Chlorantraniliprole Human Health Risk Assessment DP No. 411938

UNI TE D STATES ENVIRONM EN TAL PROT ECT ION AGENCY
WASHINGTON, 

### D.C. 20460

MEMORANDUM

Date: May 12, 2013 OFFICE OF CHEMICAL S AFETY AND POLLUTION P REV ENTION

SUBJECT: Chlorantraniliprole: Human Health Risk Assessment for Proposed Uses on Cereal Grains Group 15 (except Rice) and Cereal Grains Forage, Fodder, and Straw Group 16

, and Conversion of Citrus and Pome Fruit Groups.

PC Code: 090 I 00
Decis i on No.: 4Q7.)21

Petition No. : 2E8064 Risk Assessment T y pe: Single Chemical, Aggregate TXR No.: NA MRID No.: NA

FROM: Sheila Healy, Risk Assessor Steve Funk, Senior Chemist Kristin Rury, Biologist Ri sk Assessment Branch Ill Health Effects Division (7509P)

THROUGH: Christine Olinger, Chief Ri s k Assessment Branch I H ealth Effects Division 50 DP Barcode: 411938 Registration No.: 352-728

, 352-729,352 -730 and 352- 844 Regulatory Action: Section 3 Registration Case No.: NA CAS No.: 500008-45-7 40 CFR: 180.628

TO: Barbara Madden/Sidney Jackson (RM 05) Risk Integration

, Minor Use & Emergency Response Branch Registration Division (7505 P )

Page 1 of30Chloran t ranilipro l e Human Hea lth Ri s k Assessment DP No . 4 11938

1.0 Executive Summary

. .. . ......... . ......... . .......... .. ......... . ..... .. . .. . . . .. .. . .. .. ... . .. .. . . . .. ... . . . ... . ........ . ....... 4 2

. 0 Regu l atory Conclusions and Recommendations

. . . .. . .. .. . ... . .. . .. . ............................ . . . .. .. . . .. . 6 2.1 Data Deficiencies/Conditions of Registra t ion

. ........... . ..... . ... . .. . .. ... .. .. .. . ... . ... . ... . .. .... . ..... 6 2

. 2 Tolerance Considerations

. .. . ........ .. ........ . . .... . .. ... . . . . . .. .. .. .. .. . . .. . . .. .. . ...... . .......... . ................ 6 2.2. 1 Enforcement Analytica l M e thod

. .. .. .. . ... . ....... . .. . ................ . .. .... . .. . ... . ... . . .. .. .. .. .. .. .. . . ... . 6 2

. 2

. 2 International Harmonization

.. . ... . ... ... . . ... .. .. .. . . . . . . .. . .. .. .. ... . .. .. . .. ... . ............ . .................. 6 2.2.3 Recommended To l erances

. .. .. . ... .. .. .. . .. . . . . ... . ... . .......... . ..... . . ... . . ... ... . .. .. ... . ... . ... . ... . . .. .. ... . 6 2.2.4 Revisions to Petitioned

- For Tolerances

................ .. .. .. .. .. . . .. . .. .. ... . .. .. .. . . .. .. ... . .. ... . ... . . . . 9 2.3 Labe l Recommendations

. .... .. .. .. . . .. . . .. . ... . .. . . .. .. .. .. .. . . .. . . . . . . .. .. . ... . .......... . ........... . . . .... . ......... 9 3.0 Introduction

. .. .. .. . .. .. .. . .. .. .. .. . .. .. .. .. . .. .. . .. ... ............................ . ..................... . ... . .. . .. . . . . .. ... . .. ... . . 9 3

. 1 Chemical Identity

....... . ..... . .......... .. . . . ..... ... .. . . . . . ... . . . .. .. .. .. .. .. .. . . .. . .. ... .. .. .. .. .. . . .. . . .. . . . ... . . ....... 9 3

. 2 Physical/Chemical Characteristics

.......... .. .......... . ..... . .... . .................. . . ... . . . . ... . .. ... ....... 1 0 3.3 Pesticide Use Pattern

................. . ..... . .. .. ..... .. .. .. .. .. .. .. .. .. .. . . . . .. . ... . ... .. . .. .. . . . . . . .. ... .. .. .. .. .. .. .. . 1 1 3

. 4 Anticipated Exposure Pathways

. .. . .. .. .. .. . . . ............... . ...... . ..................... . ... .. ................ 1 4 3.5 Consideration of Environmental Justice

. .. .. ....... .. . . . .. .. . ... . . . .. .. ... . .. .. . ... .. ... . ... . ... . .. .. .. .. .. 14 4

. 0 Hazard Characterization and Dose

- Respons e Assessm e nt

....... . . . ..... . ........................ . . 14 4

. 1 Summary of T oxicological Effects

. . ....................... . ....... ... .. .. .. . ... . .. ... . . .... . .. .. . . .. . . . . . .. . . . . 1 4 4

. 2 Safety factor for Infants and Children (FQPA Safety Factor)

. .. .. . . . . . . .. . . . ... . ...... . ..... 15 4

. 2

. 1 Completeness of the Toxico l ogy Database

... . ......... .. ...... .. ... . ........................... .. .. . ... 16 4.2

. 2 E vidence of Neurotoxicity

. . . ... . .... . . .. . . . .. .. ... . .. .. . . . . . .. .. . ... .. . . .. . . .. . . . . . . .. . .. . . ... . . .. . . .. .. . . . .. . . .. 16 4

. 2

. 3 E vidence o f Sensitivity/Susceptibility in the Develo p ing or Young Animal..

. .. .. . 16 4

. 2.4 Residual Uncertainty in th e Exposure Database

................................................... 16 4.3 To x icity Endpoint and P o int of Departu r e Selections

... . ... .. ...... . ... . .. .. .. .. .. . . .. . . . .. . . .. .. . 16 5

. 0 Dietary E xposure and Risk Assessment

.. .. .. .. .. .. .. . ... . ... . .. . . . .. . .. .. ...... .. .. .. .. .. .. .. .. .. ... .. . ... .. . .. 17 5

. 1 Residues of Conce r n Summary and Rat i ona l e .

. ... . .... . .... .. .. . .... . ..... . . . ... .. ....... . .. ... . . . ... . 17 5.2 Food Residue Profile

. . .. . .. .. .. .. .. .. . . . . . . . .. ... . . ... . . .. .. .. . ... ... . .. . . ..... . ... . ... . . .. ... . . . . .. . ... .. .. .... . . . . . . .. 18 5.3 Water Residue Profile

.................................... . .... . .................. .. .......... . ......................... 19 5.4 Dietary Risk Assessment

. .. .. . .. .. .. . .. .. .. . ... . ... . ... . ... . .. . . .. .. . . . . .. . . .. .. .. . ... . ... . ... . .. . . ... . ... . ... . ... . ... 19 5.4.1 Description of Residue Data Used in Dietary Assessment

.... . .. . ....... . .... . ........... .. .. 1 9 5.4

. 2 Acute Dietary Risk Assessment

. . .. .. .. . .. .. .. . . .. . . .. .. .. . . . ... . . . . .. . .. .. .. .. .. .. . . . . .. .. .. .. .. .. ... . ... . .. . 20 5.4.3 Chronic Dietary Risk Assessment

. ...................... .. ..... .. .............. . ......................... . .. 20 5.4

. 4 Cancer Dietary Risk Assessment.

