Document ID: EPA-HQ-OPP-2013-0235-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2014-02-07T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                      OFFICE OF
                                                            CHEMICAL SAFETY AND
\* MERGEFORMAT
                                                           POLLUTION PREVENTION

MEMORANDUM

Date: 		December 9, 2013

SUBJECT:	Chlorantraniliprole: Human Health Risk Assessment for Proposed Uses on Green Onion Subgroup 3-07b, and Peanut; for the Requests to Update the Crop Groups of Stone Fruit, Tree Nut, and Spices; to Shorten the Pre-Harvest Intervals for Papaya, Passionfruit, and Mayhaw; and Evaluation of Condition of Registration Data on Rice, Coffee, Strawberry, and Tropical Fruits.
 

PC Code: 090100 
DP Barcodes:  D410513, D412173, D412170, D412171, D412169
Decision Nos.: 476038; 477960; 477964; 477967; 
477972; 477962 ; 477952; 477965; 477970; 
477963;  477954; 477966; 477971; 417413
Registration Nos.:  352-728; 352-729; 352-730; 352-820; 352-841; 352-838; 352-844
Petition Nos.: 3E8170; 3F8158
Regulatory Action: Section 3 Registration
Risk Assessment Type:  Single Chemical, Aggregate
Case No.:  NA
TXR No.:  NA
CAS No.: 500008-45-7
MRID No.:  NA
40 CFR: 180.628

FROM:	Kristin Rury, Risk Assessor
		Steve Funk, Senior Chemist
		Minerva Mercado, Toxicologist
		Risk Assessment Branch III
		Health Effects Division (7509P)

THROUGH:	Christine Olinger, Branch Chief
		Risk Assessment Branch III
		Health Effects Division (7509P)

TO:		Venus Eagle/Jennifer Urbanski, RM 01
		Insecticide-Rodenticide Branch
         Registration Division (RD; 7505P)
	
         And
	
         Barbara Madden/Laura Nollen, RM 05
		Risk Integration Minor Use, and Emergency Response Branch 
         Registration Division (RD; 7505P)

1.0	Executive Summary	3
2.0	Regulatory Conclusions and Recommendations	5
2.1	Data Deficiencies/Conditions of Registration	5
2.2	Tolerance Considerations	5
2.2.1	Enforcement Analytical Method	5
2.2.2	International Harmonization	6
2.2.3	Recommended Tolerances	7
2.2.4	Revisions to Petitioned-For Tolerances	8
2.3	Label Recommendations	8
3.0	Introduction	8
3.1	Chemical Identity	8
3.2	Physical/Chemical Characteristics	9
3.3	Pesticide Use Pattern	9
3.4	Anticipated Exposure Pathways	12
3.5	Consideration of Environmental Justice	12
4.0	Hazard Characterization and Dose-Response Assessment	13
4.1	Summary of Toxicological Effects	13
4.2	Safety factor for Infants and Children (FQPA Safety Factor)	14
4.2.1	Completeness of the Toxicology Database	14
4.2.2	Evidence of Neurotoxicity	14
4.2.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal	14
4.2.4	Residual Uncertainty in the Exposure Database	15
4.3	Toxicity Endpoint and Point of Departure Selections	15
5.0	Dietary Exposure and Risk Assessment	16
5.1	Residues of Concern Summary and Rationale	16
5.2	Food Residue Profile	17
5.3	Water Residue Profile	17
5.4	Dietary Risk Assessment	18
5.4.1	Description of Residue Data Used in Dietary Assessment	18
5.4.2	Acute Dietary Risk Assessment	18
5.4.3	Chronic Dietary Risk Assessment	19
5.4.4	Cancer Dietary Risk Assessment	19
5.4.5	Summary Table	19
6.0	Residential (Non-Occupational) Exposure/Risk Characterization	19
6.1	Residential Handler Exposure	19
6.2	Post-Application Exposure	19
6.3	Residential Bystander Post-Application Inhalation Exposure	19
6.4	Spray Drift	20
7.0	Aggregate Exposure/Risk Characterization	20
8.0	Cumulative Exposure/Risk Characterization	21
9.0	Occupational Exposure/Risk Characterization	21
10.0	References	21
Appendix A.  Toxicology Profile	23
A.1	Toxicology Data Requirements	23
A.2	Toxicity Profiles	24
Appendix B.  Physical/Chemical Properties	28
1.0	Executive Summary

Chlorantraniliprole is an anthranilic diamide insecticide that belongs to a class of compounds that acts on the ryanodine receptor (RyR).  It was developed and registered by E.I. du Pont de Nemours and Company (DuPont) to control lepidopteran pests and insects primarily via interruption of normal muscle contraction pathways, leading to paralysis and eventual death. However, the relative absence of mammalian hazard following chlorantraniliprole exposure may be due in part to chlorantranilprole's selectivity for insect RyR over mammalian counterparts.  

There are five proposed chlorantraniliprole registration actions evaluated in this risk assessment:

   1. D410513 - E.I. du Pont de Nemours and Company (DuPont) has requested a Section 3 registration and tolerances of chlorantraniliprole on peanuts. 
   2. D412169  -  The Interregional Research Project No. 4 (IR-4) of Rutgers University has requested crop group conversions for existing tolerances on the stone fruit and tree nut crop groups to correspond with the crop group commodities update in 2012.  
   3. D412173  -  The IR-4 has requested to shorten the existing pre-harvest intervals (PHIs) for papaya, passionfruit, and mayhaw.  Additionally, IR-4 has requested to delete the existing separate mayhaw tolerance because mayhaw will be supported by the existing pome fruit tolerance (crop group 11-10).  
   4. D412170  - The IR-4 requested to add greenhouse use directions to the existing chlorantraniliprole labels for fruiting vegetables and cucurbits.  The existing cucumber and tomato data will support the addition of greenhouse use directions on the labels for greenhouse tomato, pepper, and cucumber; there is no request for tolerances. 
   5. D412717  -  The IR-4 has requested chlorantraniliprole use and tolerances on green onion (crop subgroup 3-07B) and requested to raise the existing tolerance for spice subgroup 19B based on data on green onion and dill.  

Concomitant with these petitions, condition of registration field trial data were submitted for rice, coffee, and strawberry; these data confirm the existing tolerances.  Additionally, a study submitted as confirmatory data for crayfish supports lowering the current crayfish tolerance. Condition of registration residue decline data on cherry, papaya, and lychee were also submitted to support existing tolerances for certain tropical fruits and to propose lowering the PHIs from 10 days to 1 day, with a tolerance increase of 2 ppm to 4 ppm for papaya and passionfruit.  The new data for dried onions combined with previous data for alfalfa hay translated to dried basil support retention of the 90 ppm tolerance for herb subgroup 19A.  

Permanent tolerances are currently established in 40 CFR §180.628 for chlorantraniliprole in/on a variety of commodities.

Use Profile
The end-use product (EP) formulations relevant to these requests are a 5% active ingredient (ai) suspension concentrate (SC), Prevathon[(R)] Insect Control (0.43 lb ai per gallon, or 0.053 kg ai/l), EPA Reg. No. 352-844; a 18.4% ai SC, Coragen[(R)] Insect Control (1.67 lb ai/gallon or 0.200 kg ai/l), EPA Reg. No. 352-729; a 35.0% ai water dispersible granular (WDG), Altacor(R) (35 lb ai/100 lb) EPA Reg. No. 352-730; and a 50% ai Flowable Concentrate (FC), Dermacor(R) X-100 Seed Treatment (FS, 5.210 lb ai/gal), EPA Reg No. 352-820).  Chlorantraniliprole may be applied via drip irrigation, ground, handheld, seed treatment, and aerial application methods.  Chlorantraniliprole is also registered for use in residential settings on turf, landscape ornamentals, and interiorscapes.  Chlorantraniliprole may also be used on golf courses and sod farms. 

Exposure Profile 
There is a potential for occupational short- and intermediate-term inhalation and dermal exposure to chlorantraniliprole during mixing, loading, application, and post-application activities.  There is potential for short-term exposure from the registered residential uses on turf, golf courses landscape ornamentals, and interiorscapes.  There is also exposure expected through food and drinking water from the proposed and registered uses of chlorantraniliprole.

Hazard Characterization
There is sufficient toxicology information for selecting doses and endpoints for chlorantraniliprole risk assessment.  In short-term studies, the most consistent effects are those associated with non-adverse induction of liver enzymes and subsequent increase in liver weights.  Increased microvesiculation of the adrenal cortex was observed in several rat studies; however detailed histopathology and a special adrenal function study found no adverse adrenal effects in the rat.   There was only one animal toxicity study (18-month carcinogenicity study in mice) in the database that produced adverse effects following chlorantraniliprole exposure.  Chlorantraniliprole is not considered developmentally toxic, genotoxic, neurotoxic, immunotoxic, or carcinogenic.  A subchronic inhalation toxicity study is not required for chlorantraniliprole at this time.  Chlorantraniliprole is classified as Acute Toxicity Category IV for acute oral, dermal, and inhalation toxicity; acute eye irritation; and primary skin irritation.  Chlorantraniliprole is not a dermal sensitizer.  Based on the available hazard and exposure data, the Food Quality Protection Act (FQPA) Safety Factor (SF) is reduced to 1x for all population subgroups and exposure scenarios.  

