UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

DATE:	April 30, 2008

SUBJECT:	Azoxystrobin. Human Health Risk Assessment for a Section 3 New/Amended Uses on Non-grass Animal Feeds (Crop Group 18), Sorghum, Wheat, Cotton and Wild Rice.

PC Code	128810	DP Barcode	D344389

Decision No.	NA	Registration No.	NA

Petition No.	6F7106

7F7198	Regulatory Action	Section 3 Registration

Tolerance Petitions

Risk Assessment Type	Single Chemical/

Aggregate

	Case No.	NA

TXR No.	NA	CAS No.	131860-33-8

MRID No.	NA	40 CFR	§180.507

FROM:			Sheila Piper, Chemist

		Alternative Risk Integration Assessment Team (ARIA)

		Registration Division (7505P)

THROUGH:	Paula Deschamp, Branch Chief

		Barry O’Keefe, Senior Biologist

			Registration Action Branch 3

		Health Effects Division (7509P)

					and

	William Cutchin, Acting Senior Branch Scientist

	ARIA/RIMUERB/RD (7509P)

TO:	Cynthia Giles-Parker/Dan Rosenblatt/	Barbara Madden PM-05

		Registration Division (7505P)

The Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides.  The Registration Division of OPP has requested that ARIA evaluate hazard and exposure data and conduct dietary, occupational, residential and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from existing and proposed uses of azoxystrobin.

Syngenta Crop Protection submitted two separate tolerances petitions:  PP#6F7106 requesting the establishment of azoxystrobin and the Z-isomer of azoxystrobin on non-grass animal feeds (crop group 18), sorghum and wheat; and PP#7F198 requesting the establishment of azoxystrobin and the Z-isomer of azoxystrobin on cotton and wild rice.

A summary of the findings and an assessment of human risk are provided in this document.  The residue chemistry data review was provided William Cutchin (ARIA), the dietary exposure assessment by Debra Rate (ARIA), the risk assessment by Sheila Piper (ARIA), the hazard characterization and endpoint selection by Ghazi A. Dannan (RAB3), the occupational exposure assessment by Mark Dow (ARIA), and the drinking water exposure assessment by James Wolf of the Environmental Fate and Effects Division (EFED).

HED previously completed a Section 3 human-health risk assessment for the use of Azoxystrobin on foliage of legume vegetables, fruiting vegetables (except tomato), pea and bean, succulent and dried shelled (except soybeans), nongrass animal feeds, citrus and Section 18 requests for crop groups 6 and 7 to soybean rust (Memo W. Cutchin, D317291, 7/20/2006).  The hazard characterization/endpoint selection and residential (non-occupational) have not changed since the previous risk assessments on azoxystrobin and can be applied directly to this action.

Table of Contents

 TOC \f

1.0	Executive Summary	5

2.0	Ingredient Profile	11

2.1	Summary of Registered/Proposed Uses	11

2.2	Structure and Nomenclature	15

2.3	Physical and Chemical Properties	15

3.0	Hazard Characterization/Assessment	16

3.1 	Hazard and Dose-Response Characterization	16

3.1.1	Database Summary	16

<IP_ADDRESS>	Studies Available and Considered	16

<IP_ADDRESS>	Sufficiency of Studies/Data	17

<IP_ADDRESS>	Toxicological Effects	17

3.2 	Adsorption, Distribution, Metabolism and Excrection (ADME)	17

3.3 	FQPA Consideration	18

3.3.1	Adequacy of the Toxicity Database 	18

3.3.2	Evidence of Neurotoxicity	18

3.3.3	Developmental Toxicity Study	18

3.3.4	Reproductive Toxicity Study	18

3.3.5	Additional Information from Literature Sources	18

3.3.6	Pre- and/or Postnatal Toxicity	18

<IP_ADDRESS>	Determination of Susceptibility	18

3.4	FQPA Safety Factor for Infants and Children 	18

3.5	Hazard Identification and Toxicity Endpoint Selection 	19

3.5.1	Comments about Study/Endpoint/Uncertainty Factor: Acute RfD/PAD  19

3.5.2	Level of Concern for Margin of Exposure	20

3.5.3	Recommendation for Aggregate Exposure Risk Assessment	20

3.5.4	Classification of Carcinogenic Potential	20

3.5.5	Summary of Toxicological Doses and Endpoints	21

3.6	Endocrine Disruption	22

4.0  Dietary Exposure/Risk Characterization	22

4.1	Pesticide Metabolism and Environmental Degradation	22

4.1.1	Metabolism in Primary Crops	23

4.1.2	Metabolism in Rotational Crops	23

4.1.3	Metabolism in Livestock	23

4.1.4	Analytical Methodology	23

4.1.5	Multiresidue Methods	24

4.1.6	Storage Stability	25

4.1.7	Food Residue Profile	25

4.1.8	Confined and Field Rotational Crops	33

4.1.9	Pesticide Metabolites and Degradates of Concern	33

4.1.10	International Residue Limits	34

4.1.11	Environmental Degradation	34

4.1.12	Drinking Water Residue Profile	34

4.2	Dietary Exposure and Risk Characterization	35

4.2.1	Acute Dietary	36

4.2.2	Chronic Dietary	37

4.2.3	Cancer Dietary	37

4.3	Anticipated Residues and Percent Crop Treated Information ………………………..37

5.0	Residential (Non-Occupational) Exposure/Risk Characterization	37

5.1   	Residential Uses	38

5.2	Residential Handler Exposure and Risk	38

5.3	Residential Post-application Exposure and Risk	40

5.4	Recreational Post-application Exposure and Risk	41

5.5	Off Target Non-Occupational Exposure	41

6.0	Aggregate Risk Assessment and Risk Chacterization	42

6.1   	Acute Aggregate Risk	42

6.2	Short-term Aggregate Risk	42

6.3	Intermediate-Term Aggregate Risk	44

6.4	Chronic Aggregate Risk	44

6.5	Cancer Aggregate Risk	45

7.0	Cumulative Risk Characterization/Assessment	45

8.0	Occupational Handler	45

8.1	Occupational Handler	45

8.2	Short-/Intermediate-Term Post-application Risk	47

8.3	Restricted Entry Interval	47

9.0	Tolerance Summary	47

10.0	Data Needs and Label Recommendation	49

10.1	Toxicology	49

10.2	Residue Chemistry	49

10.3	Occupational and Residential Exposure	50

References…………………	50

Appendix A1: Toxicity Profile	52

Appendix A2: International Residue Limit Status Sheet	53

Executive Summary tc "1.0 EXECUTIVE SUMMARY"

sticidal compounds called β-methoxyacrylates, which are derived from the naturally occurring strobilurins.  Its biochemical mode of action is inhibition of electron transport.  The fungicide is currently registered for use on a variety of field, vegetable, fruit, and nut crops as well as on ornamental plants and turfs.  ARIA conducted a human health risk assessment for the fungicide, azoxystrobin for the purpose of making a tolerance/registration eligibility decision to establish new or amended uses on non-grass animal feeds (crop group 18), sorghum, wheat, cotton and wild rice as requested by the Interregional Research Project No. 4 (IR-4).

Use Profile

End-use products of azoxystrobin are typically formulated as water dispersible granular (WDG) and flowable concentrate (FlC) formulations.  These products may be applied as in-furrow at planting or postemergence foliar applications using ground or aerial equipment at maximum seasonal rates of 0.40-2.0 lb ai/A.  Azoxystrobin is also registered for seed treatment of many food/feed crops as well as for postharvest uses of banana/plantains and citrus fruits.

Concurrently, Syngenta wishes to amend the product label for Abound® Flowable Fungicide (EPA Reg. No. 100-1098), an FlC formulation containing 22.9% ai (2.08 lb/gal) azoxystrobin, and Heritage® Fungicide (EPA Reg. No. 100-1093), a WDG formulation containing 50% ai (0.5 lb/gal) azoxystrobin to add new foliar uses on non-grass animal feeds group and sorghum, and to amend the use directions for barley, rice (adding wild rice), wheat/triticale and cotton.  Foliar applications are to be made at maximum seasonal rates of 0.40 lb ai/A for barley and wheat, 0.45 lb ai/A for cotton, or 0.70-0.75 lb ai/A for clover, nongrass animal feeds, rice (including wild rice), and sorghum.  Applications may be made using ground or aerial equipment.  The proposed preharvest intervals (PHIs) range from 14 days (forage and hay; and sorghum matrices) to 28-45 days (mature crop commodities).

Hazard Profile

	The toxicology database is complete and there are no data gaps.  Although there is no evidence of increased susceptibility following in utero and/or postnatal exposure to azoxystrobin no NOAEL was identified in the study selected for the aRfD/PAD.  To account for the uncertainty for extrapolation from a LOAEL to a NOAEL, an FQPA SF in the form of a UFL of 3X has been retained.

Endpoints were chosen for acute and chronic dietary, short- and intermediate-term incidental oral and inhalation but not for short-, intermediate- or long-term dermal exposure assessment.  No short-, intermediate- or long-term dermal endpoints were chosen because no dermal or systemic toxicity was seen at the limit dose (1000 mg/kg/day) in a repeated-dose 21-day dermal toxicity study in rats.

	The acute dietary reference dose (RfD) is based on the results of an acute neurotoxicity study in which rats had diarrhea at the lowest-observed adverse effects level (LOAEL) of 200 mg/kg/day.  The acute RfD and the acute population-adjusted dose (aPAD) are 0.7 mg/kg/day (uncertainty factor or UF=300).  The chronic dietary RfD is based on the results of a combined chronic toxicity/carcinogenicity study in which male rats had reduced body weights, food consumption and food efficiency, and bile duct lesions at the LOAEL of 34 mg/kg/day and the LOAEL for females is 117 mg/kg/day based on reduced body weights.  The no-observed adverse effects level (NOAEL) in males is 18.2 mg/kg/day and the NOAEL for females is 22.3 mg/kg/day.  The chronic RfD and the chronic population-adjusted dose (cPAD) are 0.18 mg/kg/day (UF=100).

	The short-term incidental oral NOAEL is from a prenatal developmental oral study in rats, based on increased maternal diarrhea and other effects observed at the LOAEL of 100 mg/kg/day).  The NOAEL is 25 mg/kg/day (UF=100).  The intermediate-term incidental oral NOAEL is from a 90-day feeding study in rats, based on decreased body weight gain and clinical signs observed at the LOAEL of 211/223 mg/kg/day for males and females, respectively.  The NOAEL is 21 mg/kg/day (UF=100).  No short-, intermediate- or long-term dermal endpoints were chosen because no dermal or systemic toxicity was seen at the limit dose (1000 mg/kg/day) in a repeated-dose 21-day dermal toxicity study in rats.  The short-term inhalation NOAEL is the same as that selected for short-term incidental oral exposure.  Similarly, the intermediate-term inhalation NOAEL is the same as that selected for intermediate-term incidental oral.  A long-term inhalation endpoint was not chosen because the risk assessment is not applicable to the current use pattern for azoxystrobin.

	There is no evidence for mutagenicity or carcinogenicity.  Azoxystrobin has been classified as “not likely to be carcinogenic in humans” by Hazard Identification Assessment Review Committee (HIARC, 11/7/96); therefore, no carcinogenic risk analyses were performed.

Residue Chemistry

  SEQ CHAPTER \h \r 1 Azoxystrobin tolerances have been established in 40 CFR §180.507.  Tolerances for plant commodities are listed in 40 CFR §180.507(a)(1) and are expressed in terms of residues of the fungicide, azoxystrobin and the Z-isomer of azoxystrobin.  The established tolerances for plant commodities range from 0.01 ppm in/on pecans to 260 ppm in/on herb subgroup 10A, dried leaves.  Time-limited tolerances are also established under 40 CFR §180.507(b) for the combined residues of azoxystrobin and the Z-isomer of azoxystrobin in connection with use of the pesticide under Section 18 emergency exemptions for Brassica, head and stem subgroup 5A (30 ppm; expired 12/31/06, but a permanent tolerance has been established under 40 CFR §180.507(1)(a)), wild rice (5 ppm; expires 12/31/09), and safflower seed (1 ppm; expires 6/30/08).

Tolerances for animal commodities are listed in 40 CFR §180.507(a)(2) and are expressed in terms of residues of the azoxystrobin per se.  The established tolerances for livestock commodities range from 0.006 (milk) to 0.07 (meat byproducts) ppm; no tolerances are currently established for poultry commodities.

The nature of the residue in plants, rotational crops, and animals is adequately understood.  The residues of concern in/on plants and rotational crops, for the tolerance expression and risk assessment purposes, are azoxystrobin and its Z-isomer.  The residue of concern in livestock is parent azoxystrobin only.

Adequate cattle and poultry feeding studies are available to support the livestock dietary burdens resulting from the proposed uses.  Dietary burdens were calculated reflecting the most recent guidance concerning revisions of feedstuff percentages and reasonably balanced livestock diets were constructed.  Reassessment of tolerances indicates that no increases in the existing tolerances for milk and fat, meat and meat by products of ruminants and swine are necessary.  The proposed and amended uses of azoxystrobin on the poultry feed items are not expected to alter the Agency’s previous conclusion that there is no reasonable expectation of finite residues in poultry commodities.  No tolerances are needed for poultry and eggs.

Dietary Exposure Assessment

risk assessments were conducted using the Dietary Exposure Evaluation Model (DEEM-FCID™, Version 2.03) which uses food consumption data from the U.S. Department of Agriculture’s Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 1998.  The analyses were performed to support Section 3 requests for the use of azoxystrobin on wild rice; cotton, undelinted seed; cotton, gin byproducts and uses on aspirated grain fractions; barley, forage; non-grass animal feeds, forage, hay, crop group 18; sorghum, forage; sorghum, grain; sorghum, stover; and wheat, forage.

, and default processing factors (DEEM™ 7.81) for all existing and proposed uses.  The highest estimated drinking water concentration (EDWC) for acute exposure, 173 ppb, was used in the analysis.  The dietary exposure estimate to the U.S. population was 25% of the aPAD and the most highly exposed subgroup, children 1-2 yrs old, at 70% of the aPAD.  The results of the analysis indicate that acute risk from the dietary exposure to azoxystrobin from the existing and requested uses did not exceed HED’s level of concern for the U.S. population or any population subgroup.

, default processing factors (DEEM™ 7.81) and %CT data for some existing uses.  The EDWC for chronic exposure, 33 ppb, was used in the analysis.  The dietary exposure estimate to the U.S. population was 6% of the cPAD and the most highly exposed subgroup, children 1-2 yrs old, at 15% of the cPAD.  The results of the analysis indicate that chronic risk from the dietary exposure to azoxystrobin from the existing and requested uses did not exceed HED’s level of concern for the U.S. population or any population subgroup.

