Document ID: EPA-HQ-OPP-2007-0460-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-07-25T04:00Z

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

Template Number P25	

Dithianon import tolerance (grapes) January 2006

ATTENTION: 

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Vocabulary database (http://www.epa.gov/pesticides/foodfeed/).

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COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE

(1/1/2005)

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

		

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TEMPLATE:

[BASF Corporation]

 by establishing a tolerance for residues of [dithianon] in or on the
raw agricultural commodity [grapes] at [8] 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.

A. Residue Chemistry                                      

. [Thirty-two residue field trials were conducted in Germany, Spain,
France Greece, Italy, Brazil and Australia.  These studies cover a wide
range of geographies with diverse climates and growing conditions, as
well as various cultural practices.  The residue values reported gave
results which lead to a proposed tolerance of 8 ppm.  

A complete, valid, and reliable database of mammalian toxicology studies
supports the Import Tolerance Petition for dithianon on grapes.  

.  Dithianon technical has a moderate order of acute toxicity to rats by
the oral route of exposure with an LD50 value greater than 300 mg/kg
b.w. and less than 500 mg/kg b.w.  Since this petition is for an import
tolerance, oral toxicity data sufficiently assesses the risk of acute
exposure for this use.  

In addition, dithianon technical demonstrated low acute dermal toxicity
with an LD50 value greater than 2000 mg/kg b.w. (highest dose tested)
(HDT), for which no mortalities occurred.  Dithianon has a moderate
order of acute toxicity to rats via the inhalation route of exposure,
with an LC50 value of 0.31 mg/L for males and 0.58 mg/L for females.  In
an eye irritation study in rabbits, dithianon was classified as
irreversibly irritating, whereas it was non-irritating to rabbit skin
when tested in a dermal irritation study.  In a guinea pig dermal
sensitization study using the Maximization Method, dithianon technical
was shown to be a sensitizer.      

.  The collective data from an extensive battery of in vitro and in vivo
tests covering all major genetic end-points, including an in vivo
chromosomal aberration assay, show that dithianon does not pose a
genotoxic risk and is not likely to be a genotoxic carcinogen.

.  Results from a 2-generation reproductive toxicity study in rats
indicate that dithianon is not a reproductive toxicant, by demonstrating
an absence of increased sensitivity for the developing offspring to
dithianon.  The NOAEL for parental toxicity was 200 ppm (approximately
16 mg/kg b.w./day), based on reduced food consumption and decreased body
weight gain at 600 ppm (HDT).  The NOAEL for pup/offspring toxicity was
600 ppm (approximately 48 mg/kg b.w./day) (HDT).  Lastly, the NOAEL for
reproductive toxicity was also 600 ppm (approximately 48 mg/kg b.w./day)
(HDT).    

Developmental toxicity studies in rats and rabbits revealed no evidence
of teratogenic effects for fetuses of either species and no evidence of
development effects in the absence of maternal toxicity.  Specifically,
in a developmental (teratology) toxicity study in the rat, the results
demonstrated that the NOAEL for maternal toxicity was 20 mg/kg b.w./day,
based on decreased body weight gain and food consumption in dams at 50
mg/kg b.w./day.  The NOAEL for developmental toxicity was also 20 mg/kg
b.w./day, based on increased resorptions and subsequent reduction in
mean number of fetuses per dam at 50 mg/kg b.w./day.  Therefore,
dithianon is considered to be neither a developmental toxicant nor a
teratogenic agent in the rat.  

In a developmental (teratology) toxicity study in the rabbit, the
results demonstrated the NOAEL for maternal toxicity was 10 mg/kg
b.w./day, based on decreased body weight gain and food consumption at 25
mg/kg b.w./day.  The NOAEL for developmental toxicity was 25 mg/kg
b.w./day, based on an increase in abortions and resorptions and
subsequent reduction in the mean number of fetuses per doe at 40 mg/kg
b.w/day (HDT).  Therefore, dithianon is considered to be neither a
developmental toxicant nor a teratogenic agent in the rabbit.

