Document ID: EPA-HQ-OPP-2007-0460-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-11-04T05:00Z

<EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  >

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

 

<INSTRUCTIONS:  Please utilize this outline in preparing the pesticide
petition.  In cases where the outline element does not apply, please
insert “NA-Remove” and maintain the outline. Please do not change
the margins, font, or format in your pesticide petition. Simply replace
the instructions that appear in green, i.e., “[insert company
name],” with the information specific to your action.>

<TEMPLATE:>

<BASF Corporation>

<PP 6E7103>

<<	EPA has received a pesticide petition (PP 6E7103) from BASF
Corporation, 26 Davis Drive, Research Triangle Park, NC 27709 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 by establishing a
tolerance for residues of dithianon in or on the raw agricultural
commodity grape at 3 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  FDDCA; 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 metabolism. The nature of the residues of dithianon in plants
is adequately understood for the purposes of this tolerance.  Metabolism
studies in three diverse crops demonstrated a similar pattern of
dithianon metabolism with a significant amount of unchanged parent
compound remaining on the plant surfaces.  The metabolism of dithianon
in plants results in a large number of fragments in only trace amounts. 
Hence, parent dithianon is the only residue of concern.>

<	2. Analytical method. Analytical methods using high performance liquid
chromatography with UV detection were used to determine the residues of
dithianon on grapes.  These methods have been confirmed through
independent laboratory validations.  An LC/MS/MS method has been
validated and is adequate for tolerance enforcement for residues of
dithianon on grape and grape processed fractions.  >

<	3. Magnitude of residues. More than twenty-four residue field trials
were conducted in representative vine growing areas in Germany, Spain,
France, Greece, Italy, Brazil and the United States.  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 3 ppm.  

Grape processing studies were conducted from trials in the United
States, Germany, France, Italy and Spain.  These studies indicate that
dithianon does not concentrate in the grape processed commodities juice,
wine and raisin.  Therefore, import tolerances for grape processed
commodities are not being proposed in this petition.

>

<B. Toxicological Profile>

The submitted database of mammalian toxicology studies is sufficient to
support the Import Tolerance Petition for dithianon on grape.  The
approved and proposed tolerances for dithianon are for imported
commodities only; thus, the acute oral toxicity study is the only study
required to evaluate acute toxicity. Likewise, subchronic dermal and
inhalation studies are not required because residential and occupational
risk assessments are not necessary to set tolerances on imported
commodities. The remaining toxicology database is sufficient to
characterize the hazards associated with dithianon, with the exception
of the developmental toxicity study in rabbits, which was classified
unacceptable. To account for this database gap, a 10X database
uncertainty factor (UFDB) was applied which makes the degree of concern
for pre- and/or postnatal toxicity low.

<	1. Acute toxicity.  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.>  

Additional studies with 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.

<	2. Genotoxicty.  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.>

<	3. Reproductive and developmental toxicity.  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.  

For the developmental (teratology) toxicity study in the rabbit, EPA has
classified the study as unacceptable.  To account for this database gap,
a 10x database uncertainty factor was applied, therefore making the
degree of concern for pre- and/or postnatal toxicity low.

<	4. Subchronic toxicity. 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). >

<	5. Chronic toxicity. 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).>

<	6. Animal metabolism. 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.>

<	7. Metabolite toxicology. No toxicologically significant metabolites
were detected in plant or animal metabolism studies.  Therefore,
toxicology studies with metabolites are not required.>

<	8. Endocrine disruption. In the available toxicity studies on
dithianon, no estrogen-, androgen-, and/or thyroid-mediated toxicity was
observed.  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.  >

<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 dithianon.  This fungicide is not registered
for use in the United States but import tolerances were previously
established for pome fruit and hops.  This dietary exposure analysis
includes both the previous tolerances established for pome fruit and
hops and the currently proposed import tolerance for grape.>

<	i. Food. >

Acute Dietary Exposure Assessment

The acute dietary exposure estimates were based on actual residue
values, average processing factors, 100% crop treated (CT) value for
hops, and the percent of consumed 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, version 2.16.  The percent
import values for grapes and pome fruit were obtained from data
published by the USDA (Fruit and Tree Nuts Situation and Outlook
Yearbook/FTS-2007/October 2007, Economic Research Service, USDA).  

