Document ID: EPA-HQ-OPP-2006-0522-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-09-26T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF	

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: 09/07/2007

MEMORANDUM

SUBJECT:	Revised Pyraclostrobin: Human Health Risk Assessment for
Proposed Uses on Cotton and Belgian Endive. PC Code: 099100, Petition
Nos.: 5F7002 and 5E7014.  DP Number 343700.

		Regulatory Action: Registration Action New Section 3 Uses

		Risk Assessment Type: Single Chemical Aggregate

FROM:	Barry O’Keefe, Risk Assessor/Senior Biologist

		Registration Action Branch 3

		Health Effects Division (7509P)

		

THROUGH:	Paula Deschamp, Branch Chief

		Registration Action Branch 3

		Health Effects Division (7509P)

TO:	Barbara Madden, Team Leader

		Minor Use, Inerts and Emergency Response Branch (MUIERB)

		Registration Division (RD) (7505P)

			AND

	John Bazuin/Tony Kish, PM Team 22

		Fungicide Branch

		Registration Division (RD) (7505P)

This memorandum amends the recently completed HED risk assessment
document D326207, by B. O’Keefe, dated 06/25/07, i.e.,
“Pyraclostrobin: Human Health Risk Assessment for Proposed Uses on
Cotton and Belgian Endive. PC Code: 099100, Petition Nos.: 5F7002 and
5E7014.  DP Numbers 326207 and 327899.”   The recently completed risk
assessment document did not include intermediate-term aggregate risk
calculations and characterization.  However, these omissions do not
alter the risk findings expressed in the document.  While both short-
and intermediate-term exposures may occur during postapplication
activities for adults and children, the document only presented
short-term aggregate risk calculations for children 1-2 years of age. 
However, additional risk calculations for intermediate-term exposures
are not needed, because the toxicity endpoints and points of departure
are identical for short- and intermediate-term exposures.  The omitted
short-/intermediate-term aggregate risk calculations for adults have now
been computed and included in this revised risk assessment document.  

BASF Corporation submitted a petition (5F7002) for the establishment of
permanent tolerances for residues of pyraclostrobin (carbamic acid,
[2-[[[1-(4-chlorophenyl)-1H-pyrazol-3-yl]oxy]methyl]phenyl]methoxy-,
methyl ester) and its desmethoxy metabolite
(methyl-N-[[[1-(4-chlorophenyl) pyrazol-3-yl]oxy]o-tolyl] carbamate),
expressed as parent compound, in/on cotton, undelinted seed and cotton,
gin byproducts.  The petition also requested to increase the tolerance
on berries, group 13.

The Interregional Research Project No. 4 (IR-4) submitted a petition
(5E7014) for the establishment of a permanent tolerance for residues of
pyraclostrobin (carbamic acid,
[2-[[[1-(4-chlorophenyl)-1H-pyrazol-3-yl]oxy]methyl]phenyl]methoxy-,
methyl ester) and its desmethoxy metabolite
(methyl-N-[[[1-(4-chlorophenyl) pyrazol-3-yl]oxy]o-tolyl] carbamate),
expressed as parent compound, in/on Belgian endive. 

A summary of the findings and an assessment of human risk resulting from
the registered and proposed tolerances for pyraclostrobin are provided
in this document.  The risk assessment was provided by Barry O’Keefe
(RAB3), the residue chemistry data review by Jerry Stokes (RRB4), the
dietary risk assessment by Leung Cheng (RAB3), the hazard
characterization by Ghazi Dannan (RAB3), and the
occupational/residential exposure assessment by Jack Arthur (RAB3).

Note: Several deficiencies were noted in the subject petition (5E7014)
that preclude establishing a permanent tolerance for pyraclostrobin on
the proposed commodity Belgian endive.  Most importantly, the
application method used in the field residue trials does not agree with
the proposed use pattern, and the residue data generated from these
trials therefore do not support the proposed tolerance.  However, the
estimated risk from occupational exposure is not of concern.

Table of Contents

  TOC \f  1.0	Executive Summary	  PAGEREF _Toc176937523 \h  5 

2.0	Ingredient Profile	  PAGEREF _Toc176937524 \h  11 

2.1	Summary of Registered/Proposed Uses	  PAGEREF _Toc176937525 \h  11 

2.2	Physical and Chemical Properties	  PAGEREF _Toc176937526 \h  11 

3.0	Hazard Characterization/Assessment	  PAGEREF _Toc176937527 \h  14 

3.1	Hazard and Dose-Response Characterization	  PAGEREF _Toc176937528 \h
 14 

3.1.1	Database Summary	  PAGEREF _Toc176937529 \h  14 

3.1.1.1	Studies available and considered (animal, human, general
literature)	  PAGEREF _Toc176937530 \h  14 

3.1.1.2	Mode of action, metabolism, toxicokinetic data	  PAGEREF
_Toc176937531 \h  14 

3.1.1.3	Sufficiency of studies/data	  PAGEREF _Toc176937532 \h  15 

3.1.2	Toxicological Effects	  PAGEREF _Toc176937533 \h  16 

3.1.3	Dose-response	  PAGEREF _Toc176937534 \h  18 

3.2	FQPA Considerations	  PAGEREF _Toc176937535 \h  19 

3.2.1	Adequacy of the Toxicity Database	  PAGEREF _Toc176937536 \h  20 

3.2.2	Evidence of Neurotoxicity	  PAGEREF _Toc176937537 \h  20 

3.2.3	Developmental Toxicity Studies	  PAGEREF _Toc176937538 \h  20 

3.2.4	Reproductive Toxicity Study	  PAGEREF _Toc176937539 \h  21 

3.3	Safety Factor for Infants and Children	  PAGEREF _Toc176937540 \h 
21 

3.4	Hazard Identification and Toxicity Endpoint Selection	  PAGEREF
_Toc176937541 \h  22 

3.4.1    Acute Reference Dose (aRfD) - Females age 13-49	  PAGEREF
_Toc176937542 \h  23 

3.4.2	Acute Reference Dose (aRfD) - General Population	  PAGEREF
_Toc176937543 \h  24 

3.4.3	Chronic Reference Dose (cRfD)	  PAGEREF _Toc176937544 \h  25 

3.4.4	Incidental Oral Exposure (Short- and Intermediate-Term)	  PAGEREF
_Toc176937545 \h  26 

3.4.5	Dermal Absorption	  PAGEREF _Toc176937546 \h  27 

3.4.6	Dermal Exposure (Short- and Intermediate-Term)	  PAGEREF
_Toc176937547 \h  28 

3.4.7	Dermal Exposure (Long-Term)	  PAGEREF _Toc176937548 \h  29 

3.4.8	Inhalation Exposure (Short-, Intermediate- and Long-Term)	 
PAGEREF _Toc176937549 \h  29 

3.4.9	Level of Concern for Margin of Exposure	  PAGEREF _Toc176937550 \h
 31 

3.4.10	Recommendation for Aggregate Exposure Risk Assessments	  PAGEREF
_Toc176937551 \h  32 

3.4.11	Classification of Carcinogenic Potential	  PAGEREF _Toc176937552
\h  32 

3.4.12	Summary of Toxicological Doses and Endpoints for Pyraclostrobin
for Use in Human Risk Assessments	  PAGEREF _Toc176937553 \h  32 

3.5	Endocrine disruption	  PAGEREF _Toc176937554 \h  36 

4.0	Dietary Exposure/Risk Characterization	  PAGEREF _Toc176937555 \h 
36 

4.1  Pesticide Metabolism and Environmental Degradation	  PAGEREF
_Toc176937556 \h  37 

4.1.1	Metabolism in Primary Crops	  PAGEREF _Toc176937557 \h  37 

4.1.2	Metabolism in Livestock	  PAGEREF _Toc176937558 \h  37 

4.1.3	Analytical Methodology	  PAGEREF _Toc176937559 \h  37 

4.1.4	Storage Stability Data	  PAGEREF _Toc176937560 \h  38 

4.1.5	Magnitude of the Residue in Plants	  PAGEREF _Toc176937561 \h  39 

4.1.6	Magnitude of the Residue in Processed Food/Feed	  PAGEREF
_Toc176937562 \h  44 

4.1.7	Magnitude of the Residue in Meat, Milk, Poultry, and Eggs	 
PAGEREF _Toc176937563 \h  44 

4.1.8	Confined and Field Accumulation in Rotational Crops	  PAGEREF
_Toc176937564 \h  47 

4.1.9	Drinking Water Residue Profile	  PAGEREF _Toc176937565 \h  47 

4.1.10	Proposed Tolerances	  PAGEREF _Toc176937566 \h  48 

4.2  Dietary Exposure and Risk	  PAGEREF _Toc176937567 \h  49 

4.3 Anticipated Residue and Percent Crop Treated (%CT) Information	 
PAGEREF _Toc176937568 \h  54 

5.0	Residential (Non-Occupational) Exposure/Risk Characterization	 
PAGEREF _Toc176937569 \h  54 

6.0	Aggregate Risk Assessments and Risk Characterization	  PAGEREF
_Toc176937570 \h  55 

7.0	Cumulative Risk Characterization/Assessment	  PAGEREF _Toc176937571
\h  56 

8.0	Occupational Exposure/Risk Pathway	  PAGEREF _Toc176937572 \h  56 

8.1	Short-/Intermediate-Term Handler Risk	  PAGEREF _Toc176937573 \h  57

8.2	Short-/Intermediate-/Long-Term Postapplication Risk	  PAGEREF
_Toc176937574 \h  61 

9.0	Data Needs and Label Requirements	  PAGEREF _Toc176937575 \h  66 

9.1	Residue Chemistry Data Needs and Label Recommendations	  PAGEREF
_Toc176937576 \h  66 

9.2	Occupational and Residential Exposure	  PAGEREF _Toc176937577 \h  67

10.0	Tolerance Summary	  PAGEREF _Toc176937578 \h  67 

11.0	Appendix: Toxicity Profile	  PAGEREF _Toc176937579 \h  70 

11.1	Appendix 1.: Pyraclostrobin Toxicology Requirements and Available
Studies for Food Uses	  PAGEREF _Toc176937580 \h  70 

11.2	Appendix 2.: Acute Toxicity Data on Pyraclostrobin Technical	 
PAGEREF _Toc176937581 \h  71 

11.3	Appendix 3.: Subchronic, Chronic and Other Toxicity Profile	 
PAGEREF _Toc176937582 \h  72 

 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] (CAS nomenclature) 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, citrus, corn (field, pop and sweet),
cucurbit vegetables, fruiting vegetables, grapes, grass grown for seed,
hops, leafy vegetables, legumes (dried peas and beans, succulent shelled
peas and beans), mint, peanuts, pistachios, pome fruit, potatoes, root
vegetables, rye, soybean, strawberries, stone fruits, sugar beets,
sunflower, tuberous and corm vegetables, tree nuts, and wheat, as well
as residential and golf course turf.  The formulated end use products
evaluated in this assessment are labeled under the trade names
Headline® (EPA Reg. No. 7969-186), Cabrio® EG (EPA Reg. No. 7969-187),
and Insignia® (EPA Reg. No. 7969-184).  

Petitions were submitted by BASF Corporation (5F7002) and IR-4 (5E7014)
requesting new Section 3 registrations for use on cotton and Belgian
endive, respectively.  BASF Corporation has additionally submitted
applications for amended Section 3 registrations of pyraclostrobin on
berries, group 13 to increase the tolerance from 1.3 ppm to 4 ppm.  The
Health Effects Division (HED) has conducted a human health risk
assessment for these proposed and changed uses.  HED has high confidence
in the quality of the toxicology, chemistry and exposure databases used
to assess risk from pyraclostrobin.

An emulsifiable concentrate product (Headline® containing 23.6% ai) is
proposed for foliar application on cotton at use rates ranging from 0.1
to 0.2 lb ai/A, at intervals of 7 to 14 days.

For Belgian endive treatment, a water dispersible granule product,
Pristine® is proposed.  Pristine® contains 12.8% pyraclostrobin and
25.2% boscalid, (which is not evaluated in this assessment).  Chicory
roots, from which the endive is induced to grow, are treated by an
overhead spray bar as the roots pass underneath on a conveyor belt
headed for cold storage bins at a rate of 0.01 lb ai/850 lb roots.  Also
possible, by label instruction, is the treatment of the roots after cold
storage, at the beginning of the “forcing” stage at a rate of 0.003
lb ai/10 ft2 of forcing trays.

Hazard Assessment and Dose Response

Overall, the quality of the toxicology database for pyraclostrobin is
good and the confidence in the hazard and dose-response assessments is
high.  Pyraclostrobin has a low to moderate acute toxicity.  The main
target organs for pyraclostrobin are the upper gastrointestinal tract
(mainly the duodenum and stomach), the spleen/hematopoiesis, the immune
system, and the liver.  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.

This risk assessment is an update of the last human health risk
assessment (dated November 30, 2005, DP Barcode no. D323632) and it
includes an updated toxicology and hazard evaluation.  The update
includes results of recently submitted toxicity studies, a new
carcinogenicity evaluation, and selection of new study/endpoints for
exposure by the inhalation route.

The new toxicology studies include a supplemental carcinogenicity study
in female Wistar mice (MRID 46678201), a 28-day inhalation toxicity
study in Wistar rats (MRID 46638801), and a bacterial reverse-mutation
assay (MRID 45921201).  Both animal toxicity studies were carried out to
fulfill the toxicology data needs that were specified in an earlier risk
assessment (Section 10.1 of human risk assessment, dated August 27,
2004, DP Barcode no. D290342). The mutation assay tested pyraclostrobin
(technical) from the production plant with the complete profile of
impurities as described in BASF’s letter to the Agency dated April 10,
2003.

Inhalation exposure risk assessments:  In this risk assessment, the
occupational and residential inhalation exposure risk scenarios are
updated using the new route specific guideline acceptable 28-day
inhalation study with NOAEL/LOAEL of 0.23/6.92 mg/kg/day (0.001/0.03
mg/L air) based on adverse histopathology findings in the duodenum and
the respiratory system including duodenal mucosal hyperplasia, lung
alveolar histiocytosis, and olfactory atrophy/necrosis in the nasal
tissue.

  SEQ CHAPTER \h \r 1 Carcinogenicity:  The recent CARC reevaluation
concluded that, in accordance with the EPA’s Final Guidelines for
Carcinogen Risk Assessment (March, 2005), pyraclostrobin should be
classified 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.  The
CARC concluded that quantification of carcinogenic potential is not
required (TXR document no. 0054516, dated 2/15/07).  This decision
supersedes   SEQ CHAPTER \h \r 1 the previous decision to use the no
observable adverse effects level (NOAEL) for females from the mouse
carcinogenicity study (>33 mg/kg/day) to calculate cancer margins of
exposure (MOEs).

Drinking Water Exposure Estimates

The Environmental Fate and Effects Division (EFED) concluded that the
use rates for the proposed uses are much lower than the use rate on
turf, the crop that was previously selected for the drinking water
assessment.  Therefore, the estimated concentrations of pyraclostrobin
in drinking water associated with the last Section 3 request remain
valid.

A Tier 2 surface drinking water assessment was performed using PRZM
3.12/ EXAMS 2.7.97 modeling with index reservoir (IR) scenarios and
percent cropped area (PCA) adjustment factors.  Concentrations of
pyraclostrobin in surface water are not likely to exceed 10.2 µg/L for
the peak concentration, 0.8 µg/L for the annual average concentration,
and 0.5 µg/L for the 30 year average concentration.

The SCI-GROW model predicts the acute and chronic concentrations of
pyraclostrobin in shallow ground water to be 0.02 ppb.  Ground water
sources were not included in the dietary assessment, as the estimated
drinking water concentrations (EDWCs) for this water source are minimal
in comparison to surface water.

Dietary Exposure Assessment

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

The acute analysis was conducted using either tolerance level residues
or highest residues derived from field trial data conducted at the
maximum application rate and minimum PHI permitted on the proposed or
existing labels.  For all commodities 100% crop treated was assumed.  A
limited number of experimentally derived processing factors were used to
refine the acute analysis.  Of note is that relative contribution from
drinking water is minimal.  HED concludes that the acute exposure
estimates are unlikely to underestimate actual acute exposure.

The chronic dietary assessment was conducted using tolerance level
residues for all crops except for apple, grape, head lettuce, leaf
lettuce, celery, spinach, orange, pepper and tomato where average
residue values were derived from crop field trials.  These field trials
represent maximum application rates and minimum PHIs.  For all
commodities 100% crop treated was assumed.  A limited number of
experimentally derived processing factors were used to refine the
analysis.  Again, the relative contribution from drinking water is
minimal.  HED concludes that the chronic exposure estimates in this
analysis are unlikely to underestimate actual exposure.

Acute and chronic exposures and risks do not exceed HED’s level of
concern for the U.S. population and for all relevant population
subgroups.  At the 95th percentile, the acute dietary exposure utilized
1.4% of the aPAD for the general U.S. population and 78% of the aPAD for
females 13-49 years old, the most highly exposed population subgroup. 
The chronic dietary exposure utilized 19% of the cPAD for the general
U.S. population and 48% of the cPAD for children 1-2 years old, the most
highly exposed population subgroup.  

Aggregate Exposure Assessment

There are existing residential uses on turf which must be aggregated
with food and drinking water exposures.  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 are required for acute and chronic dietary (food +
drinking water) exposures.  These aggregate assessments are covered in
the dietary section of this executive summary.  Additionally, short- and
intermediate-term aggregate risk assessments are required.  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 kids 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 + water) and
non-occupational/residential exposure is 100 for children 1-2 years old,
which is not of concern to HED.  For adults the total combined MOE is
170, 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

Cotton

For the foliar use on cotton, handlers may experience
short-/intermediate-term exposure to pyraclostrobin while mixing/loading
and applying sprays.  No chemical-specific handler exposure data were
submitted in support of this use pattern, therefore, data from the
Pesticide Handlers Exposure Database (PHED) Version 1.1 as presented in
the PHED Surrogate Exposure Guide (8/98) were used.  The results of the
occupational handler exposure and risk assessment for cotton indicate
that risks are not of concern (MOEs > 100) with baseline clothing, or in
some cases, when gloves and a respirator are used to mitigate exposure.

