Document ID: EPA-HQ-OPP-2007-0906-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-10-24T04:00Z

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COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE

(1/1/2005)

EPA Registration Division contact:  Shaja R. Brothers, (703)-308-3194	

TEMPLATE:

Interregional Research Project Number 4 (IR-4)

7E7245

	EPA has received a pesticide petition 7E7245 from Interregional
Research Project Number 4 (IR-4), 500 College Road East, Suite 201W,
Princeton, NJ 08540 proposing, pursuant to section 408(d) of the Federal
Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR
part 180. to increase the tolerance for residues of the fungicide
pyraclostrobin, carbamic acid,
[2-[[[1-(4-chlorophenyl)-1H-pyrazol-3-yl]oxy]methyl]phenyl]methoxy-,
methyl ester and its metabolite methyl-N-[[[1-(4-chlorophenyl)
pyrazol-3-yl]oxy]o-tolyl] carbamate (BF 500-3); expressed as parent
compound in or on the raw agricultural commodity barley, grain at 1.3
parts per million (ppm), and barley, straw at 9.0 ppm.  EPA has
determined that the petition contains data or information regarding the
elements set forth in section 408(d)(2) of the FFDCA; however, EPA has
not fully evaluated the sufficiency of the submitted data at this time
or whether the data supports granting of the petition.  Additional data
may be needed before EPA rules on the petition.

A. Residue Chemistry   

                                   

	1. Plant and animal metabolism. Nature of the residue studies (OPPTS
860.1300) were conducted in grape, potato and wheat as representative
crops in order to characterize the fate of pyraclostrobin in all crop
matrices.  Pyraclostrobin demonstrated a similar pathway and fate in all
three crops. In all three crops the pyraclostrobin Residues of Concern
(ROC) of were characterized as parent (pyraclostrobin) and BAS 500-3),
methyl-N[[[1-(4-chlorophenyl) pyrazol-3yl]oxy]o-tolyl] carbamate.  In
hens the residues of concern were determined to be parent compound and a
hydroxlated metabolite, BAS 500-16.  In goats the residues of concern
were determined to be parent and a hydroxylated metabolite BAS 500-10. 

	2. Analytical method.   In plants the method of analysis is aqueous
organic solvent extraction, column clean up and quantitation by
LC/MS/MS.  In animals the method of analysis involves base hydrolysis,
organic extraction, column clean up and quantitation by LC/MS/MS or
derivatization (methylation) followed by quantitation by GC/MS.

	3. Magnitude of residues. Field trials were conducted in Colorado and
Idaho during 2004 and 2005 in support of establishing a tolerance for
residues of pyraclostrobin in barley at a reduced pre-harvest interval. 
All field trials were carried out using the maximum labeled rate,
maximum number of applications, and the proposed pre-harvest interval.

B. Toxicological Profile

	1. Acute toxicity.  Pyraclostrobin and its formulated products have
favorable acute toxicity. The acute toxicity studies place technical
pyraclostrobin in toxicity category IV for acute oral and acute
inhalation and category III for acute dermal.  Pyraclostrobin is
category III for both eye and skin irritation, and it is not a dermal
sensitizer.  Two formulated end use products are proposed, an
Emulsifiable Concentrate (EC) and an Extruded Granule (EG).  The EC has
an acute oral toxicity category of II, acute dermal of III, acute
inhalation of IV, eye and skin irritation categories of III, and is not
a dermal sensitizer.  The EG has acute oral and dermal toxicity
categories of III, acute inhalation of IV, eye irritation of III, skin
irritation of IV and is not a dermal sensitizer.

	2. Genotoxicty.  Pyraclostrobin was negative for inducing mutations in
both an in vitro Ames test and an in vitro CHO/HGPRT Locus Mammalian
Cell Mutation Assay.  Pyraclostrobin also demonstrated no chromosomal
effects in an in vitro V79 Cells CHO Cytogenetic Assay and an in vivo
Mouse Micronucleus test.  An additional in vitro study investigating DNA
damage and repair also showed no effects. Pyraclostrobin has been tested
in a total of 5 genetic toxicology assays consisting of in vitro and in
vivo studies.  It can be stated that pyraclostrobin did not show any
mutagenic, clastogenic or other genotoxic activity when tested under the
conditions of the studies mentioned above.  Therefore, pyraclostrobin
does not pose a genotoxic hazard to humans.