Dietary Risk Estimates (Food and water)
An acute dietary risk assessment was not performed because there was no acute hazard attributable to a single dose identified in the chlorantraniliprole toxicity database.  

The chronic dietary (food and drinking water) exposure assessment is considered conservative and assumed tolerance-level residues and that 100% of the proposed and registered crops were treated with chlorantraniliprole (100%CT).  Where processing data indicated a reduction (or no increase) in residue upon processing, the residue level of the raw agricultural commodity (RAC) was used without reduction.  Where processing data indicated an increase in residue in the processed commodity, a tolerance was established and used, e.g., raisins from grapes.  Where adequate processing data did not exist, default concentration factors were used if available.  Estimated drinking water concentrations (EDWCs) from ground water from the Environmental Fate and Effects Division (EFED) were also included.  The results of the chronic analysis indicate that the chronic dietary (food and drinking water) risk estimates utilized 2.3% of the chronic population adjusted dose (cPAD) for the general U.S. population and utilized 6.7% of the cPAD for children 1-2 years old, the most highly exposed population subgroup.  Therefore, the chronic dietary risk is not of concern (i.e., <100% of the cPAD).  

Aggregate Risk
Short- and intermediate-term aggregate risk assessments were not performed because there was no hazard identified over short- or intermediate-term durations.  Therefore, the aggregate risk assessment for chlorantraniliprole only includes chronic exposures to residues in food and drinking water.  The chronic dietary risk assessments for the U.S. population and all population subgroups are not of concern to HED (<100% cPAD).

Occupational Risk
Although there is potential for occupational handler and post-application exposure, the chlorantraniliprole toxicology database indicates there is no systemic hazard associated with short- and intermediate-term dermal and inhalation exposure, and therefore, no quantitative occupational exposure and risk assessment was conducted.

Environmental Justice
Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).

2.0	Regulatory Conclusions and Recommendations

HED has examined the residue chemistry, toxicity, and exposure databases for chlorantraniliprole and concluded that, provided a revised Section F is submitted, there are no deficiencies that would preclude granting a Section 3 registration on peanuts and green onion subgroup 3-07B; adding the greenhouse use directions for fruiting vegetables and cucurbits; and granting the requested crop group conversions.  A crayfish tolerance of 8 ppm was previously established based on a fish bioconcentration study and the estimated residues in water, sediment, and rice straw. The present crayfish study showed no residues (<0.01 ppm) at various sampling intervals from the use of chlorantraniliprole as a seed treatment on rice.   This reflects the actual use pattern. Therefore, a tolerance of 0.01 ppm is more appropriate and a modified Section F is required.

The specific tolerance recommendations are discussed in Section 2.2.3.  

2.1	Data Deficiencies/Conditions of Registration

There are no data deficiencies associated with the proposed uses of chlorantraniliprole.

2.2	Tolerance Considerations

2.2.1	Enforcement Analytical Method

An adequate enforcement method (liquid chromatography/tandem mass spectrometry (LC/MS/MS), DuPont-11374) is available for the determination of chlorantraniliprole residues in/on plant commodities.  The limit of quantitation (LOQ) is reported at 0.01 ppm for parent chlorantraniliprole.  The method for the determination of chlorantraniliprole and its metabolites in processed commodities is a LC/MS/MS method, DuPont-14314, which is a slightly modified version of DuPont-11374.  These methods have been accepted by the Analytical Chemistry Branch (ACB)/Biological and Economical Analysis Division (BEAD; C. Stafford, D340358, 02/06/2008).

An adequate enforcement method (LC/MS/MS) is available for the determination of residues of chlorantraniliprole and its metabolites in/on animal commodities.  Atmospheric pressure chemical ionization (APCI) MS/MS detection operated in the positive ion mode is used.  The LOQ is reported at 0.010 ppm for the parent and each of the metabolites.  The method has been accepted by ACB/BEAD (C. Stafford, D340358, 02/06/2008).

2.2.2	International Harmonization

Residue definitions are harmonized among the US, Canada, and Codex, with the common definition chlorantraniliprole.   

The existing US tolerance for the tree nut group is 0.04 ppm, whereas the tolerance in both Canada and Codex is 0.02 mg/kg.  The US tolerance is based upon the evaluation of field trial data for pecans and almonds with the use of the North American Free Trade Agreement (NAFTA) statistical spreadsheet (N. Tsaur, D357727, 03/03/2009).  The data were reevaluated using the Organization for Economic Cooperation and Development (OECD) tolerance calculation procedures.  The new tolerance estimate is 0.02 ppm.  Therefore, the tolerance for tree nuts, including pistachio, is lowered to 0.02 ppm, and harmonization with Canada and Codex is achieved.

The existing US tolerance for the pome fruit group is 1.2 ppm.  The Codex maximum residue limit (MRL) for pome fruit is 0.4 ppm, and the Canada MRL for various pome fruits (apple, pear, mayhaw, and quince) is 0.4 ppm.  The original US tolerance for pome fruits was 0.3 ppm, but it was adjusted upwards to 1.2 ppm to accommodate the use of adjuvants and a shortened PHI (D. Rate, D361791, 01/08/2010).  Therefore, the 1.2 ppm value cannot be lowered to harmonize with Codex and/or Canada.

The existing US tolerance for the stone fruit group (except cherry, chickasaw plum, and damson plum) is 4.0 ppm.  The Codex MRL for stone fruits is 1 mg/kg and the Canada MRL for various stone fruits (apricot, nectarine, peach, plum, plumcots, and cherries) is 2.5 mg/kg.  The original US tolerance for stone fruits was 1.0 ppm, but it was adjusted upwards to 4.0 ppm to accommodate the use of adjuvants and a shortened PHI (D. Rate, D361791, 01/08/2010).  Therefore, the 4.0 ppm value cannot be lowered to harmonize with Codex and/or Canada.

Codex has not established MRLs for passionfruit, papaya, peanuts, green onions, herbs, or spices.  Therefore, there is no harmonization issue with Codex.  Canada does not have MRLs for these same commodities, with the exception of green onions and peanuts.  Canada and the US are conducting a joint review for green onions and peanuts and will work to harmonize the MRLs.

2.2.3	Recommended Tolerances

The current tolerance definition is found at 40CFR§180.628.  Compliance with the tolerance is based on measuring only chlorantraniliprole for both plant and animal commodities.
 
Table 2.2.3.  Tolerance Summary for Chlorantraniliprole
Commodity
                          Established Tolerance (ppm)
                           Proposed Tolerance (ppm)
                        HED-Recommended Tolerance (ppm)
                                   Comments 
                        (correct commodity definition)
Papaya
2.0
4.0
4.0

Passionfruit
2.0
4.0
4.0

Peanut, nutmeat
-
0.06
0.06

Peanut, hay
0.20  
(exp 04/10/14)
90
90
Translation from alfalfa hay
Onion, green, subgroup 3-07B
-
3.0
3.0

Spice subgroup 19B
14[1] 
40
90

Nut, tree, group 14-12
0.04
-
0.02
Crop group conversion.
International harmonization.
Nut, tree, group 14
0.04
-
Remove
Replaced by crop group 14-12
Pistachio
0.04
-
Remove
Replaced by crop group 14-12
Fruit, pome, group 11-10
1.2
-
1.2
Crop group conversion
Fruit, pome, group 11, except mayhaw
1.2
-
Remove
Replaced by crop group 11-10
Mayhaw
0.6
-
Remove
Replaced by crop group 11-10
Fruit, stone group 12-12, except cherry, Chickasaw plum, and damson plum
4.0
-
4.0
Crop group conversion
Fruit, stone group 12, except cherry, Chickasaw plum, and damson plum
4.0
-
Remove
Replaced by crop group 12-12
Crayfish
8.0
-
0.01

Onion, green
0.20 (exp 04/10/14)
-
Remove
Replaced by Onion, green, subgroup 3-07B
Onion, welsh
0.20 (exp 04/10/14)
-
Remove
Replaced by Onion, green, subgroup 3-07B
Shallots, fresh leaves
0.20 (exp 04/10/14)
-
Remove
Replaced by Onion, green, subgroup 3-07B
Leek
0.20 (exp 04/10/14)
-
Remove
Replaced by Onion, green, subgroup 3-07B
[1] A tolerance of 14 ppm was recommended (D361791, D. Rate, 01/08/2010), but is not listed in 40CFR§180.628.  This was based on the translation of alfalfa seed data, with adjustments for adjuvant use (2x) and application rate (2x).