Belgian endive

For the use on Belgian endive, the exposure to handlers is from mixing
and loading.  Application is mechanical, and therefore, no applicator
exposure is expected.  MOEs for handlers supporting postharvest
applications to Belgian endive roots (actually chicory roots) are all
much larger than 100 with workers wearing only baseline clothing, and
therefore, are not of concern to HED.

Occupational Postapplication Exposure Assessment

Cotton

From foliar applications to cotton postapplication exposure is possible
for workers entering treated fields.  Chemical-specific dislodgeable
foliar residue (DFR) data had previously been submitted by the
registrant to support earlier registration requests for food crops.  The
DFR data were used to estimate restricted entry intervals (REIs) by
extrapolating, where possible, to cotton.  It was found that the type of
formulation used influences the DFR profile; therefore, only DFR values
for the emulsifiable concentrate formulation (i.e., the Headline®
fungicide formulation) were considered.  The results of the
postapplication exposure and risk assessment indicate that MOEs of 100
are achieved on Day 0 for all cotton scenarios and, therefore, are not
of concern.  

The pyraclostrobin technical material has been classified in Toxicity
Category III for acute dermal, primary eye irritation, and primary skin
irritation.  Per the Worker Protection Standard (WPS), a 12-hr
restricted entry interval (REI) is required for chemicals classified
under Toxicity Category III or IV.  

Belgian endive

HED has determined that there is potential exposure to persons handling
Belgian endive roots after post-harvest application is complete.  No
chemical-specific data were submitted to assess the postapplication
exposure to Belgian endive roots treated with pyraclostrobin. 
Therefore, HED used surrogate data and default assumptions.  

As a worse-case post-application exposure scenario, HED assessed the
long-term dermal exposure of workers hand-packing individual treated
roots into forcing trays.  This exposure was assessed for long-term
duration, because the operation occurs on a continuous basis throughout
the entire year.  The estimated exposure/risk is considered high end
because it is based on the assumption that contact with roots occurs on
the same day as treatment.  In reality, the pyraclostrobin residue on
the roots is likely to have dissipated by some percentage over the week
to 12 months between treatment and when the packing activity actually
occurs.

The estimated long-term postapplication dermal exposure/risk to workers
handling Belgian endive roots treated with pyraclostrobin results in an
MOE of 60.  Because the level of concern is for MOEs <100, this risk is
of concern to HED.  However, because exposure from the assessed activity
is primarily to the hands, the addition of chemical-resistant gloves
should reduce exposure by 90%, resulting in a MOE = 610; which is not of
concern to HED.  This latter activity is viewed by HED as a secondary
“handler” activity, and therefore the label should include the
aforementioned glove requirements.

Recommendations

No deficiencies were noted in the subject petition (5F7002) that would
preclude establishing permanent tolerances for pyraclostrobin on the
proposed cotton commodities.  HED  SEQ CHAPTER \h \r 1  recommends
establishing permanent tolerances for pyraclostrobin at 0.3 ppm in/on
undelinted cottonseed, and at 30 ppm in/on cotton gin byproducts.  The
additional berry data also support increasing the current tolerance on
the berries crop group from 1.3 to 4.0 ppm.  

Several deficiencies were noted in the subject petition (5E7014) that
preclude establishing a permanent tolerance for pyraclostrobin on the
proposed commodity Belgian endive.  Most importantly, the application
method used in the field residue trials does not represent the proposed
use pattern, and the residue data generated from these trials therefore
do not support the proposed tolerance. 

For the proposed use on Belgian endive the following are needed if IR4
chooses to pursue a Section 3 registration: 

Use directions in Section B must match the application method used in
Section D for residue data collection;

The tolerance proposal in Section F must be supported by the application
method used in Section D for residue data collection;

Additional residue data that adequately reflect the use directions in
Section B must be submitted (HED recommends that the petitioner submit a
protocol for HED review and comment before any residue data collection
begins.); and

The label should include a requirement for chemical-resistant gloves.

For the proposed use on Belgian endive, HED recommends that the label
rate be revised to clearly define the amounts to be used per application
and the total per season.  In addition, the petitioner should define how
the spray is applied to the roots in the forcing trays (i.e., trays are
stationary or are moving on a conveyor belt).  A revised Section B must
be submitted to adequately reflect the petitioner’s intentions as to
application rates and directions.  Refer to section 9.1 for details.

As a condition of registration, HED previously required the registrant
to conduct three additional field trials in Zones 2, 3, and 10 to
support the group tolerance on Brassica, leafy greens, subgroup 5B. 
These data have been submitted and reviewed, and satisfy the outstanding
condition of registration data requirement for additional field trial
data.

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 does not rely on any data from studies in which
human subjects were intentionally exposed to a pesticide or other
chemical.

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, citrus, corn (field, pop and sweet),
cucurbit vegetables, fruiting vegetables, grapes, grass grown for seed,
hops, leafy vegetables, legumes (dried peas and beans, succulent shelled
peas and beans), mint, peanuts, pistachios, pome fruit, potatoes, root
vegetables, rye, soybean, strawberries, stone fruits, sugar beets,
sunflower, tuberous and corm vegetables, tree nuts, and wheat, as well
as residential and golf course turf.  The proposed uses evaluated in
this assessment are summarized in Table 1.

Table 1.  Summary of Proposed Use Pattern for Cotton and Belgian Endive

Product (formulation)	Use Site	Max. Single Application Rate	Max.
Applications per Season	PHI	Application Method/Instructions

Headline® fungicide

(EC 23.6% ai)	

Cotton	

0.2 lb ai/acre	

3	

30	Groundboom sprayers and aerial application Applications should begin
prior to disease development and continue throughout the season at 7- to
14-day intervals.

Pristine® fungicide (WDG 12.8% ai)	

Belgian Endive	0.01 lb ai/850 lb roots (cold storage)	

1 prior to cold storage	

Not specified	Applied by overhead, shielded spray bars (T-Jets)as
commodity moves along on conveyor belt.

200,000 lbs roots handled per day

0.003 lb ai/10 ft2 of forcing tray (forcing)	

1 prior to forcing

Applied by overhead, shielded spray bars (T-Jets)as commodity moves
along on conveyor belt.

2000 ft2 of forcing trays handled per day

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

Common Name:	Pyraclostrobin

IUPAC 

Nomenclature:	methyl
N-{2-[1-(4-chlorophenyl)-1H-pyrazol-3-yloxymethyl]phenyl}(N-methoxy)carb
amate

CAS 

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

CAS Number:	175013-18-0

Chemical Class/Type:	β-methoxyacrylate (compound class) / Strobilurin
(fungicide class)

Mode of Action:	Acts at the cellular level by inhibiting electron
transport in the mitochondrial respiratory chain at the cytochrome-bc1
complex; this disrupts the energy producing systems and can lead to the
breakdown of the mitochondrial and cytoplasmic membranes.

Impurities

of Concern:	The technical grade pyraclostrobin does not contain any
impurities or microcontaminants of concern.

Molecular Formula:	C19H18ClN3O4		

Molecular Weight:	387.82				

Appearance:	White to light beige solid

Melting Point:	63.7 - 65.2(C

Boiling Point:	N/A		

Density:	1.285 g/cm3 at 20(C

Water Solubility:	2.41 mg/L in deionized water at 20(C

1.9 mg/L in buffer system pH 7 at 20(C

2.3 mg/L in buffer system pH 4 at 20(C

1.9 mg/L in buffer system pH 9 at 20(C

Solvent Solubility:	at 20(C in:  acetone ((160 mg/L); methanol (11
mg/L); 2-propanol (3.1 mg/L); ethyl acetate ((160 mg/L); acetonitrile
((76 mg/L); dichloromethane ((110 mg/L); toluene ((100 mg/L); n-heptane
(0.36 mg/L); 1-octanol (2.4 mg/L); olive oil (2.9 mg/L); DMF ((62 mg/L).

Vapor Pressure:	2.6 x 10-10 hPa  (at 20(C); 6.4 x 10-10 hPa  (at 25(C)

pKa:			Does not dissociate in water.  There are no dissociable moieties.

Kow:	n-Octanol/water partition coefficient (Kow) at room temperature
(=Kow of 3.80, pH 6.2; =log Kow 4.18, pH 6.5).

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

The most recent risk assessment was supported by hazard endpoint
conclusions in the HIARC report (TXR 0051553, dated 2/10/03) and the
carcinogenicity assessment in the CARC memo dated 10/22/03 (TXR No.
0051445).  Since then, new toxicology studies have been made available,
including a supplemental female mouse carcinogenicity study and a 28-day
rat inhalation study.  This hazard characterization includes results of
these new toxicity studies, a new carcinogenicity evaluation, and
selection of new endpoints for exposure by the inhalation route based on
the findings in the 28-day rat inhalation study.

3.1	Hazard and Dose-Response Characterization  TC \l2 "3.1	Hazard and
Dose-Response Characterization 

3.1.1	Database Summary  TC \l3 "3.1.1	Database Summary 

3.1.1.1	Studies available and considered (animal, human, general
literature)  TC \l4 "3.1.1.1	Studies available and considered (animal,
human, general literature) 

Acute- oral, dermal, inhalation, eye irritation, skin irritation, dermal
sensitization

Subchronic- Dermal 28-day rat; inhalation 28-day rat, oral 28-day rat,
oral 90-day rat, oral 90-day mouse, oral 90-day dog; 

Chronic- Oral rat and oral dog;

Carcinogenicity – Rat and mouse;

Reproductive/developmental- Oral prenatal developmental rat, oral
prenatal developmental rabbit, 2-generation reproductive rat; 

Other- Mutagenicity screens, and metabolism and pharmacokinetic studies;
acute and subchronic neurotoxicity studies; and dermal penetration
study.

3.1.1.2	Mode of action, metabolism, toxicokinetic data  TC \l4 "3.1.1.2
Mode of action, metabolism, toxicokinetic data 

  SEQ CHAPTER \h \r 1 Pyraclostrobin [carbamic acid,
[2-[[[1-(4-chlorophenyl)-1H-pyrazol-3-yl]oxy]methyl] phenyl]methoxy-,
methyl ester] (CAS nomenclature) belongs to the strobilurin class of
fungicides.  Other strobilurin fungicides include azoxystrobin,
kresoxim-methyl, trifloxystrobin, fluoxastrobin, and picoxystrobin. 
Strobilurins are synthetic analogs of a natural antifungal substance
(basidiomycete antibiotics) which inhibit spore germination, mycelial
growth, and sporulation of the fungus on the leaf surface. 

  SEQ CHAPTER \h \r 1 The biochemical mode of action of strobilurins
consists of interaction with the ubiquinone binding site of the
mitochondrial bc1 complex (complex III) in fungal cells, thereby
preventing the oxidation of ubihydroquinone and the transfer of
electrons to cytochrome c. Interrupting the electron transport chain in
this way prevents oxidative phosphorylation, thus causing a severe
reduction in the availability of ATP, the main energy currency of the
cell. The shortage of energy has a very wide range of biochemical
consequences, such as the breakdown of essential membrane potentials and
concentration gradients and the inhibition of nucleic acid and protein
biosynthesis. Fungal spore germination, mycelial growth and the
development of infection structures are thus prevented.

-1 hours and 8 hours (two peaks); males had lower plasma concentrations
than females (↓16-38%) during the earlier time points.  Elimination
was biphasic at the low dose with plasma half-lives of nearly 10 and 35
hours and monophasic at the high dose with a half-life of nearly 20
hours.  The distribution patterns of radioactivity in tissues were
similar between sexes (typically higher among females) reaching peak
levels at 0.5 hours post-dosing; some of the highest concentrations were
found in the liver, thyroid, kidney, lung, adrenal glands, and pancreas.
There was no evidence of tissue accumulation since levels at 42-72 hours
dropped greater than 20-fold relative to the earliest measurement at 0.5
hour.  Nearly 33 metabolites were isolated and identified in the urine,
feces, and bile; there were no sex- or dose-related differences in the
metabolite profile in urine or feces but the position of the label
seemed to alter the profile, particularly in the urine.  The metabolic
pathway included phase-I reactions such as N-demethoxylation, various
hydroxylations, and cleavage of the ether bond with subsequent
oxidation; these were followed by the phase II glucuronidation and
sulfation reactions.

3.1.1.3	Sufficiency of studies/data  TC \l4 "3.1.1.3	Sufficiency of
studies/data 

  SEQ CHAPTER \h \r 1 The available studies provide sufficient
information to determine whether and to what extent pyraclostrobin may
pose a human health hazard (see Appendices 2-3 for acute and repeated
dose studies/findings).  Acute and chronic reference doses for dietary
risks as well as doses for non-dietary risks are based on guideline
acceptable studies with well-characterized endpoints and NOAEL/LOAEL
values.  The available studies have been thoroughly evaluated for
guideline acceptability by individual reviewers and peer-review
committees and, despite inadequate dosing in some of the studies, the
database is considered sufficient to characterize and quantify risk.

This risk assessment also incorporates new toxicity studies that have
been made available recently since the previous human health risk
assessment (dated 11/30/05, DP Barcode No. D323632).  These include a
supplemental carcinogenicity study in female Wistar mice (MRID
46678201), a 28-day inhalation toxicity study in Wistar rats (MRID
46638801), and a bacterial reverse-mutation assay (MRID 45921201).  Both
animal toxicity studies were carried out to fulfill the toxicology data
needs that were specified in an earlier risk assessment (Section 10.1 of
human risk assessment dated 8/27/04, DP Barcode no. D290342). The
mutation assay tested pyraclostrobin (technical) from the production
plant with the complete profile of impurities as described in BASF’s
letter to the Agency dated 4/10/03.  An almost identical previous
mutation study (MRID 45118332) tested pyraclostrobin (technical) from
the pilot plant.

3.1.2	Toxicological Effects  TC \l3 "3.1.2	Toxicological Effects 

The toxicity profile of pyraclostrobin, including acute toxicities, may
be found in Appendices 2 and 3.

  SEQ CHAPTER \h \r 1 Acute Toxicity:  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 1).

Toxicity from Repeated Oral Exposure: Based on findings in repeated
dosing oral studies in more than one species, the main target organs for
pyraclostrobin are the upper gastrointestinal tract (mainly the duodenum
and stomach), the spleen/hematopoietic system, the liver, and the immune
system (listed in the order from most to least sensitive).  In addition,
reduced body weight/gain and feed intake/efficiency are also common
findings.  In the 90-day dietary rat, mouse, and dog feeding studies,
one or more of the following gastrointestinal (GI) changes were noted:
thickening of the duodenal wall, duodenum mucosal hypertrophy or
hyperplasia, as well as gross and microscopic ulceration/erosion in the
glandular stomach.  Mucosal hyperplasia in the duodenum was also
observed in rats of both sexes after 28-day administration of 500
(42.3/46.6 (M/F) mg/kg/day) and 1500 (120.2/126.3 (M/F) mg/kg/day) ppm
pyraclostrobin.  The upper GI-tract effects might, at least partly,
explain some of the adverse effects on food consumption/utilization, and
body weight; all these effects had a similar threshold which was lower
than that needed to elicit the other toxic responses.

The liver was a target organ in the 28-day rat and the 90-day rat and
mouse dietary feeding studies based on slight to moderate increased
relative liver weight in both species and hepatocellular hypertrophy in
the rat studies.  Liver necrosis was also increased in the two-year rat
carcinogenicity study.

hils, and lymphocytes.  In mice, there was mild hemolytic anemia
accompanied by a large decline (≥50%) in leukocytes (leukopenia),
neutrophils, and lymphocytes.  The large decline in white blood cell
(WBC) populations was accompanied by dose-dependent thymus atrophy and
increased lymph node apoptosis.  The incidences of thymus atrophy ranged
from 3/10 to 8/10 in each of the top four dose groups of both sexes
compared to 0/10 in the control and lowest dose groups; the severity
also increased dose-dependently.

Reproductive & Developmental Toxicity: The pre- and post-natal
toxicology database for pyraclostrobin include the rat and rabbit
developmental toxicity studies and the two-generation reproduction
toxicity study in rats.  There was no evidence of increased quantitative
or qualitative susceptibility following in utero exposure to rats.  The
developmental findings of increased incidences of dilated renal pelvis
and cervical ribs with no cartilage were seen at a higher dose than that
which caused maternal toxicity and these findings were within historical
control background incidences; therefore, they are considered
developmental variations rather than malformations.  In the rabbit
developmental toxicity study, there was evidence of qualitative
susceptibility; increases in resorptions/litter and post-implantation
losses were seen in the presence of maternal toxicity (decreases in body
weight gain and food consumption).  However, the concern is low for the
qualitative susceptibility in the rabbit developmental study because:
The developmental effects were seen in the presence of maternal
toxicity; there are clear NOAELs for maternal and developmental
toxicities; and this endpoint is used for the acute dietary (RfD) for
Females+ 13 as well as for short- and intermediate-term dermal risk
assessments.

In the two-generation study, there were no adverse maternal systemic
toxicity other than a marginal (non-adverse) decrease (<= 5%) in F0 and
F1 parental body weights at the high dose of 300 ppm.  The F1 and F2
pups of the 300 ppm dose group had slight decreases in body weights
during lactation which were explained to be “likely due to the fact
that pups start eating food at this time (day 7) along with potentially
receiving test compound or its metabolites in mother milk.”  The
findings were not considered adverse in part because of almost total
body weight recovery in F1 parental animals during premating, gestation,
and lactation.  The NOAEL/LOAEL were 300/>300 ppm for parental,
reproductive, and offspring toxicities.   In the one generation study,
the NOAEL/LOAEL were <200/<= 200 ppm based on dose-dependent decrease in
F1 pup body weights.

The HIARC decided that, when evaluated with the findings of the
dose-range one-generation reproduction study, there is no need to repeat
the two-generation reproduction study (document dated 2/10/03, TXR no.
0051553).  The HIARC noted that the greater body weight/body weight gain
sensitivity in the offspring of the one-generation reproduction study is
possibly due to decreased feed intake by treated pups as they start
eating solid feed around day 14; this effect was not reproduced in the
two-generation toxicity study.

It should be noted that there was some overlap in the magnitude of the
body weight decrease in F1 pups at 300 ppm (4-10%), 200 ppm (7-14%), and
400 ppm (11-20%) to the extent possible from two completely different
and independent studies.  For any end-point, some degree of variation is
to be expected between control animals from different studies for
different reasons including animal husbandry (e.g., diurnal, seasonal)
as well as differences in instruments and people who collect the
measurements.  This inter-study variation may explain the F1 pup body
weight variance and lack of a perfect dose-response among the similar
dose levels (300 ppm vs. 200 and 400 ppm) in both studies.