. . . .. ... . . ... . . . . . .. .. . ... .. . . . ... . .. . ... .. .. . ... . . . ..... . ...... . .. . ........ 20 5

. 4.5 Summary Table

. . ... . . .. .. ... . . .. .. .. ... . .. . .. .. ... . .. .. .. .. . ... .. .. .. .. . ... . ... . .. . . ...... .. .. .. .. . ... .. .. .. .. .. .. .. .. . 20 6.0 Residential (Non

- Occupational) Exposure/Risk Character i zation

.. .. . ... . ........ . ........... 21 6. 1 Residential H andle r Exposu r e

...... .. ..... . ..... . ................ . . . ....................................... . ..... 2 1 6.2 Post

- Application Exposure

. .. .. .. . . . ... . .. .. .. .. .. .. . ... . .. . . . . ... . . . .... . ... .. . .. .. ... .. .. . . . . . . . .. .. ... . . . ... . .. . . 21 6.3 Combined Exposure

.. . . . .. .... . .. .. .. . . . . . ... . .. .. .. . ... . . .. .. . . . ... . .. .. .. . ... .. .. . . . . . . . .. .. . . ... . .. .. .. .. .. .. .. . . .. .. 21 6.4 Residen t ial Bystander Postappli c ation Inhalation Exposu r e

.......... . ............... . .. . ..... 21 6

. 5 Spray Drift

...... .. ........ .. . ... . .. .. . .. .. .. .. . ... .. . ...... .. .. .. . . .. .. .. .. .. . . .. . ... . ... . ... . .. .. .. .. .. . ... . ... . ... .. .. .. .. .. 22 7.0 Aggregate Exposure/Risk Characte r ization

.............. . .......... . .. . ............ . .................. . ... . . 22 8.0 Cumulative Exposure/Risk Characterization

.. .. .. . . .. . ... . .. .. .. .. .. .. .. . . .. .. .. .. .. . ... . ... . . . . . ... .... . . 23 9

. 0 Occupational Exposure/Risk Characterization

. .. ............. . ... . .......... . ... .. .. . .. . . . . . ..... . ...... . 23 10

. 0 References

.. .. . .. .. . . . .. . .. .. .. .. . .... . . . . . ... . ..... . . . ..... .. .... . ... . . . ........... . . . . . . . .. . .......... . .......................... 23 Appendix A. Toxicology Profile

........ . .... . ... . .... . .... . ... . .... .. .. . ..... . . . ... . . . . . .. .. ...... .. . .. . . .. ... . ... .. .. .. . ... . .. 25 A. l Toxicology Data Requirements

. . .. ... . .. .. .. . ... . . .. . ....... . .. . ... .. . .. ... . .. . . . ..... . . . . . . ... . ......... . ..... . . 25 A.2 Toxicity Profiles

. .... . ......... . ...... . ... . ... . ... . .... . . .. . .. . . .. ... . .. .. . . . .. ... . .. .. .. .. .. . ... . .. . . .. .. .. . . .. .. ... . ... . .. 26

P age 2 of30Chlorantraniliprole Human Health Risk Assessment DP No. 411938

Page 3 of 30 Appendix B. Physical/Chemical Properties

................................ ................................ ............. 30Chlorantraniliprole Human Health Risk Assessment DP No. 411938

Page 4 of 30 1.0 Executive Summary

Chlorantraniliprole (DPX

- E2Y45) is a n anthranilic diamide insecticide that belongs to a class of compounds that acts on the ryanodine receptor . It is an insecticide that was developed and registered by E.I. d u Pont de Nemours and Company (DuPont) for control of lepidopteran pests and controls many insects primarily via interruption of normal muscle contraction pathways, which leads to paralysis and eventua l death of the pest.

On behalf of E.I. du Pont de Nemours and Company (DuPont), the Interregional Research Project No. 4 (IR

- 4) of Rutgers University has submitted a petition for tolerances and a Section 3 registration of chlorantraniliprole for use on cereal grains group 15 except rice and cereal grain fora g e, fodder, and straw group 16. Updating of the citrus fruit group 10 to 10

- 10 and the pome fruit group 11 except mayha w to the pome fruit group 11

- 10 was also requested

. Concurrent with these chang es, the revocation of existing tolerances for field corn commodities, pop corn commodities, and sweet corn commodities is requested. These commodities are members of the cereal grain group 15. The revocation of the mayhaw tolerance is also requested. Th e latter commodity is covered by group 10

- 10.

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 this registration request for use on cereal grains are a 5 % active ingredient (ai) suspension concentrate (SC) Prevathon ® Insect Control (0.43 lb ai per gallon, or 0.053 kg ai/l)

, EPA Reg. No. 352

- 844, a 18 .4% active ingredient (ai) suspension concentrate (SC) Coragen ® Insect Control (1.67 lbs ai/gallon or 0.200 kg ai/l)

, EPA Reg. No. 352

- 729 , and a 35.0% active ingredient (ai) water dispersible granular (WDG) Altacor ® (35 lb ai/100 lb) EPA Reg. No. 352

- 730. Chlorantraniliprole may be applied via drip irrigation, ground, handheld and aerial application methods. There is potential for short

- and intermediate

- term occupational exposure from the uses of chlorantraniliprole on the proposed crops. Chlorantranil iprole is also registered for use in residential settings on turf, landscape ornamentals and interio rscapes. C hlorantraniliprole may also be used on golf courses and sod farms.

Hazard Characterization HED has concluded that sufficient toxicology informa tion exists f o r c hlorantraniliprole for selecting doses and endpoints needed for assessing its risk to humans when used as an insecticide. Chlorantraniliprole is not genotoxic, neurotoxic, immunotoxic, carcinogenic, or developmentally toxic

. Chlorantrani liprole is classified as Acute Toxicity Category IV for oral toxicity, dermal toxicity, inhalation toxicity, eye irritation, and primary skin irritation. C hlorantraniliprole is not a dermal sensitizer. There was only one animal toxicity study (18

- month c arcinogenicity study in mice) in the toxicology database which evidenced an y adverse effect of chlorantraniliprole exposure. This study was used to establish a point of departure (POD)

, based on hepatocellular effects

, for the chronic dietary exposure scenario. A lthough residential and occupational exposure is expected over the short

- and intermediate

- term (via theChlorantraniliprole Human Health Risk Assessment DP No. 411938

Page 5 of 30 dermal and/or incidental oral route), there is no hazard expected via these routes/durations, and

, theref ore , no risk associated with these scenarios

.

