Document ID: EPA-HQ-OPP-2010-0528-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-07-21T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF	

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

Date: 		11/18/09

SUBJECT:	Pyraclostrobin. Human Health Risk Assessment for Proposed Use
on Alfalfa.

PC Code: 099100	DP Num:  D362855

Decision No.: 405748	Registration No.: 7969-186, 7969-266, & 7969-199

Petition Nos.: 9F7528	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:	W. Cutchin, Acting Senior Branch Scientist   SEQ CHAPTER \h \r 1 

		Alternative Risk Integration and Assessment (ARIA) Team

Risk Integration, Minor Use and Emergency Response Branch (RIMUERB)

		Registration Division (RD; 7505P)

THROUGH:	B. O’Keefe, Senior Biologist

P. Deschamp, Branch Chief 

Risk Assessment Branch III (RABIII)

Health Effects Division (HED; 7509P)

TO:		T. Kish/J. Bauzin PM 22

		Fungicide Branch

		RD (7509P)

RD of the Office of Pesticide Programs (OPP) has requested that ARIA
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 is proposing new uses for pyraclostrobin on alfalfa as
broadcast foliar applications and as a seed treatment.  ARIA has
conducted a human health risk assessment for these proposed uses.  ARIA
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 drinking water residue assessment was provided by
R. Miller and G. Rothman of the Environmental Fate and Effects Division
(EFED).   The residue chemistry data review, the dietary risk
assessment, and human health risk assessment were provided by W. Cutchin
of ARIA. The occupational/residential exposure assessments were provided
by K. O’Rourke of HED and M. Dow of ARIA.  

Table of Contents

  TOC \f  1.0	Executive Summary	  PAGEREF _Toc246235414 \h  4 

2.0	Ingredient Profile	  PAGEREF _Toc246235415 \h  10 

2.1	Summary of Registered/Proposed Uses	  PAGEREF _Toc246235416 \h  10 

2.2	Physical and Chemical Properties	  PAGEREF _Toc246235417 \h  11 

3.0	Hazard Characterization/Assessment	  PAGEREF _Toc246235418 \h  12 

3.1	Hazard Characterization and FQPA Considerations	  PAGEREF
_Toc246235419 \h  12 

3.1	FQPA Safety Factor for Infants and Children	  PAGEREF _Toc246235420
\h  14 

3.3	Summary of Toxicological Doses and Endpoints for Use in Human Health
Risk Assessments	  PAGEREF _Toc246235421 \h  15 

3.4	Recommendation for Aggregate Exposure Risk Assessments	  PAGEREF
_Toc246235422 \h  18 

3.5	Endocrine disruption	  PAGEREF _Toc246235423 \h  19 

4.0	Public Health and Epidemiology Data	  PAGEREF _Toc246235424 \h  19 

5.0	Dietary Exposure/Risk Characterization	  PAGEREF _Toc246235425 \h 
20 

5.1  Pesticide Metabolism and Environmental Degradation	  PAGEREF
_Toc246235426 \h  20 

5.1.1	Metabolism in Primary Crops	  PAGEREF _Toc246235427 \h  20 

5.1.2	Metabolism in Livestock	  PAGEREF _Toc246235428 \h  20 

5.1.3	Analytical Methodology	  PAGEREF _Toc246235429 \h  20 

5.1.4	Storage Stability Data	  PAGEREF _Toc246235430 \h  22 

5.1.5	Magnitude of the Residue in Plants	  PAGEREF _Toc246235431 \h  22 

5.1.6	Magnitude of the Residue in Processed Food/Feed	  PAGEREF
_Toc246235432 \h  24 

5.1.7	Magnitude of the Residue in Meat, Milk, Poultry, and Eggs	 
PAGEREF _Toc246235433 \h  24 

5.1.8	Confined and Field Accumulation in Rotational Crops	  PAGEREF
_Toc246235434 \h  27 

5.1.9	Drinking Water Residue Profile	  PAGEREF _Toc246235435 \h  27 

5.1.10	Proposed Tolerances	  PAGEREF _Toc246235436 \h  28 

5.2  Dietary Exposure and Risk	  PAGEREF _Toc246235437 \h  31 

5.3 Anticipated Residue and Percent Crop Treated (%CT) Information	 
PAGEREF _Toc246235438 \h  33 

6.0	Residential (Non-Occupational) Exposure/Risk Characterization	 
PAGEREF _Toc246235439 \h  34 

7.0	Aggregate Risk Assessments and Risk Characterization	  PAGEREF
_Toc246235440 \h  34 

8.0	Cumulative Risk Characterization/Assessment	  PAGEREF _Toc246235441
\h  36 

9.0	Occupational Exposure/Risk Pathway	  PAGEREF _Toc246235442 \h  36 

9.1	Short-/Intermediate-Term Handler Risk	  PAGEREF _Toc246235443 \h  36

9.2	Short-/Intermediate-Term Postapplication Risk	  PAGEREF
_Toc246235444 \h  40 

10.0	Data Needs and Label Recommendations	  PAGEREF _Toc246235445 \h  42

10.1	Toxicology Data Needs	  PAGEREF _Toc246235446 \h  42 

10.2	Residue Chemistry Data Needs and Label Recommendations	  PAGEREF
_Toc246235447 \h  42 

10.3	Occupational Label Recommendations	  PAGEREF _Toc246235448 \h  42 

11.0	International Residue Limit Status	  PAGEREF _Toc246235449 \h  43 

Appendix A: Toxicity Profile	  PAGEREF _Toc246235450 \h  44 

Appendix A1.: Pyraclostrobin Toxicology Requirements and Available
Studies for Food Uses	  PAGEREF _Toc246235451 \h  44 

Appendix A2.: Acute Toxicity Data on Pyraclostrobin Technical	  PAGEREF
_Toc246235452 \h  45 

Appendix A3.: Subchronic, Chronic and Other Toxicity Profile	  PAGEREF
_Toc246235453 \h  46 

Appendix B: Rationale for Toxicity Data Requirement	  PAGEREF
_Toc246235454 \h  50 

 1.0	Executive Summary  TC \l1 "1.0	Executive Summary 

Pyraclostrobin [carbamic acid,
[2-[[[1-(4-chlorophenyl)-1H-pyrazol-3-yl]oxy]methyl] phenyl]methoxy-,
methyl ester] belongs to the strobilurin 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 is proposing new uses for pyraclostrobin on alfalfa as a seed
treatment and for broadcast foliar applications.  A 2.09 lb/gal EC
formulation (Headline® Fungicide; EPA Reg. No. 7969-186) is proposed
for up to three broadcast foliar applications to alfalfa under
conditions favorable to disease development at rates of 0.098-0.147 lb
ai/A and retreatment intervals (RTIs) of 14-21 days.  The maximum
seasonal use rate is 0.44 lb ai/A, and no more than 2 applications may
be applied per cutting.  The field applications can be made using ground
or aerial equipment, and the proposed preharvest interval (PHI) is 14
days for alfalfa.  Another 1.67 lb/gal EC formulation (Stamina™ Seed
Treatment Fungicide; EPA Reg. No. 7969-266) is proposed for use as a
seed treatment on alfalfa at a rate of 0.02-0.04 lb ai/100 lb seed. 
ARIA notes that BASF has also requested registration of a WDG
formulation (Pristine® Fungicide; EPA Reg. No. 7969-199) containing
12.8% pyraclostrobin and 25.2% boscalid for field use on alfalfa under a
separate petition (PP#9F7527).  The proposed use directions for alfalfa
for this WDG multiple active ingredient (MAI) formulation are
essentially identical to the 2.09 lb/gal EC formulation.  

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 RABIII
pyraclostrobin risk assessment team previously concluded that the FQPA
safety factor can be reduced to 1X.  For further details, see the
previous pyraclostrobin risk assessment document (B. O’Keefe, DP Num
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.

Residue Chemistry

  SEQ CHAPTER \h \r 1 The nature of pyraclostrobin residues in primary
crops and livestock are adequately understood, based on the acceptable
metabolism studies on grapes, potatoes, wheat, goats and hens.  For
purposes of the tolerance expression and dietary risk assessment, the
residues of concern in plant commodities include pyraclostrobin and its
desmethoxy metabolite (BF 500-3), and the residues of concern in
livestock commodities include pyraclostrobin and its metabolites
convertible to BF 500-5 and BF 500-8.  

Adequate analytical methods are available for enforcing pyraclostrobin
tolerances and collecting data on residues in plant commodities.    SEQ
CHAPTER \h \r 1 The analytical methods, liquid chromatography with
tandem mass spectrometric detection (LC/MS/MS) and high pressure liquid
chromatography with ultra-violet detector (HPLC/UV), for plant
commodities determine pyraclostrobin and its desmethoxy metabolite (BF
500-3).  Residues in plant commodities from the current field trials
were determined using a LC/MS/MS data collection method (BASF Method
D9908).  This method was adequately validated in conjunction with the
field trial analyses, and the validated limit of quantitation (LOQ) was
0.02 ppm for pyraclostrobin and metabolite BF 500-3 in alfalfa, for a
combined LOQ of 0.04 ppm  

Adequate methods are also available for collecting residue data on
livestock commodities and for enforcing the current livestock
tolerances.  An LC/MS/MS method (BASF Method 446/1) is available for
determining residues of pyraclostrobin and its metabolites convertible
to BF 500-5 and BF 500-8, expressed in parent equivalents.  The
validated method LOQ for combined BF 500-5 and BF 500-8 residues, in
parent equivalents, is 0.02 ppm for milk and 0.10 ppm for tissues.  This
method has undergone a successful independent laboratory validation
(ILV) trial and a radiovalidation trial.  A similar LC/MS/MS method
(BASF Method D9902) is available for determining residues of
pyraclostrobin and its metabolites convertible to BF 500-5 and BF 500-9,
expressed in parent equivalents.  The validated method LOQ for combined
BF 500-5 and BF 500-9 residues, in parent equivalents, is 0.1 ppm in
eggs and poultry tissues.  Given the similarity in extraction and
purification procedures between Methods 446/1 and D9902, radiovalidation
data are not required for Method D9902.  However, an acceptable ILV
trial and tolerance method validation (TMV) is required for Method D9902
before it can be approved for tolerance enforcement.

Analytical reference standards for pyraclostrobin and its regulated
plant metabolite (BF 500-3) are available at the EPA National Pesticide
Standards Repository.  However, reference standards are not available
for the common moieties (BF 500-5, BF 500-8, and BF 500-9) determined by
the livestock analytical methods.

The available field trial data adequately support the proposed use of
the WDG formulation of pyraclostrobin on alfalfa.  An adequate number of
tests were conducted using the WDG formulation in the appropriate
geographic regions at ~1x the maximum proposed rate, and the appropriate
samples were collected from each test around the proposed PHI.  Samples
were analyzed using adequate methodology and the field trial data are
supported by the available storage stability data.  Although no alfalfa
field trials were conducted using the proposed EC formulation,
previously submitted side-by-side field trials on tomatoes, cucumbers,
and grapes comparing WDG and EC formulations have shown that residues
resulting from the two types of formulations are similar.  Therefore,
the available data for the WDG formulation will also cover the use of
the EC formulations on alfalfa.  The available data support tolerances
of 10 ppm for alfalfa forage and 30 ppm for alfalfa hay.  A revised
Section F is required.

  

No field trial data were submitted reflecting the proposed seed
treatment use on alfalfa, but none is required as the seed treatment
rate (0.008 lb ai/A) is negligible compared to the proposed foliar
applications.

Adequate cattle and poultry feeding studies are available. Based on the
calculated dietary burdens and the data from the cattle feeding study,
the current tolerances for milk and cattle, goat, horse, sheep, and hog
commodities are adequate.  Based on the dietary burden and data from the
poultry feeding and metabolism studies, tolerances at the method LOQ
(0.1 ppm) should be established for poultry meat, fat and meat
byproducts, and eggs.  A revised Section F is required.  

Adequate confined and limited rotational crop studies are available that
support the 14-day plant-back interval (PBI) specified on the labels for
rotated crops without primary uses of pyraclostrobin.  The current
rotational crop restrictions are adequate for the proposed use on
alfalfa.

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.  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).
 ARIA 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).  

ARIA 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
2% 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 8% 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.  

Residential Exposure Assessment

A product containing pyraclostrobin is registered for application to
residential turf grass and recreational sites.  Residential and
recreational turf applications are not applied by non-professionals;
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.  The short-term margins of exposure (MOE) for
each postapplication scenario resulted in MOEs above 100, and therefore,
are not of concern.  For toddlers, the combined dermal and oral
exposures result in an 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.  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.

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

Occupational pesticide handlers may experience short- and
intermediate-term exposure to pyraclostrobin.  In addition, seed
treatment handlers and occupational secondary handlers may experience
short- and intermediate-term exposure while planting
pyraclostrobin-treated alfalfa seeds.  

For the requested foliar use, exposure for mixer/loaders workers is the
worst-case scenario.  Dermal MOEs are > 100 provided mixer/loaders use
protective gloves as specified on the product label.  Inhalation MOEs
are > 100 if mixer/loaders support approximately 600 acres treated per
day or if they use a dust/mist filtering respirator while supporting
aerial applications of 1200 A treated/day.  

For the requested seed treatment use, a worker involved in “multiple
tasks” is the worst-case scenario.  Using default information, a
worker involved in “multiple tasks” would have a “baseline”
(i.e., no personal protective equipment) inhalation MOE less than 100. 
That exceeds the Agency’s level of concern.  Provided a worker
involved in “multiple tasks” uses a dust/mist filtering respirator,
the MOE is greater than 100 and would not exceed the Agency’s levels
of concern.

Occupational Postapplication Exposure Assessment

It is possible for agricultural workers to have post-application
exposure to pesticide residues during the course of typical agricultural
activities.  A MOE of 100 is adequate to protect agricultural workers
from post-application exposures.  The most conservative estimate (i.e.,
highest exposure/risk) of post-application exposure results in MOEs >
100.  Therefore, the proposed risk does not exceed ARIA/RDs level of
concern.  

Pyraclostrobin is classified in Acute Toxicity Category II for acute
inhalation toxicity.  It is classified in Toxicity Category III for
acute dermal toxicity, primary eye irritation and primary skin
irritation.  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. 

Recommendations for Tolerances

Several deficiencies related to enforcement methods and analytical
standards must be resolved as a condition of registration.  The existing
tolerances for milk, fat, meat, liver and meat byproducts of cattle,
goats, horses, sheep, and hogs will adequately cover the use of
pyraclostrobin on alfalfa.  However, new tolerances are required on
poultry commodities.  Until the data requirements in Section 10 are
fulfilled, ARIA recommends against the use of pyraclostrobin on
alfalfa..

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.  

TABLE 2.1  Summary of Directions for Use of Pyraclostrobin.

Applic. Timing, Type, and Equip.1	Formulation

[EPA Reg. No.]	Applic. Rate	Max. No. Applic. per Season	Max. Seasonal
Applic. Rate

(lb ai/A)	PHI

(days)	Use Directions and Limitations 2

Alfalfa (seed treatment)

Seed treatment using standard slurry or mist-type seed treatment
equipment	1.67 lb/gal EC [7969-266]	0.02-0.04 lb ai/100 lb seeds	1	0.008
3	NA	Do not use treated seed for food, feed or oil purposes

Alfalfa (field application)

Broadcast foliar applications when conditions are favorable to disease
development; ground or aerial equipment.	2.09 lb/gal EC

[7969-186]	0.098-0.147 lb ai/A	3 

(2 per cutting)

	0.44	14	The minimum RTI is 14 days. For aerial applications, use a
minimum of 5 gal/A

	12.8% WDG 4

[7969-199]	0.096-0.144 lb ai/A

0.43	14

	1	Ground application may be made through the following types of
irrigation systems:  center pivot, lateral move, end tow, side wheel
roll, traveler, big gun, solid set, or hand move. 

2	Use directions allow for the use of spray adjuvants, and specify a
14-day plant-back interval for rotational crops without registered uses
for pyraclostrobin.

3	The maximum field use rate for the seed treatment was calculated
assuming a planting rate of 5-20 lb of alfalfa seed/A.

4	This formulation is a MAI containing 12.8% pyraclostrobin and 25.2%
boscalid.  Use directions were obtained from PP#9F7527.

Conclusions:  The submitted use directions are sufficient to allow
evaluation of the available residue data relative to the proposed use.  

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

The chemical structure of pyraclostrobin and its physical and chemical
properties are presented in Tables 2.2.a and 2.2.b, respectively. 
Structures of pyraclostrobin metabolites are presented in Table 2.2.c.  

TABLE 2.2.a  Nomenclature of Pyraclostrobin.

Compound	

Common name	Pyraclostrobin

Company experimental name	BAS 500 F

Molecule weight	387.8

IUPAC name	methyl
N-{2-[1-(4-chlorophenyl)-1H-pyrazol-3-yloxymethyl]phenyl}(N-methoxy)
carbamate

CAS name	methyl
[2-[[[1-(4-chlorophenyl)-1H-pyrazol-3-yl]oxy]methyl]phenyl]methoxycarbam
ate

CAS registry number	175013-18-0

End-use product (EPs)	12.8% WDG (Pristine® Fungicide; EPA Reg. No.
7969-199; also contains 25.2% boscalid)

1.67 lb/gal  EC (Stamina™ Fungicide Seed Treatment; EPA Reg. No.
7969-266)

2.09 lb/gal EC (Headline® Fungicide; EPA Reg. No. 7969-186)

TABLE 2.2.b  Physicochemical Properties of Technical Grade
Pyraclostrobin.

Parameter	Value	References 1

Melting point/range	63.7-65.2ºC	D269848 & D274191

pH	Not reported	D269848 & D274191

Density	1.285 g/cm3 at 20ºC	D269848 & D274191

Water solubility at 20ºC	2.41 mg/L (deionized water)

1.9 mg/L (pH 7)

2.3 mg/L (pH 4)

1.9 mg/L (pH 9)	D269848 & D274191

Solvent solubility (g/100 mL at 20ºC)	acetone	16-20	ethyl acetate
6.7-8.0 methanol	4-5	2-propanol	<0.01 acetonitrile	4-5	dichloromethane
20-25 toluene 	2-5	n-heptane 	<0.01

1-octanol	<0.01	olive oil	2.9

N,N-DMF >25	D269848 & D274191

Vapor pressure	2.6 x 10-10 hPa  at 20ºC

6.4 x 10-10 hPa at 25ºC	D269848 & D274191

Dissociation constant, pKa	Does not dissociate in water.	D269848 &
D274191

Octanol/water partition coefficient, Log(KOW) at room temperature	3.80
at pH 6.2

λmax = 275 nm	D269848

Product Chemistry data were reviewed by the Registration Division (DP#s
269848 and 274191, S. Malak, 5/3/01, 5/15/01, and 6/7/01).

TABLE 2.2.c  Chemical Structures of Pyraclostrobin Metabolites

Metabolites	Structure

BAS 500-3

 

BAS 500-5

  SEQ CHAPTER \h \r 1 

 

BAS 500-8

 

BAS 500-9

  SEQ CHAPTER \h \r 1 1-(3-chloro-4-hydroxyphenyl)-1H-pyrazol-3-ol

	

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, RABIII 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 (TXR # 0054636, DP Num: 341293, Y. Yang, 7/24/07).  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 RABIII 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 (DP Num: 343700, B. O’Keefe, 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 HED concluded that the FQPA
safety factor can be reduced to 1X.  The recommendation is based on the
following: 

The toxicity database for pyraclostrobin is complete with the exception
of the current 40 CFR 158.500 requirement for immunotoxicity data (OPPTS
780.7800). HED has evaluated the entire pyraclostrobin toxicity database
and has concluded that an additional uncertainty factor is not needed to
account for potential immunotoxicity.  Other than high-dose thymus
effects seen in the 90-day mouse study, there is no indication that the
immune system is a primary target and no evidence of
pyraclostrobin-induced immunotoxicity in adult animals or in the
offspring following prenatal and postnatal exposures.  The point of
departure for chronic exposure is 3.4 mg/kg/day and HED does not believe
that conducting a special series 870.7800 immunotoxicity study will
result in a NOAEL less than 3.4 mg/kg/day.

There is no indication that pyraclostrobin is a neurotoxic chemical and
there is no need for a developmental neurotoxicity study or additional
safety factors to account for neurotoxicity.

There is no evidence that pyraclostrobin results in increased
susceptibility in in utero rats or rabbits in the prenatal developmental
studies or in young rats in the 2-generation  reproduction study.
Although there is qualitative evidence of increased susceptibility in
the prenatal development study in rabbits, HED did not identify any
residual uncertainties after establishing toxicity endpoints and
traditional UFs to be used in the risk assessment of pyraclostrobin. The
degree of concern for prenatal and/or postnatal toxicity is low.

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 (DP Num: 343700, B.
O’Keefe, 9/7/07).  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 3.3.a 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 3.3.b.  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. Petition for New Uses and Tolerances on
Alfalfa.  Summary of Analytical Chemistry and Residue Data, PP# 9F7528,
DP Num: 367409, W. Cutchin, 10/29/09.

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 (PP# 0F6139, DP Num: 269668, L.
Cheng, 11/28/01).  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; DP Num: 278044, 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 (PP# 0F6139, DP Num: 269668, L. Cheng,
11/28/01).  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 

Plants 

Enforcement Method

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 (DP Num: 269668, L. Cheng, 11/28/01). 
Following the SOP (ACB-019) for reviewing tolerance methods (September
15, 2008), HED has determined that Method D9904 is suitable as an
enforcement method.

Data Gathering Method

In the current alfalfa field trials, samples of forage and hay were
analyzed for residues of pyraclostrobin and BF 500-3 (expressed as
parent) using an LC/MS/MS method (BASF Method D9908).  This method is
similar to one of the proposed enforcement methods and was first
reviewed in conjunction with assorted petitions covering a wide variety
of crops (DP Num: 281042, L. Cheng, 7/26/04).  The method is adequate
for data collection based on acceptable concurrent method recovery data.

Livestock

Enforcement Method

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 (DP Num: 269668, L. Cheng,
11/28/01).  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 (PP#s 8F7385, 8F7390, and 8E7394, DP Num: 356946. B.
O’Keefe, 4/30/09). 

For enforcing tolerances on poultry commodities, BASF has purposed use
of a LC/MS/MS Method D9902, which is similar to the method for ruminant
commodities (LC/MS/MS Method 446/1).  Method D9902 is also a common
moiety method that includes a base hydrolysis step.  The principle
difference between the two methods is that Method D9902 determines
residues of pyraclostrobin and its metabolites convertible to BF 500-5
or BF 500-9.  BF 500-9 is an isomer of BF 500-8, in which the hydroxyl
group is at a different position on the chlorophenyl ring.  Adequate
method validation data have been provided for Method D9902, and the
validated LOQ for each analyte is 0.05 ppm in eggs and poultry tissues,
for a combined LOQ of 0.1 ppm.  All residues are expressed in parent
equivalents.  This method was used for data collection in the poultry
feeding study.  However, an acceptable ILV trial and tolerance method
validation (TMV) is required for Method D9902 before it can be approved
for tolerance enforcement.

Multiresidue Methodology (860.1360)

Data pertaining to the multiresidue methods testing of pyraclostrobin
and its desmethoxy metabolite were previously reviewed (PP# 0F6139, DP
Num: 269668, L. Cheng, 11/28/01).  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 Protocols 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 

Adequate storage stability studies (PP#0F6139) are available indicating
that pyraclostrobin and metabolite BF 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 (DP Num: 269668, 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 submitted data on twelve alfalfa field trials to support of a new
use for pyraclostrobin on alfalfa.  Each test site included one control
plot and four treated plots that varied the number of pyraclostrobin
applications (2 or 3) and the treatment to harvest intervals (14 or 21
days).  The total application rate ranged from 0.29-0.44 lb ai/A.  All
applications were made using ground equipment at volumes of 20-34 gal/A,
and included the use of adjuvants.  With the exception of one test site,
three cuttings of alfalfa were harvested from each plot according to
typical agricultural practices, with the 3rd cutting being made at
normal maturity (beginning bloom stage).  The exact treatment-to-harvest
intervals for each cutting are presented below along with the residue
levels in forage and hay.  At each cutting, single control and duplicate
treated samples of alfalfa forage and hay were collected from each test,
with hay samples being field-dried to a moisture content of ~10-20%
prior to sampling.  After sampling, forage and hay samples were held in
frozen (<-5°C) storage for up to 13 months prior to extraction for
analysis.  This duration is supported by the available storage stability
data.

Samples of alfalfa forage and hay were analyzed for residues of
pyraclostrobin and its desmethoxy metabolite BF 500-3 using an adequate
LC/MS/MS method (BASF Method D9908).  The validated LOQ is 0.02 ppm for
each analyte in forage and hay, and the LOQ for combined residues is
0.04 ppm.

 

Overall, combined pyraclostrobin residues were higher in forage and hay
from the treatments using 3 applications rather than 2 applications, and
the residues were higher in forage and hay from treatments having the
~14-day PHI rather than the ~21-day PHI.  The worse-case treatment was
Treatment #2, and the highest residues in forage and hay were found in
the 1st and 2nd cuttings.  For Treatment #2, average combined residues
from the 1st and 2nd cuttings were 2.99 and 2.69 ppm for forage and 7.84
and 9.28 ppm for hay. 

TABLE 5.1.5  Summary of Combined Residue Data from Alfalfa Field Trials
with Pyraclostrobin (WDG).

Commodity	Total Applic. Rate

(lb ai/A)	Trt. No.1	Cutting	PHI (days)	Combined Residue Levels (ppm) 2

	n	Min.	Max.	HAFT 3	Median	Mean	Std. Dev.

Alfalfa (proposed use = 0.44 lb ai/A total application rate, 14-day PHI)

Alfalfa Forage	0.44-0.47	2 4	1st 	12-15	24	0.44	7.24	6.69	2.07	2.99	2.02

	2nd 	12-16	24	0.85	8.15	7.41	1.55	2.69	1.97

	3rd 	43-73	22	<0.04	0.24	0.21	0.07	0.09	0.06

	0.45-0.47	3	1st 	19-23	24	0.06	3.38	3.21	0.79	0.89	0.81

	2nd 	20-23	24	0.30	2.59	2.47	0.97	1.15	0.72

	3rd 	49-76	22	<0.04	0.18	0.18	0.06	0.08	0.04

	0.29-0.31	4	1st 	12-15	24	0.40	5.94	5.35	1.91	2.31	1.56

	2nd 	12-16	24	0.57	6.56	6.42	1.97	2.65	1.77

	3rd 	43-70	22	<0.04	0.18	0.18	0.05	0.08	0.05

	0.30-0.31	5	1st 	19-23	24	<0.04	3.03	3.00	0.67	0.80	0.79

	2nd 	20-23	24	0.23	2.87	2.78	1.03	1.12	0.63

	3rd 	49-76	22	<0.04	0.20	0.20	0.05	0.08	0.05

Alfalfa Hay	0.44-0.47	2 4	1st 	12-15	24	1.42	20.49	19.77	6.60	7.84	5.27

	2nd 	12-16	24	4.02	22.87	22.19	7.07	9.28	5.47

	3rd 	43-73	22	0.05	0.87	0.64	0.22	0.27	0.23

	0.45-0.47	3	1st 	19-23	24	0.08	18.75	16.87	2.27	3.44	4.45

	2nd 	20-23	24	1.31	8.01	7.72	3.56	3.57	1.89

	3rd 	49-76	22	<0.04	0.59	0.52	0.15	0.20	0.18

	0.29-0.31	4	1st 	12-15	24	1.28	15.83	15.28	6.37	7.44	4.44

	2nd 	12-16	24	2.77	18.81	17.93	7.86	8.59	4.51

	3rd 	43-70	22	0.05	0.46	0.42	0.12	0.18	0.13

	0.30-0.31	5	1st 	19-23	24	0.20	10.48	9.88	1.72	2.61	2.80

	2nd 	20-23	24	1.47	12.21	10.70	3.18	3.90	2.34

	3rd 	49-76	22	<0.04	0.56	0.51	0.13	0.20	0.17

1 	Treatments #2 and #3 included three pyraclostrobin applications at
~0.145 lb ai/A/application with the first and second applications made
prior to the 1st cutting and the final application made prior to the 2nd
cutting.  Treatments #4 and #5 included two applications at ~0.145 lb
ai/A/application, with the first application made prior to the 1st
cutting and the second application made prior to the 2nd cutting.

2	The combined LOQ for residues of pyraclostrobin and BF 500-3 is 0.04
ppm.  For purposes of calculating median and mean and standard
deviation, the LOQ (0.04 ppm) was used for residue values <LOQ.

3	HAFT = Highest Average Field Trial.

4	The residue data used to calculate tolerances for forage and hay are
bolded.

Conclusions:  The submitted alfalfa field trial data are adequate and
will support the use of pyraclostrobin, formulated as a WDG, for foliar
applications to alfalfa.  An adequate number of tests were conducted on
alfalfa in the appropriate geographic regions, and the tests were
conducted at ~1x the proposed use rate.  Samples were collected around
the proposed PHI and analyzed for residues of both parent and metabolite
BF 500-3 using an adequate LC/MS/MS method.  The field trial data are
also supported by the available storage stability data.  The available
field trial data support tolerances of 10 ppm for alfalfa forage and 30
ppm for alfalfa hay as determined by the MRL spreadsheet calculator.  A
revised Section F for the residues of pyraclostrobin on alfalfa forage
at 10 ppm and hay at 30 ppm is required.

Although no field trial data were submitted reflecting use of the
proposed EC formulation, previously submitted side-by-side field trials
on tomatoes, cucumbers, and grapes comparing WDG and EC formulations of
pyraclostrobin have shown that residues resulting from the two types of
formulations are similar (DP# 269668, L. Cheng, 11/28/01).  Therefore,
the available data for the WDG formulation will also cover the use of
the EC formulations on alfalfa.

Field trial data were not submitted to support the proposed seed
treatment use on alfalfa; however, no seed treatment residue data are
required as the seed treatment rate is negligible compared to the
proposed foliar applications.  Based on typical seeding rates for
alfalfa (2-20 lb seed/A), the maximum seed treatment rate (0.04 lb
ai/100 lb seed) would be equivalent to a field use rate of 0.008 lb
ai/A, compared to the maximum foliar rate of 0.44 lb ai/A.

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

HED does not require residue data for any processed commodities
associated with alfalfa.  Therefore, data requirements for processed
food and feed are not relevant to this tolerance petition.

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

As alfalfa forage and hay are major livestock feedstuffs, the dietary
burdens for livestock were recalculated for this petition.  Based on the
recent changes in calculating residues in reasonably balanced livestock
diets (ChemSAC memo, 6/30/08), the dietary burden for livestock to
pyraclostrobin residues was recalculated to be 6.1 ppm for beef cattle,
12.9 ppm for dairy cattle, 2.6 ppm for poultry, and 2.1 ppm for swine
(e-mail, J. Stokes, 10/7/09; Table 5.1.7).  

TABLE 5.1.7   Calculation of Maximum Reasonably Balanced Dietary Burdens
of Pyraclostrobin Residues for Livestock. 