	3. Reproductive and developmental toxicity.  The reproductive and
developmental toxicity of pyraclostrobin was investigated in a
2-generation rat reproduction study as well as in rat and rabbit
teratology studies.  There were no adverse effects on reproduction,
systemic toxicity to adults or developmental toxicity in the
two-generation study so the NOAEL is the highest dose tested of 300 ppm
(approximately 32.6 mg/kg bw/day).  

No teratogenic effects were noted in either the rat or rabbit
developmental studies.  In the rat study, maternal toxicity observed at
the mid and high dose consisted of decreased food consumption and body
weight gain.  Developmental changes noted at the high dose were
increased incidences of dilated renal pelvis and cervical ribs with no
cartilage.  The maternal NOAEL was 10 mg/kg bw and the developmental
NOAEL was 25 mg/kg bw.  I

In the rabbit teratology study, maternal toxicity observed at the mid
and high doses consisted of decreased food consumption and body weight
gain (severe at the high dose).  An increased postimplantation loss was
also observed at the mid and high doses due to an increase in early
resorptions.  In rabbits, these types of effects are often observed with
significant stress on the mothers (as seen by the body weight gain
decrease in this study) and not indicative of frank developmental
toxicity.  The NOAEL for both maternal and developmental toxicity was 5
mg/kg bw.

	4. Subchronic toxicity. The subchronic toxicity of pyraclostrobin was
investigated in 90-day feeding studies with rats, mice and dogs, and in
a 28-day dermal administration study in rats.  A 90-day neurotoxicity
study in rats was also performed.  Generally, mild toxicity was
observed.  At high dose levels in feeding studies, general findings in
all three species were decreased food consumption and body weight gain
and a thickening of the duodenum.  Anemia occurred at high dose levels
in both rats and mice with accompanying extramedullary hematopoiesis of
the spleen in rats.  In rats only, a finding of liver cell hypertrophy
was indicative of a physiological response to the handling of the
chemical.   The lowest NOAEL in the 90-day feeding studies was from the
dog study and determined to be 5.8 mg/kg bw/day.

In the 28-day repeat dose dermal study, no systemic effects were noted
up to the highest dose tested of 250 mg/kg bw/day.   

In a 90-day rat neurotoxicity study, a direct neurotoxic effect was not
observed.

	5. Chronic toxicity. Pyraclostrobin was administered to groups of 5
male and 5 female purebred Beagle dogs in the diet at concentrations of
0, 100, 200 and 400 ppm over a period of 12 months.   Signs of toxicity
were observed at the high dose.  Diarrhea was observed throughout the
study period for both sexes. High dose males and females initially lost
weight and body weight gain was decreased for the entire study period
for females.  Hematological changes observed were an increase in white
blood cells in males, and an increase in platelets in both sexes at the
high dose.  Clinical chemistry demonstrated a decrease in serum total
protein, albumin, globulins and cholesterol in high dose animals of both
sexes possibly due to the diarrhea and reduced nutritional status of the
animals.  The NOAEL was 200 ppm (ca. 5.5 mg/kg bw/day males; 5.4 mg/kg
bw/day females).

	

In an oncogenicity study, pyraclostrobin was administered to groups of
50 male and 50 female Wistar rats at dietary concentrations of 0; 25;
75, and 200 ppm for 24 months.  In a companion chronic toxicity study,
20 rats/sex were used at the same dose levels as in the oncogenicity
study.  A body weight gain depression of 10-11% in males and 14-22% in
females with an accompanying decrease in food efficiency was observed at
the high dose.  There was no evidence that pyraclostrobin produced a
carcinogenic effect in rats.  The NOAEL for the chronic rat and the
cancer rat study is 75 ppm (ca. 3.4 mg/kg bw/day males; 4.7 mg/kg bw/day
females).

