recommendations

. . ......................... . . .. .. .. .. .. .. .. ... . . ... . .. ................. ... . ... . ... . ... . ... .. .. . .. ... 7
2

. 2 Tolerance Considerations

......... .. . .. .. .. .. .. .. .. . .. ...................... . ...... .. .. .. . .. .. .. .................... . .. 7
2.2

. 1 Enforcement Analytical Method

.. . ..................... .. .. . .. .. .. .. .. .. . .. .... . ... . . . ........... .. .. .. .. ... .. .. . . 7
2.2

. 2 Recommended Tolerances

......... . ...... . . .. . .. .. ... . ... . ... . .. . .. .......................... .. .. .. .. .. .. .. .. ... .. . ... 7 2.2.3 Revisions to Petitioned-For Tolerances

........................... . .... . .. . ... . ... .. .. . ....................... . 8
2.2.4 International Harmonization

..... .. ........................ .. .. ..... .. ... . .. .. ... . .. .. ... ... . ................... . . .. 8
3.0 Introduction

...... .. . .. .. .. . .. ... . ........................ . .... . ........ .. .. .. .. . .. . .... . ............................. .. .. .. .. ... .. . 9
3

. 1 Chemical Identity

...... .. ......... .. . .. .. .. ........ . ..... . ......................... .. . .. .. .. ... . .. .. ... . .................... 9
3.2 Physical/Chemical Characteristics

... .. .. .. . ... . .. .. .. . ... ................................. .. .. .. .. .. .. .. .. .. .. .. 9
3.3 Pesticide Use Pattern

..... . .... . .. . ...................... .. .. . ... ... . .. .. .. .. .. .......... .. .............................. 10 3.4 Anticipated Exposure Pathways

.. .. .. .. .. .. ........................................ .. .. .. .. .. .. .. .. .. .. .. .. .. ... 1 1
3.5 Consideration of Environmental Justice

.. .......... . ... . .. .. .. .. ... . ....................................... 11
4.0 Hazard Characterization and Dose

- Response Assessment

........... .. ... .. .. .. .. .. .. . ........ . .. .. 12 4.1 Summary of Toxicological Effects

............................. . .. .. ... . ....... . .. . ... . ......................... 12
4.2 Safety Factor for Infants and Children (FQPA Safety Factor)

... ............................ 13
4

. 2

. 1 Completeness of the Toxicology Database

..... . ................................................. .. .. .. ... . 13 4.2.2 Evidence of Neurotoxicity

........ .. ...................................................... . . . ... . . ... ... . .. .. .. .. .. .. . 13
4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

.. .. . ...... 1 3
4.2.4 Residual Uncertainty in the Exposure Database

......... . ....................... . ..................... 14 4

. 3 Toxicity Endpoint and Point of Departure Selections

............... . .. . ...... .. .. .. .. .. .. .. .. ... .. 14
5

. 0 Dietary Exposure and Risk Assessment..

... .. ........ . .......... .. ..... .. ...................................... 16 5.1 Residues of Concern Summary and Rationale

...................................... . ...... .. .. .. ... .. .. 16
5.2 Food Residue Profile

................ . . .. ..... ... ................ .. .. .. ... . ... . ... . .. . .. .. ... . .. .. .. .. .. .. . .. ... .. .. . ... . 16
5.3 Water Residue Profile

.......... . .. . ..... .. .. .. .......... . ... . ........................ . .......................... . ...... 1 7 5.4 Dietary Risk Assessment

.................... . ...................... . ............ . .. .. .. . .... .. .. .. .. .. .. .. . .. ... . .. ... 18 5.4.1 Description of Residue Data Used in Dietary Assessment

...... .. .. . ............................. 1 8
5.4.2 Percent Crop Treated Used in Dietary Assessment..

.. . .. ... .. .. .. .. ..... .. . .. .. ...... .. .. .. .. .. ... . 18
5.4

. 3 Acute Dietary Risk Assessment..

......... .. ............................................... .. ...... .. .. .. .. . ... .. . 1 9 5.4.4 Chronic Dietary Risk Assessment

........................................................................... . ... 1 9 5.4.5 Cancer Dietary Risk Assessment

................... .. ........................................................... 1 9 5.4.6 Summary Table

. . .. . .. . ... . .. . ...... . .. .. .. .. ..... .. .. .. ...... . ... . .. .. .. .. .. . .. ... . .. .. .. .. .. .. ... . . ... .. .. . .... . ...... .. . 19 6.0 Residential (Non-Occupational) Exposure/Risk Characterization

.. .. .. . . .... .. . .. ... .. . ... .. . 20
6.1 Residential Bystander Post

- application Inhalation Exposure

................................. 2 1
6.2 Spray Drift

...... .. ............... . .. . ..... .. .. . .. .. ...... . ...... .. ...... . ... . ... .. . .. . .. .. ... .. .. . . .. .. ... .. .. . . . . . ........... 21
7

. 0 Aggregate Exposure/Risk Characterization

....................... .. .. .. .. .. .. .. ..... .. .. .. .. .. .. .. .. .. .. .. .. 21
7.1 Acute Aggregate Risk.

. .. .. .. . .. .. . . . .. .. .. .. .. .. . .. .. .. .. .. .. . .. . ... .. ..... . .............. . ............................ 22
7.2 Short

- Term Aggregate Risk

.......... . ........... . .............. .. .. .. . .. .. .. .. .. .. .. .. . .. ... . ... . .. .. ... . ... . .. .. . 22
7.3 Intermediate-Term Aggregate Risk

................................................................... .. ...... 23
7.4 Chronic Aggregate Risk

................ .. .. . .. .. ... . .. .. . ... . ... . .. .. .. .. .. . ... . ... . .. .. .. ..... ... ................... 23 7.5 Cancer Aggregate Risk

............................................ . ....... . .. .. ...... .. .. .. .. .. .. .. . ... .. .. . . .. ...... . 23
8

. 0 Cumulative Exposure/Risk Characterization

... ... .. .. .................. .. ................................ . 23 9.0 Occupational Exposure/Risk Characterization

.. .. .. ............. .. .. .. .................................. . 23 9.1 Short-/lntermediate

- Term Handler Risk

............... .. .. .. .. . .......... .. . . .... . ....... . ................ 23
9

. 2 Short-/lntermediate-Term Post

- Application R i sk

........... .. .. .. .. .. ............. .. .. .. .. .. ........ 26
9.2.1 Dermal Post-application Risk

.... . .. . ... . ................. .. ............................................. .. ...... . 26

Page 2 of34Azoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 3 of 34 9.2.2 Inhalation Post

- application Risk

................................ ................................ ................. 26
10.0 References

................................ ................................ ................................ ......................... 27 Appendix A. Toxicology Profile

................................ ................................ ................................ 29
A.1 Toxicology Data Requirements

................................ ................................ ................... 29
A.2 Toxicity Profiles

................................ ................................ ................................ ............ 30 Appendix B. Physical/Chemical Properties

................................ ................................ ............. 33 Appendix C. Review of Human Research

................................ ................................ ................ 34Azoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 4 of 34 1.0 Executive Summary

Azoxystrobin is a β

- methoxyacrylate fungicide

, currently registered for use on a variety of field, vegetable, fruit, and nut crops as well as on ornamental plants and turf. It is also used to control mold on indoor surfaces. Its biochemical mode of action is inhibition of electron transport.

This document addresses two separate petitions : (1) one submitted by the Registrant, Syngenta Crop Protection, Inc (Syngenta) and (2) a second submitted by the Inter

- Regional Research Project Number 4 (IR

- 4). The se actions are summarized as follows:

1. PP# 3E8228: Syngenta has submitted a proposal to add import tolerances with out domestic registrations to the AmistarZtra SC label (Columbia) on coffee, to the Azoxystrobin Amistar WP 10% label (South Korea) on Asian pear, and to the Amistar 20 SC label (Japan ) on tea.

2. PP# 4E8319: IR

- 4 has submitted a proposal to add azoxystrobin use on T i palm, and to incorporate recent revisions to the crop group listings of the Stone Fruit s (Crop Group 12

- 12) and Tree Nut (Crop Group 14

- 12) crop groups on the Abound® Flow able Fungicide label (EPA Reg. No. 100

- 1098). Abound® Flowable Fungicide is a liquid concentrate containing 22.9% a i.