The percent import values were 54.9, 6.3, and 21.2% for fresh grapes,
apples, and pears, respectively.  In addition, for juice the imports
amounted to 77.2% for apples and 51% for grapes, and for dried
commodities the % imports were 39% for apples and 11.7% for grapes. 
Imported wine accounted for 26.1% of the wine consumed in the US. 
Average processing factors for apples and pears were 0.41, 0.05 and 0.07
for drying, juicing and saucing, respectively.  Average processing
factors for grapes were 0.18, 0.03, and 0.02 for drying, juicing and
wine-making.  For hops, the processing factor for beer making was 0.01,
which is an upper, conservative value.

The acute population adjusted dose (aPAD) for dithianon is 0.02 mg/kg
bw/day for females 13-49 years of age.  EPA has determined that an acute
assessment is not necessary for other sub-populations.  Considering the
exposure assumptions discussed above, dithianon acute dietary exposure
from food is less than 2% aPAD (95th percentile) and 22% aPAD (99.9th
percentile) for females 13-49 years of age.  The results of the acute
dietary assessment are presented in Table 1.

Table 1.	Summary of Dithianon Acute Dietary Exposure Analysis
Considering Actual Residue Values, revised Processing 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	Not applicable	Not applicable

All Infants (< 1 year old)

Children (1-2 years old)

Children (3-5 years old)

Children (6-12 years old)

Youth (13-19 years old)

Adults (20-49 years old)

Adults (50+ years old)

Females (13-49 years old)	0.000319	1.60	0.004304	21.52

aPAD = acute population adjusted dose 

The results of the analysis show that for the relevant sub-population,
the exposures are below the Agency's level of concern (< 100% aPAD).  

Chronic Dietary Exposure Assessment

The chronic dietary exposure estimates were based on average residue
values, average processing 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, version 2.16.  

The chronic population adjusted dose (cPAD) used for the U.S. population
and all sub-populations is 0.006 mg/kg bw/day.  Considering the exposure
assumptions discussed above, dithianon chronic dietary exposure from
food for the U.S. population was 2.3% of the cPAD.  The most highly
exposed population subgroup was children 1-2 years of age at 12.5% of
the cPAD.   Results of this chronic dietary assessment are presented in
Table 2.  The results of the analysis show that for all sub-populations,
the exposures are below the Agency’s level of concern (< 100% cPAD).  

Table 2. 	Summary of Dithianon Chronic Dietary Exposure Analysis
Considering Average Field Residue Values, Average Processing Factors,
and Percent Imports using DEEM-FCID

Population	Exposure Estimate	%cPAD

Subgroups	(mg/kg b.w./day)	 

U.S. Population	0.000137	2.3

All Infants (< 1 year old)	0.000431	7.2

Children (1-2 years old)	0.000752	12.5

Children (3-5 years old)	0.000535	8.9

Children (6-12 years old)	0.000232	3.9

Youth (13-19 years old)	0.000065	1.1

Females (13-49 years old)	0.000073	1.2

Adults (20-49 years old)	0.000065	1.1

Adults (50+ years old)	0.000087	1.4

cPAD = chronic population adjusted dose 

Average measured residue values from the field trials were utilized for
grapes (1.21 ppm), pome fruit (0.82 ppm) and hops (53.9 ppm).

<	ii. Drinking water. Since dithianon is approved or proposed for use
only on imported commodities, the sole anticipated exposure route for
the US population is via dietary (food) exposure.  With no proposed US
registration, dithianon residues are not expected in surface or ground
water that would be used for drinking water.>

Acute Aggregate Exposure and Risk (Food and water)

The aggregate acute risk includes potential residues of dithianon from
food and water. 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 with no exposure from
drinking water.  The acute dietary risk assessment results demonstrate
there are no safety concerns for the population subgroup of interest,
and that the results clearly meet the FQPA standard of reasonable
certainty of no harm. 

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. 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 with no exposure from drinking
water.  The chronic dietary risk assessment 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. 

<	2. Non-dietary exposure. Because the existing and proposed uses for
dithianon include only imported commodities, the sole anticipated
exposure route for the US population is via the diet (food only).
Therefore, residential and occupational exposure risk assessments for
the incidental oral, dermal, and inhalation exposure routes are not
required.>

<D. Cumulative Effects>

<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 dithianon and any other
substances.  In addition, dithianon does not appear to produce a toxic
metabolite produced by other substances.  Therefore, EPA has not assumed
that dithianon has a common mechanism of toxicity with other substances,
and a cumulative risk assessment is not necessary.

>

<E. Safety Determination>

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

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

<F. International Tolerances>

<	A Codex MRL has been established for residues of dithianon in or on
grape at 3 ppm; the proposed tolerance on imported grape is harmonized
with MRLs established in other countries.  There are currently no
established Canadian or Mexican MRLs for dithianon on grape.>

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