### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 3 of 36 7.4 Chronic Aggregate Risk

................................ ................................ .............................. 26
7.5 Cancer Aggregate Risk

................................ ................................ ................................ 26
8.0 Cumulative Exposure/Risk Characterization

................................ ............................... 26
9.0 Occupational Exposure/Risk Characterization

................................ ............................ 26
9.1 Short

- /Intermediate

- Term Handler Risk

................................ ................................ ... 26
9.2 Short

- /Intermediate

- Term Post

- Application Risk

................................ .................... 28
9.2.1 Dermal Post

- Application Risk

................................ ................................ ................. 28
10.0 References

................................ ................................ ................................ ......................... 29 Appendix A. Toxicology Profile

................................ ................................ ................................ 30
A.1 Toxicology Data Requirements

................................ ................................ ................... 30
A.2 Toxicity Profiles

................................ ................................ ................................ ............ 31 Appendix B . Physical/Chemical Properties

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

................................ ........................ 35 Appendix D. Review of Human Research

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

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 4 of 36 1.0 Executive Summary

Azoxystrobin [methyl (2 E )

- 2

- {2

- [6

- (2

- cyanophenoxy)pyrimidin

- 4

- yloxy]phenyl}

- 3

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

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

Syngenta Crop Protection, Inc. (Syngenta) has proposed azoxystrobin for use on sugarcane . The
most recent human health risk assessment was conducted to evaluate azoxystrobin use on post

harvest potatoes and to update the azoxystrobin use profile to include various crop group revisions (K. Rury, D389702, 0 1/18/2012). Since the last risk assessment, no additional hazard
data ha ve been submitted. In accordance with the 2007 revised 40 CFR Part 158 Toxicology data requirements, a subchronic inhalation toxicity study and an immunotoxicity study were required for azoxystrobin. The Agency has waived the inhalation toxicity study da ta requirement for azoxystrobin at this time (TXR# 0056307). An immunotoxicity study remains required for azoxystrobin.

Use Profile Azoxystrobin is proposed for use as a foliar application on sugarcane using ground, aerial

, and chemigation equipment. The use profile is summarized in Table 3 .3 . Proposed single application rates on sugarcane range from 0.15

- 0.20 lb ai/A (or 9.0

- 12.0 fl oz product /A for
Abound ® Flowable Concentrate and 16

- 22 fl oz product/A for Quilt XcelTM ). The Abound ® label specifies that no more than 0.80 lb ai/A of any azoxystrobin containing products should be applied per year; and no more than 4 foliar applications of Abound ® should be applied per year. The Quilt XcelTM label specifies no more than 88 fl oz per acre per year (0.81 lb ai/A) should be applied. Both labels require a 45

- day pre

- harvest interval (PHI) for sugarcane used for animal feed, and a 30

- day PHI for all other sugarcane treated with azoxystrobin. In addition, Syngenta is requesting to add sugarcane use on two az oxystrobin manufacturing products: Azoxystrobin Millbase Manufacturing Use Product (MUP) (EPA Reg. No. 100

- 1220) and Azoxystrobin Dry Technical Manufacturing Use Concentrate (MUC) (EPA Reg. No. 100

- 1120).

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

- characterized and nearly complete toxicology database, with the exception of an immunotoxicity stud y and an inhalation toxicity study; however the Agency has waived the inhalation toxicity study data requirement at this time (TXR# 0 056307)

. 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 a nimals ( in vivo )

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

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 5 of 36 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). Azoxyst robin is not an eye or skin irritant
and is not a skin sensitizer.

To account for the use of a LOAEL from the acute neurotoxicity study in rats, the Agency believes that a 3X FQPA SF (as opposed to a 10X) will be adequate to extrapolate a NOAEL in

asses sing acute risk. No additional safety factor is needed for short

- term, intermediate

- term, and
chronic risk assessment. Although an immunotoxicity study is needed to complete the toxicological database, there are no concerns for immunotoxicity based on th e results of the existing studies. There are no indications in the available studies that organs associated with immune function, such as the thymus and spleen, are affected by azoxystrobin, and azoxystrobin does not belong to a class of chemicals that wo uld be expected to be immunotoxic. T he selected toxicity endpoints and P O Ds for risk assessment are based on the most sensitive and relevant
data.

Dietary Exposure (Food and Water) The residue chemistry data and environmental fate data are adequate to assess human exposure. The assessments are based on reliable data and will not underestimate exposure or risk. Azoxystrobin for use on sugarcane was incorporated into the previous drinking water assessment (R. Baris, D389703, 11/28/2011); therefore, e sti mated drinking water concentrations (EDWCs) have not changed since the last risk assessment (K. Rury, D389702, 0 1/18/2012). The 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 (LOC) (<100% of the acute population adjusted dose ( a PAD ) ) for all population subgroups and were estimated at 1 8 % of the a PAD for
the general U.S. 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

- FCIDTM 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 LOC (<100% of the
chronic population adjusted dose ( c PAD)) for all population subgroups and w ere estimated at
6. 7 % of the c PAD for the general U.S. 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 No new residential uses were requested in this petition. However, a zoxystrobin is currently registered for use on several residential/non

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

Occupational Exposure

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 6 of 36 Based on the proposed use pattern of azoxystrobin on sugarcane, t here is a potential for short

and intermediate

- term occupational exposure during handling (mixing

, loading , and applying )

a nd post

- application activities. The results of the occupational handler exposure and risk

assessment estimates indicate that total short

- and intermediate

- term MOEs are not of concern to HED (i.e. MOE > 100) with baseline attire. Although occupational dermal exposure is expected following treatment of sugarcane , no dermal hazard was identified for azoxystrobin. Therefore, a quantitative post

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

- application i nhalation exposures are minimal following applications of an a ctive ingredient (ai) with low vapor pressure

. Since azoxystrobin has low acute inhalation toxicity (Toxicity Category III) and a low vapor pressure, post

- application inhalation exposures and r isks 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 data

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

- entry Task Force (ARTF) database, are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements. For certain studies that review may have included review by the Human Studies Review Board. Descriptions of data sources as well as guidance on their use can
be found at http://www.epa.gov/pesticides/science/handler

- exposure

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

- app

- exposure

- data.html

.

2.0 HED Recommendations

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

sugarcane

.

2.1 Data Deficiencies/ Prior Conditions of Registration

The following data are required a s a condition of registration:

870.7800 Imm unotoxicity Study

In 2007, the Agency revised 40 CFR Part 158.500 Toxicology data requirements to include functional immunotoxicity testing and granted a 2

- year grace peri od to allow time for registrants to develop the required data. Syngenta estimated that the immunotoxicity study w ould be completed in November 2011. The immunotoxicity study remains a condition of registration for azoxystrobin under Registration Review and is due in 2012.

2. 2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 7 of 36 Adequate residue analytical me thods are available for tolerance enforcement: a gas chromatography method with nitrogen

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

- isomer; and a GC

- NPD method, RAM 255/01, for analysis of liv estock commodities for residues of azoxystrobin.