Pyraclostrobin was administered to groups of 50 male and 50 female
B6C3F1 mice at dietary concentrations of 0, 10, 30, 120 and 180 ppm
(females only) for 18 months.  Body weights were reduced at the highest
doses tested in both males and females.  At the high dose, body weight
gain decreases of 27% in females and 29% in males with an accompanying
decrease in food efficiency were observed.  No other signs of toxicity
were noted at any dose level.  The NOAEL  was found to be 30 ppm (ca.
4.1 mg/kg bw/day) for males. The Agency determined that the body weight
effect at the high dose in females was not sufficient to determine an
MTD.  Therefore the NOAEL for females is considered greater than the
highest dose tested of 32.8 mg/kg bw/day.   There was no evidence that
pyraclostrobin produced a carcinogenic effect in mice.

	6. Animal metabolism. In a rat metabolism study with pyraclostrobin,
10-13% of the administered dose was excreted in the urine and 74-91% in
the feces within 48 hours.  Excretion via bile was significant
accounting for 35-38% of the administered dose. By 120 hours after
dosing, very little radioactivity remained in tissues. Pyraclostrobin
was rapidly and almost completely metabolized.  Very little unchanged
parent was detected.  The phase one biotransformation is characterized
by N-demethoxylation, various hydroxylations, cleavage of the ether bond
and further oxidation of the two resulting molecule parts.  Conjugation
of the formed hydroxyl groups by glucuronic acid or sulfate also
occurred. In summary, pyraclostrobin is extensively metabolized and
rapidly eliminated primarily via the bile, with no evidence of
accumulation in tissues. 

	7. Metabolite toxicology. A comparison of the rat metabolism results
with the plant metabolism/residue results indicates that toxicology
studies performed with the parent pyraclostrobin are sufficient to cover
dietary exposure.  Plant residues are primarily the parent compound with
a fraction (up to 10-20% at most) being the demethoxylated parent.  This
metabolite is referred to as BF 500-3 in the plant studies and as 500M07
in the rat study.  This metabolite in the rat is the first step in the
major biotransformation process leading to the majority of the
metabolites determined in the major excretion pathway.

	8. Endocrine disruption.  Endocrine effects. No specific tests have
been conducted with pyraclostrobin to determine whether the chemical may
have an effect in humans that is similar to an effect produced by a
naturally occurring estrogen or other endocrine effects.  However, there
were no significant findings in other relevant toxicity studies (i.e.,
subchronic and chronic toxicity, teratology and multi-generation
reproductive studies) which would suggest that pyraclostrobin produces
endocrine related effects.

C. Aggregate Exposure

	1. Dietary exposure. Exposure assessments were conducted to evaluate
the potential risk due to acute and chronic dietary exposure of the U.S.
population to residues of pyraclostrobin.  This fungicide and its
desmethoxy metabolite, in or on raw agricultural commodities, and
metabolites in or on animal fat, liver, meat and meat byproducts were
expressed as the parent compound.  The tolerance values previously
established for various cereals, vegetables, fruits, and animal products
are listed in the U.S. EPA final rule published in the Federal Register
October 29, 2004 (Vol 69, No. 209, p 63083 – 63100) and U.S. 40 CFR §
180.582.  This analysis included all current and proposed tolerance
values for barley grain (1.3 ppm), cotton (undelinted seed 0.4 ppm, gin
byproducts 30 ppm), Belgium endive (11 ppm), strawberries (1.2 ppm),
dried shelled peas and beans (0.5 ppm), fresh herbs (30 ppm), mango (0.7
ppm), papaya (0.7 ppm), avocado (0.7 ppm), black sapote (0.7 ppm), mamey
sapote (0.7 ppm), canistel (0.7 ppm), sapodilla (0.7 ppm), star apple
(0.7 ppm), oat grain (0.9 ppm), oil seed crop group 20 (0.4 ppm), and
increased tolerance values for the berry crop group (4 ppm). 