Short-term (28-day) toxicity studies were conducted in mice and rats. 
In addition, subchronic (90-day) feeding studies were conducted in rats
and in dogs.  Specifically, short-term (28-day) oral exposure of mice
and subchronic (90-day) oral exposure of rats to dithianon technical
resulted in slight anemia.  In addition, mice also exhibited hemosiderin
deposition in the liver, and rats (at 90 days) also demonstrated
increased kidney and liver weights in males and females, and
histopathological findings in the kidney (renal tubular epithelial cell
degeneration and regenerative hyperplasia) (females only).  The NOAEL
for mice in the 28-day oral toxicity study was 100 ppm (equivalent to 15
mg/kg b.w./day).  For rats in the 90-day oral toxicity study, the NOAEL
was 180 ppm (approximately 15.5 mg/kg b.w./day).  [In the 28-day oral
rat toxicity study, the NOAEL for dithianon was a dietary concentration
of 315 ppm (approximately 30 mg/kg b.w./day), based on decreased overall
body weight gains and decreased food consumption for males and females
at 1250 ppm.]    

Subchronic (90-day) oral exposure of dogs to dithianon resulted in
decreased body weight or weight gain, decreased food consumption, and
increased kidney weight.  The NOAEL for dogs in the 90-day oral study
was 200 ppm (approximately 3.0 mg/kg b.w./day).  

.  Findings similar to those observed in the short-term and/or
subchronic toxicity studies were also apparent in the long-term dietary
toxicity studies conducted in rats, mice, and dogs.  Pre-neoplastic and
neoplastic lesions were observed in the life-time rat dietary study in
females.  However, the collective evidence from this study and from two
special mechanistic studies demonstrated that these lesions occur due to
a regenerative response of the kidney basophilic tubules, which follow
persistent degenerative changes / cellular damage to kidney proximal
tubular epithelial cells.  Thus, a threshold for these lesions exists. 
Moreover, these lesions in female rats were only noted following a 24
month dietary exposure to 600 ppm of dithianon, a concentration that
exceeded the Maximum Tolerated Dose (MTD), as evidenced by markedly
decreased body weight gains in females as compared to controls.  For
this 24-month combined chronic toxicity and oncogenicity study in rats,
the NOAEL for chronic effects was 20 ppm or 1.0 mg/kg b.w./day.  The
carcinogenicity NOAEL was 120 ppm for females or 6.0 mg/kg b.w./day.

  

In contrast, pre-neoplastic or neoplastic lesions were not observed in
the life-time dietary study in mice, even at a concentration of
dithianon that exceeded the MTD.  The NOAEL for chronic effects in mice
from the 18-month combined chronic toxicity and oncogenicity study was
20 ppm (equivalent to 3.0 mg/kg/day), while the NOAEL for potential
oncogenic effects was 500 ppm (equivalent to 75 mg/kg b.w./day) (highest
concentration tested) (HCT).  Lastly, for the 1-year chronic toxicity
study in dogs, the NOAEL was 40 ppm (approximately 1.6 mg/kg b.w./day).

.  The rat and goat metabolism studies indicate that the qualitative
nature of the residues of dithianon technical in animals is adequately
understood.  Elimination of dithianon via excreta is rapid.  The
metabolism data suggests that unabsorbed dithianon is broken down in the
gastrointestinal tract, since only very low concentrations of the
unaltered parent were identified in the fecal excreta.  

In the metabolism studies using radiolabeled dithianon, examination of
organs, tissues, and milk indicated that accumulation is not of concern.
 Additionally, repeated dosing did not result in the accumulation of
total radioactive residues.

.  No toxicologically significant metabolites were detected in plant or
animal metabolism studies.  Therefore, toxicology studies with
metabolites are not required.

.  Collective organ weights and histopathological findings from the
2-generation rat reproduction study, as well as from the
short-term/subchronic and chronic toxicity studies in three different
animal species, demonstrate no apparent estrogenic effects or
treatment-related effects on the endocrine system.

. Exposure assessments were conducted to evaluate the potential risk due
to acute and chronic dietary exposure of the U.S. population to residues
of dithianon.  This fungicide is not registered in the United States but
proposed import tolerances were previously submitted for pome fruit and
hops.  This dietary exposure analysis included both the previous and
currently proposed import tolerances for pome fruit, hops, and grapes.  

Acute Dietary Exposure Assessment

The acute dietary exposure estimates were based on proposed tolerance
values, default process factors, 100% crop treated (CT) value for hops,
and the percent of grapes and pome fruit imported into the United
States.  Proposed tolerance values are 5 ppm for pome fruit, 100 ppm for
hops, and 8 ppm for grapes.  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
percent import values for grapes and pome fruit were calculated based on
data published from the USDA (Fruit and Tree Nuts Situation and Outlook
Yearbook/FTS-2005/October 2005, Economic Research Service, USDA).  The
following calculations were used with the average 2002 - 2004 data.  

