Document ID: EPA-HQ-OPP-2013-0235-0014
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2016-05-12T04:00Z

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

EPA has received a pesticide petition 5E8371 from Interregional Research Project Number 4 (IR-4), IR-4 Project Headquarters, Rutgers, The State University of New Jersey, 500 College Road East, Suite 201 W, Princeton, NJ 08450  requesting, 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 chlorantraniliprole, 3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)-carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide in or on the raw agricultural commodities: Nut, tree, group 14-12 at 0.02 parts per million (ppm); and Fruit, stone, group 12-12 at 2.5 ppm. This petition additionally requests to amend 40 CFR 180.628 by amending the existing tolerances for residues artichoke, globe from 4.0 ppm to 2.0 ppm; and hop, dried cones from 90 ppm to 40 ppm. In requesting these tolerances, IR-4 notes that the proposed tolerances for hop, artichoke, stone fruit, and tree nuts represent a lowering of established tolerances. 

Upon establishment of these tolerances, the following tolerances are to be deleted: Nut, tree, group 14 at 0.04 ppm; Pistachio at 0.04 ppm; Fruit, stone, group 12-12, except cherry, chickasaw plum, and damson plum at 4.0 ppm; Cherry, sweet at 2.0 ppm; Cherry, tart at 2.0 ppm; Plum, chickasaw at 2.0 ppm; and Plum, damson at 2.0 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 metabolism of chlorantraniliprole is adequately understood to support the proposed exemption from the requirement of 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.
   
   Livestock Metabolism. The metabolism of chlorantraniliprole in ruminants and poultry is adequately understood to support the exemption from the requirement of 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 was consistent. There is no reasonable expectation of transfer of finite residues of chlorantraniliprole and its metabolites to fat, meat, milk, and eggs.

	2. Analytical method. Since chlorantraniliprole and its metabolic degradates are not of toxicological concern, analytical methods are not applicable.  

	3. Magnitude of residues. 
Numerous residue studies have been conducted on many crops in the United States and globally by the registrant and by other organizations such as 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

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      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 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/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 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. Animal (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. [Insert text.]

      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(TM), 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 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 PRZM/EXAMS (Pesticide Root Zone Model/Exposure Analysis Modeling System), 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 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.