The pyraclostrobin chronic reference dose (cRfD) is 0.034 mg/kg bw/day
based on the NOAEL of 3.4 mg/kg bw/day in the rat chronic toxicity study
and a 100X safety factor.  The acute reference dose (aRfD) is 3 mg/kg
b.w./day for the general population based on a NOAEL from the acute
neurotoxicity study of 300 mg/kg bw/day and a 100X safety factor.  For
females of child bearing years (13-49 years), the aRfD is 0.05 mg/kg
b.w./day based on the NOAEL of 5 mg/kg bw/day from the rabbit teratology
study and a 100X safety factor.  The EPA determined that the FQPA safety
factor should be 1X for all exposure scenarios.  Therefore, the acute
Population Adjusted Dose (aPAD) and the chronic Population Adjusted Dose
(cPAD) are the same as the aRfD and cRfD, respectively.

		i. Food.  Acute Dietary Exposure Assessment

The acute dietary exposure estimates were based on tolerance values,
default processing factors, and 100% crop treated values for all
commodities except for leafy vegetables, pome fruit, stone fruit, and
citrus crop groups where the percent crop treated (%CT) and values
listed in the U.S. EPA document DP Barcode No. D323632 (November 30,
2005) were utilized.  In addition, for crops in the leafy vegetable crop
group the highest average field trial (HAFT) residue level was used in
place of the tolerance as noted in DP Barcode No. D323632.  The
consumption data was from the USDA Continuing Survey of Food Intake by
Individuals (CSFII 1994 - 1996, 1998) and the EPA Food Commodity
Ingredient Database (FCID) using Exponent's Dietary Exposure Evaluation
Module (DEEM-FCID) software.  

The acute population adjusted dose (aPAD) used for females 13-49 years
of age was 0.05 mg/kg bw/day and 3.0 mg/kg bw/day for all other
sub-populations.   Considering the exposure assumptions discussed above,
pyraclostobin acute dietary exposure from food is less than 2.5 % aPAD
for the U.S. population and all sub-populations except females 13-49
years of age that occupies 53.2% of the aPAD.  The results of the acute
dietary assessment are presented in Table 1.

Table 1.	Results for Pyraclostrobin Acute Dietary Exposure Analysis
Considering all Current and Proposed Tolerances Including Barley Grain
(1.3 ppm) Using DEEM-FCID at the 95th Percentile 

Population	Exposure Estimate	%aPAD

Subgroups	(mg/kg b.w./day)*	 

U.S. Population	0.031750	1.06

All Infants (< 1 year old)	0.045808	1.53

Children (1-2 years old)	0.072522	2.42

Children (3-5 years old)	0.056051	1.87

Children (6-12 years old)	0.034733	1.16

Youth (13-19 years old)	0.024346	0.81

Females (13-49 years old)	0.026597	53.19

Adults (20-49 years old)	0.026228	0.87

Adults (50+ years old)	0.026868	0.90

aPAD = acute population adjusted dose 

* Exposure Estimate (95th percentile) was based on tolerance values,
default processing factors, and considering 100% crop treated for all
commodities except for leafy vegetables, pome fruit, stone fruit, and
citrus fruit groups which included the percent crop treated values
listed in U.S. EPA document DP Barcode No. D323632 (November 30, 2005). 
In addition, HAFT level residues were used for leafy vegetables.

The results of the analysis show that for all sub-populations, the
exposures are below the Agency's level of concern (< 100% aPAD). 
Additional refinements in the dietary risk assessment (i.e. utilizing
anticipated residue values, processing factors, percent crop treated
values for all crops) would further reduce the estimated exposure
values.  

Chronic Dietary Exposure Assessment

The chronic dietary exposure estimates were based on tolerance or
proposed tolerance values for all commodities with the exception that
anticipated residues were utilized for leafy vegetables.  Default
processing factors, specific processing factors and % crop treated
values were used as listed in the U.S. EPA document DP Barcode No.
D323632 (November 30, 2005).   A value of 100% crop treated was used for
oat, oil seeds, fresh herbs, meat and milk, avocado, banana, Belgium
endive, canistel, mango, papaya, cotton, and mamey sapote.  The
consumption data was from the USDA Continuing Survey of Food Intake by
Individuals (CSFII 1994 - 1996, 1998) and the EPA Food Commodity
Ingredient Database (FCID) using Exponent's Dietary Exposure Evaluation
Module (DEEM-FCID) software.  

The chronic population adjusted dose (cPAD) used for U.S. population and
all sub-populations is 0.034 mg/kg bw/day. Considering the exposure
assumptions discussed above, pyraclostobin chronic dietary exposure from
food for the U.S. population was 8.0 % of the cPAD.  The most highly
exposure population sub group was children 1-2 years of age at 24.6%
cPAD.   The results of the chronic dietary assessment are presented in
Table 2. 