  SEQ CHAPTER \h \r 1 In conclusion, athough no toxicity was seen at 300
ppm (29.0 mg/kg/day) in the two-generation reproduction study, a new
study is not required since such a study would be conducted using a much
higher dose and would not provide any additional data for risk
assessment purposes.  The concern with that study is not that it did not
test at a low enough dose but the opposite.  Further, it should be noted
that acute and chronic reference doses for dietary risks as well as
doses for non-dietary risks are based on other studies with NOAELs below
the high dose in the two generation study.

Neurotoxicity: In both the acute and subchronic neurotoxicity studies,
there were no indications of treatment-related neurotoxicity including
clinical signs, qualitative or quantitative neurobehavioral effects,
brain weight, or gross/microscopic pathology.  None of the other
guideline studies reported treatment-related effects on any of these
parameters.  However, there was a large decrease (about 50%) in serum
cholinesterase (but not in erythrocyte or brain cholinesterases) among
the females in the rat 28- and 90-day dietary studies at relatively
large doses (1000/1500 ppm or about 80 - 126 mg/kg/day).  This response
might require exposure to a relatively high dose since serum
cholinesterase (ChE) was not affected at the end of the two-year chronic
toxicity feeding study in rats including the top dose of 200 ppm
(9.2/12.6 mg/kg/day in males/females).  Also, pyraclostrobin does not
seem to persist in rat tissues (see following section) which might
explain why serum ChE is not affected by a lifetime exposure to a
relatively low dose but is depressed following a short-term exposure at
a high dose.

Carcinogenicity:  In the Report of the Cancer Assessment Review
Committee (CARC) dated October 22, 2003, pyraclostrobin was classified
as “data are inadequate to assess the human carcinogenic potential”
based on the determination of inadequate dose levels in the
carcinogenicity study for female mice only (TXR No. 0051445).  In
consultation with the HED Dose Adequacy Review Team (DART), BASF
corporation initiated a supplemental carcinogenicity study in female
mice using one dose group (360 ppm) and a control (n=50 animals/group). 
In the meantime, HED used a regulatory Margin of Exposure (MOE) as a
tool for bounding any potential chronic dietary cancer risk from
pyraclostrobin as explained in the previous risk assessments (DP
Barcodes D290342 and D323632 dated 8/27/04 and 11/30/05).  The
regulatory MOE was derived from the highest dose tested in female mice
(32.8 mg/kg/day) in the inadequate mouse oncogenicity study and was 10X
higher than the NOAEL used for chronic non-cancer risk assessment.

Due to excessive body weight decrease in the treated group, BASF
requested and received permission from HED DART to terminate the
supplemental study well before its intended 18 months duration.  With
the termination of the supplemental carcinogenicity study in female mice
(MRID 46678201), the CARC reevaluated the carcinogenicity potential of
pyraclostrobin.  In accordance with the EPA’s Final Guidelines for
Carcinogen Risk Assessment (March, 2005), 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.  The
CARC concluded that quantification of carcinogenic potential is not
required (TXR document no. 0054516, dated 2/15/07).  Therefore, the
above described regulatory MOE approach is no longer needed. 

3.1.3	Dose-response  TC \l3 "3.1.3	Dose-response 

 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 will now be 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
endpoints (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.  

The selected endpoint from the acute neurotoxicity study of 300
mg/kg/day for the acute dietary (general population) risk assessment is
appropriate because the decreased body weight gain in males occurred
during the first week after a single oral high dose of 1000 mg/kg.  

The rabbit developmental toxicity study findings are used for endpoint
selections for acute dietary (Females 13+) as well as for short- and
intermediate-term dermal exposures.  For the acute dietary endpoint
(Females 13+), the rabbit developmental findings of increased
resorptions/post-implantation loss at the LOAEL of 10 mg/kg/day are
assumed to occur following a single in utero exposure.  These effects
were dose-dependently increased at the next (high) dose of 20 mg/kg/day.
The same study and developmental endpoint are used for short- and
intermediate-term dermal exposures after applying a dermal absorption
factor of 14%.  Additionally, the maternal endpoints of decreased body
weight gain and decreased food intake and food efficiency were found at
the LOAEL of 10 mg/kg/day.  This selection mitigates any concern from
the observed developmental toxicity findings in rabbits which are not
assessed in the rat dermal toxicity study.

The rat carcinogenicity study findings are used for endpoint selections
for chronic dietary and dermal exposures based on findings of decreased
body weight/gain and kidney tubular casts/atrophy in both sexes in
addition to liver necrosis and stomach lesions in males at the high dose
(LOAEL) of 9.2 mg/kg/day.  This study has the lowest NOAEL (3.4
mg/kg/day) in the most sensitive species following chronic exposure. 
The dermal absorption factors of 14% will be applied to the dermal
long-term risk scenario.

The short-, intermediate-, and long-term inhalation exposures will be
based on the new 28-day inhalation toxicity study in rats which had
dose-dependent adverse findings in the respiratory system and duodenum. 
The study’s oral equivalents NOAEL/LOAEL are 0.23/6.92 mg/kg/day
(corresponding to study’s air concentration of 0.001/0.03 mg/L air). 
The findings are well characterized in that the severity, frequency, and
location (e.g., along the respiratory tract) are dose-dependent ranging
from no effects at the NOAEL of 0.001 mg/L air to severe respiratory
effects and death at the highest dose of 0.3 mg/L air.

3.2	FQPA Considerations  TC \l2 "3.2	FQPA Considerations 

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

The toxicity data base for pyraclostrobin is adequate for evaluation of
the FQPA safety factor.  The following acceptable studies are available:

	Developmental toxicity studies in rats and rabbits

	Two-generation reproduction study in rats

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

In all studies, including the acute and subchronic guideline acceptable
neurotoxicity studies, there were no signs of neurotoxicity or
neuropathology.    SEQ CHAPTER \h \r 1 Serum cholinesterase (ChE)
activity was decreased (by 41-56%) in females (80 and 119 mg/kg/day) in
the 90-day rat study and among the 126 mg/kg/day females in the 28-day
rat study.  On the other hand, erythrocyte ChE in the 28- and 90-day rat
studies and brain ChE in the 28-day were all unchanged.  However, this
response might require a relatively high dose since serum ChE was not
affected at the end of the two-year chronic toxicity feeding study in
rats (MRID 45118329) including the top dose of 9.2/12.6 mg/kg/day in
males/females.  In the acute and subchronic toxicity studies, there were
no physiological or behavioral effects to corroborate the serum ChE
inhibition seen in female rats.    SEQ CHAPTER \h \r 1 Based on the
weight of evidence presented, the HIARC concluded that a developmental
neurotoxicity study is not required for pyraclostrobin.

3.2.3	Developmental Toxicity Studies  TC \l3 "3.2.3	Developmental
Toxicity Studies 

As discussed above, there is no evidence of increased quantitative or
qualitative susceptibility following in utero exposure to rats.  The rat
developmental findings of increased incidences of dilated renal pelvis
and cervical ribs with no cartilage were seen at a higher dose than that
which caused maternal toxicity and these findings were within historical
control background incidences; therefore, they are considered
developmental variations rather than malformations.

  SEQ CHAPTER \h \r 1 As discussed above and in the HIARC report (dated
2/10/03, TXR No. 0051553), the concern is low for the qualitative
susceptibility seen in the rabbit developmental study and there are no
residual uncertainties because: The developmental effects were seen in
the presence of maternal toxicity; there are clear NOAELs for maternal
and developmental toxicities; and this endpoint is used for risk
assessment.  

The findings in the two- and one-generation toxicity studies and
susceptibility issues were discussed earlier (3.1.2).  It was concluded
that the concern is low for the quantitative susceptibility seen in the
one-generation reproduction study and there are no residual
uncertainties because: The offspring effects seen in this study were not
repeated in the two generation study; the marginal decrease in pup
weights seen at or after PND-7 may be due to higher exposure via their
diet; and the dose (NOAEL 3.4 mg/kg/day) used for the chronic RfD risk
assessment would address the effects of concern seen in the offspring. 
Although no toxicity was seen at 300 ppm (29.0 mg/kg/day) in the
two-generation reproduction study, a new study is not required since
such a study would be conducted using a much higher dose and would not
provide any additional data for risk assessment purposes.

  SEQ CHAPTER \h \r 1 In both the acute and subchronic neurotoxicity
studies, there were no indications of treatment-related neurotoxicity
including clinical signs, qualitative or quantitative neurobehavioral
effects, brain weight, or gross/microscopic pathology.  None of the
other guideline studies reported treatment-related effects on any of
these parameters.

3.2.4	Reproductive Toxicity Study  TC \l3 "3.2.4	Reproductive Toxicity
Study 

As discussed above, there is no evidence of increased quantitative or
qualitative susceptibility following in utero exposure to rats.  Also,
the concern is low for the qualitative susceptibility seen in the rabbit
developmental study and there are no residual uncertainties because: The
developmental effects were seen in the presence of maternal toxicity;
there are clear NOAELs for maternal and developmental toxicities; and
this endpoint is used for risk assessment.

As discussed above, the concern is low for the quantitative
susceptibility seen in the one-generation reproduction study and there
are no residual uncertainties because: The offspring effects seen in
this study were not repeated in the two generation study; the marginal
decrease in pup weights seen at or after PND-7 may be due to higher
exposure via their diet; and the dose (NOAEL 3.4 mg/kg/day) used for the
chronic RfD risk assessment would address the effects of concern seen in
the offspring.  Although no toxicity was seen at 300 ppm (29.0
mg/kg/day) in the two-generation reproduction study, a new study is not
required since such a study would be conducted using a much higher dose
and would not provide any additional data for risk assessment purposes.

3.3	FQPA Safety Factor for Infants and Children  TC \l2 "3.3	Safety
Factor for Infants and Children 

This assessment reaffirms previous conclusions that the 10X FQPA safety
factor for the protection of infants and children should be removed for
all potential exposure scenarios to pyraclostrobin because the database
is complete and adequate and there are no residual uncertainties for
pre- and/or postnatal toxicity.  The doses chosen as quantitative risk
estimates are adequately protective for infants and children.  Exposure
data are complete or are estimated based on data that reasonably account
for potential exposures.  

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

The chronic dietary analysis included tolerance level or average
residues from field trial data and 100% crop treated assumptions for all
commodities.  A limited number of experimentally derived processing
factors were used for fruit juices and tomato and wheat commodities. 
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.

Based on these data and conclusions, the FQPA Safety Factor can be
reduced to 1X.

3.4	Hazard Identification and Toxicity Endpoint Selection  TC \l2 "3.4
Hazard Identification and Toxicity Endpoint Selection 

The previous pyraclostrobin risk assessments utilized toxicity studies
via the oral route to perform risk assessments for occupational and
residential inhalation exposure scenarios.   In this assessment, the
inhalation exposure risk scenarios have been updated using the guideline
acceptable 28-day inhalation study.  The study’s executive summary and
a summary of the route-to-route extrapolation to convert an inhalation
concentration (mg/L) to an oral equivalent dose (mg/kg) are provided in
section 3.4.8 and in Appendix 3.  For short- and intermediate-term
inhalation exposures, the earlier risk assessments selected the NOAEL of
5.0 mg/kg/day from the oral prenatal developmental toxicity study in
rabbits based on developmental toxicity findings of increased
resorptions.  A 100% inhalation absorption factor was used to convert
all inhalation exposures to an oral equivalent dose.    SEQ CHAPTER \h
\r 1 For long-term inhalation exposures, the NOAEL of 3.4 mg/kg/day from
the oral rat carcinogenicity study was selected; however, long-term
exposures are not expected to occur.  Herein, the NOAEL of 0.23
mg/kg/day (equivalent to 0.001 mg/L air) from the 28-day inhalation
study will be used for short- and intermediate-term residential and
occupational inhalation risk assessments.  This NOAEL is based on
duodenum mucosal hyperplasia and adverse respiratory system
histopathology findings including alveolar histiocytosis and olfactory
atrophy/necrosis in nasal tissue at 6.92 mg/kg/day (equivalent to 0.03
mg/L air).  The same study and endpoint will also be used for long-term
residential and occupational inhalation scenarios even though long-term
exposures are not likely at this time.  For long-term inhalation
exposure scenarios, the level of concern for MOE will be retained at
100, i.e., it will not be increased to account for using the short-term
study for the long-term scenario.  This decision is supported by the
large NOAEL/LOAEL dose spread (30-fold) and the fact that additional and
more severe toxicity findings were seen at the top dose which is only
10-fold higher than the LOAEL.

With the exception of inhalation endpoints and the new point of
departure for cancer, all endpoints that were selected in the previous
human health risk assessments remain valid.  As discussed above (under
3.1.2), the 28-day rat inhalation toxicity study will be used in this
risk assessment for all durations of residential and occupational
inhalation scenarios.  

3.4.1    Acute Reference Dose (aRfD) - Females age 13-49  TC \l3 "3.4.1 
  Acute Reference Dose (aRfD) - Females age 13-49 

Study Selected: Rabbit Prenatal Developmental Toxicity			§870.3700

MRID No.: 45118326/45437001

Executive Summary: In a prenatal developmental toxicity study
(Teratology) (MRID# 45118326), sexually mature, virgin Chbb:HM (outbred
strain) Himalayan rabbits (Supplier: BOEHRINGER INGELHEIM PHARMA KG)
received either 0, 5, 10, or 20 mg/kg/day BAS 500 F (Purity: 98.9%;
Batch No.: CP028719) in 0.5% Tylose CB 30.000 (in doubly distilled
water) by oral gavage from days 7 through 28 post ingestion (p.i.),
inclusive.  A check was made twice daily on working days or once daily
(Saturday, Sunday or on public holidays) (days 0 - 29 p.i.).  The
maternal animals were examined for clinical symptoms with all animals
weighed on days 0, 2, 4, 7, 9, 11, 14, 16, 19, 21, 23, 25, 28 and 29
p.i. along with consumption of food determined daily during the entire
study period.  On day 29 p.i., the surviving dams were sacrificed and
the fetuses were removed from the uterus, the dams were then necropsied
and assessed by gross pathology, the uterus and the ovaries were removed
and weighed with the number of corpora lutea, the number and
distribution of implantation sites recorded.  The fetuses were examined
for external, visceral and skeletal anomalies.

No treatment related mortality was noted.  Reduced fecal output was seen
in 1 mid dose (day 10 p.i.) and 10 high-dose animals (days 10-14 p.i.). 
Two mid-dose and 4 high-dose animals showed blood in the bedding
(between days 16-29 p.i.).  No other relevant clinical observations were
noted.  All treated groups had lower body weight gains during the dosing
period (days 7-28) and the overall gestation period (day 0-29) while the
mid and high dose groups had lower body weight gains during the post
dosing period (days 28-29).  The decreased body weight gain, among all
treated groups, can mainly be attributed to the earliest post-treatment
period, namely gestation days 7-9 (treatment days 0-2). As seen with the
body weights and body weight gains, all treated groups had reduced food
consumption during the treatment period (days 7-28), and the overall
gestation period (days 0-29).  Food efficiency was lower in all treated
groups during the same periods as food consumption and during the post
dosing period (days 28-29).  No treatment related pathological
observations were noted in the data provided.  There was reduced litter
size, increased resorptions per dam and increased post implantation loss
in the high dose group.  Maternal toxicity was further evaluated in
another study (MRID 45437001, review in Appendix I) and no significant
maternal toxicity was observed a 1, 3, or 5 mg/kg/day.  Therefore when
these two studies are used together, they support a Maternal Toxicity
NOAEL of 5 mg/kg/day.  The maternal toxicity NOAEL was 5 mg/kg/day and
the maternal toxicity LOAEL was 10 mg/kg/day based on body weight gains,
reduced food consumption and reduced food efficiency.

There was increased resorptions per dam, increased post implantation
loss and a dose related increase in dams with total resorptions in the
mid and high dose groups. There was also an increased incidence of the
anomaly: lumbar vertebrae absent in the high dose group as well as
reduced litter size.  The developmental toxicity NOAEL was 5 mg/kg/day
and the developmental toxicity LOAEL was 10 mg/kg/day based on increased
resorptions per litter, increased post-implantation loss and dams with
total resorptions.

This study is classified as Acceptable-Guideline and satisfies the
guideline requirements (§ 83-3a) for a Prenatal Developmental Toxicity
Study (Teratology) in rabbits.

Dose and Endpoint for Establishing aRfD: Developmental Toxicity NOAEL of
5.0 mg/kg/day based on increased resorptions/litter and increased total
resorptions (i.e., dams with complete litter loss).

Uncertainty Factor (UF):	100

Comments about Study/Endpoint/Uncertainty Factor: The developmental
effects are presumed to occur following a single exposure of females of
child-bearing age and, therefore, are appropriate for this risk
assessment.

	Acute RfD (Females 13-50) = 	   5.0  mg/kg (NOAEL)   = 	0.05  mg/kg 

							100 (UF)

3.4.2	Acute Reference Dose (aRfD) - General Population  TC \l3 "3.4.2
Acute Reference Dose (aRfD) - General Population 

  SEQ CHAPTER \h \r 1 Study Selected:  Rat Acute Oral Neurotoxicity			
§870.6100

MRID No.: 45118337

eral nervous system tissues.  The Systemic Toxicity LOAEL for males was
1000 mg/kg bw based on 33% decreased body weight gain (p ≤ 0.01) on
days 0-7; no similar effect was detected on days 0-14.  The Systemic
Toxicity NOAEL was 300 mg/kg bw.  The Systemic Toxicity LOAEL for
females could not be determined since there were no adverse,
treatment-related effects noted at any dose level tested.  The Systemic
Toxicity NOAEL for females was 1000 mg/kg bw.  The Neurotoxicity LOAEL
could not be determined since there were no treatment-related neurotoxic
effects noted at any dose level tested.  The Neurotoxicity NOAEL was
1000 mg/kg bw.

This acute neurotoxicity study is classified as Acceptable/Guideline and
satisfies the guideline requirement for an acute neurotoxicity study
[OPPTS 870.6100(§81-7)] in rats.  Also note that the highest dose
tested was 1000 mg/kg and not 2000 mg/kg as suggested by the guidelines.
 However, this deficiency is not considered serious enough to render the
study unacceptable because there were no changes in any of the
neurotoxicity indices up to the highest tested dose. 