2.2.4	Revisions to Petitioned-For Tolerances

The petitioned tolerances are the same as the recommended tolerances, except for spice subgroup 19B, crayfish, and increased/decreased tolerances for the crop group conversions due to international harmonization.  

Residue data on dill seed was presented in support of a spice subgroup 19B tolerance.  HED had previously recommended for a spice subgroup 19B tolerance of 14 ppm.  The petitioner requested 40 ppm, but evaluation of the dill seed data indicates that 90 ppm is appropriate.  Condition of registration data on field trial residue decline for cherry, papaya, and leechee support existing tolerances for certain tropical fruits and allow for lowering of the PHIs from 10 days to 1 day, with an increase in tolerance from 2 ppm to 4 ppm, for papaya and passionfruit.

A crayfish tolerance of 8 ppm was previously established based on a fish bioconcentration study and the estimated residues in water, sediment, and rice straw. The present crayfish study showed no residues (<0.01 ppm) at various sampling intervals from the use of chlorantraniliprole as a seed treatment on rice.  This reflects the actual use pattern. A tolerance of 0.01 ppm is appropriate.  A modified Section F is required.

A crop group conversion for tree nut group 14 to tree nut group 14-2 was requested.  This is acceptable, but the tolerance will be changed from 0.04 ppm to 0.02 ppm to harmonize with Canada and Codex.

The registrant must submit a revised Section F requesting tolerances of 90 ppm and 0.01 ppm for the spice subgroup 19B and crayfish, respectively.

2.3	Label Recommendations

There are no label recommendations for this petition. 

3.0	Introduction

The ai, chlorantraniliprole, is an anthranilic diamide insecticide that belongs to a class of compounds that acts on the RyR.  It was developed and registered by E.I. du Pont de Nemours and Company (DuPont) to control lepidopteran pests and insects primarily via interruption of normal muscle contraction pathways, leading to paralysis and eventual death.

3.1	Chemical Identity

Table 3.1.  Chlorantraniliprole Nomenclature.
Chemical structure
                                       
Common name
Chlorantraniliprole
Company experimental name
DPX-E2Y45
IUPAC name
3-bromo-4′-chloro-1-(3-chloro-2-pyridyl)-2′-methyl-6′-(methylcarbamoyl)pyrazole-5-carboxanilide
CAS name
3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide
CAS registry number
500008-45-7
End-use product (EP)
DuPont(TM) Altacor[(R)] WDG (35%; EPA Reg. No. 352-730)
DuPont(TM) Coragen(R) SC Insect Control (1.67 lb ai/gal; EPA Reg. No. 352-729)
DuPont(TM) Prevathon(R) Insect Control (0.43 lb ai/gal; EPA Reg No. 352-844)
DuPont(TM) Dermacor(R) X-100 Seed Treatment (FS, 5.210 lb ai/gal; EPA Reg No. 352-820)

3.2	Physical/Chemical Characteristics

The physical/chemical properties of chlorantraniliprole are summarized in Appendix B.  Based on the low vapor pressure (6.3 x 10[-12] Pa at 20º C) and KOW (~3 at pH ranges 4 to 9), chlorantraniliprole is not expected to volatilize, pass lipid barriers (consistent with dermal absorption findings in mammals), or bioaccumulate.  Environmental fate data indicate chlorantraniliprole is persistent and mobile in terrestrial and aquatic environments.  Major routes of chlorantraniliprole dissipation are expected to be alkaline-catalyzed hydrolysis, photodegradation in water, leaching, and runoff.  

3.3	Pesticide Use Pattern

For the proposed Section 3 registrations addressed herein there are four EPs, two SCs, one FC, and one WDG.  The proposed changes will also apply to the technical product label (EPA Reg. No. 352-728).  Proposed labels have been provided for a 5% ai SC, Prevathon(R) Insect Control (0.43 lb ai per gallon, or 0.053 kg ai/l) EPA Reg. No. 352-844; a 18.4% ai SC, Coragen[(R)] Insect Control (1.67 lb ai/gallon or  0.200 kg ai/l) EPA Reg. No. 352-729; a 35% ai WDG, Altacor(R) (35 lb ai/100 lb) EPA Reg. No. 352-730; and a 50% ai Flowable Concentrate (FC) Dermacor(R) X-100 Seed Treatment (FS, 5.210 lb ai/gal), EPA Reg No. 352-820).  Changes to the Altacor(R) label involve only crop conversions, and changes to Dermacor(R) only involves the conditional data related to seed treatment use on rice.  The WDG formulation is not proposed for use on cereal grains.  The summary of the relevant proposed uses is presented in Table 3.3. 

Table 3.3.  Summary of Proposed/Relevant Existing Chlorantraniliprole Use Directions 
Applic. Timing, Type, and Equip.
                                  Formulation
                                [EPA Reg. No.]
                                 Applic. Rate 
                                   (lb ai/A)
                          Max. No. Applic. per Season
                          Max. Seasonal Applic. Rate
                                   (lb ai/A)
                                      PHI
                                    (days)
Use Directions and Limitations
                             Proposed Use: Peanut
Foliar
(ground; aerial)

                                   18.4% SC
                                1.67 lb ai/gal
                                    Coragen
                                   [352-729]
                                0.045  -  0.065
                                       4
                  0.2 (from all chlorantranili-prole sources)
                                       1
Minimum interval between treatments is 3 days.
Foliar
(ground; aerial)
                                     5% SC
                                0.43 lb ai/gal
                                   Prevathon
                                   [352-844]
                                  0.047-0.067
                                       
                                       
                                       
                                       
        Proposed Use: Bulb Vegetables (including green onion subgroup)
Foliar
(ground; aerial)
                                   18.4% SC
                                1.67 lb ai/gal
                                    Coragen
                                   [352-729]
                                0.045  -  0.065
                                       4
                                 0.2 per crop
                                 0.6 per year
                   (from all chloroantranili-prole sources)
                                       1
Minimum interval between treatments is 4 days.
                                       
  Proposed Use: Greenhouse Cucumbers, Greenhouse Peppers, Greenhouse Tomatoes
Foliar
                                       
                                   18.4% SC
                                1.67 lb ai/gal
                                    Coragen
                                   [352-729]
                                 0.031 tomato
                            0.045 pepper, cucumber
                              3 (per crop cycle)
                             0.134 per crop cycle
                                       1
Minimum interval between treatments is 7 days.
Mix 1.6 fl oz per 100 gal spray volume (0.0209 lb ai/100 gal)
Maximum application is 150 gal spray solution per acre for tomato and 214 gal spray solution per acre for cucumber and pepper.
                                       
      Updated Use: Tropical Fruits (Papaya, Passionfruit, Lychee)[1][, 2]
Foliar
                                   35.0% WDG
                                    Altacor
                                   [352-730]
                                       
                                 0.066- 0.099
                                       3
                                      0.2
                   (from all chloroantranil-iprole sources)
                                     1[2]
                                       
                    10 (acero-la, jaboti-caba, and lychee)
Minimum interval between treatments is 7 days.
Do not apply dilute solutions of more than 200 gal water per acre.
Do not apply less than 30 gal water per acre.
                                       
              Updated Use: Low growing berry (subgroup 13-07G)[1]
Foliar
                                   35.0% WDG
                                    Altacor
                                   [352-730]
                                       
                                  0.066-0.099
                                       3
                                      0.2
                    (from all chloroantranil-prole sources)
                                       1
Minimum interval between treatments is 7 days.
Do not apply dilute solutions of more than 200 gal water per acre.
Do not apply less than 30 gal water per acre.
Do not apply to strawberry or cranberry.

Foliar
                                   18.4% SC
                                1.67 lb ai/gal
                                    Coragen
                                   [352-729]
                                  0.045-0.065
                                       4
             0.2 per crop (from all chloroantranili-prole sources)
            0.4 per year  (from all chloroantranili-prole sources)
                                       1
Minimum interval between treatments is 7 days.

