Document ID: EPA-HQ-OPP-2008-0713-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-10-07T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF	

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: 04/30/2009

MEMORANDUM

SUBJECT:	Pyraclostrobin: Human Health Risk Assessment for Proposed Uses
on Grain Sorghum (PP#8F7385); Increase of Tolerance for the Stone Fruit
Crop Group 12 to Satisfy European Union (EU) Import Requirement
(PP#8F7390); and Establishment of a Permanent Import Tolerance for
Coffee (PP#8E7394).

PC Code: 099100	DP Barcode: D356946

Decision No.: 397102	Registration No.: 7969-186, 7969-266, & 7969-199

Petition Nos.: 8F7385, 8F7390, and 8E7394 	Regulatory Action: Section 3
Registration Action

Risk Assessment Type: Single Chemical/Aggregate	Case No.: NA

TXR No.: NA	CAS No.: 175013-18-0 

MRID Nos.: NA	40 CFR: 180.582

FROM:	Barry O’Keefe, Risk Assessor

		Meheret Negussie, Chemist

		Whang Phang, Toxicologist

		Risk Assessment Branch 3 (RAB3)

		Health Effects Division (7509P)

THROUGH:	Paula Deschamp, Branch Chief

		Risk Assessment Branch 3 (RAB3)

		Health Effects Division (7509P)

TO:		John Bazuin/Tony Kish, PM Team 22

		Fungicide Branch

		Registration Division (RD) (7505P)

The Registration Division (RD) of the Office of Pesticide Programs (OPP)
has requested that HED evaluate toxicology and residue chemistry data
and conduct dietary, aggregate, and occupational exposure and risk
assessments, as needed, to estimate the risk to human health that will
result from existing and proposed uses of pyraclostrobin.

BASF Corporation submitted three separate petitions.  In petition
PP#8F7385, BASF requested the establishment of pyraclostrobin tolerances
and the addition of new foliar and seed treatment uses on grain sorghum.
 In petition PP#8F7390, BASF requested an increase in the tolerance for
the stone fruit crop group 12.  In petition PP#8E7394, BASF requested
the establishment of a tolerance for imported coffee.

The Health Effects Division (HED) has conducted a human health risk
assessment for these proposed and changed uses.  HED has high confidence
in the quality of the toxicology, chemistry and exposure databases used
to assess risk from pyraclostrobin.

A summary of the findings and an assessment of human risk resulting from
the registered and proposed tolerances for pyraclostrobin are provided
in this document.  The risk assessment and the occupational/residential
exposure assessment were provided by Barry O’Keefe.  The residue
chemistry data review and dietary risk assessment were provided by
Meheret Negussie. The toxicology update was provided by Whang Phang.  

Table of Contents

  TOC \f  1.0	Executive Summary	  PAGEREF _Toc228867774 \h  4 

2.0	Ingredient Profile	  PAGEREF _Toc228867775 \h  10 

2.1	Summary of Registered/Proposed Uses	  PAGEREF _Toc228867776 \h  10 

2.2	Physical and Chemical Properties	  PAGEREF _Toc228867777 \h  12 

3.0	Hazard Characterization/Assessment	  PAGEREF _Toc228867778 \h  13 

3.1	Hazard Characterization and FQPA Considerations	  PAGEREF
_Toc228867779 \h  13 

3.1	FQPA Safety Factor for Infants and Children	  PAGEREF _Toc228867780
\h  15 

3.3	Summary of Toxicological Doses and Endpoints for Use in Human Health
Risk Assessments	  PAGEREF _Toc228867781 \h  16 

3.4	Recommendation for Aggregate Exposure Risk Assessments	  PAGEREF
_Toc228867782 \h  19 

3.5	Endocrine disruption	  PAGEREF _Toc228867783 \h  19 

4.0	Public Health and Epidemiology Data	  PAGEREF _Toc228867784 \h  20 

5.0	Dietary Exposure/Risk Characterization	  PAGEREF _Toc228867785 \h 
20 

5.1  Pesticide Metabolism and Environmental Degradation	  PAGEREF
_Toc228867786 \h  20 

5.1.1	Metabolism in Primary Crops	  PAGEREF _Toc228867787 \h  20 

5.1.2	Metabolism in Livestock	  PAGEREF _Toc228867788 \h  20 

5.1.3	Analytical Methodology	  PAGEREF _Toc228867789 \h  21 

5.1.4	Storage Stability Data	  PAGEREF _Toc228867790 \h  22 

5.1.5	Magnitude of the Residue in Plants	  PAGEREF _Toc228867791 \h  23 

5.1.6	Magnitude of the Residue in Processed Food/Feed	  PAGEREF
_Toc228867792 \h  25 

5.1.7	Magnitude of the Residue in Meat, Milk, Poultry, and Eggs	 
PAGEREF _Toc228867793 \h  26 

5.1.8	Confined and Field Accumulation in Rotational Crops	  PAGEREF
_Toc228867794 \h  28 

5.1.9	Drinking Water Residue Profile	  PAGEREF _Toc228867795 \h  29 

5.1.10	Proposed Tolerances	  PAGEREF _Toc228867796 \h  30 

5.2  Dietary Exposure and Risk	  PAGEREF _Toc228867797 \h  31 

5.3 Anticipated Residue and Percent Crop Treated (%CT) Information	 
PAGEREF _Toc228867798 \h  34 

6.0	Residential (Non-Occupational) Exposure/Risk Characterization	 
PAGEREF _Toc228867799 \h  34 

7.0	Aggregate Risk Assessments and Risk Characterization	  PAGEREF
_Toc228867800 \h  35 

8.0	Cumulative Risk Characterization/Assessment	  PAGEREF _Toc228867801
\h  36 

9.0	Occupational Exposure/Risk Pathway	  PAGEREF _Toc228867802 \h  37 

9.1	Short-/Intermediate-Term Handler Risk	  PAGEREF _Toc228867803 \h  37

9.2	Short-/Intermediate-Term Postapplication Risk	  PAGEREF
_Toc228867804 \h  43 

10.0	Data Needs and Label Recommendations	  PAGEREF _Toc228867805 \h  45

10.1	Toxicology Data Needs	  PAGEREF _Toc228867806 \h  45 

10.2	Residue Chemistry Data Needs and Label Recommendations	  PAGEREF
_Toc228867807 \h  45 

10.3	Occupational Label Recommendations	  PAGEREF _Toc228867808 \h  45 

11.0	International Residue Limit Status	  PAGEREF _Toc228867809 \h  46 

12.0	Appendix A: Toxicity Profile	  PAGEREF _Toc228867810 \h  48 

12.1	Appendix A1.: Pyraclostrobin Toxicology Requirements and Available
Studies for Food Uses	  PAGEREF _Toc228867811 \h  48 

12.2	Appendix A2.: Acute Toxicity Data on Pyraclostrobin Technical	 
PAGEREF _Toc228867812 \h  49 

12.3	Appendix A3.: Subchronic, Chronic and Other Toxicity Profile	 
PAGEREF _Toc228867813 \h  50 

13.0	Appendix B: Rationale for Toxicity Data Requirement	  PAGEREF
_Toc228867814 \h  54 

 1.0	Executive Summary  TC \l1 "1.0	Executive Summary 

trobilurin class of fungicides (β-methoxyacrylate class of compounds). 
Strobilurins are synthetic analogs of a natural antifungal substance
which inhibit spore germination, mycelial growth, and sporulation of the
fungus on the leaf surface.

Pyraclostrobin is currently registered on barley, berries, Brassica
vegetables, bulb vegetables, canola, citrus, corn (field, pop and
sweet), cotton, cucurbit vegetables, flax, fruiting vegetables, grapes,
grass grown for seed, hops, leafy vegetables, legumes (dried peas and
beans, succulent shelled peas and beans), mint, oats, peanuts,
pistachios, pome fruit, potatoes, root vegetables, rye, soybean,
strawberries, stone fruits, sugar beets, sunflower, tropical fruits,
tuberous and corm vegetables, tree nuts, and wheat, as well as
ornamentals, and residential and golf course turf.  

BASF Corporation submitted a petition (8F7385) requesting tolerances for
residues of pyraclostrobin in/or on field grown sorghum; Headline® EC
Fungicide (a liquid concentrate) EPA Reg. No. 7969-186.  Only one
application of Headline® EC Fungicide may be applied per season at 0.1
to 0.2 lb ai/A (6-12 fl oz/A) by aerial, chemigation, or groundboom
equipment, with applications no later than the 25% flowering stage.  In
addition, the petitioner proposes to add a supplemental label to the
seed treatment label, Stamina™ (a liquid concentrate) EPA Reg. No.
7969-266.  Pyraclostrobin may be applied to sorghum seeds with
commercial seed treatment equipment at 0.01 to 0.02 lb ai/100 lb of seed
(0.8-0.15 fl oz/100 lb seed).

BASF Corporation submitted a petition (8F7390) requesting an increase in
the tolerance for the stone fruit crop group 12 from 0.9 ppm to 2.5 ppm.
 Application of Pristine® Fungicide BAS 516 04F (EPA Reg. No. 7969-199)
to stone fruits is proposed at 0.84 to 0.117 lb ai/A (10.5-14.5 fl oz/A)
with up to five re-treatments at 7 to 14 day intervals up to a maximum
seasonal application rate of 0.585 lb ai/a (72.5 fl oz/A) and with a
0-day PHI.  Pristine® Fungicide is a WDG formulation containing the
multiple active ingredients of pyraclostrobin (12.8%) and boscalid
(25.2%).  

BASF Corporation submitted a petition (8E7394) requesting the
establishment of a tolerance for imported coffee.  The supplemental
COMET® 25% EC label is proposed (supplemental for the Headline® EC
Fungicide (liquid concentrate) EPA Reg. No. 7969-186) at up to two
applications at 0.1 to 0.2 lb ai/A (150-200 g/ha).

The Health Effects Division (HED) has conducted a human health risk
assessment for these proposed and changed uses.  HED has high confidence
in the quality of the toxicology, chemistry and exposure databases used
to assess risk from the use of pyraclostrobin.



Hazard Assessment Summary

The quality of the toxicology database for pyraclostrobin is good and
the confidence in the hazard and dose-response assessments is high.  The
toxicity database for pyraclostrobin is considered adequate for endpoint
selection for exposure risk assessment scenarios and for FQPA
evaluation.  Based on the hazard and exposure data, the RAB3
pyraclostrobin risk assessment team concluded that the FQPA safety
factor can be reduced to 1X.  Please refer to Appendix A for the
toxicity profile tables.  Please also refer to a previous pyraclostrobin
risk assessment document for further extensive details (B. O’Keefe, DP
Barcode 343700, 9/7/07).  As there is no new toxicity data associated
with these current actions, the hazard characterization and endpoint
selection from the previous risk assessment are applied directly to this
action.  However, under the current 40 CFR §158.500 data requirement
guidelines, the immunotoxicity data (OPPTS 780.7800) shall be required
as a condition of registration.

Dietary (Food & Drinking Water) Exposure Assessment

Acute and chronic dietary exposure assessments were conducted for the
proposed and existing food uses and drinking water inputs.  These acute
and chronic dietary risk assessments are considered only minimally
refined.

The acute analysis was conducted using either tolerance level residues
or highest residues derived from field trial data conducted at the
maximum application rate and minimum PHI permitted on the proposed or
existing labels.  For all commodities 100% crop treated was assumed.  A
limited number of experimentally derived processing factors were used to
refine the acute analysis.  Of note is that the relative contribution
from drinking water is minimal.  For acute exposures the peak
concentration estimated drinking water concentration (EDWC) of 35.6 ppb
was directly incorporated into the DEEM_FCID into the food categories
“water, direct, all sources” and water, indirect, all sources”
(based on a maximum application rate of 3.0 lb ai/A/season for the turf
use rate).  HED concludes that the acute exposure estimates are unlikely
to underestimate actual acute exposure.

The chronic dietary assessment was conducted using tolerance level
residues for all crops except for apple, grape, head lettuce, leaf
lettuce, celery, spinach, orange, pepper and tomato where average
residues from crop field trials were used.  These field trials represent
maximum application rates and minimum PHIs.  Average percent crop
treated estimates were used when available from a recent Screening Level
Usage Analysis (SLUA).  A limited number of experimentally derived
processing factors from pyraclostrobin processing studies were also used
to refine the analysis.  Again, the relative contribution from drinking
water is minimal.  For chronic exposures the annual average
concentration EDWC of 2.3 ppb was directly incorporated into the
DEEM_FCID into the food categories “water, direct, all sources” and
water, indirect, all sources”(based on a maximum application rate of
3.0 lb ai/A/season for the turf use rate).  

HED concludes that the chronic exposure estimates in this analysis are
unlikely to underestimate actual exposure.

Acute and chronic exposures and risks do not exceed HED’s level of
concern for the U.S. population and for all relevant population
subgroups.  At the 95th percentile, the acute dietary exposure utilized
1.5% of the aPAD for the general U.S. population and 81% of the aPAD for
females 13-49 years old, the most highly exposed population subgroup. 
The chronic dietary exposure utilized 7.3% of the cPAD for the general
U.S. population and 24% of the cPAD for children 1-2 years old, the most
highly exposed population subgroup.  

Aggregate Exposure Assessment

There are existing residential uses on turf which contribute to
aggregate exposures.  Residential and recreational turf applications are
applied by professional pest control operators (PCOs) only, and
therefore, residential handler exposures do not occur.  There is,
however, a potential for exposure to homeowners in residential settings
from entering previously treated lawns where children might play and
adults might work or play.  As a result, risk assessments have been
completed for postapplication scenarios.  Postapplication short- and
intermediate-term dermal and incidental oral exposures are expected to
occur from the turf use pattern.  Common effects (i.e., decreased body
weight gain, food intake, and food efficiency) were seen in the studies
selected to evaluate dietary, dermal and incidental oral ingestion
exposures; and therefore, route-specific exposures can be aggregated.

Aggregate assessments were conducted for acute and chronic dietary (food
+ drinking water) exposures.  Additionally, short- and intermediate-term
aggregate risk assessments were conducted.  Both short- and
intermediate-term exposures may occur during postapplication activities
for adults and children.  However, because the toxicity endpoints and
points of departure are identical for short- and intermediate-term
exposures, separate risk estimates for short- and intermediate-term
exposures were not calculated.  These short-/intermediate-term aggregate
risk assessments take into account average exposure estimates from
dietary consumption of pyraclostrobin (food and drinking water) and
non-occupational/residential uses (turf), i.e., for toddlers incidental
oral, dermal, and average food plus drinking water exposures are
aggregated, and for adults, dermal and average food plus drinking water
exposures are aggregated.  

The total combined MOE from dietary (food + drinking water) and
non-occupational/residential exposure is 120 for children 1-2 years old,
which is not of concern to HED.  For adults the total combined MOE is
230, which also is not of concern to HED.  These aggregate exposure risk
assessments are considered conservative estimates, that should not
underestimate risks, because of the following inputs: 1) dietary inputs
primarily used tolerance level residues; 2) crop specific (turf)
screening level drinking water modeling data were used (i.e., Tier II
surface water model); 3) maximum application rates and minimum
application intervals were used; and 4) conservative SOPs and upper
level estimates of exposure were employed.



Occupational Handler Exposure Assessment

	Agricultural Handler Risk

The proposed supplemental Headline® label requires occupational
handlers to wear coveralls and chemical resistant gloves.  Occupational
exposure and risk resulting in MOEs greater than or equal to 100 are not
of concern to HED.  All handler scenarios resulted in MOEs greater than
the level of concern (MOEs ≥ 100) at some level of risk mitigation. 
Of note, for the scenario of mixing and loading liquid concentrates to
support aerial applications, a dust mist respirator is needed to achieve
an MOE ≥ 100, which is not already included on the proposed Headline®
label.

	Seed Treatment Handler Risk

The proposed supplemental Stamina™ label requires occupational
handlers to wear baseline attire (i.e., long-sleeve shirt, long pants,
shoes, and socks) and chemical resistant gloves.  Most seed treatment
activities result in MOEs greater than the LOC of 100 and are not of
concern with the proposed personal protective equipment (PPE).  However,
for the scenario of handlers involved in multiple commercial seed
treatment activities (“multiple activities”), a dust mist respirator
is needed to achieve an MOE ≥ 100, which is not already included on
the proposed Stamina™ label.

Occupational Postapplication Exposure Assessment

≥100.  Therefore, the restricted entry interval (REI) is based on the
acute toxicity of pyraclostrobin technical material which is classified
as Category III for acute dermal toxicity and for skin and eye
irritation potential.  Pyraclostrobin is not a dermal sensitizer.  Under
the Worker Protection Standard for Agricultural Pesticides, active
ingredients classified as acute toxicity categories III or IV for these
routes are assigned a 12-hour REI.   