Dose and Endpoint for Establishing RfD: The systemic toxicity NOAEL of
300 mg/kg based on decreased body weight gain in males at 1000 mg/kg.

Uncertainty Factor (UF):	100

Comments about Study/Endpoint/Uncertainty Factor: The decreased body
weight gain was seen after a single oral dose during the first week
after exposure and therefore is appropriate for the exposure scenario.

	Acute RfD (General Population) =     300 mg/kg (NOAEL)   = 	3.0	mg/kg

							100 (UF)

3.4.3	Chronic Reference Dose (cRfD)   TC \l3 "3.4.3	Chronic Reference
Dose (cRfD) 

  SEQ CHAPTER \h \r 1 Study Selected:  Rat Oral Carcinogenicity		
Guideline #:  870.4200

MRID No.:	45118331

Note:  The tumor findings described in the executive summary below
reflect the original HED review.  Subsequently, the HED CARC evaluated
the carcinogenicity potential for pyraclostrobin.  In its most recent
evaluation, 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 (TXR document no. 0054516, dated 2/15/07).  

Executive Summary:  In a rat carcinogenicity study (MRID 45118331),
pyraclostrobin (97.09% a.i., Lot/Batch # J.-Nr. 27882/191/c) was
administered in the diet to Wistar rats (50/sex/group) for up to 104
weeks at nominal doses of 0, 25, 75, or 200 ppm, equivalent to 0/0,
1.2/1.5, 3.4/4.7, and 9.2/12.6 mg/kg/day [M/F], respectively.  

Mortality, clinical signs, food efficiency, and hematology findings for
both sexes at all doses were unaffected by treatment.  No
treatment-related findings were observed in the 25 or 75 ppm dose
groups.

In the 200 ppm group, decreased (p≤0.05 or 0.01) body weights were
observed in the males (↓3-7%) at weeks 1 through 81 and in the females
(↓4-14%) at weeks 21 through 104; body weights in the males at 104
weeks was decreased (↓4%; not statistically significant [NS]). 
Decreased (p≤0.05 or 0.01) body weight gains were observed in the
males (↓6-10%) at weeks 1 through 81 and in the females (↓7-22%) at
weeks 21 through 104; cumulative body weight gain in the males at week
104 was decreased (↓5%; NS).  Decreased (p≤0.05 or 0.01) food
consumption was observed in the males (↓3-7%) sporadically during
weeks 1 to 13.  Increased (p≤ 0.05) relative kidney weights were
observed in the males (↑9%) and females (↑19%).  In addition,
increased incidences of kidney tubular casts in the males (15/50 treated
vs 5/50) and females (14/50 treated vs 10/50 controls) and kidney
tubular atrophy in the males (16/50 treated vs 5/50 controls) and
females (19/50 treated vs 12/50 controls) were observed.  In the males,
an increased incidence of necrosis of the liver was observed
microscopically (10/50 treated vs 1/50 control).  Additionally,
erosion/ulcer of the glandular stomach was observed grossly (12/50
treated vs 7/50 controls) in the males.  Microscopically, an increased
incidence of acanthosis (6/50 treated vs 0/50 controls) and ulcers (4/50
treated vs 2/50 controls) of the forestomach and ulcers (7/50 treated vs
2/50 controls) and erosion of the glandular stomach (10/50 treated vs
2/50 controls) were also observed in the males. 

The LOAEL is 200 ppm for males and females (equivalent to 9.2/12.6
mg/kg/day [M/F]) based on differences in body weight and body weight
gains, increased incidences of kidney tubular casts and atrophy in males
and females, and in males, an increased incidence of necrosis of the
liver, gross and microscopic evidence of erosion/ulcer of the glandular
stomach and an increased incidence of acanthosis and ulcers of the
forestomach.  The NOAEL is 75 ppm (equivalent to 3.4/4.7 mg/kg/day
[M/F]). 

The submitted study is classified as Acceptable/Guideline (§83-2[a])
and satisfies the requirements for a carcinogenicity study in rats. 

Dose and Endpoint for Establishing RfD: The NOAEL of 3.4 mg/kg/day (75
ppm) based on decreased body weight and body weight gains, increased
incidences of kidney tubular casts and atrophy in males and females, and
in males, an increased incidence of liver necrosis, gross and
microscopic evidence of erosion/ulcer of the glandular stomach and an
increased incidence of acanthosis (hyperplasia) and ulcers of the
forestomach at 9.2 mg/kg/day (200 ppm).

Uncertainty Factor(s): 	100

Comments about Study/Endpoint/Uncertainty Factor:  The lowest NOAEL in
the most sensitive species following chronic exposure.

	Chronic RfD  =        3.4 mg/kg/day (NOAEL)   = 	0.034	mg/kg/day

					100 (UF)

3.4.4	Incidental Oral Exposure (Short- and Intermediate-Term)   TC \l3
"3.4.4	Incidental Oral Exposure (Short- and Intermediate-Term) 

  SEQ CHAPTER \h \r 1 Study Selected:  13-Week Feeding Dog Study		
§870.3150

MRID No.: 45118323

Executive Summary: In a subchronic toxicity study (MRID #45118323), BAS
500 F, purity 97.09%, was administered to 5 beagles/sex/dose in the diet
at dose levels of 0, 100, 200 and 450 ppm (equal to 0, 2.8, 5.8 and 12.9
mg/kg bw/day for males, and 0, 3.0, 6.2 and 13.6 mg/kg bw/day for
females) for a 90-day period. 

No treatment-related deaths were observed at any dose level.  All
animals in the 450 ppm group vomited for the first 1 to 3 weeks, which
was considered to be a transient aversion to the test material.  In
addition, all animals in the high dose group had diarrhea throughout the
study period.  A slight increase in the incidence of diarrhea noted in
the 200 ppm group was not considered to be toxicologically significant
because of its scattered/ isolated occurrence. Decreased food intake
(-9%), a net loss in body weight (-12%) and decreased food efficiency
(-1.05% vs. 5.26% in controls) were seen in the 450 ppm group, females
only.  Clinical chemistry findings included a slight decrease at 450 ppm
in total protein, albumin, globulin (all three parameters in both sexes
ranged from -7% to -12%; only total protein was significantly different
from controls) and in glucose on days 41/43 and 90 among the 450 ppm
females (-9.4 % to -13%, p≤0.01). These findings are considered to
reflect a trend towards lower values indicative of a marginal
treatment-related effect. Gross and histopathological examination
revealed that the duodenum is a target organ in both sexes at 450 ppm as
evidenced by thickening of the duodenal wall (each sex: 2/5 vs. 0/5
controls) and mucosal hypertrophy (males: 2/5 vs. 0/5 controls and
females: 1/5 vs. 0/5 controls).   

The LOAEL is 450 ppm (equal to 12.9 mg/kg bw/day for males and 13.6
mg/kg bw/day for females), based on an increased incidence of diarrhea,
clinical chemistry changes and mucosal hypertrophy of the duodenum (both
sexes) and body weight loss, decreased food intake and decreased food
efficiency (females only). The NOAEL is 200 ppm (equal to 5.8 mg/kg
bw/day for males and 6.2 mg/kg bw/day for females).

This subchronic toxicity study in the dog is acceptable and satisfies
the guideline requirement for a subchronic oral study (OPPTS 870.3150;
OECD 409) in dogs.

Dose and Endpoint for Risk Assessment:  The NOAEL of 6 mg/kg/day based
on increased incidence of diarrhea, clinical chemistry changes, duodenum
mucosal hypertrophy, and effects on body weight and food
intake/efficiency at 13 mg/kg/day (LOAEL). 

Comments about Study/Endpoint:  The NOAEL/LOAEL in this study are
comparable to the maternal NOAEL/LOAEL (5/10 mg/kg/day) established in
the rabbit developmental toxicity study, and the end-point is
appropriate for the population of concern (toddlers).

3.4.5	Dermal Absorption  TC \l3 "3.4.5	Dermal Absorption 

The HIARC recommended that   SEQ CHAPTER \h \r 1 a dermal penetration
rate of 14% should be used for dermal exposure risk assessments for
pyraclostrobin (2nd HIARC report dated 7/22/02, TXR No. 0050932).

3.4.6	Dermal Exposure (Short- and Intermediate-Term)   TC \l3 "3.4.6
Dermal Exposure (Short- and Intermediate-Term) 

  SEQ CHAPTER \h \r 1 Study Selected:  Rabbit Prenatal Developmental
Toxicity		§870.3700

MRID No.: 45118326

Executive Summary: under above item 3.5.1

Dose/Endpoint for Risk Assessment:  Developmental Toxicity NOAEL of 5.0
mg/kg/day based on increased resorption/litter and increased total
resorptions (i.e., dams with complete litter loss) at 10 mg/kg/day
(LOAEL).

Comments about Study/Endpoint:  In its earlier meetings of July 31, 2001
and June 25, 2002, the HIARC noted that the 28-day dermal toxicity study
in rats (MRID 45118324) showed no effects at the highest tested dose of
250 mg/kg/day, which is well below the limit-dose of 1000 mg/kg/day (HED
doc. No. 014669 and TXR No. 0050932).  Therefore, it is not known if
there are systemic effects at higher doses via the dermal route; the
dermal toxicity study was, therefore, considered a data gap until it is
repeated up to the limit dose.  The HIARC selected an oral study because
of the concern for the developmental toxicity seen in the rabbits which
are not assessed in the dermal study.  Furthermore, the NOAEL/LOAEL in
the selected study are supported by the NOAEL/LOAEL of the 13-week dog
(6/13 mg/kg/day) and 1-year dog (5.4/10.8 mg/kg/day) studies.  The
dermal absorption factor of 14% should be applied to extrapolate from
the oral route to the dermal route.



In its meeting of December 17, 2003, the HIARC evaluated BASF’s
response regarding the 28-day dermal toxicity study as a data gap and
concluded that another dermal toxicity study will not be needed since an
oral end-point (developmental toxicity NOAEL of 5.0 mg/kg/day) with a
14% dermal absorption rate yield a dermal equivalent dose of 36
mg/kg/day (5 ÷ 0.14) which is well below the NOAEL of 250 mg/kg/day
established in the available study and, therefore, should address any
concerns for toxicity via the dermal route (TXR No. 0051553).

3.4.7	Dermal Exposure (Long-Term)   TC \l3 "3.4.7	Dermal Exposure
(Long-Term) 

  SEQ CHAPTER \h \r 1 Study Selected:  Rat Oral Carcinogenicity			
§870.4200

MRID No.:  45118331

	

Executive Summary:	under above item 3.5.3

Dose and Endpoint for Risk Assessment:  The NOAEL of 3.4 mg/kg/day based
on decreased body weight and body weight gains, increased incidences of
kidney tubular casts and atrophy in males and females, and in males, an
increased incidence of liver necrosis, gross and microscopic evidence of
erosion/ulcer of the glandular stomach and an increased incidence of
acanthosis (hyperplasia) and ulcers of the forestomach at 9.2 mg/kg/day.

Comments about Study/Endpoint:   This study/dose/endpoint was also used
for deriving the chronic RfD.  The dermal absorption factor of 14%
should be applied to extrapolate from the oral route to the dermal
route.

3.4.8	Inhalation Exposure (Short-, Intermediate-, and Long-Term)   TC
\l3 "3.4.8	Inhalation Exposure (Short-, Intermediate- and Long-Term) 

Study Selected: 28-Day rat inhalation

MRID No.:  46638801

EXECUTIVE SUMMARY:  In a subchronic inhalation toxicity study (MRID
46638801), Pyraclostrobin (BAS 500F) technical (98.7% a.i., Batch #
LJ27882/199/b) was dissolved in acetone and administered as an aerosol
to 10 Wistar rats/sex/concentration by nose-head only exposure at
concentrations of 0 (air), 0 (vehicle control), 0.001, 0.030, or 0.300
mg/L for 6 hours per day, 5 days/week for 28 days (i.e., 20 exposure
days).

There were no treatment-related effects on any parameters examined
during the FOB or on locomotor activity, ophthalmoscopy, clinical
chemistry, or organ weights except for decreased thymus weight and
relative weight (27-29%) in females and increased relative spleen weight
(33%) in males of the 0.300 mg/L group.

At 0.300 mg/L, several clinical signs of toxicity were observed among
males and females during daily or weekly examinations including urine
odor, slight visually increased respiration, and piloerection in
addition to abdominal position and moderate labored respiration observed
in one male on Day 21.  Additionally, at this concentration, four males
and three females died prior to scheduled termination.  Prior to death,
these animals exhibited visually increased respiration, urine odor, and
piloerection.

At 0.300 mg/L, decreases in body weights of 4-7% (not significant [NS]
except on Day 21) and decreases in cumulative body weight gains of
43-141% (p<0.05) were noted in the males throughout the study.  Food
efficiency was decreased (p<0.05) at this concentration on Day 7 (-2.6%
treated vs. 4.0% controls) and on Day 21 (6.5% treated vs. 9.9%
controls).  Additionally on Day 21, food efficiency was decreased in the
0.030 mg/L males (5.8% treated vs. 9.9% controls).  In both sexes at
this concentration, an initial decrease of 11-13% (p<0.05) in food
consumption was observed on Day 7.    

At 0.300 mg/L, absolute and relative (to body) thymus weights were
decreased (27-29%, p<0.01) in males while relative spleen weight was
increased in females (33%, p<0.01).  Minor changes were also seen in
weights of liver, kidneys, and lungs but were not considered
treatment-related. 

At 0.300 mg/L, leukocytes and neutrophils were increased in both sexes. 
As discussed below, the increased white blood cells (specifically
neutrophils) may be an inflammatory response to the treatment-related
effects on the respiratory tissues.

At 0.030 and 0.300 mg/L, diffuse mucosal hyperplasia of the duodenum was
observed in 5-7 males (vs. 0 controls) and in 5-10 females (vs. 1
control).  This finding increased with dose in both incidence and
severity.  The duodenum was also a target organ in the 90-day dietary
feeding studies in the rat, mouse, and dog (MRIDs 45118321, 45118320 and
45118323).

Other microscopic changes were effects on the respiratory system at
0.030 and 0.300 mg/L, including minimal to slight alveolar histiocytosis
in the females (5 treated vs 1 control) and minimal to moderate
olfactory atrophy/necrosis in nasal cavities II through IV in the males
(2-10) and females (3-9) compared to 0 controls.

Additional necropsy and microscopic findings in the respiratory system
in both sexes were noted at 0.300 mg/L including lung discoloration,
lung congestion, minimal to moderate hyperplasia of the respiratory
epithelium in nasal cavities I through IV, reactive inflammation in
nasal cavity I, slight olfactory regeneration/repair in nasal cavity IV,
minimal to slight respiratory hyperplasia in level III of the larynx
(males only), and minimal to slight squamous cell metaplasia in nasal
cavity III.

The LOAEL is 0.030 mg/L based on findings of hyperplasia in the
duodenum, alveolar histiocytosis in the lungs, and olfactory
atrophy/necrosis in the nasal tissues.  The NOAEL is 0.001 mg/L.

At the request of the Agency, this study was conducted for 28 days,
instead of the 90 days required by Guideline OPPTS 870.3465.  Aside from
the different study duration, this study was conducted in accordance
with Guideline OPPTS 870.3465.

This 28-day study is classified as acceptable/guideline and satisfies
the guideline requirement (OPPTS 870.3465; OECD 413) for a subchronic
inhalation study in the rat.

Dose and Endpoint for Risk Assessment:  Inhalation toxicity NOAEL of
0.001 mg/L (equivalent to 0.23 mg/kg/day) based on findings of duodenal
hyperplasia, lung alveolar histiocytosis, and nasal olfactory
atrophy/necrosis at 0.03 mg/L (equivalent to 6.92 mg/kg/day).  

Comments on Study/Endpoint/Uncertainty Factors:  Study duration and the
endpoint are appropriate for the short or intermediate scenarios of
inhalation exposure.  As stated in the study’s executive summary, HED
concurred with the duration of 28 days, instead of the 90 days required
by Guideline OPPTS 870.3465.  The same study and endpoint will also be
used for long-term residential and occupational inhalation scenarios
even though long-term exposures are not expected at this time.  For
long-term inhalation exposure scenarios, the level of concern for MOE
will be retained at 100, i.e., it will not be increased to account for
using the short-term study for the long-term scenario.  This decision is
supported by the large NOAEL/LOAEL dose spread (30-fold) and the fact
that additional and more severe toxicity findings were seen at the top
dose which is only 10-fold higher than the LOAEL.

3.4.9	Level of Concern for Margin of Exposure  TC \l3 "3.4.9	Level of
Concern for Margin of Exposure 

Table 2.  Summary of Levels of Concern for Risk Assessment.

Route	Short-Term

(1 - 30 Days)	Intermediate-Term

(1 - 6 Months)	Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	100	100	100

Inhalation	100	100	100

Residential Exposure

Dermal	100	100	100

Inhalation	100	100	100

Incidental Oral	100	100	100



3.4.10	Recommendation for Aggregate Exposure Risk Assessments  TC \l3
"3.4.10	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 was 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.

3.4.11	Classification of Carcinogenic Potential  TC \l3 "3.4.11
Classification of Carcinogenic Potential 

With the termination of the supplemental carcinogenicity study in female
mice (MRID 46678201), the CARC reevaluated the carcinogenicity potential
of pyraclostrobin.  In accordance with the EPA’s Final Guidelines for
Carcinogen Risk Assessment (March, 2005), 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.  The
CARC concluded that quantification of carcinogenic potential is not
required (TXR document no. 0054516, dated 2/15/07.

3.4.12	Summary of Toxicological Doses and Endpoints for Pyraclostrobin
for Use in Human Risk Assessments  TC \l3 "3.4.12	Summary of
Toxicological Doses and Endpoints for Pyraclostrobin for Use in Human
Risk Assessments 

With the exception of inhalation and carcinogenicity risk assessments,
all previous exposure risk assessments remain unchanged.  Below are the
updated tables.  



Table 3. 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 4.  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.



