Document ID: EPA-HQ-OPP-2006-0800-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-10-13T04:00Z

Summary of Petition

A summary of the pesticide petition is given below. The petitioner
prepared the summary of the petition. 

EPA Registration Division contact: Venus Eagle, (703) 308-8045

 E. I. DuPont de Nemours and Company, DuPont Crop Protection 

[6G7089]

	EPA has received a pesticide petition ([6G7089]) from E. I. DuPont de
Nemours and Company, DuPont Crop Protection, Wilmington, Delaware,
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 to
establish temporary tolerances for residues of DPX-E2Y45,
3-Bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chlor
o-2-pyridinyl)-1H-pyrazole-5-carboxamide in or on the raw agricultural
commodities: Apple --> 0.3 parts per million (ppm), celery-->7.0 ppm,
cucumber --> 0.09 ppm, head lettuce -->4.0 ppm, leaf lettuce -->7.5 ppm,

pear --> 0.3 ppm, pepper -->0.5 ppm, spinach -->13.0 ppm, squash -->0.25
ppm, tomato -->0.3 ppm and watermelon --> 0.2 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                                      

1. Plant metabolism.   The metabolism of DPX-E2Y45 is adequately
understood to support the proposed temporary tolerances. Studies in
apple trees, lettuce, and tomatoes showed no significant metabolites. 
The only significant residue is the parent compound. 

2. Animal Metabolism. The metabolism of DPX-E2Y45 in ruminants is
adequately understood to support the temporary tolerances.  A goat
metabolism study was conducted for 7 days in which DPX-E245 was dosed
daily at 10.4 mg/kg of food consumed.   A total of 93.57% of the
residues were excreted over the course of the study.  The highest levels
of total radioactive residues in milk were observed between the second
and third day of dosing at 0.081 ug/g and decreased to 0.047 ug/g by day
7.  The total radioactive residues in the edible tissues were low (0.02
– 0.09 ug/g) except for the liver, which contained 0.64 ug/g. 
DPX-E2Y45 was found in all tissues together with trace levels of
oxidized metabolites.  These results indicate that there is not a
significant transfer of residues of DPX-E2Y45 and its metabolites to
fat, meat or milk.

3. Analytical method.   The analytical procedure for analysis of
DPX-E2Y45 in crop matrices is based on DuPont-13294, “Method
Validation for the Analysis of DPX-E2Y45 in Various Crop Matrices”.
DPX-E2Y45 is separated from co-extracts by reversed phase liquid
chromatography (LC) and is detected by positive ion Atmospheric Pressure
Chemical Ionization (APCI) mass spectrometry/mass spectrometry (MS/MS).
The Limit of Quantitation (LOQ) is 0.010 mg/kg (ppm) and the Limit of
Detection (LOD) is estimated to be 0.003 mg/kg (ppm).  

	4. Magnitude of residues. 

Cucurbits: The average field residue value for all cucurbits was 0.046
ppm and the maximum was 0.12 ppm.  

Seven field trials were conducted on cucumber.  Two applications were
made, generating the maximum seasonal labeled use rate of 0.20 lb. ai/A
(225 g ai/ha/season).  Harvesting was conducted 1 day after the last
application (PHI- Post Harvest Interval).  The mean field residue value
for cucumbers was 0.030 ppm and the maximum at 0.083 ppm. 

Seven field trials were conducted on cantaloupe/muskmelon.  Two
applications were made, generating the maximum seasonal labeled use rate
of 0.20 lb. ai/A (225 g ai/ha/season).  Harvesting was conducted 1 day
after the last application.  The mean field residue value for
cantaloupe/muskmelon was 0.061 ppm and the maximum at 0.12 ppm.

Six field trials were conducted on summer squash.  Two applications were
made, generating the maximum seasonal labeled use rate of 0.20 lb. ai/A
(225 g ai/ha/season).  Harvesting was conducted 1 day after the last
application.  The mean field residue value for summer squash was 0.048
ppm and the maximum at 0.093 ppm.

Pome fruit:  The average field residue value for all pome fruit was
0.069 ppm and the maximum was 0.30 ppm.