Recommendations for Tolerances

HED has completed a human health risk assessment for the proposed new
uses of the active ingredient pyraclostrobin.  

For Petition #8F7385 - Provided that a revised Section F is submitted
reflecting the recommended tolerances and commodity definitions
presented in Table 12, the residue chemistry and toxicological databases
support the acceptance of a conditional registration on sorghum, and
establishment of permanent tolerances for the combined residues of
pyraclostrobin (carbamic acid, [2-[[[1-(4-chlorophenyl)-1H-
pyrazol-3-yl]oxy]methyl]phenyl]methoxy-, methyl ester) and its
desmethoxy metabolite (methyl
N-[[[1-(4-chlorophenyl)-1H-pyrazol-3-yl]oxy]methyl]phenyl carbamate),
expressed as parent compound in/on the following raw agricultural
commodities: 

Sorghum, grain, forage	5.0 ppm

Sorghum, grain, grain	0.60 ppm

Sorghum, grain, stover	0.80 ppm

For Petition #8F7390 - Provided that a revised Section F is submitted
reflecting the recommended tolerances and commodity definitions
presented in Table 12, the residue chemistry and toxicological databases
support the proposed amended use pattern for stone fruit crop group 12
and permanent tolerances for the combined residues of pyraclostrobin
(carbamic acid, [2-[[[1-(4-chlorophenyl)-1H-
pyrazol-3-yl]oxy]methyl]phenyl]methoxy-, methyl ester) and its
desmethoxy metabolite (methyl
N-[[[1-(4-chlorophenyl)-1H-pyrazol-3-yl]oxy]methyl]phenyl carbamate),
expressed as parent compound in/on the following raw agricultural
commodity: 

Fruit, stone, group	2.5 ppm

For Petition #8E7394 – Provided that a revised Section F is submitted,
the residue chemistry and toxicological databases support the
establishment of a permanent tolerance for the combined residues of
pyraclostrobin (carbamic acid, [2-[[[1-(4-chlorophenyl)-1H-
pyrazol-3-yl]oxy]methyl]phenyl]methoxy-, methyl ester) and its
desmethoxy metabolite (methyl
N-[[[1-(4-chlorophenyl)-1H-pyrazol-3-yl]oxy]methyl]phenyl carbamate),
expressed as parent compound in/on the following raw agricultural
commodity:

Coffee, bean, green	0.3 ppm

Recommendations for Labels

™ BAS 500 12 F Label

For the scenario of handlers involved in multiple commercial seed
treatment activities (“multiple activities”), a dust mist respirator
is needed to achieve an MOE ≥ 100, which is not already included on
the proposed Stamina™ label.

For the seed treatment uses, the pyraclostrobin seed treatment labeling
should be required to add specific statements regarding the personal
protective equipment required for persons planting treated seed as well
as other label restrictions, as follows:.

“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 soil/media subsurface."

Headline® Fungicide Label

For the use on sorghum, the scenario of mixing and loading liquid
concentrates to support aerial applications, a dust mist respirator is
needed to achieve an MOE ≥ 100, which is not already included on the
proposed Headline® label.

Environmental Justice Considerations

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 ).

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures. 
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by the USDA under the Continuing
Survey of Food Intake by Individuals (CSFII) and are used in pesticide
risk assessments for all registered food uses of a pesticide.  These
data are analyzed and categorized by subgroups based on age, season of
the year, ethnic group, and region of the country.  Additionally, OPP is
able to assess dietary exposure to smaller, specialized subgroups and
exposure assessments are performed when conditions or circumstances
warrant.  Whenever appropriate, non-dietary exposures based on home use
of pesticide products and associated risks for adult applicators and for
toddlers, youths, and adults entering or playing on treated areas
postapplication are evaluated.  Further considerations are currently in
development as OPP has committed resources and expertise to the
development of specialized software and models that consider exposure to
bystanders and farm workers as well as lifestyle and traditional dietary
patterns among specific subgroups.

Review of Human Research

This risk assessment relies in part on data from Pesticide Handlers
Exposure Database (PHED) studies in which adult human subjects were
intentionally exposed to a pesticide or other chemical.  These studies
have been determined to require a review of their ethical conduct, have
received that review, and have been determined to be ethical.

2.0	Ingredient Profile  TC \l1 "2.0	Ingredient Profile 

2.1	Summary of Registered/Proposed Uses  TC \l2 "2.1	Summary of
Registered/Proposed Uses 

Pyraclostrobin is currently registered on barley, berries, Brassica
vegetables, bulb vegetables, canola, citrus, corn (field, pop and
sweet), cotton, cucurbit vegetables, flax, fruiting vegetables, grapes,
grass grown for seed, hops, leafy vegetables, legumes (dried peas and
beans, succulent shelled peas and beans), mint, oats, peanuts,
pistachios, pome fruit, potatoes, root vegetables, rye, soybean,
strawberries, stone fruits, sugar beets, sunflower, tropical fruits,
tuberous and corm vegetables, tree nuts, and wheat, as well as
ornamentals, and residential and golf course turf.  

A summary of the pyraclostrobin end-use products proposed for use on the
crops discussed in this document is listed in Table 1. Table 2 presents
the summary of proposed crop use patterns. 

TABLE 1.  Summary of Proposed Pyraclostrobin End-Use Products.

Trade Name	EPA Reg. No.	% ai of Formulation	Formulation Type	Target
Crops	Label Date

Headline® Fungicide	7969-186	23.6%,

(2.09 lb ai/gal)	EC	Sorghum	Supplemental label attached in Section B.
(June 30, 2008)

Stamina BAS 500 12 F	7969-266	18.4%

(1.67 lb ai/gal)	Seed Treatment	Sorghum	Supplemental label attached in
Section B. (June 30, 2008)

Pristine® Fungicide

BAS 516 04F (Mix with Boscalid)	7969-199	12.8%

(1.1 lb ai/gal)

	WG	Stone Fruits Group-Apricot, Cherry (sweet and sour), Nectarine,
Peach, Plum and Prune.	Label March 27, 2008

Headline® Fungicide (COMET® in Brazil)	7969-186	23.6%

(2.09 lb ai/gal)	EC	Coffee	Supplemental label attached in Section B.
(June 30, 2008).



TABLE 2.  Summary of Proposed Use Patterns of Pyraclostrobin.

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

Grain Sorghum

Ground sprayer, aerial, or sprinkler irrigation systems.	[7969-186]

23.6% EC	(0.1-0.2)

6 to 12 fl ozs/A	1	(0.2)

12 fl ozs/A	 No later than 25% flowering	 Begin applications prior to
disease development. Use higher rate (0.15-0.2 lb ai/A) when disease
pressure is high (Northern leaf blight and Southern leaf blight). 

Do not use in greenhouse or transplant production systems. For
resistance management, if additional fungicide application is needed use
a labeled non-group 11 fungicide with a different mode of action. No
aerial application in NY state except as permitted under FIFRA section
24(c).

Grain Sorghum      

Apply as a water-based mixture using standard slurry or mist-type seed
treatment application equipment. 	[7969-266]

18.4%	(0.001-0.002)

0.01-0.02 lb/100 lbs seed

	N/S

	N/S

	Seed treatment	Use at commercial treatment facilities. Not for use on a
farm. Use higher rate when disease pressure is expected to be high. 

Mechanical agitation is required for proper mixing. 

Coffee

Ground sprayer, aerial, or sprinkler irrigation systems.	[7969-186]

25% EC	(0.1-0.2) 

150-200

g/ha	2	N/S

	45	Apply when leaf infection indexes up to 5% are observed. Re-apply in
dose of  0.1 lb ai/A whenever the infection index by rust reaches up to
5% again. Maximum of two applications.  

Stone Fruits Crop Group 12

Ground application, aerial, or sprinkler irrigation equipment. 
[7969-199]

12.8% WG	(0.084-0.117)

10.5-14.5 ozs of product1	5	(0.585)

72.5 ozs of product1	0	 Begin application at pink bud or prior to onset
of disease development and continue on a 7-14 day interval. Do not make
more than 5 applications of Pristine or other group 7 or 11 fungicides
per season.  Do not make more than 2 sequential applications before
alternating to a labeled fungicide with a different mode of action. For
aerial application, use no less than 10 gal of spray solution per acre. 

Do not apply when wind speed favors drift. Do not use in grrenhouse or
transplant production. No aerial application in NY state except as
permitted under FIFRA section 24(c).

N/S= not specified

1 0.128 oz (0.008lb) of pyraclostrobin in 1 oz of product.

Conclusions.  The submitted use directions are sufficient to allow
evaluation of the available residue data relative to the proposed use. 
The field trial data for grain sorghum, the stone fruit crop group 12,
and coffee reflect the proposed use patterns.  

2.2	Physical and Chemical Properties  TC \l2 "2.2	Physical and Chemical
Properties 

The chemical structure of pyraclostrobin and its metabolites are
presented in Tables 3 and 4, respectively.  Please refer to a previous
risk assessment document (DP# 334535, 02/21/08, B. O’Keefe) for a
detailed listing of the physical and chemical properties of
pyraclostrobin.

Table 3.   Pyraclostrobin Chemical Structure.

Pyraclostrobin	

Table 4.  Chemical Structures of Pyraclostrobin Metabolites.

 

BAS 500-5	

 

BAS 500-8	

 

3.0	Hazard Characterization/Assessment  TC \l1 "3.0	Hazard
Characterization/Assessment 

3.1	Hazard Characterization and FQPA Considerations  TC \l2 "3.1	Hazard
Characterization and FQPA Considerations 

The quality of the toxicology database for pyraclostrobin is good and
the confidence in the hazard and dose-response assessments is high.  The
toxicity database for pyraclostrobin is considered adequate to support
toxicity endpoint selection for risk assessment and for FQPA evaluation.
 However, under the current 40 CFR §158.500 data requirement
guidelines, the immunotoxicity data (OPPTS 780.7800) shall be required
as a condition of registration.

To address the issue of immunotoxicity data gap and the associated
database uncertainty factor, RAB3 examined the entire database of
pyraclostrobin and determined that an additional uncertainty factor is
not needed to account for potential immunotoxicity.  For pyraclostrobin,
a complete battery of subchronic, chronic, carcinogenicity,
developmental and reproductive studies as well as acute and subchronic
neurotoxicity screening studies are available for consideration.  The
immunotoxic potential of pyraclostrobin has been well characterized in
relationship to other adverse effects seen in the submitted toxicity
studies (Memorandum: Yung G. Yang to Cynthia Giles-Parker, 7/24/2007,
TXR # 0054636; DP Barcode: D341293).  Under the conditions of the
studies, the results do not indicate the immune system to be the primary
target and, other than the high dose-thymus effects seen in the 90-day
mouse study, no significant evidence of pyraclostrobin-induced
immunotoxicity was demonstrated either in the studies conducted in adult
animals or in the offspring following pre- and post-natal exposures. 
Currently, the point of departure in establishing the chronic RfD is 3.4
mg/kg/day; the RAB3 risk assessment team does not believe that
conducting a special series 870.7800 immunotoxicity study will result in
a NOAEL less than 3.4 mg/kg/day.  An additional uncertainty factor
(UFDB) for database uncertainties does not need to be applied at this
time. 

A recent pyraclostrobin risk assessment document included an updated
toxicology and hazard evaluation, including results of recently
submitted toxicity studies, a new carcinogenicity evaluation, and
selection of new study/endpoints for exposure by the inhalation route. 
Please refer to this previous pyraclostrobin risk assessment document
for further extensive details (B. O’Keefe, DP Barcode 343700, 9/7/07).
 Also, please refer to Appendices 2 and 3 of this current risk
assessment document for the toxicity profile tables.  As there is no new
toxicity data associated with these current actions, the hazard
characterization and endpoint selection, from the previous risk
assessment are applied directly to this action.

Pyraclostrobin has a low to moderate acute toxicity based on its
classification in Toxicity Category IV via the oral route, Toxicity
Category III by the dermal route, and Toxicity Category II by the
inhalation route of exposure.  Pyraclostrobin produces moderate eye
irritation (Toxicity Category III), is a moderate dermal irritant
(Toxicity Category III), and is not a dermal sensitizer (Appendix 2).

The main target organs for pyraclostrobin are the upper gastrointestinal
tract (mainly the duodenum and stomach), the spleen/hematopoiesis, and
the liver.  In the 90-day mouse oral toxicity study, thymus atrophy was
seen at doses of 30 mg/kg or above, but similar effect was not found in
the mouse carcinogenicity study at doses as high as 33 mg/kg.  In
reproductive and developmental studies, there was evidence of increased
qualitative susceptibility following in utero exposure in the rabbit,
but not in rats.  In the two-generation reproduction study, the highest
dose tested did not cause maternal systemic toxicity, nor did it elicit
reproductive or offspring toxicity.  Nonetheless, HED determined that,
when evaluated with the findings of the dose-range finding
one-generation reproduction study (MRID# 45596210), there is no need to
repeat the two-generation reproduction study.  In both the acute and
subchronic neurotoxicity studies, there were no indications of
treatment-related neurotoxicity.

  SEQ CHAPTER \h \r 1 The CARC classified pyraclostrobin into the
category “Not Likely to be Carcinogenic to Humans” based on no
treatment-related increase in tumors in both sexes of rats and mice,
which were tested at doses that were adequate to assess carcinogenicity,
and the lack of evidence of mutagenicity.

A variety of oral toxicity studies were used for the different risk
assessment scenarios including the rabbit developmental toxicity study,
the acute neurotoxicity study in rats, the rat carcinogenicity study,
and the 13-week study in dogs.  In addition, the 28-day inhalation study
in rats was used for short- and intermediate-term occupational and
residential inhalation risk assessments.  The endpoints in these studies
are well characterized and are the most sensitive among available
comparable toxicity studies in other species.  All dietary points of
departure (i.e., acute and chronic RfDs) are calculated from the
respective study’s NOAEL after applying a 100-fold safety factor (10 X
to account for interspecies extrapolation and 10X for intraspecies
variation).  For all other scenarios, including dermal, inhalation, and
incidental oral, an MOE approach will be used with a Level of Concern
(LOC) at 100.  



3.2	FQPA Safety Factor for Infants and Children  TC \l2 "3.1	FQPA Safety
Factor for Infants and Children 

Based on the hazard and exposure data, the RAB3 pyraclostrobin risk
assessment team concluded that the FQPA safety factor can be reduced to
1X.  The recommendation is based on the following: 

The toxicity database is adequate and there are no residual
uncertainties for pre- and/or postnatal toxicity.  The doses chosen as
quantitative risk estimates are adequately protective for infants and
children.

Exposure data are complete or are estimated based on data that
reasonably account for potential exposures.  

The acute dietary analysis was based on tolerance level or highest
residues and 100% crop treated assumptions for all commodities. 
Experimentally derived processing factors were used for fruit juices and
tomato and wheat commodities.  The contribution from drinking water is
minimal.  HED concludes that the acute exposure estimates in this
analysis are unlikely to underestimate actual exposure.

The chronic dietary analysis included tolerance level or average
residues from field trial data and average percent crop treated
estimates were used when available from a recent Screening Level Usage
Analysis (SLUA).  A limited number of experimentally derived processing
factors (for fruit juices, tomato and wheat commodities) from
pyraclostrobin processing studies were also used to refine the analysis.
 The field trials represent maximum application rates and minimum PHIs. 
The contribution from drinking water is minimal.  HED concludes that the
chronic exposure estimates in this analysis are unlikely to
underestimate actual exposure.

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 will not likely be exceeded.

While there is potential for postapplication residential exposure, the
best data and approaches currently available were used in the
pyraclostrobin residential assessment.  The Agency used the current
conservative approaches for residential assessment, many of which
include recent upgrades to the SOPs.  The Agency believes that the
calculated risks represent conservative estimates of exposure because
maximum application rates are used to define residue levels upon which
the calculations are based.  Exposures are unlikely to be under
estimated because the assessment was a screening level assessment.



3.3	Summary of Toxicological Doses and Endpoints for Use in Human Health
Risk Assessments  TC \l2 "3.3	Summary of Toxicological Doses and
Endpoints for Use in Human Health Risk Assessments 

HED recently completed a Section 3 human health risk assessment for the
use of pyraclostrobin on cotton and Belgian endive (Memo B. O’Keefe,
et. al., 9/7/07, DP# 343700).  As there is no new toxicity data
associated with this current action, the hazard characterization and
endpoint selection, from the previous risk assessment are applied
directly to this action.  All previous exposure risk assessments remain
unchanged.  Below are the up-to-date tables.  