Table 2. 	Results for Pyraclostrobin Chronic Dietary Exposure Analysis
Considering all Current and Proposed Tolerances Including Barley Grain
(1.3 ppm) Using DEEM-FCID 

Population	Exposure Estimate	%cPAD

Subgroups	(mg/kg b.w./day)	 

U.S. Population	0.002711	8.0

All Infants (< 1 year old)	0.003998	11.8

Children (1-2 years old)	0.008369	24.6

Children (3-5 years old)	0.006291	18.5

Children (6-12 years old)	0.003777	11.1

Youth (13-19 years old)	0.002141	6.3

Females (13-49 years old)	0.001992	5.9

Adults (20-49 years old)	0.002058	6.1

Adults (50+ years old)	0.002221	6.5

cPAD = chronic  population adjusted dose 

* Exposure estimates based on tolerance values for all commodities with
the exception of anticipated residues for leafy vegetables; processing
factors and % crop treated values were used as listed in the U.S. EPA
document DP Barcode No. D323632 (November 30, 2005) with 100% crop
treated values for oat, oil seeds, fresh herbs, meat and milk, avocado,
banana, Belgium endive, canistel, mango, papaya, cotton, and mamey
sapote.

The results of the analysis show that for all sub-populations, the
exposures are below a level of concern (< 100% cPAD).  Additional
refinements in the chronic dietary risk assessment (i.e. utilizing
anticipated residue values for all crops) would further reduce the
estimated exposure values.    

		ii. Drinking water. Based on the PRZM/EXAMS and SCIGROW models, the
peak EDWCs of pyraclostrobin for acute exposure are estimated to be 22.6
ug/L (ppb) in surface water and 0.02 ug/L in shallow ground water.  The
peak EDWCs for chronic exposure are estimated to be 1.9 ug/L in surface
water and 0.02 ug/L in shallow ground water.  These concentrations are
based on maximum applications to turf, which have the highest labeled
application rate of any pyraclostrobin use.  

Drinking water contributions were assessed based on the maximum
estimated pyraclostrobin water concentrations (acute - 22.6 ug/L,
chronic 1.9 ug/L), and water consumption and body weights reported in
CSFII, using DEEM-FCID software.  The acute and chronic estimated water
exposure values are summarized in Tables 3 and 4, respectively.  Minimal
exposure of pyraclostrobin occurs through drinking water with < 0.5% the
aPAD and cPAD for all subpopulations with the exception of females 13-49
years of age with a 2.2% aPAD.

Table 3. 	Results for Pyraclostrobin Acute Water Exposure Analysis
Considering the Maximum Estimated Acute Drinking Water Concentration
using 

DEEM-FCID 

Population	Water Exposure Estimate	%aPAD

Subgroups	(mg/kg b.w./day)	 

U.S. Population	0.001181	0.04

All Infants (< 1 year old)	0.004451	0.15

Children (1-2 years old)	0.001852	0.06

Children (3-5 years old)	0.001692	0.06

Children (6-12 years old)	0.001178	0.04

Youth (13-19 years old)	0.000958	0.03

Females (13-49 years old)	0.001100	2.20

Adults (20-49 years old)	0.001094	0.04

Adults (50+ years old)	0.000988	0.03

aPAD = acute  population adjusted dose

Based on estimated acute surface water value of 22.6 ug/L



Table 4. 	Results for Pyraclostrobin Chronic Water Exposure Analysis
Considering the Maximum Estimated Chronic Drinking Water Concentration
using DEEM-FCID 

Population	Water Exposure Estimate	%cPAD

Subgroups	(mg/kg b.w./day)	 

U.S. Population	0.00004	0.1

All Infants (< 1 year old)	0.000131	0.4

Children (1-2 years old)	0.000059	0.2

Children (3-5 years old)	0.000056	0.2

Children (6-12 years old)	0.000038	0.1

Youth (13-19 years old)	0.000029	0.1

Females (13-49 years old)	0.000037	0.1

Adults (20-49 years old)	0.000037	0.1

Adults (50+ years old)	0.000039	0.1

cPAD = chronic  population adjusted dose

Based on estimated chronic surface water value of 1.9 ug/L

Acute Aggregate Exposure and Risk (Food and water)

The aggregate acute risk includes residues of pyraclostrobin from food
and water (Table 5). Exposures from residential uses are not included in
the acute aggregate assessment.  The results demonstrate that there are
no safety concerns for any subpopulation based on established and new
uses, and that the results clearly meet the FQPA standard of reasonable
certainty of no harm.