This document assesses the exposures and risks from the propose d tolerances of azoxystrobin for
domestic uses on T i palm, stone fruit s , and tree nuts and on imported coffee, tea, and Asian pear

. HED has not previously assessed occupational exposure from azoxystrobin use on stone fruit s or tree nuts with updated policies (i.e., new assumptions for unit exposure s and acres treated ) ; therefo re, occupational exposure corresponding to the proposed crop group updates has been assessed according to current exposure policies. This document also reevaluates the existing residential scenarios for aggregate risk assessment because the points of depa rture (POD s ) for azoxystrobin have recently changed.

Proposed Use Profile Azoxystrobin may be applied at a maximum single application rate of 20 fl oz/A (0.33 lb ai/A) to
T i palm leaves and roots, 12 fl oz/A (0.20 lb ai/A) to tree nuts, and 15.5 fl oz/A (0.25 lb ai/A) to
stone fruit s . The proposed labels require occupational handlers to wear long

- sleeved shirts, long pants, shoes, socks, and chemical resistant gloves. The restricted entry interval ( REI ) listed on
the Abound® label is 4 hours.

Exposure Profile Exposure to azoxystrobin can occur from dietary (food and drinking water), residential, and occupational exposure sources. Based on all of the proposed application rates and label information, only short

- and intermediate

- term dermal an d inhalation exposures are expected for occupational handlers and post

- application workers. Based on the existing residential uses of azoxystrobin on turf and ornamentals, only short

- term dermal and inhalation exposures are expected for residential handle rs. Short

- term residential post

- application exposure is expected
for adults and children. For the proposed domestic uses of azoxystrobin, t here is also potentialAzoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 5 of 34 for acute and chronic exposure through food and drinking water ; and for the proposed import tolerances with no domestic registrations there is only potential through food.

Toxicity/Hazard The azoxystrobin database is complete and adequate for risk assessment. In repeat

- dose oral studies, the liver and bile ducts were consistently the target organs of azoxystrobin toxicity.
D evelopmental effects were not seen in rabbit or rat developmental toxicity studies . In the rat reproduction study, offspring and parental effects (decreased body weight and increased adjusted liver weight) were observed at the same dose. In a 21

- day repeated dose dermal study in the rat, neither dermal nor systemic toxicity was seen at the limit dose (1,000 mg/kg/day). Furthermore,
there was no concern for developmental or reproductive effects. Therefore, a hazard was not identified for short

- and intermediate

- term dermal exposure scenarios, and a dermal risk assessment is not applicable at this time. The acute and chronic dietary points of departure (PODs) remain unchanged since the previous risk assessment. However, t he inhalation and
incidental oral POD s have been revised by since the previous assessment. For short

- and
intermediate

- term incidental oral and inhalation exposures the P OD has been revised to be based
on the 2

- generation reproduction study in rats. The POD is based on decreased pup weights in both males and females at the lowest observable adverse effect level (LOAEL) of 165 mg/kg/day (no observable adverse effect level (NOAEL) = 35 mg/kg/day). Since inhalation absorption data

are not available, toxicity by the inhalation route is considered to be equivalent to the toxicity by the oral route of exposure. Azoxystrobin is characterized as "not likely" to be a human
carcin ogen. To account for the use of a LOAEL from the acute neurotoxicity study in rats, the Agency has applied a 3X Food Quality Protection Act ( FQPA ) Safety Factor ( SF ) will be adequate to extrapolate a NOAEL in assessing acute risk. The FQPA SF has been reduced to 1X for all other exposure durations. Azoxystrobin exhibits low acute mammalian toxicity via oral, dermal, and inhalation routes of exposure (Category III or IV for acute lethality and irritation studies) and is not a dermal irritant or sensitizer.

Dietary Exposure (Food and Water) and Risk Estimates Slightly refined acute and chronic dietary analyse s w ere conducted for the proposed and existing

uses of azoxystrobin. For both the acute and chronic assessments, t he modeled surface water estimated drinking water concentration (EDWC) from the currently registered turf application
scenario was the highest EDWC for all proposed/registered crops and was incorporated directly into the dietary assessment.

The acute assessment in corporated tolerance

- level residues for all commodities, except for citrus
fruits (which used the highes t residues from residue trials), assumed that 100 % of the crops were treated (100% crop treated; CT), and incorporated default processing factors except for where tolerances were established for processed commodities or when processing studies showed no
concentration. The results of the acute dietary analysis for food and drinking water indicate that acute dietary risks do not exceed the Agency ’s level of concern ( < 100% of the aPAD) for the U.S. population and all population subgroups. At the 95 th percentile, the acute dietary (food and drinking water) risk estimates utilized 16% of the acute population adjusted dose (aPAD) for the general U.S. populat ion and utilized 40% of the aPAD for children 1

- 2 years old, the most highly exposed subpopulation

.Azoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 6 of 34 The chronic dietary analysis incorporated tolerance

- level residues, average %CT estimate s when
available , and default processing factors except for where tolerances were established for processed commodities or when processing studies showed no concentration. T he chronic dietary (food and drinking water) risk estimates utilized 6.0% of the chronic population adjusted dose (cPAD) for the U.S. population and utilized 15 % of the cPAD for the most highly exposed subgroup, children 1

- 2 y ears old.

Aggregate Exposure and Risk Estimates There is only potential for short

- term aggregate exposure to azoxystrobin via the dietary and residential pathways; residentia l exposures include inhalation (adults and children) and incidental oral (only children 1 to <2 years). For adults and children 1 to <2 years, the short

- term aggregate risk estimates are not of concern; the margins of exposure ( MOEs ) are 2,400 and 280,

re spectively.

Occupational Exposure and Risk Estimates
A short

- and intermediate

- term occupational risk assessment was performed for azoxystrobin use

on T i palm, stone fruit s , and tree nuts. Based on the proposed use pattern of azoxystrobin, there is po tential for short

- and intermediate

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

- application activities. The o ccupational handler assessment is based on inhalation exposures only

, since dermal hazard was not identifi ed

. The results of the occupational handler risk assessment indicate that short

- and intermediate

- term inhalation MOEs are not of concern (i.e., MOE s ≥ 100) with baseline mitigation (no respirator) and engineering control for aerial applications (enclosed cockpits )). The MOEs range from 1 9 ,000 to 4,300 ,000 for occupational handlers.

Although occupational post

- application dermal exposure is expected following treatment of agricultural crops, dermal hazard was not identified for azoxystrobin. Therefore, a quantitative post

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

- cancer occupational post

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

- application inhalation exposure assessment for azoxystrobin

.

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

.

Environmental Justice

1 http://www.epa.gov/pesticides/science/handler

- exposure

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

- app

- exposure

- data.htmlAzoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 7 of 34 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 Lo w

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

2.0 HED Recommendations

There are no deficiencies that would preclude establishing the recommended to lerances for azoxystrobin on the imported commodities: Asian pear, coffee, and tea. Additionally, there are no deficiencies that would preclude establishing the recommended tolerance for Ti palm and establishing crop group conversions for stone fruit s group 12

- 12 and tree nut group 14

- 12. The specific tolerance recommendations are discussed in Section 2.2.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

A gas chromatography with a nitrogen

- phosphorus detector ( GC/NPD ) method, RAM 243/04, is available for the enforcement of tolerances for residues of azoxystrobin and its Z

- isomer in crop commodities. The method has undergone method validation by the Analytical Chemistry Branch ( ACB ) / Biological and Economic Analysis Division ( BEAD )

. The method was revised to incorporate comments made by BEAD, and the revised method (designated RAM 243, dated 5/15/98) has been submitted to FDA for inclusion in Pesticide Analytical Manual (PAM)

, Volume II. The limit of quantification ( LOQ ) is 0.01 p pm for each analyte in crop commodities.

Data have previously been submitted pertaining to the multi

- residue methods testing of azoxystrobin in conjunction with the grape petition (PP#5F4541). The data indicate that azoxystrobin could not be recovered th rough application of the multi

- residue protocols. These
data have been forwarded to the Food and Drug Administration ( FDA ) for inclusion in PAM I.

Azoxystrobin may be determined by QuEChERS.

2.2. 2 Recommended Tolerances

The residue definition (40CFR§ 180.507) complies with the recommendation of the S. Knizner
5/27/09 memo ; n o change is needed. For compliance in plant commodities, the sum of azoxystrobin and its Z

- isomer is determined.