Table 5. Summary of Toxicological Doses and Endpoints for Pyraclostrobin
for Use in Dietary and Non-Occupational Human Health Risk Assessments

Exposure/

Scenario	Point of Departure	Uncertainty/

FQPA Safety Factors	RfD, PAD, Level of Concern for Risk Assessment	Study
and Toxicological Effects

Acute Dietary (General Population, including Infants and Children)
NOAEL= 300 mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 1x

	Acute RfD = 3.0 mg/kg/day

aPAD = 3.0 mg/kg/day	Rat Acute Oral Neurotoxicity

LOAEL = 1000 mg/kg/day based on decreased body weight gain in males.

Acute Dietary

(Females 13-49 years of age)	NOAEL = 5.0 mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 1x 	Acute RfD = 0.05 mg/kg/day

aPAD = 0.05 mg/kg/day	Rabbit Prenatal Developmental Toxicity

LOAEL = 10.0 mg/kg/day based on developmental toxicity findings of
increased resorptions.  SEQ CHAPTER \h \r 1 

Chronic Dietary (All Populations)	NOAEL= 3.4 mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 1x

	Chronic RfD = 0.034 mg/kg/day

cPAD = 0.034 mg/kg/day	  SEQ CHAPTER \h \r 1 Rat Oral Carcinogenicity

LOAEL = 9.2 mg/kg/day based on decreased body weight/body weight gain,
kidney tubular casts and atrophy in both sexes; increased incidence of 
liver necrosis and erosion/ulceration of the glandular- stomach and
fore-stomach in males.

Incidental Oral Short-Term (1-30 days)	NOAEL= 5.8 mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 1x

	Residential LOC for MOE = 100	  SEQ CHAPTER \h \r 1 13-Week Feeding Dog
Study

LOAEL = 12.9 mg/kg/day based on increased incidence of diarrhea,
clinical chemistry changes, duodenum mucosal hypertrophy, and decreased
body weight and food intake/efficiency.

Incidental Oral Intermediate-Term (1-6 months)	NOAEL= 5.8 mg/kg/day	UFA=
10x

UFH= 10x

FQPA SF= 1x

	Residential LOC for MOE = 100	  SEQ CHAPTER \h \r 1 13-Week Feeding Dog
Study

LOAEL = 12.9 mg/kg/day based on increased incidence of diarrhea,
clinical chemistry changes, duodenum mucosal hypertrophy, and decreased
body weight and food intake/efficiency.

Dermal Short-Term (1-30 days)	Oral study NOAEL = 5.0 mg/kg/day

  SEQ CHAPTER \h \r 1 (dermal absorption rate = 14 %)	UFA= 10x

UFH= 10x

FQPA SF= 1x	Residential LOC for MOE = 100

	Rabbit Prenatal Developmental Toxicity

LOAEL = 10.0 mg/kg/day based on developmental toxicity findings of
increased resorptions and maternal toxicity based on decreased body
weight gain and decreased food intake/efficiency.

Dermal Intermediate-Term (1-6 months)	Oral study NOAEL = 5.0 mg/kg/day

  SEQ CHAPTER \h \r 1 (dermal absorption rate = 14 %)	UFA= 10x

UFH= 10x

FQPA SF= 1x	Residential LOC for MOE = 100

	Rabbit Prenatal Developmental Toxicity

LOAEL = 10.0 mg/kg/day based on developmental toxicity findings of
increased resorptions and maternal toxicity based on decreased body
weight gain and decreased food intake/efficiency.

  SEQ CHAPTER \h \r 1 Long-Term Dermal (>6 months)	  SEQ CHAPTER \h \r 1
Oral study NOAEL = 3.4 mg/kg/day

(dermal absorption rate = 14 %)	UFA= 10x

UFH= 10x

FQPA SF= 1x	Residential LOC for MOE = 100

	  SEQ CHAPTER \h \r 1 Rat Oral Carcinogenicity

LOAEL = 9.2 mg/kg/day based on decreased body weight/body weight gain,
kidney tubular casts and atrophy in both sexes; increased incidence of 
liver necrosis and erosion/ulceration of the glandular- stomach and
fore-stomach in males.

Inhalation Short- Term (1-30 days)	NOAEL= 0.23 mg/kg/day (air
concentration = 0.001 mg/L)	UFA= 10x

UFH= 10x

FQPA SF= 1x	Residential LOC for MOE = 100	Rat 28-day Inhalation

LOAEL = 6.9 mg/kg/day (air concentration = 0.03 mg/L) based on duodenum
mucosal hyperplasia and respiratory system findings including alveolar
histiocytosis and olfactory atrophy/necrosis in nasal tissue.

Inhalation Intermediate-Term (1-6 months)	NOAEL= 0.23 mg/kg/day (air
concentration = 0.001 mg/L)	UFA= 10x

UFH= 10x

FQPA SF= 1x	Residential LOC for MOE = 100

	Rat 28-day Inhalation

LOAEL = 6.9 mg/kg/day (air concentration = 0.03 mg/L) based on duodenum
mucosal hyperplasia and respiratory system findings including alveolar
histiocytosis and olfactory atrophy/necrosis in nasal tissue.

Inhalation Long-Term (>6 months)	NOAEL= 0.23 mg/kg/day (air
concentration = 0.001 mg/L)	UFA= 10x

UFH= 10x

FQPA SF= 1x	Residential LOC for MOE = 100

	Rat 28-day Inhalation

LOAEL = 6.9 mg/kg/day (air concentration = 0.03 mg/L) based on duodenum
mucosal hyperplasia and respiratory system findings including alveolar
histiocytosis and olfactory atrophy/necrosis in nasal tissue.

Cancer (oral, dermal, inhalation) 	Classification:  “Not likely to be
Carcinogenic to Humans” based on the absence of significant tumor
increases in two adequate rodent carcinogenicity studies.

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use
of a short-term study for long-term risk assessment.  UFDB = to account
for the absence of key date (i.e., lack of a critical study).  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.



Table 6.  Summary of Toxicological Doses and Endpoints for
Pyraclostrobin for Use in Occupational Human Health Risk Assessments

Exposure/

Scenario	Point of Departure	Uncertainty Factors	Level of Concern for
Risk Assessment	Study and Toxicological Effects

Dermal Short-Term (1-30 days)	NOAEL= 5.0 mg/kg/day 

  SEQ CHAPTER \h \r 1 (dermal absorption rate = 14 %)	UFA=10x

UFH=10x	

Occupational LOC for MOE = 100	Rabbit Prenatal Developmental Toxicity

LOAEL = 10.0 mg/kg/day based on developmental toxicity findings of
increased resorptions.

Dermal Intermediate-Term (1-6 months)	Oral study NOAEL = 5.0 mg/kg/day

  SEQ CHAPTER \h \r 1 (dermal absorption rate = 14 %)	UFA= 10x

UFH= 10x

	Occupational LOC for MOE = 100

	Rabbit Prenatal Developmental Toxicity

LOAEL = 10.0 mg/kg/day based on developmental toxicity findings of
increased resorptions.

  SEQ CHAPTER \h \r 1 Long-Term Dermal (>6 months)	  SEQ CHAPTER \h \r 1
Oral study NOAEL = 3.4 mg/kg/day

(dermal absorption rate = 14 %)	UFA= 10x

UFH= 10x

	Occupational LOC for MOE = 100

	  SEQ CHAPTER \h \r 1 Rat Oral Carcinogenicity

LOAEL = 9.2 mg/kg/day based on decreased body weight/body weight gain,
kidney tubular casts and atrophy in both sexes; increased incidence of 
liver necrosis and erosion/ulceration of the glandular- stomach and
fore-stomach in males.

Inhalation Short- Term (1-30 days)	NOAEL= 0.23 mg/kg/day (air
concentration = 0.001 mg/L)	UFA= 10x

UFH= 10x

	Occupational LOC for MOE = 100	Rat 28-day Inhalation

LOAEL = 6.9 mg/kg/day (air concentration = 0.03 mg/L) based on duodenum
mucosal hyperplasia and respiratory system findings including alveolar
histiocytosis and olfactory atrophy/necrosis in nasal tissue.

Inhalation Intermediate-Term (1-6 months)	NOAEL= 0.23 mg/kg/day (air
concentration = 0.001 mg/L)	UFA= 10x

UFH= 10x

	Occupational LOC for MOE = 100

	Rat 28-day Inhalation

LOAEL = 6.9 mg/kg/day (air concentration = 0.03 mg/L) based on duodenum
mucosal hyperplasia and respiratory system findings including alveolar
histiocytosis and olfactory atrophy/necrosis in nasal tissue.

Inhalation Long-Term (>6 months)	NOAEL= 0.23 mg/kg/day (air
concentration = 0.001 mg/L)	UFA= 10x

UFH= 10x

	Occupational LOC for MOE = 100

	Rat 28-day Inhalation

LOAEL = 6.9 mg/kg/day (air concentration = 0.03 mg/L) based on duodenum
mucosal hyperplasia and respiratory system findings including alveolar
histiocytosis and olfactory atrophy/necrosis in nasal tissue.

Cancer (oral)	Classification:  “Not likely to be Carcinogenic to
Humans” based on the absence of significant tumor increases in two
adequate rodent carcinogenicity studies.

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use
of a short-term study for long-term risk assessment.  UFDB = to account
for the absence of key date (i.e., lack of a critical study).  MOE =
margin of exposure.  LOC = level of concern.  N/A = not applicable.



3.4	Recommendation for Aggregate Exposure Risk Assessments  TC \l2 "3.4
Recommendation for Aggregate Exposure Risk Assessments 

As per the FQPA, when there are potential residential exposures to the
pesticide, aggregate risk assessment must consider exposures from three
major sources: oral, dermal and inhalation exposures.  When common
toxicity endpoints are selected for these routes of exposure they may be
aggregated.  Aggregate assessments are required for acute and chronic
dietary (food + water) exposures, and short-term residential exposures
(i.e., chronic dietary plus incidental oral and dermal exposures).

Residential short-/intermediate-term dermal exposure for adults and
toddlers were assessed using the NOAEL (5 mg/kg/day) from the rabbit
developmental study.  While the developmental effect of increased
resorptions is not applicable to toddlers, it should be noted that the
maternal NOAEL from this study is also 5 mg/kg/day, and is based on
reduced body weight gain, food consumption, and food efficiency at the
LOAEL of 10 mg/kg/day; this more relevant endpoint was used to assess
toddler dermal exposure.  For incidental oral ingestion, exposure was
assessed using the endpoint from a 13-week feeding study in the dog. 
The NOAEL from this study is 5.8 mg/kg/day, based on increased incidence
of diarrhea, clinical chemistry changes, duodenum mucosal hypertrophy,
and decreased body weight and food intake/efficiency at the LOAEL of
12.9 mg/kg/day.  A common effect (i.e., decreased body weight gain, food
intake, and food efficiency) was seen in the studies selected to
evaluate toddler dermal and incidental oral ingestion exposure;
therefore, route-specific MOEs were aggregated for toddlers. 

3.5	Endocrine disruption  TC \l2 "3.5	Endocrine disruption 	

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 recommendations of its Endocrine Disruptor Screening and
Testing Advisory Committee (EDSTAC), EPA determined that there was a
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 additional appropriate screening and/or testing protocols being
considered under the Agency’s EDSP have been developed, pyraclostrobin
may be subjected to further screening and/or testing to better
characterize effects related to endocrine disruption.



4.0	Public Health and Pesticide Epidemiology Data   TC \l1 "4.0	Public
Health and Epidemiology Data 

The Centers for Disease Control (CDC) and Prevention recently reported
and described five incident events to the Iowa Department of Public
Health (IDPH) of exposures that occurred during aerial applications of
pyraclostrobin (MMWR Weekly, 2/4/08, 56(51) pp.1343-1345).  IDPH
investigated the reports.  In one event migrant workers were
inadvertently exposed to pyraclostrobin due to pilot error and
off-target drift of pyraclostrobin to an adjacent field.  The migrant
workers experienced symptoms including upper respiratory tract pain or
irritation, chest pain, nausea, skin redness, eye pain, weakness,
headache, and dizziness.  In another event, a crop-dusting pilot
suffered first degree burns after being exposed to pyraclostrobin which
had spilled after his airplane crashed during takeoff.  Another three
events also involved acute pesticide poisoning associated with
off-target drift of pyraclostrobin from nearby aerial applications.  In
all five of these cases, symptoms subsided after the exposed persons
moved indoors or away from the pyraclostrobin treated fields.

Pyraclostrobin labels that permit aerial applications contain specific
label language stating not to apply under circumstances where possible
drift may occur and how to reduce drift potential.

5.0	Dietary Exposure/Risk Characterization  TC \l1 "5.0	Dietary
Exposure/Risk Characterization 

Reference: Pyraclostrobin: Petitions for the Establishment of Permanent
Tolerances on Grain, Sorghum Grain, Forage and Stover (PP#8F7385);
Increase of Tolerance for the Stone Fruit Crop Group 12 to satisfy
European Union (EU) import requirement (PP#8F7390); and Establishment of
a Permanent import Tolerance for Coffee (PP#8E7394).  Summary of
Analytical Chemistry and Residue Data. DP359194; M. Negussie; 04/02/09.

5.1	Pesticide Metabolism and Environmental Degradation  TC \l2 "5.1 
Pesticide Metabolism and Environmental Degradation 

5.1.1	Metabolism in Primary Crops  TC \l3 "5.1.1	Metabolism in Primary
Crops 

Adequate metabolism studies with pyraclostrobin on grapes, potatoes, and
wheat have previously been reviewed (D269668, L. Cheng, 11/28/01) in
conjunction with PP#0F06139.  The results of these studies indicate that
the metabolism of pyraclostrobin is similar in the three crops
investigated.  The HED Metabolism Assessment Review Committee (MARC)
concluded that the nature of the residue in plants is understood (HED
Metabolism Committee Decision Memo; D278044, L. Cheng, 10/9/01).  For
purposes of tolerance setting and risk assessment, the terminal residues
of concern in plants consist of pyraclostrobin and its desmethoxy
metabolite (BF 500-3).

5.1.2	Metabolism in Livestock  TC \l3 "5.1.2	Metabolism in Livestock 

Adequate metabolism studies with pyraclostrobin on ruminants and laying
hens were previously reviewed (D269668, L. Cheng, 11/28/01) in
conjunction with PP#0F06139.  The HED MARC has determined that for
purposes of tolerance setting and risk assessment, the residues of
concern in livestock commodities consist of pyraclostrobin and its
metabolites convertible to 1-(4-chlorophenyl)-1H-pyrazol-3-ol and
1-(4-chloro-2-hydroxyphenyl)-1H-pyrazol-3-ol (BF 550-5) (HED Metabolism
Committee Decision Memo; D278044, L. Cheng, 10/9/01).

5.1.3	Analytical Methodology  TC \l3 "5.1.3	Analytical Methodology 

Enforcement Method for Plants

Two adequate methods were proposed for enforcing tolerance for residues
of pyraclostrobin and BF 500-3 in/on plant commodities: a LC/MS/MS
method (BASF Method D9808), and an HPLC/UV method (BASF Method D9904). 
The validated method LOQ for both pyraclostrobin and BF 500-3 is 0.02
ppm in all tested plant matrices, for a combined LOQ of 0.04 ppm. 
Adequate independent method validation and radiovalidation data were
submitted for both methods (D269668, 11/28/01, L. Cheng).  Following the
SOP (ACB-019) for reviewing tolerance methods (September 15, 2008), HED
has determined that Method D9904 is suitable as an enforcement method.

Except for green coffee beans, samples of raw agricultural and processed
commodities from the current crop field trials (PP#8F7385, PP#8F7390 and
PP#8E7394) were analyzed for residues of pyraclostrobin and BF 500-3
using the LC/MS/MS method (BASF Method D9908, version II for sorghum). 
Briefly, residues were extracted by shaking with methanol:water:2 N HCl
(70:25:5; v:v:v), methanol:water (70:30, v:v) and centrifuged.  Residues
were then partitioned with cyclohexane and 1N HCL saturated with NaCl,
concentrated to dryness, and re-dissolved in buffered methanol:water
(80:20, v:v).  The final chromatographic analysis of residues was
determined by LC/MS/MS.  Total residues of pyraclostrobin and BF 500-3
are expressed as pyraclostrobin equivalents.  For each analyte, the
validated method LOQ is 0.02 ppm.  The method is adequate for data
collection based on acceptable concurrent method recovery data.