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

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

	Alfalfa, hay	R	89	10	30	3.38

Cotton, gin byproducts	R	90	5	30	1.67

Barley, grain	CC	88	50	1.4	0.8

Sorghum, grain, grain 	CC	86	25	0.6	0.18

Sugarcane, molasses 	CC	75	5	0.4	0.03

Canola/sunflower, meal	PC	92	5	0.3	0.016

TOTAL BURDEN	--	--	100

6.1

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

	Alfalfa, hay	R	89	20	30	6.75

Sorghum, grain, forage	R	35	25	5.0	3.57

Apple, wet pomace	CC	40	10	8.0	2.0

Barley, grain	CC	88	35	1.4	0.56

Cotton, undelinted seed	PC	90	10	0.3	0.033

TOTAL BURDEN	--	--	100	--	12.9

	Poultry CC 75%, PC 25%

	Barley, grain	CC	88	75	1.4	1.05

Canola/sunflower, meal	PC	92	20	0.3	0.06

Alfalfa, meal	PC	89	5	30	1.5

TOTAL BURDEN	--	--	100	--	2.6

	Swine CC  85%, PC 15%

	Barley, grain	CC	88	5	1.4	0.07

Sorghum, grain, grain	CC	86	80	0.6	0.48

Canola/sunflower, meal	PC	92	10	0.3	0.03

Alfalfa, meal	PC	89	5	30	1.5

TOTAL BURDEN	--	--	100	--	2.1

   Comments:  

Sugarcane molasses was added to beef diet because of high dry matter. 
Makes feed more palatable.

Alfalfa meal added to poultry and swine diets as some premixed and
bagged supplement feeds contain this feedstuff. 

R = roughage, CC = carbohydrate concentrate, PC = protein concentrate
[PC

Livestock feeding studies

Adequate feeding studies were previously reviewed (PP#0F6139, DP Num:
269668, L. Cheng, 11/28/01).  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 the calculated dietary exposure of dairy cattle
(12.9 ppm) and the residue data from the mid-dose group (27.2 ppm; 2.1x
level) in the cattle feeding study, the maximum expected combined
pyraclostrobin residues in ruminant commodities would be <0.024 ppm in
milk, <0.056 ppm in milk fat, <0.1 ppm in kidney, muscle and fat, and
0.289 ppm in liver.  These data indicate that the existing tolerances of
0.1 ppm for milk, fat, and meat, 1.5 ppm for liver, and 0.2 ppm for meat
byproducts, except liver will not need to be increased by the proposed
use on alfalfa. 

Based on the calculated dietary exposure of swine (2.1 ppm) and the
residue data from the low-dose group (8.8 ppm; 4.1x level) in the cattle
feeding study, the maximum expected combined pyraclostrobin residues
would be <LOQ in all hog commodities.  Based on the mid-dose group (27.2
ppm; 13.0x level), combined pyraclostrobin residues would also be <LOQ
in hog fat, meat, and liver at a 13.0x feeding level.  The tolerances
for pyraclostrobin on swine will not be increased by the proposed use on
alfalfa. 

Based on the recalculated dietary burden for poultry (2.6 ppm), the
high-dose group in the poultry feeding study is now considered to be
equivalent to 1.1x the poultry dietary burden.  The combined residues of
pyraclostrobin and its metabolites convertible to BF 500-5 and BF 500-9
were <LOQ in eggs and all tissues; however, because there is no dose
group in the feeding study representing a 10x feeding level, ARIA can no
longer verify that residues in poultry commodities represent a Category
180.6(a)(3) situation.

 

To further assess the need for tolerances, ARIA and HED re-examined the
data from the poultry metabolism studies, in which hens were dosed at
levels equivalent to 12.1-12.7 ppm in the diet (~4.8x dietary burden)
for 7 consecutive days.  For poultry fat and liver, which had TRRs of
0.065-0.083 ppm and 0.317-0.474 ppm respectively, the identified
residues of pyraclostrobin and its metabolites potentially convertible
to BF 500-5 or BF 500-9 were totaled for both matrices.  At dose levels
equivalent to ~4.8x the poultry dietary burden, combined pyraclostrobin
residues were estimated to be 0.041-0.042 ppm in fat and 0.082-0.143 ppm
in liver.  When extrapolated to a 10x feeding level, combined residues
could be 0.088ppm in fat and 0.299 ppm in liver.  As the combined
residues of concern could be at or above the method LOQ (0.1 ppm) in the
poultry fat and liver following only 7 days of dosing at a 10x level, it
is not possible to establish with certainty whether finite residues will
be incurred in poultry fat and meat byproduct, but there is a reasonable
expectation of finite residues.  Therefore, tolerances should be
established for poultry fat and meat byproducts at the proposed
enforcement method LOQ (0.1 ppm).  

The levels of the TRR in muscle were ≤0.009 ppm and in eggs were
≤0.037 ppm at a ~4.8x feeding level.  Considering the levels of the
TRR levels in muscle (≤0.009 ppm) and eggs (≤0.037 ppm) at a ~4.8x
feeding level, quantifiable levels (≥0.1 ppm) of the residues of
concern would normally not be expected to occur in eggs and poultry meat
at a 10x feeding level.  However, as the poultry metabolism study was
only conducted for 7 days and the TRRs may not have reached a plateau,
it is not possible to establish with certainty whether finite residues
will not be incurred in poultry meat and eggs.  Therefore, tolerances
for egg and poultry meat should be established at the proposed
enforcement method LOQ (0.1 ppm).  A revised Section F for the residues
of pyraclostrobin on poultry meat, fat and meat byproducts, and eggs at
0.1 ppm is required. 

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, DP Num: 269668, L. Cheng, 11/28/01 & DP Num:
314519, L. Cheng, 5/05/05).  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 (DP Num: 278044, 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,
DP Num: 269668, 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 Alfalfa. DP Num: 362852, R. Miller;
10/14/09

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 Nums: 336190, 340588,
342584, G. Rothman, 9/6/07

EFED reviewed the proposed use rates associated with the Section 3
request for the use of pyraclostrobin on alfalfa.  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 ai/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	Revisions to Petitioned-for 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 it desmethoxy metabolite, BF
500-3.  The residues of concern in livestock include pyraclostrobin and
its metabolites convertible to BF 500-5 and BF 500-8. Tolerances are
currently established for the combined residues of pyraclostrobin and BF
500-3, expressed as parent, in plant commodities at levels ranging from
0.02 ppm in/on wheat grain to 30 ppm in/on cotton gin byproducts [40 CFR
§180.582(a)(1)].  Tolerances for livestock commodities are established
for the combined residues of pyraclostrobin and its metabolites
convertible to BF 500-5 and BF 500-8, each expressed as parent, at
levels ranging from 0.1 ppm in milk, meat, and fat to 1.5 ppm in liver
of cattle, goats, hogs, and sheep [40 CFR §180.582(a)(2)].  No
tolerances are established for poultry commodities or rotational crops. 
The tolerances being proposed by BASF for the current petition are
listed in Table 5.1.10, along with ARIA’s recommended tolerances.  

It is recommended that the tolerance expressions [40 CFR §
180.474(a)(1), 40 CFR §180.474 (a)(2), and 40 CFR §180.474 (b)] be
amended to reflect the new Interim Guidance on Tolerance Expressions (S.
Knizner, 05/27/09).  The existing language for 40 CFR § 180.582(a)(1)
is:

(a) General. (1) Tolerances are established for combined residues of the
fungicide expressed as parent compound, in or on the following raw
agricultural commodities.

The above quoted phrase should be replaced with the following:

a)  General. (1)  Tolerances are established for residues of the
fungicide pyraclostrobin, including its metabolites and degradates, in
or on the commodities in the table below.  Compliance with the tolerance
levels specified below is to be determined by measuring only the sum of
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]phenylcarbama
te), calculated as the stoichiometric equivalent of pyraclostrobin, in
or on the commodity.