3.5	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	Dietary Exposure/Risk Characterization  TC \l1 "4.0	Dietary
Exposure/Risk Characterization 

References:

Pyraclostrobin.  PP#’s 5F7002 and 5E7014.  Petition for Tolerances on
Cotton and Belgian Endive, and An Increased Tolerance on the Berries
Crop Group. Submission of Requested Field Trial Data on Mustard Greens
(PP#3F6581).  Submission of Additional Field Trial Data on Fruiting
Vegetables (PP#0F6139), Cucurbit Vegetables (PP#0F6139), Sunflower
(PP#2F6431), Mint (PP#2F6431), and Grape(PP#0F6139).  Summary of
Analytical Chemistry and Residue Data.  (Reg. No. 7969-198). DP Number
327899; J. Stokes; 03/30/07.

Pyraclostrobin. PP5E7014.  Amendment.  Petition for Tolerance on Belgian
Endive.  Additional Discussion of Residue Data and Its Use For
Adjustment of Previous Tolerance Recommendation.  Request for Revised
Sections B and F. DP Number 339733; J. Stokes; 05/30/07.



4.1	Pesticide Metabolism and Environmental Degradation  TC \l2 "4.1 
Pesticide Metabolism and Environmental Degradation 

4.1.1	Metabolism in Primary Crops  TC \l3 "4.1.1	Metabolism in Primary
Crops 

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

4.1.2	Metabolism in Livestock  TC \l3 "4.1.2	Metabolism in Livestock 

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

4.1.3	Analytical Methodology  TC \l3 "4.1.3	Analytical Methodology 

Enforcement Method for Plants

Two adequate methods were proposed for enforcing tolerance for residues
of pyraclostrobin and BF 500-3 in/on plant commodities: a LC/MS/MS
method (BASF Method D9808), and an HPLC/UV method (BASF Method D9904). 
The validated method LOQ for both pyraclostrobin and BF 500-3 is 0.02
ppm in all tested plant matrices, for a combined LOQ of 0.04 ppm. 
Adequate independent method validation and radiovalidation data were
submitted for both methods (D269668, 11/28/01, L. Cheng), and both
methods were forwarded to ACB/BEAD for a petition method validation
(D269850, 11/8/00, L. Cheng).

Samples from the current crop field trials and cotton processing study
were analyzed for residues of pyraclostrobin and BF 500-3 using the
LC/MS/MS method (BASF Method D9908, MRID 46710001 (currently under BEAD
review)).  For all commodities, except cottonseed oil, residues were
extracted with methanol:water:2N HCl (70:25:5) and filtered.  For oil
samples, residues were extracted with hexane, partitioned into
acetonitrile, concentrated, and redissolved in methanol:water:2N HCl
(70:25:5).  Residues from all samples were then cleaned up by
partitioning into cyclohexane.  Residues of pyraclostrobin and BF 500-3
were determined by LC/MS/MS, using external standards.  For each
analyte, the validated method LOQ is 0.02 ppm and the LOD is 0.004-0.005
ppm.

Based on the concurrent method validation data, Method D9908 is adequate
collecting data on residues of pyraclostrobin and BF 500-3 in berries,
cotton commodities, cucurbit vegetables, fruiting vegetables, grape,
mint, mustard greens, and sunflower seed. 

Analytical Methods - Livestock

Two methods have also been proposed for enforcing tolerances for
livestock commodities:  HPLC/UV method 439/0 and Method 446 (consisting
of GC/MS method 446/0 and LC/MS/MS method 446/1).  The HPLC/UV method
determines residues of pyraclostrobin per se.  Method 446 has a
hydrolysis step, and determines residues of pyraclostrobin and its
metabolites as BF 500-5 and BF 500-8.  The validated method LOQs for BF
500-5 type residues, in parent equivalents, are 0.01 ppm for milk and
0.05 ppm for tissues, and the validated LOQs for BF 500-8 type residues,
in parent equivalents, are 0.01 ppm for milk and 0.05 ppm for tissues. 
Independent method validation data for the HPLC/UV and LC/MS/MS methods
are acceptable (D269668, 11/28/01, L. Cheng).  Radiovalidation data
submitted for the GC/MS and LC/MS/MS methods are adequate for liver and
milk, and marginal for muscle.  Method 446 has been forwarded to
ACB/BEAD for petition method validation.  As poultry tolerances are not
currently necessary, an enforcement method for poultry commodities is
not required at the present time.

Multiresidue Methodology (860.1360)

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

4.1.4	Storage Stability Data  TC \l3 "4.1.4	Storage Stability Data 

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

Conclusions.  Adequate storage stability data are available to support
the samples storage conditions and intervals from the current field
trials for cotton and Belgian endive, and for the cottonseed processing
study.  The storage stability data on tomato support the berry, fruit
vegetable, grape, and cucurbit vegetable field trials, and the storage
stability data on sugar beet tops support the mustard greens and mint
field trials.  The storage stability data on peanut nutmeats and oil
support the residue data on sunflower seeds and cotton seed and oil, and
the storage stability data on wheat straw support the data on cottonseed
hulls and gin byproducts.

4.1.5	Magnitude of the Residue in Plants  TC \l3 "4.1.5	Magnitude of the
Residue in Plants 

46512002.der (Cucurbit vegetables)	46512003.der (Sunflower)	46637701.der
(Berries) 46665501.der (Fruiting vegetables)	46665502.der (Mint)
46665504.der Grape)

46665506.der (Mustard greens)	46685901.der (Cotton)

BASF submitted cotton field trials supporting a new use for
pyraclostrobin (EC) on cotton, along with previously requested
additional field trials on mustard greens supporting the existing use on
Brassica leafy greens.  In addition, BASF submitted supplemental field
trials from the U.S. and Canada on berries, cucurbit vegetables,
fruiting vegetables, grape, mint and sunflower.  These field trials were
conducted to support uses on these crops in Canada, and therefore are
not discussed in detail in this document.    SEQ CHAPTER \h \r 1 The
results from these studies are summarized in Table 5 and discussed
below, along with the previously reviewed data on the above crops. 
Additionally, the data on berries were submitted to support an increase
in the berries crop group tolerance. 

Table 5.	Summary of Residue Data from Crop Field Trials with
Pyraclostrobin.

Crop/commodity	Total Applic. Rate  (lb ai/A)	PHI (days)	Combined
Pyraclostrobin Residues (ppm) 1

	n	Min.	Max.	HAFT 2	Median	Mean	Std. Dev.

Berries (0.72 lb ai/A total application rate, 0-day PHI)

Red raspberries	0.73-0.75	0	6	0.76	1.33	1.28	1.01	1.04	0.22

Blueberries	0.73-0.75	0	12	1.11	2.52	2.33	1.55	1.73	0.50

Overall Berries	0.73-0.75	0	18	0.76	2.52	2.33	1.32	1.50	0.54

Cotton (0.80 lb ai/A total application rate, 30-day PHI)

Undelinted, seed	0.80-0.85	29-33	24	<0.04	0.17	0.15	0.03	0.05	0.04

Gin byproducts 3	picker	0.80-0.85	29-30	6	2.04	25.06	20.35	3.38	8.60
9.60

	stripper

30-32	6	1.05	2.00	1.91	1.74	1.59	0.42

Cucurbit Vegetables (1.2 lb ai/A total application rate, 0-day PHI)

Cucumber	1.17-1.20	0	8	0.053	0.186	0.180	0.102	0.106	0.057

Cantaloupe	1.18-1.20	0	4	0.099	0.379	0.338	0.202	0.218	0.143

Squash	1.16-1.20	0	8	0.094	0.213	0.190	0.126	0.131	0.037

Cucurbits	1.16-1.20	0	20	0.053	0.379	0.338	0.118	0.139	0.082

Fruiting Vegetables (1.2 lb ai/A total application rate, 0-day PHI)

Tomato	0.54-0.58	0	14	0.096	0.366	0.304	0.178	0.192	0.086

Pepper	0.55-0.61	0	6	0.092	0.701	0.689	0.344	0.375	0.268

Fruiting Vegetables	0.54-0.61	0	20	0.092	0.701	0.689	0.207	0.247	0.177

Grape (0.55 lb ai/A total application rate, 14-day PHI)

Grape	0.56-0.57	13-14	8	0.56	1.93	1.86	1.28	1.30	0.48

Mustard Greens (0.80 lb ai/A total application rate, 3-day PHI)

Mustard greens	0.8	0	10	5.5	14.4	12.6	8.3	8.9	2.5

3	6	1.4	5.5	5.1	3.7	3.4	1.7

7	6	1.0	2.3	2.2	1.9	1.7	0.6

14-15	6	0.18	1.2	1.0	0.31	0.5	0.4

Sunflower (0.40 lb ai/A total application rate, 21-day PHI)

Seed	0.40	21	2	<0.04	<0.04	<0.04	0.02	0.02	NA

Mint (0.80 lb ai/A total application rate, 14-day PHI)

Mint tops	0.91-0.92	7	4	2.25	3.65	3.55	2.96	2.96	0.69

1	Residues of pyraclostrobin and BF 500-3 are expressed in parent
equivalents, and the LOQ is 0.02 ppm for each analyte or 0.04 ppm for
the combined residues.  For purposes of calculating median and mean and
standard deviation, ½ LOQ (0.01 ppm) was used for residue values of
each analyte that were <LOQ. 

2	HAFT = Highest Average Field Trial.

3	Samples of gin byproducts were obtained from trials harvested using
mechanical picker (3 tests) and strippers (3 tests).

4	A sixth application was inadvertently applied to cherries.

Brassica Leafy Green, Subgroup 5B

Mustard Greens.  The Agency previously reviewed residue data from five
mustard green field trials conducted in Zones 2, 4, 5, 6 and 10 during
2001 (PP#3F6581, D281042, L. Cheng, 7/26/04).  In each trial,
pyraclostrobin (20% WDG) was applied to mustard greens as four broadcast
foliar applications at 0.2 lb ai/A, at RTIs of with a 6 to 8 days, for a
total of 0.8 lb ai/A/season (1x rate).  Applications were made using
ground equipment at 12-31 gal/A, and included the use of a spray
adjuvant.  Samples of mustard greens were harvested 0, 3, 7, 10, and 14
DAT; the label specified PHI is 3 days.  Samples were analyzed using an
adequate LC/MS/MS method (BASF Method Number D9908), and the sample
storage conditions and intervals (6.6 months) were supported by the
available storage stability data.  

In these five field trials, the combined pyraclostrobin residues were
1.13-13.40 ppm in/on 10 samples of mustard greens harvested at the
labeled 3-day PHI.  The HAFT residues were 12.95 ppm and average
residues were 7.13 ppm.  Based on these data, the Agency established a
16 ppm tolerance for pyraclostrobin residues in/on Brassica leafy
greens.  However, as a condition of registration the Agency also
requested data from three additional field trials in Zones 2, 3, and 10.

In response to this request, BASF submitted field trial data from six
mustard green field trials conducted in Zones 2, 3 and 10 during 2004
and 2005.  In each test, pyraclostrobin (20% or 12.8% WDG) was applied
to mustard greens as four broadcast foliar applications at 0.2 lb ai/A
during vegetative crop development, for a total rate of 0.8 lb ai/A (1x
rate).  Applications were made RTIs of 6-8 days using ground equipment
at 13-32 gal/A, and each application included the use of a non-ionic
surfactant at 0.25% of the spray volume.  For the 2004 tests, single
control and duplicate treated samples of mustard greens were harvested
at 0 days after the last application (0 DAT).  For the 2005 tests,
single control and duplicate treated samples of mustard greens were
harvested at 0, 3, 7, and 14-15 DAT, with the exception of the CA test
in which 0-DAT samples were not collected.   Samples were stored frozen
for up to 8.7 months prior to analysis, an interval supported by
available storage stability data.  Samples were analyzed for residues of
pyraclostrobin and BF 500-3 using an adequate LC/MS/MS method (BASF
Method D9908), which has a LOQ of 0.02 ppm for each analyte.  

In these tests, combined pyraclostrobin residues in/on mustard greens
were 5.5-14.4 ppm at 0 DAT and declined steadily to 0.18-1.20 ppm at
14-15 DAT.  At the label-specified preharvest interval of 3 days,
combined residues were 1.4-5.5 ppm.  Average combined residues were 8.9
ppm at 0 DAT, 3.4 ppm at 3 DAT, 1.7 ppm at 7 DAT, and 0.5 ppm at ~14
DAT.  These data satisfy the outstanding condition of registration data
requirement for additional field trial data.

Belgian Endive

The submitted field trial data ( MRID 46713801) do not support the
proposed use of pyraclostrobin on Belgian endive.  The field trial data
are inadequate, because the application method used does not agree with
the proposed use pattern.  The label proposes application by an overhead
sprayer, while the roots transverse on a conveyor belt or while in place
in forcing trays.  Unfortunately, most of the submitted residue data
were generated using a hand wand and back pack sprayer (5 of 6
applications).  Only a few data points were generated using an overhead
sprayer.  The field trials were conducted in California.  The trials
represent NAFTA growing region 10.  The number of trials and geographic
representation are adequate for Belgian endive.  Two root spray
applications of BAS 510 (boscalid) and BAS 500 F (pyraclostrobin) were
made at two application rates prior to cold storage and prior to
forcing.  One set of Belgian endive was treated at rates (0.5X) of
approximately 0.011 lb pyraclostrobin per 875 lb roots (plus boscalid). 
Another set was also treated at 1X rates of approximately 0.022 lb
pyraclostrobin per 875 lb roots (plus boscalid.

The maximum storage interval for treated samples in this study was 198
days (see Table 4).  The storage stability for pyraclostrobin in/on
Belgian endive was not determined in this study.  However, in a
previously submitted storage stability study pyraclostrobin residues
were shown to be stable for 18 months.  Pyraclostrobin residues in/on
Belgian endive treated at the 0.5X rate ranged from 0.05 to 2.90 ppm
(1.55 ± 1.24).  Also, pyraclostrobin residues ranged from 1.48 to 7.96
ppm in samples treated at the 1X rate.  

If IR4 still wants a Section 3 registration, then the following are
needed: 

Use directions in Section B must match the application method used in
Section D for residue data collection;

The tolerance proposal in Section F must be supported by the application
method used in Section D for residue data collection;

Additional residue data that adequately reflect the use direction in
Section B must be submitted. (HED recommends that the petitioner submit
a protocol for HED review and comment before any residue data collection
begins.); and

The label should include a requirement for chemical-resistant gloves.

HED recommends that the label rate be revised to clearly define the
amounts to be used per application and the total per season.  In
addition, the petitioner should define how the spray is applied to the
roots in the forcing trays (.i.e., trays are stationary or are moving on
a conveyor belt).  A revised Section B must be submitted to adequately
reflect the petitioner’s intentions as to application rates and
directions.  Refer to section 9.1 for details.

Cotton

In twelve field trials conducted in Zones 2, 4, 6, 8 and 10 during 2004,
pyraclostrobin (20% WDG) was applied to cotton four times; first as an
in-furrow application at planting at 0.20-0.21 lb ai/A, followed by
three broadcast foliar applications during boll development at 0.20-0.24
lb ai/A at RTIs of 5-9 days, for a total of 0.80-0.85 lb ai/A/season (1x
proposed rate).  All applications were made using ground equipment at
5-10 gal/A for the in-furrow application and at 11-39 gal/A for the
foliar applications.  Foliar applications included the use of a
non-silicone surfactant at 0.25% of the spray volume.  Single control
and duplicate treated cotton samples were harvested by hand (1 site), or
by mechanical picker (7 sites) or stripper (4 sites) at 29-33 DAT. 
Samples of undelinted seeds were collected from all sites, and cotton
gin byproducts (gin trash) were collected from six sites (3 stripper and
3 picker).  All samples were stored at <-10 ºC for up to 6.6 months
prior to analysis, an interval which is supported by the available
storage stability data.

Samples of cottonseed and gin byproducts were analyzed for residue of
pyraclostrobin and BF 500-3 using a LC/MS/MS method (BASF Method D9908),
which was adequately validated in conjunction with the field trial
analyses.  The method LOQ and LOD for each analyte is 0.02 and 0.005
ppm, respectively.

At maturity (29-33 DAT), residues in/on 24 treated samples of undelinted
cotton seed were <0.02-0.14 ppm for pyraclostrobin and <0.02-0.028 ppm
for BF 500-3, for combined residues of <0.04-0.17 ppm.  Average combined
residues were 0.05 ppm in/on undelinted seeds, and HAFT residues were
0.15 ppm.  Residues in/on gin trash were generally higher for cotton
harvested using a picker than for cotton harvested using a stripper. 
Following harvest with a picker, combined residues in/on six samples of
gin trash were 2.04-25.06 ppm and averaged 8.60 ppm.  Following harvest
with a stripper, combined residues in/on six samples of gin trash were
1.05-2.00 ppm and averaged 1.59 ppm.



Berries, Group 13

Blueberries and Raspberries.  Adequate field trial data are available
supporting the use of pyraclostrobin (WDG) on the berries crop group in
the U.S. (PP#0F6139, D269668, 11/28/01, L. Cheng).  In a total of nine
field trials conduct in the U.S. during 1999, pyraclostrobin (20% WDG)
was applied to red raspberries (3 tests) and blueberries (6 tests) as
four broad foliar applications during fruit development at 0.18-0.19 lb
ai/A at RTIs of 6-7 days, for a total of 0.72-0.74 lb ai/A (1x rate). 
Applications were made using ground equipment in 50-102 gal/A, and
included the use of a non-silicone spray adjuvant.  Single control and
duplicate treated samples of blueberries and raspberries were harvested
from each test immediately following the last application (0 DAT). 
Samples were stored frozen for up to 3 months and then analyzed for
residues of parent and BF 500-3 using BASF Method D9808.  C  SEQ CHAPTER
\h \r 1 ombined pyraclostrobin residues were <0.12-0.69 ppm in/on
highbush blueberries and <0.46-0.97 ppm in/on red raspberries.  Based on
these residues, the Agency established a 1.3 ppm tolerance on the
berries crop group.

To support the use of pyraclostrobin on berries grown in Canada, BASF
recently submitted additional data from three raspberry field trials
conducted in Zones 5, 5B, and 12, and six blueberry field trials were
conducted in Zones 1A and 5 during 2004.  At each test location,
pyraclostrobin (12.8% WDG) was applied as four broadcast foliar
applications at 0.17-0.19 lb ai/A during fruit development at RTIs of
6-8 days, for totals of 0.73-0.75 lb ai/A (1x rate, 0.82-0.84 kg ai/ha).
 Applications were made using ground equipment at 29-85 gal/A (267-798
L/ha), and included the use of a non-ionic surfactant at 0.25% of the
spray volume.  Single control and duplicate treated samples of mature
berries were harvested from each test at 0 DAT.  Samples were stored
frozen for up to 6 months prior to analysis, and analyzed using BASF
Method D9908, which was adequately validated in conjunction with the
field trial analyses.  The method LOQ and LOD is 0.02 and 0.004 ppm for
each analyte in berries.