Samples of coffee (green beans) (PP#8E7394) in Brazil were analyzed for
residues of pyraclostrobin and its metabolite BF 500-3 using an LC/MS/MS
method according to SOP-PA.0243 based on BASF method 445/0.  Sample
extraction is similar to Method D9908 described above, except the final
extract is re-dissolved in buffered methanol:water (50:50, v:v).  For
each analyte, the validated method LOQ is 0.02 ppm, and the calculated
LODs are 0.003 ppm for pyraclostrobin and 0.001 ppm for BF-500-3.  The
method is adequate for data collection based on acceptable concurrent
method recovery data.



Analytical Methods - Livestock

In a previous petition (PP#0F06139), two methods were proposed for
enforcing tolerances for livestock commodities:  HPLC/UV method 439/0
and Method 446 (consisting of GC/MS method 446/0 and LC/MS/MS method
446/1).  The HPLC/UV method determines residues of pyraclostrobin per
se.  Method 446 has a hydrolysis step, and determines residues of
pyraclostrobin and its metabolites as BF 500-5 and BF 500-8.  The
validated method LOQs for BF 500-5 type residues, in parent equivalents,
are 0.01 ppm for milk and 0.05 ppm for tissues, and the validated LOQs
for BF 500-8 type residues, in parent equivalents, are 0.01 ppm for milk
and 0.05 ppm for tissues.  Independent method validation data for the
HPLC/UV and LC/MS/MS methods are acceptable (D269668, 11/28/01, L.
Cheng).  Radiovalidation data submitted for the GC/MS and LC/MS/MS
methods are adequate for liver and milk, and marginal for muscle. 
Following the SOP (ACB-019) for reviewing tolerance methods (September
15, 2008), HED has determined that Method 446 is suitable as an
enforcement method.  An enforcement method for poultry was reviewed in
PP#0F06139.  However, tolerances for poultry egg and tissues have not
been established and are not required for the purpose of these
petitions.

Multiresidue Methodology (860.1360)

Data pertaining to the multiresidue methods testing of pyraclostrobin
and its desmethoxy metabolite were previously reviewed (PP#0F6139,
D269668, 11/28/01, L. Cheng).  Pyraclostrobin was successfully evaluated
through several of the FDA protocols, while recovery of BF 500-3 was
unsuccessful in all protocols.  Pyraclostrobin was completely recovered
through Protocol D (in grape) and E (in grape), and partially recovered
through Protocol F (in peanut).  Metabolite BF 500-3 had poor peak shape
and inadequate sensitivity with Protocol C columns, and therefore, was
not further analyzed under Protocol D, E, and F.  The results of the
multiresidue testing for pyraclostrobin were forwarded to FDA on 1/4/02
for the purpose of updating PAM, Volume I.

5.1.4	Storage Stability Data  TC \l3 "5.1.4	Storage Stability Data 

500-3 are relatively stable at ≤-10ºC in fortified samples of grape
juice (juices), sugar beet tops (leafy vegetables), sugar beet roots
(root crop), tomato (fruit/fruiting vegetable), wheat grain (non-oily
grain) and wheat straw (dry feed) for up to 25 months, and in fortified
samples of peanut nutmeats (oilseed) and peanut oil for up to 19 months
(D269668, L. Cheng, 11/28/01).  

Conclusions.  There are adequate storage stability data from PP#0F6139
which may be translated in the current petitions to validate sample
storage conditions and durations.  There are no corrections which need
to be applied as pyraclostrobin residues of concern were found to be
relatively stable over a wide range of commodities under frozen storage
conditions for 19-25 months.

5.1.5	Magnitude of the Residue in Plants  TC \l3 "5.1.5	Magnitude of the
Residue in Plants 

BASF has submitted grain sorghum field trials supporting a new use of
pyraclostrobin (EC) and seed treatment on grain sorghum, along with an
increased tolerance petition on stone fruits.  In addition, BASF has
submitted coffee field trials plus a processing study on coffee to
support a tolerance on imported coffee.    SEQ CHAPTER \h \r 1 The
results from these studies are summarized and discussed below.

Stone Fruit Crop Group – DER Reference: 47470201.der

BASF Corporation submitted adequate field trial residue data reflecting
the maximum proposed use pattern of pyraclostrobin on stone fruits
(cherries (sweet and sour), peaches, and plums).  A summary of the
residue data from the field trials is presented in Table .  The combined
residues of pyraclostrobin and its metabolite BF 500-3 did not exceed
the proposed tolerance level of 2.5 ppm in/on stone fruits following
five applications of the 2.0 lb/gal EC formulation of pyraclostrobin
reflecting a PHI of 0-days.  Samples were analyzed using an adequate
analytical method, and are supported by the available storage stability
data.  The number and locations of field trials are in accordance with
OPPTS Guideline 860.1500, and the conducted field trials reflect the
maximum proposed foliar use pattern. 

TABLE 7.  Summary of Residues from the Crop Field Trials –
Pyraclostrobin & its Desmethoxy Metabolite.

Crop Matrix

 	Total Applic. Rate

(lb ai/A)

 	PHI (days)

 	Residues (mg/kg)

	Mean	Std. Dev.	HAFT	Min.	Max.

Stone Fruit  (proposed use = 0.585 lb ai/A total application rate, 0-day
PHI)       

Sweet Cherry	0.585	0	0.764	0.624	1.605	0.04	1.88

Sour Cherry	0.585	0	0.955	0.320	1.165	0.52	1.33

Peach	0.585	0	0.602	0.493	1.645	0.31	1.75

Plum	0.585	0	0.198	0.159	0.395	0.04	0.45

The field trial data for all stone fruits (cherry, peach, and plum)
reflecting the 0.585 lb ai/A were entered into the Agency’s tolerance
spreadsheet as specified by the Guidance for Setting Pesticide
Tolerances Based on Field Trial Data SOP to determine an appropriate
tolerance level.  The tolerance spreadsheet recommends a tolerance of
2.5 ppm for stone fruits crop group 12.

Grain Sorghum – DER Reference: 47470203.der

BASF Corporation submitted adequate field trial residue data reflecting
the maximum proposed use pattern (foliar and seed treatment) of
pyraclostrobin on grain sorghum.  A summary of the residue data from the
field trials is presented in Table 8.  The combined residues of
pyraclostrobin and its metabolite BF 500-3 did not exceed the proposed
tolerance level of 5.0 ppm and 0.5 ppm in/on sorghum forage and grain,
respectively.  However, in sorghum stover, the combined residue value
was slightly higher (0.85) than the proposed value of 0.80 ppm.  Samples
were analyzed using adequate methods and are supported by the available
storage stability data.  

TABLE 8.  Summary of Residues from the Crop Field Trials –
Pyraclostrobin & its Desmethoxy Metabolite. 

Crop Matrix

 	Total Applic. Rate

(lb ai/A)

 	PHI (days)

 	Residues (ppm)

	Mean	Std. Dev.	HAFT 	Min.	Max.

Sorghum Grain (proposed use = 0.20 lb ai/A total application rate,
13-122-day PHI)       

Sorghum forage	0.20	13-43	0.61	0.52	1.72	<0.04	1.96

Sorghum grain	0.20	46-122	0.09	0.11	0.41	<0.04	0.47

Sorghum stover	0.20	46-122	0.17	0.21	0.75	<0.04	0.85

The field trial data for grain sorghum (forage, grain, and stover)
reflecting the 0.19 - 0.22 lb ai/A application rate were entered into
the Agency’s tolerance spreadsheet as specified by the Guidance for
Setting Pesticide Tolerances Based on Field Trial Data SOP to determine
an appropriate tolerance level.  The tolerance spreadsheet recommends a
tolerance of 5.0 ppm for sorghum forage, 0.60 ppm for sorghum grain, and
0.80 ppm for sorghum stover.

Coffee – DER Reference: 47470204

BASF Corporation submitted adequate field trial residue data reflecting
the maximum proposed use pattern of pyraclostrobin on coffee beans.  A
summary of the residue data from the field trials is presented in Table
9.  The combined residues of pyraclostrobin and its metabolite BF 500-3
did not exceed the proposed tolerance level of 0.5 ppm in/on coffee
beans harvested 44 days after the last application, following two foliar
applications of an EC formulation at ~0.178 lb ai/A/application and
0.134 lb ai/A for a total seasonal application rate of ~0.312 lb ai/A. 
The combined residues were 0.04 - 0.15 mg/kg.  Samples were analyzed
using adequate methods and are supported by the available storage
stability data.  

TABLE 9.  Summary of Residues from the Crop Field Trials–
Pyraclostrobin & its Desmethoxy Metabolite  

Crop Matrix

 	Total Applic. Rate

(lb ai/A)

 	PHI (days)

 	Residues (ppm)

	Mean	Std. Dev.	HAFT1	Min.	Max.

Coffee (total application rate-not specified, 45-day PHI)       

Coffee	0.312	45	0.064	0.048	--	0.04	0.15

1 = Only one sample collected per field trial.

The field trial data for coffee reflecting 0.312 lb ai/A were entered
into the Agency’s tolerance spreadsheet as specified by the Guidance
for Setting Pesticide Tolerances Based on Field Trial Data SOP to
determine an appropriate tolerance level.  The tolerance spreadsheet
recommends a tolerance of 0.30 ppm for coffee, which is slightly lower
than the level (0.5 ppm) proposed by the petitioner.



5.1.6	Magnitude of the Residue in Processed Food/Feed  TC \l3 "5.1.6
Magnitude of the Residue in Processed Food/Feed 

Coffee – DER Reference: 47470202

In conjunction with the coffee field trials,   SEQ CHAPTER \h \r 1 BASF
Corporation submitted a processing study for pyraclostrobin on coffee. 
Two field trials were conducted in Costa Rica during the 2007 growing
season.  The treated plots received two broadcast foliar applications of
the EC at 0.82 - 0.89 lb ai/A (918 - 996 g ai/ha) (~5X the proposed
rate) and 0.68 lb ai/A (758 - 760 g ai/ha) (~5X the proposed rate) for a
total rate of 1.50 - 1.57 lb ai/A (1.678 - 1.754 kg ai/ha/season). 
There was a 61-day retreatment interval between the applications, which
were made 105 and 44 days before harvest.  Treated samples of mature
coffee were harvested 44 days after the last application.  Green coffee
beans were processed to cleaned green bean, roasted bean, coffee
extract, dried spent grounds, liquor extract and freeze-dried instant
coffee using simulated commercial procedures.  Storage stability data
are not required since the samples were stored less than 30 days from
collection to analysis.  However, adequate storage stability data are
available to support storage conditions and durations of samples. 

A summary of residue data from the coffee processing study is presented
in Table 10.  A comparison of the residues in the RAC with those in each
processed fraction indicated that residues of pyraclostrobin do not
concentrate in coffee processed fractions.  

 

TABLE 10.  Residue Data from Coffee Processing Study– Pyraclostrobin &
its Desmethoxy Metabolite.

RAC; Trial ID	Processed Commodity	Total Rate

(lb ai/A) 	PHI 

(days)	Combined Residues of Pyraclostrobin and its BF 500-3 Metabolite
(ppm)	Processing Factor

Pyraclostrobin	BF-500-3	Combined

	Green beans (RAC); RCN R070040	Green beans (RAC)	1.57	44	0.0984; 0.0997
<0.0259; 0.0237	<0.12; <0.12 	N/A; N/A

	Cleaned green bean

	0.0881; 0.0868	<0.02; <0.02	<0.11; <0.11	0.9; 0.9 

	Roasted beans

	<0.02; <0.02	<0.02; <0.02	<0.04; <0.04	0.2; 0.2 

Green beans (RAC); RCN R070040	Dried spent grounds

	<0.02; <0.02	0.0238; 0.0204	<0.04; <0.04	0.2; 0.2 

	Liquor extract

	<0.02; <0.02	<0.02; <0.02	<0.04; <0.04 	0.2; 0.2 

	Instant coffee

	<0.02; <0.02	<0.02; <0.02	<0.04; <0.04	0.2; 0.2 

Green beans

(RAC); RCN R070041  	Green beans (RAC)	1.50	44	0.0333; 0.0368
<0.02<0.02;	<0.05; <0.06	N/A; N/A 

	Cleaned green bean

	0.0350; 0.0343	<0.02<0.02;	<0.06; <0.05	1.1X; 0.9 

	Roasted beans

	<0.02; <0.02	<0.02<0.02;	<0.04; <0.04 	0.6; 0.5

Green beans (RAC); RCN R070041	Dried spent grounds

	<0.02; <0.02	<0.02<0.02;	<0.04; <0.04 	0.6; 0.5 

	Liquor extract

	<0.02; <0.02	<0.02<0.02;	<0.04; <0.04 	0.6; 0.5 

	Instant coffee

	<0.02; <0.02	<0.02<0.02;	<0.04; <0.04 	0.6; 0.5 

Conclusions.  The coffee processing study is adequate.  Residues of
pyraclostrobin were detected in the green bean RAC and cleaned green
bean from a field trial treated at an exaggerated 5x rate.  Combined
residues were non-quantifiable in all other coffee processed fractions,
with the exception of two treated dried spent grounds samples from one
of the trials (RCN R070040) that contained combined residues at 0.04
ppm.  The data indicate that residues of pyraclostrobin and its
metabolite do not concentrate in cleaned green bean, coffee roasted
beans, dried spent grounds, liquor extract, and instant coffee samples. 

Stone Fruits – Residue Chemistry Memo, DP# 269668, 11/28/01, L. Cheng
(PP#0F6139)

Field trial data was previously submitted (PP#0F6139) depicting the
potential for concentration of residues of pyraclostrobin in prunes, the
only processed commodity of plums.  The submitted plum processing data
were adequate.  The data indicate that the combined residues of
pyraclostrobin and its metabolite BF 500-3 concentrated slightly in
prunes at 1.2x and 1.3x.

Conclusions.  The HAFT residue of plums treated at 1x the maximum
seasonal rate (0.6 lb ai/A/season; 0-day PHI) from the submitted plum
field trial studies was 0.19 ppm  for pyraclostrobin and <0.02 ppm for
BF 500-3 (<0.21 ppm combined residues).  Based on the HAFT (<0.21 ppm)
and an average concentration factor of 1.3x, the maximum expected
pyraclostrobin and BF 500-3 residues in prunes would be 0.273 ppm, which
is lower than the proposed RAC tolerance of 2.5 ppm for the stone fruits
crop group.  Based on these data, a tolerance for pyraclostrobin
residues in prunes is not warranted.

5.1.7	Magnitude of the Residue in Meat, Milk, Poultry, and Eggs  TC \l3
"5.1.7	Magnitude of the Residue in Meat, Milk, Poultry, and Eggs 

Livestock dietary burdens

No new livestock feeding studies were submitted with these petitions.
The potential for transfer of pyraclostrobin residues of concern to
meat, milk, poultry, and eggs exists because there are several livestock
feedstuffs (sorghum forage, sorghum grain, and sorghum forage) that are
associated with the proposed use in the current petition (PP#8F7385). 
The livestock dietary burdens of pyraclostrobin are presented in Table
11, and reflect the most recent guidance from HED concerning revisions
of feedstuff percentages in OPPTS 860.1000 Table 1 and construction of
reasonably balanced livestock diets (RBLDs).  The new livestock
feedstuffs included in the current petition are sorghum grain, sorghum
forage, and sorghum stover. The calculated dietary burdens of
pyraclostrobin are estimated at 4.9 ppm (beef), 9.5 ppm (dairy), 0.95
ppm (poultry), and 0.55 ppm (swine).  The current dietary burdens for
cattle and poultry differ very slightly from the previous estimates
(D343754, J. Stokes, 2/12/2008).

Table 11.   Calculation of Reasonably Balanced Dietary Burdens (RBDBs)
of Pyraclostrobin Residues for  Livestock. 1

Feedstuff	Type	% Dry Matter 	% Diet 	Tolerance (ppm)	Dietary
Contribution (ppm) 

Beef Cattle R 15%, CC 80%, PC 5%

Barley, hay	R	88	10	25	2.84

Cotton, gin byproducts	R	90	5	30	1.67

Barley, grain	CC	88	20	0.4	0.091

Corn, field, grain/milled byproducts	CC	88	20	0.1	0.023

Canola/sunflower, meal	PC	92	5	0.3	0.016

Sorghum, grain, forage/silage	R	35	--	5.0	--

Sorghum, grain, grain	CC	86	40	0.6	0.27

Sorghum, grain, stover	R	88	--	0.8	--

TOTAL BURDEN	--	--	100

4.9

Dairy Cattle R 45%, CC 45%, PC 10%

Almond, hulls	R	90	5	1.6	0.09

Legume, hay (cowpea)	R	30	5	25	4.16

Barley, grain	CC	88	20	0.4	0.091

Cotton, undelinted seed	PC	90	10	0.3	0.033

Sorghum, grain, forage/silage	R	35	35	5.0	5

Sorghum, grain, grain	CC	86	25	0.6	0.15

Sorghum, grain, stover	R	88	--	0.8	--

TOTAL BURDEN	--	--	100	--	9.5

Poultry CC 75%, PC 25%

Oat, grain	CC	88	70	1.2	0.84

Canola/sunflower, meal	PC	92	25	0.3	0.075

Sorghum, grain, grain	CC	86	5	0.6	0.03

TOTAL BURDEN	--	--	100	--	0.945

Swine CC  85%, PC 15%

Barley, grain	CC	88	5	0.4	0.02

Canola/sunflower, meal	PC	92	15	0.3	0.045

Sorghum, grain, grain	CC	86	80	0.6	0.48

TOTAL BURDEN	--	--	100	--	0.545

1   All data are based on Table 1 Feedstuffs (June 2008), a revision of
feedstuffs data found in Table 1 (180.1000 OPPTS Test Guidelines). 
Residue levels for beef and dairy are corrected for moisture content and
are determined by formula: tolerance / %DM  x  % in diet.  Residue
levels for poultry and swine are considered “as-is” and are
determined by formula: tolerance  x   % in diet.  R: roughage; CC:
carbohydrate concentrate;  PC:  protein concentrate.

Typical compositions of daily rations for the animals of choice for
Table 1 data  follow: 

Feedlot beef  are fed higher amounts of CC (up to 80 %), and lower
amounts of  R (15-20 %) and PC (5-10 %) as the slaughter time (last 3
months) gets closer.  High volume milk-producing lactating dairy cows
have a daily ration of 45 % R, 40-45 % CC, and 10-15 % PC.  

A laying hen that will give a steady egg production is fed 75-80 % CC
and 20-25 % PC.   A marketable hog diet that will give steady growth
would have 80-85 % CC and 15-20 % PC.  

Livestock feeding studies: Residue Chemistry Memo, DP# 269668,
11/28/01, L. Cheng (PP#0F6139)

Adequate feeding studies were reviewed in PP#0F6139.  The current
pyraclostrobin tolerances for livestock commodities were established
based on results from these studies and the Agency’s estimated dietary
burdens for pyraclostrobin residues, which were originally calculated to
be 36.3 ppm for beef cattle, 35.4 ppm for dairy cattle, and 0.35 ppm for
poultry.  The more recent dietary burden for pyraclostrobin residues are
estimated at 4.9 ppm (beef ), 9.5 ppm (dairy), 0.95 ppm (poultry), and
0.55 ppm (swine).  In the poultry feeding study, l  SEQ CHAPTER \h \r 1
aying hens were orally dosed once daily for 30 consecutive days with
pyraclostrobin at dose levels equivalent to 0.28 ppm (0.3x), 0.88 ppm
(0.9x), and 3.01 ppm (3.0x).  At the highest feeding level of 3.01 ppm,
residues of pyraclostrobin and its metabolites hydrolyzable to BF 500-5
were less than the method LOQ (0.05 ppm) in all egg and tissue samples,
except for one egg sample (Day 17) where residues of pyraclostrobin were
detected at 0.064 ppm and <0.05 ppm upon re-analysis.  Residue analysis
of BF 500-8 was not conducted (the metabolism data show all metabolites
hydrolyzable to BF 500-8 would be less than 10% TRR), but instead an
isomeric compound (BF 500-9) was measured.  Levels of BF 500-9 also were
all <0.05 ppm.

Conclusions:  Based on these dietary exposure levels and the residue
data from the ruminant feeding study, the existing pyraclostrobin
tolerances for milk (0.1 ppm), meat (0.1 ppm), fat (0.1 ppm), meat
byproducts except liver (0.2 ppm), and liver (1.5 ppm) of cattle, goats,
hogs, horses, and sheep are adequate to support the proposed uses. 
Tolerances for eggs and poultry are not needed based on data from the
poultry feeding and metabolism studies [Category 180.6(a)(3)].  If, in
the future, the petitioner proposes a use which increases the dietary
burdens of poultry, then the Category 3 situation will be re-evaluated.

5.1.8	Confined and Field Rotational Accumulation in Rotational Crops  TC
\l3 "5.1.8	Confined and Field Accumulation in Rotational Crops 

An adequate confined rotational crop study is available on
pyraclostrobin (PP#0F6139, D269668, L. Cheng, 11/28/01; D314519, L.
Cheng, 05/05/05).  The confined study indicates that the metabolism of
pyraclostrobin in rotated crops is similar but more extensive than that
in primary crops.  Pyraclostrobin undergoes demethoxylation to yield BF
500-3, followed by further degradation to medium polar and polar
metabolites, and subsequent conjugation reactions and incorporation into
natural products.  The MARC (D278044, L. Cheng, 10/09/01) concluded that
the residues of concern in rotational crops consist of pyraclostrobin
and metabolite BF 500-3.

An adequate limited field rotational crop study is available (PP#0F6139,
D269668, L. Cheng, 11/28/01) reflecting six broadcast foliar
applications of pyraclostrobin (EC) to cucumber at 0.19-0.20 lb
ai/A/application and RTIs of 6-8 days, for a total of 1.2 lb
ai/A/season.  This rate is 1x the maximum use rate of any rotated crop. 
Average residues of pyraclostrobin and BF 500-3 were each <LOQ in/on RAC
samples from all representative rotational crops (radish, cabbage and
wheat) planted 14 days following the final application to the primary
crop.  These data indicate that the label specified 14-day plant-back
restriction is acceptable for all crops that are not registered for
direction application.

5.1.9	Drinking Water Residue Profile TC \l3 "5.1.9	Drinking Water
Residue Profile 

References: Drinking Water Exposure Assessment for the Section 3 New Use
Registration of Pyraclostrobin on Sorghum; DP Barcode 356965; R. Miller;
12/17/08

“Tier II Drinking Water Assessment for the use of Pyraclostrobin (P.C.
Code: 099100) on Oats and Oilseed (canola and flax) (Headline Fungcide);
Corn, Soybean, and Sugar beets (Headline Fungcide); Fresh Herbs (crop
group 19) and Tropical Fruits (avocado, black sapote, canistel, mamey
sapote, mango, papaya, sapodilla, and star apple) (Pristine Fungicide);
and Turf and Ornamentals (Insignia Fungicide) (DP Barcodes 336190,
340588, 342584). G. Rothman, 9/6/07”

The Environmental Fate and Effects Division (EFED) reviewed the proposed
use rates associated with the Section 3 request for the use of
pyraclostrobin on sorghum.  EFED’s assessment was based on the
application of the highest seasonal use rate (proposed or registered) of
pyraclostrobin.  The existing registered use of aerial application on
turf and ornamentals contains the highest application rate at 0.5 lbs
a.i./acre with 6 maximum seasonal applications at 14 day intervals. 
EFED believes that the aerial use of pyraclostrobin on turf and
ornamentals will pose the upper-bound concentrations in surface and
ground water since spray drift increases and application efficiency
decreases in an aerial application technique.

Measures of exposure for pyraclostrobin in the drinking water assessment
were obtained through modeling efforts only, since national-scale
monitoring data were not identified. The Tier II drinking water
assessment was performed using the Tier II PRZM/EXAMS (PE4V01 perl shell
with PRZM 3.12 beta dated 5/24/01 and EXAMS version 2.98, 7/18/02) to
assess surface water.  Ground water concentrations were estimated using
a Tier I SCI-GROW model (version 2.3, May 16, 2006) since a Tier II
model has not been developed to assess ground water.

Acute effects of pyraclostrobin residues in drinking water are expressed
in annual peak one-in-ten year concentrations, chronic effects in annual
average one-in-ten year concentrations, and cancer effects in 30-year
average concentrations.  The upper-bound Tier II modeling predicts that
the estimated drinking water concentrations (EDWCs) of pyraclostrobin in
surface water are not likely to exceed 35.6 µg/L for the peak
concentration, 2.3 µg/L for the annual average concentration, and 1.5
µg/L for the 30-year average concentration.  The SCI-GROW model
predicts the acute and chronic EDWCs of pyraclostrobin in shallow ground
water to be 0.02 µg /L (0.02 ppb).



5.1.10	Proposed Tolerances TC \l3 "5.1.10	Proposed Tolerances 

For purposes of both the tolerance expression and dietary risk
assessment, HED has concluded that the residues of concern in plant
commodities include pyraclostrobin and its desmethoxy metabolite, BF
500-3 (D278044, L. Cheng, 10/9/01), and the residues of concern in
livestock commodities include pyraclostrobin and its metabolites
convertible to 1-(4-chlorophenyl)-1H-pyrazol-3-ol (BF 500-5) and
1-(4-chloro-2-hydroxyphenyl)-1H-pyrazol-3-ol (BF 500-8).  

  SEQ CHAPTER \h \r 1 Pyraclostrobin tolerances for plant commodities
are listed in 40 CFR §180.582 (a)(1) and are expressed in terms of the
combined residues of the fungicide pyraclostrobin (carbamic acid,
[2-[[[1-(4-chlorophenyl)-1H- pyrazol-3-yl]oxy]methyl]phenyl]methoxy-,
methyl ester) and its desmethoxy metabolite (methyl
N-[[[1-(4-chlorophenyl)-1H-pyrazol-3-yl]oxy]methyl]phenyl carbamate),
expressed as parent compound.

Pyraclostrobin tolerances for animal commodities are listed in 40 CFR
§180.582 (a)(2) and are expressed in terms of the combined residues of
the fungicide pyraclostrobin and its metabolites convertible to
1-(4-chlorophenyl)-1H-pyrazol-3-ol and
1-(4-chloro-2-hydroxyphenyl)-1H-pyrazol-3-ol, expressed as parent
compound.

For petition (PP#8F7385), BASF has proposed a tolerance for the combined
residues of pyraclostrobin and its desmethoxy metabolite in/on sorghum
forage, grain, and stover at 5.0 ppm, 0.5 ppm, and 0.8 ppm,
respectively.  The submitted field trial data for sorghum forage, grain,
and stover are adequate.  The field trial data for these crops were
entered into the Agency’s tolerance spreadsheet as specified by the
Guidance for Setting Pesticide Tolerances Based on Field Trial Data SOP
to determine appropriate tolerance levels.  The tolerance spreadsheet
recommends tolerances of 5.0 ppm for sorghum forage, 0.60 ppm for
sorghum grain, and 0.80 ppm for sorghum stover. 

For petition (PP#8F7390), BASF has proposed a tolerance for the combined
residues of pyraclostrobin and its desmethoxy metabolite in/on stone
fruit crop group at 2.5 ppm.  The current EPA established tolerance for
total residues of pyraclostrobin in the stone fruit crop group is 0.9
ppm in 40 CFR §180.582.  The submitted field trial data for stone
fruits are acceptable.  The field trial data for stone fruits were
entered into the Agency’s tolerance spreadsheet as specified by the
Guidance for Setting Pesticide Tolerances Based on Field Trial Data SOP
to determine appropriate tolerance levels.  The tolerance spreadsheet
recommends a tolerance of 2.5 ppm for stone fruits.  

For petition (PP#8F7394), BASF has proposed a tolerance for the combined
residues of pyraclostrobin and its desmethoxy metabolite in/on coffee
green bean at 0.5 ppm.  The submitted field trial data for coffee is
adequate.  The field trial data for coffee were entered into the
Agency’s tolerance spreadsheet as specified by the Guidance for
Setting Pesticide Tolerances Based on Field Trial Data SOP to determine
appropriate tolerance levels.  The tolerance spreadsheet recommends
tolerances of 0.30 ppm for coffee.  An acceptable coffee processing
study has been submitted and the results suggest that no tolerances are
required for the processed commodities of coffee.  

Adequate cattle and poultry feeding studies are available.  The existing
pyraclostrobin tolerances for milk, meat, fat, meat byproducts except
liver, and liver of cattle, goats, hogs, horses, and sheep were
reassessed, and no adjustments are needed.  Tolerances for eggs and
poultry are not needed at this time based on data from the poultry
feeding and metabolism studies [Category 180.6(a)(3)].  If, in the
future, the petitioner proposes a use which increases the dietary
burdens of poultry, then the Category 3 situation will be re-evaluated.

Refer to Section 11 for the detailed discussion of established Codex
Alimentarius Commission (CAC) maximum residue limits (MRLs) for residues
of pyraclostrobin, and for a comparison of Canadian and US tolerances.

A summary of the recommended tolerances for the crop commodities
discussed in this document is presented in Table 12.  The petitioner
should submit a revised Section F reflecting the recommended tolerances
and commodity definitions presented in Table 12.

TABLE 12.	Tolerance Summary for Pyraclostrobin.

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

Tolerances Proposed Under PP#8F7385

Sorghum grain, forage	5.0	5.0	Sorghum, grain, forage.

Sorghum, grain, grain.

Sorghum, grain, stover.

Adequate field trial data are available.

Sorghum grain, grain	0.5	0.60

	Sorghum grain, stover	0.8	0.80

	Tolerances Proposed Under PP#8F7390

Fruit, stone, group 12	2.5	6.0	Fruit, stone group 12. Adequate field
trial data are available.

Tolerances Proposed Under PP#8E7394

Coffee	0.5	0.30	Coffee, green bean. Adequate field trial data are
available.

5.2	Dietary Exposure and Risk TC \l2 "5.2  Dietary Exposure and Risk 

Reference: Pyraclostrobin. Acute and Chronic Aggregate Dietary (Food and
Drinking Water) Exposure and Risk Assessments to Support New Use on 
Sorghum Grain (PP#8F7385); Increase of Tolerance for the Stone Fruit
Crop Group 12 to satisfy European Union (EU) import requirement
(PP#8F7390), and Establishment of a Permanent import Tolerance for
Coffee (PP#8E7394); DP356194.drs; 04/01/09.

Dietary risk assessment incorporates both exposure and toxicity of a
given pesticide.  The risk is expressed as a percentage of a maximum
acceptable dose (i.e., the dose which HED has concluded will result in
no unreasonable adverse health effects).  This dose is referred to as
the population adjusted dose (PAD).  HED is concerned when estimated
dietary risk exceeds 100% of the PAD.  



DEEM-FCID™ Program and Consumption Information

Pyraclostrobin acute and chronic dietary exposure assessments were
conducted using the Dietary Exposure Evaluation Model software with the
Food Commodity Intake Database (DEEM-FCID™, Version 2.03), which
incorporates consumption data from USDA’s Continuing Surveys of Food
Intakes by Individuals (CSFII), 1994-1996 and 1998.  The 1994-96, 98
data are based on the reported consumption of more than 20,000
individuals over two non-consecutive survey days.  Foods “as
consumed” (e.g., apple pie) are linked to EPA-defined food commodities
(e.g. apples, peeled fruit - cooked; fresh or N/S; baked; or wheat flour
- cooked; fresh or N/S, baked) using publicly available recipe
translation files developed jointly by USDA/ARS and EPA.  For chronic
exposure assessment, consumption data are averaged for the entire U.S.
population and within population subgroups, but for acute exposure
assessment are retained as individual consumption events.  Based on
analysis of the 1994-96, 98 CSFII consumption data, which took into
account dietary patterns and survey respondents, HED concluded that it
is most appropriate to report risk for the following population
subgroups: the general U.S. population, all infants (<1 year old),
children 1-2, children 3-5, children 6-12, youth 13-19, adults 20-49,
females 13-49, and adults 50+ years old.

Acute Dietary (Food and Drinking Water) Exposure Results and
Characterization

A slightly refined acute dietary exposure assessment was performed for
pyraclostrobin.  The analysis used tolerance level residues or highest
field trial residues, 100% crop treated, and empirical processing
factors.  Experimentally derived processing factors were used for fruit
juices, tomato and wheat commodities.  For all other processed
commodities, DEEM default processing factors were assumed.  For acute
exposures the peak concentration EDWC of 35.6 ppb was incorporated into
the DEEM_FCID into the food categories “water, direct, all sources”
and water, indirect, all sources”(based on a maximum application rate
of 3.0 lb ai/A/season for the turf use rate).

The results of the acute dietary analysis for food and drinking water
indicate that acute dietary risks do not exceed the Agency’s level of
concern (< 100% of the aPAD) for the U.S. population and all population
subgroups; see Table 13.  Combined dietary exposure from food and
drinking water at the 95th percentile of exposure is estimated to be
0.044629 mg/kg/day for the U.S. population, which is equivalent to 1.5%
of the acute Population Adjusted Dose (aPAD).  The population subgroup
with the highest estimated acute dietary exposure to pyraclostrobin is
females 13-49 years, with an estimated exposure at the 95th percentile
of 0.040558 mg/kg/day, equivalent to 81% of the aPAD.  

Chronic Dietary (Food and Drinking Water) Exposure Results and
Characterization

A moderately refined chronic dietary analysis was conducted for this
assessment.  The chronic dietary analysis included tolerance level or
average field trial residues, average percent crop treated estimates
when available, and empirical processing factors.  Percent crop treated
information from a screening level usage analysis (SLUA) of agricultural
uses of pyraclostrobin, provided by the Biological & Economic Analysis
Division (BEAD) (DP362519, 03/17/09, A. Grube) was incorporated into the
exposure estimates.  Experimentally derived processing factors were used
for fruit juices, tomato and wheat commodities.  For all other processed
commodities, DEEM default processing factors were assumed.  For chronic
exposures the annual average concentration EDWC of 2.3 ppb was
incorporated into the DEEM_FCID into the food categories “water,
direct, all sources” and water, indirect, all sources”(based on a
maximum application rate of 3.0 lb ai/A/season for the turf use rate).

The results of the refined chronic dietary analysis which represents for
food and drinking water are below the Agency’s level of concern for
all population subgroups; see Table 13. The dietary exposure for food
and drinking water is estimated at 0.002466 mg/kg/day for the general
U.S. population and 7.3%, of the chronic Population Adjusted Dose
(cPAD), and 0.008032 mg/kg/day (24%, of the cPAD) for children 1-2 yrs,
the population subgroup with the highest estimated chronic dietary
exposure to pyraclostrobin.  

Table 13.  Summary of Dietary Exposure and Risk for Pyraclostrobin –
Food & Drinking Water.

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	0.044629	1.5	0.002466	7.3	A separate
quantitative cancer risk assessment was not conducted.  

All Infants (< 1 year old)	0.063464	2.1	0.003682	11

	Children 1-2 years old	0.076275	2.5	0.008032	24

	Children 3-5 years old	0.066159	2.2	0.005827	17

	Children 6-12 years old	0.047354	1.6	0.003323	9.8

	Youth 13-19 years old	0.035393	1.2	0.001908	5.6

	Adults 20-49 years old	0.039279	1.3	0.001875	5.5

	Adults 50+ years old	0.041963	1.4	0.002000	5.9

	Females 13-49 years old	0.040558	81	0.001717	5.1

	

Conclusions

Acute and chronic exposures and risks do not exceed HED’s level of
concern for the U.S. population and for all relevant population
subgroups.  Of note is that contribution from drinking water is minimal.
 HED concludes that the acute and chronic exposure estimates are
unlikely to underestimate actual acute or chronic exposure.

5.3	Anticipated Residue and Percent Crop Treated (%CT) Information TC
\l2 "5.3 Anticipated Residue and Percent Crop Treated (%CT) Information 

The acute analysis was conducted using tolerance level residues or the
highest residues for all commodities.  These tolerance level or highest
residues were derived from field trial data conducted at the maximum
application rate and minimum PHI permitted on the proposed or existing
labels.  For all commodities 100% crop treated was assumed.  A limited
number of experimentally derived processing factors (for fruit juices,
tomato and wheat commodities) were used to refine the acute and chronic
analyses. 

The chronic dietary assessment was conducted using tolerance level
residues for all crops except for coffee, sorghum grain, stone fruits
crop group 12, apple, broccoli, celery, collard, grape, lettuce, citrus,
pepper, mustard green and tomato where anticipated average residue
values were derived from crop field trials.  These field trials
represent maximum application rates and minimum PHIs.  Average percent
crop treated estimates were used when available from a recent Screening
Level Usage Analysis (SLUA).  A limited number of experimentally derived
processing factors (for fruit juices, tomato and wheat commodities) from
pyraclostrobin processing studies were also used to refine the analysis.
 

6.0	Residential (Non-Occupational) Exposure/Risk Characterization  TC
\l1 "6.0	Residential (Non-Occupational) Exposure/Risk Characterization 

A product containing pyraclostrobin (i.e., Insignia®) is registered for
application to residential turf grass and recreational sites.  It may be
applied to turf at rates ranging from 0.28 to 0.5 lb ai/A, at intervals
of 14 to 28 days; and the maximum seasonal application rate is 3 lb
ai/A.  The residential exposure assessment was prepared in an HED
memorandum dated 8/19/04 (D298017, K. O’Rourke).  Residential and
recreational turf applications are applied by professional pest control
operators (PCOs) only, and therefore, residential handler exposures do
not occur.  There is, however, a potential for exposure to homeowners in
residential settings from entering previously treated lawns where
children might play and adults might work or play.  As a result, risk
assessments have been completed for postapplication scenarios.  The
short-term MOEs for each postapplication scenario resulted in MOEs above
100, and therefore are not of concern.  For toddlers, the short-term
dermal MOE is 180 (0.027 mg/kg/day) and the combined incidental oral MOE
is 620 (0.009425 mg/kg/day; hand-to-mouth activities), and combined
dermal and oral exposures result in and MOE of 140.  Dermal and
incidental oral exposures are combined because they share common toxic
effects; i.e., decreased body weight gain and decreased food
intake/efficiency.  For adults, the short-term dermal MOE is 260 (0.019
mg/kg/day).  

Recreational exposures to turf are expected to be similar to, or in many
cases less than, those evaluated for residential postapplication
exposure and risk; and therefore, a separate recreational exposure
assessment was not conducted.

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
pyraclostrobin.  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 data base 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.

7.0	Aggregate Risk Assessments and Risk Characterization  TC \l1 "7.0
Aggregate Risk Assessments and Risk Characterization 

In accordance with the FQPA, HED must consider and aggregate (add)
pesticide exposures and risks from three major sources: food, drinking
water, and residential exposures.  In an aggregate assessment, exposures
from relevant sources are added together and compared to quantitative
estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can
be aggregated.  When aggregating exposures from various sources, HED
considers both the route and duration of exposure.  Common effects
(i.e., decreased body weight gain, food intake, and food efficiency)
were seen in the studies selected to evaluate dietary, dermal and
incidental oral ingestion exposures; and therefore, route-specific
exposures can be aggregated.

Based on the proposed Section 3 food crop uses, aggregate assessments
were conducted for acute and chronic dietary exposures (food + drinking
water), and existing short-/intermediate-term residential exposures
(i.e., chronic dietary, plus incidental oral and dermal exposures for
kids, and chronic dietary, plus dermal exposures for adults).  Both
short- and intermediate-term exposures may occur during postapplication
activities for adults and children.  However, because the toxicity
endpoints and points of departure are identical for short- and
intermediate-term exposures, separate risk estimates for short- and
intermediate-term exposures were not calculated.  

To assess aggregate acute and chronic dietary risks, estimates of
pesticide residues in drinking water (EDWCs) were incorporated directly
into the dietary exposure analysis.  Refer to section 5.2 for these risk
estimates.  

The short-/intermediate-term aggregate risk assessment takes into
account average exposure estimates from dietary consumption of
pyraclostrobin (food and drinking water) and
non-occupational/residential uses (turf).  Postapplication exposures
from the use on turf are considered predominantly short-term (1-30
days).  To calculate the short-/intermediate-term aggregate risk
estimates, the chronic dietary exposure (food + drinking water) is added
to the residential exposures using the inverse MOE methodology described
below (see Table 14 below).  The total combined MOE from dietary (food +
water) and non-occupational/residential exposure is 120 for children 1-2
years old, which is not of concern to HED.  For adults the total
combined MOE is 230, which also is not of concern to HED.  These
aggregate exposure risk assessments are considered conservative
estimates, that should not underestimate risks, because of the following
inputs: 1) dietary inputs primarily used tolerance level residues; 2)
crop specific (turf) screening level drinking water modeling data were
used (i.e., Tier II surface water model); 3) maximum application rates
and minimum application intervals were used; and 4) conservative SOPs
and upper level estimates of exposure were employed.

Table 14.  Short-/Intermediate Term Aggregate Risk Calculations 

Population	

Dermal Exposure	

Oral Exposure	

Total Combined MOE2

	

NOAEL

mg/kg/day	

Exposure

mg/kg/day	

MOE1	

NOAEL mg/kg/day	

Incidental Oral Exposure mg/kg/day 	Chronic Dietary (Food + Water)
mg/kg/day	

MOE1

	

Children 1-2 yrs	

5	

0.027	

180	

5.8	

0.009425	

0.008032	

330	

120

Adults	

5	

0.019	

260	

5	

NA	

0.002466	

2000	

230

1 The Level of Concern MOE is 100.

2 Total Combined MOE = 1/ [(1/MOEDermal) + (1/MOEOral)]

8.0	Cumulative Risk Characterization/Assessment  TC \l1 "8.0	Cumulative
Risk Characterization/Assessment 

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to pyraclostrobin and any other
substances and pyraclostrobin 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 pyraclostrobin 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 concerning common mechanism determinations and
procedures for cumulating effects from substances found to have a common
mechanism on EPA’s website at   HYPERLINK
"http://www.epa.gov/pesticides/cumulative/" 
http://www.epa.gov/pesticides/cumulative/ .

9.0	Occupational Exposure/Risk Pathway  TC \l1 "9.0	Occupational
Exposure/Risk Pathway 

Reference: Pyraclostrobin: Occupational and Residential Exposure
Assessment for Proposed New Use on Sorghum (Headline®) and Sorghum Seed
Treatment (Stamina™).  DP 359197; B. O’Keefe; 03/16/09.

9.1	Short-/Intermediate-Term Handler Risk  TC \l2 "9.1
Short-/Intermediate-Term Handler Risk 

Pyraclostrobin may be applied to sorghum foliage with aerial,
chemigation, or groundboom equipment.  Pyraclostrobin is applied to
sorghum seeds using commercial seed treatment equipment.  Handler
exposure is expected to be short- or intermediate-term based on
information provided on proposed labels.  

Foliar Treatment

Occupational handlers may experience short- and intermediate-term
exposure to pyraclostrobin while mixing/loading, applying, flagging, or
performing other handler tasks to support application to sorghum.  No
chemical-specific handler exposure data were submitted in support of
this use pattern.  It is the policy of the HED to use data from the
Pesticide Handlers Exposure Database (PHED) Version 1.1 as presented in
PHED Surrogate Exposure Guide (8/98) to assess handler exposures when
chemical-specific monitoring data are not available ( HED Science
Advisory Council for Exposure Draft Policy # 7, dated 1/28/99).  The
results are presented in Table 15.

Exposure Scenarios for Foliar Treatments

The quantitative exposure and risk assessment developed for occupational
handlers involved in application to field-grown sorghum is based on the
following exposure scenarios:

Mixing/loading liquid concentrate to support aerial applications, 

Mixing/loading liquid concentrate to support chemigation applications, 

Mixing/loading liquid concentrate to support groundboom applications,

Applying sprays with aircraft,

Applying sprays with groundboom equipment, and 

Flagging to support aerial spray applications.

HED’s level of concern for the MOE is defined by the uncertainty
factors that are applied to the assessment.  HED applies a 10X factor to
account for inter-species extrapolation and a 10X factor to account for
intra-species sensitivity.  The total uncertainty factor that has been
applied to the non-cancer risk assessment for pyraclostrobin is 100 for
occupational exposure.  Occupational exposure and risk resulting in MOEs
greater than or equal to 100 will not be of concern to HED.



Agricultural Handlers

Summaries of the exposures and risks for handlers involved in
application to field-grown sorghum are included in Table 12.  The
maximum application rate for each exposure scenario is presented as the
worst case scenario.  All handler scenarios resulted in MOEs greater
than the level of concern (MOEs ≥ 100) at some level of mitigation. 

The dermal risks to handlers are not a concern with baseline attire
(i.e., long-sleeve shirt, long pants, shoes, and socks) for the
following scenarios:

applying sprays with groundboom equipment; and

flagging to support aerial spray applications.

If chemical-resistant gloves are worn in addition to baseline attire,
the dermal risks are not a concern for the following scenarios:

mixing and loading liquid concentrates to support aerial applications; 

mixing and loading liquid concentrates to support chemigation; and 

mixing and loading liquid concentrates to support groundboom
applications.

The inhalation risks to handlers are not a concern with baseline attire
(no respirator) for the following scenarios:

mixing and loading liquid concentrates to support chemigation; 

mixing and loading liquid concentrates to support groundboom
applications;

applying sprays with groundboom equipment; and

flagging to support aerial spray applications.

If a respirator is worn, the inhalation risks are not a concern for the
following scenario:

mixing and loading liquid concentrates to support aerial applications.

Note:  The respirator unit exposure value represents a NIOSH-approved
respirator with a dust-mist filter with MSHA/NIOSH approval number
prefix TC-21 or any N, R, P, or HE filter.  Such a respirator is
generally referred to as an 80% protection factor respirator, or a
“quarter-face, cup-style dust/mist filtering respirator”.

Only engineering control (enclosed cockpit) data are available to assess
dermal and inhalation risks to handlers operating aircraft.  The risks
are not a concern for pilots using enclosed cockpits and wearing
baseline attire and no respirator.

Table 15.  Pyraclostrobin Agricultural Handler Exposures and Risks

Exposure Scenario	Crop and Product	App. Ratea 

(lb ai/acre)	Area Treated Dailyb (acres) 	Unit Exposuresc	Dermal Dosesd
and MOEse

(LOC MOE = 100)	Inhalation Dosesfand MOEsg

(LOC MOE = 100)

Baseline Dermal (mg/lb ai)	Baseline Inhalation (µg/lb ai)	Baseline
Dermal Plus Gloves

(mg/lb ai)	Inhalation 80% PF (µg/lb ai)	Baseline Doseh

mg/kg/day	Baseline MOE  	 PPE-G Dosei

mg/kg/day 	PPE-G MOE 	Baseline Dose

mg/kg/day	Baseline MOE  	D-M Respirator

Dosej

mg/kg/day	D-M Respirator MOE

Mixing/Loading Liquid Concentrates for Aerial Application	Sorghum	0.2
1,200	2.9	1.2	0.023	0.24	1.6	3.1	0.013	390	0.0041	56	0.00082	280

Mixing/Loading Liquid Concentrates for Chemigation Applications

0.2	350	2.9	1.2	0.023	0.24	0.47	11	0.0038	1,300	0.0012	190	0.00024	960

Mixing/Loading Liquid Concentrates for Groundboom Applications

0.2	200	2.9	1.2	0.023	0.24	0.27	18	0.0021	2,300	0.00069	340	0.00014
1,700

Applying Sprays via Aerial Equipmentk

0.2	1,200	0.005 (Eng. Cont.)	0.068 (Eng. Cont.)	NA	NA	0.0028

(Eng. Cont.)	1,800

(Eng. Cont.)	NA	NA	0.00023 (Eng. Cont.)	990

(Eng. Cont.)	NA	NA

Applying Sprays via Groundboom

0.2	200	0.014	0.74	0.014	0.148	0.0013	3,800	0.0013	3,800	0.00042	540
0.000085	2,700

Flagging for Aerial Spray Applications

0.2	350	0.011	0.35	NA	0.07	0.0018	2,800	NA	NA	0.00035	660	0.00007	3,300

a. Application Rates based on proposed supplemental label for EPA Reg.
No. 7969-186.  

b. Science Advisory Council Policy # 9.1

c. Unit Exposures based on PHED Version 1.1

daily unit exposure (μg/lb ai)  x application rate (lb ai/acre) x acres
treated * inhalation absorption (100%)  x conversion factor (1 mg/1,000
μg) / body weight (70 kg).  

g. Inhalation MOE = NOAEL (0.23 mg/kg/day) / inhalation daily dose
(mg/kg/day). Level of concern = 100.

h. Baseline Dermal:  Long-sleeve shirt, long pants, and no gloves;
Baseline Inhalation: no respirator.

i. Baseline plus Gloves Dermal: Baseline plus chemical-resistant gloves.

j. D/M: The respirator unit exposure value represents a NIOSH-approved
quarter-face, cup style dust/mist filtering respirator (e.g., dust
mask), which is considered to provide an 80% reduction in inhalation
exposure.

k. Only engineering control (enclosed cockpit) data are available to
assess dermal and inhalation risks to handlers operating aircraft.  



Seed Treatment

Occupational handlers may experience short- and intermediate-term
exposure to pyraclostrobin while performing seed treatment activities in
commercial settings. In addition, occupational secondary handlers may
experience short- and intermediate-term exposure while planting
pyraclostrobin-treated sorghum seeds.  No chemical-specific handler
exposure data were submitted in support of this use pattern.  For
assessing seed treatment and seed planting activities, unit exposure
data were taken from HED Science Advisory Council for Exposure Policy
14: Standard Operating Procedures 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 Standard Operating Procedure (SOP) Policy 15.  The
results are presented in Table 16.