2.2.2 International Harmonization

There are no Canadian or Codex Maximum Residue Limits (MRLs) for residues of azoxystrobin
and its Z

- isomer for sugarcane

.

2.2.3 Recommended Tolerances

Pending submission of a revised Section B , there are no residue chemistry issues that will preclude establish ment of permanent tolerance s for azoxystrobin in/ on sugarcane

. The tolerance
value proposed by the petitioner for sugarcane is adequate and supported; HED recommends a tolerance of 0.2 ppm for sugarcane. The Organization for Economic Cooperation and Development (OECD) tolerance calculation procedures (March 2011 version) were utilized in determining the appropriate tolerance level.

Ta ble 2.2.3. Tolerance Summary for Azoxystrobin

. Commodity Established Tolerance (ppm) Proposed

Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct

Commodity Definition

Sugarcane, cane N/A 0.2 0.2



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

- 2

- (2

- (6

- (2

- cyanophenoxy) pyrimidin

- 4

- yloxy)phenyl)

- 3

- methoxyacrylate] in or on the commo dity.

2.2.4 Revisions to Petitioned

- For Tolerances

There are no revisions to the petitioned

- for tolerances.

2. 3 Label Recommendations

860.1200 Directions for Use

The following statement should be removed from the p roposed supplemental label s ( EPA
R eg. No s . 100

- 1098 and 100

- 1324 ) : ―Do not apply within 45 days of harvest [45

- day preharvest interval (PHI)] for animal feed.‖

The following statement should be removed from the proposed supplemental label for EPA Reg. No . 100

- 1098: ― An adjuvant may be used at recommended rates.‖ The

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 8 of 36 following statement should be added: ―A crop oil concentrate (COC) at 5% maximum (v/v) or a non

- ionic surfactant (NIS) at 1% maximum (v/v) may be added. ‖

The following statement should be added to the proposed supplemental label for EPA Reg. No. 100

- 1324 for use on sugarcane : ―A crop oil concentrate (COC) at 5% maximum (v/v) or a non

- ionic surfactant (NIS) at 1% maximum (v/v) may be added. ‖

The rotational crop restrictions on the registered label for Q uilt Xcel® Fungicide (EPA Reg. No. 100

- 1324) should be revised to increase the plant

- back interval (PBI) for carrot from 0 days to 36 days.

3.0 In troduction

Azoxystrobin is a broad spectrum fungicide used to 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 naturally occurring strobilurins and is structurally related. Azoxystrobin is a

- methoxyacrylate , and acts by inhibiting electron transport.

Syngenta has requested azoxystrobin be registered for use on sugarcane. Azoxystrobin 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 expected from the proposed uses of azoxystrobin. Only s hort

- and intermediate

- term oc cupational 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) (EPA Reg. No. 100

- 1098) and Quilt XcelTM (13.5% ai) (EPA Reg. No. 100

- 132 4)

. Quilt XcelTM is a multiple active ingredient (MAI) product formulation containing both azoxystrobin and propiconazole (11.7%). Propiconazole use on sugarcane has been previously assessed ( M. Dow, D337829, 04/10/2007 )

. In addition, Syngenta is request ing to add sugarcane use on two azoxystrobin manufacturing products : A zoxystrobin Millbase Manufacturing Use Product ( MUP ) (EPA Reg. No. 100

- 1220 ) and
A zoxystrobin D ry T echnical Manufacturing Use Concentrate ( MUC ) (EPA Reg. No. 100

- 1120 ).

Azoxystrobin i s proposed for use as a foliar application on sugarcane using ground, aerial

, and chemigation equipment. Proposed single application rates on sugarcane range from 0.15

- 0.20 lb ai/A (or 9

- 12 fl oz product /A for Abound ® and 16

- 22 fl oz product/A for Quilt X celTM ). The
Abound ® label specifies that no more than 0.80 lb ai/A of any azoxystrobin containing products should be applied per year

, and no more than 4 foliar applications of Abound ® should be applied per year. The Quilt XcelTM label specifies no more th an 88 fl oz per acre per year (0.81 lb ai/A) should be applied.

3.1 Chemical Identity

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

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 9 of 36 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. 100

- 1098); Quilt XcelTM (EPA Reg. No. 100

- 1 324 )

. 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 and is considered relatively insoluble in water. However, azoxystrobin has a molecular weight of 403 g/mol; therefore, the potential to cross biological barriers is somewhat limited , as indicated by the low dermal absorption in the rat dermal penetration study

. In the cattle feeding study, azoxystrobin concentrated in cream. No quantifiable azoxystrobin residues were found in cattle muscle even at the highest dosing level, whereas quantifiable residues were observed in fat. The physi c ochemical properties of azoxystrobin are summarized in Appendix B

.

3.3 Pesticide Use Pattern

Syngenta submitted two draft supplemental amended labels adding use on sugarcane for Abound® Flowable Fungicide (EPA Reg. N o. 100

- 1098) and Quilt XcelTM (EPA Reg. No. 100

- 1324) . In addition, Syngenta is requesting to add sugarc ane use on two azoxystrobin manufacturing products: Azoxystrobin Millbase Manufacturing Use Product (MUP) (EPA Reg.

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 10 of 36 No. 100

- 1220) and Azoxystrobin Dry Technical Manufacturing Use Concentrate (MUC) (EPA Reg. No. 100

- 1120). Table 3.3 provides a summary of t he proposed use sites of azoxystrobin.

Table 3. 3. Proposed Uses of Azoxystrobin

Product (EPA Registration No.) Use Site Application
Method Single

Application Rate Range Maximum

Seasonal Application
Rate (lb ai/A) Comments

Abound ® (100

- 1098)
22.9% 2.08 lb ai/gal

Sugarcane Apply Liquid via Ground, Aerial, or Chemigation 9

- 12 fl oz

product/A

0.15

- 0.20 lb
ai/A

0.8 Do not apply more than 0.80 lb ai/A of any azoxystrobin containing product per season.
Abound ® applications should begin prior to rust development and continue throughout the season every 14

- 28 days following resistance management guidelines. Do not make more than 2 sequential foliar applications of Abound ® or other Group 11 fungicide before alter nation with another fungicide not in Group 11. Do not make more than 4 applications of Abound ® or other Group 11 fungicides per acre per year. The label requires a 45

- day pre

- harvest interval (PHI) for sugarcane used for animal feed, and a 30

- day PHI for all other sugarcane treated with azoxystrobin.

Quilt XcelTM (100

- 1324)
13.5% 1.18 lb ai/gal 16

- 22 fl oz product/A

0.15

- 0.20 lb
ai/A Do not apply more than 88 fl oz/A (0.8 lb ai/A) of Quilt XcelTM per year. Applications should begin prior to rust developmental and continue throughout the season every 14

- 28 days following resistance management guidelines. The label requires a 45

- day pre

harvest interval (PHI) for sugarcane used for animal feed, and a 30

- day PHI for all other sugarcane treated with azoxystrobin.