In the 2004 field trials, combined pyraclostrobin residues were
0.76-1.33 ppm in/on six samples of red raspberries and 1.11-2.52 ppm
in/on 12 samples of blueberries.  Combined residues averaged 1.04 and
1.73 ppm for raspberries and blueberries, respectively, and HAFT
residues were 1.28 and 2.33 ppm.  For all nine berry tests, combined
residues averaged 1.50 ppm.  As residue in these field trials exceeded
the current U.S. tolerance for the berries crop group, BASF has proposed
increasing the tolerance for berries to 4.0 ppm.

Conclusions:  The required field trials on cotton and the supplemental
field trials on, mustard greens and berries are adequate and support the
proposed or existing uses of pyraclostrobin on these crops.  Together
with the previously submitted field trials, the number and geographic
distribution of the field trials on these crops are adequate, and the
appropriate samples were collected at the proposed PHIs.  

Although the cotton field trials were conducted using the 20% WDG
formulation and the proposed use on cotton is for the 2 lb/gal EC
formulation, the cotton field trial data for the WDG will support the
use of the EC formulation, as previously submitted side-by-side field
trials using tomato, cucumber and grape have shown that residues
resulting from the two types of formulations are similar.

Several deficiencies were found in the Belgian endive field residue
trials.  Most importantly, the application method used in the field
residue trials does not agree with the proposed use pattern.

The submitted supplemental field trials on fruiting vegetables (tomato
and peppers) were also adequate, but are not useful for assessing the
current U.S. tolerance as the field trials were conducted at 0.5x the
maximum seasonal use rate on existing U.S. labels.  However, sufficient
tomato and pepper field trials are already available to support the
existing use on fruiting vegetables.

4.1.6	Magnitude of the Residue in Processed Food/Feed  TC \l3 "4.1.6
Magnitude of the Residue in Processed Food/Feed 

46685902.der (cotton)

For the new cotton processing study, pyraclostrobin (20% WDG) was
applied to cotton in a single trial as a combination of an in-furrow
application at 1.0 lb ai/A followed by three broadcast foliar
applications during boll development at 1.0 lb ai/A/application, for a
total of 4.0 lb ai/A/season (5x maximum proposed rate).  Following
applications at a 5x rate, combined pyraclostrobin residues in/on
undelinted cottonseed at 30 DAT were 0.106 and 0.176 ppm and averaged
0.14 ppm.  Combined residues were <0.04 ppm in/on all cotton processed
commodities, for processing factors of <0.3x for each commodity.  The
maximum theoretical processing factor for undelinted cottonseed is 6.3x
(oil).

Conclusions.  The new cotton processing study is adequate and indicates
that residues do not concentrate in cottonseed hulls, meal or oil.

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

Adequate feeding studies were reviewed in conjunction with an earlier
pyraclostrobin petition (D269668, 11/28/01, L. Cheng).  In the ruminant
feeding study, dairy cows were dosed orally for 28 days with
pyraclostrobin at levels equivalent to 8.8, 27.2, and 89.6 ppm in their
diet, and in the poultry feeding study, laying hens were dosed orally
for 30 days with pyraclostrobin at levels equivalent to 0.28, 0.88, and
3.01 ppm in their diet. 

The current tolerances for livestock commodities were established based
on results from the available feeding studies and the Agency’s
estimated dietary burdens for pyraclostrobin residues, which were
previously calculated to be 36.3 ppm for beef cattle, 35.4 ppm for dairy
cattle, and 0.35 ppm for poultry (D269668, 11/28/01, L. Cheng). 

The new livestock feedstuffs included in the current petition are
cottonseed, hulls, meal, and gin byproducts.  The potential dietary
exposure of livestock to pyraclostrobin residues has been recalculated
below in Table 6 using recent Agency guidance on calculating dietary
exposure from “reasonably balanced” livestock diets to include all
feedstuffs with existing tolerances and those proposed.  Based on these
recalculated dietary exposure levels and the residue data from the
ruminant feeding study, the existing tolerances are adequate for milk,
meat, fat, meat byproducts (except liver), and liver of cattle, goats,
horses, and sheep.  In fact, the current tolerances of 1.5 ppm for liver
of cattle, goats, horses, and sheep could be reasonably lowered to 1.0
ppm.  

In addition, the existing tolerances for hog commodities can be deleted
as quantifiable residues are unlikely to occur in hog [40 CFR
§180.6(a)(2)] as residues of pyraclostrobin and its metabolites were
<LOQ in meat, fat, kidney and liver of cattle dosed at 8.8 ppm, which is
46x the calculated dietary burden for swine.  As noted in earlier
pyraclostrobin petitions (D269668, 11/28/01, L. Cheng), the data from
the poultry feeding and metabolism studies indicates that tolerances for
residues in poultry commodities are not required at the present time.

Table 6. Livestock dietary burdens for pyraclostrobina.

	% Diet b	Residue (ppm)

Feedstuff	Type	Tolerance,

ppm	% Dry Matter	Beef	Dairy	Poultry	Swine	Beef 	Dairy 	Poultry 	Swine 

barley hay	R	25	88	10	25	-	-	2.8	7.1	-	-

cotton gin byproducts	R	30.	90	5	-	-	-	1.7	-	-	-

legume, hay (cowpea)	R	25	86	-	15	-	-	-	4.4	-	-

barley, grain	CC	0.4	88	50	45	20	20	0.23	0.20	0.08	0.08

corn, field, grain	CC	0.1	88	20	-	60	65	0.023	-	0.06	0.065

	

cotton, undelinted seed	PC	0.3	85

15

0.053

sunflower (meal)	PC	0.3	92	15

20	15	0.049

0.06	0.045

Totals

100	100	100	100	4.8	11.8	0.20	0.19

a All data are based on Table 1 Feedstuffs (October 2006), a revision of
feedstuffs data found in Table 1 (180.1000 OPPTS Test Guidelines). 
Residue levels for beef and dairy are corrected for moisture content and
are determined by formula: tolerance / %DM x % in diet.  Residue levels
for poultry and swine are considered “as-is” and are determined by
formula: tolerance  x   % in diet.  R: roughage; CC: carbohydrate
concentrate;  PC:  protein concentrate.

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

Feedlot beef have a daily ration of 15-40 %  R, 45-80 %  CC, and 5-15 % 
PC.  As the slaughter time (last 3 months) gets closer, then the beef
cattle are fed higher amounts of CC (up to 80 %), and lower amounts of 
R (15-20 %) and PC (5-10 %).  The average life span for feedlot beef is
16-18 months   Most of feedlot beef are slaughtered in 4 major centers
located in the Midwest and the processed meat is “boxed” and shipped
to distributors for sale to local grocers.  Commercial ground beef
(75-93 % lean) is produced from the combination of feedlot beef (60-70 %
lean) and other lean meat sources, i.e., beef cows and bulls from
cow-calf operations, imported lean meat trimmings, and non-lactating
dairy cows. 

High volume milk-producing lactating dairy cows have a daily ration of
45 % R, 40-45 % CC, and 10-15 % PC.  Dairy cows usually produce 2-3
calves before slaughter. The average life span of the lactating dairy
cow is 3-4 years.  Upon slaughter, much of the meat is used in ground
beef and processed foods e.g., deli meats, soups, frozen
dinners/entrees.

A laying hen that will give a steady egg production is fed 75-80 % CC
and 20-25 % PC.   The life span can be up to 18 months.  In general,
laying hens are not processed and marketed as whole or cut-up chickens.
Much of the layer meat is used in processed food products, e.g., deli
meats, soups, canned chicken, etc.  (Note:  The laying hen is the animal
of choice.  Frying and rotisserie chickens come from the broiler, a fast
food chicken, weighing 3.5-4.0 lb.), and an animal that is raised in a
very short time.  The average life span is 38-42 days.  The broiler diet
contains 85-90 % CC and 10-15 % PC.    

A marketable hog diet that will give steady growth would have 80-85 % CC
and 15-20 % PC.  Most of the US hog production is confined to “mega”
operations.  Animals are born in in-house nurseries, and simply moved to
connecting buildings as the animal grows until slaughter (250 lb
finished animal in 6 months). These animals provide meat for the
“fresh pork” market.

Note:  These guidelines are not to be used for pesticide residues that
bioaccumulate.  Contact Health Effects Division, OPP, EPA for these
types of pesticides.



4.1.8	Confined and Field Rotational Accumulation in Rotational Crops  TC
\l3 "4.1.8	Confined and Field Accumulation in Rotational Crops 

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

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

4.1.9	Drinking Water Residue Profile TC \l3 "4.1.9	Drinking Water
Residue Profile 

Reference: Drinking Water Assessment for the Use of Pyraclostrobin (P.C.
Code: 099100) on Undelinted Cotton Seed, Cotton Gin By-Products, and
Berries Group 13 (DP Barcode D326246) A. Al-Mudallal, 2/21/07.

The Environmental Fate and Effects Division (EFED) reviewed the proposed
use rates associated with the Section 3 request for the use of
pyraclostrobin on cotton and berries group 13.  EFED concluded that the
proposed use rates are much lower than the use rate on turf, the crop
that was previously selected for the drinking water assessment. 
Additionally,  the use rates for the proposed uses on Belgian endive are
considerably lower than the use rate on turf.  Therefore, the estimated
concentrations of pyraclostrobin in drinking water associated with the
last Section 3 request remain valid.

A summation of the previous drinking water assessment is as follows:  A
Tier 2 drinking water assessment was performed using PRZM 3.12/ EXAMS
2.7.97 modeling with index reservoir (IR) scenarios and percent cropped
area (PCA) adjustment factors.  The assessment was based on the highest
registered use rate of pyraclostrobin on turf.  A Florida turf scenario
was used with six ground applications of 0.5 lbs ai/acre, at 14 day
intervals.  The modeled scenario reflects a region with high rainfall
and high vulnerability to runoff.  A default PCA factor of 0.87 was
used.  The Tier II modeling predicts that the concentrations of
pyraclostrobin in surface water are not likely to exceed 10.2 µg/L for
the peak concentration, 0.8 µg/L for the annual average concentration,
and 0.5 µg/L for the 30 year average concentrations.

The ground water concentrations were estimated using a Tier I SCI-GROW
model (version 2.2, Nov. 1, 2001).  The assessment was based on the
highest registered use rate of pyraclostrobin on turf.  The SCI-GROW
model predicts the acute and chronic concentrations of pyraclostrobin in
shallow ground water to be 0.02 ppb.  Ground water sources were not
included in the dietary assessment, as the EDWCs for this water source
are minimal in comparison to surface water.

4.1.10	Proposed Tolerances TC \l3 "4.1.10	Proposed Tolerances 

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

Tolerances for plant commodities 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 29 ppm in/on leafy vegetables, except Brassica [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 or 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, horses, and sheep [40 CFR §180.582(a)(2)].  No
tolerances are established for poultry commodities.

The tolerances proposed by BASF and IR-4 for the current petitions are
listed in Table 8, along with the Agency’s recommended tolerance
levels.  

The tolerance proposed for Belgian endive is denied, because the
application method used in the field residue trials does not agree with
the proposed use pattern, and the residue data generated from these
trials therefore do not support the proposed tolerance.  This deficiency
precludes the establishment of a permanent tolerance for pyraclostrobin
on the proposed commodity Belgian endive at this time.

As the majority of cottonseed samples from the cotton field trials had
residues below the combined LOQ (0.04 ppm), the recommended tolerance
level for undelinted seeds were not determined using the Tolerance/MRL
Harmonization Spreadsheet.  Rather, the recommended tolerance of 0.3 ppm
is based on the maximum combined residues observed in seeds (0.17 ppm). 
Tolerances for cotton gin byproducts and the berries crop group were
both determined using the Tolerance/MRL Harmonization Spreadsheet as
combined residues were readily quantifiable in these commodities.  For
the berries crop group, residue values from both the earlier and new
berry field trials were used to calculate the appropriate tolerance, and
the data from raspberries and blueberries were pooled as residue levels
were similar on both types of berries.  The calculated tolerances were
30 ppm for cotton gin byproducts and 4.0 ppm for the berries crop group.

Results from the requested mustard greens field trials and the
supplemental field trials on cucurbit vegetables, fruiting vegetables,
grape, sunflower, and mint indicate that no changes are necessary in the
existing tolerances for these crops.  For each crop, the combined
residues in the new field trials were below the established tolerances. 

With regards to the current tolerances for livestock commodities, the
existing tolerances are adequate for milk, meat, fat, meat byproducts
(except liver), and liver of cattle, goats, horses, and sheep, and the
current tolerances for liver could be lowered to 1.0 ppm.  Also, the
existing tolerances for hog commodities can be deleted as quantifiable
residues are unlikely to occur in hogs [40 CFR §180.6(a)(2)] based on
the dietary burden proposed in Table 6.  As stated previously,
tolerances are still not required for poultry commodities.

The Codex Alimentarius Commission, Mexico and Canada have not
established any maximum residue limits (MRLs) for residues of
pyraclostrobin in or on raw agricultural commodities, although a variety
of MRLs are pending in Canada (Appendix I).  Therefore, there are no
questions of compatibility of U.S. tolerances with International MRLs at
the present time.

Table 7. 	Tolerance Summary for Pyraclostrobin.

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

Belgian endive

	6	Denied	Denied, since field trial data does not support the proposed
tolerance.

Berry, group 13	1.3	4.0	Tolerance calculated using available residue
data and Tolerance/MRL Harmonization Spreadsheet.

Cotton, undelinted seed	0.4	0.3	Tolerance should be set at 0.3 ppm based
on maximum combined residues of 0.17 ppm.

Cotton, gin byproducts	30	30	Tolerance calculated using available
residue data and Tolerance/MRL Harmonization Spreadsheet.

4.2	Dietary Exposure and Risk TC \l2 "4.2  Dietary Exposure and Risk 

References:  Pyraclostrobin. Acute and Chronic Aggregate Dietary and
Drinking Water Exposure and Risk Assessments to Support New Use on
Cotton, Belgian Endive, and Increased Tolerance on the Berries Crop
Group. PC Code: 099100; Decision Number: 363131; DP Number: 337818; L.
Cheng; 04/09/07.

Pyraclostrobin. Amended Acute and Chronic Aggregate Dietary and Drinking
Water Exposure and Risk Assessments to Support New Use on Cotton,
Belgian Endive, and Increased Tolerance on the Berries Crop Group. PC
Code: 099100; Decision Number: 363131; DP Number: 340582; L. Cheng;
06/13/07.

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.

For chronic dietary exposure assessment, an estimate of the residue
level in each food or food-form (e.g., orange or orange juice) on the
food commodity residue list is multiplied by the average daily
consumption estimate for that food/food form to produce a residue intake
estimate.  The resulting residue intake estimate for each food/food form
is summed with the residue intake estimates for all other food/food
forms on the commodity residue list to arrive at the total average
estimated exposure.  Exposure is expressed in mg/kg body weight/day and
as a percent of the cPAD.  This procedure is performed for each
population subgroup.

For acute exposure assessments, individual one-day food consumption data
are used on an individual-by-individual basis.  The reported consumption
amounts of each food item can be multiplied by a residue point estimate
and summed to obtain a total daily pesticide exposure for a
deterministic exposure assessment, or “matched” in multiple random
pairings with residue values and then summed in a probabilistic
assessment.  The resulting distribution of exposures is expressed as a
percentage of the aPAD on both a user (i.e., only those who reported
eating relevant commodities/food forms) and a per-capita (i.e., those
who reported eating the relevant commodities as well as those who did
not) basis.  In accordance with HED policy, per capita exposure and risk
are reported for all tiers of analysis.  However, for tiers 1 and 2, any
significant differences in user vs. per capita exposure and risk are
specifically identified and noted in the risk assessment.

Drinking Water Inputs

The drinking water residues used in the dietary risk assessment were
provided by the Environmental Fate and Effects Division (EFED) in the
following memorandum: “Drinking Water Assessment for the Use of
Pyraclostrobin (PC Code: 099100) on Undelinted Cotton Seed, Cotton Gin
By-Products, and Berries Group 13” (A. Al-Mudallal, D326246,
2/21/2007) and incorporated directly into this dietary assessment.  EFED
concluded that the proposed use rates are much lower than the use rate
on turf, the site that was selected for the drinking water assessment. 
Therefore, the estimated concentrations in drinking water associated
with the turf use assessed in the previous Section 3 request for the use
of pyraclostrobin in-furrow on potatoes remain valid (D303496,
10/6/2004).  The drinking water assessment provides Tier II (PRZM
3.12/EXAMS 2.7.97) surface water modeling and Tier I (SCI-GROW)
groundwater modeling.  The modeling was conducted for the parent
compound only.  The residue concentrations from Tier II surface water
modeling are not expected to exceed 10.2 µg/L for the peak
concentration, 0.8 µg/L for the annual average concentration, and 0.5
µg/L for the 30 year average concentration. Residue concentration from
Tier I groundwater modeling is not expected to exceed 0.02 µg/L.  For
acute exposures the 10.2 µg/L peak concentration was used.  For chronic
exposures the 0.8 µg/L annual average concentration was used.  These
drinking water residues were incorporated in the DEEM-FCID into the food
categories “water, direct, all sources” and “water, indirect, all
sources.”

Residue Data used for Acute and Chronic Assessments

For the acute dietary analysis, tolerance level or highest field trial
residues were used for all crops.  One hundred percent crop treated was
assumed for all commodities in the assessment.  Default processing
factors were applied to all commodities except for apple juice, grape
juice, citrus juices, cottonseed oil, tomato paste, tomato puree, wheat
flour, and wheat germ where experimental factors were used. 

