Document ID: EPA-HQ-OPP-2012-0635-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-11-07T05:00Z

EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING FOR PESTICIDE
PETITION  

Docket ID Number:  EPA-HQ-OPP-2012-0635

EPA Registration Division Contact:  Sidney Jackson (703) 305-7610 

Interregional Research Project Number 4 

Pesticide Petition Number:  PP 2E8064

	EPA has received a pesticide petition (PP 2E8064) from the
Interregional Research Project Number 4 (IR-4), IR-4 Project
Headquarters, 500 College Road East, Suite 201 W, Princeton, New Jersey,
08540, 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 tolerances for residues of chlorantraniliprole,
3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chlor
o-2-pyridinyl)-1H-pyrazole-5-carboxamide in or on grain, cereal, group
15, except rice at 6.0 parts per million (ppm); grain, cereal, forage,
fodder and straw, group 16 at 30.0 ppm; fruit, citrus, group 10-10 at
1.4 ppm; fruit, pome, group 11-10 at 1.2 ppm; and concurrent deletion of
tolerances for mayhaw; fruit, citrus, group 10; fruit, pome, group 11;
corn, field, forage; corn, field, grain; corn, field, milled byproducts;
corn, field, stover; corn, pop, forage; corn, pop, grain; corn, pop,
stover; corn, sweet, forage; corn, sweet, kernel plus cobs with husk
removed; and corn, sweet, stover.  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
support granting of the petition.  Additional data may be needed before
EPA rules on the petition.

A. Residue Chemistry                                      

1. Plant metabolism.   The metabolism of chlorantraniliprole is
adequately understood to support the proposed tolerances. Studies in
apple, lettuce, rice, tomato, and cotton when treated at proposed label
rates showed no significant metabolites.  The only significant residue
is the parent compound. 

2. Livestock Metabolism. The metabolism of chlorantraniliprole in
ruminants and poultry is adequately understood to support the proposed
tolerances.  Lactating goat and laying hen metabolism studies were
conducted.  The goat and hen rapidly excreted >93% and >98% of the dosed
radiolabeled residues, respectively.  

The metabolic pathway in poultry and ruminant (goat) animals is
understood.

3. Analytical method. Adequate enforcement methodology (liquid
chromatography mass spectrometry (LC/MS/MS)) is available to enforce the
tolerance expression. The method may be requested from: Chief,
Analytical Chemistry Branch, Environmental Science Center, 701 Mapes
Rd., Ft. Meade, MD 20755-5350; telephone number: (410) 305-2905; e-mail
address: residuemethods@epa.gov.

4. Magnitude of residues. Field residue trials were conducted with
chlorantraniliprole on raw agricultural commodities of barley, grain
sorghum (milo) and wheat.  Eleven MOR trials were conducted. The
locations of the field trials were selected to represent the regions
with most production per crop. A foliar broadcast spray of
chlorantraniliprole was applied at the rate of 0.1 lb ai/A/application.
The treated plots received two applications targeted at 1 day before
harvest (1-day PHI) of mature grain.  Maximum residue levels in barley
grain were 2.17 ppm, in sorghum grain were 1.52 ppm and in wheat grain
were 0.428.  The maximum residue levels in wheat and sorghum forage were
5.0 ppm, in barley and wheat hay were 12.4 ppm, in sorghum stover were
6.9 ppm and in barley and wheat straw were 15.4 ppm.

Processing study.  A wheat processing study was conducted and the
processing factors observed as compared to the raw agricultural
commodity were 33.7X for the aspirated grain fraction, 1.2X for wheat
germ, 1.1X for wheat bran, 0.7X for shorts, 0.4X for flour and 0.3X for
middlings.

Numerous residue studies have been conducted on many crops in the United
States and globally by the registrant, E. I. du Pont de Nemours &
Company, and by other organizations including the IR-4 Project.  The
relevant U.S. and foreign residue study reports required to support use
of chlorantraniliprole and existing tolerances in the United States have
been submitted to EPA and reviewed as part of prior registration actions
for this active ingredient.

B. Toxicological Profile

	1. Acute toxicity. Based on EPA criteria, chlorantraniliprole 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: >5,000 mg/kg (Rat)

LD50: >5,000 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 chlorantraniliprole.  The acute inhalation toxicity for
the suspension concentrate formulation could not be determined above the
maximum practically attainable atmospheric aerosol concentration of 2
milligram per liter (mg/L).  

There was no evidence of neurotoxicity in rats following a single limit
dose of 2,000 mg/kg

	2. Genotoxicty.  Chlorantraniliprole 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, chlorantraniliprole 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/kilogram body weight per
day (kg bw/day).  

	No reproductive toxicity was observed in a two-generation reproduction
study with chlorantraniliprole 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 3,118 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 (1,188 mg/kg bw/day for
males and 1,526 mg/kg bw/day for females), 7,000 ppm in mice (1,135
mg/kg bw/day for males and 1,539 mg/kg bw/day for females) and 40,000
ppm in dogs (1,163 mg/kg bw/day for males and 1,220 mg/kg bw/day for
females).  Chlorantraniloprole showed no evidence of immunotoxicity in
28-day feeding studies in rats or mice and no evidence of neurotoxicity
in a 90-day feeding study in rats at dietary concentrations greater than
the limit dose of 1,000 mg/kg bw/day.