HED recommend s that the FQPA SF be reduced to 1X because 1) the toxicology database for chlorantraniliprole is complete for the purposes of this risk assessment and the characterization of potential pre

- and p ostnatal risks to infants and children is adequate ; 2) no susceptibility was identified in the toxicological database, and there are no residual uncertainties with respect to
pre

- and/or postnatal exposure ; 3) there were no treatment

- related neurotoxic find ings in the acute

or subchronic ora l neurotoxicity studies in rats ; and 4) the exposure assessment is protective: the dietary food exposure assessment utilizes tolerance level residues for all commodities and assumes that 100% or the registered and propose d crops are treated with chlorantraniliprole ; the drinking water assessment utilizes values generated by models and associated modeling parameters which are designed to provide conservative, health protective, high

- end estimates of water concentration s.

Dietary Risk Estimates (Food + water) An acute assessment was not performed as n o acute dietary toxicity endpoint could be identified based on the toxicology data currently available for chlorantraniliprole.

A conservative chronic dietary risk assessment was conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID TM , Version 3.16 ) . DEEM TM default processing factors and 100% crop treated (CT), and tolerance

- level residues were assumed for all commodities. Drinking water was incorporated directly into the dietary exposure assessment using the chronic EDWC of 39

. 87 μ g/L for surface water ( non

cancer, 1 in 10 year annual mean )

. The chronic dietary risk assessment shows that the chronic dietary risk estimates do not exceed HED ’s level of concern [i.e., <100% of the chronic population

- adjusted dose (cPAD)]. For the general U.S. population

, the exposure for food and water utilized approximately 2 % of the cPAD. The chronic dietary risk estimate for the highest exposed population subgroup, children 1

- 2 years old, is 6

. 3 % of the cPAD

.
Aggregate Risk Acute and cancer aggregate risks were not assessed due to the absence of an acute dietary endpoint and to the fact that chlorantraniliprole is not likely to be carcinogenic to humans

. The chronic aggregate risk assessment for chlorantraniliprole includes exposure to residues in food and water. N o risk is expected from residential exposures or from spray drift.

Occupational Risk There is a potential for occupational short

- and intermediate

- term inhalation and dermal exposure to chlorantraniliprole during mixing, loading, application, and postappl ication activities. However, the chlorantraniliprole toxicology database indicates there is no systemic hazard associated with short

- and intermediate

- term dermal and inhalation exposure, and therefore, no occupational exposure and risk assessment was con ducted.

Environmental JusticeChlorantraniliprole Human Health Risk Assessment DP No. 411938

Page 6 of 30 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

2.1 Data Deficiencies /Conditions of Registration

None

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

A d equate method s are available for the enforcement of tolerances for chlorantraniliprole residues in/on crops ( liquid chromatography with tandem mass spectrometric detection ( LC/MS/MS ) ; Method DuPont

- 11374). . The limit of quantification (LOQ) is reported at 0.01 ppm for parent chlorantraniliprole. The method for the determination of chlorantraniliprole and its metabolites in processed commodities is an LC

- MS/MS method, DuPont

- 14314, which is a slightly modified version of DuPont

- 11374.

The enforcement method for livestock commodities is an LC

- MS/MS method

. The LOQ is reported at 0.010 pp m for parent and each of the metabolites. The described plan t and animal methods have been reviewed and accepted by Agency chemists in the Analytical Chemistry Branch (ACB) of the Biological and Economic Analysis Division (BEAD) (D P# 340358, C. Stafford, 0 2/ 0 6/08).

The requirements for multiresidue methods data are fulfilled. Chlorantraniliprole is not recovered by the U.S. Food and Drug Administration’s (FDA’s) multiresidue methods

.

2.2.2 International Harmonization

CODEX and Canada ha ve established chlorantraniliprole maximum residue limits ( MRLs ) for a number of crop and animal commodities

. There are no Mexican MRLs for chlorantra niliprole as Mexico adopts Codex or US standards for its export purposes . Canada does not have MRLs for cereal grains, so there is no issue of harmonization relevant to this petition. The Codex MRL for cereal grains is significantly lower than the recommended US tolerance for cereal grain. The US tolerance cannot be harmonized (lowered), as this would create a possible situation of tolerance violation from use accordin g to the the labels. In general US tolerances for livestock commodities are not harmonized with Canada or Codex. Again, US values are higher and result from the increased exposure in livestock diets from treated cereal grain crops.

2.2.3 Recommended To lerancesChlorantraniliprole Human Health Risk Assessment DP No. 411938

Page 7 of 30 Tolerances are established under 40 CFR §180.628 for residues of the insecticide chlorantraniliprole

, including its metabolites and degradates , in or on the commodities in Table 2.2.3 below. Compliance with the tolerance levels specified below i s to be determined by measuring only chlorantraniliprole, 3

- bromo

- N

- [4

- chloro

- 2

- methyl

- 6

- [(methylamino)carbonyl]phenyl]

- 1

- (3

- chloro

- 2

- pyridinyl)

- 1 H

- pyrazole

- 5

- carboxamide

. Pending revisions to Section F, HED has no objections to the establishment of tole rances for Cereal Grains, Except Rice (Crop Group 15), Cereal Grain Forage (Crop Group 16), Pome Fruit (Crop Group 11

- 10) and citrus (Crop Group 10

- 10). With the establishment of these subgroup tolerances, a number of individual grain forage, fodder, and or/straw tolerances and inadvertent tolerances need to be removed. See Table 2.2.3 for a list of recommended tolerances and tolerance revocations

.

Table 2.2.3 . Tolerance Summary for Chlorantraniliprole. Commodity Existing Tolerance (ppm) Proposed

Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity

Definition

180.628 (a) General Grain, cereal, group 15, except rice - 6.0 6.0 Grain, cereal, group15, except rice and corn. Field corn grain, pop corn grain, and sweet corn must be excluded from the group as their residues are much lower than 6.0 resulting from the barley grain. Grain, cereal, forage, fodder and straw, group 16 - 30 40 OECD statistical calculation based

on barley straw.

Fruit, citrus, group 11 1.4 Remove Remove Replaced by group 11

- 10 Fruit, citrus, group 11

- 10 - 1.4 1.4 Crop group conversion.

Fruit, pome, group 11, except mayhaw 1.2 Remove Remove Replaced by group 11

- 10

Mayhaw 1.2 Remove Remove Replaced by group 11

- 10 Fruit, pome, group 11

- 10 - 1.2 1.2 Crop group conversion.