Residential Risk

	Azoxystrobin is currently registered for use on residential turfgrass and ornamentals, as well as indoor surfaces.  Short-term exposures may occur during adult residential handling activities.  HED’s Draft Standard Operating Procedures (SOPs) for Residential Exposure Assessments and Recommended Revisions (ExpoSAC Policy Number 12, revised 2/22/01), were used as the basis for all residential handler exposure calculations.  Some of the handler exposure data used in this assessment are from the Outdoor Residential Exposure Task Force (ORETF; the risk manager is encouraged to pursue data compensation in the event the registrant is not a member of the task force).  Non-occupational handler inhalation margins of exposure (MOE) were 1,700,000 for mixing, loading and applying the WDG formulation to indoor surfaces, and 2,700,000 and 230,000 for mixing, loading and applying liquid formulation to turf, for spot application with a low-pressure handwand and for broadcasting with a garden hose-end sprayer to turf, respectively.  These MOEs are well above the level of concern (LOC) for non-occupational handler scenarios.

	Short- and intermediate-term exposures may occur during postapplication activities for adults and children (however, adult postapplication is not assessed because no dermal hazard was identified).  Toddlers may experience short- and intermediate-term exposure to azoxystrobin via incidental (non-dietary) ingestion during postapplication activities on treated turf (i.e., hand-to-mouth, object-to-mouth [turfgrass], and soil ingestion) and during postapplication activities on treated indoor surfaces (i.e., hand-to-mouth).  The postapplication risk assessment is based on generic assumptions as specified by the Recommended Revisions to the Residential SOPs and recommended approaches by HED’s ExpoSAC.  Postapplication non-dietary ingestion MOEs ranged from 280 to 530,000 for short-term exposure from hand-to-mouth activities on treated indoor surfaces and soil ingestion on treated turf, respectively.  All calculated non-occupational postapplication MOEs are greater than 100 on the day of application, and do not exceed HED's level of concern.

Aggregate Risk

	Acute, short-term, intermediate-term, and chronic aggregate risk estimates resulting from aggregate exposure to azoxystrobin from food, drinking water, and residential uses are below HED’s level of concern.

	For the acute aggregate risk scenario, food and drinking water exposures were taken into account in the dietary exposure assessment.  The estimated dietary exposures (food and water) for the U.S. population at 25% of the aPAD and the most highly exposed subgroup, children 1-2 yrs old, at 70% of the aPAD and does not exceed HED’s level of concern.

	For the short-term aggregate risk scenario, food, drinking water and residential exposures are taken into account.  No endpoint has been selected for short-term dermal exposure to azoxystrobin; therefore, this assessment will combine dietary/incidental oral exposure with inhalation exposure.  The chronic dietary exposure estimate to the U.S. population was 6% of the cPAD and the most highly exposed subgroup, children 1-2 yrs old, was 15% of the cPAD.  The aggregate short-term MOEs, combining food, drinking water and residential exposures ranged from 216 for children 1-2 yrs old to 3052 for females 13-49 yrs old.  Risk estimates for all population subgroups are below HED’s level of concern.

	For the intermediate-term aggregate risk scenario, food, drinking water and residential exposures are taken into account.  No endpoint has been selected for intermediate-term dermal exposure to azoxystrobin; therefore, this assessment will combine dietary/incidental oral exposure with inhalation exposure.  An intermediate-term risk assessment was conductd for adults because intermediate-term residential handler scenarios are not expected to occur.  However, an intermediate-term risk assessment was conducted for infants and children because there is a residential post-application oral exposure scenario.  The chronic dietary exposure estimate to the most highly exposed subgroup, children 1-2 yrs old, at 15% of the cPAD.  The aggregate intermediate-term MOE, combining food, drinking water and residential exposures for the most highly exposed subgroup was 291 for children 1-2 yrs old.  Risk estimates for all population subgroups are below HED’s level of concern.

	For the chronic aggregate risk scenario, food, drinking water, and residential exposures were taken into account.  In this case, chronic exposure in residential settings is not expected and the aggregate chronic assessment included food and drinking water only.  Since the dietary exposure assessment already includes the highest chronic exposure from the drinking water modeling data, no further calculations are necessary.  The dietary exposure estimate to the U.S. population was 8% of the cPAD and the most highly exposed subgroup, children 1-2 yrs old, was 19% of the cPAD.  Risk estimates for all population subgroups are below HED’s level of concern (100% of the cPAD).  Therefore, chronic aggregate risk is below HED’s level of concern.

Occupational Risk

Occupational handlers may be exposed to azoxystrobin during mixing/loading using open-pour loading of liquids; aerial applications; applications using open-cab ground-boom sprayers and handlers preparing irrigation systems to apply by “chemigation.”  Handlers are assumed to have potential short-term (1-30 days) and intermediate-term (31-180 consecutive days) dermal and inhalation exposure to azoxystrobin.  Long-term handler exposure is not expected.  Because no dermal toxicity endpoint was identified for azoxystrobin, only inhalation exposures and risks were assessed.

No chemical specific data were available with which to assess potential exposure to pesticide handlers.  The estimates of exposure to pesticide handlers are based upon surrogate study data available in the PHED (v. 1.1, 1998).   For pesticide handlers, it is HED standard practice to present estimates of dermal exposure for “baseline” that is, for workers wearing a single layer of work clothing consisting of a long sleeved shirt, long pants, shoes plus socks and no protective gloves as well as for “baseline” and the use of protective gloves or other PPE as might be necessary.   The proposed label directs applicators and other handlers to wear long-sleeved shirt, long pants, chemical resistant gloves made of any waterproof material such as polyvinyl chloride, nitrile rubber or butyl rubber and shoes plus socks.

	Occupational handlers’ inhalation MOEs range from 3,900 for intermediate-term exposure from mixing and loading liquid formulations for aerial application and chemigation to 86,000 for short-term mixing and loading liquids for aerial application.  These MOEs are well above the LOC for occupational scenarios, which is an MOE of 100 or below.

	Although occupational postapplication dermal exposure is possible following treatment of use sites with azoxystrobin, because no dermal endpoints were identified for this exposure potential (and inhalation exposure is expected to be negligible for reentry activities) a postapplication risk assessment was not conducted.  Nevertheless, per the Worker Protection Standard (WPS), a 12-hour restricted entry interval (REI) is required for chemicals classified under Toxicity Category III or IV, which are the Toxicity Categories azoxystrobin is classified under (Toxicity Category III for acute dermal and primary eye irritation, and Toxicity Category IV for primary skin irritation).  As noted earlier, the label lists a REI of 4 hours.  The ARIA team suggests that the product management team confirm or correct the REI listed on the label as per the guidance provided in PR Notice 95-03 and Chapter 40 Code of Federal Regulations § 156.208 (2) (iii).

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,”   HYPERLINK "http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf"  http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf .

The Office of Pesticide Programs (OPP) typically considers the highest potential exposures from the legal use of a pesticide when conducting human health risk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability of diets within the U.S. (including different ages, regions, and ethnicities), and people who may be exposed when harvesting crops.  Should these highest exposures indicate potential risks of concern, OPP further refines the risk assessments to ensure that the risk estimates are based on the best available information.

Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These studies, which comprise the Pesticide Handlers Exposure Database (PHED) and the Outdoor Residential Exposure Task Force (ORETF), have been determined to require a review of their ethnical conduct, and have received that review.  The studies in PHED were considered appropriate (or ethnically conducted) for use in risk assessments.

Recommendations for Tolerances

Provided revised Section F’s are submitted, there are no residue chemistry issues that would preclude granting a conditional registration for the crops requested in PP#6F7106 and PP#7F7198.  The proposed uses and the submitted and/or translated data support the following tolerances for residues of azoxystrobin and the Z-isomer of azoxystrobin in/on the following raw agricultural commodities:

Grain, aspirated fractions	420 ppm

Barley, forage	25 ppm

Animal feed, nongrass, forage, group 18	45 ppm

Animal feed, nongrass, hay, group 18	120 ppm

Sorghum, forage	25 ppm

Sorghum, grain	11 ppm

Sorghum, stover	40 ppm

Wheat, forage	25 ppm

Cotton, undelinted seed	0.6 ppm

Cotton, gin byproducts	45 ppm

Rice, wild, grain	5.0 ppm

The required revisions to Section F’s are summarized below and listed in Section 9.0 (Data Needs/Requirements) of this memorandum.

A revised Section F is required removing the requested tolerance increases in milk and the fat, meat, and meat byproducts of cattle, goat, horse, sheep, and swine.

A revised Section F is required removing the requested tolerance increases in eggs and the fat, meat, and meat byproducts of poultry.

A revised Section F to specify a tolerance level of 25 ppm for barley forage is required.

A revised Section F is required at 45 ppm for forage and 120 ppm for hay of the nongrass animal feeds crop group 18.

An amended Section F is required to revise the proposed tolerance for sorghum grain from 9 ppm to 11 ppm.  A revised Section F is required at 420 ppm for aspirated grain fractions.

An amended Section F is required to revise the proposed tolerance for wheat forage to 25 ppm.

An amended Section F is required to revise the proposed tolerances for undelinted cottonseed at 0.6 ppm and for cotton gin byproducts at 45 ppm.

2.0 	Ingredient Profile

Azoxystrobin is a broad spectrum fungicide for control of many plant diseases.  It has the same biochemical mode of action as the naturally occurring strobilurins and is structurally related to them.  Azoxystrobin is a (-methoxyacrylate.  It is in the same chemical class as trifloxystrobin.  Azoxystrobin acts by inhibiting electron transport.

2.1 	Summary of Registered/Proposed Uses

The label directions are adequate to allow evaluation of the residue data relative to the proposed uses. A summary of the azoxystrobin end-use products proposed for use on the crops discussed in this document is listed in Table 2.1a.  Table 2.1b presents the summary of proposed crop use patterns.

Table 2.1a.   Summary of Proposed Azoxystrobin End-Use Products.

Trade Name	Reg. No.	% ai of formulation	Formulation

Type	Target Crops	Label Date

Abound® Flowable Fungicide 1	100-1098	22.9% ai

(2.08 lb/gal) 	Flowable

Concentrate	Barley;  nongrass animal feeds forage, fodder, straw, and hay group;  clover (and stands containing clover);  rice and wild rice; sorghum; wheat and triticale	Undated supplemental label included in Section B

Heritage® Fungicide 2	100-1093	50% ai

(0.5 lb/gal)	Water dispersible

Granular	Cotton and wild rice	Undated supplemental label included in Section B

1   The label in Section B of PP#7F7198 was for Quadris® Flowable Fungicide, which has the same EPA Reg. No. as the Abound® Flowable Fungicide.

2   The petition transmittal letters stated that the Heritage® Fungicide will be amended to include new or amended uses on barley, clover, cotton, nongrass animal feeds, sorghum, wheat, and wild rice.  The petitioner stated that they will submit an amended label for Heritage® (EPA Reg. No. 100-1093) in the future as a ‘me-too use’.

Table 2.1b.   Summary of Directions for Use of Azoxystrobin.

Applic. Timing, Type, and Equip. 	Formulation

[EPA Reg. No.]	Applic. Rate

(lb ai/A)	Max. No. Applic. per Season	Max. Seasonal Applic. Rate

(lb ai/A)	PHI

(days)	Use Directions and Limitations

Barley

Foliar

Ground, aerial or chemigation	2.08 lb/gal FlC

[100-1098]	0.10-0.20	2	0.40	14 (forage & hay)

45 (grain & straw)	Begin applications prior to disease development and up to when barley is at the late head emergence (Feekes 10.5 or Zadok’s 59) stage.  A crop oil concentrate adjuvant may be added at 1.0% v/v.

Clover (and stands containing Clover)

Foliar

Ground, aerial or chemigation	2.08 lb/gal FlC

[100-1098]	0.10-0.25	Not specified	0.75 for pure stands of clover or mixed with grasses	14 (forage & hay)	Begin applications prior to disease development and throughout the season with 7-14 day retreatment intervals.  Use of an adjuvant such as crop oil concentrate or non-ionic surfactant is recommended.

Cotton

Foliar

Ground, aerial	2.08 lb/gal FlC

[100-1098]	0.1-0.15	3	0.45	45	Begin applications prior to or in the early stages of disease development and when cotton is at the pinhead to first bloom stage; subsequent applications are to be made on a 14-21 day schedule.  Minimum volumes for air and ground applications are 5 and 10 gal/A, respectively.  An adjuvant may be added at recommended rates.

In-furrow at planting	2.08 lb/gal FlC

[100-1098]	0.10-0.20 oz ai/1,000 row ft 1 	NA	0.20 oz ai/

1000 row ft	NA	Apply in 3-7 gallons of water at planting, directed into the furrow just before seed is covered.

Nongrass Animal Feeds Forage, Fodder, Straw and Hay

[Stands including:  Alfalfa, Bean, Velvet, Kudzu, Lespedeza, Lupin, Sainfoin, Trefoil, Vetch, Vetch crown, Vetch milk, and Clover (see clover specific instructions)]

Foliar

Ground, aerial or chemigation	2.08 lb/gal FlC

[100-1098]	0.10-0.25	Not specified	0.75	14 (forage & hay)	Not for use on rangeland; for pure stands of grasses see uses established for grasses (grown for seed).  Begin applications prior to disease development.  Use of an adjuvant such as crop oil concentrate or non-ionic surfactant is recommended.

Rice and Wild Rice

Foliar

Ground, aerial or chemigation	2.08 lb/gal FlC

[100-1098]	0.10-0.30	2	0.70	28	Do not treat rice fields used for aquaculture of fish or crustaceans; and do not release irrigation or flood water for at least 14 days after last application.  For foliar and panicle diseases, apply prior to disease development and for panicle blast, when rice is at the mid-boot to boot-split stage but prior to full head emergence; a second application may be made when panicles are ~60-90% emerged from the boot (7-14 days later).  For other stem/sheath diseases apply when disease is <4 inches above water line usually between panicle differentiation (PD) 6 days PD +10 days PD (wild rice: apply during tillering, boot, early heading or at initial sign of disease).  Minimum volume for air applications is 5 gal/A.  An adjuvant may be added at recommended rates.

Sorghum

Foliar

Ground, aerial or chemigation	2.08 lb/gal FlC

[100-1098]	0.10-0.25	Not specified	0.5 (forage)

0.75 (grain & stover)	14	Begin applications prior to disease development.  An adjuvant may be added at recommended rates.

In-furrow

0.1-0.2  oz ai/1,000 row ft	NA	Not specified	NA	For soilborne/seedling disease control; apply in 3-15 gal/A water directed into the furrow before seed is covered (master label).

Wheat and Triticale

Foliar

Ground, aerial or chemigation	2.08 lb/gal FlC

[100-1098]	0.07-0.20	Not specified	0.40	14 (forage & hay)

45 (grain & straw)	Begin applications prior to disease development and up to when wheat is at the late head emergence (Feekes 10.5 or Zadok’s 59) stage.  A crop oil concentrate adjuvant may be added at 1.0% v/v.