Seventeen field trials were conducted on apples.  Two applications were
made, generating the maximum seasonal labeled use rate of 0.20 lb. ai/A
(225 g ai/ha/season).  Harvesting was conducted 14 days after the last
application.  The mean field residue value for apples was 0.069 ppm and
the maximum at 0.30 ppm.

Eleven field trials were conducted on pears.  Two applications were
made, generating the maximum seasonal labeled use rate of 0.20 lb. ai/A
(225 g ai/ha/season).  Harvesting was conducted 14 days after the last
application.  The mean field residue value for pears was 0.069 ppm and
the maximum at 0.14 ppm.

Fruiting Vegetables:  The average field residue value for all fruiting
vegetables was 0.088 ppm and the maximum was 0.43 ppm.

Twenty field trials were conducted on tomatoes.  Two applications were
made, generating the maximum seasonal labeled use rate of 0.20 lb. ai/A
(225 g ai/ha/season).  Harvesting was conducted 1 day after the last
application.  The mean field residue value for tomatoes was 0.079 ppm
and the maximum at 0.19 ppm.

Eleven field trials were conducted on bell pepper.  Two applications
were made, generating the maximum seasonal labeled use rate of 0.20 lb.
ai/A (225 g ai/ha/season).  Harvesting was conducted 1 day after the
last application.  The mean field residue value for bell pepper was
0.077 ppm and the maximum at 0.19 ppm.

Nine field trials were conducted on non-bell pepper.  Two applications
were made, generating the maximum seasonal labeled use rate of 0.20 lb.
ai/A (225 g ai/ha/season).  Harvesting was conducted 1 day after the
last application.  The mean field residue value for non-bell pepper was
0.12 ppm and the maximum at 0.43 ppm.

Leafy Vegetables:  The average field residue value for all leafy
vegetables was 3.7 ppm and the maximum was 9.7 ppm.

Seven field trials were conducted on head lettuce.  Two applications
were made, generating the maximum seasonal labeled use rate of 0.20 lb.
ai/A (225 g ai/ha/season).  Harvesting was conducted 1 day after the
last application. The mean field residue value for head lettuce was 0.99
ppm and the maximum at 2.5 ppm.

Seven field trials were conducted on leaf lettuce.  Two applications
were made, generating the maximum seasonal labeled use rate of 0.20 lb.
ai/A (225 g ai/ha/season).  Harvesting was conducted 1 day after the
last application. The mean field residue value for leaf lettuce was 4.4
ppm and the maximum at 6.3 ppm.

Seven field trials were conducted on celery.  Two applications were
made, generating the maximum seasonal labeled use rate of 0.20 lb. ai/A
(225 g ai/ha/season).  Harvesting was conducted 1 day after the last
application. The mean field residue value for celery was 2.3 ppm and the
maximum at 3.8 ppm.

Seven field trials were conducted on spinach.  Two applications were
made, generating the maximum seasonal labeled use rate of 0.20 lb. ai/A
(225 g ai/ha/season).  Harvesting was conducted 1 day after the last
application. The mean field residue value for spinach was 6.9 ppm and
the maximum at 9.7 ppm.

Processing Studies –DPX-E2Y45 residues in apples concentrated in wet
and dry pomace relative to the unprocessed fruit by average factors of
2.6 and 11, respectively.  DPX-E2Y45 residues were either not detected
or reduced in concentration relative to the unprocessed fruit upon
processing to juice, apple sauce, apple preserves and canned apples. 

DPX-E2Y45 residues in tomatoes concentrated in puree and paste relative
to the unprocessed fruit by an average factor of 1.5 for both
commodities.  No concentration was observed in canned tomatoes, juice
and ketchup (average processing factors).

Cattle Feeding Study.   A cattle feeding study was conducted with
DPX-E2Y45 at doses of 1, 3, 10, and 50 mg/kg feed.  Based on final
residue values for the directly treated pome commodities contributing to
the cattle diet (apple dry pomace), the potential dietary burden in beef
and dairy cattle is less than 1 mg/kg in the feed. There were no
quantifiable residues (greater than 0.010 mg/kg)  in any matrix (milk,
skim milk, cream, liver, kidney, fat, or muscle) at  the 1 mg/kg dietary
feeding level.