 	Product available for U.S. population consumption = (production in
U.S. that is utilized  - export) + import  

 

% import value = (imported product / product available for U.S.
consumption)*100

The percent import values were 9, 5, and 11% for grapes, apples, and
pears, respectively.  The dietary exposure assessment is very
conservative since juice and wine were considered to contain residues of
dithianon at the tolerance level (5 ppm pome fruit, 8 ppm grapes). 
Process studies have shown dithianon residues either decrease or are
non-detectable in wine and juice (BASF ID No. 2003/1014014, DT-713-031
thru DT-713-039, 2002/1011555, 2002/1011501, 2002/1011501DT-711-094 and
-095).

The acute population adjusted dose (aPAD) for dithianon is 0.120 mg/kg
bw/day for females 13-49 years old and all other sub-populations.  
Considering the exposure assumptions discussed above, dithianon acute
dietary exposure from food is less than 10 % aPAD (95th percentile) and
67% (99.9th percentile) for the U.S. population and all sub-populations
except children 1-2 years of age that occupies 14.1 % of the aPAD.  The
results of the acute dietary assessment are presented in Table 1.

Table 1.	Summary of Dithianon Acute Dietary Exposure Analysis
Considering all Current and Proposed Import Tolerances, Default Process
Factors, and Percent Imports using DEEM-FCID at the 95th and 99.9th
Percentile 

Population	Exposure Estimate	%aPAD	Exposure Estimate	%aPAD

Subgroups	(mg/kg b.w./day)	 	(mg/kg b.w./day)	 

	95th Percentile

99.9th Percentile

	U.S. Population	0.007458	6.2	0.051801	43.2

All Infants (< 1 year old)	0.011451	9.5	0.051317	42.8

Children (1-2 years old)	0.016915	14.1	0.079187	66.0

Children (3-5 years old)	0.010958	9.1	0.037982	31.7

Children (6-12 years old)	0.004754	4.0	0.019675	16.4

Youth (13-19 years old)	0.002338	1.9	0.040646	33.9

Females (13-49 years old)	0.004130	3.4	0.035771	29.8

Adults (20-49 years old)	0.008877	7.4	0.057864	48.2

Adults (50+ years old)	0.004411	3.7	0.030333	25.3

aPAD = acute population adjusted dose 

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, and percent import values
for hops) would further reduce the estimated exposure values.  

Chronic Dietary Exposure Assessment

The chronic dietary exposure estimates were based on proposed import
tolerance values, default process factors, 100% crop treated (CT) value
for hops, and the percent of grapes and pome fruit imported into the
United States.    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
are 5 ppm for pome fruit, 100 ppm for hops, and 8 ppm for grapes.

The chronic population adjusted dose (cPAD) used for U.S. population and
all sub-populations is 0.01 mg/kg bw/day. Considering the exposure
assumptions discussed above, dithianon chronic dietary exposure from
food for the U.S. population was 14.1% of the cPAD.  The most highly
exposed population sub group was children 1-2 years of age at 45.3%
cPAD.   Results of the chronic dietary assessment are presented in Table
2.  An additional chronic assessment was conducted considering average
anticipated residue values from the field trials rather than the
tolerance values.  Average residues used were 0.82 ppm for pome fruit
and 1.78 ppm for grapes (BASF ID No. 2002/1008746, 2003/1004349,
DT-713-031 thru -039, DT-713-047 thru -049, DT-713-058).  The estimated
exposure to children 1-2 years old decreased to 8.6% of the cPAD.  
Results for this assessment are listed in Table 3.  

Table 2. 	Summary of Dithianon Chronic Dietary Exposure Analysis
Considering all Current and Proposed Import Tolerances, Default Process
Factors, and Percent Imports using DEEM-FCID

Population	Exposure Estimate	%cPAD

Subgroups	(mg/kg b.w./day)	 

U.S. Population	0.001406	14.1

All Infants (< 1 year old)	0.002780	27.8

Children (1-2 years old)	0.004525	45.3

Children (3-5 years old)	0.002719	27.2

Children (6-12 years old)	0.000994	9.9

Youth (13-19 years old)	0.000584	5.8

Females (13-49 years old)	0.000800	8.0

Adults (20-49 years old)	0.001580	15.8

Adults (50+ years old)	0.000883	8.83

cPAD = chronic  population adjusted dose 

Table 3. 	Summary of Dithianon Chronic Dietary Exposure Analysis
Considering Average Field Residue Values, Default Process Factors, and
Percent Imports using DEEM-FCID