1  According to the most recent label for Abound® Flowable Fungicide approved 6/30/06, the in-furrow rate of 0.10-0.20 oz ai/1,000 row ft is equivalent to 0.08-0.30 lb ai/A based on 22-40 inch row spacing.

For all crops listed in Table 2.2, the use directions for Abound® Flowable Fungicide specify that it should be integrated into an overall disease and pest management strategy and that for resistance management, no more than two foliar applications of Abound® Flowable Fungicide or other Group 11 fungicides should be made before alternating with a fungicide having a different mode of action (not in Group 11).  For rice, resistance management further specifies that when Abound® Flowable Fungicide is applied for panicle blast on continuous rice acreage (no rotation to other crops), no more than 2 sequential foliar applications of Abound® Flowable Fungicide or other Group 11 fungicides be made over multiple years before alternating with a different acting fungicide.

The label for the Abound® Flowable Fungicide specifies the following rotational crop restrictions: “Do not plant the following crops for a period of 12 months (unless an azoxystrobin product is registered for use on that crop): buckwheat, millet, oats and rye.  A plantback interval of 36 days is required for leafy vegetables (except Brassica) group; Brassica, leafy greens subgroup; vegetables, root subgroup; vegetable (tuberous and corm subgroup; and vegetables, leaves of root and tuber group.  Crops with registered azoxystrobin may be planted immediately after the last treatment.”  It is noted that the above rotational crop restrictions is a revision of the rotational crop restrictions on the currently registered label dated 2/23/2007, to remove the 12-month plantback interval restriction for barley, nongrass animal feeds (alfalfa and clover), sorghum, triticale, wheat, and wild rice.

Conclusions:  The label directions are adequate to allow evaluation of the residue data relative to the proposed use.

2.2	Structure and Nomenclature

The chemical structure and nomenclature of azoxystrobin and its Z-isomer are listed below in Table 2.2.  The physicochemical properties of azoxystrobin are listed in Table 2.4.

Common name	Azoxystrobin

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

IUPAC name	methyl (E)-2-{2-[6-(2-cyanophenoxy)pyramidin-4-yloxy]phenyl}-3-methoxyacrylate

CAS name methyl-(E)-2-[[6-(2-cyanophenoxy)-4-pyrimidinyl]oxy]-(methoxymethylene)- benzeneacetate

CAS registry number	131860-33-8

End-use products (EP)	Abound® Flowable Fungicide (EPA Reg. No. 100-1098)

Common name	Azoxystrobin, Z-isomer

Chemical name	methyl (Z)-2-{2-[6-(2-cyanophenoxy)pyramidin-4-yloxy]phenyl}-3-methoxyacrylate

2.3	Physical and Chemical Properties

Table 2.4.   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/cm3

	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	(mg/mL at 20°C)

Hexane		0.057

Octanol		1.4

Methanol		20

Toluene		55

Acetone		86

Ethyl Acetate	130

Acetonitrile	340

Dichloromethane 400

	Vapor pressure	(20°C) 1.1x10-13 kPa (8.2x10-13 mmHg)

	Dissociation constant, pKa	Not dissociable

	Octanol/water partition coefficient, Log(KOW)	log POW = 2.5

	UV/visible absorption spectrum	Not available

Hazard Characterization/Assessment

Hazard and Dose-Response Characterization

3.1.1	 Database Summary tc "3.0  HAZARD CHARACTERIZATION"

	All toxicological data requirements for azoxystrobin technical have been satisfied.  HED has a high degree of confidence in the toxicology database. The toxicity database for azoxystrobin has been reviewed by the Cancer Peer Review Committee (TXR#0012133), the Toxicology Endpoint Selection Committee (TXR#0013102), the HIARC (TXR#0014329) and the FQPA Safety Factor Committee (TXR#0012844).  These studies were reviewed and considered for the overall hazard profile, endpoint selection, and susceptibility of infants and children as required by FQPA.  The toxicity profiles for azoxystrobin are summarized in Table A1 in the appendix.

<IP_ADDRESS>	  Studies Available and Considered  TC \l4 "<IP_ADDRESS>	Studies available and considered

Data from the following studies were used to evaluate the hazard potential of azoxystrobin:

Acute studies:  acute oral rat, acute dermal rat, acute inhalation rat, acute eye irritation rabbit, acute dermal irritation rabbit, skin sensitization guinea pig, and an oral, acute neurotoxicity study

Subchronic:  90-day oral rat, mouse, dog studies; 21-day dermal rat study;

Chronic:  52-week oral rat and dog studies, 18-month mouse carcinogenicity study and a 24-month rat carcinogenicity study.

Reproduction/developmental:  Developmental toxicity studies in rat and rabbit and a two-generation reproduction study in the rat.

Other: mouse cancer study, mutagenicity screens, metabolism studies, subchronic neurotoxicity study, and dermal penetration studies in rat, rabbit and guinea pig.

<IP_ADDRESS>	  Sufficiency of Studies/Data  TC \l4 "<IP_ADDRESS>	Sufficiency of studies/data

The toxicity database for azoxystrobin is complete and adequate for required endpoint selection for exposure risk assessment scenarios and for FQPA evaluation.

<IP_ADDRESS>	 Toxicological Effects  TC \l3 "<IP_ADDRESS>	Toxicological Effects

Azoxystrobin has a low acute toxicity via the oral, dermal and inhalation routes of exposure (Toxicity Categories III and IV).  Azoxystrobin is not an eye or skin irritant and is not a skin sensitizer.  The most common toxicity findings from administration of azoxystrobin to rats, via the oral route, were decreased body weight, decreased food intake/utilization, increased diarrhea, and other clinical toxicity observations such as, increased urinary incontinence, hunched postures and distended abdomens.  The pre- and post-natal toxicology data base for azoxystrobin is adequate and includes the rat and rabbit developmental toxicity studies and the 2-generation reproduction toxicity study in rats. There were no developmental effects in the rat and rabbit developmental studies.  In the reproduction study, decreased body weights and increased adjusted liver weights were observed at the same dose in both offspring and parental animals.  In both the acute and subchronic neurotoxicity studies, there were no consistent indications of treatment-related neurotoxicity.  There was no evidence of carcinogenicity in rats and mice at acceptable dose levels.  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.

3.2 Absorption, Distribution, Metabolism, and Excretion (ADME)  TC \l2 "3.2	Absorption, Distribution, Metabolism, Excretion (ADME)

Based on pharmacokinetics and metabolism studies in rats, azoxystrobin was widely distributed following oral administration as single gavage doses of 1 or 100 mg/kg or 14-day repeated doses of 1 mg/kg.  The greatest amounts of absorbed azoxystrobin were detected in organs associated with excretory function, especially the liver and kidneys.  However, less than 0.5% of the administered dose was detected in the tissues at seven days postdosing and there was no apparent sex-related differences in distribution and no evidence of potential for bioaccumulation.  Excretion via expired air was minimal.  The primary route of excretion was via the feces ((73-89%), although (9-18% was detected in the urine of the various dose groups.  The fecal vs. urinary route of excretion did not vary considerably with dose or sex.  However, a definitive quantitative assessment of absorption was difficult because of fecal sample extraction difficulties.  Biliary metabolites were assessed using rats with cannulated bile ducts given a single 100 mg/kg gavage dose of azoxystrobin.  For the single high-dose group, assessment of biliary excretion suggested approximately 70% absorption with approximately 32% of administered radioactivity remaining as parent compound in the gastrointestinal tract.  Absorbed azoxystrobin appeared to be extensively metabolized with minor sex-related qualitative and quantitative differences in biliary metabolites.  With the exception of metabolite V (a glucuronide conjugate) which represented 29.3% (males) and 27.4% (females) of the administered dose, individual biliary metabolites represented less than 10% of the administered dose.  A metabolic pathway was proposed showing hydrolysis and subsequent glucuronide conjugation as the major biotransformation process.

3.3	  FQPA Considerations  TC \l2 "3.3	FQPA Considerations

3.3.1	  Adequacy of the Toxicity Database  TC \l3 "3.3.1	Adequacy of the Toxicity Database

The database for azoxystrobin is adequate for FQPA consideration.

3.3.2	 Evidence of Neurotoxicity  TC \l3 "3.3.2	Evidence of Neurotoxicity

No evidence of neurotoxicity was observed in studies conducted with azoxystrobin in rats.  In an acute neurotoxicity study in the rat, there was no indication of neurotoxicity from single gavage doses up to 2000 mg/kg.  Based on the toxicity profile, a developmental neurotoxicity study in rats is not required.”  (FQPA Report dated 9/3/98, HED Doc. No. 012844)

3.3.3 	Developmental Toxicity Studies  TC \l3 "3.3.3	Developmental Toxicity Studies

In a rat developmental toxicity study, diarrhea, urinary incontinence and salivation were observed in maternal animals; in the rabbit developmental toxicity study, decreased body weight gain was observed in maternal animals.  No adverse treatment related developmental effects in were seen in either study.

3.3.4 Reproductive Toxicity Study  TC \l3 "3.3.4	Reproductive Toxicity Study

In the two-generation reproduction study in rats, NOAELs/LOAELs were the same for offspring and parental system toxicity. There was no evidence of reproductive toxicity.

3.3.5	   Additional Information from Literature Sources  TC \l3 "3.3.5 Additional Information from Literature Sources

No additional information relevant to the protection of infants and children were identified.

3.3.6	 Pre-and/or Postnatal Toxicity  TC \l3 "3.3.6	Pre-and/or Postnatal Toxicity

<IP_ADDRESS>	 Determination of Susceptibility  TC \l4 "<IP_ADDRESS>	Determination of Susceptibility

The available studies indicate no evidence of increased susceptibility and there are no residual uncertainties with regard to prenatal toxicity in rats or rabbits following in utero and/or postnatal exposure to azoxystrobin.  In the prenatal developmental toxicity studies in rats and rabbits and the two-generation reproduction study in rats, any observed toxicity to the offspring occurred at equivalent or higher doses than did toxicity to parental animals.

3.4	FQPA Safety Factor for Infants and Children tc "3.4  FQPA Safety Factor for Infants and Children" \l 2

The azoxystrobin risk assessment team has reconsidered the HIARC/FQPA Safety Factor Committee’s conclusions and the quality of the exposure data in light of HED’s recent policy supplement to the 2002 FQPA 10X Guidance.  The team reaffirms that the available studies indicated no increased susceptibility of rats or rabbits to in utero and/or postnatal exposure to azoxystrobin and that there are no data deficiencies or other uncertainties that are unique to the FQPA.  However, the team recommends that FQPA SF be retained at 3X to account for uncertainties related to the LOAEL to NOAEL extrapolation for setting the aRfD/aPAD.  The recommendation is based upon the following:

The toxicology data base is complete:

The developmental and reproductive toxicity data did not indicate increased susceptibility of rats or rabbits to in utero and/or postnatal exposure;

A 3X (as opposed to a 10X) is adequate to extrapolate a NOAEL due to the low concern for the effect seen taking into account the nature of the effect seen and the overall toxicity of this chemical;

The acute dietary food exposure assessment utilizes existing and proposed tolerance level residues and 100% crop treated information for all commodities;

The chronic dietary exposure analysis for azoxystrobin is a somewhat refined assessment using %CT information for selected crops;

The exposure assessments will not underestimate the potential dietary (food and drinking water) or non-dietary exposures for infants and children from the use of azoxystrobin;

The dietary drinking water assessment utilizes water concentration values generated by model and associated modeling parameters which are designed to provide conservative, health protective, high-end estimates of water concentrations which are not likely to be exceeded; and

The residential postapplication assessment is based upon the residential SOPs.  The assessment is based upon surrogate study data.  These data are reliable and are not expected to underestimate risk to adults or children. The residential SOPs are based upon reasonable “worst-case” assumptions and are not expected to underestimate risk.

3.5 	Hazard Identification and Toxicity Endpoint Selection

With the exception of a change in terminology regarding the FQPA SF (the FQPA SF has been retained at 3x for a LOAEL to NOAEL extrapolation), the hazard characterization/endpoint selection have not changed since the previous risk assessments on azoxystrobin and can be applied directly to this action.

3.5.1 Comments about Study/Endpoint/Uncertainty Factor: Acute RfD/PAD

The aRfD/aPAD applicable to all populations including infants and children was derived from an acute neurotoxicity study in rats.  The study is appropriate for the acute exposure via the oral route as effects in the study were seen after a single oral dose. The occurrence of diarrhea at the lowest tested dose of 200 mg/kg is supported by the similar findings at 100 mg/kg/day in the rat prenatal developmental toxicity study.  An uncertainty factor of 3X (as opposed to a 10X) is adequate to extrapolate a NOAEL due to the low concern for the effect seen taking into account the nature of the effect seen and the overall toxicity of this chemical.

The weight of evidence in this case includes the following: 1) the observed diarrhea is transient, i.e., it was seen only at the 2-hour observations and not seen at the later observation periods; 2) diarrhea appears to be species specific as it was observed only in the rat by gavage administration (acute neurotoxicity and developmental rat studies); 3) it is possible that corn oil vehicle used may have contributed to this effect since in both studies corn oil was the vehicle; 4) diarrhea was not seen after repeated dosing either in rabbits after gavage dosing or in mice, rats and dogs after dietary administration; and 5) the acute LD50 was >5000 mg/kg. Based on these considerations, HED is confidant that a 3X safety factor is sufficient to account for the uncertainty for the lack of a NOAEL and that risks from acute dietary exposure to azoxystrobin will not be underestimated.

Level of Concern for Margin of Exposure

Table 3.5.2   Summary of Levels of Concern for Risk Assessment.

Route	Short-Term

(1 - 30 Days)	Intermediate-Term

(1 - 6 Months)	Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	NA	NA	NA

Inhalation	MOE < 100	MOE < 100	NA

Residential Exposure

Dermal	NA	NA	NA

Inhalation	MOE < 100	MOE < 100	NA

Incidental Oral	MOE < 100	MOE < 100	NA

Dietary (Food and Water)	Exposure > 100% aPAD

(acute, 1-day exposure)	NA	exposure > 100% cPAD

(chronic exposure)

The levels of concern (LOCs) for the inhalation and incidental oral routes (MOEs) are based on the conventional interspecies extrapolation (10x) and intraspecies variation (10x) uncertainty factors

3.5.3	 Recommendation for Aggregate Exposure Risk Assessments   TC \l3 "3.5.8	Recommendation for Aggregate Exposure Risk Assessments

As per FQPA, when there are potential residential exposures to a pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal, and inhalation routes.  The toxicity endpoints selected for short-, intermediate- and long-term aggregate risk assessments, the oral, dermal, and inhalation exposures can be combined due to the presence of a common toxicity endpoint.

3.5.4 Classification of Carcinogenic Potential

	The HED RfD/Peer Review Committee, in its meeting of November 7, 1996, determined that azoxystrobin should be classified as "not likely to be a human carcinogen” according to the revised Cancer Guidelines, based on lack of evidence of carcinogenicity in the long-term rat and mouse feeding studies (HED Document No. 012133, 1/14/97).  Therefore, cancer risk assessments were not performed.

 Summary of Toxicological Doses and Endpoints

On August 15, 2000, the HIARC evaluated the toxicology database for azoxystrobin with regard to the acute and chronic reference doses (RfDs) and the toxicological endpoint selection for use as appropriate in occupational exposure/risk assessments.  The doses and toxicological endpoints selected for various exposure scenarios are summarized in Table 3.5.5.

Table 3.5.5  Summary of Toxicological Doses and Endpoints for Azoxystrobin for Use in Human Risk Assessment

Exposure/

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

Acute Dietary

(General population, including Infants and Children)	LOAEL

200

 mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 3x

	Acute RfD = 0.67

mg/kg/day

aPAD = 0.67 mg/kg/day	Acute Neurotoxicity - Rat LOAEL = 200 mg/kg based on diarrhea at two-hours post dose at all dose levels up to and including the LOAEL.

Chronic Dietary

(All Populations)	NOAEL =18

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

	Chronic RfD =  0.18 mg/kg/day

cPAD =  0.18 mg/kg/day	Combined Chronic Toxicity/Carcinogenicity Feeding study - Rat LOAEL in males/females = 34/117 mg/kg/day 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

UFA= 10x

UFH=10x

FQPA SF= 1x

	Residential

LOC for MOE =100	Prenatal Developmental Oral Toxicity - Rat LOAEL = 100 mg/kg/day based on increased maternal diarrhea, urinary incontinence, and salivation.

Incidental Oral Intermediate-Term (1 week to 6months)

	NOAEL= 20

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

	Residential

LOC for MOE =100	90-Day Feeding - Rat LOAEL = 211/223 mg/kg/day in males/females based on decreased body weight gain in both sexes and clinical signs indicative of reduced nutrition.

Dermal Short- Intermediate- and Long-Term 	none

	21-Day Repeated Dose Dermal – Rat

[No dermal or systemic toxicity was seen at the limit dose (1000 mg/kg/day)]

Inhalation

Short-Term (1-30 days)

	Oral NOAEL= 25 mg/kg/day

UFA= 10x

UFH=10x

FQPA SF=1X

	Occupational/

Residential

LOC for MOE =100	Prenatal Developmental Oral Toxicity - Rat LOAEL = 100 mg/kg/day based on increased maternal diarrhea, urinary incontinence, and salivation.

Inhalation

Intermediate-Term (1 week to 6months)

	Oral NOAEL= 20 mg/kg/day

UFA= 10x

UFH=10x

FQPA SF=1X	Occupational/

Residential

LOC for MOE =100	90-Day Feeding - Rat LOAEL = 211/223 mg/kg/day in males/females based on decreased body weight gain in both sexes and clinical signs indicative of reduced nutrition.

Long-Term (> 180 days) Inhalation	NOAEL = N/A

	This risk assessment is not applicable to the use scenario of azoxystrobin.

Cancer	Classification: "Not Likely to be Carcinogenic to Humans" based on the revised Cancer Guidelines (TES Document, 12/10/1996)

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.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  FQPA SF = FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c = chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level of concern.  N/A = not applicable.

3.6 	Endocrine Disruption  tc "3.4  Endocrine Disruption " \l 2

	EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances (including all pesticide active and other ingredients) "may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate."  Following the recommendations of its Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC), EPA determined that there was scientific basis for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system.  EPA also adopted EDSTAC’s recommendation that the Program include evaluations of potential effects in wildlife.  For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations.  As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program (EDSP).

	When the appropriate screening and/or testing protocols being considered under the Agency’s EDSP have been developed, azoxystrobin may be subjected to additional screening and/or testing to better characterize effects related to endocrine disruption.

4.0 	Dietary Exposure/Risk Characterization

4.1	Pesticide Metabolism and Environmental Degradation

4.1.1			Metabolism in Primary Crops

Adequate metabolism studies on grapes, peanuts, and wheat were submitted in conjunction with earlier azoxystrobin petitions, PP#s 5F4541 and 6F4762.  Azoxystrobin undergoes photochemical isomerization to produce the Z-isomer and is extensively metabolized in plants.  The parent compound undergoes cleavage of the ether linkages between the phenylacrylate and pyrimidinyl rings and the cyanophenyl and pyrimidinyl rings, with subsequent oxidation, hydrolysis, and/or reduction of the primary metabolites to form numerous secondary metabolites.  Azoxystrobin is systemic.  HED has determined that the residues of concern in/on plants for the tolerance expression and risk assessment purposes are azoxystrobin and its Z-isomer.

4.1.2	Metabolism in Rotational Crops

  SEQ CHAPTER \h \r 1 Adequate confined studies have previously been presented in PP#6F4762 and re-evaluated in PP#9F6058.  Total radioactive residues (TRR), expressed as [14C]azoxystrobin equivalents, accumulated at >0.01 ppm in the RACs of lettuce, radishes, and wheat planted in sandy loam soil 30, 200, and 365 DAT of the soil with [14C]azoxystrobin at 1.8 lb ai/A.  Residues were highest in RACs from the 30-DAT interval and declined in subsequent plantback intervals.

Azoxystrobin was identified in all raw agricultural commodities (RACs) at the 30-days after treatement (DAT) interval.  In 30-DAT samples, the Z-isomer was only identified in wheat forage and straw.  Compound 42 was the major metabolite identified in 30-DAT lettuce and wheat forage and straw.  In 30-DAT radish roots, azoxystrobin was the major metabolite and in 30-DAT radish tops, metabolites G2, N1, and N2 were the major metabolites.  In 30-DAT wheat grain, 14C-starch was found to account for the largest portion of radioactivity.  Several conjugated metabolites (compound 42 and the M, N, and O metabolites) of primary crop metabolites were identified, indicating that azoxystrobin is more extensively metabolized in rotational crops than in primary crops.  The residues of concern in rotational crops are parent and the Z-isomer.

No tolerances are required for inadvertent of azoxystrobin residues of concern in/on rotational crops.  There are adequate rotational crop restrictions on registered and proposed product labels which preclude the need for tolerances.

Metabolism in Livestock

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

4.1.4	Analytical Methodology

There are adequate residue analytical methods for tolerance enforcement.  For analysis of plant commodities for residues of azoxystrobin and its Z-isomer, a GC/NPD method (RAM 243/04) has undergone method validation by Analytical Chemistry Branch (ACB/BEAD).  BEAD comments have been incorporated, and the revised method (designated RAM 243, dated 5/15/98) has been submitted to FDA for inclusion in PAM, Volume II.  The method limit of quantitation (LOQ) is 0.01 ppm for each analyte in various crop matrices.

For analysis of animal commodities for residues of azoxystrobin per se, a GC/NPD method (RAM 255/01) has been validated by an independent laboratory for the analysis of milk, liver and eggs, and by the EPA analytical laboratory for the analysis of milk and liver.  The EPA laboratory written report (with an EPA addendum to accompany the method) and the method were submitted to FDA for inclusion in PAM, Volume II. In the interim, copies are available from PIRIB/IRSD (7502P) and ACB/BEAD (7503P).  The method LOQ is 0.0025 ppm and 0.01 ppm for each analyte, azoxystrobin and its Z-isomer in milk and tissues, respectively.

necessary for LC/MS/MS analysis.  The LC/MS/MS method uses a single ion transition, m/z 404.2→372.4, to quantitate azoxystrobin and R230310 residues in/on plant commodities.  For confirmation, the LC/MS/MS method may be used to monitor an additional ion transition, m/z 404.2→343.8.  The validated LOQ was 0.01 ppm and the limit of detection (LOD) was estimated at 0.005 ppm for each analyte in each matrix.

Concurrent method recovery data were included with the crop field trial studies and the processing study; however, the fortification levels and samples used in method validation are not adequate to bracket expected residue levels.  Adequate concurrent recovery data were submitted for alfalfa and clover forage (0.01-2 ppm); alfalfa and clover hay (0.01-20 ppm); cottonseed (0.01-2 ppm) and gin byproducts (0.01-15 ppm); sorghum forage (0.01-10 ppm), stover (0.01-10 ppm), grain (0.01-20 ppm), and aspirated grain fractions (0.01-2 ppm); and wheat forage (0.01-20 ppm).  Fortification levels in the concurrent recovery studies were not adequate to bracket expected residue levels for azoxystrobin in aspirated grain fractions (106 ppm), cotton gin byproducts (31 ppm), nongrass animal feeds, hay (52 ppm), or sorghum stover (15 ppm); however, wheat forage validation data will support the expected levels of residues in nongrass animal feeds, forage.

4.1.5	Multiresidue Methods

The requirments for multiresidue methods testing data for azoxystrobin are fulfilled.  Data have previously been submitted pertaining to the multiresidue methods testing of azoxystrobin in conjunction with the grape petition (PP#5F4541).  The data indicate that azoxystrobin could not be recovered through application of the multiresidue protocols.  These data have been forwarded to FDA for inclusion in PAM I.

4.1.6 	Storage Stability

There are adequate storage stability data from previous submissions to validate sample storage conditions and durations.  Residues of azoxystrobin and its Z-isomer were found to be relatively stable over a wide range of commodities under frozen storage conditions for 1-2 yrs.

Table 4.1.6   Summary of Storage Conditions and Durations of Samples from Crop Field Trials

Matrix 	MRID	Storage

Temperature (°C)	Actual Storage

Duration (Months)	Interval of Demonstrated Storage Stability

Alfalfa, forage	46924301	~-20	9.3-17.0	2 years in/on diverse crops including wheat forage and straw

Alfalfa, hay

	9.3-17.2

	Clover, forage

	6.3-17.3

	Clover, hay

	9.3-17.3

	Cotton, undelinted seed	47096402	~-20	6.3-10.0	2 years in/on diverse crops including oil seed rape and wheat matrices (20% decline in grain)

Cotton, gin byproducts

	6.3-11.1

	Cotton, undelinted seed

(for processing)	47096402	~-20	8.6-9.7	2 years in/on diverse crops including oil seed rape

Cotton processed hulls,

meal and refined oil

<-10	2.3-4.4	1 year in/on diverse processed commodities including peanut and soybean meal, and peanut and orange oil

Sorghum, forage	46924302	~-20	3.2-17.7	2 years in/on diverse crops including wheat forage and straw

Sorghum, stover

	12.5-16.7

	Sorghum, grain

	3.5-16.7	2 years in/on diverse crops including wheat grain (20% decline)

Wheat, forage	46924303	<-20	0.1-12.2	2 years in wheat forage

4.1.7		Food Residue Profile

The field trial data submitted in support of the proposed/amended uses were generated using a flowable concentrate formulation of azoxystrobin.  Adequate bridging data (PP#9F06058, DP#283588 and 287062, 2/6/03, N. Dodd) are available to support the use of WDG and FlC formulations on the crops discussed herein.  Based on bridging studies from the 80 WG formulation (also called 80 WDG, a water dispersible granular) to the SC formulation (also called FlC, a flowable concentrate) in celery, green onion, orange, garden beet, spinach, peaches, and tomatoes the ChemSAC (in a meeting on 12/18/02) concluded that statistical differences in resulting residues between the WG and SC formulations may be considered equivalent in terms of the expected residue levels.  Hence, no further side-by-side azoxystrobin trials are needed for these two formulations.

Barley

Azoxystrobin tolerances for barley grain (0.1 ppm), hay (15.0 ppm), and straw (4.0 ppm) have been established based on residue data translated from corresponding wheat commodities (PP#9F6058).  No residue data for barley forage were submitted to support the requested tolerance of 30 ppm for this commodity.  Since the use patterns of wheat and barley remain identical, the submitted data for wheat forage may be used in support of a tolerance on barley forage.  However, the proposed tolerance level is not appropriate.  A revised Section F to specify a tolerance level of 25 ppm for barley forage is required.

Nongrass Animal Feeds (Forage, Fodder, Straw, and Hay) (Crop Group 18)

The submitted residue data for alfalfa and clover, the representative crops of nongrass animal feeds, crop group 18, are adequate.  Seventeen field trials were conducted at three foliar broadcast applications of a 2.08 lb/gal FlC formulation of azoxystrobin at 0.24-0.26 lb ai/A/application, for a total rate of 0.73-0.76 lb ai/A (1x the maximum proposed seasonal rate of 0.75 lb ai/A).  Applications were made to clover with 12- to 16-day RTIs, while applications to alfalfa were made without a set RTI.  Alfalfa was harvested after each application and allowed to re-grow prior to the next application.  A summary of residue data from the alfalfa and clover field trials is presented in Table 4.1.7a.

Geographic representation of residue data submitted for nongrass animal feeds, crop group 18, is not in full compliance with the guideline.  According to Table 2 of OPPTS 860.1500, a total of 18 field trials are required to establish a tolerance for crop group 18; only 17 field trials were conducted.  However, no additional field trial data will be required since the Agency has previously determined in PP#4E6823 (DP# 328894, W. Cutchin, 6/19/06) that a reduced number of trials may be conducted to establish tolerances for this crop group.

The field trial data for alfalfa and clover forage and hay were entered into the Agency’s tolerance spreadsheet as specified by the Guidance for Setting Pesticide Tolerances Based on Field Trial Data SOP to determine appropriate tolerance levels. The tolerance spreadsheet indicates that the proposed tolerances are inadequate.  A revised Section F is required at 45 ppm for forage and 120 ppm for hay of the nongrass animal feeds crop group 18.

Table 4.1.7a   Summary of Residue Data from Alfalfa and Clover Field Trials with Azoxystrobin.

Commodity	Total Applic. Rate

 (lb ai/A)	PHI (days)	Combined Residue Levels of Azoxystrobin and its Z-Isomer (ppm)

	n	Min.	Max.	HAFT	Median

(STMdR)	Mean

(STMR)	Std. Dev.

Proposed Use Pattern:  Maximum seasonal rate of 0.75 lb ai/A with a 14-day PHI

Clover Forage	0.73-0.77	13-15	16	0.64	16.0	13.87	4.45	6.01	4.95

Clover Hay	0.73-0.77	13-15	16	3.37	55.5	47.60	16.29	18.42	14.83

Alfalfa Forage	0.25-0.26	14	18	<0.10	4.66	4.44	0.58	1.05	1.32

	0.50-0.51	13-14	18	<0.10	8.54	6.95	0.82	2.28	2.64

	0.75-0.76	13-14	18	<0.12	8.75	8.48	1.91	3.33	3.07

Alfalfa Hay	0.25-0.26	14	18	0.35	15.86	15.77	1.87	3.19	4.69

	0.50-0.51	13-14	18	0.46	45.30	43.85	2.32	9.61	14.5

	0.75-0.76	13-14	18	0.27	30.74	26.17	6.60	8.63	8.07

Sorghum

The submitted residue data for sorghum are inadequate because they do not fully reflect the proposed use patterns.  Twelve sorghum field trials were conducted at two foliar broadcast applications of a 2.08 lb/gal FlC formulation of azoxystrobin at 0.24-0.26 lb ai/A/application for a total of 0.49-0.51 lb ai/A.  For the harvest of grain and stover, a second plot received three foliar broadcast applications of the 2.08 lb/gal FlC at the same single application rate for a total of 0.74-0.78 lb ai/A.  The total applied rates are 1x the proposed maximum foliar seasonal rates for harvest of forage and grain/stover.  Applications were made with 6- to 8-day retreatment intervals using ground equipment in spray volumes of 3-20 gal/A with an adjuvant added to the spray solutions.  A summary of residue data from the sorghum field trials is presented in Table 4.1.7b.

Although geographical representation is adequate, the submitted residue data for sorghum are not adequate because they do not fully reflect the proposed use patterns.  The residue data only reflect the proposed use pattern for postemergence foliar applications and did not reflect the in-furrow treatment.  Previously submitted data showed non-detectable residues (<0.01 ppm for azoxystrobin and its Z isomer) on undelinted cottonseed and cotton gin byproducts when cotton was treated foliarly following an in-furrow application (PP#9F6058, DP# 260134, 9/26/00, M. Nelson).  It is likely that the bulk of residues will result from foliar uses.

The field trial data for sorghum forage, grain, and stover were entered into the Agency’s tolerance spreadsheet as specified by the Guidance for Setting Pesticide Tolerances Based on Field Trial Data SOP to determine appropriate temporary tolerance levels.  The tolerance spreadsheet recommends tolerances of 25 ppm for sorghum forage, 11 ppm for sorghum grain, and 40 ppm for sorghum stover.  The proposed tolerances for sorghum forage (25 ppm) and stover (40 ppm) are identical with the tolerance spreadsheet recommended tolerances.  However, an amended Section F is required to revise the proposed tolerance for sorghum grain from 9 ppm to 11 ppm.

The field trial data for the aspirated grain fractions of sorghum from bulk samples treated at 1x for foliar treatments showed that the combined residues of azoxystrobin and its Z-isomer were 110.6 ppm; the combined residues concentrated 49.4x.  Based on a processing factor of 49.4x and the HAFT residue for sorghum grain (8.46 ppm), the expected residues in the aspirated grain fractions of sorghum is 417.9 ppm.  It is noted that 40 CFR §180.507(a)(1) currently lists two tolerances for aspirated grain fractions.  The 10 ppm tolerance was based on aspirated grain fraction data from wheat (PP#7F4864; DP# 249657, 1/25/99, D. Dotson), and the 30 ppm tolerance was based on aspirated grain fraction data from soybean seed (PP#9F6058; DP# 260134, 9/26/00, M. Nelson).  Since it is Agency policy to establish a tolerance for aspirated grain fraction based on the RAC with the highest residues in the dust, the appropriate tolerance for aspirated grain fractions is 420 ppm.  A revised Section F is required to specify a tolerance of 420 ppm for aspirated grain fractions.

Note to PM:  The currently listed 10 and 30 ppm tolerances for this RAC should be removed and replaced with this recommended tolerance level.

Table 4.1.7b      Summary of Residue Data from Sorghum Field Trials with Azoxystrobin.

Commodity	Total Applic. Rate

 (lb ai/A)	PHI (days)	Combined Residue Levels of Azoxystrobin and its Z-Isomer (ppm)

	n	Min.	Max.	HAFT	Median

(STMdR)	Mean

(STMR)	Std. Dev.

Proposed Use Pattern:   In-furrow application at 0.1-0.2 oz ai/1,000 row ft + multiple postemergence foliar sprays at maximums of 0.5 lb ai/A (for forage) or 0.75 lb ai/A (for grain & stover).  The proposed PHI is 14 days.

Forage	0.49-0.51	14-15	24	0.16	10.0	8.00	1.56	2.36	2.60

Stover	0.74-0.78	13-17	24	0.38	17.0	16.45	3.35	4.86	4.83

Grain	0.74-0.78	13-17	24	0.38	8.57	8.46	2.04	2.65	2.08

Aspirated grain fractions 1	0.75	13	1	110.6 1	N/A	N/A	N/A	N/A

1  Processed from a bulk sorghum grain sample bearing combined residues of 2.24 ppm.  The calculated processing factor is 49.4x.

Wheat

The submitted residue data for wheat forage are adequate.  Twenty wheat field trials were conducted at two foliar broadcast applications of a 2.08 lb/gal FlC formulation of azoxystrobin at 0.24-0.27 lb ai/A/application, with 6- to 10-day retreatment intervals, for a total rate of 0.49-0.52 lb ai/A (1.2-1.3x the maximum proposed seasonal rate of 0.4 lb ai/A.  Wheat forage was collected 12-15 days after last application and additional samples were collected from three trial sites at 0, 7 and 21 days after last application to generate residue decline data. A summary of residue data from the wheat field trials is presented in Table 4.1.7c.

The field trial data for wheat forage were entered into the Agency’s tolerance spreadsheet as specified by the Guidance for Setting Pesticide Tolerances Based on Field Trial Data SOP to determine an appropriate tolerance level.  The tolerance spreadsheet recommends a tolerance of 25 ppm for wheat forage.  An amended Section F is required to revise the proposed tolerance for wheat forage from 30 ppm to 25 ppm.

Azoxystrobin tolerances for wheat grain (0.10 ppm), hay (15 ppm), and straw (4.0 ppm) have been established.  These tolerances are supported by adequate residue data, which were presented in PP#6F4762 (DP#s 230634, 230635, 230636 and 230637, 4/25/97, L. Kutney) and subsequently re-evaluated in PP#7F4864 (DP# 249657, 1/25/99, D. Dotson).  The requirements for data on aspirated grain fractions of wheat are fulfilled.

Table 4.1.7c   Summary of Residue Data from Wheat Field Trials with Azoxystrobin.

Commodity	Total Applic. Rate

 (lb ai/A)	PHI (days)	Combined Residue Levels of Azoxystrobin and its Z-Isomer (ppm)

	n	Min.	Max.	HAFT	Median

(STMdR)	Mean

(STMR)	Std. Dev.

Proposed Use Pattern:  Maximum seasonal rate of 0.40 lb ai/A with a 14-day PHI for forage and hay and a 45-day PHI for grain and straw.

Wheat forage	0.49-0.52	12-15	40	<0.02	11.43	8.79	0.64	1.86	2.55

Cotton

The submitted residue data for cotton commodities are adequate to support an amended use pattern reflecting in-furrow treatment at planting followed by multiple postemergence foliar treatments; currently, only the in-furrow use pattern is registered.  Twelve cotton field trials were conducted at one in-furrow application of a 2.08 lb/gal FlC formulation of azoxystrobin at planting of cotton at a target rate 0.15 lb ai/A, followed by three foliar broadcast applications of the 2.08 lb/gal FlC formulation at a rate of 0.14-0.16 lb ai/A/application.  The in-furrow rate treatment of 0.15 lb ai/A is equivalent to 0.5-1.9x the proposed rate of 0.10-0.20 oz ai/1,000 row based on 22-40 inch row spacing.  The total rate of 0.42-0.48 lb ai/A from foliar treatments is 1x the maximum seasonal rate for this use pattern.  The second application (first foliar) was made as an over-the-top broadcast spray 64-126 days after the in-furrow at-planting application.  The following two foliar applications were made with 9- to 12-day retreatment intervals. A summary of residue data from the cotton field trials is presented in Table 4.1.7d.

The field trial data for cottonseed and cotton gin byproducts were entered into the Agency’s tolerance spreadsheet as specified by the Guidance for Setting Pesticide Tolerances Based on Field Trial Data SOP to determine appropriate tolerance levels.  The tolerance spreadsheet recommends tolerances of 0.60 ppm for undelinted cottonseed and 45 ppm for cotton gin byproducts.  An amended Section F is required to revise the proposed tolerances for undelinted cottonseed at 0.6 ppm and for cotton gin byproducts at 45 ppm.

Table 4.1.7d      Summary of Residue Data from Cotton Field Trials with Azoxystrobin.

Commodity	Total Applic. Rate

 (lb ai/A)	PHI (days)	Combined Residue Levels of Azoxystrobin and its Z-Isomer (ppm)

	n	Min.	Max.	HAFT	Median

(STMdR)	Mean

(STMR)	Std. Dev.

Proposed Use Pattern:  In-furrow application at planting at 0.1-0.2 oz ai/1000 ft row + 3 postemergence foliar sprays at 0.15 lb ai/A/application.  The proposed PHI is 45 days.

Cottonseed	0.59-0.61	45	24	<0.02	0.62	0.57	0.02	0.07	0.15

Cotton gin byproducts	0.59-0.61	45	12	<0.02	34.4	32.1	0.41	6.19	12

Wild rice

No wild rice data were submitted to support the proposed tolerance for the combined residues of azoxystrobin and its Z-isomer at 5.0 ppm.  The petitioner indicated that previously reviewed rice data in PP#7F4864 should be translated to wild rice.   Although previous requests to translate data were denied (PP#9F6058), ChemSAC (7/18/2007 minutes) now recommends that rice grain data can be used to translate to wild rice based on similarities in cultural practices.  The rice grain data may be translated to support the requested tolerance for wild rice since the use patterns of rice and wild rice are identical.  The Agency recommends for the proposed tolerance of 5.0 ppm on wild rice.

Processed Studies:  A sorghum processing study is not required for this action.  Table 1 of OPPTS 860.1000 indicates that residue data are not needed at this time for sorghum flour since it is used exclusively in the United States as a component for drywall, and not as either a human food or a feedstuff.  Acceptable wheat processing studies have also been submitted in PP#6F4762 (DP#s 230634, 230635, 230636 and 230637, 4/25/97, L. Kutney) and PP#7F4864 (DP# 249657, 1/25/99, D. Dotson).

The submitted cotton processing study is acceptable.  The results indicate that the combined residues of azoxystrobin and its Z-isomer did not concentrate in cotton meal, hulls, or refined oil processed from undelinted cottonseed treated at up to 5x the maximum proposed seasonal rate.  The results of this study are consistent with another cottonseed processing study (MRID 44915231) reviewed in PP#9F6058 (DP# 260134, 9/26/00, M. Nelson).  The observed processing factors did not exceed the theoretical concentration factors based on separation into components (OPPTS 860.1520, Table 3) for cottonseed hulls (3.8x), meal (2.2x) and oil (6.3x).

No tolerances are required for the processed commodities of cotton.  A summary of residue data from the cotton processing study is presented in Table 4.1.7e.

Table 4.1.7e     Residue Data from Cotton Processing Study with Azoxystrobin.

Location

(City, State; Year)

Trial ID	Processed

Commodity	Total Rate

(lb ai/A) 	PHI

(days)	Residues (ppm)	Processing

Factor

Azoxystrobin	R230310	Combined Residues

	Wharton, TX; 2005

(SA-FR-05-6019)	Undelinted seed (RAC)	3.02	45	0.04

0.06	Not analyzed	--	--

0.03

0.07	<0.01

<0.01	<0.04

<0.08	--

	Cotton Hulls

	0.06

0.02	<0.01

<0.01	<0.07

<0.03	1.2x

0.5x

	Cotton Meal

	<0.01

<0.01	<0.01

<0.01	<0.02

<0.02	0.3x

0.3x

	Refined Oil

	0.02

0.02	<0.01

<0.01	<0.03

<0.03	0.5x

0.5x

Edmonson, TX; 2005

(SC-FR-05-6021)	Undelinted seed (RAC)	0.59	45	0.02

0.03

0.02

0.02	<0.01

<0.01

<0.01

<0.01	<0.03

<0.04

<0.03

<0.03	--

	Cotton Hulls

	0.02

0.02	Not

analyzed	--	0.9x

0.9x

	Cotton Meal

	<0.01

<0.01	Not

analyzed	--	<0.4x

<0.4x

	Refined Oil

	0.01

0.01	Not

analyzed	--	0.4x

0.4x

	Undelinted seed (RAC)	3.02	45	not

analyzed	0.02

0.05	--	--

	Cotton Hulls

	not

analyzed	0.02

0.02	--	0.6x

0.6x

	Cotton Meal

	not

analyzed	<0.01

<0.01	--	<0.3x

<0.3x

	Refined Oil

	not

analyzed	<0.01

<0.01	--	<0.3x

<0.3x

Livestock:  Tolerances for residues of azoxystrobin per se are currently established [40 CFR §180.507(a)(2)] for the fat (0.03 ppm), meat (0.01 ppm), and meat byproducts (0.07 ppm) of cattle, goat, horse, and sheep.  A tolerance of 0.01 ppm each has been established for hog fat, meat, and meat byproducts.  A milk tolerance of 0.006 ppm is also established.  The existing azoxystrobin tolerances for milk and the fat, meat, and meat byproducts of ruminants and swine were established using maximum theoretical dietary burdens (MTDB) that are higher than the current dietary burdens; therefore, no increases in associated livestock items of regulatory interest are required.  A revised Section F is required removing the requested tolerance increases in milk and the fat, meat, and meat byproducts of cattle, goat, horse, sheep, and swine.

The potential for secondary transfer of azoxystrobin residues in meat, milk, poultry, and eggs exists because there are several livestock feedstuffs which are relevant to this action; these include barley (grain, hay, and straw), cotton (seed, gin byproducts, meal, and hulls), nongrass animal feeds (forage, hay, meal, and silage), rice (grain, straw, hulls, and bran), sorghum (grain, forage, stover, and aspirated grain fractions), and wheat (grain, forage, hay, straw, aspirated grain fractions, and milled byproducts).  In addition, numerous livestock feedstuffs are currently registered with established tolerances.  The Agency previously calculated the MTDB of azoxystrobin to livestock in conjunction with PP# 9F6058.  Using the worst-case scenario for the previously requested and established tolerances, the calculated MTDBs were 105.8 ppm for beef cattle, 73.7 ppm for dairy cattle, 9.5 ppm for swine, and 7.3 ppm for poultry.

Using the most recent guidance concerning revisions of feedstuff percentages in Table 1 Feedstuffs (October 2006) and constructing reasonably balanced livestock diets, the livestock dietary burdens of azoxystrobin are presented in Table 4.1.7f (email, J. Stokes, 2/15/08).  The calculated dietary burdens of azoxystrobin are 47.9 ppm for beef cattle, 58.7 ppm for dairy cattle, and 9.0 ppm for poultry and swine.

Table 4.1.7f   Calculation of Dietary Burdens of Azoxystrobin Residues to Livestock.

Feedstuff	Type1	% Dry Matter2	% Diet2	Recommended/

Established Tolerance (ppm)	Dietary Contribution (ppm)3

Beef Cattle

Nongrass animal feeds, hay 	R	89	10	120	13.5

Aspirated grain fractions	CC	85	5	420	24.7

Sorghum grain	CC	86	75	11	9.6

Canola meal	PC	88	10	1.0	0.13

TOTAL BURDEN	--	--	100	--	47.9

Dairy Cattle

Nongrass animal feeds, hay 	R	89	15	120	20.2

Nongrass animal feeds, forage	R	35	10	45	12.9

Corn, field, silage	R	40	10	12	 3.0

Turnip tops	R	30	10	50	16.7

Sorghum grain	CC	86	45	11	5.8

Canola meal	PC	88	10	1.0	0.13

TOTAL BURDEN	--	--	100	--	58.7

Poultry

Sorghum grain	CC	86	80	11	8.8

Canola meal	PC	88	15	1.0	0.15

Cottonseed meal 	      PC	89	5	0.6	0.03

TOTAL BURDEN	--	--	100	--	9.0

Swine

Sorghum grain	CC	86	80	11	8.8

Canola meal	PC	88	15	1.0	0.15

Soybean meal 	      PC	92	5	0.5	0.03

TOTAL BURDEN	--	--	100	--	9.0

1 R:  Roughage; CC:  Carbohydrate concentrate; PC:  Protein concentrate.

2 OPPTS 860.1000 Table 1 Feedstuffs (October 2006).

3 Contribution = ([tolerance /% DM] X % diet) for beef and dairy cattle; contribution = ([tolerance] X % diet) for poultry and swine.

Comments:

1)  Removed nongrass forage from beef—not available to finishing feedlot beef

2)  Turnip tops removed from beef--- not available to finishing feedlot beef

3)  Turnip tops in dairy—used in PA, VA, and TN as forage/green chop for dairy

4)  Added corn silage to dairy—Can not feed more that 25% nongrass commodities as bloats dairy cows.

5)  Soybean hay removed—very small amount produced and fed to local growing beef and nonlactating cows—not high quality forage for high production milk cows

6)   Other feedstuffs listed in 180.507 maybe more readily available to finishing beef and mature dairy cows, but the nongrass entries will always be the drivers.  Alfalfa is readily fed to beef and dairy cattle across the US.

Poultry:  A poultry feeding study with azoxystrobin was previously submitted and reviewed in conjunction with PP#7F4864.  In the referenced poultry feeding study, the dosing level was 60 ppm (6.67x the recalculated dietary burden of 8.98 ppm for poultry).  Since no residues of the Z-isomer were identified in the poultry metabolism study, egg and tissue samples from the feeding study were analyzed for azoxystrobin residues only.  The LOQ of the method (RAM 255) was 0.01 ppm.  No quantifiable residues of azoxystrobin were reported in any egg or poultry tissue sample.

The proposed and amended uses of azoxystrobin on the poultry feed items addressed in this document are not expected to alter the Agency’s previous conclusion that there is no reasonable expectation of finite residues in poultry commodities [Category 3 of §180.6(a)].  No tolerances are needed for poultry and eggs.  The Agency will periodically assess this determination if additional poultry feed items are proposed in the future.  A revised Section F is required removing the requested tolerance increases in eggs and the fat, meat, and meat byproducts of poultry.

Confined and Field Rotational Crops

There are adequate field rotational crop data to support the following rotational crop restrictions on the product labels:  “Do not plant the following crops for a period of 12 months (unless an azoxystrobin product is registered for use on that crop):  buckwheat, millet, oats, and rye.  A plantback interval of 36 days is required for leafy vegetables (except Brassica) group; Brassica, leafy greens subgroup; vegetables, root subgroup; vegetable (tuberous and corm subgroup; and vegetables, leaves of root and tuber group.  Crops with registered azoxystrobin uses may be planted immediately after the last treatment.”  As tolerances on the commodities of primary crops (barley, nongrass animal feeds (alfalfa and clover), sorghum, triticale, and wheat) are being proposed, the rotational crop restrictions for these crops are no longer required and have been removed from the product labels.

4.1.9	Pesticide Metabolites and Degradates of Concern

Table 4.1.9  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

4.1.10	International Residue Limits

No Codex maximum residue limits (MRLs) have been established for azoxystrobin.  Canadian MRLs have been established for residues of azoxystrobin, including the isomer (Z)-methyl 2-[[6-(2-cyanophenoxy)-4-pyrimidinyl]oxy]--(methoxymethylene)benzeneacet ate in livestock commodities; no MRLs have been established for the requested crops.  Mexican MRLS have also been established for residues of ‘azoxistrobin’; however, no MRLs have been established for the requested crops. Refer to Table A2 in the Appendix.

4.1.11 	Environmental Degradation

Azoxystrobin is relatively persistent, but not highly mobile.  Azoxystrobin is stable to hydrolysis at pH 5, 7, and 9 at 25 (C.  Azoxystrobin degrades through photolysis in water and soil and to a lesser extent by microbial-mediated degradation.  The dissipation half-life (T½) of azoxystrobin by photolysis on soil ranges between = 17.6 to 28.4 days (DT50=11 days).   The dissipation of azoxystrobin by photodegradation half-life in the surface waters ranges between 11.1 to 17 days).  Photolysis will be less effective when the water is not clear or is shaded.  Azoxystrobin biotransforms slowly in aerobic and anaerobic soils.  The aerobic soil metabolism half-lives range from 72 to 164 days.

The soil/water partitioning coefficients (Kads) for azoxystrobin ranged from 1.5 to 23 mL/g in seven soils.  Azoxystrobin exhibits a low to moderate mobility in all soils tested in the mobility studies.  The relatively low mobility was confirmed in the field studies where azoxystrobin dissipated slowly on the surface (0-6 inch) of non-flooded soils.  No azoxystrobin residue was found in soil layers deeper than 6 inches.

Three major degradates, (Compound 2, Compound 30 and Compound 28), were detected and found to have greater potential to move through soil than the parent compound.  However, based on terrestrial field studies, Compound 2 did not leach into soil deeper than 18 inches and its concentration in the 12 to 18-inch layer was minimal.  The other two degradates were also detected in the field, but only in the surface soils and at minimal concentrations (D218292).  Previous assessment by the HED has determined that the only residue of concern for dietary exposure is parent azoxystrobin.  Thus, only the parent was considered in this drinking water assessment.

4.1.12 Drinking Water Residue Profile

EFED provided Tier 1 Estimated Drinking Water Concentrations (EDWCs) for azoxystrobin in surface water and in ground water for use in human health risk assessment.  The simulation model FIRST (FQPA Index Reservoir Screening Tool) was used to calculate the surface water EDWCs, and the SCI-GROW model was used to calculate the groundwater EDWC.  No azoxystrobin monitoring data were available.  HED determined that the residue of concern in water is azoxystrobin per se because the parent compound is the most likely residue to be found in surface water.  Although moderately persistent in soils and stable to hydrolysis, the likelihood of azoxystrobin moving into ground and surface water is low due to high soil/water partitioning coefficients and low single application rates.  However, with multiple applications and repeated usage, azoxystrobin and especially the degradate (“compound 2", [(E)-2-{2-[6-(2-cyanophenoxy) pyrimidin-4-yloxy]-3-methoxyacrylic acid]) may eventually build up in environmental compartments and move into drinking water resources.

Based on the Tier I modeling results using the FIRST model, azoxystrobin EDWCs in surface water are not likely to exceed 173 ppb for the acute (peak) concentration or 33 ppb for the chronic (annual average) concentration.  These values represent upper-bound estimates of the concentrations that might be found in surface water which result from the use of azoxystrobin on turf.  In the case of azoxystrobin, the turf application rate (0.55 lb ai/A, 9 applications per year with 10 days interval between application) was used in the acute and chronic analysis.

The SCI-GROW screening model developed in EFED estimates potential ground water concentrations under hydrologically vulnerable conditions.  Based on the highest use rate (turf use, 9 applications per year, 10-day interval, and 0.55 lb ai/A/application), the upper-bound concentration of azoxystrobin was estimated at 3.1 ppb.  The model and its description are available at the EPA internet site:   HYPERLINK "http://www.epa.gov/oppefed1/models/water/"  http://www.epa.gov/oppefed1/models/water/ .

Table 4.1.12:  Azoxystrobin Drinking Water Concentrations in Surface and Ground Water

Water Body: Model	Turf

Surface water: FIRST- peak (acute)	173 ppb

FIRST- annual average	33 ppb

Ground Water: SCI-GROW	3.1 ppb

4.2	Dietary Exposure and Risk Characterization

 tc "4.2.2  Dietary Analysis " \l 3

ssessments were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID™, Version 2.03), which incorporates consumption data from USDA’s Continuing Surveys of Food Intakes by Individuals (CSFII), 1994-1996 and 1998.  Azoxystrobin has been classified as “not likely” carcinogenic; therefore, cancer risk from exposure to azoxystrobin is not of concern. The analyses were performed to support Section 3 requests for the use of azoxystrobin on wild rice; cotton, undelinted seed; cotton, gin byproducts and uses on aspirated grain fractions; barley, forage; non-grass animal feeds, forage, crop group 18; non-grass animal feeds, hay, crop group 18; sorghum, forage; sorghum, grain; sorghum, stover; and wheat, forage.

Based on the Tier I modeling results using the FIRST model, azoxystrobin EDWCs in surface water are not likely to exceed 173 ppb for the acute (peak) concentration or 33 ppb for the chronic (annual average) concentration.  These values represent upper-bound estimates of the concentrations that might be found in surface water which result from the use of azoxystrobin on turf and were used in the dietary exposure assessment.

The acute assessment is based on tolerance levels, assumes 100% crop treated, and default processing factors (DEEM™ 7.81) for all existing and proposed uses.  Combined dietary exposure from food and drinking water at the 95th percentile of exposure is estimated to be 0.166 mg/kg/day for the overall U.S. population, equivalent to 25% of the acute Population Adjusted Dose (aPAD).  The population subgroup with the highest estimated acute dietary exposure to azoxystrobin is children 1-2 yrs old, with an estimated exposure at the 95th percentile of 0.468 mg/kg/day, equivalent to 70% of the aPAD.

, default processing factors (DEEM™ 7.81) and %CT data for some existing uses.  The dietary exposure estimate at 0.010 mg/kg/day for the U.S. population was 6% of the cPAD and the most highly exposed subgroup, children 1-2 yrs old, at 15% (0.027 mg/kg/day) of the cPAD.  The results of the analysis indicate that chronic risk from the dietary exposure to azoxystrobin from the existing and requested uses did not exceed Agency’s level of concern for the U.S. population or any population subgroup.

4.2.1	Acute Dietary  tc "<IP_ADDRESS>  Acute Dietary " \l 4

TABLE 4.2.1  Results of Acute Dietary (Food and Drinking Water) Exposure and Risk Estimates for Azoxystrobin

Population Subgroup	aPAD (mg/kg/day)	95th Percentile

Exposure (mg/kg/day)	% aPAD

General U.S. Population	0.67	0.165906	25

All Infants (< 1 year old)	0.67	0.110998	17

Children 1-2 years old	0.67	0.468388	70

Children 3-5 years old	0.67	0.351755	52

Children 6-12 years old	0.67	0.220394	33

Youth 13-19 years old	0.67	0.169495	25

Adults 20-49 years old	0.67	0.137480	21

Adults 50+ years old	0.67	0.118963 	18

Females 13-49 years old	0.67	0.146596	22

4.2.2	Chronic Dietary

Table 4.2.2  Results of Chronic Dietary (Food and Drinking Water) Exposure and Risk Estimates for Azoxystrobin

Population Subgroup	cPAD

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

General U.S. Population	0.18	0.009878	6

All Infants (< 1 year old)	0.18	0.008347	5

Children 1-2 years old	0.18	0.026629	15

Children 3-5 years old	0.18	0.022079	12

Children 6-12 years old	0.18	0.013623	8

Youth 13-19 years old	0.18	0.009499	5

Adults 20-49 years old	0.18	0.007879	4

Adults 50+ years old	0.18	0.007799	4

Females 13-49 years old	0.18	0.008081	4

4.2.3	Cancer Dietary

The HED Cancer Assessment Review Committee (CARC) evaluated the carcinogenic potential of azoxystrobin and classified azoxystrobin as “not likely to be a human carcinogen” and, therefore, quantification of human cancer risk is not required (TES Document, 10-DEC-1996). tc "<IP_ADDRESS>  Cancer Dietary " \l 4

4.3	Anticipated Residues and Percent Crop Treated (%CT) Information

The residue levels used in the acute assessment were the assumption of tolerance level residues for all commodities with existing and proposed tolerance and 100% crop treated (%CT).  The chronic assessment was based on the assumption of tolerance level residues for all commodities and %CT for some commodities (almonds, apricot, beans (dried and succulent), beet, berries, cabbage, melon, carrot, celery, cherry, cotton, filbert, grape, citrus, lettuce, mustard greens, onion, parsley, peanut, pepper, plum, potato, rice, soybean, spinach, squash, strawberry, tomato and wheat).  An updated screening level usage analysis (SLUA) was provided by BEAD (Alan Halvorson, 3/10/2006, Biological and Economic Analysis Division).

5.0	Residential (Non-Occupational) Exposure/Risk Characterization

 tc "4.4  Residential Exposure/Risk Pathway " \l 2

There are no residential (non-occupational) changes since the previous risk assessment on azoxystrobin (D317291, W. Cutchin, 7/20/2006).   Azoxystrobin is currently registered for use on residential turf grass and ornamentals, as well as indoor surfaces.  Short-term exposures may occur during adult residential handling activities.   HED’s Draft Standard Operating Procedures (SOPs) for Residential Exposure Assessments, and Recommended Revisions (ExpoSAC Policy Number 12, revised 2/22/01), were used as the basis for all residential handler exposure calculations.  Some of the handler exposure data used in this assessment are from the Outdoor Residential Exposure Task Force (ORETF; the risk manager is encouraged to pursue data compensation in the event the registrant is not a member of the task force).  The MOEs are well above the LOC for non-occupational handler scenarios, and therefore, are not of concern.

5.1	Residential Uses  tc "4.4.1  Home Uses " \l 3

Residential handlers may receive short-term dermal and inhalation exposure to azoxystrobin when mixing, loading and applying the formulations.  Adults and children may be exposed to azoxystrobin residues from dermal contact with foliage/surfaces during postapplication activities.  Toddlers may receive short- and intermediate-term oral exposure from incidental ingestion during postapplication activities.  As no dermal endpoint was selected by the HIARC, a dermal exposure and risk assessment was not conducted for residential handlers or postapplication activities.