Field corn forage 14 Remove Remove Replaced by crop group 16 Field corn grain 0.04 Remove 0.04 Retain, as 0.04 differs from the crop group 15 tolerance by a factor >5X.
Field corn milled byproducts 0.1

- 0.1 Corn, field, milled byproducts Retain, in accordance with the retention of the field corn grain tolerance. Pop corn gra i n 0.04 Remove 0.04 Corn, pop, grain Pop corn grain cannot be included in group 15 (see grain, cereal, group 15 except rice and corn)Chlorantraniliprole Human Health Risk Assessment DP No. 411938

Page 8 of 30 Table 2.2.3 . Tolerance Summary for Chlorantraniliprole. Commodity Existing Tolerance (ppm) Proposed

Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity

Definition

Pop corn forage 14 Remove Remove Replaced by crop group 16 Pop corn stover 14 Remove Remove Replaced by crop group 16 Sweet corn forage 14 Remove Remove Replaced by crop group 16 Sweet corn kernels plus cob with husk removed 0.02 Remove 0.02 Corn, sweet, kernel plus cobs with husk removed Sweet corn cannot be included in group 15 (see grain, cereal, group 15 except rice and corn)
Sweet corn stover 14 Remove Remove Replaced by crop group 16 Cattle, liver 0.3

- Remove Replace with Cattle, meat byproducts Liver is grouped with other meat byproducts. Cattle, meat byproducts, except liver 0.2

- 0.5 Cattle, meat byproducts Cereal grain group 15 and group 16 elevated the cattle dietary
exposure. Milk 0.05

- 0.1 Cereal grain group 15 and group 16 elevated the cattle dietary
exposure Goat, liver 0.3

- Remove Replace with Goat , meat byproducts Liver is grouped with other meat byproducts. Horse, liver 0.3

- Remove Replace with Horse , meat byproducts Liver is grouped with other meat byproducts. Sheep, liver 0.3

- Remove Replace with Sheep , meat byproducts Liver is grouped with other meat byproducts. Hog, meat byproducts 0.02

- 0.05 Cereal grain group 15 elevated the hog dietary exposure. Goat, meat byproducts, except liver 0.2

- 0.5 Goat, meat byproducts

Horse, meat byproducts, except liver 0.2

- 0.5 Horse , meat byproducts

Sheep, meat byproducts, except liver 0.2

- 0.5 Sheep , meat byproducts

Hog, meat

- - 0.02 Cereal grain group 15 elevated the hog dietary exposure. Hog, fat 0.02

- 0.05 Cereal grain group 15 elevated the hog dietary exposure. Eggs 0.2

- 1.0 Cereal grain group 15 elevated the laying hen dietary exposure.Chlorantraniliprole Human Health Risk Assessment DP No. 411938

Page 9 of 30 Table 2.2.3 . Tolerance Summary for Chlorantraniliprole. Commodity Existing Tolerance (ppm) Proposed

Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity

Definition

Poultry, meat byproducts 0.02

- 0.2 Cereal grain group 15 elevated the laying hen dietary exposure. Poultry, meat

- - 0.05 Cereal grain group 15 elevated the laying hen dietary exposure. Poultry, fat 0.01

- 0.2 Cereal grain group 15 elevated the laying hen dietary exposure. 180.628(d) Indirect or inadvertent residues Grain, cereal, forage, fodder and straw, group 16 0.20 Expires 04/10/14 Remove Replaced by crop group 16 as a primary crop.

2.2.4 Revisions to Petitioned

- For Tolerances

The cereal grain group 15 except rice proposal of 6.0 ppm is not acceptable. EPA is recommending a tolerance of 6.0 ppm for group 15 except rice and except corn. The existing tolerance for pop corn (0.04 ppm), sweet corn ( 0.02 ppm), and field corn ( 0.04 ppm) are much lower than the 6.0 ppm appropriate for other cereal grains. Therefore the group 15 tolerance will exclude corn (including field corn, pop corn, and sweet corn) , and the existing tolerances for corn grain s will remain.

The cereal grain fora ge, fodder, and straw group 16 proposal of 30 ppm is not acceptable. EPA is recommending establishment of a 40 ppm tolerance based on the analysis of the field trial data with the OECD tolerance calculation procedure.

The tolerances for certain livestoc k commodities will need to be created or increased because the expansion of use to more cereal grains and cereal grain forages, fodders, and straws increased the dietary exposure of livestock to chlorantraniliprole. Additionally , the tolerances for the li ver of cattle, goat, horse, and sheep are replaced by tolerances for meat byproducts. These are detailed in Table 2.2.3

2.3 Label Recommendations

There are no label recommendations for this tolerance petition.

3.0 In troduction

3.1 Chemical IdentityChlorantraniliprole Human Health Risk Assessment DP No. 411938

Page 10 of 30 Table 3.11. 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

- b Bromo

- N

- [4

- chloro

- 2

- methyl

- 6

- [(methylamino)carbonyl]phenyl]

- 1

- (3

- chloro

2

- p yridinyl)

- 1 H

- pyrazole

- 5

- carboxamide CAS registry number 500008

- 45

- 7

End

- use product (EP) Altacor ® WG (35%; EPA Reg. No. 352

- 730) DuPontTM Coragen® SC Insect Control ( 1.67 lb ai/gal; EPA Reg. No. 352

- 729)

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 ) and K OW (~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 envir onments. Major routes of chlorantraniliprole dissipation are expected to be alkaline

- catalyzed hydrolysis, photodegradation in water, leaching, and runoff.Chlorantraniliprole Human Health Risk Assessment DP No. 411938

Page 11 of 30 3.3 Pesticide Use Pattern

For the proposed Section 3 registrations addressed herein there are two end

- use products, two suspension concentrates and one water dispersible granule. Proposed labels have been provided for a 5% active ingredient (ai) suspension concentrate (SC) Prevathon ® Insect Control (0.43 lb ai per gallon, or 0.053 kg ai/l) EPA Reg. No. 352

- 844, a 18.4% active ingre d ient (ai) suspension concentrate (SC) Coragen ® Insect Control (1.67 lbs ai/gallon or 0.200 kg ai/l) EPA Reg. No. 352

- 729, and a 35.0% active ingredient (ai) water dispersible granular (WDG) Altacor® (35 lb ai/100 lb) EPA Reg. No. 352

- 730. Changes to the Altacor® label involve only crop conversions. The WDG formulation is not proposed for use on cereal grains. The summary of the relevant proposed uses is presented in Table 3 .3

.Chlorantraniliprole Human Health Risk Assessment DP No. 411938

Page 12 of 30 .

Table 3 .3 : Proposed Use Pattern for (SC) Prevathon ® Insect Control and (SC) Coragen ® Insect Control

Crop Group Crop Appl. Type Max # of Appl. Volume

(g al/A) [L/ha] Rate/Appl.

(lb ai/A) [ k g ai/ha] Max.

Rate/Season (lb ai/A) [ k g ai/ha] Min.

RTI (d ays) PHI

(d ays) Comment

Cereal grains group 15, except rice, except corn Barley

Buckwheat Pear millet Proso millet Oats Rye Sorghum (milo) Sorghum (grain sorghum, sudangrass) Teosinte Triticale Wheat Wild rice foliar 4 N/S 0.047

– 0.067 (0.053

– 0.075) 0.20

(0.22) 7 14 Minimum 5 gpa
water for aerial for Coragen and 2 gpa water for Prevathon, 10 gpa for ground application. May be applied by ground, aerial, overhead sprinkler irrigation. Adjuvants allowed.