Exposure Scenarios for Seed Treatments

The quantitative exposure and risk assessment developed for occupational
handlers involved in commercial application to sorghum seed is based on
the following exposure scenarios:

Loading the pesticide into seed treatment equipment and applying to
sorghum seeds (“loader/applicator”),

Loading seeds into bags (“bagger”),

Sewing seed bags (“sewer”), and 

Handlers involved in multiple commercial seed treatment activities
(“multiple activities”)

In addition, a quantitative exposure/risk assessment was developed for
occupational secondary handlers involved in planting treated sorghum
seeds.

Commercial Seed Treatment Handlers

Summaries of the exposures and risks for handlers involved in commercial
application to sorghum seed and planting treated sorghum seed are
included in Table 13.  The maximum application rate for each exposure
scenario is presented as the worst case scenario.  All seed treatment
activities result in MOEs greater than the LOC of 100 and are not of
concern at some level of risk mitigation.  

The dermal risks to handlers are not a concern with baseline attire
(i.e., long-sleeve shirt, long pants, shoes, and socks) for the
following scenarios:

loading treated seeds into bags (“bagger”), and

sewing the bags of seed (“sewer”)

There are no data to estimate dermal exposure and risk at baseline
attire for the following scenarios:

loading the pesticide into seed treatment equipment and applying to
sorghum seeds (“loader/applicator”); 

handlers involved in multiple commercial seed treatment activities
(“multiple activities”); and

planting treated seeds (“planter”).

The dermal risks are not a concern at baseline attire plus
chemical-resistant gloves for these scenarios.

The inhalation risks to handlers are not a concern at baseline attire
(no respirator) for the following scenarios:

loading the pesticide into seed treatment equipment and applying to
sorghum seeds (“loader/applicator”);

loading treated seeds into bags (“bagger”); 

sewing the bags of seed (“sewer”); and

planting treated seeds (“planter”).

If a respirator is worn in addition to baseline attire, inhalation risk
is not a concern for the following scenario:

handlers involved in multiple commercial seed treatment activities
(“multiple activities”).

Note:  The respirator unit exposure value represents a NIOSH-approved
respirator with a dust-mist filter with MSHA/NIOSH approval number
prefix TC-21 or any N, R, P, or HE filter.  Such a respirator is
generally referred to as an 80% protection factor respirator, or a
“quarter-face, cup-style dust/mist filtering respirator”.



Table 16. Pyraclostrobin Seed Treatment Handler Exposures and Risks

Exposure Scenario	lbs seed treated or planted per daya	Appl. Rateb 

(lb ai/100 lb	Unit Exposuresc 	Dermal Dosesg and MOEsh

(LOC MOE = 100)	Inhalation Dosesi and MOEsj

(LOC MOE = 100)

	Dermal Baselined (mg/lb ai) 	Dermal PPE-Ge (mg/lb ai) 	Inhalation
Baselinef (µg/lb ai)	D-M Respirator

(µg/lb ai)	Baseline Dose	Baseline MOE  	 PPE-G Dose 	PPE-G MOE 
Baseline Dose	Baseline MOE  	D-M Respirator

Dose	D-M Respirator MOE

Sorghum

Loader/ Applicator	718,000	0.02	No Data	0.023	0.34	0.068	No Data	No Data
7.70E-3	650	6.97E-4	330	1.39E-4	1,600

Sewer

	0.0062	No Data	0.23	0.046	2.10E-3	2,400	No Data	No Data	4.72E-4	490
9.44E-5	2,400

Bagger

	0.0091	No Data	0.16	0.032	3.00E-3	3,600	No Data	No Data	3.28E-4	700
6.56E-5	3,500

Multiple Activities

	No Data	0.042	1.6	0.32	No Data	No Data	1.40E-2	360	3.28E-3	70	6.56E-4
350

Planter 

(Secondary Handler)	12,000	0.02	No Data	0.25	3.4	0.68	No Data	No Data
1.40E-3	3,600	1.20E-4	2,000	2.72E-5	8,500

The amount of seed treated or planted per day are HED estimates based on
HED Science Advisory Council for Exposure Policy 15:  Amount of Seed
Treated or Planted per Day, March 2, 2004, and values submitted by
industry. 

Application rates are the maximum application rates determined from
proposed labels for pyraclostrobin.

The unit exposures are from HED Science Advisory Council for Exposure
Policy 14: Standard Operating Procedures for Seed Treatment. For the
tuberous and corm vegetable commercial seed treatment scenario, however,
the unit exposures are from the Pesticide Handlers Exposure Database
(PHED) Version 1.

Dermal Baseline:  Long-sleeve shirt, long pants, and no gloves.

Dermal PPE-G: Baseline plus chemical-resistant gloves.

Inhalation Baseline: no respirator.

D/M: The respirator unit exposure value represents a NIOSH-approved
quarter-face, cup style dust/mist filtering respirator (e.g., dust
mask), which is considered to provide an 80% reduction in inhalation
exposure.

h. 	Dermal Dose (mg/kg/day) = daily unit exposure (mg/lb ai) x
application rate (lb ai/lb seed) x lbs seed treated or planted per day x
dermal absorption (14%) / body weight (60 kg, adult female).

i. 	Dermal MOE = NOAEL (5 mg/kg/day) / dermal daily dose (mg/kg/day). 
Level of concern = 100.

Inhalation daily dose (mg/kg/day) = daily unit exposure (μg/lb ai)  x
(lb ai/lb seed) x lbs seed treated or planted per day x conversion
factor (1 mg/1,000 μg) / body weight (70 kg).

k.	Inhalation MOE = NOAEL (0.23 mg/kg/day) / inhalation daily dose
(mg/kg/day). Level of concern = 100.



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

One of the proposed uses for pyraclostrobin involves foliar applications
to field-grown sorghum.  Therefore, postapplication exposure is possible
for workers entering treated fields for activities such as scouting,
irrigating, and hand weeding.  There are also potential postapplication
exposures to workers entering fields after pyraclostrobin-treated
sorghum seeds are planted.

HED assumes that inhalation exposures are minimal compared to dermal
exposures following outdoor applications of an active ingredient with
low vapor pressure.  Since pyraclostrobin is applied only in outdoor
settings and has a very low vapor pressure, postapplication inhalation
exposures and risks were not assessed.

Postapplication dermal exposure and risk was estimated. 
Chemical-specific dislodgeable foliar residue (DFR) data had previously
been submitted by the registrant to support earlier registration
requests for food crops (MRID#s: 45118727, 45118724, 45118726, and
45118728 and 45118729).  A summary of the results and an overview of
each study was provided in a previous assessment (D269670, K.
O’Rourke, 9/30/2002).

The DFR data were used to estimate restricted entry intervals (REIs) by
extrapolating to the proposed use on sorghum.  It was found that the
type of formulation used influences the DFR profile.  Since the proposed
product is an EC formulation, the DFR data for the liquid concentrate
formulations were considered.  Average percent initial DFR values were
calculated (i.e., 18% for liquid concentrates) and used to estimate
surrogate residue values for field-grown sorghum.  Although
uncertainties are introduced into the assessment when crop-specific
residues are used to estimate residues for other types of crops, it is
believed to be more realistic than using default assumptions. 

In addition to these residue data, transfer coefficients (Tc) are used
to relate the foliage residue values to activity patterns (e.g.,
scouting) to estimate potential human exposure.  The transfer
coefficients used in this assessment are from an interim transfer
coefficient policy developed by HED’s Science Advisory Council for
Exposure using proprietary data from the Agricultural Re-entry Task
Force (ARTF) database (policy # 3.1).

The postapplication exposure and risk associated with sorghum crops is
summarized in Table 17.  All scenarios resulted in MOEs greater than 100
on day 0 (12 hours after application), and therefore are not of concern
to HED.  Since the postapplication risks are not a concern on Day 0 (12
hours following application), the restricted entry interval (REI) is
based on the acute toxicity of pyraclostrobin technical material which
is classified as Category III for acute dermal toxicity and for skin and
eye irritation potential.  Pyraclostrobin is not a dermal sensitizer. 
Under the Worker Protection Standard for Agricultural Pesticides, the
default restricted-entry interval is 12 hours for active ingredients
classified as acute toxicity categories III or IV for these routes of
entry. 

Potential postapplication exposures and risks to workers entering fields
after pyraclostrobin-treated sorghum seeds are planted were not
quantitatively assessed.  HED believes that the 12-hour restricted-entry
interval established for foliar uses on sorghum is sufficiently
protective for workers entering fields following planting of treated
seeds.  Note:  A standard WPS exception to this REI states that once
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 seeds or the soil/media
subsurface.

For the seed treatment uses, the pyraclostrobin labeling 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 soil/media subsurface."

Table 17.  Summary of Postapplication Risks for Proposed Use on
Field-Grown Sorghum

Crop	Application Rate

(lb ai/A) 1	DAT 2	DFR 3

(μg/cm2)	TC 4

(cm2/hr)	Activity 4	Short- & Intermediate-Term Dose5	Short- &
Intermediate-Term MOE 6

Sorghum 	0.20	0	0.404	100	Scouting and hand weeding of low  growth
foliage plants	0.00075	6,600

1,000	Irrigating and scouting of high growth foliage plants	0.0075	660

Maximum application rate indicated on proposed label (see Table 2). 

DAT = Days after treatment needed to reach the LOC of 100; DAT 0 = the
day of treatment, after sprays have dried; assumed to be approximately
12 hours.  

DFR (µg/cm2) = Application rate (lb ai/A) x CF (4.54E+8 ug/lb) x CF
(2.47E-8 A/cm2) x Initial Fraction of ai Retained on the Foliage (from
Table 6, used LC average [18%] ).  This data was derived from summaries
of results presented in MRIDs 45118727, 45118724, 45118726, and 45118728
and 45118729.

TC (cm2/hr) = transfer coefficients and associated activities from
ExpoSAC Policy Memo #003.1 “Agricultural Transfer Coefficients”,
8/17/2000.

Daily Dose = [(DFR x TC x 14% Dermal absorption x 8-hr Exposure Time)] /
[(CF: 1000 µg/mg) x (60-kg Body Weight)]  Short-/intermediate-term
Dermal NOAEL = 5 mg/kg/day.  The LOC is 100.

MOE = NOAEL/Daily Dose

10.0	Data Needs and Label Recommendations  TC \l1 "10.0	Data Needs and
Label Recommendations 

10.1	Toxicology Data Needs  TC \l2 "10.1	Toxicology Data Needs 

870.7800 Immunotoxicity study

As part of the new 40CFR §158 Guidelines, an immunotoxicity study in
rats and/or mice is required (see Appendix B).  

10.2	Residue Chemistry Data Needs and Label Recommendations  TC \l2
"10.2	Residue Chemistry Data Needs and Label Recommendations 

For Petitions #8F7385, #8F7390, and #8F7394

860.1550 Proposed Tolerances

The petitioner should submit revised Section Fs reflecting the
recommended tolerances and commodity definitions presented in Table 9.

10.3	Occupational Label Recommendations  TC \l2 "10.3	Occupational Label
Recommendations 

™ BAS 500 12 F Label

For the scenario of handlers involved in multiple commercial seed
treatment activities (“multiple activities”), a dust mist respirator
is needed to achieve an MOE ≥ 100, which is not already included on
the proposed Stamina™ label.

For the seed treatment uses, the pyraclostrobin seed treatment labeling
should be required to add specific statements regarding the personal
protective equipment required for persons planting treated seed as well
as other label restrictions, as follows:.

“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 soil/media subsurface."

Headline® Fungicide Label

For the use on sorghum, the scenario of mixing and loading liquid
concentrates to support aerial applications, a dust mist respirator is
needed to achieve an MOE ≥ 100, which is not already included on the
proposed Headline® label.

11.0	International Residue Limit Status  TC \l1 "11.0	International
Residue Limit Status 

The Codex Alimentarius Commission (CAC) has established maximum residue
limits (MRLs) for residues of pyraclostrobin on stone fruit and coffee
beans.  The residue definitions are not harmonized.  The CAC definition
contains parent only, whereas the US residue definition includes a
metabolite.  The MRL values are harmonized for coffee beans, but the MRL
values for stone fruits are not.  The CAC value for stone fruits of 1
mg/kg is based on evaluation of US residue data for cherries, where the
highest residue was 0.63 mg/kg.  The recommended US tolerance of 2.5 ppm
results from new trials conducted in 2007 on cherries, peaches, and
plums using a WDG formulation of pyraclostrobin and boscalid (M.
Negussie, D359194).  Use of this particular formulation requires an
increase in the US tolerance from its present value of 0.9 ppm (40 CFR
180.582) because measured residues were as high as 1.9 ppm.

Canada has established tolerances for various stone fruits at 0.7 ppm. 
The US and Canadian residue definitions are harmonized.  The US
tolerance for stone fruits is higher than the Canadian tolerances for
individual stone fruit commodities because of the new formulation uses.



INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name:  methyl
[2-[[[1-(4-chlorophenyl)-1H-pyrazol-3-yl]oxy]methyl]phenyl]methoxy
carbamate	Common Name:

Pyraclostrobin	(   Proposed tolerances

(  Reevaluated tolerance

(  Other	Date: 03/19/2009

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 Numbers:  PP#8F7385, PP#8F7390, PP#8E7394

DP#359194

Other Identifier: 

Residue definition (step 8/CXL):  pyraclostrobin	Reviewers/Branch: M.
Negussie, T. Morton, L. Cheng

	Residue definition in PP#8F7385, PP#8F7390, and PP#8E7394:  Combined
residues of pyraclostrobin and BF 500-3, expressed as pyraclostrobin.

Crop (s)	MRL (mg/kg)	Crop (s)	Recommended Tolerance (ppm)

PP#8F7385

   Sorghum, grain,  forage	5.0

Sorghum, grain, grain	0.6

Sorghum,  grain, stover	0.8

PP#8F7390

	Stone Fruits	1.	Fruits, Stone,  group 12 	2.5

PP#8F7394	 

Coffee beans	0.3	   Coffee, bean, green 	0.3

Limits for Canada	Limits for Mexico

(No Limits

(No Limits for the crops requested	xNo Limits

(No Limits for the crops requested

Residue definition:

plant: methyl
[2-[[[1-(4-chlorophenyl)-1H-pyrazol-3-yl]oxy]methyl]phenyl]methoxycarbam
ate, including the metabolite [2-[[[1(4-chlorophenyl)-1H-pyrazol
-3-yl]oxy]methyl]phenyl]carbamate

livestock: methyl
[2-[[[1-(4-chlorophenyl)-1H-pyrazol-3-yl]oxy]methyl]phenyl]methoxycarbam
ate, including the metabolites

convertible to 1-(4-chlorophenyl)-1H-pyrazol-3-ol and
1-(4-chloro-2-hydroxyphenyl)-1H-pyrazol-3-ol

	Residue definition: N/A

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

Apricot	0.7

Nectarines	0.7

Peaches	0.7

Plumcots	0.7

Plums	0.7

Prune plums	0.7

Sweet cherries	0.7

Tart cherries	0.7

S.Funk, 03/31/2009.



12.0	Appendix A: Toxicity Profile  TC \l1 "12.0	Appendix A: Toxicity
Profile 

12.1	Appendix A1. Pyraclostrobin Toxicology Requirements and Available
Studies for Food Uses  TC \l2 "12.1	Appendix A1.: Pyraclostrobin
Toxicology Requirements and Available Studies for Food Uses 

Appendix A1: Pyraclostrobin Toxicology Requirements and Available
Studies for Food Uses.

  SEQ CHAPTER \h \r 1 Test 

	Technical

	Required	Satisfied

870.1100	Acute Oral Toxicity	

870.1200	Acute Dermal Toxicity	

870.1300	Acute Inhalation Toxicity	

870.2400	Primary Eye Irritation	

870.2500	Primary Dermal Irritation	

870.2600	Dermal Sensitization		yes

yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

yes

870.3100	Oral Subchronic (rodent)	

870.3150	Oral Subchronic (dog)	

870.3200	28-Day Dermal	

870.3465	28-Day Inhalation		yes

yes

yes

yes	yes

yes

yes

yes

870.3700a	Developmental Toxicity (rat)	

870.3700b	Developmental Toxicity (rabbit)	

870.3800	Reproduction		yes

yes

yes	yes

yes

yes

870.4100a	Chronic Toxicity (rat)	

870.4100b	Chronic Toxicity (dog)	

870.4200a	Oncogenicity (rat)	

870.4200b	Oncogenicity (mouse)		yes

yes

yes

yes	yes

yes

yes

yes

870.5100	Mutagenicity—Gene Mutation - bacterial	

870.5300	Mutagenicity—Gene Mutation - mammalian	

870.5375	Mutagenicity—Structural Chromosomal Aberrations	

870.5395	Mutagenicity—Microneucleus - mammalian

870.5550	Mutagenicity—Unscheduled DNA - mammalian 		yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

870.6100a	Acute Delayed Neurotox. (hen)	

870.6100b	90-Day Neurotoxicity (hen)	

870.6200a	Acute Neurotox. Screening Battery (rat)	

870.6200b	90 Day Neuro. Screening Battery (rat)	

870.6300	Develop. Neuro		no

no 

yes

yes

no

	-

- 

yes

yes

-

870.7485	General Metabolism	

870.7600	Dermal Penetration		yes

yes	yes

yes

870.7800	Immunotoxicity		yes	no



12.2	Appendix A2.: Acute Toxicity Data on Pyraclostrobin Technical  TC
\l2 "12.2	Appendix A2.: Acute Toxicity Data on Pyraclostrobin Technical 

  SEQ CHAPTER \h \r 1 Appendix A2. Acute Toxicity Profile:

  SEQ CHAPTER \h \r 1 Acute Toxicity Data on Pyraclostrobin Technical

Study/ Species	MRID	Results	Toxicity  Category

870.1100 Acute Oral, Rats	45118302	LD50 = > 5000 mg/kg	IV

870.1200 Acute Dermal, Rabbits	45118305	LD50 = >2000mg/kg	III

870.1300 Acute Inhalation, Rats	45118308	0.31 mg/L < LC50 < 1.07 mg/L	II

870.2400 Primary Eye Irritation, Rabbits	45118311	Moderate eye
irritation; MAS 4.6/110	III

870.2500 Primary Skin Irritation, Rabbits	45118314	Moderate skin
irritation; MAS 2.2/8.0	III

870.2600 Dermal Sensitization, Guinea pig	45118317	Not a skin sensitizer
N/A

12.3	Appendix A3.: Subchronic, Chronic and Other Toxicity Profile  TC
\l2 "12.3	Appendix A3.: Subchronic, Chronic and Other Toxicity Profile 

  SEQ CHAPTER \h \r 1 Appendix A3. Subchronic, Chronic and Other
Toxicity Profile

Guideline No./Study Type	MRID No. (year)/ Classification/Doses	Results

870.3100

90-Day oral toxicity (rat)	45118321 (1999)

Acceptable/guideline

0, 50, 150, 500, 1000, 1500 ppm 

M: 0, 3.5, 10.7, 34.7, 68.8, 105.8 mg/kg/day; 

F: 0, 4.2 12.6, 40.8, 79.7,118.9  mg/kg/day	NOAEL = 10.7 mg/kg/day

 ↓body weight/ weight gain in males, ↓food intake (both sexes), ↑
relative liver wt and spleen wt in females and histopathology of
duodenum and liver in males, and spleen in both sexes.

870.3100

90-Day oral toxicity

(mouse)	45118320 (1999) 

Acceptable/guideline

0, 50, 150, 500, 1000, 1500 ppm

M: 0, 9.2, 30.4, 119.4, 274.4, 475.5 mg/kg/day

F:0, 12.9, 40.4, 162.0, 374.1, 634.8 mg/kg/day	NOAEL = 9.2 mg/kg/day

LOAEL =  30.4 mg/kg/day based on ↓body weight/ weight gain in males,
changes in clinical chemistry in both sexes (increased urea and
decreased triglycerides), and increased incidences in females of lymph
node apoptosis, thymus atrophy, and ulcer/erosion in the glandular
stomach.

870.3150

90-Day oral toxicity (dog)	45118323 (1999) 

Acceptable/guideline

0, 100, 200, 450 ppm

M: 0, 2.8, 5.8, 12.9 mg/kg/day

F: 0, 3.0, 6.2, 13.6 mg/kg/day	NOAEL = 5.8 mg/kg/day

LOAEL = 12.9 mg/kg/day based on ↑diarrhea, clinical chem. changes, and
increased incidence of thickening/ mucosal hypertrophy of the duodenum
in both sexes; body weight loss, and ↓food intake/efficiency in
females.

870.3050

28-Day oral toxicity (rat)       

	MRID 45118322 (1999) 

Acceptable/guideline

0, 20, 100, 500, 1500 ppm 

M: 0, 1.8, 9.0, 42.3, 120.2 mg/kg/day 

F: 0, 2.0 9.6, 46.6, 126.3  mg/kg/day	NOAEL =  9.0 mg/kg/day

LOAEL = 42.3 mg/kg/day based on changes in hematology parameters,
increased absolute and relative spleen weight, histopathology in spleen
and liver, in addition to increased duodenal mucosal hyperplasia in both
sexes. 

870.3200

28-Day dermal toxicity (rat)	45118324 (1999) Unacceptable/guideline (a
higher dose could be tolerated and the limit dose is 1000 mg/kg/day)

0, 40, 100, 250 mg/kg for 5 days/wk	Dermal NOAEL = 40 mg/kg/day

Dermal LOAEL = 100 mg/kg/day based on scale formation, hyperkeratosis,
and epidermal thickening.

Systemic NOAEL = 250 mg/kg/day

Systemic LOAEL > 250 mg/kg/day

The HIARC (TXR 0051553) determined that a repeat study at a higher dose
is not needed since an oral end-point (developmental toxicity NOAEL of
5.0 mg/kg/day) with a 14% dermal absorption rate yields a dermal
equivalent dose of 36 mg/kg/day (5 ÷ 0.14) which is well below the
apparent systemic toxicity NOAEL of 250 mg/kg/day in the dermal study.

870.3465

28-Day inhalation toxicity (rat)	46638801 (2005)

Acceptable/guideline

0.001, 0.030, or 0.300 mg/L for 6 hours per day, 5 days/week (20
exposure days) – Test substance was dissolved in acetone and
administered as an aerosol	Inhalation NOAEL = 0.001 mg/L (oral
equivalent dose = 0.23 mg/kg/day)

Inhalation LOAEL = 0.030 mg/L (oral equivalent dose = 6.9 mg/kg/day)
based on findings of hyperplasia in the duodenum, alveolar histiocytosis
in the lungs, and olfactory atrophy/necrosis in the nasal tissues.

870.3700a

Prenatal developmental (rat)	45118325 (1999)

Acceptable/guideline

0, 10, 25, 50 mg/kg/day	Maternal NOAEL = 10 mg/kg/day

LOAEL = 25 mg/kg/day based on ↓body wt/ wt gain and ↓food
intake/efficiency.

Developmental NOAEL = 25 mg/kg/day

LOAEL = 50 mg/kg/day based on ↑ incidences of dilated renal pelvis and
cervical ribs with no cartilage.

870.3700b

Prenatal developmental (rabbit)	45118326 and 45437001 (1999)
Acceptable/guideline

0, 1, 3, 5, 10, 20 mg/kg/day	Maternal NOAEL = 5 mg/kg/day

LOAEL = 10 mg/kg/day based on ↓ body wt gain and ↓food
intake/efficiency.

Developmental NOAEL = 5 mg/kg/day

LOAEL =10 mg/kg/day based on ↑ resorption/post-implantation loss.

870.3800

Reproduction and fertility effects

(rat)	Two Generation: MRID 45118327 (1999) Acceptable/guideline when
combined with the one generation preliminary study (below)

0, 25, 75, 300 ppm

F0 M/F: 0, 2.5/2.6, 7.4/7.8, 29.0/30.4 mg/kg/day

F1 M/F: 0, 2.8/3.0, 8.6/9.0, 35.0/36.0 mg/kg/day

One Generation: MRID 45596210 (2002)

0, 200, 400, 600 ppm

F0 M/F: 0, 20.5/21.3, 39.9/42.5, 59.1/60.4 mg/kg/day	Parental/Systemic
NOAEL = 29 mg/kg/day

LOAEL > 29 mg/kg/day based on no effects.

Reproductive NOAEL = 29 mg/kg/day

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Offspring NOAEL =  29 mg/kg/day

LOAEL > 29  mg/kg/day based on no effects.

Offspring NOAEL < 20.5 mg/kg/day 

Offspring LOAEL = 20.5 mg/kg/day based on decreased pup body weight and
body weight gain on and after post-natal day 7.

870.4100a

Chronic toxicity

(rat)	45118329 (1999) Unacceptable/guideline

0, 25, 75, 200 ppm 

M: 0, 1.1, 3.4, 9.0 mg/kg/day 

F: 0, 1.5, 4.6, 12.3 mg/kg/day	NOAEL =  9.0 mg/kg/day

LOAEL > 9.0 mg/kg/day.

870.4100b

Chronic toxicity (dog)	45118328 (1999)

Acceptable/guideline

0, 100, 200, 400 ppm

M: 0, 2.7, 5.4, 10.8 mg/kg/day

F: 0, 2.7, 5.4, 11.2 mg/kg/day	NOAEL = 5.4 mg/kg/day

LOAEL = 10.8 mg/kg/day based on ↑ diarrhea and clinical chemistry
changes in both sexes (decreased cholesterol, protein, albumin, and
globulin), and ↓ body weight gain and ↓food intake/efficiency in
females.

870.4200

Carcinogenicity

(rat)	45118331 (1999)

Acceptable/guideline

0, 25, 75, 200 ppm 

M: 0, 1.2, 3.4, 9.2 mg/kg/day

F: 0, 1.5, 4.7, 12.6 mg/kg/day	NOAEL = 3.4 mg/kg/day

LOAEL =  9.2 mg/kg/day based on ↓ body weight and body weight gain,
and kidney atrophy/tubular casts in both sexes; hepatic necrosis and
gross/ microscopic ulcerations/lesions in the glandular and
fore-stomachs in males.

No evidence of carcinogenicity

870.4300

Carcinogenicity

(mouse)	45118330 (1999) Unacceptable/guideline 

M: 0, 10, 30, 120 ppm 

0, 1.4, 4.1, 17.2 mg/kg/day

F: 0, 10, 30, 120, 180 ppm 

0, 1.6, 4.8, 20.5, 32.8 mg/kg/day	NOAEL =  M: 4.1 mg/kg/day

	     F:  32.8 mg/kg/day

LOAEL =  M: 17.1 mg/kg/day based on decrease in body weight gain (20%)
at 13 weeks which was supported by the results of a 90-day study.

	    F >32.8 mg/kg/day

Inadequate dosing in females based on CARC Report dated 10/22/03 (TXR #
0051445) 

No evidence of carcinogenicity

Gene Mutation

870.870.5100

Bacterial reverse mutation assay	45118332 (1997)

Acceptable/guideline	Negative  ± S9 up to 5,000 μg/plate by standard
plate and tube preincubation. No cytotoxicity at any dose but there was
precipitation at ≥2,500 μg/plate.

Gene Mutation

870.5300

Mammalian cell culture	45118335 (1998)

Acceptable/guideline	Negative  ± S9 up to cytotoxic and precipitating
concentration of 20 μg/mL

Cytogenetics (in vitro) 

870.5375 Chromosomal aberrations	45118333 (1999)

Acceptable/guideline	Negative ± S9 for clastogenic/aneugenic activity
up to 25 μg/mL.  Precipitation and cytotoxicity (reduced cell
attachment and poor quality of metaphases) were seen at concentrations
≥50  μg/mL.

Cytogenetics 

870.5395

Micronucleus test in mouse	45118334 (1998)

Acceptable/guideline	Negative for clastogenic/aneugenic activity up to
the highest dose tested (300 mg/kg).  In a preliminary study, doses
≥400 mg/kg caused death.

Unscheduled DNA synthesis

870.5550 

Rat hepatocyte culture	45118336 (1998)

Acceptable/guideline	Negative up to a cytotoxic concentration of 1.0
µg/mL. 

870.6200a

Acute neurotoxicity screening (rat)	45118337(1999)

Acceptable/guideline

0, 100, 300, 1000 mg/kg	Neurotoxicity NOAEL = 1000 mg/kg

M/F LOAEL >1000 mg/kg

Systemic M/F NOAEL = 300/〱〰洠⽧杫

M/F LOAEL 1000/ >1000 mg/kg based on ↓body weight gain in males.

870.6200b

Subchronic neurotoxicity screening (rat)	45118401 (1999)

Acceptable/guideline

0, 50, 250, 750 (M)/1500 (F) ppm

M: 0, 3.5, 16.9, 49.9 mg/kg/day

F: 0, 4.0, 20.4, 111.9 mg/kg/day	Neurotoxicity M/F NOAEL =  49.9/111.9
mg/kg/day

M/F LOAEL  >49.9/111.9 mg/kg/day.

Systemic M/F NOAEL =  16.9/20.4 mg/kg/day 

M/F LOAEL =  49.9/111.9 mg/kg/day based on ↓ body weight gain, and ↓
food intake/efficiency. 

870.7485

Metabolism and pharmacokinetics

(rat)	 45118403 (1998) 

 45118404 (1999)

Acceptable/guideline	Nearly 35% of an oral dose of pyraclostrobin is
absorbed with urinary and fecal excretions accounting for about 15% and
85%, respectively, and bile elimination accounted for about 30%. Two
peak plasma concentrations were reached at 0.5-1 and 8 hours with lower
plasma concentrations in males than females (by 16-38%) during the early
peak phase.  Elimination was biphasic at a low dose with plasma half
lives of nearly 10/35 hours and monophasic at a high dose with a
half-life of nearly 20 hours.  Tissue distribution was fast, peaking at
0.5 hours, and was slightly higher among females.  Some of the highest
concentrations were found in the liver, thyroid, kidney, lung, adrenal
glands, and pancreas but all levels dropped by more than 20-fold within
72 hours. About 33 metabolites were identified in urine, feces, and bile
with no sex- or dose-related differences but the position of the label
seemed to alter the profile, particularly in the urine.  Desmethoxy
pyraclostrobin (500M07) is one of the major metabolites in rat and is
also found in large amounts in plants (BF 500-3) and livestock (500M07).
 The rat metabolic pathway included phase-I reactions such as
N-demethoxylation, various hydroxylations, and cleavage of the ether
bond with subsequent oxidation; these reactions were followed by phase
II glucuronidation and sulfation.

870.7600

Dermal penetration

(rat)	45118402 (1999) Unacceptable/guideline (most of the test material
was retained on the dressing and was unavailable for absorption;
therefore, actual dose cannot be determined. 	The HIARC calculated and
recommended a dermal penetration rate of 14% (report dated 2/10/03; TXR
# 0051553)



13.0	Appendix B: Rationale for Toxicity Data Requirement  TC \l1 "13.0
Appendix B: Rationale for Toxicity Data Requirement 

Appendix B:  Rationale for Toxicity Data Requirements

OPPTS Guideline Number:  870.7800

Study Title:  Immunotoxicity

Rationale for Requiring the Data

	The immunotoxicity study is a new data requirement under 40CFR §158 as
a part of the data requirements for registration of a pesticide (food
and non-food uses).  

 such as tuberculosis (TB), Severe Acquired Respiratory Syndrome (SARS),
or neoplasia.  Because the immune system is highly complex, studies not
specifically conducted to assess immunotoxic endpoints are inadequate to
characterize a pesticide’s potential immunotoxicity.  While data from
hematology, lymphoid organ weights, and histopathology in routine
chronic or subchronic toxicity studies may offer useful information on
potential immunotoxic effects, these endpoints alone are insufficient to
predict immunotoxicity.  

Practical Utility of the Data

How will the data be used?

	Immunotoxicity studies provide critical scientific information needed
to characterize potential hazard to the human population on the immune
system from pesticide exposure.  Since epidemiologic data on the effects
of chemical exposures on immune parameters are limited, and are
inadequate to characterize a pesticide’s potential immunotoxicity in
humans, animal studies are used as the most sensitive endpoint for risk
assessment.  These animal studies can be used to select endpoints and
doses for use in risk assessment of all exposure scenarios, and are
considered a primary data source for reliable reference dose
calculation.  For example, animal studies have demonstrated that
immunotoxicity in rodents is one of the more sensitive manifestations of
TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) among developmental,
reproductive and endocrinologic toxicities.  Additionally, the EPA has
established an oral reference dose (RfD) for tributyltin oxide (TBTO),
based on observed immunotoxicity in animal studies (IRIS, 1997).  

How could the data impact the Agency's future decision-making? 

	If the immunotoxicity study shows that the test material poses either a
greater or a diminished risk than that given in the interim decision’s
conclusion, the risk assessments for the test material may need to be
revised to reflect the magnitude of potential risk derived from the new
data.  

 	If the Agency does not have these data, a 10X database UF may be
applied for conducting a risk assessment from the available studies.  

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