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

Banana, coffee, 

Template Number P25	

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COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE

(1/1/2005)

EPA Registration Division contact: 

[Cynthia Giles-Parker, 

Registration Division (7505C), 

Office of Pesticide Programs, 

Environmental Protection Agency, 

1200 Pennsylvania Ave., NW.

Washington, DC 20460–0001; 

Telephone number: (703) 305–7740; 

e-mail address: giles-parker.cynthia@epa.gov.]

	

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TEMPLATE:

 by establishing a tolerance for residues of [Boscalid (BAS 510F);
[3-pyridinecarboxamide, 2-chloro-N-(4'-chloro(1,1'-biphenyl)-2-yl)] in
or on the raw agricultural commodity for the Coffee, green bean at
[0.05] parts per million (ppm), and increasing the established tolerance
for the residues of boscalid in/on Banana from 0.2 ppm to [0.5] parts
per million (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.

                                      

.  [Based on available acute toxicity data, boscalid and its formulated
products do not pose acute toxicity risks.  The acute toxicity studies
place technical Boscalid (BAS 510 F) in toxicity category IV for acute
oral; category III for acute dermal and category IV for acute
inhalation.  Boscalid is category IV for both eye and skin irritation
and it is not a dermal sensitizer. For the proposed Oilseed Crop Group
20, the product proposed is Endura® fungicide (BAS 510 02/04F)
containing boscalid (BAS 510F) as the active ingredient.  Endura®
fungicide (BAS 510 02/04F) has an acute oral toxicity category of III,
acute dermal of category III, acute inhalation of category IV, eye
irritation of category III, skin irritation of category IV, and is not a
dermal sensitizer.]

.  [Ames Test (1 Study; gene point mutation): Negative; In Vitro
CHO/HGPRT Locus Mammalian Cell Mutation Assay (1 Study; point gene
mutation): Negative; In Vitro V79 Cell Cytogenetic Assay (1 Study;
Chromosome Damage): Negative; In Vivo Mouse Micronucleus (1 Study;
Chromosome Damage): Negative; In Vitro Rat Hepatocyte (1 Study; DNA
damage and repair): Negative. Boscalid has been tested in a total of 5
genetic toxicology assays consisting of in vitro and in vivo studies. 
It can be stated that Boscalid did not show any mutagenic, clastogenic
or other genotoxic activity when tested under the conditions of the
studies mentioned above.  Therefore, boscalid does not pose a genotoxic
hazard to humans.]

.  [The potential reproductive and developmental toxicity of boscalid
was investigated in a two-generation rat reproduction study as well as
in rat and rabbit teratology studies.  There were no adverse effects on
reproduction in the two-generation study at any dose tested.  The
reproductive NOAEL is 10,000 ppm (1165 and 1181 for males and females,
respectively), the highest dose tested. .  Toxicity to the offspring was
seen at 1,000 ppm in the form of decreased pup weights in the F2 males,
and at 10,000 ppm in the form of decreased pup weights for both males
and females of both the F1 and F2 generations.  The offspring NOAEL is
100 and 1000 ppm (11 and 116 mg/kg b.w./day) for males and females,
respectively. In males of the F1 generation, reduced body weight and
reduced body weight gain were observed at 10,000 ppm. Additionally,
hepatocyte degeneration was observed in male animals of both the F0 and
F1 generations at 10,000 ppm.  The parental systemic NOAEL is 1000 and
10,000 (113 and 1181 mg/kg b.w./day) for males and females, respectively


No teratogenic effects were noted in either the rat or rabbit
developmental studies. In the rat study, evidence of maternal or
developmental toxicity was not observed at any dose (highest dose tested
of 1,000 mg/kg b.w./day).  In the rabbit teratology study, at the high
dose of 1,000 mg/kg b.w./day a maternal body weight gain decrease
compared to controls of 81% was observed during the treatment period. 
Reduced food consumption, reduced body weight and abortions in three
dams, were also seen at 1,000 mg/kg b.w./day.  The NOAEL for both
maternal and developmental toxicity was determined to be 300 mg/kg
b.w/day.  

Neurotoxicity was not observed at any dose in the developmental
neurotoxicity study.  Reduced pup body weights were observed at the high
and mid dose levels of 1000 and 10,000 ppm (118 and 1,183 mg/kg
b.w./day, respectively).  No developmental toxicity was seen at the low
dose of 14 mg/kg b.w./day (100 ppm).  Although no maternal toxicity was
seen in this study, other studies which evaluated more parameters at
similar doses of boscalid demonstrated maternal toxicity.