The existing language for 40 CFR § 180.582(a)(2) is 

(2) Tolerances are established for combined residues of the fungicide
pyraclostrobin carbamic acid,
[2-[[[1-(4-chlorophenyl)-1H-pyrazol-3-yl]oxy]methyl]phenyl]methoxy-,
methyl ester 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, in or on the following raw agricultural commodities.

The above quoted phrase should be replaced with the following:

(2) Tolerances are established for residues of the fungicide
pyraclostrobin, including its metabolites and degradates, in or on the
commodities in the table below.  Compliance with the tolerance levels
specified below is to be determined by measuring only those
pyraclostrobin (carbamic acid,
[2-[[[1-(4-chlorophenyl)-1H-pyrazol-3-yl]oxy]methyl]phenyl]methoxy-,
methyl ester) residues convertible to 1-(4-chlorophenyl)-1H-pyrazol-3-ol
and 1-(4-chloro-2-hydroxyphenyl)-1H-pyrazol-3-ol, expressed as the
stoichiometric equivalent of pyraclostrobin, in or on the commodity.

The existing language for 40 CFR § 180.582(b) is 

(b) Section 18 emergency exemptions. A time-limited tolerance is
established for 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) pyrazol-3-yl]oxy]o-tolyl]carbamate) in
connection with use of the pesticide under section 18 emergency
exemptions granted by EPA. The time-limited tolerance will expire and is
revoked on the date specified in the following table. 

The above quoted phrase should be replaced with the following:

(b) Section 18 emergency exemptions. A time-limited tolerance is
established for residues of the fungicide pyraclostrobin, including its
metabolites and degradates, in or on the commodities in the table below.
 Compliance with the tolerance levels specified below is to be
determined by measuring only those pyraclostrobin (carbamic acid,
[2-[[[1-(4-chlorophenyl)-1H-pyrazol-3-yl]oxy]methyl]phenyl]methoxy-,
methyl ester) residues convertible to 1-(4-chlorophenyl)-1H-pyrazol-3-ol
and 1-(4-chloro-2-hydroxyphenyl)-1H-pyrazol-3-ol, expressed as the
stoichiometric equivalent of pyraclostrobin, in or on the commodity in
connection with use of the pesticide under section 18 emergency
exemptions granted by EPA. The time-limited tolerance will expire and is
revoked on the date specified in the following table.

Note to PM:  The tolerance for horse liver was established at 0.1 ppm in
40CFR 180.582(a)(2). However, the tolerance was established in error. 
The body of the FR Notice indicates that the tolerance was intended to
be 1.5 ppm while the final table lists 0.1 ppm ([FR Doc. 02-24487, Filed
9/26/02).  This should be corrected.

An adequate number of alfalfa field trials conducted at ~1x the proposed
use rate are available to support permanent tolerances.  The Agency’s
SOP “Guidelines for Setting Pesticide Tolerances Based on Field Trial
Data” was utilized for determining the appropriate tolerances
(Appendix II).  For alfalfa forage and hay, residue data from both the
1st and 2nd cuttings of Treatment #2 (1x rate) were used to assess
tolerances as both cuttings were collected around the proposed 14-day
PHI, and residue levels were similar for the two cuttings.  The
recommended tolerances for alfalfa forage and hay are 10 and 30 ppm,
respectively as determined by the MRL spreadsheet calculator.

With regards to the current tolerances for livestock commodities, the
existing tolerances are adequate for milk, meat, fat, liver, and meat
byproducts (except liver) of cattle, goats, horses, sheep, and hogs.  

Based on the recalculated dietary burden for poultry and data from the
poultry feeding and metabolism studies, it is not possible to establish
with certainty whether finite residues will be incurred in poultry
commodities, but the residues of concern could occur ≥LOQ at a 10x
feeding level.  Therefore, tolerances should be established for poultry
meat, fat and meat byproducts, and eggs at the proposed enforcement
method LOQ (0.1 ppm).  The tolerances for poultry commodities should be
established under 180.582(a)(3), and the tolerance expression should
read as follows:  

“Tolerances are established for combined residues of the fungicide
pyraclostrobin carbamic acid,
[2-[[[1-(4-chlorophenyl)-1H-pyrazol-3-yl]oxy]methyl]phenyl]methoxy-,
methyl ester and its metabolites convertible to
1-(4-chlorophenyl)-1H-pyrazol-3-ol and
1-(3-chloro-4-hydroxyphenyl)-1H-pyrazol-3-ol, expressed as parent
compound, in or on the following raw agricultural commodities.”

TABLE 5.1.10 	Tolerance Summary for Pyraclostrobin.

Commodity	Proposed/ Established

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

40 CFR 180.582(a)(1)

Alfalfa, Forage	9	10	Adequate alfalfa forage and hay residue data are
available.  The tolerances were calculated using the tolerance
harmonization spreadsheet and the residue data from the 1st and 2nd
cuttings of Treatment #2.

Alfalfa, Hay	27	30

	40 CFR 180.582(a)(3) 1

Poultry, fat	None	0.1	Based on the calculated dietary burden for poultry
and the data from the poultry feeding and metabolism studies, tolerances
are required at the method LOQ.

Poultry, meat byproducts	None	0.1

	Poultry, meat	None	0.1

	Eggs	None	0.1

	1	For poultry commodities, tolerances should be expressed as the
combined residues of the pyraclostrobin and its metabolites convertible
to 1-(4-chlorophenyl)-1H-pyrazol-3-ol (BF 500-5) and
1-(3-chloro-4-hydroxyphenyl)-1H-pyrazol-3-ol (BF 500-9), expressed as
parent compound. 

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
Alfalfa. PP# 9F7528, DP Num: 369379, W. Cutchin, 10/30/09

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 5.2.  Combined dietary exposure from food and
drinking water at the 95th percentile of exposure is estimated to be 2%
of the 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 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; DP Num: 362519, A. Grube, 3/17/09) 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 for the general U.S. population at 8%
cPAD and 24%, of the cPAD for children 1-2 yrs, the population subgroup
with the highest estimated chronic dietary exposure to pyraclostrobin.  

Table 5.2     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	0.044524	2	0.002674	8	A separate quantitative
cancer risk assessment is not required.  

All Infants (< 1 year old)	0.063536	2	0.003752	11

	Children 1-2 years old	0.076338	3	0.008265	24

	Children 3-5 years old	0.066375	2	0.006119	18

	Children 6-12 years old	0.047154	2	0.003496	10

	Youth 13-19 years old	0.035370	1	0.002064	6

	Adults 20-49 years old	0.039340	1	0.002062	6

	Adults 50+ years old	0.041949	1	0.002269	7

	Females 13-49 years old	0.040480	81	0.001855	6

	

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.
 ARIA 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 

Reference: Occupational and Residential Risk Assessment to Support
Request for a Section 3 Registration of Pyraclostrobin on a Variety of
Crops and Residential Turf.  DP Num: 298017, K. O’Rourke, 8/19/04

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.  Residential and recreational turf applications are applied by
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 an 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, ARIA 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 7.0 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 7.0  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	

0.008265	

330	

120

Adults	

5	

0.019	

260	

5	

NA	

0.002674	

1900	

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 – Human, Occupational Exposure/Risk
Assessment for the Proposed Use as Foliar and Seed Treatments on
Alfalfa.  DP Num: 366927, M. Dow, 7/23/09

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

Occupational pesticide handlers may experience short- and
intermediate-term exposure to pyraclostrobin.  No chemical specific data
were available with which to assess potential exposure to pesticide
handlers.  The estimates of exposure to pesticide handlers are based
upon surrogate study data available in the PHED (v. 1.1, 1998).  In
addition, seed treatment handlers and occupational secondary handlers
may experience short- and intermediate-term exposure while planting
pyraclostrobin-treated alfalfa seeds.  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.  For seed uses, the amount of active ingredient
handled depends on the application rate 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.  