Corn (sweet) 1
Corn (seed) 1 Sweet corn

Seed corn Soil at

planting

In

- furrow
spray 4 N/S 0.067

– 0.098 (0.075

– 0.11) 0.20

(0.22) 1 1 Minimum 5 gpa water for aerial for Coragen and 2 gpa water for Prevathon, 10 gpa for ground application. May be applied by ground, aerial, overhead sprinkler irrigation. Adjuvants allowed. Foliar N/S 0.047

– 0.067 (0.053

– 0.075)

Corn (field) 1 Corn (pop) 1 Field corn

Pop corn Soil at

planting

In

- furrow
spray 4 N/S 0.067

– 0.098 (0.075

– 0.11) 0.20

(0.22) 7 14 Minimum 5 gpa water for aerial for Coragen and 2 gpa water for Prevathon, 10 gpa for ground Foliar N/S 0.047

– 0.067 (0.053

– 0.075)Chlorantraniliprole Human Health Risk Assessment DP No. 411938

Page 13 of 30 Table 3 .3 : Proposed Use Pattern for (SC) Prevathon ® Insect Control and (SC) Coragen ® Insect Control

Crop Group Crop Appl. Type Max # of Appl. Volume

(g al/A) [L/ha] Rate/Appl.

(lb ai/A) [ k g ai/ha] Max.

Rate/Season (lb ai/A) [ k g ai/ha] Min.

RTI (d ays) PHI

(d ays) Comment

application. May be applied by ground, aerial, overhead sprinkler irrigation. Adjuvants allowed
1 Consistent with existing approved labels for Coragan ® Registration No. 352

- 729 (05/15/2011) and for Prevathon ® Registration No. 352

- 844 (11/08/2011).Chlorantraniliprole Human Health Risk Assessment DP No. 411938

Page 14 of 30 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 resident ial 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/environmentaljust ice/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 fr om 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 subgr oups 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 toddlers, 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

- Respo nse 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

, 05 / 17 / 12

, D399493 ).

4.1 Summary of Toxicological EffectsChlorantraniliprole Human Health Risk Assessment DP No. 411938

Page 15 of 30 Chlorantraniliprole is an anthranilic diamide insecticide that belongs to a class of compounds that acts on the ryanodine receptor (RyR) . It control s lepidopteran pests and insects primarily via interruption of normal muscle contraction pathways, which le ads to paralysi s 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 studies, the most consistent effects are those associated with non

- adverse pharmacological response to the xenobiotic, induction of liver enzymes and subsequent increase in liver weights. In a 28

- day dermal toxicity study in rats, increased microvesiculation of adrenal cortex was observed in males only, with no ligh t or electronic microscopic evidence of adrenal cellular degeneration or toxicity. Supporting data demonstrated n o effect on the capacity of the adrenal gland to produce corticosterone under either basal or following ACTH stimulatio n. Therefore, adrenal cortex effects observed in the dermal toxicity study were not considered adverse

. Chlorantraniliprole is not genotoxic, neurotoxic, immunotoxic, carcinogenic, or developmentally toxic. Furthermore, it does not exhibit pre

- or postnatal toxicity as there were no maternal or fetal effects in studies conducted in rats and rabbits. Based on the results of a 28

- day dermal study in rats, as well as the dermal LD 50 study, DPX

- E2Y45 has relatively low dermal toxicity. Chlorantraniliprole is not acute ly toxic vi a the oral, dermal, and inhalation routes of exposure. The LD 50 for oral and dermal acute exposure is ≥5000 mg/kg/day and the LC 50 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 e xposure

.
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 ranged from 38

- 82 hours. Tissue distribution of the absorbed dose was extensive and indicated low potential for accumulation. The tissue residues were highe r in female rats than in male rats, which is consistent with female rats having a longer elimination half

- life and higher area under the curve ( AUC) in plasma. Excretion in both high

- and low

- dose groups was substantially complete by 48

- 72 hours after dos ing. Fecal excretion was the primary route of elimination followed by 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 a lso 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 s tructures for these compounds can be found in : S . Healy, 02/28/11, D381810)

. Based on studies conducted in rats, dermal penetration of chlorantraniliprole (20SC and 35WG formulations) is less than 3%.

4. 2 Safety factor for Infants and Children (FQPA Safety Factor)Chlorantraniliprole Human Health Risk Assessment DP No. 411938

Page 16 of 30 Based on the hazard and exposure data, the HED chlorantraniliprole risk assessment team recommend s t hat the FQPA SF be reduced to 1X

. The rationale for this recommendation is provided in the following sections.

4. 2 .1 Completeness o f the T oxicology 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 postnatal risks to infants and children. Acceptable developmental toxicity and 2

- generation reproduction studies have been submitted and reviewed , as well as a complete neurotoxicity screening battery and immunotoxicity study.

4. 2 .2 Evidence of N eurotoxicity

No evidence of neurotoxicity was observed in studies conduct ed with chlorantraniliprole in rats. The 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 (grea ter 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 oncog enicity 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

- t erm or long

- term exposure studies in rats, mice, or dogs.

4. 2 .3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

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 weig hts, skeletal ossification, and external, visceral, or skeletal malformations or variations.

4. 2 .4 Residual Uncertainty in the Exposure Datab ase

There are no residual uncertainties in the exposure database. Since the dietary and non

- dietary
exposure e stimates were based on several conservative assumptions, HED does not believe that the exposure estimates are underestimated. The chro n ic dietary assessment utilized tolerance level residues for all crops and assumed that 100% crop of the proposed and reg istered crops

were treated with chlorantraniliprole

. D efault processing factors were used as appropriate. The DEEM

- FCID analysis also assumed that all drinking water will contain chlorantraniliprole at the highest EDWC levels modeled by EFED for ground w ater or surface water. For these reasons it can be concluded that the DEEM

- FCID analysis does not underestimate risk from chronic exposure to chlorantraniliprole.

4. 3 Toxicity Endpoint and Point of D eparture SelectionsChlorantraniliprole Human Health Risk Assessment DP No. 411938

Page 17 of 30 The details for selecting toxici ty endpoints and points of departure for various exposure scenarios are presented in the original risk assessmen t for Section 3 Registration (S. Winfield, DP336983, 03/07/08). T here 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 Ri sk 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 UF A = 10x

UF H =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, reproduct ive 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 t umors 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. NOAEL = no ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = 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 RationaleChlorantraniliprole Human Health Risk Assessment DP No. 411938

Page 18 of 30 A summary of the residues of concern and rationale can be found in a previous risk assessment (D. Rate, DP#361397, 01/12/2010 )

.

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 Chlorantraniliprole

Drinking Water Chlorantraniliprole N/A

5 .2 Food Residue Profile

The submitted magnitude of the residue data is adequate for risk assessment and tolerance assessment. For all crops, the number and locations of field trials are adequate. Barley , grain sorghum and wheat trials reflect the proposed label maximum application rate and other conditions, with the exception of the preharvest interval (PHI). The proposed label PHI is 14 days, whereas the trials were conducted with a 1 day PHI

. Residue decline studies on other commodities show that chlorantraniliprole residues decline with increasing PHI. Residues at the proposed 14 days PHI will be less than residues at the tested 1 day PHI , and therefore the tolerance estimate will be adequate.

The field trial studies are supported by adequate storage stability data.

The wheat processing study is adequate. Residues d o not concentrate in wheat processed commodit ies relative to the wheat grain, except aspirated grain fractions. Only one tolerance is established for aspirated grain fractions from all commodity sources, and soybeans yields higher aspirated grain fraction residues. Therefore, the existing aspirated grain fraction tolerance based on soybean remains.

