Document ID: EPA-HQ-OPP-2008-0352-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-06-17T04:00Z

<EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  (7/1/2007)>

<EPA Registration Division contact: [Dan Kenny, Chief, Herbicide Branch,
703-305-7546]>

 

<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]>

<[Insert petition number]>

<	EPA has received a pesticide petition ([insert petition number]) from
[BASF Corporation], [26 Davis Drive, P.O. Box 13528, Research Triangle
Park, North Carolina 27709-3528] 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.>

<(Options (pick one)>

<	1. by establishing a tolerance for residues of>

<	[combined residues of BAS 800 H
(N'-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dih
ydro-1(2H)-pyrimidinyl)benzoyl]-N-isopropyl-N-methylsulfamide) plus
metabolite M800H11
(N-[2-chloro-5-(2,6-dioxo-4-(trifluoromethyl)-3,6-dihydro-1(2H)-pyrimidi
nyl)-4-fluorobenzoyl]-N'-isopropylsulfamide) and plus metabolite M800H35
(N-[4-chloro-2-fluor-5-({[(isopropylamino)sulfonyl]amino}
carbonyl)phenyl]urea)] in or on the raw agricultural commodity [legume
vegetables (group 06), citrus fruits (group 10), pome fruits (group 11),
stone fruits (group 12), tree nuts (group14), pistachio, cereal grains
(group 15), undelinted cotton seed, cotton gin by products, grape] at
[0.03] parts per million (ppm) and commodity [foliage of legume
vegetables (group 07), forage, fodder and straw of cereal grains (group
16), sorghum stover] at [0.1] parts per million (ppm) and commodity
[almond hulls] at [0.2] parts per million (ppm) and commodity [sunflower
seed] at [0.7] 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.[Nature of the residue studies (OPPTS Harmonized
Guideline 860.1300) were conducted in corn, soybean and tomato as
representative crops in order to characterize the fate of BAS 800 H in
all crop matrices. Two radiocarbon labeling were studied in each crop,
with 14-C labels positioned in phenyl and uracil ring structures. In all
crops the BAS 800 H Residues of Concern (ROC) were characterized as
parent BAS 800 H plus metabolites M800H11 and M800H35. A confined
rotational crop study also confirmed that parent BAS 800 H plus
metabolites M800H11 and M800H35 were the residues of concern in the
representative crops of wheat, radish, and lettuce.]>

<	2. Analytical method. [Independently validated analytical methods have
been submitted for analyzing residues of parent BAS 800 H plus
metabolites M800H11 and M800H35 with appropriate sensitivity in all the
crop and processed commodities for legume vegetables (group 06), foliage
of legume vegetables (group 07), citrus fruits (group 10), pome fruits
(group 11), stone fruits (group 12), tree nuts (group14), pistachio,
cereal grains (group 15), forage, fodder and straw of cereal grains
(group 16), cotton, sunflower and grape and in animal liver and kidney
matrices which tolerances are being requested.]>

<	3. Magnitude of residues. [Field trials were carried out to determine
the magnitude of the residue in/on legumes vegetables (crop group 6 and
7 including soybean), citrus fruits (crop group 10), pome fruits (crop
group 11), stone fruits (crop group 12), tree nuts (crop group 14),
cereal grains (crop groups 15 and 16), cotton, sunflower, and grape. The
number and locations of field trials are in accordance with OPPTS
Guideline 860.1500. Field trials were carried out using the maximum
label rates, the maximum number of applications, and the minimum
pre-harvest interval (PHI) for all the crops. Detected combined residues
of BAS 800 H plus metabolites in all crops support the proposed
tolerances.]>

<B. Toxicological Profile>

<	1. Acute toxicity.  [BAS 800 H and its formulated products have
favorable acute toxicity. The acute toxicity studies place technical BAS
800 H in toxicity category III for acute oral and dermal and category IV
for acute inhalation.  BAS 800 H is category III for both eye and skin
irritation, and it is not a dermal sensitizer.]>

<	2. Genotoxicty. [BAS 800 H was negative for inducing mutations in both
an in vitro Ames test and an in vitro CHO/HGPRT Locus Mammalian Cell
Mutation Assay. No evidence of a clastogenic effect was observed in
vitro without metabolic activation, but a positive finding occurred with
metabolic activation. More importantly, no clastogenicity was observed
in an in vivo assay.  Overall, the weight of the evidence demonstrates
that BAS 800 H is not genotoxic.]>