### 3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed new use of azoxystrobin on sugarcane. Humans may be exposed to azoxystrobin in drinking water, since application may result in azoxystrobin reaching surface and ground water sources of drinking water . Humans may also be exposed through their diet from applications to agricultural commodities

. There are residential uses of azoxy strobin , 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 fo r post

- application exposure 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

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 11 of 36 uses of a zoxystrobin , 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://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 populatio n 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 compi led 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 group and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary

exposures based on home use of pesticide products and associated risks for adult applicators and
for children 3 to < 6 years old , youths and adults entering or playing on treated areas post

application are evaluated. Further considerations are currently in developm ent 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 Character ization and Dose

- Response Assessment

- Azoxystrobin: Human Health Risk Assessment for Proposed Uses on Dragon Fruit, Wasabi, and Tuberous and Corm Vegetables (Subgroup 1C), and from the Revisions to Various Crop Groups (Onion Subgroups 3

- 07 A, B; Fruiting V egetable 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, DP# 389702, 01/18/2012.



### A detailed hazard characterization with a list of available toxicity studies for azoxystrobin is presented in the previous risk assessment (K. Rury, D389702, 01/18/2012). The submitted studies are of good quality and provide sufficient information to determine whether azoxystrobin poses a human health hazard. In addition, the regist rant, Syngenta, has committed to submitting an adequate functional immunotoxicity study that is currently underway and expected to be submitted to the Agency in 2012

.

4. 1 Toxicological Effects

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. Dietary administration of azoxystrobin to rats resulted in decreased body weights, decreased foo d intake and utilization, increased
diarrhea

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

, and distended abdomens). In addition, liver effects

, characterized by increased liver

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 12 of 36 weights, increases in alkaline phosphatase and gama glutamyltransferase, decreases in albumin

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

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

. There were no indications of

treatment

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

In the rat developmental toxicity study, diarrhea, urinary incontinence

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

- related developmental effects were seen in either study. In the rat reproduction study, offspring and parental effects (decreased body weights and increased adjusted liver weights) were observed at the same dose.

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

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

EPA has retained the FQPA SF, reduced to 3X, in assessing acute dietary ri sk. An additional safety factor is needed for acute risk assessment to account for the use of a LOAEL from the acute neurotoxicity study in rats in deriving the acute reference dose used for assessing acute dietary exposure for all populations including i nfants and children. To account for the use of a LOAEL from the acute neurotoxicity study in rats, the Agency believes that a 3X FQPA SF (as opposed to a 10X) will be adequate to extrapolate a NOAEL in assessing acute risk and that no additional safety fa ctor is needed for short

- term, intermediate

- term, and chronic risk assessment based on the following considerations:

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

c. the very high dose level needed to reach the acute oral leth al dose (LD) 50 

### (>5000 milligrams/kilogram (mg/kg)), and the overall low toxicity of azoxystrobin. However, EPA has determined that reliable data show that it would be safe for infants and children to reduce the FQPA safety factor to 1X for short

- term, int ermediate

- term, and chronic risk assessment. This determination is based on the following considerations:

4. 2 .1 Completeness o f the Toxicology Database

The toxicity database for azoxystrobin is complete except for immunotoxicity and subchronic
inhalati on toxicity testing. Changes to 40 CFR part 158 make immunotoxicity testing (OPPTS Guideline 870.7800) required for pesticide registration; however, the existing data are sufficient

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 13 of 36 for endpoint selection for exposure/risk assessment scenarios, and for ev aluation of the requirements under the FQPA. There are no indications in the available studies that organs associated with immune function, such as the thymus and spleen, are affected by azoxystrobin and azoxystrobin does not belong to a class of chemicals that would be expected to be immunotoxic. Based on the above considerations, EPA does not believe that conducting the immunotoxicity study will result in a dose less than the point of departure already used in this risk assessment, and an additional datab ase uncertainty factor for potential immunotoxicity does not need to be applied

.

A subchronic inhalation toxicity study is not required for azoxystrobin at this time (TXR# 0056307).

4. 2 .2 Evidence of N eurotoxicity

Clinical signs , including transient diarrhea 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 is no need for a developmental neurotoxicity study

or additional UFs to account for neurotoxicity.

4. 2 .3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

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

- generation reproduction study.

4. 2 .4 Residual Uncertainty in the Exposure Datab ase

There are no residual uncertainties in the azoxystrobin exposure database. While some

r efinements 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 ass essment utilized conservative

upper

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

level residues for all existing and proposed commodities, except citrus fruits where the highest
field trial residue was used as a r efinement

. The chronic dietary exposure assessment was partially refined, and used tolerance

- level residues for all commodities and (% CT ) estimates when available (Screening Level Usage Analysis (SLUA), 07/13/11)

. Although the acute and chronic assessments included minor refinements, the use of field trial and % CT estimates ensures that actual exposures/risks from residues in food will not be underestimated. The drinking water assessment utilized water concentrati on 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 updated 2012 Residential SOPs employing surrogate study data, including con servative exposure assumptions based on Day 0

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 14 of 36 dermal/oral contact to turf and surfaces treated at the maximum application rate. These data are reliable and are not expected to underestimate risks to adults or children. The Residential SOPs are based upon reasonable ―worst

- case‖ assumptions are not expected to underestimate risk.

4. 3 Toxicity Endpoint and Point of D eparture Selections

4. 3 .1 Summary of Points of Departure and Toxicity Endpoints Used in Human Health
Risk Assessment

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

.

Table 4. 3.1

. Summary of Toxic ological 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 A cute RfD =

0. 67 mg/kg/day

a PAD = 0.67 mg/kg/day Acute Neurotoxicity

- Rat. LOAEL

= 200 mg/kg/day based on diarrhea at

two

- hours post dose at all dose levels including the LOAEL

.

Chronic Dietary (All Populations) NOAEL = 18

mg/kg/day UF A = 10 X

UF H = 10 X FQPA SF =
1 X Chronic RfD = 0. 18

mg/kg/day

cPAD = 0. 18 mg/kg/day Combined Chronic

Toxicity/Carcinogenicity Feeding Study

– Rat. LOAEL = 82.4/117 mg/kg/day (M/F) based on reduced body weights in both sexes and bile
duct lesions in males.
Incidental
Oral Short

Term (1

- 30 days) NOAEL = 25

mg/kg/day UF A = 10 X

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

MOE = 100 Prenatal Developmental Oral

Toxicity

– Rat. LOAEL = 100 mg/kg/day based on increased maternal diarrhea, urinary incontinence, and salivation.
Incidental
Oral
Intermediate

Term (1

- 6 months) NOAEL = 20

mg/kg/day UF A = 10 X

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

MOE = 100 90

- day Feeding Study

– Rat.