The alfalfa foliar applications are requested amendments to Headline®
Fungicide (EPA Reg. No. 7969-186) which is formulated as a 2.09 lb ai
(23.6%) pyraclostrobin per gallon emulsifiable concentrate liquid.  The
rate of application ranges from 6-9 fl oz/A (0.098-0.147 lb ai/A). 
There is a maximum of 3 applications per season.  There is a maximum of
0.45 lb ai/A/season with a PHI of 14 days.  Repeat applications may be
made at 14-21 day intervals.  No more than 2 applications should be made
per cutting or 3 applications per season.  The restricted entry interval
(REI) is 12 hours.  The product may be applied aerially, by ground spray
machinery or via irrigation systems (chemigation).

The seed treatment use is a requested amendment to the product StaminaTM
Fungicide Seed Treatment (EPA Reg. No. 7969-266).  StaminaTM is
formulated as a 1.67 lb ai (18.4%) pyraclostrobin per gallon liquid. 
StaminaTM is currently registered as a seed treatment for barley,
Brassicas, bulb vegetables, corn, cotton, cucurbits, legume vegetables,
peanut, rye, soybean, sugar beet, sunflower, and wheat.  The proposed
rate of application to alfalfa seed is 1.5-3.1 fl oz/cwt seed which is
the same rate at which cotton seed is treated.  

In the Agency’s 2009 assessment (PP#s 8F7385, 8F7390, and 8E7394, DP
Num: 356946. B. O’Keefe, 4/30/09) , short-term and intermediate-term
duration dermal toxicological endpoints were identified.  The Agency
indentified a dermal absorption rate of 14% to extrapolate dermal
exposure from an oral study.  A 60 kg body weight is used to calculate
risk from dermal exposure.  The Agency also identified short- and
intermediate-term duration inhalation toxicological endpoints.  A 70 kg
body weight is used to calculate risk from inhalation exposure.  HED and
ARIA assume 100% absorption via the inhalation route of exposure.

The Agency’s level of concern for occupational dermal and inhalation
exposure is an MOE < 100.  See the Table 3.3.a for a summary of
toxicological endpoints used for risk assessment.  

Foliar Use

Based upon the proposed use pattern, RD believes the most highly exposed
occupational pesticide handlers will be: 1) mixer/loader using open pour
loading of liquids, 2) applicator using open cab ground boom sprayer, 3)
aerial applicator, and 4) flagger.

Private (i.e., grower) applicators may perform all functions, that is,
mix, load and apply the material.  The ExpoSAC standard procedure
directs that although the same individual may perform all those tasks,
they shall be assessed separately.  By separating the job functions,
HED/RD determine the most appropriate levels of personal protective
equipment (PPE) for each aspect of the job without requiring an
applicator to wear unnecessary PPE that might be required for a
mixer/loader (e.g., chemical resistant gloves may only be necessary
during the pouring of a liquid formulation).  These exposure scenarios
are outlined in the Pesticide Handler Exposure Database (PHED) Surrogate
Exposure Guide (August 1998).  Most exposure scenarios for hand-held
equipment (such as hand wands, backpack sprayers, and push-type granular
spreaders) are assessed as a combined job function.  With these types of
hand held operations, all handling activities are assumed to be
conducted by the same individual.

See Table 9.1.a for a summary of exposures and risks to occupational
handlers.  

Table 9.1.a  Summary of Exposure & Risk to Occupational Handlers From
Applying Pyraclostrobin to Alfalfa

Unit Exposure1

mg ai/lb handled	Applic. Rate2

lb ai/unit	Units Treated3	Avg. Daily Exposure4

mg ai/kg bw/day	MOE5

Mixer/Loader – Liquid- Open Pour

Dermal:

SLNoGlove      2.9 SLWithGlove   0.023 

Inhal.            0.0012 

Inhal.DMR*  0.00024	0.147

lb ai/A	1200 A/day	Dermal:

SLNoGlove    1.19

SLWithGlove 0.00945

Inhal.              0.00302

                       0.0006048	No Glove

4

With Glove

530

76

380

Applicator – Ground-boom - Open-cab

Dermal:

SLNoGlove       0.014 

SLWithGlove    0.014 

Inhal.              0.00074 	0.147

lb ai/A	200 A/day	Dermal:

SLNoGlove    0.00096

SLWithGlove 0.00096

Inhal.              0.00031	No Glove

5,200

With Glove

5,200

742

Aerial Applicator (Pilots not required to wear gloves)

Dermal:

SLNoGlove       0.005

Inhal.               0.000068	0.147

lb ai/A	1200 A/day	Dermal:

SLNoGlove    0.00206

Inhal.              0.000171	No Glove

2400

1,345

Flagger

Dermal:

SLNoGlove       0.012

Inhal.               0.00035	0.147

lb ai/A	350 A/day	Dermal:

SLNoGlove    0.00144

Inhal.              0.000257	No Glove

3,500

900

1.  Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE”,
Estimates of Worker Exposure from The Pesticide Handler Exposure
Database Version 1.1, August 1998.    Dermal = Single Layer Work
Clothing No Gloves; Single Layer Work Clothing With Gloves;  Inhal. =
Inhalation.  Units = mg a.i./pound of active ingredient handled.  

2.  Applic. Rate. = Taken from proposed label.

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

4.  Average Daily Dose = Unit Exposure * Applic. Rate * Units Treated *
14% dermal absorption  ( 60 kg body wt for  dermal and 70 kg Body Weight
for inhalation

5.  MOE = Margin of Exposure = NOAEL  ( ADD.   Dermal NOAEL = 5.0 mg/kg
bw/day; inhalation NOAEL = 0.23 mg/kg bw/day.

* Dust Mist Respirator

A MOE of 100 is adequate to protect occupational pesticide handlers from
exposures to pyraclostrobin.  The dermal exposure MOE for a mixer/loader
is < 100 if protective gloves are not worn.  The product label directs
applicators and other handlers to wear protective gloves.  In addition,
the inhalation MOE for a mixer/loader supporting aerial operations at
1200 A treated/day, is < 100.  

In order to support aerial operations of 1200 A treated/day, additional
respiratory protection is needed.  HED standard procedure, based on
study data in the PHED, indicates a dust/mist filtering respirator will
reduce inhalation exposure by 80%.  An 80% reduction in the mixer/loader
inhalation exposure results in a MOE > 100 and thus not exceeding the
level of concern.  

Dermal MOEs are > 100 provided mixer/loaders use protective gloves as
specified on the product label.  Inhalation MOEs are > 100 if
mixer/loaders support approximately 600 acres treated per day or if they
use a dust/mist filtering respirator while supporting aerial
applications of 1200 A treated/day.  

Seed Treatment

RD in consultation with HED and the registrant, determined that
commercial treatment of alfalfa seeds occurs by one of two methods: 1) a
coated/prilled method at a capacity of about 2,000 lbs/hr, 8 hours/day
thus approximately 16,000 lb seed might be treated per day, or 2)
continuously, at a low rate per hour, approximately 96,000 lb of seed
might be treated per day.  As a conservative, screening level
assessment, ARIA uses the high rate of application (3.1 fl oz
formulation/cwt seed) combined with the highest rate of seed treated per
day (96,000 lb).

The quantitative exposure and risk assessment developed for occupational
handlers involved in commercial application to alfalfa seed is based on
the following exposure scenarios: 1) loading the pesticide into seed
treatment equipment and applying to alfalfa seeds
(“loader/applicator”), 2) loading seeds into bags (“bagger”), 3)
sewing seed bags (“sewer”), and 4) 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 alfalfa
seed.

Summaries of the exposures and risks for handlers involved in commercial
application of pyraclostrobin to alfalfa seed and planting treated
alfalfa seed are included in Table 9.1.b below.  The maximum application
rate for each exposure scenario is presented.  All seed treatment
activities result in MOEs greater than the LOC of 100 and are not of
concern.  