No chemical-specific exposure or residue dissipation data for handler or postapplication activities were submitted to HED in support of the registered lawn uses or indoor carpet/other surfaces uses.  HED’s Draft Standard Operating Procedures (SOPs) for Residential Exposure Assessments, and Recommended Revisions (HED Policy Number 12, revised 2/22/01), were used as the basis for all residential handler exposure calculations.  Some of the handler exposure data used in this assessment are from the ORETF (the risk manager is encouraged to pursue data compensation in the event the registrant is not a member of the task force).  The ORETF data were designed to replace the present PHED data with higher-confidence, higher quality data that contain more replicates than the PHED data for those scenarios.

5.2	Residential Handler Exposure and Risk  tc "4.4.2  Residential Handler Exposure and Risk " \l 3

Indoor Carpet and Other Surfaces

Although the currently registered label for use on indoor carpets/other surfaces prohibits non-commercial applicators from mixing, loading and applying azoxystrobin, the label amendment for the Heritage® Fungicide label does not.  Furthermore, the currently registered label for use on indoor carpets/other surfaces specifies use restrictions, whereas the Heritage® Fungicide label does not.  Therefore, inhalation daily doses for residential handlers were calculated for the WDG formulation using data for mixing, loading and applying a liquid. As shown in Table 5.2a, the inhalation MOE for residential handlers applying azoxystrobin indoors is well above the LOC of an MOE of 100 or less.

Table 5.2a  Handler Exposure and Risk Estimates for Residential Indoor Surface Applicators

Handler

Scenario

	 Rate

(lb ai/

ft2) 	Area Treated

(ft2/

day)	PHED Unit Exposure1

(mg/lb ai) 	Short-term Daily

Inh. Dose 2

(mg/kg/day)	Short-term

Inhalation MOE  3

Open Mixing, Loading, and Applying Liquid using a Low Pressure Handwand 3.4E-5	1000	0.03	1.5E-5	1,700,000

1 Data Confidence for inhalation unit exposures: low-pressure handwand:  80 replicates, ABC grade, medium confidence

2 Daily Dose = [Rate (lb ai/ft2) x Area Treated (ft2/day) x Unit Exposure# (mg/lb ai handled)] / Body Weight (70 kg)

3 MOE = NOAEL (25 mg/kg/day) / Daily Inhalation Dose (mg/kg/day)

Although there is a potential for residential bystander exposure, the exposure scenario is not assessed for the following reasons: the label specifically restricts humans (other than the applicator) and domestic animals from being present while applications are being made, until after the application has dried; and bystander exposure is expected to be less than applicator exposure, and the MOEs for the applicator exposure scenario are high, indicating bystanders would be subject to even less exposure and risk.

Turf and Ornamentals

The currently registered labels for turf and ornamentals do not prohibit non-commercial applicators from mixing, loading and applying either the liquid or the WDG formulations.  The residential exposure and risk assessment for turf and ornamentals was conducted using the application rate for turf because it is the highest use rate.  As shown in Table 5.2b, the inhalation MOEs for residential handlers are well above the LOC of an MOE of 100 or below.

Table 5.2b  Handler Exposure and Risk Estimates for Residential Lawn Applicators

Handler

Scenario

	 Rate

(lb ai/

acre) 	Acres Treated

(acres/

day)	PHED/ORETF

Unit Exposure1

(mg/lb ai) 	Short-term Daily

Inh. Dose 2

(mg/kg/day)	Short-term

Inhalation MOE  3

1.  mix/load and spot application of liquid formulation (low-pressure hand sprayer)

0.95

0.023

0.030

9.4E-06

2,700,000

2.  mix/load and broadcast application of liquid formulation (garden hose-end sprayer)

0.95

0.5

0.016

1.1E-04

230,000

1 Data Confidence for inhalation unit exposures: low-pressure hand sprayer:  80 replicates, ABC grade, medium confidence garden hose-end sprayer: 30 replicates, A grade, high confidence

2 Daily Dose  = [Rate (lb ai/A) x Acres Treated (A/day) x Unit Exposure# (mg/lb ai handled)] / Body Weight (70 kg)

3 MOE = NOAEL (25 mg/kg/day) / Daily Inhalation Dose (mg/kg/day)

5.3	Residential Postapplication Exposure and Risk  tc "4.4.3  Residential Postapplication Exposure and Risk " \l 3

Indoor Carpet and Other Surfaces

Commercial and residential applicators (when formulation and application rates are the same) deposit the same amount of residue on the treated site.  The residential postapplication scenario for use of azoxystrobin on indoor carpets and other surfaces has been recently assessed in an Antimicrobial Division (AD) memorandum (DP Num: 299065, D. Aviado, 7/2/04).  Both the Heritage® Fungicide label and the formulation assessed in the AD memorandum (2.08 SC) call for a liquid spray to indoor surfaces, and both have similar application rates (2.08 SC: 3.3E-5 lb ai/ft2; Heritage®: 3.4E-5 lb ai/ft2).  As shown in Table 5.3a, both the short-term and intermediate- term MOEs for each scenario are well above the LOC.

Table 5.3a  Short- and Intermediate-Term Incidental Ingestion Exposure and Risk from Treated Indoor Surfaces

Scenarios	ISR

(mg/cm2)	Short-Term

PDR0-norm

(mg/kg/day)	Int-Term

PDR0-norm

(mg/kg/day)	Short-Term

MOE	Int-term

MOE*

(1) Hand-to-Mouth (vinyl/hard surfaces)	1.7E-3	0.089	0.042	280	480

(2) Hand-to-Mouth (carpet/textile surfaces)	8.34E-4	0.089	0.042	280	480

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

Turf and Ornamentals

Postapplication exposures from various activities following lawn treatment are considered to be the most common and significant in residential settings.  The exposure via incidental ingestion of other plant material may occur but is considered negligible.  The exposure and risk estimates for the residential exposure scenarios are assessed for the day of application (day “0”) because it is assumed that toddlers could contact the lawn immediately after application.  The equations used for the exposure calculations are presented below and the results are presented in Table 5㌮⹢ऍ名扡敬㔠㌮桓牯⵴愠摮䤠瑮牥敭楤瑡ⵥ敔浲 䤠据摩湥慴湉敧瑳潩硅潰畳敲愠摮删獩牦浯吠敲 瑡摥吠牵ݦഇ捓湥牡潩ݳ

TTR/GR/SR0 (μg  /cm2 or g)	Short-Term

PDR0-norm

(mg/kg/day)	Int-Term

PDR0-norm

(mg/kg/day)

Short-Term

MOE

Int-term

MOE*

(1) Hand-to-Mouth	0.53	0.014	0.0067	1,800	3,000

(2) Mouthing Grass	2.13	0.0035	0.0035	7,000	5,600

(3) Soil Ingestion	7.1	0.000048	0.000048	530,000	420,000

Combined	N/A	0.018	0.010	1,400	1,900

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

Both short-term and intermediate-term MOEs for each scenario, and the combined MOE resulting from all three exposures, are above the LOC.

5.4	Recreational Postapplication Exposure and Risk  tc "4.4.4  Recreational Postapplication Exposure and Risk " \l 3

Recreational exposures to turf and indoor surfaces are expected to be similar to, or in many cases less than, those evaluated in Section 5.3 Residential Postapplication Exposure and Risk; therefore, a separate recreational exposure assessment was not included.  Although azoxystrobin may be applied to golf courses, a risk assessment for the golfing scenario is not required because no dermal endpoint was selected by the HIARC.

5.5	Off Target Non-Occupational Exposure  tc "4.4.5  Off Target Non-Occupational Exposure " \l 3

Spray drift is always a potential source of exposure to residents nearby to spraying operations.  This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for azoxystrobin.  The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices.  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 methods.  After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift and risks associated with aerial as well as other application types where appropriate.

Please note that as indicated in this assessment, azoxystrobin is directly applied to residential turf and does not result in exposures of concern.  It is unlikely that the potential for risk of exposure to spray drift from agricultural uses would be higher than that estimated for the turf use of this chemical.

6.0	Aggregate Risk Assessment and Risk Characterization

In accordance with the FQPA, the Agency must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures.  In an aggregate assessment, exposures from relevant sources are added together and compared to 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, the Agency considers both the route and duration of exposure. tc "5.0  AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION"

6.1	Acute Aggregate Risk  tc "5.1  Acute Aggregate Risk " \l 2

The aggregate acute risk estimates include exposure to residues of azoxystrobin in food and water, and does not include dermal, inhalation or incidental oral exposure.  Since the dietary exposure assessment already includes the highest acute exposure from the drinking water modeling data, no further calculations are necessary.  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 level of concern.  The food and drinking water exposure estimates for the U.S. population is 25% of the aPAD and the most highly exposed subgroup, children 1-2 yrs old, is 70% of the aPAD.

6.2	Short-Term Aggregate Risk  tc "5.2  Short-Term Aggregate Risk " \l 2

The short-term aggregate risk assessment estimates risks likely to result from 1- to 30-day exposure to azoxystrobin residues from food, drinking water, and residential pesticide uses.  High-end estimates of residential exposure are used in the short-term assessment, while average values are used for food and drinking water exposure (i.e. chronic exposures).

No endpoint has been selected for short-term dermal exposure to azoxystrobin; therefore it will not be included in this assessment.  The same endpoints were identified for short-term incidental oral and inhalation risk assessment (based on increased maternal diarrhea, urinary incontinence, and salivation).  Therefore, this assessment will combine dietary/incidental oral exposure with inhalation exposure.

A short-term risk assessment was conducted for adults because there is a residential handler inhalation exposure scenario.  In addition, a short-term risk assessment was conducted for toddlers and children because there is a residential post-application oral exposure scenario.  Average food and drinking water exposures are already included in the chronic dietary exposure assessment in Table 4.2.2, above.  Adult inhalation risks are summarized for indoor and outdoor uses in Tables 5.2a and 5.2b, above.  Toddlers’ incidental oral exposure is assumed to include hand-to-mouth exposure, object-to-mouth exposure and exposure through incidental ingestion of soil.  Incidental oral risks for children are summarized for indoor and outdoor uses in Tables 5.3a and 5.3b, above.

As shown below in Table 6.2, the aggregate short-term MOEs for the U.S. population at 2503 and children 1-2 years old at 216 do not exceed HED’s level of concern, a MOE of 100.   HED does not consider short-term aggregate risk for adults and children to be a concern.

Table 6.2.  Short-Term Aggregate Risk (Food, Water and Incidental Oral Exposure)

Population	Short-Term Scenario

	 NOAEL

mg/kg/day	LOC

MOE1	Average

Food + Water Exposure

mg/kg/day	Residential Exposure2

mg/kg/day	Aggregate MOE

 (food and residential)3

U.S. Population

25

100	0.009878	0.00011	2503

Youth (13-19 years)

	0.009499	0.00011	2602

Children (1-2 years)

	0.026629	0.089	216

Females (13-49 years old)

	0.008081	0.00011	3052

1 The level of concern (LOC) MOE is 100, based on inter- and intra-species safety factors totaling 100.

2 Residential Exposure = [Incidental Oral exposure from all possible sources or Inhalation exposure].  No residential oral exposure is expected for adults.

3 Aggregate MOE = [NOAEL (25 mg/kg/day) ÷ (Avg Food Exposure + Residential Exposure)].

6.3	Intermediate-Term Aggregate Risk  tc "5.3  Intermediate-Term Aggregate Risk " \l 2

The intermediate-term aggregate risk assessment estimates risks likely to result from one to six months of exposure to azoxystrobin residues from food, drinking water, and residential pesticide uses.  High-end estimates of residential exposure are used in the intermediate-term assessment, while average values are used for food and drinking water exposure (i.e. chronic exposures).

No endpoint has been selected for intermediate-term dermal exposure to azoxystrobin; therefore it will not be included in this assessment.  The same endpoints were identified for intermediate-term incidental oral and inhalation risk assessment (based on decreased body weight gain in both sexes and clinical signs indicative of reduced nutrition. the basis for the oral endpoint is increased maternal diarrhea, urinary incontinence, and salivation).  Therefore, this assessment will combine dietary/incidental oral exposure with inhalation exposure.

An intermediate-term risk assessment was not conducted for adults because intermediate-term residential handler scenarios are not expected to occur.  However, an intermediate-term risk assessment was conducted for toddlers and children because there is an intermediate-term oral exposure scenario.

Table 6.3  Intermediate-Term Aggregate Risk (Food, Water and Incidental Oral Exposure)

Population	Intermediate-Term Scenario

	 NOAEL

mg/kg/day	LOC

MOE1	Average

Food + Water Exposure

mg/kg/day	Residential Exposure2

mg/kg/day	Aggregate MOE

 (food and residential)3

Children (1-2 years)	20	100	0.026629	0.042	291

1 The level of concern (LOC) MOE is 100, based on inter- and intra-species safety factors totaling 100.

2 Residential Exposure = [Incidental Oral exposure from all possible sources + Inhalation exposure].  No residential oral exposure is expected for adults.

3 Aggregate MOE = [NOAEL (20 mg/kg/day) ÷ (Avg Food Exposure + Residential Exposure)].

As shown above in Table 6.3, the aggregate intermediate-term MOEs for children 1-2 years old, which is the population subgroup with the highest exposure, at 291 do not exceed HED’s level of concern, a MOE of 100.  HED does not consider intermediate-term aggregate risk for children to be a concern.

6.4	Chronic Aggregate Risk  tc "5.4  Chronic Aggregate Risk " \l 2

The aggregate chronic risk assessment takes into account average exposure estimates from dietary consumption of azoxystrobin (food and drinking water) and residential uses.  Since the exposure from all the residential uses is considered short-term, the aggregate chronic assessment included food and drinking water only.  Since the dietary exposure assessment already includes the highest chronic exposure from the drinking water modeling data, no further calculations are necessary.  The general U.S. population and all population subgroups have exposure and risk estimates which are below Agency’s level of concern (i.e., the percentages of the chronic population adjusted doses (cPADs) are all below 100%).  The exposure to the U.S. population was 6% of the cPAD and the most highly exposed subgroup, children 1-2 yrs old, at 15% of the cPAD.  Therefore, chronic risk estimates resulting from aggregate exposure to azoxystrobin in food and drinking water are below the Agency’s level of concern from all population subgroups.

6.5	Cancer Aggregate Risk  tc "5.5  Cancer Aggregate Risk " \l 2

The HED RfD/Peer Review Committee, in its meeting of November 7, 1996, determined that azoxystrobin should be classified as "not likely to be a human carcinogen.”  Due to the classification, no cancer risk assessment was performed.

7.0	Cumulative Risk Characterization/Assessment

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to azoxystrobin and any other substances and azoxystrobin does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that azoxystrobin has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

8.0	Occupational Exposure/Risk Pathway

Workers may be exposed to azoxystrobin during mixing, loading, application, and postapplication activities.  Based on the proposed use pattern, short-, and intermediate-term exposures may occur.  Chronic exposures (more than 6 months of continuous exposure) are not expected.

8.1	Occupational Handler  tc "7.1  Occupational Handler " \l 2

Handlers are assumed to have potential short- (1-30 consecutive days) and intermediate-term (31-180 consecutive days) dermal and inhalation exposure to azoxystrobin.  Although treatment blocks may be quite large, it is unlikely that pesticide handlers would be exposed continuously for 30 days or more (short-term duration exposures).  The HED ExpoSAC maintains it is possible for handlers to have intermediate-term exposure; therefore, estimates of intermediate-term exposures (1 - 6 months) are presented. Long-term handler exposure is not expected via any route.

As previously stated, there is no hazard via the dermal route, therefore, only risk via the inhalation route is considered in this document.  The short-term inhalation toxicity endpoint is based on increased maternal diarrhea, urinary incontinence, and salivation seen in the rat prenatal developmental oral toxicity study at the LOAEL of 100 mg/kg/day (NOAEL = 25 mg/kg/day). The intermediate-term inhalation toxicity endpoint is based on decreased body weight gain in both sexes and clinical signs indicative of reduced nutrition in the rat 90-day feeding study at the LOAEL of 211/223 mg/kg/day in males/females (LOAEL = 20 mg/kg/day).  Daily doses were calculated assuming a 70 kg body weight for adults (because the toxicity endpoints are not gender-specific) and a 100% inhalation absorption factor.

No chemical specific data were available with which to assess potential exposure to pesticide handlers.  The estimates of exposure to pesticide handlers are based upon surrogate study data available in the PHED (v. 1.1, 1998).   For pesticide handlers, it is HED standard practice to present estimates of dermal exposure for “baseline” that is, for handlers wearing a single layer of work clothing consisting of a long sleeved shirt, long pants, shoes plus socks and no protective gloves as well as for “baseline” and the use of protective gloves or other PPE as might be necessary.  The proposed label directs applicators and other handlers to wear long-sleeved shirt, long pants, chemical resistant gloves made of any waterproof material such as polyvinyl chloride, nitrile rubber or butyl rubber and shoes plus socks.

Based upon the proposed new use patterns, the most highly exposed occupational pesticide handler scenarios are:

Mixer/loaders using open-pour loading of liquids

Aerial applicators

Applicators using open-cab ground-boom sprayers and

Handlers preparing irrigation systems to apply by “chemigation”

HED believes that the latter will not be more highly exposed than mixer/loaders using open-pour loading.  Typically chemigation involves the insertion of a siphon tube into a container of concentrate.  The concentrate is metered off, via the siphon tube, into the irrigation stream as it is being pumped.  Thus, there is essentially no “loading” or “handling” in the sense of other application systems. See Table 8.1 for a summary of exposure and risk to occupational pesticide handlers. A MOE of 100 is adequate to protect occupational pesticide handlers from exposures to azoxystrobin.  The estimated MOEs are > 100.   Therefore, these exposures do not exceed HED’s levels of concern.

Table 8.1  Summary of Exposure & Risk for Occupational Handlers Applying Azoxystrobin to Cotton and Wild Rice

Unit Exposure1

mg ai/lb handled	Applic. Rate2

lb ai/unit	Units Treated3	Avg. Daily Exposure4

mg ai/kg bw/day	MOE5

Short term

Interm term

Mixer/Loader Open-pour Liquids

Inhal.           0.0012 HC	0.25 lb ai/A	1200 A/day	Inhal. 0.00514	Short term       4,900

Interm term     3,900

Aerial Applicator (Pilots not required to wear protective gloves)

Inhal.           0.000068 MC	0.25 lb ai/A	1200 A/day	Inhal.  0.0002914 Short term      86,000

Interm term    69,000

Applicator Ground-boom Open-Cab

Inhal.           0.00074 HC	0.25 lb ai/A	200 A/day	Inhal.  0.00053	Short term       47,000

Interm term     38,000

1.  Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE”, Estimates of Worker Exposure from The Pesticide Handler Exposure Database Version 1.1, August 1998.   Inhal. = Inhalation.  Units = mg a.i./pound of active ingredient handled.  Data Confidence:  MC = Medium Confidence, HC = High Confidence.

2.  Application Rate = Taken from the draft supplemental labeling for Abound® Flowable Fungicide.

3.  Units Treated are taken from “Standard Values for Daily Acres Treated in Agriculture”; SOP No. 9.1.   Science Advisory Council for Exposure; Revised 5 July 2000;

4.  Average Daily Dose = Unit Exposure * Applic. Rate * Units Treated ( Body Weight (70 kg since short term NOAEL is identified from a developmental study with maternal effects; intermediate term NOAEL not from developmental study)

5.  MOE = Margin of Exposure = No Observable Adverse Effect Level (NOAEL)  ( ADD.  Short-term NOAEL = 25 mg a.i./kg bw/day; Intermediate-term NOAEL = 20.0 mg ai/kg bw/day

8.2	Short-/Intermediate-Term Postapplication Risk  tc \l2 "9.2 Short-/Intermediate-Term Postapplication Risk

Postapplication exposure is possible for workers tending treated food crops and nursery and landscape ornamentals, however, because no dermal toxicity endpoint was identified for flonicamid, occupational postapplication exposures were not assessed. ARIA/RD believes post-application inhalation exposure is negligible.  Volatilization is not expected after the REI.  Therefore, postapplication exposures are not assessed.

8.3	Restricted Entry Interval

Axoxystrobin is classified in Acute Toxicity Category III for acute dermal toxicity, acute inhalation toxicity and primary eye irritation.  It is classified in Category IV for primary skin irritation.  It is not a dermal sensitizer.  The interim worker protection standard REI of 12 hours is adequate to protect agricultural workers from post-application exposures to azoxystrobin.  As noted earlier, the label lists a REI of 4 hours.  The ARIA team suggests that the product management  team confirm or correct the REI listed on the label as per the guidance provided in PR Notice 95-03 and Chapter 40 Code of Federal Regulations § 156.208 (2) (iii).

9.0	Tolerance Summary

HED previously determined that the residue of concern for the purposes of risk assessment and tolerance expression should include parent azoxystrobin and its Z-isomer for plants and azoxystrobin per se for livestock. A summary of the recommended tolerances for the fungicide azoxystrobin in/on the commodities is presented in Table 9.0 below.

Tolerances for azoxystrobin residues are currently established on plant commodities at levels ranging from 0.01 to 260 ppm (40 CFR §180.507(a)(1)).  Time-limited tolerances are also established under 40 CFR §180.507(b) for Brassica, head and stem subgroup 5A (30 ppm; expired 12/31/06, but a permanent tolerance has been established under 40 CFR §180.507(1)(a)), wild rice(5 ppm; expires 12/31/09), and safflower seed (1 ppm; expires 6/30/08).

Tolerances for livestock commodities are listed in 40 CFR §180.507(a)(2) and range from 0.006 (milk) to 0.07 (meat byproducts) ppm; no tolerances are currently established for poultry commodities.

Tolerances for rotational crop commodities are not needed.  The existing rotational crop plantback intervals are acceptable to preclude the need for rotational crop trials.

Table 9.0. Tolerance Summary for Azoxystrobin

Commodity	Proposed Tolerance (ppm)	Recommended Tolerance (ppm)	Comments

(Correct Commodity Definition)

Tolerances Proposed Under PP#6F7106 for 40 CFR §180.507(a)(1)

Aspirated grain fractions	112	420	The listed 10 (based on wheat) and 30 (based on soybean) ppm tolerances for this RAC should be removed and replaced with this recommended tolerance level.

Grain, aspirated fractions

Barley, forage	30	25

	Non-grass Animal Feeds

--Forage	35	45	Animal feed, nongrass, forage, group 18

Non-grass Animal Feeds

--hay	100	120	Animal feed, nongrass, hay, group 18

Sorghum – forage	25	25	Sorghum, grain, forage

Sorghum – grain	9	11	Sorghum, grain

Sorghum – stover	40	40	Sorghum, grain, stover

Wheat – forage	30	25	Wheat, forage

Tolerances Proposed Under PP#6F7106 for 40 CFR §180.507(a)(2)

Cattle, fat	0.13	0.03

	Cattle, kidney	1.00	Not needed; covered by tolerance for meat byproducts

	Cattle, liver	5.10

Cattle, meat	0.07	0.01

	Cattle, meat byproducts (except liver and kidney)	0.07	0.07	Cattle, meat byproducts

Goat, fat	0.13	0.03

	Goat, kidney	1.00	Not needed; covered by tolerance for meat byproducts

	Goat, liver	5.10

Goat, meat	0.07	0.01

	Goat, meat byproducts (except liver and kidney) 	0.07	0.07	Goat, meat byproducts

Egg White	0.01	Not needed

	Egg Yolk	0.15

Hog, fat	1.10	0.01

	Hog, kidney	0.03	Not needed

	Hog, liver	0.23

Hog, meat	0.01	0.01

	Hog, meat byproducts (except liver and kidney) 	0.01	0.01	Hog, meat byproducts

Horse, fat	--	0.03

	Horse, kidney	1.00	Not needed; covered by tolerance for meat byproducts

	Horse, liver	5.10

Horse, meat	0.07	0.01

	Horse, meat byproducts	0.07	0.07

	Milk	0.05	0.006

	Poultry, Fat	0.01	Not needed

	Poultry, Liver	0.12

Poultry, Meat	0.02

Sheep, fat	0.13	0.03

	Sheep, kidney	1.00	Not needed; covered by tolerance for meat byproducts

	Sheep, liver	5.10

Sheep, meat	0.07	0.01

	Sheep, meat byproducts (except liver and kidney)	0.07	0.07	Sheep, meat byproducts

Tolerances Proposed Under PP#7F7198 for 40 CFR §180.507(a)(1)

Cotton, undelinted seed	0.7	0.6

	Cotton, gin byproducts	35.0	45

	Wild rice	5.0	5.0	Rice, wild, grain

10.0 Data Needs and Label Recommendations

10.1	Toxicology

 tc "8.1  Toxicology " \l 2

The HIARC determined that a 28-day inhalation toxicity study (nose-only) is required due to concern for occupational/residential exposure via this route based on the current use pattern; the 90-day protocol should be followed with an exposure duration of 28-days. However, the registrant has submitted a waiver request for the 28-day study and the waiver request will be addressed in a separate memo.

10.2	Residue Chemistry  tc "8.2  Residue Chemistry " \l 2

A revised Section F is required removing the requested tolerance increases in milk and the fat, meat, and meat byproducts of cattle, goat, horse, sheep, and swine.

	A revised Section F is required removing the requested tolerance increases in eggs and the fat, meat, and meat byproducts of poultry.

	Barley:  A revised Section F to specify a tolerance level of 25 ppm for barley forage is required.

Nongrass Animal Feed:  A revised Section F is required at 45 ppm for forage and 120 ppm for hay of the nongrass animal feeds crop group 18.

	Sorghum:  An amended Section F is required to revise the proposed tolerance for sorghum grain from 9 ppm to 11 ppm.  A revised Section F is required at 420 ppm for aspirated grain fractions.

	Wheat:  An amended Section F is required to revise the proposed tolerance for wheat forage to 25 ppm.

	Cotton:  An amended Section F is required to revise the proposed tolerances for undelinted cottonseed at 0.6 ppm and for cotton gin byproducts at 45 ppm.

10.3 Occupational and Residential Exposure

None Identified

References

Azoxystrobin: Human Health Risk Assessment for New Uses on Foliage of Legume Vegetables, Group 7; Fruiting Vegetables, Group 8 (Except Tomato); Pea and Bean, Succulent and Dried Shelled (Except Soybeans), Subgroups 6B and 6C; Nongrass Animal Feeds, Group 18; and Citrus; and Section 18 Requests for Groups 6 and 7 to Control Soybean Rust. DP#s 317291, 317331, 317333; W. Cutchin; 7/20/2006.

Azoxystrobin: Report of the Hazard Identification Assessment Review Committee. TXR#0014329; Ghazi A. Dannan; 9/25/2000.

HED Metabolism Assessment Review Committee Decision Memo. PP#5F4541, DP#s 218318 and 218448; J. Garbus; 3/19/96; PP#6F4762, DP#s 230634, 230635, 230636 and 230637, L. Kutney; 4/25/97; DP# 251683; W. Wassell; 2/30/98.

Drinking and Aquatic Exposure Water Assessment for Azoxystrobin for a Number of New Uses or Tolerance Assessments. Environmental Risk Branch 3, EFED; DP Barcodes 301948, 312950, 312952, 312954, 313858, and 317292; J. K. Wolf; 3/16/2006.

Aquatic Exposure Assessment of Azoxystrobin on Artichoke, Head and Stem Brassica, Asparagus and Herbs (except chives). Environmental Risk Branch 3, EFED; DP Barcodes 285061, 285064, 285068, and 285078; K.Costello;11/5/2002. tc "4.3  Water Exposure/Risk Pathway " \l 2

Azoxystrobin. Petitions for the Establishment of Permanent Tolerances for New/Amended Uses on Non-grass Animal Feeds (Crop Group 18), Sorghum, Wheat, Cotton and Wild Rice; PP#s6F7106 & 7F7198;  Summary of Analytical Chemistry and Residue Data. DP#s 334751 and 340016; W. Cutchin; 3/12/08.

Azoxystrobin: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for Section 3 Registration Action For New Uses on Wild Rice; Cotton, Undelinted Seed; Cotton, Gin Byproducts (Petition# 7F7198); and Uses on Aspirated Grain Fractions; Barley, Forage; Nongrass Animal Feeds, Forage, Group 18; Nongrass Animal Feeds, Hay, Group 18; Sorghum, Forage; Sorghum, Grain; Sorghum, Stover; and Wheat, Forage. Petition# 6F7106; D348594;D. Rate; 3/5/08.

Azoxystrobin. Occupational and Residential Risk Assessment for Proposed Uses on Citrus (post-harvest), Fruiting Vegetables, Legume Vegetables (foliage), Peas and Beans (Subgroups 6B and 6C) and Nongrass Animal Feeds (Crop Group 18). D317293; S. Winfield; 7/6/2006.

Azoxystrobin – Occupational Exposure/Risk Assessment for the Proposed New Use of Azoxystrobin on Cotton and Wild Rice. D346544; M. Dow; 10/5/2007.

Appendix A:

Table A1. Toxicity Profile

Guideline

 No.

Study Type

MRID #

Results

Toxicity Category

870.1100

Acute Oral - Rat

43678122

LD50 > 5000 mg/kg (Limit Test) in Males & Females

IV

870.1200

Acute Dermal - Rat

43678124

LD50 > 2000 mg/kg (Limit Test) in Males & Females

III

870.1300

Acute Inhalation - Rat

43678126

LC50 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

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