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 establishe d previously or appropriate label restrictions were implemented

.Chlorantraniliprole Human Health Risk Assessment DP No. 411938

Page 19 of 30 Extensive primary crop or crop group tolerances have been established, and therefore there are few inadvertent tolerances needed

.

5.3 Water Residue Profile

For surface water, the EDWCs for the scenarios modeled in this assessment did not exceed the previo us EDWCs for use on cranberries generated by the Provisional Cranberry Model which is a provisional refinement to the Tier I Rice Model ( C. Koper, DP#3881819, 12/01/2010)

. . Refinements inc lude the addition of simple degradation processes in dry and flooded conditions and a water depth of twelve inches, rather than the water depth of four inches used in the rice mode l. The previously reported acute concentration of 55.30 μg/L, annual mean (c hronic) concentration of 39.87μg/L and the 30 year annual average concentration of 39.87μg/L are greater than the reported EDWCs from the proposed uses for all scenarios reported in Table 3.3

.

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

0.842 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 SCI

- GROW model, assuming a maximum seasonal use rate of 0.200 lb s ai/ acre (2 X 0.100 lb ai/acre), a K oc of 153, and a half

- life of 410 days from the aerobic soil metabolism study. This is lower than the previous estimate of 1.06 ppb.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Recommended or established t olerance

- level residues and 100% CT were used for all commodities included in th is assessment and

, therefore, this assessment is considered conservative

. Processed commodity tolerance

- level residues were used. DEEM default concentration factors for proce ssed commodities w ere used if available

. The drinking water residues used in the dietary risk assessment were provided by EFED ( C. Koper, 1/17/2013, D404711; C. Koper, 2/29/2012, D397882; and C. Koper, 12/01/2010, D3881819) and incorporated directly into this dietary assessment. Water residues were incorporated in the DEEM

- FCID TM into the food categories “water, direct, all sources” and “water, indirect, all sources.” T he estimated surface water concentration of 39.87 ppb was usedChlorantraniliprole Human Health Risk Assessment DP No. 411938

Page 20 of 30 for this assessment sinc e it is higher than the ground water concentration of 0.842 ppb. This value of 39.87 ppb is the one in ten year annual mean.

5.4.2 Acute Dietary Risk Assessment

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

.

5.4.3 Chronic Dietary Risk Assessment

The c hro nic dietary (food and drinking water) exposure assessment for chlorantraniliprole assumed recommended and/or established tolerance

- level residues and 100% crop treated (CT). DEEM default processing factors were used. Estimated drinking water concentration s (EDWCs) from EFED ( 39.87 ppb ) were also included. The results of this chronic analysis indicate that chronic dietary (food and drinking water) exposure and risk does not exceed HED’s level of concern for the general U.S. population and all population su bgroups. The results of the DEEM

FCIDTM analysis indicate that the risks are about 2% of the chronic population

- adjusted dose for the general U.S. population and 6 .3 % of the cPAD for children (1

- 2 years old), the most highly exposed subgroup.

5.4.4 Cancer Dietary Risk Assessment

C hlorantraniliprole is classified as “ n ot 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 0.03 2474 2.1 All Infants (<1 year old) 0.051597 3.3
Children 1

- 2 years old* 0.099596 6. 3
Children 3

- 5 years old 0.076426 4.8
Children 6

- 12 years old 0.042431 2.7
Youth 13

- 19 years old 0.024386 1.5
Adults 20

- 49 years old 0.026971 1.7 Adults 50+ years old 0.026545 1.7
Females 13

- 49 years old 0.025763 1.6 *The subpopulation(s) with the highest risk estimates (Insert an asterisk after the population subgroups with the highest risk estimates and highlight the subpopulations in bold print)Chlorantraniliprole Human Health Risk Assessment DP No. 411938

Page 21 of 30 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 assessed due to the lack of toxicity via inhalation and dermal route s. No risk is expected from residential handler exposure to chlora ntraniliprole.

6.2 Post

- Application Exposure

D ue to the lack of toxicity via inhalation and dermal route s 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 a ssessment is not required.

6.3 Combined Exposure

Residential postapplication pesticide exposure can occur within a scenario from multiple routes of exposure (e.g., dermal, inhalation, and oral). These exposures to pesticides do not occur as single, isolated events, but rather as a series of sequential or concurrent events that may overlap or be linked in time and space. Based on this, r isk estimates resulting from different exposure routes may be combined when it is likely that they can occur simult aneously based on the use pattern and when the toxicological effects across different routes of exposure are the same. If appropriate for an exposure scenario, the recommended routes of exposure for combining include dermal, inhalation, and hand

- to

- mouth.

For the chronic, non

- cancer assessment, combined exposures were not necessary to assess for chlorantraniliprole since no hazard was identified for the inhalation and dermal route s of
exposure.

6.4 Residential Bystander Postapplication Inhalation Exposur e

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 press ure (6.3 X10 - 12 Pa @ 20 ̊C), and the low proposed use rate (0.2 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 ( http://www.epa.gov/scipoly/SAP/meetings/ 2009/120109meeting.html ). 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 A gency'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

.Chlorantraniliprole Human Health Risk Assessment DP No. 411938

Page 22 of 30 6. 5 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application metho d employed for chlorantraniliprole . The Agency has been working with the Spray Drift Task Force, 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 at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/lab eling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off

- target drift with specific products w ith significant risks associated with drift.

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 variou s sources, HED considers both the route and duration of exposure.

Aggregate exposure risk assessments were assessed by incorporating the drinking water directly into the dietary exposure assessment for the chronic exposure scenario. D ue to the lack of
to xicity over the acute, short

- and intermediate

- term via the oral route and dermal and inhalation
routes of exposure , no risk is expected from these exposures. Acute and cancer aggregate risk assessments were not performed because no appropriate endpoint w as available to determine the aRfD for the general population or any population subgroup, as well as the fact that chlorantraniliprole is not carcinogenic.

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 n o hazard was identified

over a short

- or intermediate

- term duration

.

The chronic dietary exposure es timates are not of concern to HED for the general U.S. population and all population subgroups (see Table 5.4 .5 ). Therefore, the chronic aggregate risk for chlorantraniliprole does not exceed HED’s level of concern for the general U.S. population or
any p opulation subgroups.Chlorantraniliprole Human Health Risk Assessment DP No. 411938

Page 23 of 30 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 chlorantr aniliprole 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 release d 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://ww w.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

T here is potential for short

- and intermediate

- term occupational exposure to chlorantraniliprole during both handler [mixing, loading, and application (via the dermal and inhal ation routes)] and postapplication 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 occupational exposure and risk assessment was conducted.