<	3. Reproductive and developmental toxicity. [The reproductive and
developmental toxicity of BAS 800 H was investigated in a 2-generation
rat reproduction study as well as in rat and rabbit developmental
toxicity studies. In the reproduction study, there were no effects on
fertility. At the highest dose tested, reduced body weight gain and
anemia were observed in parental animals.  Also at this dose, pup
mortality and reduced pup weights occurred. The pup effects are
considered secondary to the parental anemia and not due to a direct
toxic effect of BAS 800 H. The NOAEL for systemic toxicity was 5 mg/kg
bw/day and for developmental toxicity is 15 mg/kg bw/day.>  

In the rat developmental toxicity study, maternal toxicity was observed
in the form of reduced body weight gain and anemia. Increased incidences
of skeletal variations and malformations also occurred at doses where
maternal anemia was evident. The maternal and developmental NOAEL was 5
mg/kg bw.

At the highest dose tested in the rabbit teratology study, maternal
toxicity observed consisted of abortion, mortality clinical signs and
stomach ulceration. There was no evidence of developmental toxicity. The
NOAEL for systemic toxicity was 200 mg/kg bw/day, and the NOAEL for
developmental toxicity was 600 mg/kg bw/day, the highest dose tested.]

<	4. Subchronic toxicity. [A similar toxicity was observed across rats,
mice and dogs following subchronic exposure to BAS 800 H. These effects
are mostly related to the mode of action of BAS 800 H, i.e., inhibition
of protoporphyrinogen IX oxidase. Typical indicator effects for this
mode of action were observed and included increased total porphyrins in
urine, feces and liver as well as increased total bilirubin and urinary
bilinogen. Decreased hematological parameters indicative of microcytic
hypochromic anemia also occurred as expected. Other evidence of anemia
included increased normoblasts, reticulocytes and polychromasia,
increased microcytosis and anisoscytosis, increased spleen weight,
extramedullary hematopoiesis in liver and spleen and erythroid
hyperplasia in bone marrow. At high doses, an indication of liver
toxicity was observed which included increased serum liver enzymes,
centrilobular fatty change and lymphoid cell infiltration. Decreased
body weight gain and in some cases body weight loss were observed at the
highest doses evaluated. The lowest NOAEL in subchronic oral toxicity
studies was 10 mg/kg bw/day in the dog 90-day study.

No systemic toxicity was observed in a 28-day repeat dose dermal
toxicity study at doses as high as 1000 mg/kg bw/day in females and as
high as 300 mg/kg bw/day in males. The only effect observed in males at
1000 mg/kg bw/day was a slight decrease (97% of control) in hemoglobin
concentration.

The neurotoxic potential of BAS 800 H was studied following both acute
and subchronic oral administration in the rat. In the acute study, the
overall motor activity was decreased in males at 2000 mg/kg bw/day. This
change was not considered toxicologically relevant since it was noted
only when evaluated over the entire evaluation period, was only at the
Day 0 timepoint, was observed only in one sex, and was not accompanied
by any functionally observational battery changes or neuropathological
changes. The change is considered a weak pharmacological effect noted
only at a high acute limit dose.  No evidence of neurotoxicity was
observed in the subchronic neurotoxicity study. Overall, BAS 800 H is
not considered to be neurotoxic. The acute neurotoxicity NOAEL was the
highest dose tested, 2000 mg/kg bw/day. The NOAEL from the subchronic
study was based on signs of anemia at 250 ppm (16.6 mg/kg bw/day in
males and 19.4 mg/kg bw/day in females).]>

<	5. Chronic toxicity. [The results of long-term oral exposure studies
indicate that BAS 800 H is not carcinogenic in mice or rats.  At high
doses in long term oral exposure studies with rats, mice and dogs,
observations demonstrate evidence of effects on hematological parameters
indicative of porphyria and anemia.  This is consistent with the
mechanism of action of BAS 800 H as an inhibitor of protoporphyrinogen
IX oxidase.  NOAEL’s in the mouse oncogenicity study were 25 ppm (4.6
mg/kg bw/day) in males and 75 ppm (18.9 mg/kg bw/day) in females.  In
the rat chronic/oncogenicity study, the NOAEL in males was 250 ppm (12
mg/kg bw/day) and in females was 100 ppm (6.2 mg/kg bw/day).  In a
chronic dog study, the NOAEL was 20 mg/kg bw/day.]>