B. Toxicological Profile

	1. Acute toxicity. Based on EPA criteria, DPX-E2Y45 is classified as
follows for Toxicity Categories:

	

Guideline	Title	Results	Category

870.1100

870.1200

870.1300

870.2400

870.2500

870.2600	Acute Oral Toxicity

Acute Dermal Toxicity

Acute Inhalation Toxicity

Primary Eye Irritation

Primary Dermal Irritation

Skin Sensitization	LD50: >5000 mg/kg (Rat)

LD50: >5000 mg/kg (Rat)

LC50: >5.1 mg/L (Rat)

Mild irritation (Rabbit)

No irritation (Rabbit)

Not a sensitizer (Mouse LLNA)	Category IV

Category IV

Category IV

Category IV

Category IV

---------------

	Formulated products are as equally non-toxic following acute exposures
as is technical DPX-E2Y45.  The acute inhalation toxicity for the 20 SC
formulation could not be determined above the maximum practically
attainable atmospheric aerosol concentration of 2 mg/L.  

	2. Genotoxicty.  DPX-E2Y45 has shown no genotoxic activity in the
following listed in-vitro and in-vivo tests: 

Bacterial reverse mutation  

In-vitro mammalian gene mutation (CHO/HGPRT) 

In-vitro chromosomal aberration (human lymphocytes) 

In-vivo mouse micronucleus

	3. Reproductive and developmental toxicity.  In developmental toxicity
studies in rats and rabbits, DPX-E2Y45 exhibited no effects on any
parameter in pregnant females or their offspring at levels up to and
including the maximum tested dose of 1,000 mg/kg bw/day.  

	No reproductive toxicity was observed in a two-generation reproduction
study with DPX-E2Y45 in rats.  No adverse effects were observed on
reproduction, fertility, sperm parameters, estrous cycle, litter size,
pup survival and developmental landmarks up to the maximum tested dose
of 20,000 ppm in the diet.  There were no adverse histological findings
indicative of reproductive toxicity.  There was a slight reduction in
the F1 pup (but not F2 pup) weight during lactation at the highest dose
level (mean maternal intake during lactation equal to 3118 mg/kg
bw/day); this was attributed, in part, to weight loss in one dehydrated
dam during lactation which had a litter with some of the lowest pup
weights.  The slight change in pup weight was without subsequent effects
since overall body weight, weight gain and development in F1 rats fed
20,000 ppm were similar to control animals.  

	4. Subchronic toxicity.     

	Subchronic (90-day) feeding studies were conducted with rats, mice and
dogs. No adverse effects were observed at the highest dietary
concentrations tested of 20,000 ppm in rats (1188 mg/kg bw/day for males
and 1526 mg/kg bw/day for females), 7,000 ppm in mice (1135 mg/kg bw/day
for males and 1539 mg/kg bw/day for females) and 40,000 ppm in dogs
(1163 mg/kg bw/day for males and 1220 mg/kg bw/day for females). 

	A 28-day dermal toxicity study in rats was conducted at doses of 100,
300 and 1000 mg/kg bw/day.  The NOAEL for male and female rats was 300
mg/kg bw/day based on reductions in body weight gain and food efficiency
at 1000 mg/kg bw/day.

	No adverse target organ effects were observed in any subchronic
toxicity study.

5. Chronic toxicity. Chronic toxicity studies with DPX-E2Y45 are
ongoing.

	6. Animal metabolism. A rat metabolism study is ongoing.  The majority
of the dose (> 92%) is excreted within 7 days of a single gavage dosing.
 DPX-E2Y45 undergoes extensive metabolism in the rat; the distribution
of residues in the tissues is extensive and the residues are
non-accumulating.

