### Cyantraniliprole Human Health Risk Assessment DP No. 404762



### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460

MEMORANDUM

DATE: March 7

, 2013 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### SUBJECT: Cyantraniliprole. Aggregate Human Health Risk Assessment for the Proposed New Uses of the New Active Insect i cide

, including Agricultural Uses on Brassica 

### (Cole) Leafy Vegetables (Group 5), Bulb Vegetables (Group 3-07)

, Bushberries (Group 13 -07B ), Citrus Fruit (Group 10-10), Cotton, Cucurbit Vegetables (Group 9), Fruiting Vegetables (Group 8-10), Leafy Vegetables (non -Br a s sica) 

### (Group 4), Oilseeds (Group 20 )

, Pome Fruits (Group 11-1 0), Stone Fruits (Group 12), Tree Nuts (Group 14), Tuberous and Corm Vegetab l es (Subgroup IC); Seed Treatment Uses on Canola (Rapeseed), Mustard Seed, Sunflowers

, and Potatoes; and Residential

, Commercial, and Agricultural U ses on Ornamentals, Turfgrass (including Sod Farms and Golf Courses), and Structural Buildings (including Indoor Crack/Crevice and Outdoor Broadcast).

PC Code: 090098 Decision No.: 451670 DP Barcode: 0404762,0407979 Registration Nos.: 352-IAE

, 352-IAG

, 352-IAI

, 352

- IAL

, 25 3 -IAN

, 3 52 -ILA

, 3 52 -ILI

, 3 5 2 -ILO

, 352 -ILT, 100-RUEE

, 100-RUEG

, 100-RUE N, 100-R U ER, 100

- RUEU, 100-RURI Regulatory Action: Section 3 Petition No.: I F7894 Risk Assessment Type: Aggregate Huma n Health TXRNo.: NA CaseNo.: NA CAS No

. : 73 6994-6 3

- 1 MRIDNo.: NA 40 CFR: to be determined (new active ingredient)



### FROM: Nancy J. Tsaur

, Chemist

, Risk Assessor

## t}f~ Whang Phang, Senior Tox icol ogist 

## II

. J

.. . A., .-

### ~-**11 0** **~"'(** 

## _ Steve Funk, Senior Chemist**~ ~~**  

### · 

## 'J 

## f
Meheret Negussie, Chemist 

## Heherd-

## ,J(j~-e_ Risk Assessment Branch 3 (RAB3) Health Effects D i vision (7509P)

THROUGH: Christine Olinger, Branch Chief 

# tJ / ? /

Risk Assessment Branch 3 (RAB3) 

# t, ·· 

# :/' 0

and 

### v Wade Britton, Industrial Hygienist, Designated Review r Ray Kent, Senior Chemist, