Document ID: EPA-HQ-OPP-2009-0076-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-10-16T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF           

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

DATE:	August 20, 2009

SUBJECT:	Azoxystrobin.  Human Health Risk Assessment for a Section 3
Amendment to Reduce the Preharvest Interval for Barley Grain and Straw
and to Add Seed Treatment Uses on Head and Stem Brassica Vegetables
(Subgroup 5A) and Sorghum, Grain.  

		

PC Code:  128810	DP Barcodes:  360153 & 367067

Decision Nos.:  403237 & 401489	Registration Nos.:  100-1098 & 100-1159

Petition No.: 8E7474	Regulatory Action:  Amended Section 3

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:			Meheret Negussie, Chemist/Risk Assessor

	Barry O’Keefe, Senior Biologist

	Whang Phang, Toxicologist

			Risk Assessment Branch III

Health Effects Division (7509P)

THROUGH:	Paula Deschamp, Branch Chief

		Risk Assessment Branch III

		Health Effects Division (7509P)

	

TO:	Tony Kish, RM# 22/	Barbara Madden RM# 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 Health Effects Division (HED)
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. 

Under PP#8E7474, Interregional Research Project No. 4 (IR-4), on behalf
of the Agricultural Experiment Stations of CO, ID, ND, and SD, is
requesting revision of the established tolerances for the combined
residues of the fungicide azoxystrobin and the Z-isomer of azoxystrobin
on barley grain and straw.  Separately, Syngenta Crop Protection, Inc.
(Syngenta) has requested to amend the label for Dynasty® Fungicide (EPA
Reg. No. 100-1159), a suspension concentrate (SC) formulation containing
9.6% ai (0.83 lb ai/gal) azoxystrobin, to add seed treatment uses on
sorghum, grain and the head and stem Brassica subgroup 5A.  The proposed
seed treatment rates correspond to field equivalent rates of
0.0012-0.002 lb ai/A.

No data pertinent to the hazard assessment have been submitted since the
most recent risk 

assessment conducted on non-grass animal feeds (Crop Group 18), sorghum,
wheat, cotton, and 

wild rice (S. Piper, 04/30/2008, DP# 344389).  The hazard
characterization/endpoint 

selection and residential exposure (non-occupational) assessment have
not changed since 

the previous risk assessments on azoxystrobin and can be applied
directly to this action.  This

document provides a summary of the findings from the data evaluation and
assessment of 

human health risk that results from proposed modification of the
registered foliar uses on barley 

to reduce the preharvest interval (PHI) for grain and straw from 45 days
to 14 days and to add 

seed treatment uses on sorghum, grain and the head and stem Brassica
subgroup 5A.

A summary of the findings and an assessment of human risk are provided
in this document.  The hazard characterization and endpoint selection
were provided by Whang Phang (HED), the occupational exposure assessment
by Barry O’Keefe (HED), the residue chemistry data review, the dietary
exposure assessment, and the risk assessment by Meheret Negussie (HED),
and the drinking water exposure assessment by James Wolf of the
Environmental Fate and Effects Division (EFED).

Table of Contents

  TOC \o "1-7" \h \z \u    HYPERLINK \l "_Toc237503914"  1.0   Executive
Summary	  PAGEREF _Toc237503914 \h  5  

  HYPERLINK \l "_Toc237503915"  2.0   Ingredient Profile	  PAGEREF
_Toc237503915 \h  11  

  HYPERLINK \l "_Toc237503916"  2.1   Summary of Registered/Proposed
Uses	  PAGEREF _Toc237503916 \h  11  

  HYPERLINK \l "_Toc237503917"  2.2   Structure and Nomenclature	 
PAGEREF _Toc237503917 \h  13  

  HYPERLINK \l "_Toc237503918"  2.3   Physical and Chemical Properties	 
PAGEREF _Toc237503918 \h  14  

  HYPERLINK \l "_Toc237503919"  3.0   Hazard Characterization/Assessment
  PAGEREF _Toc237503919 \h  14  

  HYPERLINK \l "_Toc237503920"  3.1	Hazard and Dose-Response
Characterization	  PAGEREF _Toc237503920 \h  14  

  HYPERLINK \l "_Toc237503921"  3.1.1   Database Summary	  PAGEREF
_Toc237503921 \h  14  

  HYPERLINK \l "_Toc237503922"  3.1.2	 Toxicological Effects	  PAGEREF
_Toc237503922 \h  15  

  HYPERLINK \l "_Toc237503923"  3.1.3    Absorption, Distribution,
Metabolism, and Excretion (ADME)	  PAGEREF _Toc237503923 \h  15  

  HYPERLINK \l "_Toc237503924"  3.2	  FQPA Considerations	  PAGEREF
_Toc237503924 \h  15  

  HYPERLINK \l "_Toc237503925"  3.2.1	  Adequacy of the Toxicity
Database	  PAGEREF _Toc237503925 \h  15  

  HYPERLINK \l "_Toc237503926"  3.2.2	 Evidence of Neurotoxicity	 
PAGEREF _Toc237503926 \h  16  

  HYPERLINK \l "_Toc237503927"  3.2.3 	Developmental Toxicity Studies	 
PAGEREF _Toc237503927 \h  16  

  HYPERLINK \l "_Toc237503928"  3.2.4   Reproductive Toxicity Study	 
PAGEREF _Toc237503928 \h  16  

  HYPERLINK \l "_Toc237503929"  3.2.5	   Additional Information from
Literature Sources	  PAGEREF _Toc237503929 \h  16  

  HYPERLINK \l "_Toc237503930"  3.2.6	 Pre-and/or Postnatal Toxicity	 
PAGEREF _Toc237503930 \h  16  

  HYPERLINK \l "_Toc237503931"  3.2.7 FQPA Safety Factor for Infants and
Children	  PAGEREF _Toc237503931 \h  16  

  HYPERLINK \l "_Toc237503932"  3.3 	Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc237503932 \h  17  

  HYPERLINK \l "_Toc237503933"  3.3.1 Comments about
Study/Endpoint/Uncertainty Factor: Acute RfD/PAD	  PAGEREF _Toc237503933
\h  17  

  HYPERLINK \l "_Toc237503934"  3.3.2   Level of Concern for Margin of
Exposure	  PAGEREF _Toc237503934 \h  18  

  HYPERLINK \l "_Toc237503935"  3.3.3	 Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc237503935 \h  18  

  HYPERLINK \l "_Toc237503936"  3.3.4 Classification of Carcinogenic
Potential	  PAGEREF _Toc237503936 \h  19  

  HYPERLINK \l "_Toc237503937"  3.3.5  Summary of Toxicological Doses
and Endpoints	  PAGEREF _Toc237503937 \h  19  

  HYPERLINK \l "_Toc237503938"  3.4	Endocrine Disruption	  PAGEREF
_Toc237503938 \h  20  

  HYPERLINK \l "_Toc237503939"  4.0	DIETARY EXPOSURE/RISK
CHARACTERIZATION	  PAGEREF _Toc237503939 \h  21  

  HYPERLINK \l "_Toc237503940"  4.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc237503940 \h  21  

  HYPERLINK \l "_Toc237503941"  4.1.1	  Metabolism in Primary Crops	 
PAGEREF _Toc237503941 \h  21  

  HYPERLINK \l "_Toc237503942"  4.1.2	Metabolism in Rotational Crops	 
PAGEREF _Toc237503942 \h  21  

  HYPERLINK \l "_Toc237503943"  4.1.3	Metabolism in Livestock	  PAGEREF
_Toc237503943 \h  22  

  HYPERLINK \l "_Toc237503944"  4.1.4	Analytical Methodology	  PAGEREF
_Toc237503944 \h  22  

  HYPERLINK \l "_Toc237503945"  4.1.5	Multiresidue Methods	  PAGEREF
_Toc237503945 \h  23  

  HYPERLINK \l "_Toc237503946"  4.1.6 	Storage Stability	  PAGEREF
_Toc237503946 \h  23  

  HYPERLINK \l "_Toc237503947"  4.1.7	Food Residue Profile	  PAGEREF
_Toc237503947 \h  23  

  HYPERLINK \l "_Toc237503948"  4.1.8	Confined and Field Rotational
Crops	  PAGEREF _Toc237503948 \h  26  

  HYPERLINK \l "_Toc237503949"  4.1.9	Pesticide Metabolites and
Degradates of Concern	  PAGEREF _Toc237503949 \h  27  

  HYPERLINK \l "_Toc237503950"  4.1.10	International Residue Limits	 
PAGEREF _Toc237503950 \h  27  

  HYPERLINK \l "_Toc237503951"  4.1.11 	Environmental Degradation	 
PAGEREF _Toc237503951 \h  28  

  HYPERLINK \l "_Toc237503952"  4.1.12 Drinking Water Residue Profile	 
PAGEREF _Toc237503952 \h  28  

  HYPERLINK \l "_Toc237503953"  4.2	Dietary Exposure and Risk
Characterization	  PAGEREF _Toc237503953 \h  29  

  HYPERLINK \l "_Toc237503954"  4.2.1	Acute and Chronic Dietary	 
PAGEREF _Toc237503954 \h  30  

  HYPERLINK \l "_Toc237503955"  4.2.2	Cancer Dietary	  PAGEREF
_Toc237503955 \h  31  

  HYPERLINK \l "_Toc237503956"  4.3	Anticipated Residues and Percent
Crop Treated (%CT) Information	  PAGEREF _Toc237503956 \h  31  

  HYPERLINK \l "_Toc237503957"  5.0	Residential (Non-Occupational)
Exposure/Risk Characterization	  PAGEREF _Toc237503957 \h  32  

  HYPERLINK \l "_Toc237503958"  5.1	Residential Uses	  PAGEREF
_Toc237503958 \h  32  

  HYPERLINK \l "_Toc237503959"  5.2	Residential Handler Exposure and
Risk	  PAGEREF _Toc237503959 \h  32  

  HYPERLINK \l "_Toc237503960"  5.3	Residential Postapplication Exposure
and Risk	  PAGEREF _Toc237503960 \h  34  

  HYPERLINK \l "_Toc237503961"  5.4	Recreational Postapplication
Exposure and Risk	  PAGEREF _Toc237503961 \h  36  

  HYPERLINK \l "_Toc237503962"  5.5	Off Target Non-Occupational Exposure
  PAGEREF _Toc237503962 \h  36  

  HYPERLINK \l "_Toc237503963"  6.0	Aggregate Risk Assessment and Risk
Characterization	  PAGEREF _Toc237503963 \h  36  

  HYPERLINK \l "_Toc237503964"  6.1	Acute Aggregate Risk	  PAGEREF
_Toc237503964 \h  36  

  HYPERLINK \l "_Toc237503965"  6.2	Short-Term Aggregate Risk	  PAGEREF
_Toc237503965 \h  37  

  HYPERLINK \l "_Toc237503966"  6.3	Intermediate-Term Aggregate Risk	 
PAGEREF _Toc237503966 \h  38  

  HYPERLINK \l "_Toc237503967"  6.4	Chronic Aggregate Risk	  PAGEREF
_Toc237503967 \h  39  

  HYPERLINK \l "_Toc237503968"  6.5	Cancer Aggregate Risk	  PAGEREF
_Toc237503968 \h  39  

  HYPERLINK \l "_Toc237503969"  7.0	Cumulative Risk
Characterization/Assessment	  PAGEREF _Toc237503969 \h  39  

  HYPERLINK \l "_Toc237503970"  8.0	Occupational Exposure/Risk Pathway	 
PAGEREF _Toc237503970 \h  39  

  HYPERLINK \l "_Toc237503974"  8.1	Occupational Handler	  PAGEREF
_Toc237503974 \h  40  

  HYPERLINK \l "_Toc237503975"  8.2	Short-/Intermediate-Term
Postapplication Risk	  PAGEREF _Toc237503975 \h  42  

  HYPERLINK \l "_Toc237503976"  8.3	Restricted Entry Interval	  PAGEREF
_Toc237503976 \h  43  

  HYPERLINK \l "_Toc237503977"  9.0	Tolerance Summary and Revisions to
Petitioned-for Barley Tolerances	  PAGEREF _Toc237503977 \h  43  

  HYPERLINK \l "_Toc237503978"  10.0 Data Needs and Label
Recommendations	  PAGEREF _Toc237503978 \h  44  

  HYPERLINK \l "_Toc237503979"  10.1	Toxicology	  PAGEREF _Toc237503979
\h  44  

  HYPERLINK \l "_Toc237503980"  10.2	Residue Chemistry	  PAGEREF
_Toc237503980 \h  44  

  HYPERLINK \l "_Toc237503981"  10.3 Occupational and Residential
Exposure	  PAGEREF _Toc237503981 \h  45  

  HYPERLINK \l "_Toc237503982"  Appendix A: Toxicity Profile	  PAGEREF
_Toc237503982 \h  48  

  HYPERLINK \l "_Toc237503983"  Table A1.  Acute Toxicity Data on
Technical Azoxystrobin	  PAGEREF _Toc237503983 \h  48  

  HYPERLINK \l "_Toc237503984"  Table A2.  Azoxystrobin Toxicity Results
From Repeated Dosing and Other Studies	  PAGEREF _Toc237503984 \h  48  

  HYPERLINK \l "_Toc237503985"  Appendix B:	International Residue Limit
Status Sheet	  PAGEREF _Toc237503985 \h  52  

 

1.0   Executive Summary

 tc "1.0 EXECUTIVE SUMMARY" 

Azoxystrobin [methyl (E)-2-(2-(6-(2-cyanophenoxy) pyrimidin-4-yloxy)
phenyl)-3-

methoxyacrylate] is a broad-spectrum fungicide and belongs to a class of
pesticidal compounds 

called β-methoxyacrylates, which are derived from the naturally
occurring strobilurins.  Its 

biochemical mode of action is inhibition of electron transport.  The
fungicide is currently

registered for use on a variety of field, vegetable, fruit, and nut
crops as well as on ornamental 

plants and turf.  HED conducted a human health risk assessment for the
fungicide azoxystrobin 

to support a proposed tolerance increase and  modification of the
registered foliar uses on 

barley to reduce the PHI for grain and straw from 45 days to 14 days,
and to add seed treatment 

uses on sorghum, grain and the head and stem Brassica subgroup 5A.

The existing tolerances on barley grain and straw supported by data
translated from wheat, were established as national tolerances.  The
proposed barley grain and straw tolerance increase and requested
reduction in PHI was intended to support a regional registration.  HED
recommends the Office of General Counsel (OGC) be consulted to determine
whether separate tolerances with regional registration should be
established under 40 CFR §180.507(c) for barley bran, grain, and straw,
or the existing national tolerances for barley bran, grain, and straw
[under 40 CFR §180.507(a)(1)] should be increased (ChemSAC 05/27/09).

The current risk assessment on azoxystrobin evaluates the proposed
amendment to the existing

uses of barley which results in an increase of tolerance (from 0.1 ppm
to 3.0 ppm).  The 

increase of tolerance has no effect in the acute dietary exposure, and a
lower chronic population 

adjusted dose (cPAD) is calculated for the chronic dietary exposure.  A
new screening level 

usage analysis (SLUA; 04/09/2009) was incorporated in the chronic
dietary exposure 

assessment.  Treated paint use (preservative incorporation) was included
in the residential exposure assessment.  In addition, a new occupational
exposure assessment was conducted to evaluate the new seed treatment use
on Head and Stem Brassica and sorghum, grain.  In the current assessment
a newly required immunotoxicity study is required.

 

The hazard characterization elements, i.e., endpoint selection, FQPA
safety factor (SF), and 

residential exposures (use on turfgrass and indoor surfaces) and the
estimated drinking water 

concentration (EDWC), remain unchanged relative to the previous risk
assessment (S. Piper, 04/30/2008, DP# 344389).  

Use Profile

End-use products of azoxystrobin are typically formulated as water
dispersible granular (WDG) and suspension concentrate (SC) 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
bananas/plantains and citrus fruits.

IR-4 wishes to amend the product label for Abound® Flowable Fungicide
(EPA Reg. No. 100-1098), a SC formulation containing 22.9% ai (2.08 lb
ai/gal) of azoxystrobin on barley.  Applications are to be made prior to
disease development up to late head emergence (BBCH-59) using foliar,
ground, aerial or chemigation equipment.  Foliar broadcast applications
are to be made at 0.192-0.207 lb ai/A/application for a total seasonal
rate of 0.391-0.411 lb ai/A with a 14-day PHI.

In addition, Syngenta Crop Protection, Inc. has requested to amend the
label for Dynasty® Fungicide (EPA Reg. No. 100-1159), a SC formulation
containing 9.6% ai (0.83 lb ai/gal) azoxystrobin, to add seed treatment
uses on sorghum, grain and the head and stem Brassica subgroup 5A.  The
proposed seed treatment rates correspond to field equivalent rates of
0.0012-0.002 lb ai/A applied as a water-based slurry using seed
treatment application equipment. 

Hazard Profile

The toxicology database is essentially complete with the exception of a
newly required immunotoxicity study. 

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.  In dogs, effects on the liver
and biliary functions were found with oral administration.  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.  The reproduction and developmental toxicity data
indicate no increase in susceptibility to pre and postnatal exposure to
azoxystrobin.  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.

The study selected for the acute reference dose (aRFD) and population
adjusted dose (aPAD) did not identify a no adverse effect level (NOAEL).
 To account for the uncertainty for extrapolation from a low observed
effect level (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.  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 and there is no
concern for developmental or neurotoxic effects.  

	

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.  

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

The nature of the residue in plants, rotational crops, and livestock 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 maximum reasonably balanced
livestock diets were constructed.  Reassessment of tolerances indicates
that no increases in the existing tolerances for milk, fat, meat and
meat byproducts 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

Acute and chronic aggregate dietary (food and drinking water) exposure
and 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 the Section 3 petition
(PP#8E7474) to revise established tolerances for the combined residues
of the fungicide azoxystrobin and the Z-isomer on barley grain and
straw, due to a reduction in the PHI from 45 days to 14 days. 

An acute dietary analysis for azoxystrobin was conducted using tolerance
levels and 100% crop treated (CT).  DEEM version 7.81 default processing
factors were assumed except for where tolerances were established for
processed commodities.  The highest estimated drinking water
concentration (EDWC) for acute exposure, 173 ppb, was used in the
analysis.  The dietary exposure estimate was 25% of the acute population
adjusted dose (aPAD) for the U.S. population and was 70% of the aPAD for
the most highly exposed subgroup, children 1-2 yrs old.  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 (LOC) for the U.S. population or any population
subgroup. 

A chronic dietary analysis for azoxystrobin was conducted using
tolerance levels and average % CT estimates when available.  DEEM
version 7.81 default processing factors were assumed except for where
tolerances were established for processed commodities.  The EDWC for
chronic exposure, 33 ppb, was used in the analysis.  The dietary
exposure estimate was 4.3% of the chronic population adjusted dose
(cPAD) for the U.S. population and was 9.6% of the cPAD for the most
highly exposed subgroup, children 1-2 yrs old.  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
LOC for the U.S. population or any population subgroup. 

 

Residential Risk

Residential handler exposures are not assessed in this document because
the proposed uses of azoxystrobin do not involve applications by
homeowners or commercial applicators in residential settings at this
time.  However, azoxystrobin is currently registered for use on
residential turf grass and ornamentals, indoor surfaces, and treated
paints (preservative incorporation).  Residential post-application
exposure and risks from use on turfgrass, indoor surfaces, and treated
paints (preservative incorporation) were assessed in previous separate
documents.  

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 (turf use and treated paints) are
below HED’s LOC.

	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 drinking water) for the U.S.
population at 25% of the aPAD and for the most highly exposed subgroup,
children 1-2 yrs old, at 70% of the aPAD do not exceed HED’s LOC. 

	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 aggregate short-term MOEs, combining food, drinking water
and residential exposures, ranged from 240 for children 1-2 yrs old to
1000 for females 13-49 yrs old.  Risk estimates for all population
subgroups are below HED’s LOC.

	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 not
conducted 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
post-application incidental oral exposure scenario.  The aggregate
intermediate-term MOE, combining food, drinking water, and residential
exposures for the most highly exposed subgroup is 340 for children 1-2
yrs old.  Risk estimates for all population subgroups are below HED’s
LOC. 

	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.  The dietary
exposure estimate for the U.S. population was 4.3% of the cPAD and the
most highly exposed subgroup, children 1-2 yrs old, was 9.6% of the
cPAD.  Risk estimates for all population subgroups are below HED’s LOC
(100% of the cPAD).  Therefore, chronic aggregate risk is below HED’s
LOC.

Occupational Risk	

Occupational handler exposure is expected for individuals involved in
commercial and on-farm seed treatment (primary handlers) and planting
treated seeds (secondary handlers).  Occupational handler assessments
for azoxystrobin were based on surrogate unit exposures from the HED
Science Advisory Council for Exposure (ExpoSAC) Policy 14: Standard
Operating Procedures (SOPs) for Seed Treatment.  Defaults for the amount
of seed treated per day and the amount of treated seed planted per day
were based on ExpoSAC Policy 15:   SEQ CHAPTER \h \r 1 Amount of Seed
Treated or Planted per Day.

The results of the occupational handler exposure and risk assessment
indicate that short- and intermediate-term inhalation risks do not
exceed HED’s LOC (i.e.; MOEs = 100) at baseline level of risk
mitigation (i.e., no respirator) for any of the head and stem Brassica
and sorghum, grain treatment scenarios.  

Sustained levels of contact with treated seed after it has been placed
in the soil or other planting media would not be expected because no
routine cultural practice required for the production of agricultural
commodities involves such an activity as defined in the no/low contact
criteria in the Worker Protection Standard (WPS).  Therefore, no
quantitative postapplication assessment is required for exposure to
treated seeds that have already been planted.

The azoxystrobin active ingredient has been classified in Acute Toxicity
Category III for acute dermal toxicity and primary eye irritation and
Category IV for primary skin irritation.  The WPS requires a 12-hour
restricted entry interval (REI) for active ingredients classified as
Toxicity Category III or IV for these routes of exposure.  However, if
certain criteria are met, the 12-hour REI may be reduced to 4 hours. 
The proposed label lists a REI of 4 hours.  HED 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).  

HED recommends that the Registration Division ensure that appropriate
language is placed on the product label, i.e., to require the label on
treated seed to include the REI following the planting of treated seed.

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 Seed Treatment SOPs have
been determined to require a review of their ethical conduct, have
received that review, and have been determined to be ethical.

Recommendations for Tolerances

Pending submission of revised Sections B and F, there are no residue
chemistry issues that would preclude granting a conditional registration
for the requested seed treatment uses of azoxystrobin on head and stem
Brassica vegetables (subgroup 5A) and sorghum, grain, and the regionally
restricted request to reduce the PHI for barley grain and straw
(PP#8E7474). The conditional registration can be made permanent pending
submission of the remaining deficiencies (newly required immunotoxicity
study) listed in Section 9.0.

The proposed reduced PHI for barley grain 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, as summarized in Table 1.

	0.2	--	6.0

	Barley, grain	0.1	3.0	3.0

	Barley, straw	4.0	7.0	7.0

	

The proposed seed-treatment uses on head and stem Brassica vegetables
and sorghum, grain are not expected to have an impact on residues in the
related commodities; therefore, no changes are needed to the established
tolerances for the commodities of head and stem Brassica subgroup 5A and
sorghum, grain.  

Revisions to Petitioned-for Tolerances

Based on previously submitted wheat processing data (PP#6F4762), a
tolerance for barley bran was established at 0.2 ppm.  The proposed
reduced PHI for barley grain results in higher residues in the grain,
and therefore the potential for increased residues in barley bran. 
Using the highest average field trial (HAFT) for barley grain harvested
at the 14-day PHI  (1.85 ppm) and the concentration factor for wheat
bran (3x), expected residues in barley bran would be 5.55 ppm, which
exceeds the recommended increased tolerance of 3 ppm for barley grain
and the existing tolerance of 0.2 ppm for barley bran.  Therefore, HED
recommends an increase of tolerance for barley bran at 6.0 ppm.  A
revised Section F to propose an increase of tolerance for residues of
azoxystrobin and its Z-isomer in barley bran at 6.0 ppm is required.

Conditions of Registration

HED recommends conversion of conditional registration to unconditional
registration for the barley grain and straw upon adequate resolution of
data pertaining to immunotoxicity.

	

2.0   Ingredient Profile

Azoxystrobin is a broad spectrum fungicide for control of many plant
diseases such as early and late leaf spot in peanuts, late blight in
pistachios, brown rot blossom blight and fruit rot in stone fruits, and
leaf and fruit spot in tree nuts.  It has the same biochemical mode of
action as the naturally occurring strobilurins and is structurally
related.  Azoxystrobin is a (-methoxyacrylate.    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 Crop
Label Date

Abound® Flowable Fungicide	100-1098	22.9% ai 

(2.08 lb ai/gal) 	SC	Barley	Proposed supplemental label dated 7/10/08;

undated text use directions

Dynasty® Fungicide	100-1159	9.6% ai 

(0.83 lb/gal)	SC	Head and stem Brassica vegetables and sorghum, grain
Proposed label dated 10/15/08

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 ai/gal SC

[100-1098]	0.10-0.20	2	0.40	14 	Applications are to be made prior to
disease development up to late head emergence (Feekes 10.5 or Zadok’s
59, BBCH-59) stage.  A crop oil concentrate adjuvant may be added at
1.0% v/v.  The 14-day PHI for grain and straw is specified for AZ, CO,
ID, MT, NV, NM, OR, west TX, UT, WA, and WY only.  

Head and Stem Brassica Subgroup 5A (broccoli, Brussels sprouts, cabbage,
cauliflower, Cavolo broccolo, Chinese broccoli, Chinese cabbage (napa),
Chinese mustard cabbage, kohlrabi)

Seed treatment	0.83 lb/gal SC

[100-1159]	0.001-0.024

lb ai/100 lb seed

(0.0012 lb ai/A)1	Not specified	Apply as a water-based slurry using seed
treatment application equipment; use with an EPA-approved dye.  The use
of treated seed for food, feed, or oil purposes is prohibited.

Sorghum, Grain

Seed treatment	0.83 lb/gal SC

[100-1159]	0.010-0.020

lb ai/100 lb seed

(0.0020 lb ai/A)2	Not specified	Apply as a water-based slurry using seed
treatment application equipment; use with an EPA-approved dye.  The use
of treated seed for food, feed, or oil purposes is prohibited.

1Calculated using the maximum head and stem Brassica seeding rate of 5
lb/A, specified for kohlrabi in HED EXPOSAC SOP 15 (“Amount of Seed
Treated or Planted Per Day,” 3/2/04).

2Calculated using the maximum seeding rate for sorghum, grain of 10 lb/A
(HED EXPOSAC SOP 15). 

The proposed supplemental label for the 2.08 lb ai/gal SC formulation
specifies that all applicable directions, restrictions, and precautions
on the EPA-registered label are to be followed.  The most recent label
for Abound® Flowable Fungicide (EPA Reg. No. 100-1098, main label dated
7/27/07 and supplemental label accepted 7/10/08) specifies that the
product 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).  The following plantback intervals
(PBIs) have been established:  12 months for buckwheat, millet, oats,
and rye; 36 days for leafy vegetables (except Brassica) group, Brassica
leafy greens subgroup, root vegetables subgroup, tuberous and corm
vegetable subgroup, and leaves of root and tuber vegetables group; and 0
days for all other crops.  

The text description of the proposed uses on barley specifies a minimum
RTI of 14 days; no retreatment intervals are specified on the
supplemental label.  The text use directions also specify that the
proposed use is to be restricted to “Western Montana (W. of Rt. 87 /
I-15), Western Wyoming (W. of I-25 / I-90), Colorado, West Texas (W. of
Rt. 283 / 377), New Mexico, Arizona (N. of I-10), Utah, Nevada, Idaho,
Oregon and Washington.”

The 2.08 lb ai/gal SC formulation is currently registered for use on
barley at a 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 (supplemental label
accepted 7/10/2008). 

 

The 2.08 lb ai/gal SC formulation is also registered for foliar
applications to head and stem Brassica vegetables at a maximum seasonal
rate of 1.50 lb ai/A with a 0-day PHI (label dated 7/27/07).  In
addition, the 2.08 lb ai/gal SC formulation is registered for foliar
applications to sorghum, grain at maximum seasonal rates of 0.50 lb ai/A
for sorghum, grain, forage and 0.75 lb ai/A for sorghum, grain, grain
and stover; a 14-day PHI has been established for sorghum, grain forage,
grain, and stover (supplemental label accepted 7/10/2008). 

The label directions are adequate to allow evaluation of the residue
data relative to the proposed uses.  The proposed supplemental label for
seed treatment use on head and stem Brassica vegetables and sorghum,
grain is adequate; no amendments are required. 

 

The required revisions to Section B are summarized in Section 10.0 (Data
Needs/Label Recommendations) of this memorandum.

2.2   Structure and Nomenclature

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

 

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  

Refer to Section 2.3: Physical and Chemical Properties of risk
assessment document (S. Piper, 04/30/2008, DP# 344389).

3.0   Hazard Characterization/Assessment 

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

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

Piper, 04/30/2008, DP# 344389.

The toxicology data for azoxystrobin are sufficient to support an
amendment of the established tolerance on barley.  However, under the
new rule for toxicology data requirements (40 CFR §158.500), an
immunotoxicity study is now required.  The currently available toxicity
data on azoxystrobin suggest that this chemical does not directly target
the immune system.  At this time, HED believes that the points of
departure (POD) selected for risk assessment provide sufficient
protection for human health, and an additional factor (UFDB) for
database uncertainty is not needed to account for lack of this study. 
The toxicity endpoints and the PODs selected for risk assessment remain
the same relative to the most recent risk assessment (S. Piper,
04/30/2008, DP# 344389, Table 3.5.5). 

Hazard and Dose-Response Characterization

3.1.1   Database Summary tc "3.0  HAZARD CHARACTERIZATION" 

	With the exception of a newly required immunotoxicity study, all
toxicological data requirements for azoxystrobin technical have been
satisfied.  The toxicity database is adequate for required endpoint
selection for exposure risk assessment and for FQPA evaluation.  HED has
a high degree of confidence in the toxicology database.  The toxicity
profiles for azoxystrobin are summarized in Tables A1 and A2 in Appendix
A.

3.1.2	 Toxicological Effects  TC \l3 "3.1.1.3	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.  In dogs, effects on the liver
and biliary functions were found with oral administration.  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.  The reproduction and developmental toxicity data
indicate no increase in susceptibility to pre and postnatal offspring. 
Although azoxystrobin induced a weak mutagenic response in the mouse
lymphoma assay, the activity expressed in vitro is not expected to be
expressed in whole animals.  There was no evidence of carcinogenicity in
rats and mice at acceptable dose levels; azoxystrobin is classified as
not likely to be carcinogenic to humans.

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

Pharmacokinetics and metabolism studies in rats showed that azoxystrobin
was absorbed and distributed broadly following oral administration. The
greatest amounts of azoxystrobin were detected in organs associated with
either metabolism or excretory function, especially the liver and
kidneys.  Less than 0.5% of the administered dose was detected in the
tissues on the 7th day after dosing which suggests minimal potential for
bioaccumulation. The primary route of elimination was via the feces
((73-89% of the administered dose).  Absorbed azoxystrobin appeared to
be extensively metabolized.  A metabolic pathway was proposed showing
hydrolysis and subsequent glucuronide conjugation as the major
biotransformation process. 

3.2	  FQPA Considerations  TC \l2 "3.3	FQPA Considerations 

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

The database for azoxystrobin is adequate for FQPA consideration.

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

In both the acute and subchronic neurotoxicity studies in rats, there
were no consistent indications of treatment-related neurotoxicity.  In
an acute neurotoxicity study in the rat, there was no indication of
neurotoxicity from single gavage doses up to 2000 mg/kg.  In the
subchronic neurotoxicity study in the rat, no indication of
neurotoxicity was observed at the highest dose tested, 201 mg/kg/day. 
Based on the toxicity profile, a developmental neurotoxicity study in
rats is not required” (FQPA Report dated 9/3/98, HED Doc. No. 012844).
 

3.2.3 	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
were seen in either study. 

3.2.4   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.

3.2.5	   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.

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

Determination of Susceptibility:    TC \l4 "3.3.6.1	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.

3.2.7 FQPA Safety Factor for Infants and Children

A detailed analysis of the data supporting HED’s FQPA evaluation is
presented in the most recent risk assessment (S. Piper, 04/30/2008, DP#
344389).  No additional data have been submitted and no new policy
changes have been implemented that would change the conclusions of the
FQPA SF analysis presented in the 2008 risk assessment.  With the
exception of a new data requirement for an immunotoxicity study, the
conclusions regarding the FQPA SF in the previous risk assessment are
applicable to the current action and are summarized below.

HED has determined that available data show there is no increased
susceptibility in rats and rabbits exposed in-utero and or postnatally
to azoxystrobin.  However, HED recommends that the FQPA SF be retained
at 3x to account for using a LOAEL to extrapolate a NOAEL for
establishing a POD for risk assessment for the acute dietary exposure
scenario.  The reasons for retaining a 3x FQPA SF rather than the
default 10x are the following: 

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 oral LD50 was >5000 mg/kg. Based on this and other
considerations, HED is confidant that a 3x SF is sufficient to account
for the uncertainty for the lack of a NOAEL, and that the risks from
acute dietary exposure to azoxystrobin will not be underestimated; (not
needed for chronic)

The acute dietary food exposure assessment utilizes existing and
proposed tolerance level residues and 100% CT 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.

3.3 	Hazard Identification and Toxicity Endpoint Selection 

3.3.1 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/day 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, and taking into account 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 was 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 oral LD50 was >5000 mg/kg.  Based on
these considerations, HED is confidant that a 3x SF 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. 

3.3.2   Level of Concern for Margin of Exposure

Table 3.3.2   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.

3.3.3	 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. 

 

HED recommended the following for aggregation of exposures from
azoxystrobin:

For acute aggregate exposure risk assessment, combine the high-end
exposure values from food + water and compare it to the acute RfD
established for the general population.

For chronic aggregate exposure risk assessment, combine the average
exposure values from food + water and compare it to the chronic RfD.

For short- and intermediate-term aggregate exposure risk assessment, the
short-term and intermediate-term inhalation exposures should be
converted to oral equivalent doses (using 100% inhalation absorption
rate), and should be added to the oral exposures (from food + water) and
compared to the respective oral NOAELs. 

No long-term aggregate risk estimate is needed due to the lack of
long-term exposure.

3.3.4 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 and 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.

3.3.5  Summary of Toxicological Doses and Endpoints 

HED has 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 and
residential exposure/risk assessments.  The doses and toxicological
endpoints selected for various exposure scenarios are summarized in
Table 3.3.5.

Table 3.3.5  Summary of Toxicological Doses and Endpoints for
Azoxystrobin for Use in Human Risk Assessment

Exposure/

Scenario	Point of Departure

(mg/kg/day)	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

	

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 

	

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 = 82.4/117 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 

	

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 (1-6 months) 

	NOAEL= 20

	

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 (1-30 days) & Intermediate Term (1-6 months) 	

No hazard was identified for this exposure scenario.	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 	

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 (1-6months)

	Oral NOAEL= 20 

	

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.

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).  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.

3.4	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.

DIETARY EXPOSURE/RISK CHARACTERIZATION

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, W. Cutchin, 3/12/08, DP#s 334751 and 340016.

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

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

Piper, 04/30/2008, DP# 344389.

Azoxystrobin: Acute and Chronic Aggregate Dietary (Food and Drinking
Water) Exposure and 

Risk Assessments for Section 3 Amendment to Reduce the Preharvest
Interval for Barley Grain 

and Straw (PP#8E7474), M. Negussie, 07/30/2009, DP# 363047.

Azoxystrobin.  Section 3 Amendment to Reduce the Preharvest Interval for
Barley Grain and 

Straw and to Add Seed Treatment Uses on Head and Stem Brassica
Vegetables (Subgroup 5A) 

and Sorghum.  Summary of Analytical Chemistry and Residue Data, M.
Negussie, 08/03/2009,

DP# 362963.

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 raw agricultural commodities (RACs) of lettuce,
radishes, and wheat planted in sandy loam soil 30, 200, and 365 days
after treatment (DAT) of the soil with [14C]azoxystrobin at 1.8 lb ai/A.
 Azoxystrobin was identified in all raw agricultural commodities (RACs)
at the 30- DAT interval.  Residues were highest in RACs from the 30-DAT
interval and declined in subsequent plantback intervals.

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

Analytical Methodology

There are adequate residue analytical methods for tolerance enforcement
in crop and livestock commodities.  

Crop commodities:  A GC/NPD method, RAM 243/04, is available for the
enforcement of tolerances for residues of azoxystrobin and its Z-isomer
in crop commodities.  The method has undergone method validation by
ACB/BEAD.  The method was revised to incorporate comments made by BEAD,
and the revised method (designated RAM 243, dated 5/15/98) has been
submitted to FDA for inclusion in Pesticide Analytical Manual (PAM),
Volume II.  The limit of quantitation (LOQ) is 0.01 ppm for each analyte
in crop commodities.  

Livestock commodities:  A GC/NPD method, RAM 255/01, is available for
the enforcement of tolerances for residues of azoxystrobin in livestock
commodities.  The method has been validated by ACB/BEAD 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.  The method LOQ is 0.0025 ppm and
0.01 ppm for each analyte in milk and tissues, respectively.

Samples from the barley field trials submitted with the current petition
were analyzed for residues of azoxystrobin and its Z-isomer using
LC/MS/MS Method 305/03.  This method has been reviewed previously by
HED, under PP#s 6F7106 and 7F7198.  In addition, RAM 305/03 was
adequately validated at fortification levels ranging from 0.01-1.0 ppm
for barley grain and 0.01-5.0 ppm for barley straw.  The fortification
levels adequately bracketed expected residue levels.  The LC/MS/MS
method used for determination of azoxystrobin and Z-isomer in barley
grain and straw, RAM 305/03, was adequate for data collection purposes
based on acceptable concurrent method recoveries. 

4.1.5	Multiresidue Methods

The requirements 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

Adequate storage stability data are available from previous submissions
indicating that azoxystrobin and its Z-isomer are reasonably stable
under frozen conditions in/on fortified samples of diverse crops. 
Residues were determined to be stable for two years in/on apple, banana,
carrot, cucumber, grape, leaf lettuce, rape seed, peach, winter wheat
straw, wheat forage, and wine.  Over the two-year period, residues of
both azoxystrobin and its Z-isomer decreased by up to 20% in winter
wheat grain and by up to 27% (azoxystrobin only) in tomato, peanut, and
pecan, but all recoveries were >70%; residues in these crops were stable
(without decrease) for up to 6-8 months of storage.

Previous studies conducted on processed commodities demonstrated that
fortified residues of azoxystrobin and its Z-isomer were generally
stable under frozen conditions in peanut oil and meal, tomato juice and
paste, and wheat bran for up to one year, and in soybean meal, corn
grits, and orange oil, juice and pulp for at least two years.

Samples of barley grain and straw from the submitted barley field trial
study were stored frozen from harvest to analysis for up to 366 days (12
months).  The available wheat grain and straw storage stability data may
be translated to barley grain and straw.  Recoveries in wheat grain were
>70% after 24 months storage, and residues did not decline until after
6-8 months.  There is minimal concern of residue decline in samples
stored for 12 months (maximum storage duration for barley grain
samples).

Food Residue Profile

Barley

DER Reference: 47486501.der.doc

Azoxystrobin tolerances for barley grain (0.1 ppm), hay (15.0 ppm), and
straw (4.0 ppm) have been established based on translation of residue
data from wheat (PP#s 9F6058 and 6F7106).  The available wheat data
support use of SC and WDG formulations on barley at a 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.

The submitted field trial data to support a reduced PHI for barley grain
and straw with regional restrictions are adequate to satisfy data
requirements provided the proposed use is amended as requested in
section 10.0.  Four barley field trials were conducted in the United
States in Zones 8 (CO; 2 trials) and 11 (ID; 2 trials) during the 2004
and 2005 growing seasons.  The areas of the country for which the
reduced PHI was proposed by IR-4 represent Zones 8, 9, 10, 11, and 12.  

A summary of residue data from the barley field trials is presented in
Table 4.1.7a.

Table 4.1.7a   Summary of Residue Data from Barley Field Trials with
Azoxystrobin.

Commodity	Total Applic. Rate

 (lb ai/A)	PHI (days)	Analyte	Residue Levels (ppm)

n	Min.	Max.	HAFT1	Median	Mean	Std.

Dev.

Barley (proposed use = 0.40 lb ai/A total application rate, 14-day PHI
for grain and straw grown in AZ, CO, western MT, NM, NV, ID, OR, west
TX, UT, WA, and western WY)

Barley, grain	0.392-0.403	14-15	Azoxystrobin	8	0.75	2.0	1.7	1.25	1.26
0.44

	Z-isomer	8	0.07	0.18	0.15	0.11	0.11	0.04

	Total	8	0.82	2.18	1.85	1.36	1.37	0.48

	0.391-0.411	21-23	Azoxystrobin	8	0.09	1.5	1.5	0.72	0.82	0.59

	Z-isomer	8	<0.01	0.14	0.14	0.07	0.08	0.05

	Total	8	<0.10	1.64	1.64	0.79	0.90	0.64

Barley, straw	0.392-0.403	14-15	Azoxystrobin	8	0.72	3.3	3.3	1.85	1.90
0.99

	Z-isomer	8	0.06	0.26	0.26	0.15	0.15	0.08

	Total	8	0.78	3.56	3.56	2.00	2.05	1.07

	0.391-0.411	21-23	Azoxystrobin	8	0.47	2.9	2.7	1.90	1.80	0.99

	Z-isomer	8	0.03	0.32	0.31	0.15	0.16	0.12

	Total	8	0.50	3.22	2.96	2.10	1.96	1.11

HAFT = Highest Average Field Trial.

The Agency’s Guidance for Setting Pesticide Tolerances Based on Field
Trial Data was utilized for determining appropriate tolerance levels for
barley, grain and straw.  The available data will support the proposed
tolerances of 3.0 ppm for barley, grain and 7.0 ppm for barley, straw.  

 

Head and stem Brassica vegetable subgroup 5A

A tolerance of 3.0 ppm has been established for the combined residues of
azoxystrobin and its Z-isomer in/on the head and stem Brassica subgroup
[40 CFR §180.507(a)(1)].  The tolerance was based on residue data for
broccoli and cabbage reflecting foliar applications of a 80% WDG
formulation at a total seasonal rate of 1.50 lb ai/A, with a 0-day PHI. 

Syngenta has proposed seed treatment use of the 0.83 lb ai/gal SC
formulation on head and stem Brassica vegetables at a maximum rate of
0.024 lb ai/100 lb seed.  The treatment rate corresponds to a field
equivalent rate of 0.0012 lb ai/A [calculated using the maximum head and
stem Brassica seeding rate of 5 lb/A, specified for kohlrabi in HED
EXPOSAC SOP 15 (“Amount of Seed Treated or Planted Per Day,”
3/2/04)].  Because the proposed seed treatment use rate is much lower
than the registered foliar use rate, no additional data will be required
to support seed treatment uses on head and stem Brassica vegetables. 
All Syngenta products with foliar uses on head and stem Brassica specify
that no more than 1.50 lb ai/A per season of azoxystrobin-containing
products be applied to head and stem Brassica crops.

The proposed seed treatment use on head and stem Brassica subgroup 5A is
not expected to increase residue levels in treated head and stem
Brassica matrices; therefore, no change to the established tolerance is
needed.  The maximum seasonal rate from application of any
azoxystrobin-containing products remains unchanged. 

Sorghum, Grain

Tolerances have been established for the combined residues of
azoxystrobin and its Z-isomer in/on sorghum, grain commodities at 25 ppm
for forage, 11 ppm for grain, and 40 ppm for stover [40 CFR
§180.507(a)(1)].  In addition, a tolerance has been established for
aspirated grain fractions at 420 ppm.  The tolerances were based on
residue data for sorghum, grain commodities reflecting foliar
applications of a 2.08 lb ai/gal SC formulation at a total seasonal rate
of ~0.50 lb ai/A for sorghum, grain, forage, and ~0.75 lb ai/A for grain
and stover, with a 14-day PHI.  

Syngenta has proposed seed treatment use of the 0.83 lb ai/gal SC
formulation on sorghum, grain at a maximum rate of 0.020 lb ai/100 lb
seed.  The treatment rate corresponds to a field equivalent rate of
0.002 lb ai/A (calculated using the seeding rate of 10 lb/A, specified
for sorghum, grain in HED EXPOSAC SOP 15).  Because the proposed seed
treatment use rate is much lower than the registered foliar use rate, no
additional data will be required to support seed treatment use on
sorghum, grain.  All Syngenta products with foliar uses on sorghum,
grain specify that no more than 0.50 lb ai/A per season of
azoxystrobin-containing products be applied to sorghum, grain grown for
forage and no more than 0.75 lb ai/A per season of
azoxystrobin-containing products be applied to sorghum, grain grown for
grain and stover.  

The proposed seed-treatment use on sorghum, grain is not expected to
increase residue levels in treated sorghum, grain matrices; therefore,
no changes to the established tolerances for sorghum, grain commodities
are needed.  The maximum seasonal rate from application of any
azoxystrobin-containing products remains unchanged. 

HED notes that additional field trial data were required to support
in-furrow applications of azoxystrobin to sorghum, grain in conjunction
with PP#s 6F7106 & 7F7198.  These data have not yet been submitted (due
date for the bridging studies is 07/10/2011).

Processed Studies:  No new processing studies were submitted with this
petition.  Residue data are not required for any processed commodities
of head and stem Brassica vegetables or sorghum, grain.  

RAB2 (L. Kutney, 04/25/97; DPs# 230634-637) previously concluded that it
was appropriate to establish tolerances on barley processed commodities
based on wheat processing data.  In a wheat processing study submitted
under PP#6F4762, residues of azoxystrobin were found to concentrate in
wheat bran (3x) but not in wheat middlings, shorts, germ, and flour. 
Processing factors for the Z-isomer could not be determined because
residues of the Z-isomer were nonquantifiable in wheat grain and its
processed commodities.  Based on the available wheat processing data, a
tolerance for barley bran was established at 0.2 ppm.  The proposed
reduced PHI for barley grain results in higher residues in the grain,
and therefore the potential for increased residues in barley bran. 
Using the HAFT for barley grain harvested at the 14-day PHI  (1.85 ppm)
and the concentration factor for wheat bran (3x), expected residues in
barley bran would be 5.55 ppm, which exceeds the recommended increased
tolerance of 3 ppm for barley grain and the existing tolerance of 0.2
ppm for barley bran.  Therefore, an increased tolerance is needed for
barley bran at 6.0 ppm.

Livestock:  Tolerances for residues of azoxystrobin 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.  No
tolerances for eggs and poultry meat and meat byproducts have been
established.  

The livestock feedstuffs associated with this petition are barley grain
and straw; in addition, there are established tolerances for numerous
livestock feedstuffs.  Adequate cattle and poultry feeding studies are
available to support the livestock dietary burdens resulting from the
proposed uses.   The maximum theoretical dietary burdens (MTDB) of
azoxystrobin were recalculated for beef (51.3 ppm), dairy cattle (40.4
ppm), poultry (14.4 ppm), and swine (15.0 ppm) (M. Negussie, 08/03/2009,
DP# 362963).  The calculations reflect the most recent guidance from HED
concerning revisions of feedstuff percentages in Table 1 Feedstuffs
(June 2008) and construction of maximum reasonably balanced diets (MRBD)
for livestock (email, J. Stokes, 07/22/2009).  

									

Adequate livestock feeding studies have been submitted previously for
azoxystrobin (PP#6F4762 and PP#7F4864).  The existing azoxystrobin
tolerances for milk and the fat, meat, and meat byproducts of cattle,
goat, hog, horse, and sheep are adequate; no revision to the existing
tolerances is needed to support the proposed uses of azoxystrobin.  

The proposed uses of azoxystrobin addressed in this document do not
alter the HED previous conclusion that there is no reasonable
expectation of finite residues in poultry commodities [Category 3 of
§180.6(a)].  No tolerances are needed for poultry tissues or eggs.  

 

Confined and Field Rotational Crops

Limited field rotational crop studies, reflecting applications made to
the primary crop at a seasonal rate of 0.8 lb ai/A, were initially
submitted in PP#6F4762.  Subsequently, additional limited field
rotational crop studies, with applications made to the primary crop at
seasonal rates of 1.6 or 2.0 lb ai/A, were submitted and reviewed in
PP#9F6058.  Under PP#s 6F7106 and 7F7198, HED concluded that the
following PBIs were appropriate to support a maximum seasonal
application rate of 2.0 lb ai/A to rotated crops:  12 months for
buckwheat, millet, oats and rye; and 36 days for the leafy vegetables
(except Brassica) crop group; the Brassica leafy greens subgroup; the
root vegetables subgroup; the tuberous and corm vegetable subgroup; and
the leaves of the root and tuber vegetables group.  Crops with
registered uses may be planted immediately after the last treatment
unless otherwise specified.  For crops not on the label, a 12-month PBI
must be observed unless otherwise specified. 

Because the proposed amended uses on barley, the head and stem Brassica
subgroup, and sorghum, grain do not result in increased maximum seasonal
application rates of azoxystrobin, no changes to the existing rotational
crop restrictions are needed.  The rotational crop restrictions on the
labels for EPA Reg. Nos. 100-1098 and 100-1159 are adequate.  

  SEQ CHAPTER \h \r 1 Adequate confined studies have previously been
presented in PP#6F4762 and re-evaluated in PP#9F6058.  Total radioactive
residues, 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 days after treatment of the soil with
[14C]azoxystrobin at 1.8 lb ai/A.  Azoxystrobin was identified in all
rotated crop commodities at the 30-day PBI.  Residues were highest in
rotated crop commodities from the 30-day PBI and declined in subsequent
PBIs.  

Azoxystrobin is more extensively metabolized in rotational crops than in
primary crops.  HED has concluded that the residues of concern in
rotational crops are parent and the Z-isomer.

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

Codex maximum residue limits (MRLs) have been established for
azoxystrobin in barley, grain (0.5 ppm) and straw and fodder (dry) of
cereal grains (except maize) at (15 ppm).  There are no Canadian MRLs
for residues of azoxystrobin and its (Z)-isomer for the requested crops.
 Mexican MRLS have been established for residues of ‘azoxistrobin’;
MRLs have been established for barley, grain (0.3 ppm).  Refer to
Appendix B.

The Codex MRLs for barley grain and straw are based on trials conducted
in Europe and on residues present at a 35-42 day PHI.  The recommended
US tolerances on barley grain (3.0 ppm) and straw (7.0 ppm) are based on
residues present at a 14-day PHI.  The US MRL for grain is higher due to
shorter PHI.  The Codex MRL for straw is for cereal grains straw and
encompasses barley, corn, sweet corn, oats, rice, and wheat data from
Europe.  Moreover, Codex MRLs for forages, straws, and the like are set
on a dry-weight basis, whereas US tolerances are set on an as-fed basis.

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 from 17.6
to 28.4 days (DT50=11 days).   The dissipation of azoxystrobin by
photodegradation half-life in surface water ranges from 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,
[(E)-2-{2-[6-(2-cyanophenoxy) pyrimidin-4-yloxy]-3-methoxyacrylic
acid]),   SEQ CHAPTER \h \r 1 “Compound” 30, 2-[6-(2-cyanophenoxy)
pyrimidin-4-yloxy]benzoic acid,

and “Compound” 28, 4-(2-cyanophenoxy)-6-hydroxypyrimidine) 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 (DP# 218292).  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 

(J. Wolfe, 16/MAR/2006, DP#s: 301948, 312950, 312952, 312954, 313858,
and 317292); and “Aquatic Exposure Assessment of Azoxystrobin on
Artichoke, Head and Stem Brassicas, Asparagus and Herbs (except
chives)” (K. Costello, 05/NOV/2002, DP#s: 285061, 285064, 285068 and
285078) and incorporated directly into this dietary assessment.

EFED provided Tier 1 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 ground water EDWC.  No azoxystrobin monitoring data were available. 
HED determined that the residue of concern in water is azoxystrobin
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) 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 a 10 day
interval between applications) 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

Dietary Exposure and Risk Characterization

e (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
to be carcinogen”; therefore, cancer risk from exposure to
azoxystrobin is not of concern.  The analyses were performed to support
a petition (PP#8E7474) to revise established tolerances for the combined
residues of the fungicide azoxystrobin and the Z-isomer on barley grain
and straw, due to a reduction in the PHI from 45 days to 14 days.

 

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 and assumes 100% crop
treated.  DEEM version 7.81 default processing factors were assumed
except for where tolerances were established for processed commodities. 
Combined dietary exposure from food and drinking water at the 95th
percentile of exposure is estimated to be 0.17 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 0.47 mg/kg/day,

equivalent to 70% of the aPAD.

Chronic dietary analysis for azoxystrobin was conducted using tolerance
levels and %CT data for some existing uses.  DEEM version 7.81 default
processing factors were assumed except for where tolerances were
established for processed commodities.  The dietary exposure estimate at
0.0076 mg/kg/day for the U.S. population was 4.3% of the cPAD and the
most highly exposed subgroup, children 1-2 yrs old, at 9.6% (0.017
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 LOC for the U.S. population
or any population subgroup.  

Acute and Chronic Dietary 

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

Population Subgroup	Acute Dietary

(95th Percentile)	Chronic Dietary	Cancer

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

(mg/kg/day)	% cPAD	Dietary Exposure

(mg/kg/day)	Risk

General U.S. Population	0.166573	25	0.007650	4.3	

Not Applicable

All Infants (< 1 year old)	0.111320	17	0.007743	4.3

	Children 1-2 years old	0.469796	70	0.017311	9.6

	Children 3-5 years old	0.352375	53	0.014919	8.3

	Children 6-12 years old	0.220566	33	0.009225	5.1

	Youth 13-19 years old	0.169103	25	0.006889	3.8

	Adults 20-49 years old	0.137959	21	0.006653	3.7

	Adults 50+ years old	0.119144	18	0.006526	3.6

	Females 13-49 years old	0.146795	22	0.006344	3.5

	

 tc "4.2.2	Cancer Dietary "  

4.2.2	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 a cancer assessment was
not conducted. 

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

SLUA April 9, 2009.

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 listed below in Table 4.3.1.

4.3.1.     %CT for Azoxystrobin Dietary Risk Assessment.

Crop	Avg. %CT	Crop	Avg. %CT

Almonds	25	Lettuce	<2.5

Apricot	15	Mustard greens	15

Artichoke	25	Onion	10

Asparagus	<2.5	Orange	5

Beans, Green	5	Peas, Green	<2.5

Beets, sugar	5	Peach	5

Blackberries	5	Peanut	15

Blueberries	10	Pecan	<2.5

Broccoli	5	Pepper	15

Cabbage	5	Pistachios	20

Cantaloupes	10	Potato	30

Carrot	10	Pumpkin	20

Cauliflower	<2.5	Raspberry	5

Celery	10	Rice	35

Cherry	5	Soybean	<2.5

Corn, field	<2.5	Spinach	10

Corn, sweet	10	Squash	15

Cotton	5	Strawberry	30

Cucumber	15	Tangerine	20

Dry Beans/Peas	<1	Tomato	15

Filbert	5	Walnut	<1

Garlic	60	Watermelon	20

Grape	5	Wheat	<2.5

Grapefruit	25

5.0	Residential (Non-Occupational) Exposure/Risk Characterization

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

Residential exposures are not assessed in this document because the
proposed uses of azoxystrobin do not involve applications by homeowners
or commercial applicators in residential settings at this time. 
Azoxystrobin is currently registered for use on residential turf grass
and ornamentals, indoor surfaces, and treated paints (preservative
incorporation).  Residential exposure and risks from use on turfgrass
and indoor surfaces was assessed in a previous separate document (K.
O’Rourke, 07/18/2002, DP# 278803).  

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 HED,
a dermal exposure and risk assessment was not conducted for residential
handlers or postapplication activities.  

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

Indoor Carpet and Other Surfaces

Currently registered azoxystrobin labels permit use on indoor
carpets/other surfaces by non-commercial applicators (e.g., Heritage®
Fungicide label).  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, and therefore, is not of concern.

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 MOE for the applicator
exposure scenario is 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, and therefore, are not of concern.  

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)

Treated Paints (preservative incorporation)

The currently registered AZO-ShieldTM is a water soluble concentrate
used as fungistatic preservative.  It can be incorporated into
paper/paperboard/wallboard, latex emulsion paints/stains/coatings, latex
caulks/sealants/adhesives/binders, natural and synthetic fibers, and
rubber/plastic products as a materials preservative (industrial
manufacturing settings only).  Short-term inhalation exposures for adult
residential handlers of Azoxystrobin-treated paints were assessed as
amateur painter scenarios using paint brush/roller and airless sprayer
techniques.  The water damage/mold remediation spray applications were
not assessed for residential handlers since these uses are at industrial
sites only.  The scenarios relied on the 

Pesticide Handlers Exposure Database (PHED) data and standard approaches
to develop dose estimates (D. Aviado, 10/17/2006, DP#D329386).

	As shown in Table 5.2c, the inhalation MOEs for short-term durations of
exposure were above the LOC of an MOE of 100 (i.e., they do not pose a
risk concern). 

Table 5.2c. Short-term Inhalation Exposures and MOEs for Adult
Residential Handlers of Azoxystrobin-treated Paint

Exposure Scenario/Application Method	Application Ratea	Quantity Handled/
Treated per dayb	Baselinec Inhalation Unit Exposure 

(mg/lb ai)	Inhalation Daily Dosed (mg/kg/ day)	Short-term

 Inhalation

(Baseline)

MOEe

LOCMOE=100

Use Site IV - Residential and Public Access

Brush/Roller --

paint	1.0

% a.i. weight 	20 lb	0.284	8.11E-04	31,000

Airless Sprayer --

paint	1.0

% a.i. weight	150 lb	0.83	0.0178	1,400

   aApplication rates are the maximum application rates determined from
amended labeling for AZO-Shield ™

   bQuantity handled per day values are estimates based on Residential
SOPs.		

   c		PHED Unit Exposure value Baseline = No respirator

  dDaily dose (mg/kg/day) = [unit exposure (mg/lb ai) * application rate
(% ai weight or lb ai/gallon) *      quantity 	treated/handled (lb/day
or gallons/day) * inhalation absorption factor (1)]/ Body weight (70
kg).

  eMOE = NOAEL (mg/kg/day) / daily dose [Where oral NOAEL = 25 mg/kg/day
for short-term inhalation]. 

 	LOC MOE = 100.

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 previously assessed in an
Antimicrobial Division (AD) memorandum (D. Aviado, 7/2/2004, DP#
299065).  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 of an MOE of 100, and therefore, are not of
concern.

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 to toddlers from various activities following
lawn treatment are considered to be the most common and significant in
residential settings.  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
5.3b.  Both short-term and intermediate-term MOEs for each scenario and
the combined MOE resulting from all three exposures are above the LOC of
an MOE of 100, and therefore, are not of concern.

Table 5.3b Short- and Intermediate-Term Incidental Ingestion Exposure
and Risk from Treated Turf

Scenarios	

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.

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 HED.

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"

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.  The acute risk estimate for the U.S.
population and all other population subgroups, resulting from aggregate
exposure to azoxystrobin in food and drinking water is below the
Agency’s LOC.  The food and drinking water exposure estimates are 25%
of the aPAD for the U.S. population and 70% of the aPAD for the most
highly exposed subgroup, children 1-2 yrs old.  

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 aggregate risk assessment was conducted for toddlers because
there is a residential post-application incidental oral exposure
scenario.  Average food and drinking water exposures are already
included in the chronic dietary exposure assessment in Table 4.2.1,
above.  Adult inhalation risks are summarized for indoor, outdoor, and
treated paint uses in Tables 5.3a, 5.3b, and 5.3c 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 980 (inhalation-treated paint) and children 1-2 years old
at 240 (incidental oral-indoor surfaces) do not exceed HED’s LOC, 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	0.007650	0.0178	 980

Youth (13-19 years)

	0.006889	0.0178	1000

Children (1-2 years)

	0.017311	0.089	240

Females (13-49 years old)

	0.006344	0.0178	1000

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 on turf, indoor surfaces or Inhalation exposure for treated
paint scenario].  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	0.017311	0.042	340

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 340 do not exceed HED’s LOC, a MOE of 100.  HED
does not consider intermediate-term aggregate risk for children to be a
concern.

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 LOC (i.e., the percentages
of the chronic population adjusted doses (cPADs) are all below 100%). 
The exposure to the U.S. population was 4.3% of the cPAD and the
exposure to the most highly exposed subgroup, children 1-2 yrs old, was
9.6% of the cPAD.  Therefore, chronic risk estimates resulting from
aggregate exposure to azoxystrobin in food and drinking water are below
the Agency’s LOC 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.

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.  Additionally, 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/.

Occupational Exposure/Risk Pathway

Azoxystrobin:  Occupational and Residential Exposure Assessment for Seed
Treatment Use on Head and Stem Brassica (Subgroup 5A) and Sorghum Grain,
B. O’Keefe, 07/24/09, DP# 367125. 

Based upon the proposed use on seeds, occupational handler exposure is
expected for individuals involved in commercial seed treatment, on-farm
seed treatment, and during planting.

Occupational Handler 

Occupational handlers may experience short- and intermediate-term
exposure to azoxystrobin while performing seed treatment activities in
commercial and on-farm settings.  In addition, occupational secondary
handlers may experience short- and intermediate-term exposure while
planting azoxystrobin-treated seeds.  No chemical-specific handler
exposure data were submitted in support of these use patterns.  For
assessing commercial seed treatment and seed planting activities, unit
exposure data were taken from HED ExpoSAC Policy 14: SOP for Seed
Treatment.  The amount of active ingredient handled depends on the
application rate (lb ai/100 lb seed) and the pounds of seed treated in a
day or the pounds of seed that can be planted in a day, all of which
vary depending upon the seed type.  Values for the amount of seed
treated and planted per day were obtained from HED’s ExpoSAC Policy
15.  The results are presented in Tables 8.1.a, 8.1.b, and 8.1.c.

Commercial Seed Treatment

Commercial seed treatment equipment is designed to apply accurately
measured quantities of pesticides to a given weight of seed.  Potential
occupational exposure scenarios from the use of azoxystrobin as a
commercial seed treatment include: mixing, loading, applying liquid
formulations; bagging treated seed; sewing bags; and multiple
activities.

In addition to the tasks listed above, workers also may perform multiple
activities throughout the day.  As a result a “multiple activities”
scenario (i.e., where one worker performs all seed treatment tasks such
as   SEQ CHAPTER \h \r 1 loading/applying, sewing, bagging, cleaning,
calibration, repair, forklift driver, etc.) was addressed.

Planting Treated Seed

Potential occupational exposure scenarios from the use of azoxystrobin
as a commercial seed treatment include planting treated seed (secondary
handler).  Planting treated seed consists of the farmer purchasing bags
of treated seed, placing the seed in the hopper and applying seed to
fields.  This is considered a secondary handler exposure scenario.

On-Farm Seed Treatment

For growers who want to treat a smaller volume of seed on their farm,
there are a number of seed treaters that are compact and suitable for
on-farm seed treatment.  Various equipment are used for on-farm seed
treatment, such as drum mixers, homemade devices using augers, cement
mixers, hand cranked revolving drums, and gravity-feed systems.  The
more sophisticated on-farm treaters are essentially miniature versions
of the commercial treaters.  Simpler, more versatile units consist of
reusable chemical container(s), a power source (such as a vehicle
battery), valve and pump (or compressed air for the Agsco treaters) and
tubing spray nozzles.  These units are mounted directly on a truck box
or wagon to dispense seed treatment directly into an auger conveyance
system.  Seed may be treated as it is augured from the farmer’s truck
to the storage bin (at the farmstead), or from the truck to the seeder
(field) or from the farmer's storage bin into either a truck or seeder. 
Potential occupational exposure scenarios for the on-farm seed treatment
include: mixing, loading, applying liquid formulations; and planting
treated seed (secondary handler). 

Chemical-specific data for assessing exposure during seed treatment and
seed planting were not submitted to the Agency in support of this
Section 3 application.  Unit exposures are from ExpoSAC Policy 14:
Standard Operating Procedures (SOPs) for Seed Treatment, May 1, 2003. 
Unit exposure values from ExpoSAC Policy 14 are based on data for open
mixing/loading/application systems. 

HED is currently in the process of revising ExpoSAC Policy 15: Amount of
Seed Treated or Planted per Day issued in March 2, 2004, in efforts to
update the daily amount of seed treated in commercial seed treatment
facilities.  With the increasing demand for hybridized treated seeds,
there have been modifications not only in the seed treatment equipment,
but in the market shares of new and currently registered pesticide
products.  HED understands that due to high cost to produce hybrid
seeds, direct seeding is done in a precision manner which requires lower
volumes of seed per acre. However, this does not provide a direct
correlation to the amount of seed which is treated in the commercial
seed treatment facilities.   