LOAEL = 211/223 mg/kg/day (M/F) based on decreased body weight gain in both sexes and clinical signs
indicative of reduced nutrition.
Dermal ( All
Durations ) No hazard was identified for this exposure scenario. 21

- Day Repeated Dose Dermal Study

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

- Term (1

- 30 days) Oral NOAEL

= 25 UF A = 10 X

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

Residential LOC for
MOE = 100 Prenatal Developmental Oral

Toxicity

– Rat. LOAEL = 100 mg/kg/day based on increased maternal diarrhea, urinary incontinence, and salivation.
Inhalation
Intermediate

Term ( 1

- 6 months ) Oral NOAEL

= 20 UF A = 10 X

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

Residential LOC for
MOE = 100 90

- day Feeding Study

– Rat.

LOAEL = 211/223 mg/kg/day (M/F) based on decreased body weight gain in both sexes and clinical signs
indicative of reduced nut rition.

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 15 of 36 Table 4. 3.1

. Summary of Toxic ological 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 with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from anima l 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 expo sure. LOC = level of concern. N/A = not applicable.



### Based on the available toxic ological 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 in put on issues related to this route to route extrapolation approach (i.e. the use of oral toxicity studies for inhalation risk assessment) from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The A gency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, re

- examine and develop new policies and procedures for conducting inhalation risk assessments, including route to route extrapolation of toxicity data. If any new policies or procedures are developed, the Agency may revisit the need for an inhalation toxicity study for azoxystrobin and/or re

- examine the inhalation toxicity risk assessment.

5.0 Dietary Exposure and Risk Assessment

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
G rowing 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/ 20 11

.

- Azoxystrobin: Section 3 Petition for Uses On Tuberous and Corm Ve getables Subgroup 1C (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 G rowing Berry 13

- 07G, Except Cra nberry; 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

, 0 1/04/ 20 12

.

- Azoxystrobin: Human Health Risk Assessment for Proposed Uses on Dragon Fruit, Wasabi, and Tuberous and Corm Vegetables (Subgroup 1C), and from the Revisions to Various Crop Groups (Onion Subgroups 3

- 07 A, B; Fruiting Vegetable Subgroups 8

- 10 A,B; Small Fru it and Berry Subgroups 13

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

- 10). K. Rury, DP# 389702, 01/18/2012.

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 16 of 36 - Drinking Water Exposure Assessment for New Uses of Azoxystrobin on Wasabi, Dragon

- fruit and Sugarcane, and the Propose d Tolerances for Residues of Azoxystrobin for Use on Onion S ubgroups, 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 / 20 11

.

- Azoxystrobin. Petition for Registration of Use on Sugarcane (PP#1F7891). Summary of Analytical and Chemistry and Residue Data, M

. Negussie

, DP# 393151, DP#393155, DP#393156, DP#393157

, 0 3 / 14 / 20 1 2

.

- 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/ 20 10.



### 5.1 Metabolite/Degradate Residue Profile

5.1.1. Summary of Metabolism Studies , Environmental Degradation, and Metaboli c Pathway Comparison

The nature of the residue in plants and livestock are adequately understood for the purposes of
th e Sy n genta petition . Metabolism studies in grapes, peanuts, and wheat were submitted in conjunction with earlier azoxystrobin petitions, PP#s 5F4541 and 6F4762

. No new plant or metabolism studies have been submitted for azoxystrobin since the last human health risk assessment; therefore, the metabolic profile remains unchanged (K. Rury, D389702, 01/18/2012). A more detailed des cription of the plant and animal metabolism studies is presented in the previous risk assessment (K. Rury, D389702, 01/18/2012). The database is adequate for determining azoxystrobin residues of concern

. The summary of environmental degradation of azoxy strobin also remains unchanged and has been summarized in the previous human health risk assessment (K. Rury, D389702, 01/18/2012). A summary of the metabolites and degradates of azoxystrobin for human health risk assessment is summarized in Table 5.1.2

.

5.1. 2 Residues of Concern Summary

Table 5.1 .2 . Summary of Metabolites and Degradates included in the Azoxystrobin Risk Assessment and Tolerance Expression

.

Matrix Residues included in

Risk Assessment Residues included in
Tolerance Expression

Plants Primary Crop Azoxystrobin and Z

- isomer Azoxystrobin and Z

- isomer

Rotational Crop Azoxystrobin and Z

- isomer Azoxystrobin and Z

- isomer

Livestock Ruminant Azoxystrobin Azoxystrobin

Poultry Azoxystrobin Azoxystrobin

Drinking Water Azoxystrobin Not Applicable



### 5.2 Food Residue Profile

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 17 of 36 Adequate residue data are available to support dietary risk assessment as well as the proposed
tolerances of azoxystrobin on sugarcane.

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

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

- isomer are stable for at least 24 months in water

- starch

- , protein

- , oil

- , and acid containing commodities under frozen conditions.

Proposed Uses
Other than the sugarcane field trial data (MRID 48496901 )

, no new resi due field trial data were submitted to support the proposed tolerances. Six field trials were conducted in the United States during the 2008

- 2009 growing season

. Although geographic representation is technically inadequate, HED concludes that the available data are sufficient to support registration of azoxystrobin on sugarcane because trials were conducted in zones representing 100% of sugarcane production in the U.S., and there is not a great deal of variability in the residue values
across the trial sites. A summary of the residue data from the sugarcane field trials is provided in
Table 5.2.a.

T able 5.2. a. Summary of Residue Data from Sugarcane Crop Field Trials with Azoxystrobin.

Commodity Analyte Total App.
Rate (lb ai/A) PHI Residue Levels (ppm) 1

n Sample
Min. Sample

Max. LAFT 2 HAFT 2 Median Mean Std.
Dev. Sugarcane (proposed use = 0.15

- 0.20 lb ai/A total application rate, 30

- day PHI & 45

- day PHI for animal feed)

Sugarcane Azoxystrobin 0.761

- 0.802 27

- 30 6 <0.01 0.111 0.029 0.089 0.049 0.053 0.024

R230310 6 <0.01 <0.01 0.01 0.01 0.01 0.01 N/A

Total Residues 6 < 0.02 < 0.121 0.039 0.099 0.059 0.063 0.024

1

. Except for sample min/max, values reflect per trial averages; n = no. of field trials. For calculation of median, mean, and
standard deviation, the LOQ (0.01 ppm) was used for any results reported as <LOQ. N/A = Not applicable.
2

. LAFT = lowest

- average

- field

- trial; HAFT = highest

- average

- field

- trial.



### Syngenta submitted an acceptable processing study for azoxystrobin on sugarcane. Quantifiable residues of azoxystrobin, Z

- isomer ( R230310 ), and total residues (azoxystrobin and Z

- isomer ) did not concentrate in molasses or refined sugar. All of the processing factors calculated in this study were less than the maximum theor etical concentration factors for sugarcane (11.8x for sugar and 20x for molasses)

.

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

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

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 18 of 36 1 The LOQ = 0.01 ppm. Per trial averages are calculated using the LOQ for all residues reported as <LOQ.