                             Updated Use: Rice[1]
Seed treatment
                                    50% FS
                                5.21 lb ai/gal
                              Dermacor [352-820]
                                     0.084
                                       1
                                      N/S
                                      N/S
Do not use DERMACOR(R) X-100 treated rice field
for the aquaculture of edible fish or Crustacea
(including crawfish) during the rice production cycle
(planting through harvest).
                            Updated Use: Coffee[1]
Foliar
                                   35.0% WDG
                                    Altacor
                                   [352-730]
                                       
                                  0.066-0.099
                                       3
                 0.2 (from all chloroantranili-prole sources)
                                       7
Minimum interval between treatments is 14days.
Do not apply dilute solutions of more than 200 gal water per acre.
Do not apply less than 30 gal water per acre.
                                       
                       Updated Use: Herb Subgroup 19A[1]
Foliar
                                   18.4% SC
                                1.67 lb ai/gal
                                    Coragen
                                   [352-729]
                                0.045  -  0.065
                                       4
             0.2 per crop (from all chloroantranili-prole sources)
             0.8 per year (from all chloroantranili-prole sources)
                                       1
Minimum interval between treatments is 3 days.
                      Updated Use: Spices Subgroup 19B[1]
Foliar 
                                   18.4% SC
                                1.67 lb ai/gal
                                    Coragen
                                   [352-729]
                                0.045  -  0.065
                                       4
             0.2 per crop (from all chloroantranil-iprole sources)
             0.8 per year (from all chloroantranil-iprole sources)
                                       1
Minimum interval between treatments is 3 days.
1Uses associated with condition of registration data evaluated in association with the Section 3 and crop group conversion requests.
[2]The PHI for papaya and passionfruit has been reduced from 10 days to 1 day.

3.4	Anticipated Exposure Pathways

Humans may be exposed to chlorantraniliprole in food and drinking water, since chlorantraniliprole may be applied directly to growing crops and application may result in chlorantraniliprole reaching surface and ground water sources of drinking water.  There are registered residential uses of chlorantraniliprole, so there is likely to be exposure in residential or non-occupational settings.  In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application.  There is a potential for post-application exposure for workers re-entering treated fields.

This risk assessment considers all of the aforementioned exposure pathways based on the proposed new uses of chlorantraniliprole, but also considers the existing uses as well, particularly for the dietary assessment.

3.5	Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," http://www.epa.gov/environmentaljustice/resources/policy/exec_order_12898.pdf.  As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture's National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are analyzed and categorized by subgroups based on age and ethnic group.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for children 1-2 years, youths, and adults entering or playing on treated areas post-application are evaluated.  Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0	Hazard Characterization and Dose-Response Assessment

No new toxicity and/or metabolism data have been received since the last risk assessment.  This assessment includes summaries of prior assessments (S. Healy, D399493, 05/17/2012).  The Hazard and Science Policy council waived the required subchronic inhalation toxicity study (TXR#0056851).  

4.1	Summary of Toxicological Effects

Chlorantraniliprole is an anthranilic diamide insecticide that belongs to a class of compounds that acts on the RyR.  It controls lepidopteran pests and insects primarily via interruption of normal muscle contraction pathways, which leads to paralysis and eventual death.  The relative absence of mammalian hazard may be due in part to chlorantranilprole's selectivity for insect RyR over mammalian counterparts.  In short-term mammalian studies, the most consistent effects are increased liver weights and mild induction of liver enzymes.  In oral and dermal toxicity studies in rats, increased incidence of adrenal cortex microvesiculation was observed (usually in males only). However, an additional special study to assess the capacity of the adrenal gland to produce corticosterone found no effects in male rats (with or without microvesiculation) following ACTH stimulation. Therefore, adrenal cortex microvesiculation observed in rat studies was not considered adverse.  Chlorantraniliprole does not exhibit pre- or postnatal toxicity as there were no maternal or fetal effects in studies conducted in rats and rabbits.  Chlorantraniliprole is not genotoxic, neurotoxic, immunotoxic, carcinogenic, or developmentally toxic.  Chlorantraniliprole is classified as "Not likely to be Carcinogenic to Humans".  No treatment-related tumors were reported in the submitted chronic and oncogenicity studies in rats and mice (18-month carcinogenicity study) or in the subchronic studies in mice, dogs and rats.

Based on the results of short-term and acute dermal studies, chlorantraniliprole has relatively low dermal toxicity.  Chlorantraniliprole is not acutely toxic via the oral, or inhalation routes of exposure.  The LD50 for both oral and dermal acute exposure is > 5000 mg/kg/day and the LC50 for acute inhalation exposure is > 5.1 mg/L.  Chlorantraniliprole is not an eye or skin irritant and does not cause skin sensitization.  The acute inhalation study did not report any portal of entry effects or acute irritation via the inhalation route of exposure.  

Absorption, Distribution, Metabolism, Excretion (ADME)
Chlorantraniliprole metabolism was studied extensively in rats, mice, and dogs.  In rats, absorption of chlorantraniliprole was rapid with peak concentrations occurring at 5-12 hours after low or high (10 or 200 mg/kg) oral single dose administration.  The plasma elimination half-lives after single dose ranged from 41 hours in males to 79 hours in female rats.  Tissue distribution of the absorbed dose was extensive and indicated low potential for accumulation.  The tissue residues were higher in female rats than in male rats, which is consistent with female rats having a longer elimination half-life.  Rapid excretion was observed via bile (49-53%) within 48 hours and 88-97% total excretion was observed within 7 days after single or multiple doses.  Fecal excretion was the primary route of elimination followed by excretion in the urine with no significant excretion occurring by exhalation.  Metabolism of the absorbed dose was extensive and involved sex differences (greater hydroxylation in males).  Results also suggest possible species differences in the primary metabolites formed in all three species tested.  Metabolites represented in the rat metabolism cascade were: IN-K9T00, IN-HXH44, IN-KAA24, IN-H2H20, and IN-GAZ70 (chemical nomenclature and molecular structures for these compounds can be found in:  S. Healy, D381810, 02/28/2011).

Based on studies conducted in rats, dermal penetration of chlorantraniliprole formulations is approximately <= 1.09% for undiluted concentrates and 2.10-2.79% for 0.75 g/L aqueous dilutions of the concentrates.

4.2	Safety factor for Infants and Children (FQPA Safety Factor)

Based on the hazard and exposure data, the HED chlorantraniliprole risk assessment team recommends that the FQPA SF be reduced to 1x.  The rationale for this recommendation is provided in the following sections.

4.2.1	Completeness of the Toxicology Database

The toxicity database for this chemical is complete for the purposes of this risk assessment and considered adequate for the characterization of potential pre- and post-natal risks to infants and children.  Acceptable developmental toxicity, 2-generation reproduction toxicity, acute neurotoxicity, subchronic neurotoxicity, and immunotoxicity studies have been submitted and reviewed. The Hazard and Science Policy council waived the required subchronic inhalation toxicity study based on chlorantraniliprole's physical chemical properties, including low vapor pressure; low acute inhalation toxicity (Toxicity Category IV); and the use of a conservative, chronic oral POD that results in screening-level MOEs >12,000 (TXR#0056851).  

4.2.2	Evidence of Neurotoxicity

There is no indication that chlorantraniliprole is a neurotoxic chemical and there is no need for a developmental neurotoxicity study or additional uncertainty factors (UFs) to account for neurotoxicity.  The no observed adverse effect level (NOAEL) in an acute oral gavage neurotoxicity study was 2000 mg/kg, the limit dose.  In a subchronic neurotoxicity study, the NOAEL was 1313/1586 mg/kg/day (M/F), the maximum dietary concentration administered (greater than the limit dose).  The NOAELs were based on the absence of treatment related effects on systemic toxicity and neurotoxicity parameters, including microscopic neuropathology.  Neurological assessments conducted in conjunction with the 18-month oncogenicity study in mice following 45, 60, and 90 days of dietary administration of chlorantraniliprole confirmed the lack of potential neurotoxicity.  Further, no treatment related clinical signs indicative of potential neurotoxicity were observed in short-term or long-term exposure studies in rats, mice, or dogs.  

4.2.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There is no evidence that chlorantraniliprole results in increased susceptibility in in utero rats or rabbits in the prenatal developmental studies or in young rats in the 2-generation reproduction study.  There were no effects on prenatal fetal growth or postnatal development up to the limit dose of 1000 mg/kg/day in rats or rabbits.  There were no treatment-related effects on the numbers of litters, fetuses (live or dead), resorptions, sex ratio, or post-implantation loss.  There were no effects on fetal body weights; skeletal ossification; and external, visceral, or skeletal malformations or variations.  

4.2.4	Residual Uncertainty in the Exposure Database

There are no residual uncertainties identified in the exposure databases. The chronic dietary assessment utilized tolerance-level residues for all crops and assumed 100% CT of the proposed and registered crops were treated with chlorantraniliprole.  Where processing data indicated a reduction (or no increase) in residue upon processing, the residue level of the RAC was used without reduction.  Where processing data indicated an increase in residue in the processed commodity, a tolerance was established and used, e.g., raisins from grapes.  Where adequate processing data did not exist, default concentration factors were used if available.  EPA made conservative (protective) assumptions in the ground and surface water modeling used to assess exposure to chlorantraniliprole in drinking water. Moreover, there is a lack of toxicity via the dermal route, as well as the lack of toxicity over the acute-, short- and intermediate-term via the oral route. These assessments will not underestimate the exposure and risks posed by chlorantraniliprole.

4.3	Toxicity Endpoint and Point of Departure Selections

The details for selecting toxicity endpoints and points of departure for various exposure scenarios are presented in the original risk assessment for Section 3 Registration (S. Winfield, DP336983, 03/07/2008).  There have been no changes to the prior dose-response assessment or recommendations for combining routes of exposure and/or cancer classification.  Refer to Table 4.3.1.

Table 4.3.1. Summary of Toxicological Doses and Endpoints for Chlorantraniliprole for Use in Dietary, Non-Occupational, and Occupational Human Health Risk Assessments
Exposure/
Scenario
                              Point of Departure
                        Uncertainty/FQPA Safety Factors
                RfD, PAD, Level of Concern for Risk Assessment
                        Study and Toxicological Effects
Acute Dietary (All Populations)
N/A
N/A
N/A
No acute hazard attributable to a single dose was identified; therefore, an acute dietary endpoint was not selected for quantitative risk assessment.
Chronic Dietary (All Populations)
NOAEL= 158 mg/kg/day
UFA= 10x
UFH=10x
FQPA SF= 1x
Chronic RfD = 1.58 mg/kg/day

cPAD = 1.58 mg/kg/day
                         18-Month Oral (feeding)/mouse
                                       
LOAEL = 935 mg/kg/day based on eosinophilic foci accompanied by hepatocellular hypertrophy and increased liver weight (males only).
Incidental Oral Short-/Intermediate-Term 
N/A
N/A
N/A
There was no hazard identified via the oral route over the short- and intermediate-term and, therefore, no endpoint was selected for quantitative risk assessment.
Dermal Short-/Intermediate-Term 
N/A
N/A
N/A
There was no hazard identified via the dermal route (and no concerns for developmental, reproductive or neurotoxic effects) and, therefore, no dermal endpoint was selected for quantitative risk assessment.
Inhalation Short-/Intermediate-Term 
N/A
N/A
N/A
Based on the lack of hazard identified in the acute inhalation study, lack of acute irritation, and extremely low oral toxicity, no inhalation endpoint was selected for quantitative risk assessment.
Cancer (oral, dermal, inhalation)
Classification:  "Not likely to be Carcinogenic to Humans" based on weight of evidence of data: no treatment-related tumors reported in the submitted chronic and oncogenicity studies in rats and mice, subchronic studies in mice, dogs and rats and  no mutagenic concern was reported in the genotoxicity studies. 
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  RfD = Reference Dose.  PAD = Population Adjusted Dose.  NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human population (intraspecies).  MOE = margin of exposure.  LOC = level of concern.  N/A = not applicable.

5.0	Dietary Exposure and Risk Assessment

5.1	Residues of Concern Summary and Rationale

The residues of concern for tolerance enforcement and risk assessment in plants, livestock, and water are summarized below in Table 5.1.  See Appendix B for names and structures.  HED also recalculated the dietary burdens for beef and dairy cattle (S. Funk, D416101, 11/12/2013).  The resulting residue estimates were below the established tolerances for ruminants; therefore, tolerance-levels were used in the dietary risk assessment for cattle.

Table 5.1.  Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression
Matrix
Residues included in Risk Assessment
                   Residues included in Tolerance Expression
Plants
Primary Crop
Chlorantraniliprole
                              Chlorantraniliprole

Rotational Crop
Chlorantraniliprole
                              Chlorantraniliprole
Livestock
Ruminant
Chlorantraniliprole, IN-HXH44, IN-K9T00.  
                              Chlorantraniliprole

Poultry
Chlorantraniliprole
Eggs: Chlorantraniliprole, IN-H2H20, IN-K7H29, IN-GAZ70, IN-F9N04
                              Chlorantraniliprole
Drinking Water
Chlorantraniliprole
                                      N/A

5.2	Food Residue Profile

The submitted magnitude of the residue data are adequate for risk assessment and tolerance assessment.  For all crops, the number and locations of field trials are adequate.  Greenhouse tomato, greenhouse pepper, greenhouse cucumber, rice, coffee, and strawberry trials reflect the proposed label maximum application rate and other conditions and demonstrate that the existing tolerances are adequate.  The crayfish trials show that the existing tolerance may be reduced.  Residues in passionfruit, papaya, and mayhaw will increase with decreased PHIs, but the existing respective group tolerances are protective.  Trials for proposed uses on green onions and peanuts are adequate both in number of trials and geographic distribution and are conducted under conditions reflective of the proposed labels.  The new feed item, peanut hay, does not increase the calculated dietary exposure of ruminants and therefore does not change the existing tolerances for ruminant commodities. The dill seed trials provide a tolerance estimate of 90 ppm for the spices subgroup 19B.  This is an increase from the previous recommendation of 14 ppm, and the registrant request for 40 ppm.  The new data for dried onions combined with previous data for alfalfa hay translated to dried basil support retention of the 90 ppm for herb subgroup 19A.  The field trial studies are supported by adequate storage stability data.

The existing cotton seed processing study is translated to peanut, and no concentration of residue occurs in the oil or meal.   

Adequate confined and limited field rotational crop data are available.  HED previously concluded that the residue of concern in rotational crops is parent only.  All necessary rotational crop tolerances were established previously or appropriate label restrictions were implemented.   Several inadvertent tolerances will now be replaced with primary crop commodity tolerances.  Extensive primary crop or crop group tolerances have been established, and therefore there are very few inadvertent tolerances needed.

5.3	Water Residue Profile

The EDWC for groundwater from the assessment evaluating the proposed uses is greater than the surface and groundwater estimates from the previous assessment.  Thus, the groundwater concentration of 207 ppb (one-in-ten-year annual mean) based on the Wisconsin corn scenario was used in the dietary exposure assessment (C. Koper, D414839, 09/23/2013).  
  
Table 5.3.  Summary of Estimated Surface Water and Ground Water Concentrations for Chlorantraniliprole.

                          Surface Water Concentration
                                    (ppb a)
                          Ground Water Concentration 
                                    (ppb b)
Acute
                                     55.30
                                      207
Chronic (non-cancer, 1 in 10 year annual average)
                                     39.87
                                       
Chronic (cancer, 30-year annual average)
                                     39.87
                                       
[a] Pesticide Root Zone Model (PRZM v3.12.2, May 12, 2005) and Exposure Analysis Modeling System (EXAMS v2.98.04.06, April 25, 2005), simulation models, were coupled with the input PE5.pl.shell.  The Provisional Cranberry Model was used to assess cranberry.  The model does incorporate a degradation component
[b] From the PRZM-GW model

5.4	Dietary Risk Assessment

5.4.1	Description of Residue Data Used in Dietary Assessment

HED used tolerance-level residues for the proposed and registered crops and 100% crop treated was assumed for all commodities included in this assessment; therefore, this assessment is considered conservative.  Where processing data indicated a reduction (or no increase) in residue upon processing, the residue level of the RAC was used without reduction, for example mint oil from spearmint.  Where processing data indicated an increase in residue in the processed commodity, a tolerance was established and used, e.g., raisins from grapes.  Where adequate processing data did not exist, default concentration factors were used if available.  Default concentration factors were used for the following:  dried apple, apple juice, dried apricot, dried banana, dried beef meat, cherry juice, field corn syrup, cranberry juice, grape juice, grapefruit juice, lemon juice, lime juice, dried lychee, dried (dehydrated) bulb onion, orange juice, dried peach, dried pear, peanut butter, dried pineapple, pineapple juice, dried plantain, dried plum prune, plum juice, dried potato (flakes, granules), potato flour, tangerine juice, tomato paste, tomato puree, dried tomato, and tomato juice.  

The drinking water residues used in the dietary risk assessment were provided by EFED (C. Koper, D414839, 09/23/2013) and incorporated directly into this dietary assessment.  Water residues were incorporated in the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID(TM)) into the food categories "water, direct, all sources" and "water, indirect, all sources."  The estimated groundwater concentration of 207 ppb was used for this assessment.  

5.4.2	Acute Dietary Risk Assessment

No acute dietary toxicity endpoint could be identified based on the toxicology data currently available for chlorantraniliprole; therefore, an acute assessment was not performed.  

5.4.3	Chronic Dietary Risk Assessment

The results of the chronic analysis indicate that the chronic dietary (food and drinking water) risk estimates utilized 2.3% of the cPAD for the general U.S. population and utilized 6.7% of the cPAD for children 1-2 years old, the most highly exposed population subgroup.  Therefore, the chronic dietary risk is not of concern (i.e., <100% of the cPAD).  A summary of these results is shown in Table 5.4.5.

5.4.4	Cancer Dietary Risk Assessment

Chlorantraniliprole is classified as "not likely to be carcinogenic to humans"; therefore, a cancer assessment was not performed.

5.4.5	Summary Table

 Table 5.4.5.  Summary of Dietary (Food and Drinking Water) Exposure and Risk for Chlorantraniliprole.
                              Population Subgroup
                                Chronic Dietary
                                        
                                Dietary Exposure
                                  (mg/kg/day)
                                    % cPAD*
 General U.S. Population
                                    0.036207
                                      2.3
 All Infants (<1 year old)
                                    0.060811
                                      3.8
 Children 1-2 years old*
                                    0.105269
                                      6.7
 Children 3-5 years old
                                    0.081499
                                      5.2
 Children 6-12 years old
                                    0.046110
                                      2.9
 Youth 13-19 years old
                                    0.027234
                                      1.7
 Adults 20-49 years old
                                    0.030559
                                      1.9
 Adults 50+ years old
                                    0.030166
                                      1.9
 Females 13-49 years old
                                    0.029398
                                      1.9
*The subpopulation with the highest risk estimate. 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

6.1	Residential Handler Exposure

Although there are existing residential uses for chlorantraniliprole, residential exposure to chlorantraniliprole was not quantitatively assessed due to the lack of toxicity via inhalation and dermal routes. No risk is expected from residential handler exposure to chlorantraniliprole.

6.2	Post-Application Exposure

Due to the lack of toxicity via inhalation and dermal routes of exposure, as well as the lack of toxicity over the acute, short- and intermediate-term via the oral route, a residential post-application risk assessment is not required.

6.3	Residential Bystander Post-Application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for chlorantraniliprole at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure (6.3 x 10[-12] Pa @ 20˚C), and the low proposed use rate (0.099 lb ai/A).  However, volatilization of pesticides may be a source of post-application inhalation exposure to individuals nearby pesticide applications.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010.  The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are developed, the Agency may revisit the need for a quantitative post-application inhalation exposure assessment for chlorantraniliprole.

6.4	Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications.  This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for chlorantraniliprole.  The Agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call-In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency's Spray Drift website for more information).  The Agency is also taking means to qualitatively and qualitatively address spray drift as a potential source of exposure in risk assessments for pesticides through existing programs such as Ag Drift and chemical specific properties of pesticides.  The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently.  

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures.  In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated.  When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

An acute aggregate risk assessment was not performed because no appropriate endpoint was available to determine the aRfD for the general U.S. population or any population subgroup.  Short- and intermediate term aggregate risk was not performed because no hazard was identified over short- or intermediate-term durations.

Therefore, the aggregate risk assessment for chlorantraniliprole only includes chronic exposures to residues in food and drinking water.  The chronic dietary risk assessments for the U.S. population and all population subgroups are not of concern to HED (<100% cPAD).  The results of the chronic analysis indicate that the chronic dietary (food and water) risk estimates utilized 2.3% of the cPAD for the general U.S. population and utilized 6.7% of the cPAD for children 1-2 years old, the most highly exposed population subgroup.  

8.0 Cumulative Exposure/Risk Characterization

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 chlorantraniliprole and any other substances and chlorantraniliprole does not appear to produce a toxic metabolite produced by other substances.  For the purposes of this tolerance action, therefore, EPA has not assumed that chlorantraniliprole has a common mechanism of toxicity with other substances.  For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

There is potential for short- and intermediate-term occupational exposure to chlorantraniliprole during both handler [mixing, loading, and application (via the dermal and inhalation routes)] and post-application activities (via the dermal route) based on the proposed uses.  However, the chlorantraniliprole toxicology database indicates there is no hazard associated with short- and intermediate-term dermal and inhalation exposure, and, therefore, no quantitative occupational exposure and risk assessment was conducted.

10.0	References

Kristin Rury, D416093, 12/03/2013.  Chlorantraniliprole: Chronic Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section (3) Registration Actions on Green Onion Subgroup 3-07b, and Peanut; and for the Requests to Update the Crop Groups of Stone Fruit, Tree Nut, and Spices; and to Shorten the Pre-Harvest Intervals for Papaya, Passionfruit, and Mayhaw.  

Christopher Koper, D414839, 09/23/2013.  Tier II Drinking Water Assessment to Establish Tolerances of Chlorantraniliprole on Various Crops with Multiple Seasons.  

Steve Funk, D416101, 11/12/2013. Chlorantraniliprole. Petition for the Establishment of Permanent Tolerances and Registration for Use on Peanuts and on Green Onion, Addition of Use on Greenhouse Tomato and Greenhouse Pepper  and Greenhouse Cucumber, Crop Group Conversions for Stone Fruit and Tree Nuts, and Label Amendment to Shorten the PHI for Passionfruit, Papaya, and Mayhaw.   Condition of Registration Data for Rice, Crayfish, Coffee, Strawberry, and Livestock Analytical Methods.  Summary of Analytical Chemistry and Residue Data.

Appendix A.  Toxicology Profile 

A.1	Toxicology Data Requirements
The requirements (40 CFR 158.500) for food use for chlorantraniliprole are in Table A.1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

                                     Test 

                                   Technical

                                   Required
                                   Satisfied
870.1100    Acute Oral Toxicity	
870.1200    Acute Dermal Toxicity	
870.1300    Acute Inhalation Toxicity	
870.2400    Primary Eye Irritation	
870.2500    Primary Dermal Irritation	
870.2600    Dermal Sensitization	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.3100    Oral Subchronic (rodent)	
870.3150    Oral Subchronic (non-rodent)	
870.3200    21-Day Dermal	
870.3250    90-Day Dermal	
870.3465    90-Day Inhalation	
                                      yes
                                      yes
                                      yes
                                      no
                                      no*
                                      yes
                                      yes
                                      yes
                                       -
                                       -
870.3700a  Developmental Toxicity (rodent)	
870.3700b  Developmental Toxicity (non-rodent)	
870.3800    Reproduction	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.4100a  Chronic Toxicity (rodent)	
870.4100b  Chronic Toxicity (non-rodent)	
870.4200a  Oncogenicity (rat)	
870.4200b  Oncogenicity (mouse)	
870.4300    Chronic/Oncogenicity	
                                      yes
                                      yes
                                      yes
                                      yes
                                      no
                                     yes**
                                      yes
                                     yes**
                                      yes
                                     yes**
870.5100    Mutagenicity -- Gene Mutation - bacterial	
870.5300    Mutagenicity -- Gene Mutation - mammalian	
870.5385    Mutagenicity -- Structural Chromosomal Aberrations	
870.5395    Mutagenicity -- Micronucleus	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.6100a  Acute Delayed Neurotox. (hen)	
870.6100b  90-Day Neurotoxicity (hen)	
870.6200a  Acute Neurotox. Screening Battery (rat)	
870.6200b  90-Day Neurotox. Screening Battery (rat)	
870.6300    Develop. Neurotox	
                                      no
                                      no
                                      yes
                                      yes
                                      no
                                       
                                       -
                                       -
                                      yes
                                      yes
                                       -
                                       
870.7485    General Metabolism	
870.7600    Dermal Penetration	
870.7800    Immunotoxicity	
                                      yes
                                      no
                                      yes
                                     yes 
                                       -
                                      yes
* Based on a weight of evidence approach a subchronic inhalation toxicity study is not required for the current uses (TXR#0056851).
** Submittal of 870.4300 fulfills the requirement for 870.4100a and 870.4200a.

A.2	Toxicity Profiles

Table A.2.1	Acute Toxicity Profile of Chlorantraniliprole
                                 Guideline No.
                                  Study Type
                                    MRID(s)
                                    Results
                               Toxicity Category
870.1100
Acute oral - rat
                                   46889112
LD50 > 5000 mg/kg
                                      IV
870.1200
Acute dermal - rat
                                   46889113
LD50 > 5000 mg/kg
                                      IV
870.1300
Acute inhalation - rat
                                   46889121
LC50 > 5.1 mg/L
                                      IV
870.2400
Acute eye irritation -rabbit
                                   46889115
Iritis score of 1 in 1/3 rabbits, conjuctival redness score of 1 in 2/3 rabbits.  All eyes returned to normal after 72 hours.
                                      IV
870.2500
Acute dermal irritation - rabbit
                                   46889114
No dermal irritation, clinical signs or body weight loss
                                      IV
870.2600
Skin sensitization - mouse
                                   46889221
Not a dermal sensitizer
                                   Negative

Table A.2.2	Subchronic, Chronic and Other Toxicity Profile of Chlorantraniliprole
                                Guideline No. 
                                  Study Type
                    MRID No. (year)/ Classification /Doses
                                    Results
870.3050
28 - Day oral toxicity (rat)
46979941, 46979942 (2006)
Acceptable - Nonguideline
0, 300, 1500, 8000 ppm (M: 0, 20.7, 106, 584 mg/kg/d; F: 24, 128, 675 mg/kg/d)
NOAEL = 584/675  (M/F) mg/kg/d
LOAEL not established. F had dose-dependent increase in liver weight and hepatocellular hypertrophy without corresponding histopathological evidence of adverse liver effects.
870.3050
28 - Day oral toxicity (mouse)
46979303 (2003)
Acceptable - Nonguideline
0, 300, 1000, 3000, 7000 ppm  (M: 0, 52, 182, 538, and 1443 mg/kg/d; F: 0, 64, 206, 658, and 1524 mg/kg/d)
NOAEL = 1443/1524  (M/F) mg/kg/d
LOAEL not established. F had dose-dependent increase in liver weight; M and F had dose-dependent increase in CYP content and decreased hepatic β-oxidation at HDT; these effects occurred without corresponding histopathological evidence of adverse liver effects.
870.3100