10.0 References

Chlorantraniliprole: Chronic Aggregate Dietary (Food plus Drinking Water) Exposure and Risk Assessment for the Section 3 Registration Action on Cereal Grains, Except Rice (Crop Group 15), Cereal Grain Forage (Crop Group 16), Pome Fruit (Crop Group 11

- 10) and Citrus (Crop Group 10

- 10), Kristin Rury

, D 411997 , 05/ 29 /1 3

Chlorantraniliprole (DPX

- E2Y45). Section 3 Registration for Proposed Uses on Cereal Grains Group 15 (except Rice) and Cereal Grains Forage, Fodder, and Straw Group 16. Request for Crop Group Conversions for Pome Fruit Group 11

- 10 and Citrus Fruit Group 10

- 10. Poultry Feeding Study. Summary of Analytical Chemistry and Residue Data, Steve Funk, D 4 04708

, 3 / 29 /1 3

Tier II Drinking Water Exposure Assessment to Establish Tolerances of Chlorantraniliprole on Bushberries Subgroup 13

- 07B, Cucurbit Vegetables Group 9, Fruiting Vegetables Group 8, Large Shrub/Tree Berries Subgroup 13

- 07C, Low Growing Berri es Subgroup 13

- 07G, Okra, Onion (bulb) Subgroup 3

- 07A, Peanut (hay, nutmeat), Root and Tuber Vegetables Group 1, Sugar Beet Molasses, Ti Palm, Leaves of Root and Tuber Vegetables Group 2, Dried Tea Leaves and Corn , Christopher Koper, DP# 381819, 12/01/10

Tier II Drinking Water Exposure Assessment to Establish Tolerances of Chlorantraniliprole on Citrus Fruits Group 10

- 10, Pome Fruits Group 11

- 10, Cereal Grain Crop Group 15 (exceptChlorantraniliprole Human Health Risk Assessment DP No. 411938

Page 24 of 30 Rice), and Cereal Grain Forage, Fodder, and Straw, Crop Group 16

, Christophe r Koper, DP#404711, 1/17/13 Chlorantraniliprole (DPX

- E2Y45): Human Health Risk Assessment for Section 3 Registration Request to Expand Uses of Coragen®, Altacor®, and Demacor TM X

- 100 Labels on Various Field, Vegetable, and Fruit Crops, Debra Rate, DP#361397, 01/12/2010

Chlorantraniliprole (DPX

- E2Y45): Human Health Risk Assessment for Proposed Uses on Pome fruit, Stone fruit, Leafy vegetables, Brassica leafy vegetables, Cucurbit vegetables, Fruiting vegetables, Cotton, Grapes, Potatoes, Turf and Orn amentals

, S

. Winfield, DP#336983, 03/07/08 ).Chlorantraniliprole Human Health Risk Assessment DP No. 411938

Page 25 of 30 A ppendix 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

................................ ...................... y es 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

................................ .......................... y es yes yes

no

no yes

yes
yes

-

- 870.3700a Developmental Toxicity (rodent)

................................ ... 870.3700b Developmental Toxicity (non

- rodent)

........................... 870.3800 Reproduction

................................ ................................ . y es 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

................................ .................... y es yes yes yes yes 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

................................ ........ y es 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 Neuro tox . Screening Battery (rat)

..................... 870.6300 Develop. Neuro tox

................................ ........................ n o

no yes yes

no -

- yes yes

-

870.7485 General Metabolism

................................ ...................... 870.7600 Dermal Penetration

................................ ........................ 870.7 8 00 Immunotoxicity

................................ ............................. y es

no yes yes

- yesChlorantraniliprole Human Health Risk Assessment DP No. 411938

Page 26 of 30 A.2 Toxicity Profile s

Table A.2.1 Acute Toxicity Profile of Chlorantraniliprole a

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral

- rat 46889112 LD 50 > 5000 mg/kg IV

870.1200 Acute dermal

- rat 46889113 LD 50 > 5000 mg/kg IV

870.1300 Acute inhalation

- rat 46889121 LC 50 > 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
STUDY/ SPECIES DOSES

(mg/kg/day) NOAEL

(mg/kg/day) LOAEL

(mg/kg/day) EFFECTS

Non

- guideline 14

- day Oral Gavage/ rat 0, 25, 100, 1000 1000 Not established No adverse effects. Weak inducer of cytochrome

P450 3A at all dose levels, with statistical significance at 100 and 1000 mg/kg/day. Non

- guideline 28

- Day Oral (feed)/rat 0, 20.7, 106 and

584 (male); 0, 24, 128 and 675 (female) 584 (male)

and 675 (female) Not

established No adverse effects. Slight increase in liver weight

at 128 and 675 mg/kg/day in females and minimal hepatocellular hypertrophy at 675 mg/kg that is attributed to enzyme induction characterized by increased amount of eosinophilic cytoplasm with hepatocytes but no histomorphologic evidence of hepatocellular damage. In 128 and 675 mg/kg females, a statistically significant increase in UDP

GT activity was observed in HDT female rats, with a similar increase in males. These changes are consistent with a pharmacological response and were not considered adverse. Non

- guideline 28

- Day Oral (feed)/mouse 0, 52, 182, 538

and 1443 (male); 0, 64, 206, 658 and 1524 (female) 1443 (male)

and 1524 (female) Not

established No adverse effects. Slight increase in liver wt. in

658 and 1524 mg/kg/day females corresponded with a mild increase in cytochrome P450 enzyme activity. No histopathological evidence of liver toxicity was observed.

A reduction in body weight gain was observed in HDT males (52%) but not in females. No statistically significant decrease in absolute body

we ight was observed therefore, this effect was not considered adverse. Non

- guideline 28

- day Oral (capsule)/ Dog 0, 300, 1000 1000 Not established No adverse effects. Induction of cytochrome P450

enzyme activity (58%) in both males and females at 1000 mg /kg/day, specifically 1A1 and 2B1/2 at 300 and 1000 mg/kg/day. Non

- guideline 28

- day Oral 0, 26, 138, 266,

797 and 1302 1302 (male)

and 1240 Not

established No adverse effects. Food consumption generally

increased as the study progressed with malesChlorantraniliprole Human Health Risk Assessment DP No. 411938

Page 27 of 30 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile of Chlorantraniliprole
STUDY/ SPECIES DOSES

(mg/kg/day) NOAEL

(mg/kg/day) LOAEL

(mg/kg/day) EFFECTS
(feed)/dog

– Palatability study (male); 0, 28,

138, 298, 888, and 1240 (female) (female) generally demonstrating the highest food consumption when fed the HDT.

870.3100 90

- day Oral (feed)/rat 0, 36.9, 120, 359,

1188 (male); 0, 47, 157, 460, 1526 (fema le) 1188 (male)

and 1526 (female) Not

established No adverse effects. A slight increase in liver

weight at HDT females and reduc tion in bilirubin in females at ≥157 mg/kg/day, with no corresponding histopathological evidence of liver toxicity. 870.3100 9 0

- day Oral (feed)/mouse 0, 32.6, 115, 345,

1135 (male); 0, 40.7, 158, 422, 1529 (female) 1135 (male)

and 1529 (female) Not

established No adverse effects. Hyperactivity and

hyperreactivity in females were observed near the end of the study and one male in the upper mid dose had convulsions, but these effects were considered spurious as they were not reproducible in the 18

- month mouse study with a FOB.