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



### Livestock The only livestock feedstuff associated with this petition is sugarcane molas ses; this commodity is fed to beef and dairy cattle but is not fed to poultry or swine. The dietary burdens of azoxystrobin to livestock, based on reasonably balance diets, were calculated most recently in
D390152 (M. Negussie, 01/04/ 20 12) . Dietary burde ns were 51.3 and 40.4 ppm for beef and dairy cattle, respectively, and 14.4 and 15.0 ppm for poultry and swine, respectively . Dietary
burdens were calculated based on tolerances of cereal grain, non

- grass animal feeds, canola, cotton, and soybean commodit ies. The addition of sugarcane to the dietary burden calculation would not be expected to alter the dietary exposure of ruminants to azoxystrobin. Sugarcane molasses contributes no more than 0.03 ppm azoxystrobin to the dietary burden, about 0.1% of
the existing burden.

The existing azoxystrobin tolerances for milk

, milk fat

, meat, and the meat byproducts of goat ; hog

, horse

, and sheep are adequate . R evision s to the existing tolerances are not needed to support the proposed uses of azoxystrobin. The proposed uses of azoxystrobin addressed in this document do not alter the Agency’s previous conclusion that there is no reasonable expectation of finite residues in poultry commodities [Category 3 of §180.6(a)]. T olerances are not needed for poultry t issues 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 use on sugarcane does not result in increased maximum seasonal application rates of azoxystrobin, no changes to the existing rotational crop restrictions are needed. However, revisions to the rotational crop restrictions are recommend ed for EPA Reg. No. 100

- 1324; the label should be revised to increase the PBI for carrot from 0 days to 36 days.

5. 3 Water Residue Profile

The drinking water inputs provided in the previous drinking water assessment on turf (J. Wolf, D371383, 01/6/ 20 10 ) were more conservative than the most recent drinking water assessment on wasabi, dragon

- fruit and sugarcane (R. Baris, D389703/394475, 11/28/ 20 11). EFED estimates drinking water concentrations of a chemical based on the highest rate of application of th e chemical on all registered and proposed crops. In the case of azoxystrobin, turf, a previously registered use , has the highest application rate (0.55 lb ai/A, 9 applications per year with a 10

- day interval between applications). The assessment was completed with the Tier 1 screening Table 5.2.b. Residue Data from Sugarcane Processing Studies with Azoxystrobin.

RAC Processed

Commodity Total Rate

(lb ai/A) PHI Average of Total (Azoxystrobin and
Z

- isomer) Residues (ppm) 1 Processing Factor 2

Sugarcane Cane

(RAC)

3.93

- 3.94 27

- 30 0.420

--

Molasses 0.218 0.52x

Refined Sugar <0.02 <0.05x

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 19 of 36 model, FQPA Index Reservoir Screening Tool (FIRST). The model and its description is
available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/

.

The proposed rates of application for sugarcane are lower than for turf. Therefore, the EDWCs reported for turf are used . EDWCs recommended for use in the human health risk assessment for all proposed/registered crops are listed in Table 5. 2. For gro und water, the estimated drinking water concentration is 3.1 ppb.

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 e xisting 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 asses sment was partially refined, based on tolerance level residues for all existing and proposed commodities. A SLUA was provided by the Biological and Economic Analysis Division (BEAD) ( 07/13/ 20 11). % CT estimates were used when available.

HED utilized BEAD’s estimated % CT for the existing uses as follows: Almonds, 25%; apricots, 10%; artichokes, 25%; asparagus, 2.5%; green beans, 10%; blackberries, 5%; blueberries, 10%, broccoli, 5%; cabbage, 10%; cantaloupes, 10%; carrots, 10%; cauliflower, 2.5%; cele ry, 10%; cherries, 5%; corn, 2.5%; cotton, 5%; cucumbers, 20%; dry beans/peas, 1%; garlic, 60%; grapefruit, 20%; grapes, 5%; hazelnuts (filberts), 5%; lettuce, 2.5%; onions, 10%; oranges, 5%; peaches, 5%; peanuts, 15%; green peas, 2.5%; pecans, 2.5%; peppe rs, 15%; pistachios, 15%; potatoes, 35%; prunes, 2.5%; pumpkins, 20%; raspberries, 5%; rice, 35%; soybeans, 2.5%; spinach, 10%; squash, 15%; strawberries, 30%; sugar beets, 5%; sweet corn, 10%; tangerines, 15%; tomatoes, 15%; walnuts, 1%; watermelon, 20%; and wheat, 2.5%.

5. 4

. 2 Acute Dietary Risk Assessment

An acute dietary exposure assessment was conducted for the general U.S. population and all population subgroups (all infants, children 1

- 2, children 3

- 5, children 6

- 12, youth 13

- 19, adults
20

- 49, adult s 50+ and females 13

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

- 2 yea rs old , utilized

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 20 of 36 4 2 % of the aPAD. The results are reported in Table 5 .4.4 . All population subgroups were below
the LOC

.

The acute dietary exposure assessment is partially refined, i.e.

, based on the assumption of
tolerance

- level residues for all commo dities, 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 reported exposed population subgroup, children 1

- 2 years old , utilized 1 6 % of the cPAD. The
results are reported in table 5. 4.4 . All population subgroups were be low the LOC

.

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 fo r the crops listed in Section 5.4.1.

5. 4

. 4 Summary Table

Table 5. 4

. 4

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

.

Population Subgroup Acute Dietary 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 18 0.012050 6.7

N/A N/A All Infants (< 1 year old) 0.146102 22 0.015196 8.4

Children 1

- 2 years old 0.279450 42 0.027847 16

Children 3

- 5 years old 0.218767 33 0.024065 13

Children 6

- 12 years old 0.144459 22 0.015268 8.5

Youth 13

- 19 years old 0.115468 17 0.011208 6.2

Adults 20

- 49 years old 0.100143 15 0.010190 5.7

Adults 50+ years old 0.094256 14 0.010004 5.6

Females 13

- 49 years old 0.102333 15 0.009822 5.5



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

Reference s :

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 21 of 36 - Azoxystrobin. Occupational and Residential Exposure Assessment to Evaluate the Risk from Proposed Uses on Sugarcane , K. Rury, D P #394287

, 03/30/2012

.


### This document addresses the proposed new agricultural use of azoxystrobin on sugarcane; therefore, no new residential exposure is expected. However, there are currently registered uses of azoxystrobin by both commercial and residential handlers on residential use sites, including turf, ornamenta ls, indoor uses (carpet and hard surfaces)

, and in paints. Each of these existing residential use patterns has previously been assessed by HED and the resulting exposures and risk estimates do not exceed HED’s LOC . However, HED has recently updated the r esidential standard operating procedures (SOPs) and body weights to be used in all human health assessments. Therefore, all the existing residential use patterns have been reassessed for residential handler and post

- application exposures using these new p rocedures and data (K. Rury, D394287, 03/30/ 20 12)

.

6.1 Residential Handler Exposure

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

- agric ultural use sites; i.e.