The dermal risks to handlers are not a concern with baseline attire
(i.e., long-sleeve shirt, long pants, shoes, and socks) for baggers and
sewers.  There are no data to estimate dermal exposure and risk at
baseline attire for loader/applicators, multiple activities, and
planter.  The dermal risks are not a concern at baseline attire plus
chemical-resistant gloves for handlers using baseline attire (no
respirator).   

It should be noted that, lacking crop specific information regarding the
amount of seed that might be treated in a working day, HED uses a
default of 718,000 lb of seed treated per day.  If that default is used
in this assessment, a worker involved in “multiple tasks” (see Table
9.1.b) would have a “baseline” (i.e., no personal protective
equipment) inhalation MOE less than 100.  That exceeds the Agency’s
level of concern.  As Standard Operating Procedure, HED uses data that
are in the PHED which indicate the use of a dust/mist filtering
respirator will reduce inhalation exposure to contaminated dusts by a
factor of 80%.  Thus, a worker involved in “multiple tasks” and who
uses a dust/mist filtering respirator will have a MOE greater than 100
and would not exceed the Agency’s levels of concern. 

TABLE 9.1.b  Pyraclostrobin Seed Treatment Handler Exposures and Risks
– Alfalfa Seed

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

(lb ai/100 lb	Unit Exposuresc 	Dermal Doses and MOEsg

(LOC MOE = 100)	Inhalation Dosesh and MOEsj

(LOC MOE = 100)

	Dermal Baselined (mg/lb ai) 	Dermal PPE-Ge (mg/lb ai) 	Inhalation
Baselinef (mg/lb ai)	Baseline Dose	Baseline MOE  	 PPE-G Dose 	PPE-G MOE
	Baseline Dose	Baseline MOEj  

Loader/ Applicator	96,000	0.04	No Data	0.023	0.00034	No Data	No Data
2.061E-3	2426	1.87E-4	1,230

Sewer

	0.0062	No Data	0.00023	5.55E-4	9000	No Data	No Data	1.26E-4	1,825

Bagger

	0.0091	No Data	0.00016	8.15E-4	6132	No Data	No Data	8.778E-5	2,620

Multiple Activities

	No Data	0.042	0.0016	No Data	No Data	3.76E-3	1330	8.777E-4	262

Planter 

(Secondary Handler)	4,000	0.04	No Data	0.25	0.0034	No Data	No Data
9.3E-4	5400	7.8E-5	3,000

The amount of seed treated or planted per day are from HED consultation
with the registrant. 

Application rates are the maximum application rates determined from
proposed labels for pyraclostrobin.  Application rate = lb ai/hundred lb
seed (cwt).

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.

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

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

i. 	Inhalation daily dose (mg/kg/day) = daily unit exposure (mg/lb ai) 
x (lb ai/lb seed) x cwt seed treated or planted per day  ÷  body weight
(60 kg for dermal exposures and 70 kg for inhalation exposures).

j.	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 

It is possible for agricultural workers to have post-application
exposure to pesticide residues during the course of typical agricultural
activities.  HED in conjunction with the Agricultural Re-entry Task
Force (ARTF) has identified a number of post-application agricultural
activities that may occur and which may result in post-application
exposures to pesticide residues.  HED has also identified transfer
coefficients (TC) (cm²/hr) relative to the various activities which
express the amount of foliar contact over time, during each of the
activities identified.   

The highest (i.e., most conservative) TC for all the proposed new uses
is 1,500 cm2/hr for scouting.  As a “screening” level assessment, RD
herein uses the TC of 1,500 cm2/hr for scouting alfalfa.

The TCs used in this assessment are from HED Policy # 3.1.  It is the
intention of HED’s ExpoSAC that this SOP will be periodically updated
to incorporate additional information about agricultural practices in
crops and new data on transfer coefficients.  Much of this information
will originate from exposure studies currently being conducted by the
ARTF, from further analysis of studies already submitted to the Agency,
and from studies in the published scientific literature.

Lacking compound specific dislodgeable foliar residue (DFR) data, HED
assumes 20 % of the application rate is available as dislodgeable foliar
residue on day zero after application.  This is adapted from the ExpoSAC
SOP No. 003 (7 May 1998 - Revised 7 August 2000).  

The following convention may be used to estimate post-application
exposure.  

Average Daily Dose (ADD) (mg a.i./kg bw/day) = DFR µg/cm2 * TC cm2/hr *
hr/day * 0.001 mg/µg * 1/60 kg bw 

 and where:

Surrogate Dislodgeable Foliar Residue (DFR) = application rate * 20%
available as dislodgeable residue * (1-D)t * 4.54 x 108 µg/lb * 2.47 x
10-8 A/cm2 .  

0.147 lb a.i./A * 0.20 * (1-0)0 * 4.54 x 108 µg/lb *  2.47 x10-8 A/cm²
= 0.3297 µg/cm2 , therefore,

0.3297µg/cm2 * 1,500 cm2/hr * 8 hr/day * 0.001 mg/µg * 0.14 (14 %
dermal absorption) ( 60 kg bw = 0.00923 mg/kg bw/day.

MOE = NOAEL ( ADD then 5.0 mg/kg bw/day ( 0.00923 mg/kg bw/day = 540.

A MOE of 100 is adequate to protect agricultural workers from
post-application exposures.  The most conservative estimate (i.e.,
highest exposure/risk) of post-application exposure results in MOEs >
100.  Therefore, the proposed risk does not exceed ARIA/RDs level of
concern.  

Restricted Entry Interval (REI)

Pyraclostrobin is classified in Acute Toxicity Category II for acute
inhalation toxicity.  It is classified in Toxicity Category III for
acute dermal toxicity, primary eye irritation and primary skin
irritation.  It is not a skin sensitizer.  

As the Agency noted in its 2009 assessment:  “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 [in this case alfalfa] 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.

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 

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

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

The proposed LC/MS/MS tolerance enforcement method for poultry
commodities (BASF Method D9902) must undergo an acceptable Independent
Laboratory Validation (ILV) and Tolerance Method Validation (TMV) prior
to being approved as an enforcement method.

Analytical standards for BF 500-5, BF 500-8 and BF 500-9, which are the
common moiety analytes determined by the livestock commodity enforcement
methods, must be submitted to the EPA National Pesticide Standards
Repository.

A revised Section F for the residues of pyraclostrobin on alfalfa forage
at 10 ppm and alfalfa hay at 30 ppm is required.

Based on the calculated dietary burden for poultry and data from the
poultry feeding and metabolism studies, tolerances should be established
for poultry meat, fat and meat byproducts, and eggs each at 0.1 ppm. 
Poultry tolerances for poultry commodities should be established under
180.582(a)(3), and the tolerance expression should read as follows:

“Tolerances are established for 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 metabolites convertible to
1-(4-chlorophenyl)-1H-pyrazol-3-ol and
1-(3-chloro-4-hydroxyphenyl)-1H-pyrazol-3-ol, expressed as parent
compound, in or on the following raw agricultural commodities.”

	A revised Section F is required

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

None

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

There are currently no proposed or established Codex, Canadian, or
Mexican Maximum Residue Limits (MRLs) for residues of pyraclostrobin on
alfalfa.  However, there are Canadian MRLs for various livestock
commodities, including poultry meat, meat byproducts and eggs.  The U.S.
tolerance and Canadian MRL expressions are the same for both plant and
livestock commodities, but several of the recommended changes in
tolerances on livestock commodities will result in differences between
the U.S. tolerances and the respective Canadian MRLs.



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

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



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

Appendix A3.: Subchronic, Chronic and Other Toxicity Profile

  TC \l2 "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

LOAEL = 34.7 mg/kg/day based on ↓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

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

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)

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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 = 300/1000 mg/kg

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)



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

	The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes
functional immunotoxicity testing, and is designed to evaluate the
potential of a repeated chemical exposure to produce adverse effects
(such as suppression) on the immune system.  Immunosuppression is a
deficit in the ability of the immune system to respond to a challenge of
bacterial or viral infections, 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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