Table 2.2.2 . Tolerance Summary for Azoxystrobin Commodity Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments

( correct commodity definition ) Coffee, bean, green 0.03 0.03 Coffee, green bean
Asian Pear 0.07 0.07 Pear, Asian

Tea 10.0 20.0 Tea, dried Ti palm, leaves 50 50.0 Ti, leaves Translation of existing group 2 (leaves of root and tuber vegetables) tolerance.Azoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 8 of 34 Table 2.2.2 . Tolerance Summary for Azoxystrobin Commodity Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments

( correct commodity definition ) Ti palm, roots 0.5 0.5 Ti, roots Translation of existing subgroup 1A (root vegetable) tolerance. Stone Fruit Group 12 Revoke Revoke Crop Group conversion to 12

- 12 Fruit, s tone, Group 12

- 12 2.0 2.0 Crop Group conversion.
Harmonization with Codex. Nut, Tree, Group 14 Revoke Revoke Crop Group conversion to 14

- 12 Nut, tree, group 14

- 12 0.02 0.02 Nut, tree, group 14

- 12, except pistachio. Crop Group conversion.
Pistachio remains at a higher tolerance (0.50 ppm)

2.2. 3 Revisions to Petitioned

- For Tolerances

The proposed tolerance of 10.0 ppm for tea is insufficient, as the trials were conducted at 50% of the label maximum rate. Correction by proportionality to the maximu m label rate provides a tolerance recommendation of 20 ppm.

2.2. 4 International Harmonization

The residue definitions for plants and livestock are not harmonized with Codex; t he US and the
Canadian residue definition s include both the predominant E

- isomer and the minor Z

- isomer
whereas t he Codex includes only the E

- isomer.

A Codex Maximum Residue Limit (MRL) has been established for coffee beans at 0.03 mg/kg,
but no MRLs have been established for Asian pear or tea. Codex recommended an increase i n its coffee bean tolerance from 0.02 to 0.03 ppm in 2013. The recommended US tolerance for coffee is harmonized with Codex. No MRLs have been established in Canada for tea, coffee, or pears.

Codex has not established an MRL for T i palm leaves or root s. Canada has not established a
tolerance for T i palm leaves or roots. There is no issue of harmonization.

For the crop group conversions, Codex has established an MRL for stone fruit at 2 mg/kg. Canada has a tolerance for peach at 0.8 ppm. For purp oses of harmonization with Codex, the
stone fruit s group 12

- 12 will be increased to 2.0 ppm from the current tolerance of 1.5 ppm for
stone fruit s group 12.

Codex has established an MRL of 0.01 mg/kg for tree nuts. Canada has established tolerances of
0. 02 ppm for the various tree nuts, which is harmonized with the US. The US crop group tolerance is based on a residue definition of azoxystrobin plus the Z

- isomer (R230310 ). Residues were <0.01 ppm for each component in the almond and pecan trials. There fore, the tolerance estimate is 0.02 ppm, the sum of the components. The Codex residue definition is parent only, which support the 0.01 mg/kg MRL. The US tolerance cannot be harmonized with
Codex.Azoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 9 of 34 3.0 In troduction

Azoxystrobin is a broad

- spectrum fung icide and belongs to a class of pesticidal compounds called β

- methoxyacrylates, which are derived from the naturally occurring strobilurins (Group 11 fungicide). The biochemical mode of action is inhibition of electron transport.

3.1 Chemical Identity

Table 3.1

. Azoxystrobin Nomenclature.
Compound

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

IUPAC name methyl ( 2 E )

- 2

- {2

- [6

- (2

- cyanophenoxy)pyr i midin

- 4

- yloxy]phenyl}

- 3

- methoxyacrylate

CAS name methyl ( α E )

- 2

- [[6

- (2

- cyanophenoxy)

- 4

- pyrimidinyl]oxy]

- α

- (methoxymethylene)

- benzeneacetate
CAS registry number 131860

- 33

- 8

End

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

- 1098 ) containing 22.9% ai Regulated metabolite, Z

isomer

Common name Azoxystrobin, Z

- isomer
Company experimental name R230310

Chemical name methyl ( 2 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 and is considered relatively insoluble in water. However, azoxystrobin has a molecular weight of 403 g/mol; therefore, the potential to cross biological barriers is somewhat limited, as indicated by the low dermal absorption in the rat de rmal penetration study. The physicochemical properties of azoxystrobin are summarized in Appendix B

.Azoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 10 of 34 3.3 Pesticide Use Pattern

In addition to the domestic registrations outlined below, Syngenta has submitted a proposal to add import tolerances with no domestic registrations to the AmistarZtra SC label (Columbia) on coffee at a maximum single application rate of 0.14 lb ai/A, to the Azoxystrobin Amistar WP 10% label (South Korea) on Asian pear at a maximum single application rate of 0.4 lb ai/A, and

on tea to the Amistar 20 SC label (Japan) at a maximum single application rate of 0.39 lb ai/A.

Table 3.3. Summary of Proposed Directions for Use of Azoxystrobin. Applic. Timing, Type, and Equip. Formulation Applic.
Rate
lb ai/ A Max. No.

Applic. per
Season Max. Seasonal

Applic. Rate
lb ai/A PHI

(days) Use Directions and

Limitations

Import Tolerances with out Domestic US Registration (PP # 3E8228 ) 1

Coffee

Foliar with ground equipment. AmistarZtra

SC (200 g/L azoxystro

bin; 80 g/L Cyprocon

azole)

Colombia 0.089

-

0.14 3 0.40 2 15 Start application 90 days after principal flowering followed by 2 consecutive applications with a 45 day interval.
Use a mixture volume of 50 cc per tree after diluting 1.8 ml of commercial product to 1 liter of water. App ly when the coffee crop (leaves, branches, and fruits) is dry. The reentry interval is 4
hours.
Asian Pear

Foliar Azoxystro

bin Amistar
WP 10% (South Korea) 0.40 3 5 2.0 7 Apply at beginning of infestation with a 10 day
retreatment interval.

Tea

Foliar Amistar 20

SC (0.22 kg/L) 4 0.098

-

0.39 3 1.17 14 Dilution rate 1 g product per 1 L water. Apply
mixture at a maximum
of 4000 L/ha. Domestic US Registrations/Crop Group Conversions Proposed By IR

- 4 ( PP# 4E8319 )

Ti Palm

Foliar Abound

Flowable ( EPA R eg

. N o

. 100

- 1098) (2.08 lb/gal) 0.10

-

0.33 Not

specified 2.00 0

Soil Abound

Flowable 0.0065

-

0.013 lb
ai/1000
row feet Not

specified 2.00 0 Band application
between rows.Azoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 11 of 34 Table 3.3. Summary of Proposed Directions for Use of Azoxystrobin. Applic. Timing, Type, and Equip. Formulation Applic.
Rate
lb ai/ A Max. No.

Applic. per
Season Max. Seasonal

Applic. Rate
lb ai/A PHI

(days) Use Directions and

Limitations

( EPA Reg.
No. 100

- 1098) (2.08 lb/gal) Use for soilborne/seedling
disease control. Apply in a minimum of 10 gallons per acre

Tree Nuts

Foliar Abound®

Flowable ( EPA R eg

. N o

. 100

- 1098) (2.08 lb/gal) 0.195 Not Specified 1.2 45 Apply every 7

- 21 days

Stone Fruit s (Crop Group 12

- 12)

Foliar Abound®

Flowable ( EPA Reg.
No. 100

- 1098) (2.08 lb/gal) 0.25 Not Specified 1.5 0 Apply every 7

- 14 days

1 Based on foreign label translations provided in Section B of the petition . There are no domestic registrations for the proposed new uses on coffee, Asian pear, and tea

. 2 Calculated based on a maximum of 8333 trees per ha.

3 1 g product is diluted to 1 liter. Calculated from an application of 4500 liters spray solution per ha.

4 Density 1.1 g/cm 3

.

3.4 Anticipated Exposure Pathways

Humans may be exposed to azoxystrobin in food and drinking water since azox ystrobin may be applied directly to growing crops and application may result in azoxystrobin reaching surface and ground sources of drinking water. In an occupational setting, applicators may be exposed while handling the pesticide prior to application as well as during application. There is also a potential for post

- application exposure for workers re

- entering treated fields.