90-Day oral toxicity (rat)
46889010 (2005) 
Acceptable - Guideline 
0, 600, 2000, 6000, or 20,000 ppm (M: 0, 36.9, 120, 359, 1188 mg/kg/d; F: 0, 47, 157, 460, 1526  mg/kg/d) 
NOAEL = 1188/1526  (M/F) mg/kg/d
LOAEL not established. F had slight increase in liver weight at HDT and dose-dependent decreased bilirubin without corresponding histopathological evidence of adverse liver effects.
870.3100

90-Day oral toxicity (mouse)
46889013 (2006)
Acceptable - Guideline 
0, 200, 700, 2000, or 7000  ppm (M: 0, 32.6, 115, 345, 1135 mg/kg/d; F: 0, 40.7, 158, 422, 1529 mg/kg/d)

NOAEL = 1135/1529  (M/F) mg/kg/d
LOAEL not established. M and F had slight increase in liver weight at HDT but no corresponding histopathological evidence of adverse liver effects. Hyperactivity/ hyperreactivity seen in 1529 mg/kg/d F near end of study and convulsions in one male were not reproducible in 18-month mouse study with FOB (MRID 46979720).
870.3150

90-Day oral toxicity (dog)
46889012 (2004)
Acceptable - Guideline 
0, 1000, 4000, 10,000, and 40,000 ppm (M: 0, 32.2, 119, 303, 1163 mg/kg/d; F: 0, 36.5, 133, 318, 1220 mg/kg/d)

NOAEL = 1163/1220  (M/F) mg/kg/d
LOAEL not established. M had slight increase in liver weight at HDT but no corresponding histopathological evidence of adverse liver effects.
870.3200

21/28-Day dermal toxicity (rat)
46889128 (2006)
Acceptable - Guideline 
0, 100, 300, 1000 mg/kg/d

Systemic NOAEL = 1000 mg/kg/d
LOAEL not established. Increased incidence of adrenal cortex microvesiculation in males was not associated with changes in adrenal function (MRID 48889214) and is not considered adverse.
Dermal irritation NOAEL= 1000 mg/kg/d
LOAEL not established.  
870.3700a

Prenatal developmental in rat
46889108 (2004)
Acceptable - Guideline 
0, 20, 100, 300, 1000  mg/kg/d

Maternal NOAEL = 1000 mg/kg/d
LOAEL not established due to the absence of maternal effects at any dose.
Developmental NOAEL = 1000 mg/kg/d
LOAEL not established due to the absence of developmental effects at any dose.
870.3700b

Prenatal developmental in rabbit
46889109 (2005)
Acceptable - Guideline 
0, 20, 100, 300, 1000  mg/kg/d
Maternal NOAEL = 1000 mg/kg/d
LOAEL not established due to the absence of maternal effects at any dose.
Developmental NOAEL = 1000 mg/kg/d
LOAEL not established due to the absence of developmental effects at any dose.
870.3800

Reproduction and fertility effects  -  
2 generation (rat)
46889107, 46979722 (2006)
Acceptable - Guideline 
0, 200, 1000, 4000, or 20,000 ppm (M: 0, 12.0, 60.4, 238, 1199  mg/kg/d; F: 0, 15.5, 77.8, 319, 1594  mg/kg/d)

Parental/Systemic NOAEL = 1199/1594 (M/F) mg/kg/d
LOAEL not established. Increase in adrenal weights and microvesiculation incidence (M/F) was not associated with changes in adrenal function (MRID 48889214) and is not considered adverse. Increase in liver weight (F) was not associated with adverse effects (MRID 46889010).  
Reproductive NOAEL = 1000 mg/kg/day
LOAEL not established due to the absence of reproductive effects at any dose.
Offspring NOAEL = 1199/1594 (M/F) mg/kg/day
LOAEL not established due to absence of adverse effects in pups during lactation.
870.4100a

Chronic toxicity
(rodents)
Combined chronic / carcinogenicity study available (see below)
870.4100b

Chronic toxicity (dog)
46979718 (2006)
Acceptable - Guideline 
0, 1000, 4000, 10000, or 40000  ppm (M: 0, 32, 112, 317, 1164 mg/kg/d; F: 0, 34, 113, 278, 1233 mg/kg/d)

NOAEL = 1164/1233 (M/F) mg/kg/day
LOAEL not established. M and F had slight increase in liver weight at HDT but no corresponding histopathological evidence of adverse liver effects. 
870.4300a 

Chronic / Carcinogenicity
(rat)
46979719 (2006)
Acceptable - Guideline 
0, 200, 1000, 4000, 20000  ppm (M: 0, 7.71, 39.0, 156, 805  mg/kg/d; F: 0, 10.9, 51.0, 212, 1076 mg/kg/d)

NOAEL = 805/1076 (M/F) mg/kg/d
LOAEL not established. Increase incidence of adrenal microvesiculation (M) was not associated with changes in adrenal function (MRID 48889214) and is not considered adverse. Increase in relative liver weight (F) without corresponding histopathological evidence of adverse liver effects. 
No evidence of carcinogenicity
870.4200

Carcinogenicity
(mouse)
46979720 (2006)
Acceptable - Guideline 
0, 20, 70, 200, 1200, 7000  ppm (M: 0, 2.60, 9.20, 26.1, 158, 935  mg/kg/d; F: 0, 3.34, 11.6, 32.9, 196, 1155   mg/kg/d)
NOAEL = 158/1155 (M/F) mg/kg/d
LOAEL = 935 (M) mg/kg/d based on mild eosinophilic foci in 5/70. A LOAEL in F was not established. M and F (>= 158/196 mg/kg/d) had increase in absolute and relative liver weight and minimal-mild hepatocellular hypertrophy.
No evidence of carcinogenicity
870.5100
Bacterial Reverse Mutation Test 
46889103 (2004)
Acceptable - Guideline 
Initial assay: 8 concs. (2.5 to 5000 ug/plate) 
Confirmatory assay: 5 concs. (50 to 5000 ug /plate)
Negative with and without metabolic activation (S9) in Salmonella strains TA98, TA100, TA 1535 and TA 1537, and in E. Coli WP2 uvrA strain.
870.5100
Bacterial Reverse Mutation Test 
46979921 (2006)
Acceptable - Guideline 
Initial assay: 8 concs. (33.3 to 5000 ug/plate) 
Confirmatory assay: 5 concs. (333 to 5000 ug /plate)
Negative with and without metabolic activation (S9) in Salmonella strains TA98, TA100, TA 1535 and TA 1537, and in E. Coli WP2 uvrA strain.
870.5300 
In vitro Chinese Hamster Ovarian Cell Gene Mutations at HGPRT Locus Test  
46889106 (2004)
Acceptable - Guideline 
0, 15.6, 31.3, 62.5, 125, 250 g/mL
Negative with and without metabolic activation (S9).
870.5375
In vitro Human Lymphocyte Chromosome Aberration Test
46979922 (2006)
Acceptable - Guideline 
0, 50, 100, 500 ug/mL (no S9); 1, 10, 25 ug/mL (w/ S9)

Negative with and without metabolic activation (S9).
870. 5375
In vitro Human Lymphocytes Chromosome Aberration Test 
46889105 (2004)
Acceptable - Guideline 
0, 125, 250, 500 ug/mL 
Negative with and without metabolic activation (S9).
870. 5375
In vitro Human Lymphocytes Chromosome Aberration Test 
46979922 (2006)
Acceptable - Guideline 
0, 1, 10, 25, 50, 100, 500, 1000, 2000, 4831.5 ug/mL 
Negative with and without metabolic activation (S9).
870.5395
Mouse Erythrocyte Micronucleus Assay
46889104 (2006)
Acceptable - Guideline 
0, 500, 1000, or 2000 mg/kg/d
Negative in the bone marrow of M and F Crl:CD-1[(R)](ICR)BR mice.
870.6200a

Acute neurotoxicity screening battery (rat)
46979312 (2004)
Acceptable - Guideline 
0, 200, 700, 2000 mg/kg/d

NOAEL = 2000 mg/kg/day
LOAEL not established due to absence of adverse systemic or neurological effects.
870.6200b

Subchronic neurotoxicity screening battery (rat)
46979721 (2006)
Acceptable - Guideline 
0, 200, 1000, 4000, 20,000 ppm (M: 0, 12.7, 64.2, 255, and 1313 mg/kg/d; F: 0, 15.1, 77.3, 304, 1586  mg/kg/d)