The amount of seed treated per day at a commercial facility is
summarized below for each crop.   

Head and Stem Brassica Subgroup 5A: 5,500 lbs; this amount is based on
the amount for small vegetable seeds.

Sorghum Grain: 718,000 lbs.

Based on ExpoSAC Policy 15: Amount of Seed Treated or Planted per Day
issued in March 2, 2004, the amount of seed treated per day on-farm and
the amount of seed planted per day is summarized below for each crop.   

Head and Stem Brassica Subgroup 5A:  400 lbs (5 lb seed/A X 80 A/day).

This amount is based on kohlrabi, which is the crop with the maximum
amount of seed planted per day in this subgroup.  The amount of seed
planted per day is 320 lbs for Chinese cabbage, 160 lbs for broccoli and
Brussels sprouts, and 120 lbs for cabbage and cauliflower.

Sorghum: 800 lbs (10 lb seed/A X 80 A/day).

A summary of the inhalation risks for each exposure scenario is
presented below in Tables 8.1a, 8.1b, and 8.1c. for short-term and
intermediate-term inhalation exposures.  

The results of the short- and intermediate-term occupational handler
exposure and risk assessment indicate that inhalation risks do not
exceed HED’s LOC (i.e. an MOE = 100) at baseline level of risk
mitigation (i.e., no respirator) for any of the head and stem Brassica
and sorghum, grain treatment scenarios.  

Table 8.1a. Short- and Intermediate-Term Handler Exposures and Risks for
Commercial Seed Treatment with Azoxystrobin.

Crop	Exposure

 Scenario	lbs seed treated

 or 

planted/

 daya	Application

 Rateb

(lb ai/lb seed)	Baseline Inhalation

 Unit Exposurec,d

(µg/lb ai)	Baseline Inhalation

 Dosee (mg/kg/day)	Baseline Inhalation MOEf

(Target MOE = 100)

Short-Term	Intermediate-Term

Head and Stem Brassica 	Loader/Applicator	5,500	0.00024	0.34	0.0000064
3,900,000	3,100,000

	Sewer	5,500	0.00024	0.23	0.0000043	5,800,000	4,600,000

	Bagger	5,500	0.00024	0.16	0.000003	8,300,000	6,600,000

	Multiple Activities	5,500	0.00024	1.6	0.00003	830,000	660,000

Sorghum Grain	Loader/Applicator	718,000	0.00020	0.34	0.0007	36,000
29,000

	Sewer	718,000	0.00020	0.23	0.00047	53,000	42,000

	Bagger	718,000	0.00020	0.16	0.00033	76,000	61,000

	Multiple Activities	718,000	0.00020	1.6	0.0033	7,600	6,100

Table 8.1b. Short- and Intermediate-Term Handler Exposures and Risks for
On-Farm Seed Treatment with

 Azoxystrobin

Crop	lbs seed treated

or planted/ daya	Application Rateb

(lb ai/lb seed)	Baseline Inhalation

 Unit Exposurec,d

(µg/lb ai)	Baseline Inhalation

 Dosee (mg/kg/day)	Baseline Inhalation MOEf

(Target MOE = 100)

	Short

-Term	Intermediate

-Term

Head and Stem Brassica	400	0.00024	1.2	0.0000016	15,000,000	12,000,000

Sorghum Grain	800	0.00020	1.2	0.0000027	9,100,000	7,300,000

Table 8.1c. Short- and Intermediate-Term Handler Exposures and Risks for
Planting Seed Treated with Azoxystrobin

Crop	lbs seed treated 

or planted/ daya	Application Rateb

(lb ai/lb seed)	Baseline Inhalation

 Unit Exposurec,d

(µg/lb ai)	Baseline Inhalation

 Dosee (mg/kg/day)	Baseline Inhalation MOEf

(Target MOE = 100)

	Short-

Term	Intermediate

-Term

Head and Stem Brassica	400	0.00024	3.4	0.0000047	5,400,000	4,300,000

Sorghum Grain	800	0.00020	3.4	0.0000078	3,200,000	2,600,000

a HED default for lb seed planted per day from HED Science Advisory
Council for Exposure Policy # 15.   

daily unit exposure (μg/lb ai)  x application rate (lb ai/lb seed) x
amount treated or planted (lb seed/day) x conversion factor (1 mg/1,000
μg) x absorption factor (100%) / body weight (70 kg adult).

fInhalation MOE = NOAEL (25 mg/kg/day for short-term exposure and 20
mg/kg/day for intermediate-term exposure) / inhalation daily dose
(mg/kg/day). LOC = 100.

Short-/Intermediate-Term Postapplication Risk 

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

Sustained levels of contact with treated seed after it has been placed
in the soil or other planting media would not be expected because no
routine cultural practice required for the production of agricultural
commodities involves such an activity as defined in the no/low contact
criteria in the WPS.  Therefore, no quantitative postapplication
assessment is required for exposure to treated seeds that have already
been planted.

The REI is based on the acute toxicity of azoxystrobin technical
material.  The WPS allows workers to enter treated areas without
restriction if there will be no worker contact with the treated seeds in
the soil or planting media.  Certain tasks, even though they are not
routine, may involve contact with the soil subsurface (e.g. repair of
certain irrigation equipment) and they are covered by the REI.  HED
recommends that the Registration Division ensure that appropriate
language is placed on the product label to require the label on treated
seed to include the REI following the planting of treated seed.

Restricted Entry Interval

Azoxystrobin is not a dermal sensitizer.  The azoxystrobin active
ingredient has been 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.  The WPS
requires a 12-hour REI for active ingredients classified as Toxicity
Category III or IV for these routes of exposure.  A standard WPS
exception to this REI is that once seeds are planted in soil or other
planting media, the WPS allows workers to enter the treated area without
restriction if there will be no worker contact with the treated seeds in
the soil or planting media.  The proposed label lists a REI of 4 hours. 
The HED 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 and Revisions to Petitioned-for Barley Tolerances

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 for livestock.
 A summary of the recommended tolerances for the fungicide azoxystrobin
in/on the commodities is presented in Table 9.0 below.

Note to PM:  HED recommends that the tolerance definition entry in 40
CFR 180.507 be revised as follows:  (a) General. (1)  Tolerances are
established for residues of the fungicide, azoxystrobin, [methyl( E
)-2-(2-(6-(2-cyanophenoxy) pyrimidin-4-yloxy)phenyl)-3-methoxyacrylate],
including its metabolites and degradates, in or on the commodities in
the table below.  Compliance with the tolerance levels specified below
is to be determined by measuring only the sum of azoxystrobin and the
Z-isomer of azoxystrobin [methyl( Z
)-2-(2-(6-(2-cyanophenoxy)pyrimidin-4-yloxy)phenyl)-3 methoxyacrylate]
in or on the commodity.

(a) General. (2) Tolerances are established for residues of the
fungicide, azoxystrobin, [methyl( E )-2-(2-(6-(2-cyanophenoxy)
pyrimidin-4-yloxy)phenyl)-3-methoxyacrylate], in or on the commodities
in the table below.  Compliance with the tolerance levels specified
below is to be determined by measuring only azoxystrobin  [methyl( E
)-2-(2-(6-(2-cyanophenoxy) pyrimidin-4-yloxy)phenyl)-3-methoxyacrylate]
in or on the commodity.

	

Table  9.0. 	Tolerance Summary for Azoxystrobin.

Commodity	Established Tolerance (ppm)	Proposed Tolerance (ppm)
Recommended Tolerance (ppm)	Comments; Correct Commodity Definition

Barley, bran	0.2	--	6.0

	Barley, grain	0.1	3.0	3.0

	Barley, straw	4.0	7	7.0

	

10.0 Data Needs and Label Recommendations

10.1	Toxicology 

 tc "8.1  Toxicology " \l 2 

HED 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.  Based on the new rule for
toxicology data requirements (40 CFR §158.500), an immunotoxicity study
is now required.  

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

	Barley:  A revised Section F to propose a tolerance of 6.0 ppm for
barley bran is needed.

A revised Section B for EPA Reg. No. 100-1098 for use on barley.

The label should state that the use directions only apply to barley
grain and straw grown in the following areas/states:   Arizona (north of
I-10), Colorado, Idaho, western Montana (west of Route 87 and I-15),
Nevada, New Mexico, Oregon, western Texas (west of Route 283 and
northwest of Route 377), Utah, Washington, and western Wyoming (west of
I-25 and south of I-90).  

The statement that application to barley should be made no later than
Feekes growth stage 10.5 (Zadok’s growth stage 59) should be removed
from the label.  

A 14-day minimum retreatment interval should be proposed.  

The label must state that no adjuvants may be added to the spray mixture
for this type of application to barley.

Note to PM: The label (EPA Reg. No. 100-1098) states that Azoxystrobin
is registered for use on all other rotated crops and all other crops may
be planted immediately after the last treatment.  The label should be
revised to state “Crops with registered uses may be planted
immediately after the last treatment unless otherwise specified.  For
crops not on the label, a 12-month PBI must be observed unless otherwise
specified”. 

10.3 Occupational and Residential Exposure

The labeling (EPA Reg. No. 100-1159) should state: Seed that has been
treated with this product that is then packaged or bagged for future use
must contain the following labeling on the outside of the seed package
or bag. 

"Treated Seed - Do Not Use for Food, Feed, or Oil Purposes.”

"When opening this bag or loading/pouring the treated seed, wear
long-sleeved shirt, long pants, shoes, socks, and chemical resistant
gloves."

"After the seeds have been planted, do not enter or allow worker entry
into treated areas during the restricted-entry interval (REI) of 12
hours. Exception: Once the seeds are planted in soil or other planting
media, the Worker Protection Standard allows workers to enter the
treated area without restriction if there will be no worker contact with
the treated seeds in the soil or planting media." 

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# 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#s 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; DP# 348594;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). DP# 317293; S. Winfield; 7/6/2006.

Azoxystrobin – Occupational Exposure/Risk Assessment for the Proposed
New Use of Azoxystrobin on Cotton and Wild Rice. DP# 346544; M. Dow;
10/5/2007.

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; DP# 344389; S. 

Piper; 04/30/2008.

Azoxystrobin.  Section 3 Amendment to Reduce the Preharvest Interval for
Barley Grain and 

Straw and to Add Seed Treatment Uses on Head and Stem Brassica
Vegetables (Subgroup 5A) 

and Sorghum.  Summary of Analytical Chemistry and Residue Data; DP#
362963; M. Negussie, 

08/20/2009.

 

Azoxystrobin: Acute and Chronic Aggregate Dietary (Food and Drinking
Water) Exposure and 

Risk Assessments for Section 3 Amendment to Reduce the Preharvest
Interval for Barley Grain 

and Straw (PP#8E7474); DP# 363047; M. Negussie, 07/30/2009.