Table 5. 	Estimated Acute Aggregate Exposure and Risk of Pyraclostrobin 

Population Subgroup	aPAD (mg/kg/day)	Food Exposure (mg/kg/day)	Water
Exposure (mg/kg/day)	Total Exposure (mg/kg/day)	% aPAD

U.S. Population	3	0.031750	0.001181	0.032931	1.10

All Infants (< 1 yr old)	3	0.045808	0.004451	0.076973	2.57

Children 1-2 years	3	0.072522	0.001852	0.057903	1.93

Children 3-5 years	3	0.056051	0.001692	0.036425	1.21

Children 6 – 12 years	3	0.034733	0.001178	0.025524	0.85

Youth 13-19 years	3	0.026228	0.000958	0.027186	0.91

Females 13-49 years	0.05	0.026597	0.001100	0.027697	55.39

Adults 20-49 years	3	0.026228	0.001094	0.027962	0.93

Adults + 50	3	0.026868	0.000988	0.027585	0.92

Short- and Intermediate Term Aggregate Exposure and Risk (food,water,
and residential)

Short-term aggregate risk from pyraclostrobin takes into account
exposures from dietary consumption (food and water) and residential
exposure from turf use.  Post application exposure from the turf use is
considered short-term.  The aggregate MOEs from food, water, and
residential exposure are 129 and 267 for children 1-2 years old and the
US population, respectively.  These MOEs are greater than the target MOE
of 100 which indicates there is no safety concern.  The results of the
analysis are shown in Table 6. 

Table 6. 	Estimated Short/Intermediate Term Aggregate Exposure and Risk
of Pyraclostrobin  

Population	NOAEL (mg/kg/day)	Target MOE1	Food Exposure (mg/kg/day)	Water
Exposure (mg/kg/day)	Residential Exposure (mg/kg/day)	Total Exposure
(mg/kg/day)	MOE2

US	5.8	100	0.002711	0.00004	0.019	0.021751	267

Child 1-2 yr old	5.8	100	0.008369	0.000059	0.036425	0.044853	129

1 Target MOE is 100.

2 Aggregate MOE = (NOAEL / (Food + Water + Residential Exposure)

 Chronic Aggregate Exposure and Risk (food and water)

The aggregate chronic risk includes residues of pyraclostrobin from food
and water (Table 7). Exposures from residential uses are not included in
the chronic aggregate assessment.  The results demonstrate there are no
safety concerns for any subpopulation based on established and new uses,
and that the results clearly meet the FQPA standard of reasonable
certainty of no harm. 

  Table 7. 	Estimated Chronic Aggregate Exposure and Risk of
Pyraclostrobin  

Population Subgroup	cPAD (mg/kg/day)	Food Exposure (mg/kg/day)	Water
Exposure (mg/kg/day)	Total Exposure (mg/kg/day)	% cPAD

U.S. Population	0.034	0.002711	0.000040	0.002751	8.09

All Infants (< 1 yr old)	0.034	0.003998	0.000131	0.004129	12.14

Children 1-2 years	0.034	0.008369	0.000059	0.008428	24.79

Children 3-5 years	0.034	0.006291	0.000056	0.006347	18.67

Children 6 – 12 years	0.034	0.003777	0.000038	0.003815	11.22

Youth 13-19 years	0.034	0.002141	0.000029	0.002170	6.38

Females 13-49 years	0.034	0.001992	0.000037	0.002029	5.97

Adults 20-49 years	0.034	0.002058	0.000037	0.002095	6.16

Adults + 50	0.034	0.002221	0.000039	0.002260	6.65

Aggregate Cancer Risk for U.S. Population

The aggregate MOE value (considering food and drinking water) was
calculated for pyraclostrobin and is shown in Table 8.  The 36-year
average of pyraclostrobin in surface water that was estimated by
PRZM/EXAMS for use in the chronic/cancer risk assessment is 1.2 ug/L. 
The results demonstrate there are no safety concerns for US population
based on established and new uses, and that the results clearly meet the
FQPA standard of reasonable certainty of no harm. 