For the chronic dietary analysis, average field trial residue values
were used for certain crops (grape, celery, spinach, tomato, pepper,
citrus, apple, leaf lettuce, head lettuce), which are the major dietary
contributors based on preliminary runs.  One hundred percent crop
treated was assumed for all commodities in the assessment. 
Experimentally derived processing factors for apple juice, grape juice,
citrus juices, cottonseed oil, tomato paste, tomato puree, wheat flour,
and wheat germ were applied.  Note: Compared to the previous analysis,
dated 11/30/05, the following changes occurred: 1) Percent crop treated
information is no longer applied in the current chronic assessment; 2)
Anticipated residues were derived for the following crops in the chronic
assessment: apple, grape, head lettuce, leaf lettuce, orange, pepper,
and tomato; and 3) A cancer risk assessment has not been conducted since
cancer is no longer a concern for this chemical.  

For risk assessment purposes only, i.e., to help set an upper bound risk
level, the available residue data for Belgian endive resulting from the
back pack sprayer method were used in the dietary assessment.  

Results of Acute Dietary Exposure Analysis

The results of the acute dietary analysis for food only indicate that
acute dietary risks (food only) do not exceed HED’s level of concern
(less than 100% of the acute population adjusted dose (aPAD)) for the
U.S. population and all subgroups.  At the 95th percentile, the U.S.
population has an exposure from food only that results in a risk
estimated at < 2% of the aPAD.  The most highly exposed subpopulation is
“females 13-49 years” due to a substantially more sensitive
endpoint.  At the 95th percentile, this population subgroup has an
exposure from food only that results in a risk estimated at 78% of the
aPAD.

The results of the aggregate acute dietary analysis for food and water
indicate that acute dietary risks (food and water) do not exceed HED’s
level of concern (less than 100% of the acute population adjusted dose
(aPAD)) for the U.S. population and all subgroups. At the 95th
percentile, the U.S. population has an exposure from food and water that
results in a risk that is practically unchanged at <2% of the aPAD.  The
most highly exposed subpopulation is “females 13-49 years”.  At the
95th percentile, this population subgroup has an exposure from food and
water that is without change at 78% of the aPAD.

Results of Chronic Dietary Exposure Analysis

The results of the chronic dietary analysis for food only indicate that
chronic dietary risks (food only) do not exceed HED’s level of concern
(less than 100% of the chronic population adjusted dose (cPAD)) for the
U.S. population and all subgroups.  The U.S. population exposure from
food only results in a risk estimated at 19% of the cPAD.  The most
highly exposed is “children 1-2 years of age” with an exposure
estimated at 47% of the cPAD.

The results of the aggregate chronic dietary analysis for food and water
indicate that chronic dietary risks (food and water) do not exceed
HED’s level of concern for the U.S. population and all subgroups.  The
U.S. population exposure from food and water results in a risk estimated
at 19% of the cPAD.  The most highly exposed population subgroup is
“children 1 -2” with an exposure estimated at 48% of the cPAD.

The results of the chronic dietary exposure analysis (with and without
water) are reported in Tables 8 and 9, below.

Cancer Dietary Exposure Results and Characterization

The HED CARC has recently revisited the cancer classification for
pyraclostrobin, and reclassified pyraclostrobin as “not likely to be
carcinogenic to humans" and determined that regulation of cancer risk
using an MOE approach is no longer appropriate.

Table 8.  Summary of Dietary Exposure and Risk for Pyraclostrobin –
Food Only

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	0.041	1.4	0.0064	19	A separate quantitative
cancer risk assessment is not required.  

All Infants (< 1 year old)	0.051	1.7	0.0099	29

	Children 1-2 years old	0.069	2.3	0.016	47

	Children 3-5 years old	0.061	2.0	0.012	36

	Children 6-12 years old	0.045	1.5	0.0074	22

	Youth 13-19 years old	0.034	1.1	0.0045	13

	Adults 20-49 years old	0.037	1.2	0.0053	16

	Adults 50+ years old	0.039	1.3	0.0065	19

	Females 13-49 years old	0.039	78	0.0051	15

	

Table 9.  Summary of Dietary Exposure and Risk for Pyraclostrobin –
Food & 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	0.041	1.4	0.0066	19	A separate quantitative
cancer risk assessment is not required.  

All Infants (< 1 year old)	0.052	1.7	0.010	31

	Children 1-2 years old	0.070	2.3	0.016	48

	Children 3-5 years old	0.061	2.0	0.012	36

	Children 6-12 years old	0.045	1.5	0.0075	22

	Youth 13-19 years old	0.034	1.1	0.0046	14

	Adults 20-49 years old	0.037	1.2	0.0054	16

	Adults 50+ years old	0.040	1.3	0.0066	20

	Females 13-49 years old	0.039	78	0.0053	16

	

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.  Since risk estimates are below HED’s level of concern, a
more highly refined analysis is not needed at this time.  Of note is
that contribution from drinking water is minimal.  HED concludes that
the acute and chronic exposure estimates are unlikely to underestimate
actual acute or chronic exposure.

4.3	Anticipated Residue and Percent Crop Treated (%CT) Information TC
\l2 "4.3 Anticipated Residue and Percent Crop Treated (%CT) Information 

The acute and chronic dietary risk assessments are considered only
minimally refined.

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 were used to refine
the acute analysis.  

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 anticipated
average residue values were derived from crop field trials.  These field
trials represent maximum application rates and minimum PHIs.  For all
commodities 100% crop treated was assumed.  A limited number of
experimentally derived processing factors were used to refine the
analysis.

5.0	Residential (Non-Occupational) Exposure/Risk Characterization  TC
\l1 "5.0	Residential (Non-Occupational) Exposure/Risk Characterization 

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

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 near
spraying operations.  This is particularly the case with aerial
applications, but, to a lesser extent, could also be a potential source
of exposure from ground application methods.  As indicated in this
assessment, pyraclostrobin is directly applied to residential turf and
does not result in exposures of concern.  Based on this assessment, HED
believes that it is unlikely that there is a higher potential for risk
of exposure to spray drift from agricultural uses of this chemical.

6.0	Aggregate Risk Assessments and Risk Characterization  TC \l1 "6.0
Aggregate Risk Assessments and Risk Characterization 

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

Based on the proposed Section 3 food crop uses, aggregate assessments
are required 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 4.2 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 10 below).  The total combined MOE from dietary (food +
water) and non-occupational/residential exposure is 100 for children 1-2
years old, which is not of concern to HED.  For adults the total
combined MOE is 170, 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 10.  Short-/Intermediate Term Aggregate Risk Calculations 

Population	

Dermal Exposure	

Residential 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

	

Kids 1-2 yrs	

5	

0.027	

180	

5.8	

0.009425	

0.0162	

230	

100

Adults	

5	

0.019	

260	

3.4	

NA	

0.0066	

520	

170

1 The Level of Concern MOE is 100.

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

7.0	Cumulative Risk Characterization/Assessment  TC \l1 "7.0	Cumulative
Risk Characterization/Assessment 

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to 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/ .

8.0	Occupational Exposure/Risk Pathway  TC \l1 "8.0	Occupational
Exposure/Risk Pathway 

Reference: Pyraclostrobin: Occupational and Residential Risk Assessment
to Support Request for Section 3 Registrations on Cotton and Belgian
Endive. (DP#: 339336; PC#: 099100) J. Arthur; 05/24/07.



8.1	Short-/Intermediate-Term Handler Risk  TC \l2 "8.1
Short-/Intermediate-Term Handler Risk 

Cotton (foliar)

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

The results of the occupational handler exposure and risk assessment for
cotton indicate that risks are not of concern with baseline clothing, or
in some cases, when gloves are used to mitigate exposure.  Exposure
assumptions and MOE estimates are summarized in Table 11. 

The minimum level of PPE for handlers is based on acute toxicity for the
end-use products.  The Registration Division (RD) is responsible for
ensuring that PPE listed on the label is in compliance with the Worker
Protection Standard (WPS).

	Table 11.  Summary of  MOEs for Occupational Handlers of Pyraclostrobin
- Cotton

Exposure Scenario (Scenario #)	

Dermal Unit Exposure (mg/lb ai) 1	

Inhalation Unit Exposure   (mg/lb ai) 2	Application 

Rate

(lb ai/A) 3	Amount Treated

(A/day) 4	Short-/Int-

term

Dermal MOE 5	Short-/Int-term Inhalation

MOE 6

Mixer/Loader

Mixing/Loading Liquid (open pour) for Groundboom application (1)	0.023
(w/gloves)	0.0012	

0.20	

200	2300	340

Mixing/Loading Liquid (open pour) for Aerial application (2)	0.023
(w/gloves)	0.00024	

0.20	

1200	390	280*

Applicator

Groundboom application (3)	0.014	0.00074	

0.20	200	3800	540

Aerial application (4)	0.0050	0.000068	

0.20	1200	1800	990

Flagger

Flagging for Aerial application (5) 	0.011	0.00035	0.20	350	2800	660

1 Dermal unit exposure values represent baseline clothing (long pants,
long sleeved shirts, shoes, and socks), except where the addition of
gloves is indicated.

2 Inhalation unit exposure values represent no respirator, unless
otherwise indicated.

3 Application rates are based on maximum proposed values.

4 Amount treated is the area or gallons that can be reasonably applied
in a single day for each exposure scenario of concern, based on the
application method and formulation/packaging type. (standard EPA/OPP/HED
values).

5  Short-/Intermediate-Term Dermal MOE = NOAEL (5 mg/kg/day) / Daily
Absorbed Short-/Intermediate-Term Dermal Dose.  The LOC is 100. Daily
Absorbed Dermal Dose (mg/kg/day) = [(Dermal unit exposure * 14% Dermal
absorption) * Application rate * Area treated] / 60-kg Body weight.

6  Short-/Intermediate-Term Inhalation MOE = NOAEL (0.23 mg/kg/day) /
Daily Absorbed Short-/Intermediate-Term Inhalation Dose.  Daily Absorbed
Inhalation Dose (mg/kg/day) = [(Inhalation unit exposure * 100%
absorption)] * Application rate * Area treated} / 70-kg Body weight.

* Without a respirator, this MOE would be 60, which would be of concern
to HED.

Belgian Endive

Exposure to handlers is from mixing and loading.  Application is
mechanical and, therefore, no applicator exposure is expected.  The
handler scenario assessed for the proposed uses is: 

Mixing/Loading Dry Flowables for T-Jet or Similar Mechanical Spray
Equipment Attached to a Conveyor Belt (high volume/dilute application).

Equations/Calculations for Mixing and Loading

The following equations were used to estimate handler (mixer/loader)
exposure and risk:

Dermal Dose =	Rate (lb ai/gal or /lb crop) x UE (mg/lb ai) x DA x Gal or
Crop Handled per Day

(mg/kg/day)  				BW (kg)

Inhalation Dose =	 Rate (lb ai/gal or /lb crop) x UE (mg/lb ai) x Gal or
Crop Handled per Day

(mg/kg/day)				BW (kg)

Where:

Rate (Application Rate)		=	Maximum application rate on product label (lb
ai/gal or lb ai/lb fruit or root treated)

UE (Unit Exposure)		=	Exposure value taken from August 1998 PHED
Surrogate Exposure Table (mg/lb ai handled)

DA (dermal absorption factor)	=	Factor to account for dermal absorption
(14%) when endpoint is selected from an oral study.

Product or Crop Handled per Day	=	Maximum number of gallons mixed/loaded
per day (gal/day) or maximum pounds of fruit or root treated per day
(lb/day).

	BW				=	Body weight (kg)

	MOE				=	NOAEL 

						Daily Dose

Application Rate

For application to roots by T-Jet on a conveyor belt, the proposed label
indicates up to 1.4 oz of product in 2.5 gallon of water per 850 lbs of
root, and up to 0.4 oz of product in approximately 3 quarts of water
applied to 10 square feet of forcing try.  See footnote to Table 15 for
unit conversions.

Unit Exposure

Baseline dermal unit of exposure represents long pants, long sleeved
shirt, no gloves, open mixing/loading.  Baseline inhalation unit
exposure represents no respiratory protection, and open mixing and
loading (PHED v. 1.1; 8/98)

Dermal and Inhalation Absorption Factors

A dermal absorption factor of 14% was determined to be appropriate and
is used because the endpoint is based on an oral study.  No inhalation
factor is needed because the endpoint is based on an inhalation study.

Product (ai) or Crop Handled per Day

HED consulted Dr. Rich Collins at California Vegetable Specialties about
the post-harvest applications to Belgian endive.  Dr. Collins indicated
that exposure to handlers is only from mixing and loading since
application is mechanical and workers are located at a distance from the
application site.  Inhalation exposure is minimal since the spray area
is in a shrouded/ enclosed area over the conveyor belt.  Dr. Collins
estimated that up to 200,000 lbs of endive roots could be treated per
day (i.e., 200forcing trays at 10 ft2 per tray.

Body Weight

Body weight is assumed to be 70 kg for inhalation exposure, but 60 kg
for dermal, because the dermal endpoint is female-specific.

Summary of Exposure/Risk

MOEs for handlers supporting postharvest applications to Belgian endive
root are all much larger than 100 with workers wearing only baseline
clothing and, therefore, are not of concern to HED.  A summary of the
exposures/risks for handlers is presented in Table 12.

Table 12  Handlers Exposures and Risks from Post-Harvest Application
of Pyraclastrobin

Exposure Scenario	Crop or Target	Application Ratea	Baseline Dermal Unit
Exposureb mg/lb ai	Baseline Inhalation Unit Exposurec mg/lb ai	Amount
Treated Dailyd	Baseline Daily Dermal Dosee mg/kg/day	Baseline Daily
Inhalation Dosef mg/kg/day	Dermal MOE g 	Inhalation MOEh 

Mixing/Loading Dry Flowables For T-jet or Similar Mechanical Spray
Equipment Attached To A Conveyor Belt

	Belgian endive roots (prior to cold storage)	0.000013

lb ai/root	0.066	0.00077	200,000 lb root	0.0004	0.000029	13,000	8,000

	Belgian endive roots (in forcing trays)	0.00032

lb ai/sq ft forcing tray	0.066	0.00077	2,400 

sq ft	0.00011	0.0000082	51,000	33,000

a.	1.4 oz * 12.8% of formulation product is active ingredient = 0.179 oz
ai per 850 lbs roots

0.179 oz ai/850 lbs root * 1 lb/16 oz = 0.0000132 lb ai/lb root.

0.4 oz * 12.8% of formulated product is active ingredient = 0.05 oz of
ai per 10 ft2 of forcing tray

0.05 oz/10 ft2 * 1 lb/16 oz = 0.00032 lb ai/ft2 of forcing tray

b.	Baseline Dermal Unit Exposure represents long pants, long sleeved
shirt, no gloves, open mixing/loading.  Source: PHED Version1.1, August,
1998.

c.	Baseline Inhalation Exposure represents no respiratory protection,
open mixing/loading.  Source: PHED Version1.1, August, 1998.

d.	Daily amount treated values are from experts' estimates of gallons of
spray that would be mixed/loaded in a day or pounds of root that would
be treated in a day. 

e.	Daily dermal dose (mg/kg/day) = [unit dermal exposure (mg/lb ai) *
dermal absorption (0.14) * application rate (lb ai/gal or lb ai/lb
fruit) * daily amount treated / body weight (60 kg)].

f.	Daily inhalation dose (mg/kg/day) = [unit inhalation exposure (mg/lb
ai) * inhalation absorption (100%) * application rate (lb ai/gal or lb
ai/lb fruit) * daily amount treated / body weight (70 kg)].

g.	Dermal MOE = Dermal NOAEL (5 mg/kg/day)/ dermal daily dose
(mg/kg/day)

h.	Inhalation MOE = Inhalation NOAEL (0.23 mg/kg/day)/ inhalation daily
dose (mg/kg/day).



8.2	Short-/Intermediate-/Long-Term Postapplication Risk  TC \l2 "8.2
Short-/Intermediate-/Long-Term Postapplication Risk 

Cotton (foliar)

This Section 3 action for pyraclostrobin involves foliar applications to
cotton.  Therefore, postapplication exposure is possible for workers
entering treated fields.  Chemical-specific dislodgeable foliar residue
(DFR) data have previously been submitted by the registrant to support
earlier registration requests for food crops.  The studies were
conducted on peaches, peanuts, strawberries and grapes (MRID #’s:
45118727, 45118724, 45118726, and 45118728, respectively), and one study
comparing the effect of two different formulations of pyraclostrobin on
grape DFR (MRID#: 45118729).  An overview of each study was provided in
a previous assessment (D269670, K. O’Rourke, 9/30/2002); a summary of
the results is provided in Table 13. 

The DFR data were used to estimate restricted entry intervals (REIs) by
extrapolating, where possible, to cotton.  It was found that the type of
formulation used influences the DFR profile; therefore, only DFR values
for the emulsifiable concentrate formulation (i.e., the Headline®
fungicide formulation) were considered.  An average percent initial DFR
value was calculated (i.e., 18%) and used to estimate surrogate residue
values, and an average daily dissipation rate was estimated (i.e., 13%)
based on the individual daily dissipation rates.  Although uncertainties
are introduced into the assessment when crop-specific residues are used
to estimate residues for other types of crops, it is believed to be more
realistic than using default assumptions. 

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

The estimated short-/intermediate-term MOEs are presented in Table 14. 
The results of the postapplication exposure and risk assessment indicate
that MOEs of 100 are achieved on Day 0 for all cotton scenarios and,
therefore, are not of concern.  

The pyraclostrobin technical material has been classified in Toxicity
Category III for acute dermal, primary eye irritation, and primary skin
irritation.  Per the Worker Protection Standard (WPS), a 12-hr
restricted entry interval (REI) is required for chemicals classified
under Toxicity Category III or IV.  



Table 13.  Summary of DFR Study Results

Crop	

Location

(state)	

Formu-lation	

Application Rate

(lb ai/A)	

Number 

of Apps.	