<	6. Animal metabolism. [The rat, goat and hen metabolism studies were
conducted to determine the nature of the BAS 800 H residues in animals.
All studies were conducted with radiolabeled BAS 800 H with 14-C labels
positioned in phenyl and uracil ring structures. BAS 800 H was either
excreted rapidly in urine and feces or transformed to a number of
metabolites after administration to animals. All relevant metabolites
were identified. However, unchanged parent compound was found as the
predominant component in most animal matrices. The metabolism of BAS 800
H in the animals is well understood. Degradation proceeds via different
dealkylation steps or hydrolytic opening of the uracil ring to produce
metabolites that are rapidly excreted, along with parent, and do not
readily accumulate in tissues or milk. Residues in milk and most edible
tissues are very low. All metabolic reactions were observed in each of
the animals studied, so there is a consistent picture of the metabolism
of BAS 800 H in animals.]>

<	7. Metabolite toxicology. [No metabolites of toxicological concern
were identified.]>

<	8. Endocrine disruption. [No specific tests have been conducted with
BAS 800 H 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 (e.g., sub-chronic and chronic
toxicity, developmental toxicity and multi-generation reproductive
studies) which would suggest that BAS 800 H produces any endocrine
disruption.]>

<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 combined residues of BAS 800 H and metabolites M800H11 and
M800H35.  The analysis included all the proposed tolerance values for
legumes vegetables (crop group 6 and 7, including soybean), citrus
fruits (crop group 10), pome fruits (crop group 11), stone fruits (crop
group 12), tree nuts (crop group 14), pistachio, cereal grains (crop
group 15 and 16), cotton, sunflower, and grape and animal matrices.]>

<	i. Food. [

Acute Dietary Exposure Assessment

Acute dietary exposure estimates were based on proposed tolerance
values, default process factors, and 100% of all crops treated.  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 resulting exposure estimates were compared against the BAS 800 H
acute Population Adjusted Dose (aPAD) of 0.05 mg/kg b.w./day for all
populations.  This endpoint is based on the NOAEL of 5 mg/kg/day with an
FQPA safety factor of 1.  The most highly exposed sub-population was
infants less than 1 year old with 5.8% utilization of the aPAD.  The
results of the acute dietary assessment are presented in Table 1.

Table 1.	Results for BAS 800 H Acute Dietary Exposure Analysis
Considering all Proposed Tolerances using DEEM-FCID at the 95th
Percentile 

Population	Exposure Estimate	%aPAD

Subgroups	(mg/kg b.w./day)	 

U.S. Population	0.001071	2.1

All Infants (< 1 year old)	0.002884	5.8

Children (1-2 years old)	0.002792	5.6

Children (3-5 years old)	0.00205	4.1

Children (6-12 years old)	0.001262	2.5

Youth (13-19 years old)	0.000788	1.6

Adults (20-49 years old)	0.000654	1.3

Adults (50+ years old)	0.000576	1.2

Females (13 – 49 years old)	0.000678	1.4

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

Chronic Dietary Exposure Assessment

Chronic dietary exposure estimates were based on proposed tolerance
values, default process factors, and 100% crop treated values for all
commodities.  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 0.046 mg/kg bw/day. This endpoint is based on the
NOAEL value of 4.6 using a FQPA safety factor of 1.  The most highly
exposed population sub-group was children 1-2 years of age which
utilized 2.3 % cPAD.  The results of the chronic dietary assessment are
presented in Table 2. 

Table 2. Results for BAS 800 H Chronic Dietary Exposure Analysis
Considering all Proposed Tolerances using DEEM-FCID 

Population	Exposure Estimate	%cPAD

Subgroups	(mg/kg b.w./day)	 

U.S. Population	0.000297	0.6

All Infants (< 1 year old)	0.000756	1.6

Children (1-2 years old)	0.001053	2.3

Children (3-5 years old)	0.000808	1.8

Children (6-12 years old)	0.000457	1.0

Youth (13-19 years old)	0.000269	0.6

Adults (20-49 years old)	0.000206	0.4

Adults (50+ years old)	0.000189	0.41

Females (13-49 years old)	0.000208	0.5

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

<	ii. Drinking water. [All BAS 800 H uses were examined at maximum use
rates, maximum number of applications, and all proposed application
methods to determine which use would result in the highest water
concentrations.  The highest water concentrations occurred from the
Mississippi corn scenario (model) from an aerial application at 0.134 lb
ai/A.  Based on results from the PRZM/EXAMS and SCI-GROW models
estimates, the highest acute Estimated Drinking Water Concentrations
(EDWC) for BAS 800 H were estimated to be 8.1 ug/L (ppb) in surface
water and 0.36 ug/L in ground water.  The highest chronic EDWC’s for
BAS 800 H were estimated to be 2.5 ug/L in surface water and 0.36 ug/L
in ground water.  