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

3.5 Consideration of 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://ww w.epa.gov/environmentaljustice/resources/policy/exec_order_12898.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 risk s to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and waterAzoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 12 of 34 consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patt erns are compiled by the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analy zed and categorized by subgroups based on age and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

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

- application are evaluated. Spray drift can also potentially result in p ost

- application exposure and it is also being considered whenever appropriate. Further considerations are also currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposu re to other types of possible bystander

exposure s and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

A detailed hazard characterization with a list of available toxicity studies for azoxystrobin is presented in the previous risk assessment (K. Rury, D389702, 01/18/2012). The submitted studies are of good quality and provide sufficient information to determine whether azoxystrobin poses a human health ha zard. Since the previous assessment, t he inhalation and incidental oral
PODs have been revised and the changes have been summarized below; all other PODs have remained unchanged since the previous assessment.

4.1 Summary of Toxicological Effects

Repe ated oral dosing of azoxystrobin resulted in decreased body weights, decreased food intake and utilization, increased diarrhea

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

, and distended abdomens) in rats . In addition, liver effects

, characterized by increased liver weights, increase d serum levels of alkaline phosphatase and gamma glutamyltransferase, decrease d serum levels of albumin

, and gross and histological lesions in the liver and bile ducts, were seen i n rats. In dogs, effects on liver/biliary function
were found after oral administration.

In the acute neurotoxicity study in rats, increased incidence of diarrhea was observed at all dose levels tested including the LOAEL. Decrease s in body weight and food utilization w ere noted in the rat subchronic neurotoxicity study

. There were no indications of treatment

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

In the rat developmental toxicity study, diarrhea, urinary inco ntinence

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

- related developmental effects were seen in either study. In the rat reprod uction study, offspring and parental effects (decreased body weight and increased adjusted liver weight) were observed at the same dose.Azoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 13 of 34 There was no evidence of carcinogenicity in rats and mice. As a result, EPA has classified azoxystrobin as “not likel y to be carcinogenic to humans.” Azoxystrobin induced a weak mutagenic response in the mouse lymphoma assay, but the activity expressed in vitro is not expected to be expressed in whole animals.

Azoxystrobin has a low acute toxicity via the oral, dermal and inhalation routes of exposure. It is not an eye or skin irritant and is not a skin sensitizer.

4. 2 Safety F actor for Infants and Children (FQPA Safety Factor)

EPA has retained an FQPA SF of 3X, in assessing acute dietary risk to account for the use of a LOAEL from the acute neurotoxicity study in rats in deriving the acute reference dose used for assessing acute dietary exposure for all populations including infants and children. T he Agency believes that a 3X FQPA SF (as oppos ed to a 10X) will be adequate to extrapolate a NOAEL in assessing acute risk based on the following considerations:

a. the LOAEL is based on a transient effect (diarrhea in rats ) expected to be relatively insignificant in nature . This effect is also seen in other chemicals of the

same class ; b. the diarrhea was only seen in studies using gavage dosing in the rat

, but not in studies using repeat dosing through dietary administration in rats or mice, and not through gavage dosing in rabbits; and

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

Furthermore , EPA has determined that for short

- term, intermediate

- term and chronic risk

assessments the available data show that it w ould be safe for infants and children to reduce the FQPA SF to 1X. Th e s e determination s are also based on the considerations in the sections
below :

4.2.1 Completeness o f the Toxicology Database

The toxicity database for azoxystrobin is complete and adequate for risk assessment. A subchronic inhalation toxicity study (TXR# 0056307) and an immunotoxicity study (TXR# 0057071) are not required for azoxystrobin at this time

.

4.2.2 Evidence of N eurotoxicity

Clinical signs , including transient dia rrhea and decreased body weight, body weight gain, and food utilization, were noted in the acute and subchronic neurotoxicity studies , but were not considered indicative of neurotoxicity ; there were no other effects seen in those studies that
would be indi cative of neurotoxicity. There is no need for a developmental neurotoxicity study
or additional uncertainty factors to account for neurotoxicity.

4.2.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young AnimalAzoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 14 of 34 There is no evidence that az oxystrobin results in increased quantitative sensitivity to developing
fetuses i n rats or rabbits in the prenatal developmental studies or in young rats in the 2

- generation reproduction study. In the reproduction study, the offspring and the parental effe cts occurred at the same dose level.

4.2.4 Residual Uncertainty in the Exposure Datab ase

There are no residual uncertainties in the azoxystrobin exposure database. While some refinements were incorporated into the dietary exposure calculations, EPA is confident that the aggregate risk from exposure to azoxystrobin in food, drinking water, and residential pathways will not be underestimated. The acute dietary (food) exposure assessment utilized conservative

upper

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

- level residues for all existing and proposed commodities, except citrus fruits where the highest field trial residue was used as a refinement. The chronic dietary exposure assessment was partially refined, and used tolerance

- level residues for all commodities and (% CT) estimates
when avai lable (Screening Level Usage Analysis (SLUA), 10/14/14). Although the acute and chronic assessments included minor refinements, the use of field trial and % CT estimates ensures that actual exposures/risks from residues in food will not be underestimated. The drinking water assessment utilized water concentration values generated by models and associated modeling parameters which are designed to produce conservative, health protective, high

- end estimates of water concentrations which are not likely to be exceeded. The dietary (food and drinking water) exposure assessment does not underestimate the potential exposure for infants, children, or women of child bearing age.

In addition, the residential exposure assessment is based on the 2012 Residential SOPs employing surrogate study data, including conservative exposure assumptions based on Day 0 dermal/oral contact to turf and surfaces treated at the maximum application ra te. These data are reliable and are not expected to underestimate risks to adults or children. The Residential SOPs are based upon reasonable “worst

- case” assumptions are not expected to underestimate risk.

4. 3 Toxicity Endpoint and Point of D epartur e Selections

A detailed hazard characterization and a discussion of the POD selection is presented in the previous azoxystrobin risk assessment (K. Rury, D389702, 01/18/2012). The inhalation and
incidental oral POD s have been revised by the risk assessme nt team since the previous
assessment. For short

- and intermediate

- term incidental oral and inhalation exposures, the POD
is now based on the 2

- generation reproduction study in rats. For incidental oral and inhalation exposures, the results from the 2

- ge neration reproduction study in rats were selected to establish the toxicity endpoints and PODs for short

- and intermediate

- term exposures. There are three
candidate studies to be considered for selecting POD s for incidental oral and inhalation risk

assessme nt because the duration s of exposure and sensitivity of the effects are relevant. The
NOAELs of these three studies are very similar as indicated below:Azoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 15 of 34 NOAEL (mg/kg/day) LOAEL (mg/kg/day )
2

- generation reproduction

- rats 35 (offspring) 165 (offspring) Developmental toxicity

- rats 25 100
90

- Day oral toxicity

– rats 20 211

Th e NOAEL (35 mg/kg/day) from the reproduction study, where the pups were adversely affected as demonstrated by decreased in pup bo dy weight at various intervals ranging from 8

- 21% relative to the controls, will be protective of the effects seen in th e developmental toxicity study (LOAEL = 100 mg/kg/day) and in the 90

- day oral toxicity study (LOAEL=211 mg/kg/day). The difference in t he NOAEL s derived from these three studies were also
influence d by the dose selection. Therefore, the NOAEL of 35 mg/kg/day of the developmental study was selected as the POD for incidental oral and inhalation risk assessments. Since inhalation absorption data are not available, toxicity by the inhalation route is considered to be equivalent to the toxicity by the oral route of exposure.

Azoxystrobin is characterized as "not likely" to be a human carcinogen , and a cancer risk
assessment is not needed.

Table 4. 3.1. Summary of Toxicological Doses and Endpoints for Azoxystrobin for Use in Dietary, Non

Occupational and Occupational Human Health Risk Assessments

. 1

Exposure/
Scenario Point of

Departure Uncertainty/

FQPA Safety
Factors RfD, PAD, Level of

Concern for Risk
Assessment Study and Toxicological Effects

Acute Dietary (All Populations) LOAEL = 200

mg/kg/day UF A = 10 X

UF H = 10 X FQPA SF =
3X Acute RfD =

0. 67 mg/kg/day

a PAD = 0.67 mg/kg/day Acute Neurotoxicity

- Rat. LOAEL

= 200 mg/kg/day based on diarrhea

at two

- hours post dose at all dose
levels tested

.