A slight increase in liver weight at the HDT males and females, with no corresponding histopathological evidence of liver toxicity. 870.3150 90

- day Oral (feed)/dog 0, 32.2, 119, 303,

1163 (male); 0, 36.5, 133, 318, 1220 (female) 1163 (male)

and 1220 (female) Not

established No adverse effects. A mild increase in liver weight

was observed in males at 1163 m g/kg/day, with no corresponding histopathological evidence of liver toxicity. 870.3200 28

- day Dermal/rat 0, 100, 300 and

1000 1000 Not established No adverse effects. Reductions in mean body

weight gain (22% and 19% for males and females) and food effici ency (19% and 17% for males and females) over the 28

- day at the HDT. Increased microvesiculation of adrenal cortex in males only, with no light or electronic microscopic evidence of adrenal cellular degeneration or toxicity. No effect on the capacity of the adrenal gland to produce corticosterone under either basal or following ACTH stimulation. Therefore, these effects were not considered adverse. 870.4100 52

- week Oral (feed)/dog 0, 32, 112, 317,

1164 (male); 0, 34, 113, 278, 1233 (female) 1164 (male)

and 1233 (female) Not

established No adverse effects. A mild increase in liver weight

in HDT males and females, and increase in alkaline phosphatase in HDT males, with no corresponding histopathological evidence of liver toxicity.

Body weight gain increa se in HDT males for weeks 8

- 9 compared to controls, with an increase in food efficiency in week 9. 870.4300 2

- Year Oral (feeding)/rat 0, 7.71, 39, 156,

805 (male); 0, 10.9, 51, 212, 1076 (female) 805 (male)

and 1076 (female) Not

established No evidence of carcinogenicity and no adverse

findings. Increased adrenal cortical microvesiculation due to lipid was present in the zona fasciculata region of the adrenal gland of some male rats in all dose groups in both the one

year and main studies. T his finding was considered test substance related but was not considered adverse as the adrenal morphology was generally in the range of what was observed in control rats, and the finding was not associated with any indication of cytotoxicity or other evid ence of structural or functional impairment of the adrenal gland.

870.4200 18

- Month 0, 2.6, 9.2, 26.1,

158, 935 (male); 158 (male)

and 1155 935 (male),

no LOAEL No evidence of carcinogenicity. Eosinophilic foci

accompanied by hepatocellular hypertrophy andChlorantraniliprole Human Health Risk Assessment DP No. 411938

Page 28 of 30 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile of Chlorantraniliprole
STUDY/ SPECIES DOSES

(mg/kg/day) NOAEL

(mg/kg/day) LOAEL

(mg/kg/day) EFFECTS

Oral (feeding)/ Mouse 0, 3.34, 11.6,

32.9, 196, 1155 (female) (female) established for female increased liver weight form the bases for the male

LOAEL of 935 mg/kg/day.

870.3800 Two

generation oral study/rat 0, 200, 1000,

4000, 20000
ppm, mg/kg bw/d

e quivalents:
pre

- mating: P1 m: 0, 12, 60, 238, 1199 F1 m: 0, 18, 89, 370, 1926 P1 f: 0, 16, 78, 318, 1594 F1 f: 0, 20, 104, 406, 2178, 1199 (male)

and 1594 (female) Not

established A slight increase in mean liver weights in P1

and F1 males and females at 238/318.9 mg/kg/day and above, slight increase in mean adrenal weight at 238/318.9 mg/kg/day and 1199/1594 mg/kg/day P1 and F1 males and females. Mean body weight of 1199/1594 mg/kg/day F1 pups was slightly reduced on lactation days 7, 14 and 21. No eff ects on F2 offspring weights during lactation.

Minimal to mild increase in adrenal cortical microvesiculation in P1 adult males and F1 adult males and females. P1 adult at 60.4/77.8 mg/kg/day and greater. F1 adult males at 12 mg/kg/day and greater. Thes e effects were not observed in weanlings. No cytotoxicity or abnormal cellular structures were observed under light or electron microscopy. 870.3700 Develop mental study/rat 0, 20, 100, 300,

1000 1000 Not established No adverse effects.

870.3700 Develop mental study/rabbit 0, 20, 100, 300,

1000 1000 Not established No adverse effects.

870.6200a Acute oral

neuro

toxicity/rat 0, 200, 700,

2000 in 0.5% methyl cellulose 2000 Not established No evidence of neurotoxicity was observed at

any dose

870.6200b Subchronic oral neuron

toxicity/rat 0, 12.7, 64.2,

255, 1313 (male); 0, 15.1, 77.3, 304, 1586 (female) 1313 (male)

and 1586 (female) Not

established No evidence of neurotoxicity was observed at

any dose.

870.7485 Metabolism and kinetics The absorption of 14 C

- chlorantraniliprole was rapid with peak concentrations occurring at 5

- 12 hours after low or high (10 or 200 mg/kg bw) dose administration. The percent absorption decreased after high dose administration. The plasma elimination half

lives ranged from 38

- 82 hours. Tissue distribution of the absorbed dose was extensive and indicated low potential for accumulation. The tissue residues were higher in female than male rats consistent with female rats having a longer elimination half

life and higher AUC in plasma. Excretion was substantially complete by 48

- 72 hourChlorantraniliprole Human Health Risk Assessment DP No. 411938

Page 29 of 30 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile of Chlorantraniliprole
STUDY/ SPECIES DOSES

(mg/kg/day) NOAEL

(mg/kg/day) LOAEL

(mg/kg/day) EFFECTS

after dosing. Faecal excretion was the primary route of elimination followed by the urine with no significant excretion occurring by exhalation. Metabolism of the absorbed dos e was extensive and involved sex differences primarily in initial methylphenyl and N

- methyl carbon hydroxylations. Further metabolism of the hydroxylated metabolites included N

- demethylation, nitrogen

- to

- carbon cyclisation with loss of a water molecule,

o xidation of alcohols to carboxylic acids, amide bridge cleavage, amine hydrolysis, and O

- glucuronidation

870.7800 28

- day Immuno

toxicity/rat 0, 74, 363, 1494

(male); 0, 82, 397, 1601 (female) 1494 (male)

and 1601 (female) Not

established No evidence of treatment

- related effects on

the sheep red blood cells specific antibody (IgM) responses in either male or female rats at any dietary concentration tested. 870.7800 28

- day Immuno

toxicity/ Mouse 0, 48, 264, 1144

(male); 0, 64, 362, 1566 (female) 1144 (mal e)

and 1566 (female) Not

established No evidence of treatment

- related effect on the

sheep red blood cells specific antibody (IgM) responses in either male or female mice at any dietary concentration tested.

a Studies are described and listed, along with MRID numbers, in TXR 0054555Chlorantraniliprole Human Health Risk Assessment DP No. 411938

Page 30 of 30 Appendix B

. Physical/Chemical Properties

Table B. Physicochemical Properties of Tec hnical Grade of Chlorantraniliprole

. Parameter Value Reference 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, pK a 10.88 ± 0.71 46889034 Octanol/water partition coefficient, K OW (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