The Agency concluded that there are no residual uncertainties for pre-
and postnatal toxicity as the degree of concern is low for the
susceptibility seen in the above studies, and the dose and endpoints
selected for the overall risk assessments will address the concerns for
the body weight effects seen in the offspring.  Although the dose
selected for overall risk assessments (21.8 mg/kg b.w./day) is higher
than the NOAEL's in the 2-generation reproduction study (11 mg/kg
b.w./day) and the developmental neurotoxicity study (14 mg/kg b.w./day),
these differences are considered to be an artifact of the dose selection
process in these studies.  For example, there is a 10-fold difference
between the LOAEL (113 mg/kg b.w./day) and the NOAEL (11 mg/kg b.w./day)
in the two generation reproduction study. A similar pattern was seen
with regard to the developmental neurotoxicity study, where there is
also a 10-fold difference between the LOAEL (147 mg/kg b.w./day) and the
NOAEL (14 mg/kg b.w./day).  There is only a 2-3-fold difference between
the LOAEL (57 mg/kg b.w./day) and the NOAEL (21.8 mg/kg b.w./day) in the
critical chronic dog study which was used for risk assessment.  Because
the gap between the NOAEL and LOAEL in the 2-generation reproduction and
developmental neurotoxicity studies was large and the effects at the
LOAEL's were minimal, the true no-observed-adverse-effect-level was
probably considerably higher. Therefore, the selection of the NOAEL of
21.8 mg/kg b.w./day from the 1-year dog study is conservative and
appropriate for the overall risk assessments.  In addition, the
endpoints for risk assessment are based on thyroid effects seen in
multiple species (mice, rats and dogs) and after various exposure
durations (subchronic and chronic exposures) which were not observed at
the LOAEL's in either the 2-generation reproduction or the developmental
neurotoxicity studies.  Based on these data, the Agency concluded that
there are no residual uncertainties for pre- and post-natal toxicity.]

[The subchronic toxicity of boscalid was investigated in 90–day
feeding studies with rats, mice and dogs, and in a 28–day dermal
administration study in rats.  Additionally a 90–day neurotoxicity
study in rats was performed.  Generally, mild toxicity was observed
including alterations in various clinical chemistry parameters and
effects on the liver and thyroid.  In the rat, effects observed were
increased thyroid weight and increased incidence of thyroid hyperplasia
as well as follicular epithelial hypertrophy.  Increased liver weights
and an increased incidence of marked fatty changes in the liver were
observed in mice  Changes observed in dogs were increased serum alkaline
phosphatase and liver weights.  The lowest subchronic toxicity NOAEL was
from the dog study (7.6/8.1 mg/kg b.w./day in males and females,
respectively).

In the 28–day repeat dose dermal study, no systemic effects were noted
up to the highest dose tested of 1,000 mg/kg b.w./day.

In a 90–day rat neurotoxicity study, no signs of neurotoxicity were
observed in the pups or adults.  The NOAEL is the highest tested of
15,000 ppm (1,050/1,272 mg/kg b.w./day in males and females,
respectively).]

. [The chronic toxicity/oncogenicity studies with boscalid include a
12–month feeding study with Beagle dogs, an 18–month B63CF1 mouse
feeding study, a 24–month Wistar rat chronic feeding study and a
24–month Wistar rat oncogenicity study. At the highest dose tested in
dogs, effects observed consisted primarily of increased liver and
thyroid weights and some serum clinical chemistry changes.  The NOAEL
was 800 ppm (21.8 mg/kg b.w./day males; 22.1 mg/kg b.w./day females).

In the mouse oncogenicity study, decreased body weights were seen in
both males and females at 8000 ppm (1345 and 1804 mg/kg b.w./day for
males and females, respectively) and in males at 2000 ppm (331 mg/kg
b.w./day).  Also in males at 8000 ppm, increased liver weights  and an
increased incidence of peripherial hypertrophy of the liver were
observed.  The NOAEL was 400 ppm and 2000 ppm (65 and 443 mg/kg
b.w./day) for male and female mice, respectively.  

In both the rat chronic and oncogenicity studies, the highest dose
tested of 15,000 ppm exceeded a maximum tolerated dose (MTD) and was
discontinued after 17 months.  Effects observed at the next highest dose
of 2,500 ppm (110/ 150 mg/kg b.w./day for males and females,
respectively) were increased thyroid weights and histopatholigical
changes in the thyroid which included follicular cell hypertrophy,
hyperplasia and adenomas.  The NOAEL was 500 ppm (22 and 30 mg/kg
b.w./day for male and female rats, respectively).