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) &
Intermediate

term (1

- 6 months) NOAEL = 35

mg/kg/day UF A = 10X

UF H = 10X FQPA SF =
1X Residential LOC for

MOE = 100 2

- generation reproduction study

–

rats LOAEL = 165 mg/kg/day based on decreased pup weights in both males and females (↓8

- 21%).

Dermal (All Durations) No hazard was identified for this exposure scenario. 21

- Day Repeated Dose Dermal Study

– Rat. No dermal or systemic toxicity was seen at the limit dose (1,000 mg/kg/day).
Inhalation 2

Short

- Term (1

- 30 days) &
Intermediate

Term (1

- 6 months) Oral NOAEL 3

= 35 UF A = 10X

UF H = 10X FQPA SF =
1X Occupational &

Residential LOC for
MOE = 100 2

- generation reproduction study

–

rats LOAEL = 165 mg/kg/day based on decreased pup weights in both males and females (↓8

- 21%).Azoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 16 of 34 Table 4. 3.1. Summary of Toxicological Doses and Endpoints for Azoxystrobin for Use in Dietary, Non

Occupational and Occupational Human Health Risk Assessments

. 1

Exposure/
Scenario Point of

Departure Uncertainty/

FQPA Safety
Factors RfD, PAD, Level of

Concern for Risk
Assessment Study and Toxicological Effects

Cancer (oral, dermal, inhalation) Azoxystrobin is classified as "Not Likely" to be carcinogenic to humans

.

1. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated wit h lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.
2. To protect for the body weight decreases seen in the pups, a 69 kg body weight was used for estimating short

and intermediate

- term inhalation doses because the pup body weight decrease also influenced by the maternal
health. 3. Toxic ity via the inhalation route is assumed to be equivalent to the oral route.

5.0 Dietary Exposure and Risk Assessment

5.1 Residues of Concern Summary and Rationale

The residues of concern for dietary risk assessment and the tolerance expression are summarized
in Table 5.1. The residue definition and residues of concern have not changed since the previous
risk assessment. Further information on the metabolism and de gradation may be found in the HED Metabolism Assessment Review Committee Decision memo (W. Wassell, D251683, 12/30/1998).

Table 5.1

. Summary of Metabolites and Degradates to be included in the Risk Assessment and

Tolerance Expression for Azoxystrobin 1

Matrix Residues included in Risk
Assessment Residues included in Tolerance Expression

Plants Primary Crop Azoxystrobin + Z

- isomer Azoxystrobin + Z

- isomer Rotational Crop Azoxystrobin + Z

- isomer Azoxystrobin + Z

- isomer

Livestock Ruminant Azoxystrobin Azoxystrobin

Poultry Azoxystrobin Azoxystrobin Drinking Water Azoxystrobin Not Applicable

1 HED Metabolism Assessment Review Committee Decision Memo; D251683, 12/30/98, W. Wassell

5 .2 Food Residue Profile

There are adequate residue data on plant food and feed commodities for the purposes of risk
assessment and tolerance assessment.

New food commodity uses for azoxystrobin include Asian pear, tea, coffe e, and Ti palm leaves
and roots . These contribute minor incremental increases in exposure. T here are no significant differences from prior assessments.Azoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 17 of 34 Crop field trials generally reflect foliar applications with some soil applications ( e.g., T i palm )

. Residues from foliar applications are generally quantifiable and significant . Residues do

co ncentrate in some processed commodities such as oils (peanut oil) and reduced water content commodities (tomato paste). However, residues did not concentrate in instant coffee or roasted
coffee beans. Trials with banana and citrus fruits indicate that t he residue s remain mainly on the surface (peel) and do not extensively translocate. Residues also decline with time.

Livestock feeding studies indicate low transfer of residues to meat and milk with the highest
transfer in liver. Q uantifiable residues w ere not found in any poultry commodit ies

.

Storage stability studies show that azoxystrobin and its Z

- isomer are stable on food commodities stored under frozen conditions for extended periods ( 1 to 2 years ). The available studies cover all existing crop f

ield trial studies supplied in support of tolerance requests.

The metabolism in rotational crops is similar to that in primary crops but with larger amounts of conjugated metabolites than found in the primary rotational crop studies. Residues are very low in rotational crops, and the plant

- back interval is 0 days for all crops with registered uses, except
buckwheat and millet.

5.3 Water Residue Profile

The drinking water residues for the proposed uses of azoxystrobin were provided by the Environmental Fate and Effects Division (EFED) (Ibrahim Abdel

- Saheb, D422726, 09/11/2014 ) including use of the new surface and ground water models (Surface Water Concentration Calculator; SWCC, and Pesticide Root Zone Model

- Ground Wa ter; PRZM

- GW)

. EFED estimates drinking water concentrations of a chemical based on the highest rate of application of the chemical on all registered and proposed crops. Existing uses on turf result in the highes t registered application rate (0.55 lb ai /A , 9 applications per year with a 10

- day interval between applications) ( T. Nguyen; D278783, D279444, and D279561; 02/04/ 2002). Therefore, EFED
recommended that the EDWCs from turf use be incorporated into the dietary exposure assessment for the proposed u ses of azoxystrobin, as they are the most conservative. Water residues were incorporated in the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database ( DEEM

- FCID ) into the food categories “water, direct, all sources” and “water , indirect, all sources.”

Table 5.3. Estimated Drinking Water Concentrations (EDWCs) For Use in Azoxystrobin Dietary

Assessment.

Scenario
Model (application rate lb ai/A, frequency, interval) Surface Water (μg/L) 1 Ground W ater (μg/L) (Acute/Chronic)

Peak (1

- in

- 10 yr) 365

- day

Average (1

- in

- 10 yr) Entire

Simulation
Mean SCI

- GROW 2

Turf
SWCC (0.55, 9x, 10 d) 70.2 48.5 38.5 3.1

1 Bolded values are recommended for use in the human health risk assessment

1 SCI

- GROW = Screening Concentration In Ground WaterAzoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 18 of 3 4 5.4 Dietary Risk Assessment

Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using DEEM

- FCID Version 3.16, which is based on NHANES 2

- day food consumption data from 2 003

- 2008.

5.4.1 Description of Residue Data Used in Dietary Assessment

A slightly refined acute dietary analysis was conducted

. T he assumptions of the dietary

assessment included tolerance

- level residues for all commodities except citrus fruits (which used the highest residues from residue trials) and 100% CT for all crops

. DEEM default processing
factors were assumed except for where tolerances were established for processed commodities or when processing studies showed no concentration. Field trial data were translated from the representative commodities to the non

- representative commodities according to HED SOP 2000.1:”Guidance for Translation of Field Trial Data from Representative Commodities in the Crop Group Regulation to other Commoditie s in Each Crop Group/Subgroup.”

The chronic assessment was based on the assumption of tolerance

- level residues for all
commodities and average percent crop treated ( %CT ) estimate s when available ( J. Alsadek,
SLUA , 10/14/2014 ). DEEM default processing factors were assumed except for where tolerances were established for processed commodities or when processing studies showed no
concentration.

The addition of coffee, tea, and Asian pears does not alter the dietary burdens of azoxystrobin to ruminants or poultry , and the existing tolerances for ruminant commodities will not be exceeded
with the proposed uses on coffee, tea, and pears

.

The modeled surface water EDWC from the turf application scenario (currently registered) wa s incorporated directly into the dietary assessment s (highest EDWC for all proposed/registered crops). The highest estimates for acute exposure, 70.2 ppb, and chronic exposure, 48.5 ppb, were used in the analysis. T he new uses on Asian pears, tea, and co ffee do not impact the water values, as there are no requested domestic uses.