	A 28-day dermal toxicity study in rats was conducted at doses of 100,
300 and 1,000 mg/kg bw/day.  The no-observed-adverse-effects-level
(NOAEL) for male and female rats was 300 mg/kg bw/day based on
reductions in body weight gain and food efficiency at 1,000 mg/kg
bw/day.

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

5. Chronic toxicity. 

	Chlorantraniliprole was not carcinogenic in either a 2-year study in
rats or an 18-month study in mice.  The NOAEL for chronic toxicity in
the 18-month mouse study was 1,200 ppm (158 mg/kg bw/day in males) and
was based on eosinophilic foci accompanied by hepatocellular hypertrophy
and increased liver weight. 

 

	In rats, there were no adverse effects on any in-life parameter in
either males or females administered chlorantraniliprole up to and
including a maximum dietary concentration of 20,000 ppm for 2 years (805
and 1,076 mg/kg bw/day, respectively).   

	In a one-year feeding study in dogs, the NOAEL was the highest dose
tested, 40,000 ppm (1,164 and 1,233 mg/kg/day in males and females,
respectively).

	6. Rat metabolism. 

The absorption of [14C]-chlorantraniliprole in rats was rapid with peak
concentrations occurring at 5-12 hours after single dose administration.
Tissue distribution of the absorbed dose was extensive and indicated low
potential for accumulation.  Excretion was substantially complete by
48-72 hours after dosing (>90%).  

  Following 14 days of oral administration 14C residues were readily
eliminated from the plasma and tissues and confirmed minimal potential
for accumulation. The profile of metabolites in urine and feces
indicated extensive metabolism consistent with that observed for the
single dose study.

	7. Metabolite toxicology. Due to the extremely low toxicity of the
parent compound and the extensive metabolism observed in mammalian
systems, chlorantraniliprole metabolites are not expected to result in
any significant toxicity.  Toxicology studies conducted with metabolites
support this conclusion.

	8. Endocrine disruption.  No adverse effects were observed on any
endocrine tissue in short- and long-term studies in rats, mice and dogs.

C. Aggregate Exposure

	1. Dietary exposure -- i. Food.  Because an endpoint attributable to a
single dose was not identified, the dietary exposure assessment
considered only chronic exposure.  

Chronic dietary exposure assessments were conducted using the Dietary
Exposure Evaluation Model (DEEM-FCID™, Version 2.03) which uses food
consumption data from the U.S. Department of Agriculture’s Continuing
Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 1998.
The chronic dietary exposure assessment was conducted using a chronic
reference dose of 1.58 mg/kg bw/day based on the NOAEL established in
the 18-month study in mice.  DuPont has conducted chronic assessments
which assume that 100% of all crops – including those not labeled -
are treated with chlorantraniliprole and that all crops contain residues
at tolerance level or at residue levels equal to tolerance levels for
similar crops.  In particular all leafy vegetables, including leaves of
root and tuber vegetables and leafy vegetables including brassica
vegetables, are assumed to have residues of 15 parts per million.  All
other human foods (including plant and animal commodities) are assumed
to have residues of 2 parts per million.

These assumptions result in conservative, health-protective estimates of
exposure which are well below the Agency’s level of concern (100% of
the chronic population-adjusted dose (cPAD)). The maximum estimate is
less than 11% of the cPAD for all population subgroups.  

	ii. Drinking water.  A drinking water assessment for
chlorantraniliprole, conducted based on Pesticide Root Zone
Model/Exposure Analysis Modeling System (PRZM/EXAMS), was used to
calculate the surface water estimated drinking water concentrations
(EDWCs) and the Screening Concentration in Ground Water (SCI-GROW) model
was used to calculate the groundwater EDWC. The EDWCs do not exceed the
Agency’s level of concern.

	2. Non-dietary exposure.  Residential exposure (non-occupational,
non-dietary exposure to consumers) was conservatively assessed for
dermal post-application exposure (children and adults), and for children
the oral exposures via hand-to-mouth, object-to-mouth, and incidental
ingestion of soil were also assessed.  The margins of exposure (MOE)
greatly exceed the 100-fold MOE required for these routes and from the
combined children’s incidental oral ingestion.  Therefore, residential
non-dietary exposure is not a concern.

D. Cumulative Effects

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

E. Safety Determination

	1. U.S. population. Based on risk assessments performed using
worst-case exposure assumptions there is a reasonable certainty that no
harm will result to the general population from the aggregate exposure
to chlorantraniliprole.  No additional safety factors are warranted.

	2. Infants and children. Based on the risk assessments performed using
worst-case exposure assumptions there is a reasonable certainty that no
harm will result to the infants and children from the aggregate exposure
to chlorantraniliprole.  No additional safety factors are warranted.

F. International Tolerances

 Numerous chlorantraniliprole maximum residue levels (MRLs) have been
established or are expected to be established supporting registrations
in 82 countries.  Codex MRLs have also been established for
chlorantraniliprole on numerous crops.

 

 

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E. I. DuPont de Nemours & Company                                       
            	Chlorantraniliprole

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