, outdoor residential (lawns, ornamentals, flower gardens, vegetables, fruit and nut trees, berries and vines) and recreational (golf courses, parks and athletic fields) sites. Additionally, residential and commercial applicators ma y use azoxystrobin on indoor carpets/other surfaces, and in treated paints (preservative incorporation). All existing r esidential exposures have been
reassessed to account for updates to HED’s 2012 Residential SOPs along with policy changes for body weigh t assumptions. 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

. Beca use there was no dermal endpoint chosen for azoxystrobin, risk from exposure to azoxystrobin was assessed for the inhalation route only. Although PODs from an oral study were used to assess residential handler
inhalation risks for azoxystrobin , HED does n ot believe this assessment is under

- protective of
adult handlers.

HED’s LOC 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 acc ount 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 greater than or equal to 100 will n ot be of concern to HED.

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

- end sprayer).

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 22 of 36 Table 6.1. Residential Handler Summary of Registered Azoxystrobin Use Sites

Activity Application
Rate Area

Treated/Amount Applied (per day) Inhalation

UE (mg/lb ai) 1 Short

- Term

Inhalation
Dose 2 (mg/kg/day) Short

- Term

Inhalation
MOE 3

Painting with Airless Sprayer 1.0% ai by weight 15 one

- gallon cans 0.56 0.0149 2,400

Painting with a Brush 1.0% ai by weight 2 one

- gallon cans 0.2 0.0005 50,000

Indoor Manually

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

Indoor Manually

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

M/L/A Wettable Powders to Turf [Hose End Sprayer] 0.95 (lb ai/A) 0.5 acres 0.022 0.00013 190,000

M/L/A Wettable Powder to Turf [Manually Pressurized Handwand or Backpack Sprayer] 0.011 (lb ai/gal) 5 gallons 1.1 0.00076 33,000

M/L/A Wettable Powders in WSB to Turf [Hose End Sprayer] 0.95 (lb ai/A) 0.5 acres 0.034 0.0002 120,000

M/L/A Wettable Powder in WSB to Turf [Manually Pressurized Handwand or Backpack Sprayer] 0.011 (lb ai/gal) 5 gallons 0.018 0.000012 2,000,000

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

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

M/L/A Wettable Powder Azoxystrobin to Gardens and Trees [Hose

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

M/L/A Wettable Powder Water Soluble Packets Azoxystrobin to Gardens and
Trees [Manually

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

M/L/A Wettable Powder Water Soluble Packets Azoxystrobin to Gardens and Trees [Hose

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

1. Inhalation Unit Exposures taken from the 2012 Residential SOPs

2. Inhalation Dose = (Daily Unit Exposure (mg/lb ai) x application rate x area treated daily or amount applied per day)/body weight (80 kg)

3. Inhalation MOE = NOAEL (25 mg/kg/day for short

- term exposures)/Daily Dose (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. No dermal endpoint was chosen for azoxystrobin; therefore, a dermal post

- application risk

assessmen t was not conducted. Residential post

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

- application inhalation exposure has
been assessed. Post

- application e xposure in residential settings is expected to be short

- term in duration only. Table s 6.2a and 6.2b lists t he updated assessments of residential post

- application exposures and risk estimates. The MOEs ranged from 250 to 810 ,000 for incidental oral ingestion. The MOE for adults was 220,000,000 and was 52,000,000,000 for children for indoor post

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

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 23 of 36 post

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

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

Table 6 .2 a. Exposure and Risk from Post

- Application Exposure to Azoxystrobin

- Children

Scenarios Short

- Term Dose (mg/kg/day) 1 Short

- Term MOE 2

Post

- Application Inhalation (Indoor) 0.00000000087 52,000,000,000
Incidental Oral Indoor Scenarios
Hand

- to

- Mouth (vinyl/hard surfaces) 0.0327 760
Hand

- to

- Mouth (carpet/textile surfaces) 0.0982 250 Object

- to

- Mouth (vinyl/hard surfaces) 0.0087 2900 Object

- to

- Mouth (carpet/hard surfaces) 0.013 1900
Incidental Oral Treated Turf Scenarios
Hand

- to

- Mouth Liquid 0.0142 1,800 Object

- to

- Mouth Liquid 0.00043 57,000 Soil Ingestion (Liquid) 0.000031 810,000
Hand

- to

- Mouth Granular 0.0142 18,000 Object

- to

- Mouth Granular 0.000087 290,000 Soil Ingestion (Granular) 0.000031 810,000 Granular Ingestion 0.082 2,500

1. Inhalation Dose = ((((Inhalation Rate (m 3 /hr) (0.64 for adults, 0.33 children)* mass of ai (mg))/(ACH (0.45 (1/hr))*Vol of room (33

m 3 ))*(1

- (((ACH (0.45 (1/hr))*EXP(

- (1.4E

- 11(1/hr)*ET (18 hrs children))))

- (1.4E

- 11(1/hr)*EXP(

- (ACH*ET (hrs)))))/(ACH (0.45)

- 1.4E

- 11 (1/hr)))))*Inhalation Absorption/Inhalation POD)
Hand

- to

- Mouth Dose = [(Hand residue loading (mg/cm 2 ) x Fraction of hand mouthed (0.13) x surface area of 1 hand (150 cm 2 ) x Exposure Time ( 1.5 hrs /day) x #Replenishment intervals/hr (4) x (1

- ((1

- Frac tion Saliva Extraction (0.48))^(Number of hand

- to

mouth events per hour (events/hr)/Number of replenishment intervals/hr (4))]/ body weight (11 kg) Object

- to

- Mouth Dose = ((Object Residue (μg/cm 2 )*CF1 (1.0E

- 3 mg/μg)*Object Surface Area Mouthed/Event (10

cm 2 /event))*(Exposure Time ( 1.5 hrs/day)*#Replenishment intervals/hr (4) )*(1

- ((1

- Extraction by Saliva (0.4 8 ))^(#Object

- to

- Mouth Events/hr ( 8.8 events/hr )/#Replenishment inte rvals/hr))))/Body Weight (11kg) Soil Ingestion = (Soil Residue (7.0746975 μ g/g) *Inge stion Rate (50 mg/day)*Conversion Factor (0.000001))/body weight ( 11 kg) Granule Ingestion = ((% ai in the product)*Ingestion Rate (0.3 g/day)*Conversion Factor (1000))/body weight ( 11 kg)
2. MOE = NOAE L/LOAEL /Daily Dose (mg ai/kg/day) ; Inhalation NOAEL = 25 mg/kg/day, Acute oral NOAEL (for assessing granular ingestion) = 200 mg/kg/day.

Table 6 .2b. Exposure and Risk from Post

- Application Exposure to Azoxystrobin

- Adults

Scenarios Short

- Term Dose 1 (mg/kg/day) Short

- Term MOE 2

Post

- Application Inhalation (Indoor) 0.00000000011 220,000,000,000

1. Inhalation Dose = ((((Inhalation Rate (m 3 /hr) (0.64 for adults, 0.33 children)* mass of ai (mg))/(ACH (0.45 (1/hr))*Vol of room (33

m 3 ))*(1

- (((ACH (0.45 (1/hr))*EXP(

- (1.4E

- 11(1/hr)*ET (16 hrs adults))))

- (1.4E

- 11(1/hr)*EXP(

- (ACH*ET (hrs)))))/(ACH (0.45)

- 1.4E

- 11 (1/hr)))))*Inhalation Absorption/Inhalation POD)

2. MOE = NOAEL (25 mg/kg/day for short

- term exposures)/Daily Dose (mg ai/kg/day)



### 6. 3 Combined Exposure

FQPA requires residential exposures that could reasonably be expected to occur on the same day

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 24 of 36 to be combined and compared to the appropriate toxicity endpoint. In general, residential handler and post

- application scenarios generally should not be combined. Additionally, no dermal endpoint was chosen for azoxystrobin and outdoor inhalation post

- application exposures are considered negligible . Therefore, residential post

- application exposure scenarios for azoxystrobin were not combined.