5.4.2 Percent Crop Treated Used in Dietary Assessment

The acute assessment assumed that 100% of the proposed and existing crops were treated with azoxystrobin. However, t he fo llowing average percent crop treated (%CT) estimates were used in the chronic dietary risk assessments for the following currently registered crops (J. Alsadek,
SLUA , 10/14/2014): almonds, 20%; apricots, 10%; artichokes, 20%; asparagus, <2.5%; barley,

< 2.5%; green beans, 15%; blueberries, 15%; broccoli, 10%; cabbage, 10%; caneberries, 5%; cantaloupes, 20%; carrots, 10%; cauliflower, <2.5%; celery, 10%; corn, <2.5%; cotton, <2.5%; cotton (seed treatment), 25%; cucumbers, 20%; dry beans/peas, <2.5%; egg plant, 30%; garlic, 70%; grapefruit, 20%; grapes, 5%; hazelnuts, 5%; lemons, <2.5%; lettuce, <2.5%; nectarines, <2.5%; onions, 5%; oranges, 5%; peaches, 5%; peanuts, 20%; peanuts (seed treatment), 30%; green peas, <2.5%; pecans, 5%; peppers, 20%; pistachio s, 5%; plums/prunes, <2.5%; potatoes, 40%; potatoes (seed treatment), <1%; pumpkins, 20%; rice, 40%; soybeans, 5%; soybeans (seedAzoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 19 of 34 treatment), <1%; spinach, 10%; squash, 20%; strawberries, 25%; sugar beets, 10%; sugar beets (seed treatment), <2.5%; sweet co rn, 15%; tangelos, 25%; tangerines, 10%; tobacco, 15%; tomatoes, 25%; walnuts, >2.5%; watermelons, 15%; wheat, 5%; wheat seed (seed treatment),
<1%. For all other crops in the chronic assessment, 100% CT was assumed

.

5.4.3 Acute Dietary Risk Assessment

The results of the acute dietary analysis for food and drinking water indicate that acute dietary
risks do not exceed the Agency ’s level of concern ( < 100% of the aPAD) for the U.S. population and all subgroups. At the 95 th percentile, the acute dietary ( food and drinking water) risk estimates utilized 16% of the acute population adjusted dose (aPAD) for the general U.S. population and utilized 40% of the aPAD for children 1

- 2 years old, the most highly exposed population subgroup

.

5.4.4 Chronic Dietary Risk Assessment

The results of the chronic dietary analysis for food and drinking water indicate that chronic dietary risks do not exceed the Agency ’s level of concern ( < 100% of the aPAD) for the U.S. population and all subgroups. T he chronic dietary (food and drinking water) risk estimates utilized 6.0% of the chronic population adjusted dose (cPAD) for the U.S. population and
utilized 15 % of the cPAD for the most highly exposed population subgroup, children 1

- 2 y ears old.

5.4.5 Can cer Dietary Risk Assessment

Azoxystrobin is classified as “not likely to be carcinogenic to humans”; therefore

, a cancer dietary exposure assessment was not performed.

5.4.6 Summary Table

Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Azoxystrobin.

Population Subgroup Acute Dietary (95th Percentile) Chronic Dietary

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

General U.S. Population 0.110459 16 0.010724 6.0

All Infants (< 1 year old) 0.131716 20 0.017593 9.8

Children 1

- 2 years old 0.269743 40 0.027728 15

Children 3

- 5 years old 0.228330 34 0.022261 12

Children 6

- 12 years old 0.129649 19 0.013336 7.4

Youth 13

- 19 years old 0.094863 14 0.008376 4.7

Adults 20

- 49 years old 0.096366 14 0.009213 5.1

Adults 50+ years old 0.089088 13 0.009308 5.2Azoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 20 of 34 Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Azoxystrobin.

Population Subgroup Acute Dietary (95th Percentile) Chronic Dietary

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

Females 13

- 49 years old 0.097704 15 0.008883 4.9
The values for the highest exposed population for each type of risk assessment are bolded

.

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

This document addresses the proposed new agri cultural uses of azoxystrobin ; therefore, new residential exposure is not expected. However, there are currently registered uses of azoxystrobin by both commercial and residential handlers on residential use sites, including turf, ornamentals, indoor uses (carpet and hard surfaces)

, and in paints. Each of these existing residential use patterns has previously been re

- assessed by HED to incorporate up to date policies in the Residential SOP s (K. Rury, D294387, 03/30/2012). Furthermore , the inhalation and incidental oral PODs have changed since the previous assessment. Therefore, the scenarios for aggregate risk assessment have been updated to account for these changes.

Table 6.0 reflect s the residential risk estimates that are recommended for use in the aggregate assessment for azoxystrobin. The proposed uses do not impact the aggregate risk assessment; however, the scenarios that do impact the aggregate assessment have been re

- evaluate d in this
assessment to reflect the revised incidental oral and inhalation PODs.

 The recommended residential exposure for use in the adult aggregate assessment reflects inhalation exposure from handlers applying paint via airless sprayers.

 The recommende d residential exposure for use in the children 1 to <2 years old aggregate
assessment reflects inhalation and hand

- to

- mouth exposures from post

- application exposure to indoor applications to carpets.

Table 6.0 . Recommendations for the Residential Exposur es for the Azoxystrobin Aggregate Assessment. 1

Lifestage Handler Exposure

(mg/kg/day) 2 Residential

Handler Total
MOE 3 Post

- a pplication Exposure

(mg/kg/day) Residential Post

a pplication Total Exposure (mg/kg/day) 4 Residential Post

a pplication
MOE 5 Inhalation Inhalation Oral

Short

- Term

Adult 0. 0041

(Inhalation Handler Exposure

- Airless Paint Sprayers) 8,600 N/A N/A N/A N/A

Child 1 to <2 years old N/A N/A 0.000000000 48 (Post

- application Inhalation, Surface Directed Sprays) 0.098 3

(Hand

- to

Mouth
from
Indoor Application to Carpets) 0.098 3 360

1 N/A = not applicable. Adult post

- application exposures do not need to be aggregated with the handler exposures, and children handler exposures are not expected. F or adults, the r esidential total exposure is equivalent to the inhalation exposure (Table 5.1). For children 1 to < 2 years old , total residential exposure combines high

- end inhalation and post

- application incidental oral exposure (Table 5.2). These tables are located in DP394287 (K. Rury, 03/30/2012)

. 2 Handler exposure represents high

- end handler exposure (i.e. the highest handler exposure of all scenarios assessed).Azoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 21 of 34 3 Total MOE = Inhalation MOE = NOAEL / Inhalation Exposure. Short

- Term Inhalation NOAEL = 35 mg/kg/day.
4 Post

- ap plication exposure represents high

- end inhalation and/or incidental oral exposure for the relevant exposure duration.
5 Total MOE = NOAEL ÷ (Inhalation Exposure + Incidental Oral Exposure). Inhalation NOAEL & Incidental Oral NOAEL = 35 mg/kg/day.

6. 1 Res idential Bystander Post

- application Inhalation Exposure

Volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The agency sought expert advice and input on issues
related to vola tilization 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 has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219). During Registration Review, the agency will u tilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is required for azoxystrobin.

A quantitative residential post

- application inhalation exposure assessment was completed as part
of this assessment to re

- evaluate the scenarios for aggregate risk assessment using the revised inhalation POD. The screening

- level indoor inhalation post

- application MOEs for surface directed applications were 73,000,000 ,000 (children 1 to < 2 years old) and 270,000,000,000 (adults).

6. 2 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for azoxystrobin

. The agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data
Call

- In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the agency’s Spray
Drift website for more i nformation). 2 The agency has also developed a policy on how to appropriately consider spray drift as a potential source of exposure in risk assessments for pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide dur ing
the Registration Review process which ensures that all uses for that pesticide will be considered concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs)

- Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification
of indirect non

- occupational exposure to drift.

7.0 Aggregate Exposure/Risk Characterization

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

2 Available: http://www.epa.gov/o pp00001/factsheets/spraydrift.htmAzoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 22 of 34 relevant sources are added together and compared to quantitative estimates of hazard (e.g. a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. For azoxystrobin, potential exposures from food, drinking water and residential scenarios were

a ggregated.

This assessment has utilized the Residential Standard Operating Procedures (SOPs) implemented in January of 2012 and the updated PODs for incidental oral and inhalation scenarios . HED confirms that there are no risks of concern resulting from the proposed or existing uses of azoxystrobin.

7.1 Acute Aggregate Risk

The aggregate acute risk estimates include exposure to residues of azoxystrobin in food and water, and do not inclu de dermal, inhalation

, or incidental oral exposure. The acute risk estimate for the U.S. population and all other population subgroups, resulting from aggregate exposure to azoxystrobin in food and drinking water

, is below the Agency’s LOC . The food and drinking water exposure estimates are 1 6 % of the aPAD for the general U.S. population, and 4 0 % for the most highly exposed subgroup, children 1

- 2 years old.

7.2 Short

- Term Aggregate Risk

There is potential short

- term exposure to azoxystrobin via dietary (w hich 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 w as chosen for each population ( e.g

. , hand

- to

mouth exposure from carpets and textiles for children 1

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

, see K. Rury, D 394287

, 03/30/2012

.