NOAEL = 1313/1586 (M/F) mg/kg/d 
LOAEL not established due to absence of adverse systemic or neurological effects.
870.7485

Metabolism and pharmacokinetics (rat)
46979330 (2006)
Acceptable - Guideline 
10 or 200 mg/kg single dose

Readily absorbed after low (10 mg/kg bw) or high (200 mg/kg bw) single oral gavage.  Plasma levels peak 5-12 hours after dosing. Extensive tissue distribution and low tissue:plasma ratios (<1)  show low potential for accumulation. Tissue levels slightly greater in F than M. Distribution 7 days after low dose: 24-29% urine, 62-64% feces, 0.8-3.3% tissues; after high dose, 3.8-5.2% urine, 91-92% feces, 0.2-0.5% tissues. Urinary excretion slightly greater in M than F. Extensive metabolism characterized by methylphenyl and N-methyl hydroxylation, followed by N-demethylation, nitrogen-to-carbon cyclisation, alcohols oxidation to carboxylic acids, amide bridge cleavage, amine hydrolysis, and O-glucuronidation.
870.7485

Metabolism and pharmacokinetics (rat)
46979331 (2006)
Acceptable - Guideline 
10 mg/kg/d for 4, 8, 11, or 14 days
Tmax 14 days administration in male rats; female rats were near steady state.  After cessation of dosing, readily eliminated from the plasma and tissues.  Tissue distribution at 1 and 7 days similar to that found after single dose and confirmed minimal accumulation potential.  Feces was the predominate route of elimination.  Extensive metabolism consistent with that observed for the single dose study.
870.7800
Immunotoxicity (rat)
46979343 (2006)
0, 1000, 5000, or 20,000 ppm (M: 0, 74, 363,  1494 mg/kg/d; F: 0, 82, 397, 1601 mg/kg/d)
NOAEL = 1494/1601 (M/F) mg/kg/d 
LOAEL not established due to absence of adverse systemic or immune effects.
870.7800
Immunotoxicity (mice)
47231202 (2007)
0, 300, 1700, or 7000 ppm (M: 0, 48, 264, 1144 mg/kg/d; F: 0, 64, 362, 1566 mg/kg/d)
NOAEL = 1494/1601 (M/F) mg/kg/d 
LOAEL not established due to absence of adverse systemic or immune effects.
Special Study
28-day repeated-dose dermal mechanistic study in males (rat)
46889214 (2006)
Acceptable - Non-Guideline
1000 mg/kg/d
Chlorantraniliprole had no effect on adrenal function after ACTH challenge in male rats at a dermal dose that resulted in an increase incidence of adrenal cortical microvesiculation.  
Special Study
Development of methods for evaluation of adrenal cortex (rat)
46979749, 46979927 (2006)
Acceptable - Non-Guideline
Method was able to detect a reduction of ACTH-stimulated serum corticosterone level at a positive control dose that did not alter basal serum corticosterone. In some rats from several studies (28-day dermal, 90-day oral, multigeneration reproduction, 2-year chronic) a slight, treatment-related increased in microvesiculation was observed in zona fasciculata cells of the adrenal cortex.
Special Study
14-day toxicity, metabolism and pharmacokinetics (rat)
46979935 (2006)
Acceptable - Non-Guideline
0, 25, 100, 1000 mg/kg/d
NOAEL = 1000 mg/kg/day
LOAEL not established due to absence of adverse effects.
Decreased absorption was observed at higher doses.  Estimated T1/2 was 3.4 - 4.0 hr. Tmax was 0.25 - 2.75 hr.  Cmax was similar at all dose levels. 
Weak induction of CYP3A in F only. Total CYP in M and β-oxidation in M or F were not altered.
Special Study
28 - Day oral (capsule) toxicity (dog)
46979711 (2003)
Acceptable - Nonguideline
0, 300 or 1000 mg/kg/d
NOAEL = 1000 mg/kg/d
LOAEL not established. An increase in hepatic CYP content at HDT without corresponding histopathological evidence of adverse liver effects.
T1/2 = 8.1-9.3/13.3-17.2 hr (M/F). Cmax  = 2.5-3.0 ug/mL (M and F)
Special Study
28 - Day oral (feed) toxicity (dog)
46979713 (2003)
Acceptable - Nonguideline
Group 1: 1000 (Wk 1), 5000 (Wk 2), 10,000 (Wk 3-4) ppm; 
Group 2: 30,000 (Wk 1-2) 40,000 (Wk 3-4) ppm 
(M: 0, 26, 138, 266, 797, 1302 mg/kg/d; F: 0, 28, 138, 298, 888, 1240 mg/kg/d)
NOAEL = 1302/1240 (M/F) mg/kg/d
LOAEL not established due to absence of adverse effects.
Palatability of the diet was not affected by inclusion of the test material
F = females; M = males; HDT = highest dose tested; dose-dependent = a change was observed in at least the two highest doses; CYP = cytochrome P450 enzymes; CYP3A = CYP isoenzyme 3A; Cmax = maximum (i.e. steady-state) serum concentration; Tmax = time at maximum serum concentration; T1/2 = half-life in serum, i.e. time at half of maximum serum concentration. Wk = week
Appendix B.  Physical/Chemical Properties

Table B.   Physicochemical Properties of Technical Grade of Chlorantraniliprole.
Parameter
Value
Reference (MRID)
Melting point/range (°C)
200-202 (95.9%)/208  -  210 (99.2%)
46889033
pH
5.77 +- 0.087 at 20°C
46889031
Relative Density
1.5189 (95.9%)/1.507 (99.2%) at 20°C
46889033
Water solubility (20°C)

Deionized Water            1.023 mg/L
pH 4                                0.972 mg/L
pH 7                                0.880 mg/L
pH 9                                0.971 mg/L
46889026

Solvent solubility (20°C)
Acetone                          3.446 +- 0.172 g/L
Acetonitrile                     0.711 +- 0.072 g/L
Ethyl Acetate                  1.144 +- 0.046 g/L
Dichloromethane            2.476 +- 0.058 g/L
Dimethylformamide        124 +- 4 g/L
n-Octanol                        0.386 +- 0.01 g/L
Methanol                         1.714 +- 0.057 g/L
n-Hexane                         <0.0001 g/L
o-Xylene                          0.162 +- 0.01 g/L
46889030

Vapor pressure
6.3 x 10-12 Pa @ 20°C, 2.1 x 10-11 Pa @ 25°C
46889130
Dissociation constant, pKa
10.88 +- 0.71
46889034
Octanol/water partition coefficient, KOW (20°C)
Deionized Water              589
pH 4                                 588
pH 7                                 721
pH 9                                 654
46889032
UV/visible absorption (max)
pH <2 no absorption max >200 nm, at 290 ε = 3941
pH 7 no absorption max >200 nm, at 290 ε = 4185
pH >10 absorption max at ~320 nm which may be
due to decomposition of DPX-E2Y45, at 290 ε = 6082
46889027

Structures of Chlorantraniliprole and Possible Metabolites
 
          Structures of Chlorantraniliprole and Possible Metabolites.
Chemical Name; Company Code
                                   Structure
3-Bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide
Chlorantraniliprole
DPX-E2Y45

                                       
3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid
IN-DBC80

                                       
2-[3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-3, 8-dimethyl-4(3H)-quinazolinone
IN-EQW78

                                       
5-Bromo-N-methyl-1H-pyrazole-3-carboxamide
IN-F6L99

                                       
N-[2-(Aminocarbonyl)-4-chloro-6-methylphenyl]-3-bromo-1-(3-chloro-2-pyridinyl)1H-pyrazole-5-carboxamide
IN-F9N04

                                       
2-[3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4(3H)-quinazolinone
IN-GAZ70

                                       
3-Bromo-N-[4-chloro-2-[[(hydroxymethyl)amino]carbonyl]-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide
IN-H2H20

                                       
N-[2-Aminocarbonyl]-4-chloro-6-(hydroxymethyl)phenyl]-3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide
IN-HXH40

                                       
3-Bromo-N-[4-chloro-2-(hydroxymethyl)-6-[(methylamino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide
IN-HXH44

                                       
2-[3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-(hydroxymethyl)-4(3H)-quinazolinone
IN-K7H29

                                       
3-Bromo-N-[4-chloro-2-(hydroxymethyl)-6-[[(hydroxymethyl)amino)carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxamide
IN-K9T00

                                       
6-Chloro-1, 2, 3, 4-tetrahydro-2, 4-dioxo-8-quinazolinecarboxylic acid
IN-K9X71

                                       
2-[[[3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]carbonyl]amino]-5-chloro-3-[(methylamino)carbonyl]benzoic acid
IN-KAA24

                                       
2-Amino-5-chloro-3-[(methylamino)carbonyl]benzoic acid
IN-L8F56

                                       
IN-E5F18
                                 Not provided