  SEQ CHAPTER \h \r 1 FILE NAME:   company.wpt   (1/1/2005) (xml)

Template Number P25	

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COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE

(1/1/2005)

EPA Registration Division contact:  Tony Kish, Product Manager 22
(703)-308-9443	

		

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TEMPLATE:

 by establishing a 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 commodities herbs, fresh, 30
parts per million (ppm), avocado, 0.7 ppm, mango, 0.7 ppm, papaya, 0.7
ppm, black sapote, 0.7 ppm, mamey sapote, 0.7 ppm, canistel, 0.7 ppm,
sapodilla, 0.7 ppm, and star apple, 0.7 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.

                                      

.  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.

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.   

. 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.

. 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, including fresh
herbs (30 ppm), mango (0.7 ppm), papaya (0.7 ppm), black sapote (0.7
ppm), mamey sapote (0.7 ppm), canistel (0.7 ppm), sapodilla (0.7 ppm),
and star apple (0.7 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.

Acute Dietary Exposure Assessment

The acute dietary exposure estimates were based on tolerance values,
default process factors, 100% crop treated values for all commodities
except for leafy vegetables, pome fruit, stone fruit, and citrus crop
groups where the tolerance and percent crop treated (%CT) values listed
in the U.S. EPA document DP Barcode No. D323632 (November 30, 2005) were
utilized.  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 53.3 % 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 using DEEM-FCID at the
95th Percentile 

Population	Exposure Estimate	%aPAD

Subgroups	(mg/kg b.w./day)*	 

U.S. Population	0.031449	1.05

All Infants (< 1 year old)	0.044759	1.49

Children (1-2 years old)	0.07164	2.39

Children (3-5 years old)	0.055231	1.84

Children (6-12 years old)	0.034292	1.14

Youth (13-19 years old)	0.02442	0.81

Females (13-49 years old)	0.026636	53.3

Adults (20-49 years old)	0.026011	0.87

Adults (50+ years old)	0.026845	0.89

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 tolerance and percent crop
treated values listed in U.S. EPA document DP Barcode No. D323632
(November 30, 2005) 

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, process 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 values
for all commodities with the exception that anticipated residues were
utilized for leafy vegetables, apples, and pears; default process
factors; % crop treated values listed in the U.S. EPA document DP
Barcode No. D323632 (November 30, 2005); and 100% crop treated values
for herbs, fresh, mango, papaya, ), black sapote, mamey sapote,
canistel, sapodilla, and star apple.  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
proposed tolerance values for fresh herbs (30 ppm), mango (0.7 ppm),
papaya (0.7 ppm), black sapote (0.7 ppm), mamey sapote (0.7 ppm),
canistel (0.7 ppm), sapodilla (0.7 ppm), and star apple (0.7 ppm), were
included.

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 8.2 % of the cPAD.  The most highly
exposure population sub group was children 1-2 years of age at 25.1 %
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 using DEEM-FCID 

Population	Exposure Estimate	%cPAD

Subgroups	(mg/kg b.w./day)	 

U.S. Population	0.002779	8.2

All Infants (< 1 year old)	0.00408	12.0

Children (1-2 years old)	0.008525	25.1

Children (3-5 years old)	0.006374	18.7

Children (6-12 years old)	0.003804	11.2

Youth (13-19 years old)	0.002192	6.4

Females (13-49 years old)	0.002083	6.1

Adults (20-49 years old)	0.002135	6.3

Adults (50+ years old)	0.002281	6.7

cPAD = chronic  population adjusted dose 

* Exposure estimates based on tolerance values for all commodities with
the exception of anticipated residues for leafy vegetables, apples, and
pears; default processing factor; and considering % crop treated values
listed in the U.S. EPA document DP Barcode No. D323632 (November 30,
2005); and 100% crop treated values for herbs, fresh, mango, papaya,
black sapote, mamey sapote, canistel, sapodilla, and star apple

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.    

. 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	0.031449	0.001181	0.03263	1.09

All Infants (< 1 yr old)	3	0.044759	0.004451	0.04921	1.64

Children 1-2 years	3	0.07164	0.001852	0.073492	2.45

Children 3-5 years	3	0.055231	0.001692	0.056923	1.90

Children 6 – 12 years	3	0.034292	0.001178	0.03547	1.18

Youth 13-19 years	3	0.02442	0.000958	0.025378	0.85

Females 13-49 years	0.05	0.026636	0.0011	0.027736	55.47

Adults 20-49 years	3	0.026011	0.001094	0.027105	0.90

Adults + 50	3	0.026845	0.000988	0.027833	0.93



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 MOE from food, water, and
residential exposure are 129 and 266 for the children 1-2 years old and
the US population, respectively.  These MOE 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 Exposure2 (mg/kg/day)	Total Exposure
(mg/kg/day)	MOE3

US	5.8	100	0.002779	0.00004	0.019	0.021819	266

Child 1-2 yr old	5.8	100	0.008525	0.000059	0.036425	0.045009	129

1 Target MOE is 100.

2  Residential Exposure = Exposure to adult while playing golf.

3 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	0.002779	0.00004	0.002819	8.29

All Infants (< 1 yr old)	0.034	0.00408	0.000131	0.004211	12.39

Children 1-2 years	0.034	0.008525	0.000059	0.008584	25.25

Children 3-5 years	0.034	0.006374	0.000056	0.00643	18.91

Children 6 – 12 years	0.034	0.003804	0.000038	0.003842	11.30

Youth 13-19 years	0.034	0.002192	0.000029	0.002221	6.53

Females 13-49 years	0.034	0.002083	0.000037	0.00212	6.24

Adults 20-49 years	0.034	0.002135	0.000037	0.002172	6.39

Adults + 50	0.034	0.002281	0.000039	0.00232	6.82



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	0.002779	0.000025	0.002804	11698



	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. BAS 500F inhibits spore
germination, germ tube growth and penetration into the host tissues

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