Azoxystrobin:  Occupational and Residential Exposure Assessment for Seed
Treatment Use on Head and Stem Brassica (Subgroup 5A) and Sorghum Grain;
DP# 367125; B. O’Keefe, 07/24/2009.

Appendix A: Toxicity Profile

Table A1.  Acute Toxicity Data on Technical Azoxystrobin     

Table A1.       Acute Toxicity Data on Technical Azoxystrobin.     

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

due to mortality pattern	III

870.2400	Primary Eye  Irritation - Rabbit	43678128	Slight to moderate
erythema and slight chemosis in all rabbits within one hour, but effects
resolved within 48 hours of treatment.	III

870.2500	Primary Skin Irritation - Rabbit	43678130	Very slight erythema
and edema that persisted for three days on one rabbit and for one hour
on another.	IV

870.2600	Dermal Sensitization - Guinea Pig	43678132	No erythema or edema
were found 38 or 48 hrs after challenge with test material.	Not a dermal
sensitizer

870.6200	Acute Neurotoxicity	43678134,

44182013,

44182015	No indication of neurotoxicity at any dose level tested. 
NOAEL/LOAEL based on transient diarrhea in both sexes.

  NOAEL =  < 200 mg/kg

  LOAEL = 200 mg/kg

	

Table A2.  Azoxystrobin Toxicity Results From Repeated Dosing and Other
Studies

Table A2.      Azoxystrobin Toxicity Results From Repeated Dosing and
Other Studies.

Study Guideline/Study	MRID	Results

870.3100

90-Day oral toxicity in rats	43678135 (1992) 

Acceptable/guideline

0, 200, 2000, 4000 ppm

M: 0, 20.4, 211.0, 443.8 mg/kg/day

F: 0, 22.4, 223.0, 448.6 mg/kg/day	NOAEL = 20 mg/kg/day

LOAEL = 211 mg/kg/day based on decreased weight gain in both sexes,
clinical observations of distended abdomens and reduced body size, and
clinical pathology findings attributable to reduced nutritional status.

870.3150

90-Day oral toxicity in dogs	43678136 (1993)

Acceptable/guideline

M & F: 0, 10, 50, 250 mg/kg/day 	NOAEL =  50 mg/kg/day

LOAEL = 250 mg/kg/day based on treatment-related clinical observations
and clinical chemistry alterations indicative of effects on
liver/biliary function in both sexes.

870.3200

21-Day dermal toxicity in rats	43678137 (1994)

Acceptable/guideline

M & F: 0, 200, 500, 1000	NOAEL = 1000 mg/kg/day (limit dose)

LOAEL > 1000 mg/kg/day.

870.3700a

Prenatal developmental in rats	43678142 (1994)

Acceptable/guideline

0, 25, 100, 300 mg/kg/day

	Maternal NOAEL = 25  mg/kg/day

LOAEL = 100 mg/kg/day based on the maternal clinical signs of increased
diarrhea, urinary incontinence, and salivation.

Developmental NOAEL = 100 mg/kg/day

LOAEL  > 100 mg/kg/day.

870.3700b

Prenatal developmental in rabbits	44058701 (1995)

Acceptable/guideline

0, 50, 150, 500 mg/kg/day	Maternal NOAEL = 150 mg/kg/day

LOAEL = 500 mg/kg/day based on decreased body weight gain.

Developmental NOAEL = 500 mg/kg/day

LOAEL  > 500 mg/kg/day.

870.3800

Reproduction and fertility effects in rats	43678144 (1994)

Acceptable/guideline

0, 60, 300, 1500 ppm

M: 0, 6.4, 32.3, 165.4 mg/kg/day

F: 0, 6.8, 33.8, 175.0 mg/kg/day	Parental/Systemic NOAEL = 32 mg/kg/day 

LOAEL = 165 mg/kg/day based on reduced body weight, reduced food
consumption, and increased adjusted liver weights in both sexes in
addition to gross and histopathologic lesions of the bile duct and liver
in males.

Reproductive NOAEL = 165 mg/kg/day

LOAEL > 165 mg/kg/day.

Offspring NOAEL = 32 mg/kg/day

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

870.4100

Chronic toxicity in dogs	43678140 (1994)

Acceptable/guideline

0, 3, 25, 200 mg/kg/day	NOAEL = 25 mg/kg/day

LOAEL = 200 mg/kg/day based, in both sexes, on clinical observations,
increased liver weight, and clinical chemistry changes indicative of
effects on liver/biliary function.

870.4200

Carcinogenicity in mice	43678141 (1995)

Acceptable/guideline

0, 50, 300, 2000 ppm

M: 0, 6.2, 37.5, 272.4 mg/kg/day

F: 0, 8.5, 51.3, 363.3 mg/kg/day	NOAEL = 38 mg/kg/day

LOAEL = 272 mg/kg/day based on reduced body weights in both sexes.

There was no evidence of carcinogenicity.

870.4300

Combined Chronic toxicity/ Carcinogenicity in rats	43678139 (1995)

Acceptable/guideline

0, 60, 300, &1500/750 ppm for males (due to excessive death the high
dose was reduced beginning at week 52-104)

For females: 0, 60, 300,& 1500 ppm

M: 0, 3.6, 18.2, 82.4 mg/kg/day

F: 0, 4.5, 22.3, 117.1 mg/kg/day	NOAEL = 18 mg/kg/day

LOAEL = 82.4 mg/kg/day in males and 117 mg/kg/day in females based on
reduced body weights in both sexes and bile duct lesions in males.

There was no evidence of carcinogenicity.

870.5100

Bacterial reverse gene mutation	43668146 (1992)

Acceptable/guideline

100, 200, 500, 1000, 2500, 5000 µg/plate	Negative in increasing
revertant colonies up to 5000 µg/plate +/-S9 using both plate
incorporation and preincubation protocols and Salmonella strains TA98,
TA100, TA1535, and TA1537 as well as the E. Coli strains WP2P and
WP2PuvrA.  Cytotoxicity and compound precipitation were seen at the high
dose.

870.5300

Mammalian cell forward gene mutation (mouse lymphoma cells)	43678145
(1993)

Acceptable/guideline

8 to 80 µg/mL in three assays	Nonlinear, slight but significant
increases in the mutation frequency (MF) of mouse lymphoma L5178Y TK+/-
at 15-60 µg/mL +/-S9.  Despite the absence of a dose response,
increased MFs were reproducible; therefore, Azoxystrobin is considered
positive in this test system.  Colony sizing was not performed.

870.5375

Cytogenetics chromosomal aberration 	43678147 (1992)

Acceptable/guideline

0.5 to 50 µg/mL without S-9 1 to 300 µg/mL with S-9

	The in vitro test in human lymphocytes was positive for the induction
of chromosomal aberrations in both the presence and absence of S9 at
doses (5-50 µg/mL -S9; 100-200 µg/mL +S9) that were moderately to
severely cytotoxic (i.e., >16-70% reductions in mitotic cells,
respectively)

870.5385 

Cytogenetics bone marrow	43678148 (1992)

Acceptable/guideline

5000 mg/kg

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

870.5550

Other: Unscheduled DNA synthesis	43678149 (1992)

Acceptable/guideline

1250 and 2000 mg/kg

	The in vivo/in vitro unscheduled DNA synthesis test in rat hepatocytes
was negative.  No toxicity to the treated animals or cytotoxic effects
on recovered hepatocytes up to the limit dose for acute testing (2000
mg/kg) when administered once by oral gavage.

870.6200a

Acute neurotoxicity screening battery in rats	43678134 (1994)

Acceptable/guideline

0, 200, 600, 2000 mg/kg	NOAEL < 200 mg/kg/day

LOAEL = 200 mg/kg/day based on transient diarrhea in both sexes. 

870.6200b

Subchronic neurotoxicity screening battery in rats	43678138 (1994)

Acceptable/guideline

0, 100, 500, 2000 ppm

M: 0, 8.0, 38.5, 161 mg/kg/day 

F: 0, 9.1, 47.9, 201.5 mg/kg/d	NOAEL = 39 mg/kg/day.

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

870.7485

Metabolism and pharmacokinetics	43678150 4367815143678152
4367815343678154

issues at seven days postdosing. The primary route of excretion was via
the feces (≈73-89%) followed by urine (≈9-18%).  There were no
apparent sex- or dose-related differences in distribution or in the
pattern of excretion. In a bile duct cannulated single high-dose group,
assessment of biliary excretion suggested approximately 70% absorption
with ≈32% of the administered dose remaining as parent compound in the
gastrointestinal tract.  Absorbed azoxystrobin appeared to be
extensively metabolized with minor sex-related qualitative and
quantitative differences in biliary metabolites.  A metabolic pathway
was proposed showing hydrolysis and subsequent glucuronide conjugation
as the major biotransformation process.

870.7600

Dermal penetration (rat)	43678155 (1994)

Acceptable/guideline

0.01, 0.1, 0.9, 13.3 mg/kg	2 - 4 % Dermal Absorption 

Appendix B:	International Residue Limit Status Sheet

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䀀&摧㠎¥܀) pyrimidin-4-yloxy)phenyl)-3-methoxyacrylate	Common Name:

Azoxystrobin	( Proposed tolerance

X Reevaluated tolerance

( Other	Date: 07/16/09

Codex Status (Maximum Residue Limits)	U. S. Tolerances

(    No Codex proposal step 6 or above

(    No Codex proposal step 6 or above for the crops requested	Petition
Number:  PP#8E7474

DP#s:  362963 & 363046

Other Identifier:  

Residue definition (step 8/CXL):  Azoxystrobin	Reviewer/Branch:  Meheret
Negussie, RAB3

	Residue definition in PP#8E7474

for plant commodities:  Combined residues of azoxystrobin and its
Z-isomer

 No Limits

√No Limits for the crops requested.	 No Limits

 No Limits for the crops requested

Residue definition  (αE)-methyl
2-[[6-(2-cyanophenoxy)-4-pyrimidinyl]oxy]-α
-methoxymethylene)benzeneacetate,

including the isomer (Z)-methyl 2-[[6-(2-

cyanophenoxy)-4-pyrimidinyl]oxy]--(methoxymethylene)benzeneacetate
Residue definition:  Azoxistrobin

Crop(s)	MRL (mg/kg)	Crop(s)	MRL (mg/kg)

Barley	0.3

Notes/Special Instructions:  Codex barley value based on European trials
only:  Combined azoxystrobin residues in barley grain from the trials in
Europe (n = 38), in ranked order median underlined, were: 0.01 (4), 0.02
(6), 0.03 (4), 0.04 (3), 0.05, 0.08 (3), 0.09, 0.10 (2),0.11 (4), 0.12,
0.13 (4), 0.14, 0.19, 0.20, 0.23, and 0.28 mg/kg. Typical label in
Europe is 2 X 0.25 kg ai/ha, 35 day PHI.

	

No information is available of the derivation of the Mexican MRL for
barley, 0.3 ppm.  This is from 2004 and may have changed.  Mexico
typically adopts Codex or US standards for its export purposes.

S.Funk, 07/17/2009.

Page   PAGE  44  of   NUMPAGES  53 

Should I delete it since it was not proposed.