Interval	

r2	

Initial DFR

(% of 

Appl. Rate)	

Dissipation

(% per day)	

Half-life (days)

peaches	

CA	

WDG	

0.12	

5	

7 days	

0.84	

22	

2	

27.8

peaches	

GA	

WDG	

0.12	

5	

7 days	

0.97	

15	

11	

6

peaches	

PA	

WDG	

0.12	

5	

7 days	

0.94	

22	

9	

7.7

Peaches Average	

	

	

	

	

	

20	

7	

strawberries	

NC	

WDG	

0.18	

5	

7 days	

0.77	

26	

15	

4.2

strawberries	

CA	

WDG	

0.18	

5	

7 days	

0.98	

25	

15	

4.4

strawberries	

OR	

WDG	

0.18	

5	

7 days	

0.91	

12	

13	

4.9

      Strawberry Average	

	

	

	

	

	

21	

14	

peanuts	

NC	

EC	

0.25	

5	

14 days	

0.91	

18	

26	

2.3

peanuts	

GA	

EC	

0.25	

5	

14 days	

0.77	

17	

61*	

0.74

peanuts	

TX	

EC	

0.25	

5	

14 days	

0.91	

18	

24	

2.5

  Peanuts Average	

	

	

	

	

	

18	

25*	

grapes	

CA	

WDG	

0.18	

3	

14 days	

0.97	

22	

6	

11.1

grapes	

WA	

WDG	

0.18	

3	

14 days	

0.94	

25	

6	

11.8

grapes	

PA	

WDG	

0.18	

3	

14 days	

0.82	

14	

4	

15.6

      Grapes WDG Average	

	

	

	

	

	

20	

5	

grapes	

CA	

EC	

0.18	

3	

14 days	

0.95	

14	

9	

7.4

grapes	

WA	

EC	

0.18	

3	

14 days	

0.9	

22	

9	

7.5

grapes	

PA	

EC	

0.18	

3	

14 days	

0.79	

12	

5	

13.9

grapes	

CA	

EC	

0.15	

6	

10 days	

0.9	

6	

6	

12

grapes	

NY	

EC	

0.15	

6	

10 days	

0.92	

28	

6	

11.2

grapes	

WA	

EC	

0.15	

6	

10 days	

0.9	

24	

4	

17.3

      Grapes EC Average	

	

	

	

	

	

18	

7	

EC Average	

	

	

	

	

	

18	

13	

    WDG Average	

	

	

	

	

	

20	

9	

WDG = water dispersible granule

EC = emulsifiable concentrate

* The results from the Georgia site reflect uncharacteristically high
rainfall during the monitoring period.  This is not representative of
typical conditions, therefore, the dissipation from this site was not
included in the average.



Table 14.  Summary of Estimated Postapplication Risks (Cotton)

Crop	

Studies used 

to Estimate

DFR 	DAT 1	DFR 2

(μg/cm2)	TC 3

(cm2/hr)	Activity 	

Short-/Int-

Term MOE 4

Cotton	EC average from peanut and grape studies	0	0.39	100	Irrigation,
scouting, hand weeding (low foliage)	6800

1500	Irrigation, scouting, hand weeding (full foliage)	450

2500	Hand harvesting*	270

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

2 DFR (ug/cm2) = Application rate (0.2 lb ai/A) x CF (4.54E+8 ug/lb) x
CF (2.47E-8 A/cm2) x Initial Fraction of ai Retained on the Foliage (18%
from Table 13) x [(1- Fraction of Residue That Dissipates Daily - see
Table 5) Postapplication day]. 

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

4 MOE = MOE on the corresponding DAT.  MOE = NOAEL / Daily Dose. 

Daily Dose = [(DFR x TC x 14% Dermal absorption x 8-hr Exposure Time)] /
[(CF: 1000 ug/mg) x (60-kg BW for Short-/Int-term)]

Short-/intermediate-term NOAEL = 5 mg/kg/day.  The LOC is 100.

* Most cotton is expected to be mechanically harvested.  Only minimal
hand-harvesting is expected.

Belgian Endive

HED has determined that there is potential exposure to persons handling
Belgian endive roots after post-harvest application is complete.  No
chemical-specific data were submitted to assess the postapplication
exposure to Belgian endive roots treated with pyraclostrobin. 
Therefore, HED used surrogate data and default assumptions.  

HED consulted Dr. Rich Collins at California Vegetable Specialties about
postapplication exposures following post-harvest applications to Belgian
endive roots.  He indicated that there is no dermal contact from moving
storage bins into cold storage; bins were moved with a forklift.  Also,
roots flow directly on the conveyor belt into the cold storage bins with
no dermal contact in  that process either.  Dr. Collins indicated that
there is the potential for exposure to workers planting the roots into
forcing trays (anywhere from one week to 11-12 months after treatment). 
HED also consulted Dr. Stephen Flanagan in the IR-4 Western Region
office who indicated that there is potential dermal contact by
postapplication workers with the treated endive roots or the
recirculating water when:

closing the fruit bins before cold storage,

moving the forcing trays into forcing rooms,

contact with recirculating water pumped through forcing trays,

contact with endive (roots) during growth check by management, 

cutting/harvesting endive (27 days after forcing), and

packing harvested endive.

As a worse-case post-application exposure scenario, HED assessed the
long-term dermal exposure of workers hand-packing individual treated
roots into forcing trays. This exposure was assessed for long-term
duration, because the operation occurs on a continuous basis throughout
the entire year.  The estimated exposure/risk is considered high end
because it is based on the assumption that contact with roots occurs on
the same day as treatment.  In reality, the pyraclostrobin residue on
the roots is likely to have dissipated by some percentage over the week
to 12 months between treatment and when the packing activity actually
occurs.

Equations and Calculations for Postapplication Dermal Exposure

The following equation was used to estimate postapplication exposure and
risk:

Dermal Dose (mg/kg/day)	=	DR0 (μg/cm2) x Tc (cm2/hr) x DA x ET (hrs)

BW (kg)

Where:

DR0	=	dislodgeable residue (on the root) on day “0” (μg/cm2)

Tc	=	transfer coefficient (1500 cm2/hr) for handling treated root
estimated using Nigg et.

al. (1984) study described below.

DA	=	dermal absorption factor (0.14)

ET	=	exposure time (2 hr/day)

BW	=	body weight (60 kg)

Dislodgeable Residue at Day Zero

(μg/cm2)		 =	AR x F x CF

Where:

Application Rate	(AR)	=	application rate (lb ai/cm2)

Fraction Retained	 (F)	=	fraction of ai retained on root is 20%
(unitless)

Conversion Factor (CF)	=	conversion factor to convert lbs ai in the
application rate to mg for the

DR0 value (4.54E5 mg/lb)

Application Rate: Convert application rate from oz ai/lbs of root, to lb
ai/cm2 

The application rate can be expressed as 0.000013 lb ai/lb of root (see
Table 4).

The number of roots per pound was determined by dividing the number of
grams in a pound (454 gm) by the average weight of a Belgian endive
root, (obtained via personal communication with Dr. Rich Collins of
California Vegetable Specialties).

454 gm/1lb * 1 root/156 gm = 2.9 roots per pound

The rate of active ingredient (lb ai) per root was determined by
dividing the rate of pyraclostrobin per pound of root by the number of
roots per pound.

0.000013 lb ai/1 lb root * 1 lb root/2.9 roots = 0.0000045 lb ai/root

2πr2 + 2πrH).  The dimensions of a Belgian endive root are 5.5 inches
height (14 cm) and 1.5 inches in diameter (3.8 cm) (personal
communication with R. Collins).

Surface area of one root = 2π(1.92)2 + 2π(1.9)(14) = 189 cm2 /root

The amount of active ingredient per square centimeter (lb ai/cm2) was
determined by dividing the amount of active ingredient per root by the
surface area of one root.

0.0000045 lb ai/root * 1 root/189 cm2 = 0.000000024 lb ai/cm2

Transfer Coefficient (Tc)

HED used the following study to estimate a transfer coefficient for
determining postapplication exposures following post-harvest
applications to Belgian endive roots: 

Nigg, H.N., J.H. Stamper, and R.M. Queen (1984) The Development and Use
of a Universal Model to Predict Tree Crop Harvester Pesticide Exposure. 
Am. Ind. Hygiene. Association Journal 45:182-186.

This study examined dislodgeable foliar residue (DFR) of chlorbenzilate
on Valencia orange trees. This study was used to calculate dermal hand
transfer coefficients and exposures of ten harvesters. The pesticide was
applied by airblast at the maximum label rate of 2.5 lbs ai per acre in
200 gallons of water.  The ten harvesters wore cotton shirts with
exposure pads pinned inside on shoulders, chest, back, both forearms,
and both upper arms.  Thigh and shin pads were taped outside the working
clothing.  Hand exposures were monitored by hand rinse with 95 percent
ethanol.  Only the handwash data were used for the estimation of the
chemical exposure to sorters and packers on an assembly line. 
Dislodgeable foliar and fruit residues were collected on days 1, 2, 3,
4, and 7 after treatment.  The dislodgeable residues on fruit remained
fairly constant on days 1 to 3, followed by a large decrease on day 4. 
Exposure data were only presented for days 2, 3, and 4.  Data from days
2 and 3 only, were used for estimation of pyraclostrobin exposure.  The
exposures of the hands are presented in Table 18.  Data presented in
Table 15 are taken from the Occupational and Residential Exposure
Assessment and Recommendations for the Reregistration Eligibility
Decision Document for Imazalil (D250163, 263162). 

ting Exposures (μg/hr)

Replicate	1	2	3	4	5	6	7	8	9	10	Total	Mean

2nd day	40	58	227	37	85	210	953	33	159	54	186	185

3rd day	169	98	170	39	42	1050	71	70	89	183	183

	

The following assumptions and equations were used to determine a
transfer coefficient for post-application exposure:

Transfer coefficients for the hands only:

Dislodgeable residues for the 2nd day was 0.103μg/cm2  

Dislodgeable residues for the 3rd day was 0.129 μg/cm2

Average dislodgeable residue for two days = 0.12 μg/cm2

Transfer Coefficient (Tc) cm2/hr =	185 μg/hr / 0.12 μg/cm2 = 1500
cm2/hr

Summary of Exposure/Risk 

Table 16 summarizes the estimated long-term dermal exposure/risk to
workers handling Belgian endive roots treated with pyraclostrobin.  The
dermal MOE calculated for postapplication activities is 60.  Because the
level of concern is for MOEs <100, this risk is of concern to HED.

Because exposure from the assessed activity is primarily to the hands,
the addition of chemical-resistant gloves should reduce exposure by 90%
(i.e., the absorbed dermal dose would become 0.0061 mg/kg/day), and the
resulting MOE = 610; a risk that is not of concern to HED.  This latter
activity is viewed by HED as a secondary “handler” activity, and
therefore the label should include the aforementioned glove
requirements.

Table 16. Postapplication Long-term Dermal Exposures and Risks for
Pyraclostrobin on Belgian Endive Roots

Fruit	Application Ratea

	Transfer Coefficient

(cm2/hr)	Default Transferable Residue

(day 0)	Conversion Factor (mg/lb)	Dermal Absorption (%)	Exposure Time

(hours)	Absorbed Dermal Doseb (mg/kg/day)	Long-term Dermal MOEc

Belgian endive root prior to cold storage	2.4E-8 lb ai/cm2	1,500	20%
4.5E+05	14%	8	0.061	60

a.	Application rate = lb ai/cm2 of root

b.	Absorbed dermal dose = application rate x 20% x 1500 x 4.5E+5 x 14% x
8 hours) / 60 kg body weight

c.	Dermal MOE = Long-term dermal NOAEL (3.7 mg/kg/d) / absorbed dermal
dose.  UF = 100.

9.0	Data Needs and Label Recommendations  TC \l1 "9.0	Data Needs and
Label Requirements 

9.1	Residue Chemistry Data Needs and Label Recommendations  TC \l2 "9.1
Residue Chemistry Data Needs and Label Recommendations 

For the proposed use on Belgian endive the following are needed if IR4
chooses to pursue a Section 3 registration: 

Use directions in Section B must match the application method used in
Section D for residue data collection;

The tolerance proposal in Section F must be supported by the application
method used in Section D for residue data collection; and

Additional residue data that adequately reflect the use directions in
Section B must be submitted. (HED recommends that the petitioner submit
a protocol for HED review and comments before any residue data
collection begins.)

HED recommends that the label rate be revised to clearly define the
amounts to be used per application and the total per season.  In
addition, the petitioner should define how the spray is applied to the
roots in the forcing trays (.i.e., trays are stationary or are moving on
a conveyor belt).  A revised Section B must be submitted to adequately
reflect the petitioner’s intentions as to application rates and
directions.  Additionally, HED suggests that the application rates
should be set on a unit basis; i.e., for applications prior to cold
storage the label should indicate an amount of active ingredient per 100
lbs of roots, and for applications prior to forcing the label should
indicate an amount of active ingredient per 1 square foot of forcing
tray.

9.2	Occupational and Residential Exposure  TC \l2 "9.2	Occupational and
Residential Exposure 

For the proposed use on Belgian endive, if IR4 chooses to pursue a
Section 3 registration, then the label should include a requirement for
chemical-resistant gloves.

10.0	Tolerance Summary  TC \l1 "10.0	Tolerance Summary 

The tolerance expression for pyraclostrobin in plant commodities include
pyraclostrobin and its desmethoxy metabolite, and the residues of
concern in livestock commodities include pyraclostrobin and its
metabolites convertible to 1-(4-chlorophenyl)-1H-pyrazol-3-ol (BF 500-5)
and 1-(4-chloro-2-hydroxyphenyl)-1H-pyrazol-3-ol (BF 500-8).  

Tolerances for plant commodities 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 29 ppm in/on leafy vegetables, except Brassica [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 or 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, horses, and sheep [40 CFR §180.582(a)(2)].  No
tolerances are established for poultry commodities.

The tolerances proposed by BASF and IR-4 for the current petitions are
listed in Table 7, along with the Agency’s recommended tolerance
levels.  As the majority of cottonseed samples from the cotton field
trials had residues below the combined LOQ (0.04 ppm), the recommended
tolerance level for undelinted seeds were not determined using the
Tolerance/MRL Harmonization Spreadsheet.  Rather, the recommended
tolerance of 0.3 ppm is based on the maximum combined residues observed
in seeds (0.17 ppm).  Tolerances for Belgian endive, cotton gin
byproducts and the berries crop group were both determined using the
Tolerance/MRL Harmonization Spreadsheet as combined residues were
readily quantifiable in these commodities.  For the berries crop group,
residue values from both the earlier and new berry field trials were
used to calculate the appropriate tolerance, and the data from
raspberries and blueberries were pooled as residue levels were similar
on both types of berries.  The residue datasets used for the tolerance
calculations and the supporting spreadsheet outputs are presented in
Appendix II.  The calculated tolerances were 30 ppm for cotton gin
byproducts and 4.0 ppm for the berries crop group.

Results from the requested mustard greens field trials and the
supplemental field trials on cucurbit vegetables, fruiting vegetables,
grape, sunflower, and mint indicate that no changes are necessary in the
existing tolerances for these crops.  For each crop, the combined
residues in the new field trials were below the established tolerances. 

With regards to the current tolerances for livestock commodities, the
existing tolerances are adequate for milk, meat, fat, meat byproducts
(except liver), and liver of cattle, goats, horses, and sheep, and the
current tolerances for liver could be lowered to 1.0 ppm.  Also, the
existing tolerances for hog commodities can be deleted as quantifiable
residues are unlikely to occur in hogs [40 CFR §180.6(a)(2)] based on
the dietary burden proposed in Table 6.  As stated previously,
tolerances are still not required for poultry commodities.

Table 17. 	Tolerance Summary for Pyraclostrobin.

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

Belgian endive

	6	Denied	Denied, since field trial data does not support the proposed
tolerance.

Berry, group 13	1.3	4.0	Tolerance calculated using available residue
data and Tolerance/MRL Harmonization Spreadsheet.

Cotton, undelinted seed	0.4	0.3	Tolerance should be set at 0.3 ppm based
on maximum combined residues of 0.17 ppm.

Cotton, gin byproducts	30	30	Tolerance calculated using available
residue data and Tolerance/MRL Harmonization Spreadsheet.

The Codex Alimentarius Commission, Mexico and Canada have not
established any maximum residue limits (MRLs) for residues of
pyraclostrobin in or on raw agricultural commodities, although a variety
of MRLs are pending in Canada (Appendix I).  Therefore, there are no
questions of compatibility of U.S. tolerances with International MRLs at
the present time.



INTERNATIONAL RESIDUE LIMIT STATUS

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

Pyraclostrobin	( Proposed tolerances

( Reevaluated tolerance

No Codex proposal step 6 or above

(No Codex proposal step 6 or above for the crops requested 	Petition
Number: 5F7002, 5E7014

DP Barcode: 337807, 337817

Other Identifier: 

Residue definition (step 8/CXL):   	JStokes/HED/RRB4

	Residue definition: Combined residues of pyraclostrobin and BF 500-3,
expressed as parent

Crop (s)1	MRL (mg/kg)	Crop(s)	Recommended Tolerance (ppm)

Cotton, undelinted seed	0.3

Cotton, gin byproducts	30

Berries, group 13	4.0

	Limits for Canada	Limits for Mexico

( No Limits

( No Limits for the crops requested	( No Limits

(  No Limits for the crops requested

Residue definition:  Cyhalothrin-lambda	Residue definition:   
Lambda-cyhalothrin

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

	Notes/Special Instructions:



11.0	Appendix: Toxicity Profile  TC \l1 "11.0	Appendix: Toxicity Profile

11.1	Appendix 1.: Pyraclostrobin Toxicology Requirements and Available
Studies for Food Uses  TC \l2 "11.1	Appendix 1.: Pyraclostrobin
Toxicology Requirements and Available Studies for Food Uses 

Appendix 1: 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



11.2	Appendix 2.: Acute Toxicity Data on Pyraclostrobin Technical  TC
\l2 "11.2	Appendix 2.: Acute Toxicity Data on Pyraclostrobin Technical 

  SEQ CHAPTER \h \r 1 Appendix 2. Acute Toxicity Profile:

  SEQ CHAPTER \h \r 1 Table 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

11.3	Appendix 3.: Subchronic, Chronic and Other Toxicity Profile  TC
\l2 "11.3	Appendix 3.: Subchronic, Chronic and Other Toxicity Profile 

  SEQ CHAPTER \h \r 1 Appendix 3. 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

 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) 

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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

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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)

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

Cytogenetics 

870.5395

Micronucleus test in mouse	45118334 (1998)

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

Unscheduled DNA synthesis

870.5550 

Rat hepatocyte culture	45118336 (1998)

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

870.6200a

Acute neurotoxicity screening (rat)	45118337(1999)

Acceptable/guideline

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

M/F LOAEL >1000 mg/kg

Systemic M/F NOAEL = 300/〱〰洠⽧杫

㐀ۖĀ̊dਃ昀Ĵ瑹ྷí଀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)

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