No evidence of treatment-induced oncogenicity was observed in the mouse
study.  In the rat, a slight increase in thyroid follicular cell
adenomas was seen in both sexes at the high dose when the data from both
chronic and oncogenicity bioassays are combined.

	A non-genotoxic (threshold) mode of action (MOA) for the thyroid
follicular cell adenomas was demonstrated from results of several
studies.

Based on review of the available data, the Reference Dose (RfD) for
boscalid was based on a 1-year feeding study in dogs with a NOAEL of 
21.8 mg/kg b.w./day.  Using an uncertainty factor of 100, the RfD is
calculated to be 0.218 mg/kg b.w./day.  Based on the acute toxicity
data, an acute dietary risk assessment is not needed.

Threshold effects.  

	Boscalid was shown to be non-carcinogenic in mice.  There was a slight
increase in thyroid follicular cell adenomas at the high dose in both
sexes in the rat.  A non-genotoxic (threshold) MOA was demonstrated for
the thyroid tumors.  The Agency concluded a carcinogenicity
classification of “suggestive evidence of carcinogenicity” and that
a dose response assessment for cancer was not needed.]

. [In the rat, the predominant route of excretion of boscalid (BAS 510F)
is fecal with urinary excretion being minor.  The half-life of boscalid
is less than 24 hours.  Saturation of absorption appears to be occurring
at the high dose level. Boscalid is rapidly and intensively metabolized
to a large number of biotransformation products.  The hydroxylation of
the diphenyl moiety was the quantitatively most important pathway. 
Second most important was the substitution of the Cl of the
2-chloropyridine part against SH by conjugation with glutathione.  No
major differences were observed.  In hens and goats the residues of
concern were determined to be parent, the hydroxylated metabolite M510
F01 (2-chloro-N-(4'chloro-5-hydroxy-biphenyl-2-yl)nicotinamide), and the
glucuronic acid of the metabolite M510 F02.]

. [No additional studies were required for metabolite toxicology.]

.  [No specific tests have been conducted with boscalid 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 boscalid
produces endocrine related effects.] 

. [An assessment was conducted to evaluate the potential risk due to
chronic dietary exposure of the U.S. population and sub-populations to
residues of boscalid.  Tolerance values for boscalid (BOSCALID) have
previously been established and are listed in U.S. 40 CFR § 180.589.   

This analysis included all crops with established boscalid tolerance
values, crops pending tolerance assignment (vegetable, leafy group 4
with celery 45 ppm and spinach 60 ppm; almond hulls 17 ppm; Belgian
Endive 12 ppm), increased tolerance values (berries, crop group 13 at 8
ppm; strawberries at 4.5 ppm), and proposed import tolerances for banana
pulp 0.5 ppm, and coffee 0.05 ppm. ]

.  

[Acute Dietary Exposure Assessment

An acute assessment was not needed since the U.S. EPA Toxicological
Endpoint Selection (TES) Committees had previously evaluated the
boscalid toxicity data and determined there were no toxic effects
attributable to a single dose.  Therefore, a quantitative acute dietary
exposure and risk assessment were not required.]

Chronic Dietary Exposure Assessment

A Tier 1 chronic dietary exposure assessment was conducted assuming
tolerance level residues, default processing factors, 100% crop treated
factors for all crops and consumption data 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.  Residues in animal
commodities (i.e. meat, meat byproducts, fat, milk, eggs) were included
at the tolerance levels currently established and listed in U.S. 40 CFR
§ 180.589.  

Dietary exposure estimates were compared against the established
boscalid chronic Population Adjusted Dose (cPAD) of 0.218 mg/kg b.w./day
for all populations.  Results of the chronic dietary assessments are
listed in the Table 1.  The estimated chronic dietary exposure from
crops and animal commodities was less than 38.2 % of the cPAD for all
subpopulations.  Additional refinements such as the use of anticipated
residues and adjusted crop treated factors would further reduce the
estimated chronic dietary exposure.  The results in Table 1 demonstrate
there are no safety concerns for any subpopulation based on established
and new uses, and the results clearly meet the FQPA standard of
reasonable certainty of no harm.