6. 4 R esidential Bystander Post

- A pplication Inhalation Exposure

Although a quantitative residential post

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

exposure scenario is representative of a worse case inhalation exposure and should be considered protective of most post

- application inhalation exposure scenarios.

6. 5 Spray Drift

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

. The Agency has been working with the Spray Drift Task Force, EPA 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 information at http://www.epa.gov/opp00001/factsheets/sprayd rift.htm). On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic met hods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off

- target drift with specific products with significant risks
associated with drift.

7.0 Aggregate Exposure/Risk Characterization

In accordance 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 com pared 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 expo sures from food, drinking water and residential scenarios were aggregated.

This assessment has considered the changes in the new Residential Standard Operating Procedures (SOPs) implemented in January of 2012. HED confirms that there are no risks of

co ncern resulting from sugarcane use , nor from utilizing the new Residential SOPs to estimate residential exposure and risk.

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 25 of 36 7.1 Acute Aggregate Risk

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

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

, is below the Agency’s LOC. The food and drinking water exposure estimates are 18 % of the aPAD for the general U.S. population, and 4 2 % 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 d ietary (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 s cenario was chosen for each population ( e.g

. , hand

- to

mouth exposure from carpets and textiles for children 1

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

, see Section 6.0.

The adult (inhalation) aggregate MOE (for adult males) is 460, and the adult (inhalation) aggregate MOE for females 13

- 49 years was 470 . 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 200 , 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

- 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 0.012 0.042 0.054 460
Females 13

- 49

years 25 100 1 0.011 0.042 0.089 470

Children 1

- 2

years 25 100 1 0.02 8 0.098 0.1 3 200

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 ). Exposure estimate for Children 1

- 2 years includes post

- application inhalation exposure (0.00000000087 mg/kg/day)+ incidental oral ingestion from treating carpets (0.0982 mg/kg/day) = 0.098 mg/kg/day.
4

. Total Exposure = Avg Food & Water Exposure + Res idential Exposure)
5

. Aggregate MOE = [NOAE L , 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

. In the previous risk assessment

, both short

- and intermediate

- term incidental

- oral residential risks were included in the aggregate risk assessment for azoxystrobin

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 26 of 36 (K. Rury, D389702, 1/18/2012) . Based on the azoxystrobin use pattern, and the 2012 Revised Residential SOPs (2012), only s hort

- term residential handler and post

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

7.4 Chronic Aggregate Risk

Chronic exposure is not expected for the adult residential (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 t o 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 t oxicity, 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 determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemical s, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/ cumulative/.

9.0 Occupational Exposure/Risk Characterization

Reference s :

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

, 03/30/2012

.



### 9 .1 Short

- /Intermediate

- Term Handler Risk

Azoxystrobin is proposed for use as a foliar application to sugarcane

. Application methods, maximum application rates and use sites are summarized in Table 9. 1

. Based on the proposed use pattern of azoxystrobin, t here is a potential for sho rt

- and intermediate

- term occupational exposure during handling (mixing

, loading , and applying ) and post

- application activities (sorting, packing and culling) . Chronic exposure is not expected 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 ). Both the Quilt XcelTM and Abound® require handlers to wear long sleeved shirts, long pants, chemical resistant gloves, shoes, and socks. Quilt XcelTM also req uires the use of protective eyewear.

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 27 of 36 Sugarcane farms are typically large in scale ; the share of sugarcane production in the US of farms larger than 2,000 acres is disproportionately high 1

, 2 

### . Therefore, based on HED ExpoSAC Policy No. 9.1 and informat ion gathered on typical sugarcane farm size, sugarcane was treated as a ―high acreage crop

. ‖

HED’s LOC for the MOE is defined by the uncertainty factors that are applied to the assessment. HED applies a 10X factor to account for interspecies extrapolat ion 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 occupational exposure. Occupational exposure and
risk estimates resulting in M OEs 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 sugarcane are include d in Table 9 .1. No dermal hazard was identified for azoxystrobin ; 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) with base line attire.
The short

- term inhalation MOE s range from 38,000 to 230,000 for occupational application of azoxystrobin to sugarcane. The intermediate

- term MOEs range from 30,000 to 180,000 for occupational application of azoxystrobin to sugarcane.

Tab le 9.1 . Occupational Handler Short

- and Intermediate

- Term Dermal and Inhalation Exposure and Risk Estimates for Azoxystrobin on Sugarcane

Scenario Maximum Single Application Rate (lb ai/A) 1 Acres

Treated per Day 2 Inhalation

Baseline Unit Exposure (mg/lb ai) 3 Inhalation

Daily Dose 4 (mg/kg/day) Baseline

Inhalation
MOE 5

Short

- Term Occupational Handler

M/L for Aerial Applications 0.2 1200 0.000219 0.000657 38,000

M/L for Groundboom Applications 0.2 200 0.000219 0.0001095 230,000

M/L for Chemigation Applications 0.2 350 0.000219 0.000191625 130,000

Aerial Application 0.2 1200 0.000068 0.000204 120,000

Groundboom Application 0.2 200 0.00034 0.00017 150,000

Flagger 0.2 350 0.00035 0.00030625 82,000

Intermediate

- Term Occupational Handler

M/L for Aerial Applications 0.2 1200 0.000219 0.000657 30,000

M/L for Groundboom Applications 0.2 200 0.000219 0.0001095 180,000

M/L for Chemigation Applications 0.2 350 0.000219 0.000191625 100,000

Aerial Application 0.2 1200 0.000068 0.000204 98,000

Groundboom Application 0.2 200 0.00034 0.00017 120,000

Flagger 0.2 350 0.00035 0.00030625 65,000

1 http://www.sweetenerusers.org/sugarstructure.pdf

2 http://www.ipmcenters.org/cropprofiles/docs/FLsugarcane.pdf

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 28 of 36 Tab le 9.1 . Occupational Handler Short

- and Intermediate

- Term Dermal and Inhalation Exposure and Risk Estimates for Azoxystrobin on Sugarcane

Scenario Maximum Single Application Rate (lb ai/A) 1 Acres

Treated per Day 2 Inhalation

Baseline Unit Exposure (mg/lb ai) 3 Inhalation

Daily Dose 4 (mg/kg/day) Baseline

Inhalation
MOE 5

1. Application Rates based on the proposed labels Abound® Flowable Fungicide (EPA Reg. No. 100

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

- 1324).
2. Acres Treated based on ExpoSAC Policy #9

- Standard Values for Daily Acres Treated in Agriculture (7/5/2000) and information gathered on sugarcane production in the US.
3. Unit Exposures based on the Occupational Pesticide Handler Unit Exposure Surrogat e Reference Table (9/26/2011) available at: http://www.epa.gov/pesticides/science/handler

- exposure

- data.html
4. Inhalation Dose = (Daily unit exposure (mg/lb ai) * application rate (lb ai/A) * acres treated daily) / body weight (80kg).
5. Inhalation MOE = NOAEL (25 mg/kg/day for short

- term exposures, 20 mg/kg/day for intermediate

- term exposures)/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 application to sugarcane, resulting in the potential for exposure to azoxystrobin during scouting, hand weeding, and possibly hand harvesting. However, no appropriate derma l endpoint 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 grapes, but has not been employed in this or previous
risk assessments because HED determined there is no hazard via the dermal route.