Drinking water exposure contributions were assessed based on the maximum
estimated BAS 800 H water concentrations (acute 8.1 ug/L, chronic 2.5
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.  Drinking water
exposure accounts for less than 4% of the aPAD and 1 % of the cPAD for
all populations. 

Table 3. Results for BAS 800 H 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	0.000423	0.8

All Infants (< 1 year old)	0.001535	3.1

Children (1-2 years old)	0.000664	1.3

Children (3-5 years old)	0.000607	1.2

Children (6-12 years old)	0.000422	0.8

Youth (13-19 years old)	0.000343	0.7

Adults (20-49 years old)	0.000392	0.8

Adults (50+ years old)	0.000354	0.7

Females (13-49 years old)	0.000394	0.8

Table 4. Results for BAS 800 H 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	0.000053	0.1

All Infants (< 1 year old)	0.000173	0.4

Children (1-2 years old)	0.000078	0.2

Children (3-5 years old)	0.000073	0.2

Children (6-12 years old)	0.000051	0.1

Youth (13-19 years old)	0.000038	0.1

Adults (20-49 years old)	0.000049	0.1

Adults (50+ years old)	0.000052	0.1

Females (13-49 years old)	0.000049	0.1

Acute Aggregate Exposure and Risk (food and water)

The aggregate acute risk includes exposure of BAS 800 H from food and
water (Table 5). The results demonstrate that there are no safety
concerns for any subpopulation based on the proposed uses and the
results meet the FQPA standard of reasonable certainty of no harm.   

Table 5. 	Estimated Acute Aggregate Exposure and Risk of BAS 800 H.  

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	0.05	0.001071	0.000423	0.00149	3.0

All Infants (< 1 yr old)	0.05	0.002884	0.001535	0.00442	8.8

Children 1-2 years	0.05	0.002792	0.000664	0.00346	6.9

Children 3-5 years	0.05	0.00205	0.000607	0.00266	5.3

Children 6 – 12 years	0.05	0.001262	0.000422	0.00168	3.4

Youth 13-19 years	0.05	0.000788	0.000343	0.00113	2.3

Adults 20-49 years	0.05	0.000654	0.000392	0.00105	2.1

Adults + 50	0.05	0.000576	0.000354	0.00093	1.9

Females 13-49 years	0.05	0.000678	0.000394	0.00107	2.1

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

Short- and intermediate-term aggregate risk assessments include exposure
from food, water, and residential uses.  There are no residential uses
for BAS 800 H, therefore, a short- and intermediate-term aggregate risk
assessment is not required.   

Chronic Aggregate Exposure and Risk (food and water)

The aggregate chronic risk includes exposure of BAS 800 H from food and
water (Table 6). The results demonstrate there are no safety concerns
for any subpopulation based on the proposed uses and the results meet
the FQPA standard of reasonable certainty of no harm. 

Table 6. 	Estimated Chronic Aggregate Exposure and Risk of BAS 800 H 

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	0.046	0.000297	0.000053	0.00035	0.8

All Infants (< 1 yr old)	0.046	0.000756	0.000173	0.00093	2.0

Children 1-2 years	0.046	0.001053	0.000078	0.00113	2.5

Children 3-5 years	0.046	0.000808	0.000073	0.00088	1.9

Children 6 – 12 years	0.046	0.000457	0.000051	0.00051	1.1

Youth 13-19 years	0.046	0.000269	0.000038	0.00031	0.7

Adults 20-49 years	0.046	0.000206	0.000049	0.00026	0.6

Adults + 50	0.046	0.000189	0.000052	0.00024	0.5

Females 13-49 years	0.046	0.000208	0.000049	0.00026	0.6

]>

<	2. Non-dietary exposure. [There are no residential uses for BAS 800 H.
 Therefore, a non-dietary exposure and risk evaluation was not
conducted.]>

<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." 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
BAS 800 H. In addition, BAS 800 H does not appear to produce a toxic
metabolite produced by other substances. For the purposes of this
tolerance action, therefore, BASF has not assumed that BAS 800 H has a
common mechanism of toxicity with 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 BAS 800 H from the
proposed uses.]>

<	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 BAS 800 H from the
proposed uses.]>

<F. International Tolerances>

<	[There are no CODEX maximum residue levels established or proposed for
residues of BAS 800 H in legume vegetables (crop group 6), foliage of
legume vegetables (crop group 7), citrus fruits (crop group 10), pome
fruits (crop group 11), stone fruit (crop group 12), tree nuts (crop
group 14), pistachio. almond hulls, cereal grains (crop group 15),
sorghum stover, forage, fodder and straw of cereal grains (crop group
16), cotton, sunflower, grape and animal matrices.]>

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