 

Table 1.  Summary of Chronic Dietary Exposure Assessment 

Considering Crops with Established and Proposed Tolerances

for Boscalid

Population

Subgroups	Exposure Estimate

(mg/kg b.w./day)	%cPAD

U.S. Population	0.023544	10.8

All Infants	0.052826	24.2

Children 1-2 years	0.083357	38.2

Children 3-5 years	0.057443	26.4

Children 6-12 years	0.028847	13.2

Youth 13-19 years	0.016424	7.5

Adults 20-49 years	0.017511	8.0

Adults 50+ years	0.019488	8.9

Females 13 - 49	0.017734	8.1

%cPAD = percent of chronic population adjusted dose 

Exposure estimates based on tolerance values, default processing 

	

]

	

.  

[Based on PRZM/EXAMS and SCI-GROW models, the estimated drinking water
exposure concentrations of boscalid for chronic exposure were 26 ppb for
surface water and 0.63 ppb for ground water.  Drinking water
contributions were assessed based on the maximum estimated boscalid
water concentrations (26 ug/L), and water consumption and body weights
reported in CSFII, using DEEM-FCID software.  The chronic estimated
water exposure values are summarized in Table 2.  Minimal exposure of
boscalid occurs through drinking water with < 1.0% cPAD for all
subpopulations.

Table 2. 	Results for Boscalid Chronic Water Exposure Analysis
Considering the Maximum Estimated Chronic Drinking Water Concentration
using 

DEEM-FCID 

Population	Water Exposure Estimate	%aPAD

Subgroups	(mg/kg b.w./day)	 

U.S. Population	0.000548	0.3

All Infants (< 1 year old)	0.001797	0.8

Children (1-2 years old)	0.000814	0.4

Children (3-5 years old)	0.000762	0.3

Children (6-12 years old)	0.000525	0.2

Youth (13-19 years old)	0.000396	0.2

Females (13-49 years old)	0.000510	0.2

Adults (20-49 years old)	0.000512	0.2

Adults (50+ years old)	0.000538	0.2

cPAD = chronic  population adjusted dose

Based on estimated acute surface water value of 26 ug/L

Acute Aggregate Exposure and Risk (Food and water)

Since the U.S. EPA Toxicological Endpoint Selection (TES) Committees has
evaluated the Boscalid toxicity data and determined there was no
toxicological endpoints for acute dietary exposure, the determination of
an acute aggregate exposure and risk evaluation was not required.  

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

Short- and intermediate-term aggregate exposure takes into account
residential exposure plus chronic exposure from food and water. 
Residential exposure is used to refer to non-occupational and
non-dietary exposure.  No new residential uses are currently being
registered for boscalid that would increase non-dietary exposure.  The
residential exposure value used in this risk assessment was previously
determined by the EPA (Federal Register, Volume 68, No 146, July 30,
2003) and considers dermal exposure to adults from the golf course use. 
 The MOE presented in the Table 3 is considered to be representative for
youth playing golf because youth and adults possess similar body surface
area to weight rations and because the dietary exposure for youth (13-19
years old) is less than that of the general US population.    

Table 3. 	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	21.8	100	0.023544	0.000548	0.0008	0.024892	876

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 boscalid from food and
water (Table 4). 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 4. 	Estimated Chronic Aggregate Exposure and Risk of Boscalid 

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	0.218	0.023544	0.000548	0.024092	11.05

All Infants (< 1 yr old)	0.218	0.052826	0.001797	0.054623	25.06

Children 1-2 years	0.218	0.083357	0.000814	0.084171	38.61

Children 3-5 years	0.218	0.057443	0.000762	0.058205	26.70

Children 6 – 12 years	0.218	0.028847	0.000525	0.029372	13.47

Youth 13-19 years	0.218	0.016424	0.000396	0.01682	7.72

Adults 20-49 years	0.218	0.017734	0.00051	0.018244	8.37

Adults + 50	0.218	0.017511	0.000512	0.018023	8.27

Females 13 - 49	0.218	0.019488	0.000538	0.020026	9.19

]

	[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.’’ BAS 510 F is a foliar fungicide
chemically belonging to the carboxin class of fungicides. BAS 510 F acts
in the fungal cell by inhibiting mitochondrial respiration through
inhibition of the succinate-ubiquinone oxidase reductase system in
Complex II of the mitochondrial electron transport chain. BAS 510 F
shares this mode of action with only one other currently registered U.S.
pesticide - carboxin. 

The EPA is currently developing methodology to perform cumulative risk
assessments. At this time, there is no available data to determine
whether BAS 510F 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, BAS
510F does not appear to produce a toxic metabolite produced by other
substances.]

E. Safety Determination

.  [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.]

]

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