Population	Exposure Estimate	%cPAD

Subgroups	(mg/kg b.w./day)	 

U.S. Population	0.000837	8.4

All Infants (< 1 year old)	0.000492	4.9

Children (1-2 years old)	0.000862	8.6

Children (3-5 years old)	0.000519	5.2

Children (6-12 years old)	0.000191	1.9

Youth (13-19 years old)	0.000321	3.2

Females (13-49 years old)	0.000495	5.0

Adults (20-49 years old)	0.001305	13.1

Adults (50+ years old)	0.000549	5.5

cPAD = chronic  population adjusted dose 

Average estimated residue values from the field trials were utilized for
grapes (1.78 ppm) and pome fruit (0.82 ppm).  Proposed tolerance value
of 100 ppm was used for hops

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 and process factors) would further reduce the
estimated exposure values.    

. Dithianon is not registered for use within the United States

 and therefore a drinking water exposure assessment is not required.

Acute Aggregate Exposure and Risk (Food and water)

The aggregate acute risk includes potential residues of dithianon from
food and water (Table 4). Exposures from residential uses are not
included in the acute aggregate assessment.  Since dithianon is not
registered for use within the United States the only potential exposure
of dithianon to the U.S. population is through food consumption and not
water exposure.  The results demonstrate there are no safety concerns
for any subpopulation based on the proposed import tolerances (grapes,
pome fruit, hops), and that the results clearly meet the FQPA standard
of reasonable certainty of no harm.   

Table 4. 	Estimated Acute Aggregate Exposure and Risk of Dithianon 

Population Subgroup	aPAD (mg/kg/day)	99.9th Percentile

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

U.S. Population	0.12	0.051801	NA	0.051801	43.2

All Infants (< 1 yr old)	0.12	0.051317	NA	0.051317	42.8

Children 1-2 years	0.12	0.079187	NA	0.079187	66.0

Children 3-5 years	0.12	0.037982	NA	0.037982	31.7

Children 6 – 12 years	0.12	0.019675	NA	0.019675	16.4

Youth 13-19 years	0.12	0.040646	NA	0.040646	33.9

Females 13-49 years	0.12	0.035771	NA	0.035771	29.8

Adults 20-49 years	0.12	0.057864	NA	0.057864	48.2

Adults + 50	0.12	0.030333	NA	0.030333	25.3

NA = not applicable, dithianon is not registered for use within the
United States

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

Short-term aggregate risk from dithianon takes into account exposures
from dietary consumption (food and water) and residential exposure. 
Dithianon is not registered for residential use within the United States
and therefore this assessment is not required.

 Chronic Aggregate Exposure and Risk (food and water)

The aggregate chronic risk includes residues of dithianon from food and
water (Table 5). Exposures from residential uses are not included in the
chronic aggregate assessment.  Since dithianon is not registered for use
within the United States the only potential exposure of dithianon to the
U.S. population is through food consumption and not water exposure.  The
results demonstrate there are no safety concerns for any subpopulation
based on the proposed import tolerances, and that the results clearly
meet the FQPA standard of reasonable certainty of no harm. 

  Table 5. 	Estimated Chronic Aggregate Exposure and Risk of Dithianon 

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	0.01	0.001406	NA	0.001406	14.1

All Infants (< 1 yr old)	0.01	0.002780	NA	0.002780	27.8

Children 1-2 years	0.01	0.004525	NA	0.004525	45.3

Children 3-5 years	0.01	0.002719	NA	0.002719	27.2

Children 6 – 12 years	0.01	0.000994	NA	0.000994	9.9

Youth 13-19 years	0.01	0.000584	NA	0.000584	5.8

Females 13-49 years	0.01	0.000800	NA	0.000800	8.0

Adults 20-49 years	0.01	0.001580	NA	0.001580	15.8

Adults + 50	0.01	0.000883	NA	0.000883	8.83

.  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.'  

The EPA is currently developing methodology to perform cumulative risk
assessments.  At this time, there is no available data to determine
whether dithianon has a common mechanism of toxicity with other
substances or how to include this pesticide in a cumulative risk
assessment. 

	Codes maximum residue levels (MRLs) have been established for residues
of dithianon on grapes. 

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