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

- application inhalation exposure assessment was not per formed for azoxystrobin primarily because of its low acute inhalation toxicity (Toxicity Category III), and low vapor pressure

. However, there are multiple potential sources of post

- application inhalation exposure to individuals performing post

- applicatio n activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency i s in the process of evaluating the SAP report as well as available post

- application inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, subsequent ly, the way to incorporate occupational post

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

- application inhalation exposure assessment for azoxystrobin

.

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 after harvest is likely to result in higher exposure than post

- application exposure. Therefore, it is expected that these

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 29 of 36 handler inhalation exposure estimates would be protective of most occupational post

- application
inhal ation 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 usually is the shortest waiting period permitted under the WPS, REIs may be further reduced from 12 hours if certain
criteria are met for both the technical material and the different end

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

- 3 [Reduction of Worker protection Standard (WPS) Interim Restricted Entry Intervals (REIs) for Certain Low Risk Pesticides]. Previously,
HED determined that the criteria for the technical 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 REI of 12 hours listed on the multiple ai product Quilt Xcel® with both azoxystrobin and propiconazole, is acceptable under the WPS.

10 .0 References

R. Baris, 11/28/ 20 11, DP#389703/394475, 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 S ubgroups, Fruiting Vegetables Subgroups, Small
Fruit & B erry Subgroups, Oilseed Subgroups; and the Proposed Increased Tolerance for Tuberous & Corm Vegetables Subgroup.

M. Negussie, 11/29/ 20 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 S ubgroup 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

- 07 F, 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, 03/14/2012 , DP# 393151, DP#393155, DP#393156, DP#393157 , Azoxystrobin: Petition for Registration of Use on Sugarcane (PP#1F7891). Summary of Analytical Chemistry
and Residue Data.

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

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

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

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 30 of 36 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 (19 98) guideline protocols were used.

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ .................. 870.1300 Acute Inhalation Toxicity

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

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

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

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

yes
yes
yes
yes
yes

870.3100 Oral Subchronic (rodent)

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

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

- Day Dermal

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

- Day Dermal

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

- Day Inhalation

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

no CR 1 yes

yes
yes

no yes*

870.3700a Developmental Toxicity (rodent)

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

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

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

yes
yes

870.4100a Chronic Toxicity (rodent)

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

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

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

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

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

yes
yes
yes

yes
870.5100 Mutagenicity

— Gene Mutation

- bacterial

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

— Gene Mutation

- mammalian

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

— Structural Chromosomal Aberrations

... 870.5385 Mutagenicity

— Other Genotoxic Effects

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

yes
yes
yes

870.6100a Acute Delayed Neurotoxicity (hen)

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

- Day Neurotoxicity (hen)

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

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

- Day Neurotoxicity Screening Battery (rat)

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

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

no
yes
yes

no -

- yes
yes

no

870.7485 General Metabolism

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

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

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

no

yes yes

yes

no
Special Studies for Ocular Effects

Acute Oral (rat)

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

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

- month Oral (dog)

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

no
yes -

-

-

1 CR = Conditionally Required
* The requirement for a subchronic inhalation toxicity study has been waived (TXR#0056307)

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 31 of 36 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

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 32 of 36 Table A

. 2 .2 . Azoxystrobin Toxicity Results From Repeated Dosing and Other Studies. Study Guideline/Study MRID Results LOAEL > 500 mg/kg/day

. 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

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

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

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

870.4300
Combined Chronic toxicity/ Carcinogenicity
in rats 43678139 (1995) Acceptable/guideline 0, 60, 300, &1500/750 ppm for males (due to excessive death the high dose was reduced beginning at week
52

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

.

870.5100 Bacterial reverse gene
mutation 43668146 (1992) Acceptable/guideline 100, 200, 500, 1000, 2500, 5000 μg/plate Negative in increasing revertant colonies up to 5000 μg/plate +/

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

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

assays Nonlinear, slight but significant increases in the mutation frequency (MF) of mouse lymphoma
L5178Y TK +/

- at 15

- 60 μg/mL +/

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

870.5375 Cytogenetics 43678147 (1992) Acceptable/guideline The in vitro test in human lymphocytes was positive
for the induction of chromosomal aberrations in both

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Page 33 of 36 Table A

. 2 .2 . Azoxystrobin Toxicity Results From Repeated Dosing and Other Studies. Study Guideline/Study MRID Results
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 severely cytotoxic (i.e. > 16

- 70% reductions in mitotic cells, respectively)

870.5385 Cytogenetics bo ne

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

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

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

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

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

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

sexes.

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

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

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

- 89%) followed by urine (≈9

- 18%). There were no apparent sex

- or dose

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

- 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

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Page 34 of 36 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

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Page 35 of 36 Appendix C

. International Residue Limit Status Sheet

.



## Azoxystrobin (PC Code 128810; 10/13/11)

Table C. Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 2 Codex 3

40 CFR 180.507:
Plant: sum of azoxystrobin, [methyl( E )

- 2

- (2

- (6

- (2

- cyanophenoxy) pyrimidin

- 4

- yloxy)phenyl)

- 3

- methoxyacrylate]

, and
the Z

- isomer of azoxystrobin [methyl( Z )

- 2

- (2

- (6

- (2

- cyanophenoxy)pyrimidin

- 4

- yloxy)phenyl)

- 3 methoxyacrylat e] (αE)

- methyl 2

- [[6

- (2

- cyanophenoxy)

- 4

- pyrimidinyl]oxy]

- α

- methoxymethylene)benze
neacetate, including the isomer (Z)

- methyl 2

- [[6

- (2

- cyanophenoxy)

- 4

- pyrimidinyl]oxy]

-- (methoxymethylene)benz

eneacetate Azoxystrobin.
The residue is fat
soluble.

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 2 Codex 3
Sugarcane, cane 0.2

Completed: M. Negussie; 10/14/2011

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 = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed ha ve not been finalized by the CCPR and the CAC.

### Azoxystrobin Human Health Risk Assessment DP No. 394285

Page 36 of 36 Appendix D

. Review of Human Research

Studies reviewed for ethical conduct:

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

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

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