The general US population (inhalation) aggregate MOE is 2,400 . Therefore, adult aggregate exposure and risk do es not exceed HED’s LOC (MOE < 100). The aggregate MOE for children
1

- 2 years old , including incidental oral exposures from treated carpets, is 280 , which indicates
that aggregate exposure and risk is greater than 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

- and Intermediate Term A ggregate Risk Calculations

.

Population Short

- and Intermediate

- Term Scenario s

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 s 35 100 0.35 0.010724 0.0041 0.014824 2,400
Child 35 100 0.35 0.027728 0.0983 0.126028 280

1 The LOC i nclude s the standard inter

- (10X) and intra

- (10X) species uncertainty factors totaling 100

. 2 Maximum Allowable Exposure (mg/kg/day) = NOAEL (35 mg/kg/day) /LOC (100).Azoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 23 of 34 3 Residential Exposure = [Oral exposure + Inhalation Exposure]. For updated residential scenarios for aggregate risk assessment, see K. Rury, D418012 and D423961, 12/17/2014

. 4 T otal Exposure = Avg Food & Water Exposure + Residential Exposure.

5 Aggregate MOE = [NOAEL (35 mg/kg/day) / (Avg Food & Water Exposure + Residential Exposure)]

.

7.3 Intermediate

- Term Aggregate Risk

Intermediate

- term residential exposure is not expected for azoxystrobin due to the intermittent application by homeowners. Therefore, the intermediate

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

.

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

This document presents an assessment of the proposed uses of azoxystrobin on Ti palm, stone fruit s , and tree nuts. HED has not previously assessed azoxystrobin use on stone fruit or tree nuts with the new unit exposure and acres treated assumptions, so occupational exposure corresponding to the proposed crop group updates has been assessed according to current exposure policies.

9.1 Short

- /Intermediate

- Term Handler RiskAzoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 24 of 34 T here is potential for short

- and intermediate

- term occupational exposure to azoxystrobin during both handler [mixing, loading, and application (via the dermal and inhal ation routes)] and post

application activities (via the dermal route) based on the proposed uses.

The o ccupational handler assessment is based on inhalation exposures only since no dermal
hazard was identified

. Additionally, for inhalation exposures, the POD selected is considered protective of both short

- and intermediate

- term durations. The results of the occupational handler
risk asses sment indicate that short

- and intermediate

- term inhalation MOEs are not of concern (i.e., MOE s > 100) with baseline mitigation (no respirator) and engineering control for aerial applications (enclosed cockpits )). The MOEs range from 1 9 ,000 to 4,300 ,000 f or occupational
handlers.Azoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 25 of 34 Table 6.1.1. Occupational Handler Non

- Cancer Short

- and Intermediate

- Term Exposure and Risk Estimates for Azoxystrobin

.

Exposure Scenario Crop or Target LOC Inhalation Unit Exposure ( μ g/lb ai) 1 Maximum

Application Rate Area Treated

or Amount Handled Daily 2 Inhalation

Baseline Dose (mg/kg/day) 3 MOE 4

Mixer/Loader
Mixing/Loading Liquids for Aerial Application Orchard Crops 5 100 0.219 0.33 lb ai/A 350 0.00037 95,000

Mixing/Loading Liquids for Airblast Application Orchard Crops 5 100 0.219 0.33 lb ai/A 40 acres 0.000042 840,000

Mixing/Loading Liquids for Chemigation Application Orchard Crops 5 100 0.219 0.33 lb ai/A 350 acres 0.00037 95,000

Applicator
Aerial Application Orchard Crops 5 100 0.0049 0.33 lb ai/A 350 acres 0.0000082 4,300,000
Airblast Application Orchard Crops 5 100 4.71 0.33 lb ai/A 40 acres 0.000901 39,000
Flagger
Flagging for Aerial Application Orchard Crops 5 100 0.35 0.33 lb ai/A 350 acres 0.00059 720,000

Mixer/Loader/Applicator
Mixing/Loading/Applying with Mechanically Pressurized Handgun

– Foliar & Ground Directed Orchard Crops 5 100 3.9 0.033 lb ai/A 1000 gal 0.0018 19,000

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table”; Level of mitigation: Baseline, PPE, Eng. Controls. Aerial applicators = Eng. Controls, all other estimates
are baseline PPE.
2 Exposure Science Advisory Council Policy #9.1.
3 Inhalation Dose = Dermal Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Ap plication Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW ( 69 kg).
4 Inhalation MOE = Inhalation NOAEL ( ST = 35 mg/kg/day) ÷ Inhalation Dose (mg/kg/day) ; LOC=100

. 5 Orchard crops = Stone Fruit s , Tree Nuts, and Ti Palm. The proposed application rate is the highest for T i palm, so it has been used as a worst

- case screen for this group.Azoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 26 of 34 9.2 Short

- /Intermediate

- Term Post

- Application Risk

9.2.1 Dermal Post

- application Risk

The proposed occupational uses for azoxystrobin addressed in this document result in the potential for exposure following azoxystrobin application. However, an appropriate dermal endpoint was not identified for azoxystrobin. Therefore, an assessment of o ccupational dermal post

- application exposure to azoxystrobin was not conducted. A c hemic al

- specific DFR stud y is available for the use of azoxystrobin on grapes, but has not been employed in this or previous
risk assessments because HED determined there i s no hazard via the dermal route.

Restricted Entry Interval Abound® Flowable Fungicide EPA Reg. No. 100

- 1098 Azoxystrobin is classified as Toxicity Category III based upon data for acute dermal toxicity, Toxicity Category III for acute inhalation toxici ty, Toxicity Category IV for primary skin irritation, and Toxicity Category III for primary eye irritation. Typically, the REI specified on the proposed label is based on the acute toxicity of the active ingredient. Under 40
CFR § 156.208 (c) (2) (iii), ac tive ingredients classified as Acute III or IV for acute dermal, eye irritation, and primary skin irri t ation are assigned a 12

- hour REI. However, it is noted that the proposed product label has a 4

- hr REI listed. REIs may be further reduced from 12 hours if
certain criteria are met for both the technical material and the different end

- use products in accordance with the Pesticide Registration (PR) Notice 95

- 3 [Reduction of Worker Protection Standard (WPS) Interim Restricted Entry Intervals (REIs) for Cert ain Low Risk Pesticides] 3

. Based only on the acute toxicity categories, azoxystrobin is a possible candidate for
a 4

- hr REI, however, RD should ensure that the additional criteria listed in PR Notice 95

- 3 are met for the active ingredient and the end

- use product.

9.2.2 Inhalation Post

- application Risk

There are multiple potential sources of post

- application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources
include volatilizat ion of pesticides and resuspension of dusts and/or particulates that contain pesticides. The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Ad visory 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 has evaluated the SAP report and has developed a Volatilization Screening Tool and a su bsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

OPP

- 2014

- 0219 ). During Registration Review, the agency will utilize this a nalysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is required for azoxystrobin.

In addition, the Agency is continuing to evaluate the available post

- application inhalation exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the

3 Available: http://www.epa.gov/PR_Notices/pr95

- 3.htmlAzoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 27 of 34 Agency will continue to identify the need for and, subsequently, the w ay to incorporate occupational post

- application inhalation exposure into the agency's risk assessments.

Although a quantitative occupational post

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

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

- application inhalation exposure scenarios.

The Worker Protection Standard for Agricultural Pesticides contains requirements for protecting workers from inhalation exposures during and after greenhouse applicatio ns through the use of ventilation requirements.[40 CFR 170.110, (3) (Restrictions associated with pesticide applications)]

.

It should be noted that there is the potential for inhalation exposure during the mechanical sweeping and windrowing of the tree nuts. However , since there is a long PHI of 4 5 days, the post

- application inhalation exposure potential is negligible and was not quantitatively assessed.

Furthermore, inhalation exposure during dusty mechanical activities such as shaking and
mechanical harvesting is another potential source of post

- application inhalation

exposure. However, the airblast applicator scenario is believed to represent a reasonable worst case surrogate estimate of post

- application inhalation exposure during these dusty mechan ical harvesting activities. The non

- cancer inhalation risk estimate for commercial airblast application is not of concern (i.e., MOE > 100)

10.0 References

K. Rury. Azoxystrobin. Occupational and Residential Exposure Assessment for Proposed Uses
on Ti Palm, and on Ornamentals and Vegetable Transplants Grown Outdoors and in Greenhouses. This assessment also includes updates to the Stone Fruit Group 12

- 12 and Tree Nut Group 14

- 12 Crop Groups. D418012 and D423961. 12/17 /2014.