	Daily dosing of DPX-E2Y45 to goats at a level of 10 ug/g in the diet
for 7 days resulted in total residues less than or equal to 0.02 mg/kg
in the meat, 0.07 mg/kg in the fat, 0.64 mg/kg in the liver and 0.08
mg/kg in the milk.  The majority of the residues (90%) were excreted in
the feces and urine.  DPX-E2Y45 is a significant residue in all tissues
and 1-4 additional residues were identified in the liver, kidney, muscle
and fat; additional minor components (<0.01 ug/g) were also observed. 
The metabolism of DPX-E2Y45 is well understood.

	7. Metabolite toxicology. Due to the extremely low toxicity of the
parent compound and the extensive metabolism observed in mammalian
systems, DPX-E2Y45 metabolites are not expected to result in any
significant toxicity.  

	8. Endocrine disruption.  No adverse effects were observed on any
endocrine tissue in repeat dose studies in rats, mice and dogs.

C. Aggregate Exposure

	1. Dietary exposure. No acute exposure assessment was conducted since
an aRfD was not established as an effect attributable to a single
exposure was not observed in the oral toxicity studies conducted with
DPX-E2Y45.  An assessment was conducted to determine the chronic
exposure of the US population and population subgroups to DPX-E2Y45. 
Tolerance values are being proposed for leafy vegetable crop group 4,
fruiting vegetable crop group 8, cucurbit vegetables crop group 9, and
pome fruit crop group 11; tolerances are not being proposed for meat and
milk, since residues are not expected in these commodities.  The chronic
exposure analysis included all crops with proposed tolerance values.

	i. Food.  The chronic dietary exposure assessment of the currently
proposed uses of DPX-E2Y45 was determined with the chronic module of the
Dietary Exposure Evaluation Model software with Food Commodity Intake
Database (DEEM-FCIDTM ), version 2.14, from Exponent, Inc. using the
chronic reference dose (cRfD) of 1.135 mg/kg bw/day, derived from a NOEL
of 1135 mg/kg bw/day (90-day subchronic study in mice), and uncertainty
factors of 10X for interspecies variation, 10x for intraspecies
variation, and 10X for the current incompleteness of the toxicology
database.  The analysis used proposed tolerance values and no
adjustments for processing or percent crop treated (100% crop treated
was assumed); the actual dietary exposure will be much less than that
discussed here.  The chronic exposure to DPX-E2Y45 for the overall US
Population in this very conservative analysis is 0.005539 mg/kg bw/day,
which is less than 1% of the cRfD.  The exposure of the most sensitive
subgroup, Children 1-2 years, is 0.008101 mg/kg bw/day, which is less
than 1% of the cRfD.  There are large margins of safety for all
population groups.

	ii. Drinking water.  The FIRST (Version 1.0) and SCI-GROW (version 2.3)
models were used to estimate conservative concentrations of DPX-E2Y45 in
surface and ground water, respectively.  The highest average annual
surface water value from FIRST, 4.2 ug/L, was used in the DEEM-FCIDTM
software to determine aggregate exposure to food and water on a chronic
basis, since it was higher than the average annual ground water value. 
The resultant aggregate exposure values (0.005627 mg/kg bw/day for the
US Population, 0.008232 mg/kg bw/day for Children 1-2 years) were not
significantly greater than the exposure values determined on the basis
of food alone and continue to be less than 1% of the cRfD described
above. The margins of safety for all population groups remain large.

	2. Non-dietary exposure.  There are no residential uses of DPX-E2Y45,
and therefore no need to assess non-dietary exposure.  

D. Cumulative Effects

	It is not necessary at this time to consider cumulative effects because
there is no indication that toxic effects of DPX-E2Y45 have a common
mechanism with those of any other chemical compounds.  

E. Safety Determination

	1. U.S. population. Based on the risk assessments described above there
is a reasonable certainty that no harm will result to the general
population from the aggregate exposure to DPX-E2Y45.  No additional
safety factors are warranted.

	2. Infants and children. Based on the risk assessments described above
there is a reasonable certainty that no harm will result to the infants
and children from the aggregate exposure to DPX-E2Y45.  No additional
safety factors are warranted.

E. I. DuPont de Nemours & Company                                       
            	DPX-E2Y45

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