Table 8. 	Aggregate Cancer Risk of Pyraclostrobin to the U.S. Population

Population	NOAEL (mg/kg/day)	Food Exposure (mg/kg/day)	Water Exposure
(mg/kg/day)	Total Exposure (mg/kg/day)	Total MOE

U.S. Population	32.80	0.002711	0.000025	0.002736	11988

		2. Non-dietary exposure. Pyraclostrobin is registered for use on
residential and recreational turf.  The applications to turf will be
made only by professional pest control operators.  Therefore,
residential handler exposure was not evaluated.  The exposure assessment
cited in this notice of filing was transcribed from the most recent
Federal Register Notice on pyraclostrobin (U.S. EPA final rule published
in the Federal Register October 29, 2004 [Vol 69, No. 209, p 63083 –
63100).  The EPA evaluated the following post-application exposure
scenarios 1) adults and toddler post-application dermal exposure 2)
toddlers’ incidental ingestion of pesticide residues on lawns form
hand-to-mouth transfer, 3) toddlers’ object-to-mouth transfer from
mouthing pesticide-treated turfgrass, and 4) toddlers’ incidental
ingestion of soil from pesticide-treated residential areas.  The
post-application exposure assessment was based on generic assumptions
specified in the Recommended Revisions to the Residential Standard
Operating Procedures and recommended approaches by an EPA science
advisory council.  A dermal absorption value of 14% was used in the
assessment of pyraclostrobin. The exposure and risk estimates for the
residential exposure scenarios are assessed for the day of application
because adults and toddlers could contact treated turf immediately after
application.  All short-/intermediate term MOE were greater than 100
which indicates that exposure from all residential scenarios result in
exposures below a level of concern.   

D. Cumulative Effects

	Section 408(b)(2)(D)(v) requires that, when considering whether to
establish, modify, or revoke a tolerance, the Agency consider
``available information'' concerning the cumulative effects of a
particular pesticide's residues and ``other substances that have a
common mechanism of toxicity.'  Pyraclostrobin is a foliar fungicide
which belongs to the new class of strobilurin chemistry.  It is a
synthetic analog of strobilurin A, a naturally occurring antifungal
metabolite of the mushroom Strobillurus tenacellus (Anke et. al., 1977).
The active ingredient acts in the fungal cell through inhibition of
electron transport in the mitochondrial respiratory chain at the
position of the cytochrome-bc1 complex.  The protective effect is due to
the resultant death of the fungal cells by disorganization of the fungal
membrane system.  Pyraclostrobin also acts curatively to prevent the
increase and spread of fungal infections by inhibiting mycelial growth
and sporulation on the leaf surface. Pyraclostrobin inhibits spore
germination, germ tube growth and penetration into the host tissues.

The EPA is currently developing methodology to perform cumulative risk
assessments.  At this time, there is no available data to determine
whether pyraclostrobin has a common mechanism of toxicity with other
substances or how to include this pesticide in a cumulative risk
assessment. Unlike other pesticides for which EPA has followed a
cumulative risk approach based on a common mechanism of toxicity,
pyraclostrobin does not appear to produce a toxic metabolite common to
other substances.

E. Safety Determination

	1. U.S. population. Based on this risk assessment, BASF concludes that
there is a reasonable certainty that no harm will result to the general
population from the aggregate exposure to pyraclostrobin residues.

	2. Infants and children. Based on this risk assessment, BASF concludes
that there is a reasonable certainty that no harm will result to infants
or children from the aggregate exposure to pyraclostrobin residues.

F. International Tolerances

	No Codex or Mexican maximum residue levels (MRLs) have been proposed or
are established for residues of pyraclostrobin.  Therefore, no tolerance
discrepancies exist between countries for this chemical.  Since the
application for registration of pyraclostrobin was reviewed jointly with
the Pest Management Regulatory Agency (PMRA) of Canada, several Canadian
MRLs for pyraclostrobin are proposed and are expected to be published
soon.  However, the joint review is expected to have eliminated the
potential for discrepancies between U.S. tolerances and Canadian MRLs.