K. Rury. Azoxystrobin. Human Health Risk Assessment for the Proposed Use on Sugarcane.
D394285. 04/30/2012.

M. Negussie. Azoxystrobin: Revised Human Health Risk Assessment for Use on Ginseng (Import), Rye, and Oats, and Section 3 Amendments to Revise the Established Tolera nces on Cereal Grains (Barley and Wheat) Due to Changes of Pre

- Harvest Intervals. D402285 and
D402289. 03/21/2013.

S. Funk. Azoxystrobin. Petition for the Establishment of Permanent Tolerances on Imported Pear, Imported Tea, and Imported Coffee. Pet ition for the Establishment of Permanent Tolerance on Ti Palm, and for Crop Group Conversions for Stone Fruit Group 12

- 12 and Tree Nut Group 14

- 12. Summary of Analytical Chemistry and Residue Data. D423334 and
D423718. 11/12/2014.Azoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 28 of 34 S. Funk. Azoxystro bin: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for Section 3 Petitions for the Establishment of Tolerances on Coffee, Pear, and Tea (Import, PP#3E8228). Petition for the Establishment of Tolerances and Reg istration for Use on Ti Palm Roots and Leaves (PP#4E8319) and Crop Group Conversions for Stone Fruit Group 12

- 12 and Tree Nut Group 14

- 12. D423337 and D423720. 10/29/2014.

I. Abdel

- Saheb. Drinking Water Exposure Assessment for new use of Azoxystrobin on Ornamental Plants and Vegetable Transplants . D422726. 09/11/2014.Azoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 29 of 34 A ppendix A . Toxicology Profile

A.1 Toxicology Data Requirements The requirements (40 CFR 158.500) for non

- food use for azoxystrobin are below . 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 waived *

870.3700a Developmental Toxicity (rodent)

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

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

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

yes
yes

870.4100a Chronic Toxicity (rodent)

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

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

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

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

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

yes
yes
yes

yes
870.5100 Mutagenicity

— Gene Mutation

- bacterial

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

— Gene Mutation

- mammalian

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

— Structural Chromosomal Aberrations

... 870.5385 Mutagenicity

— Other Genotoxic Effects

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

yes
yes
yes

870.6100a Acute Delayed Neurotoxicity (hen)

............................... 870.6100b 90

- Day Neurotoxicity (hen)

................................ .......... 870.6200a Acute Neurotoxicity Screening Battery (rat)

................. 870.6200b 90

- Day Neurotoxicity Screening Battery (rat)

.............. 870.6300 Develop. Neurotoxicity

................................ ................. no

no
yes
yes

no -

- yes
yes

no

870.7485 General Metabolism

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

................................ ........................ 870.7800 Immunotoxicity

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

no

yes yes

yes
waived **

Special Studies for Ocular Effects

Acute Oral (rat)

................................ ........................... Subchronic Oral (rat)

................................ .................. Six

- month Oral (dog)

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

no
yes -

-

-

1 CR = Conditionally Required * The requirement for a subchronic inhalation toxicity study has been waived (TXR#0056307) ** The requirement for an immunotoxicity study has been waived (TXR#0057071)Azoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 30 of 34 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 chemistry findings attributable to reduced nutritional

status.

870.3150
90

- Day oral toxicity in dogs 43678136 (1993) Acceptable/guideline M & F: 0, 10, 50, 250 mg/kg/day NOAEL = 50 mg/kg/day LOAEL = 250 mg/kg/day based on treatment

- related clinical observations and clinical chemistry alterations indicative of effects on liver/biliary
function in both sexes.

870.3200
21

- Day dermal toxicity in

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

.

870.3700a Prenatal developmental in

rats 43678142 (1994) Acceptable/guideline 0, 25, 100, 300 mg/kg/day Maternal NOAEL = 25 mg/kg/day LOAEL = 100 mg/kg/day based on the maternal clinical signs of 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

.Azoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 31 of 34 Table A

. 2 .2 . Azoxystrobin Toxicity Results From Repeated Dosing and Other Studies. Study Guideline/Study MRID Results
870.3800 Reproduction and fertility
effects in rats 43678144 (1994) Acceptable/guideline 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 Parental/Systemic NOAEL = 32 mg/kg/day LOAEL = 165 mg/kg/day based on reduced body 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 (for body weight) 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 43678147 (1992) Acceptable/guideline The in vitro test in human lymphocytes was positive
for the induction of chromosomal aberrations in bothAzoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 32 of 34 Table A

. 2 .2 . Azoxystrobin Toxicity Results From Repeated Dosing and Other Studies. Study Guideline/Study MRID Results Cytogenetics chromosomal
aberration 0.5 to 50 μg/mL without S

9 1 to 300 μg/mL with S

- 9 the presence and absence of S9 at doses (5

- 50 μ g/mL

- S9; 100

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

- 70% reductions in mitotic cells, respectively)
870.5385 Cytogenetics bone marrow 43678148 (1992) Acceptable/guideline
5000 mg/kg The in vivo mouse bone marrow micronucleus assay

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

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

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

870.6200b Subchronic neurotoxicity screening battery in rats 43678138 (1994) Acceptable/guideline 0, 100, 500, 2000 ppm M: 0, 8.0, 38.5, 161 mg/kg/day F: 0, 9.1, 47.9, 201.5 mg/kg/d NOAEL = 39 mg/kg/day

. LOAEL = 161 mg/kg/day based on decreased body weight and food utilization in both sexe s.

870.7485
Metabolism and pharmacokinetics 43678150
43678151
43678152
43678153
43678154 1 or 100 mg/kg (single gavage) or 1 mg/kg (14

- day repeated) Following oral administration as a single gavage dose of 1 or 100 mg/kg or 15

- day repeated doses of 1 mg/kg, azoxystrobin was widely distributed with the liver and kidneys having the highest concentrations; however, less than 0.5% of the administered dose was detected in the tissues at seven days postdosing. The primary route of excretion was via the feces (≈73

- 89%) followed by urine (≈9

- 18%). There were no apparent sex

- or dose

- related differences in distribution or in the pattern of excretion. In a bile duct cannulated single high

- dose group, assessment of biliary excretion suggested approximately 70%
ab sorption with ≈32% of the administered dose remaining as parent compound in the gastrointestinal tract. Absorbed azoxystrobin appeared to be extensively metabolized with minor sex

- related qualitative and quantitative differences in biliary
metabolites. A metabolic pathway was proposed showing hydrolysis and subsequent glucuronide conjugation as the major biotransformation process.
870.7600 Dermal penetration (rat) 43678155 (1994) Acceptable/guideline 0.01, 0.1, 0.9, 13.3 mg/kg 2

- 4 % Dermal AbsorptionAzoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 33 of 34 Appendix B

. Physical/Chemical Properties

Table B

. Physicochemical Properties of Technical Grade Azoxystrobin.

Parameter Value Reference
Melting point/range 114

- 116oC DP#s 218318 and 218448, 3/19/96, J. Garbus pH 6.4
Density 1.25 g/cm 3

Water solubility (20°C) pH 5.2 6.7 mg/L pH 7.0 6.7 mg/L pH 9.2 5.9 mg/L
Solvent solubility (20°C) Hexane 0.057 mg/L
Octanol 1.4 mg/L
Methanol 20 mg/L
Toluene 55 mg/L
Acetone 86 mg/L Ethyl Acetate 130 mg/L
Acetonitrile 340 mg/L
Dichloromethane 400 mg/L
Vapor pressure (20°C) 1.1x10

- 13 kPa (8.2x10

- 13 mm Hg)
Dissociation constant, pK a Not dissociable
Octanol/water partition coefficient, Log(K OW ) log P = 2.5Azoxystrobin Human Health Risk Assessment DP Nos. D423691, D418374

Page 34 of 34 Appendix C

. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include PHED 1.1; the AHETF database; the Residential SOPs (Residential Handlers), are (1) subject to ethics review

pursuan t to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use,
can be fou nd at the Agency website 4

.

4 http://www.epa.gov/pesti cides/science/handler

- exposure

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

- app

- exposure

- data.html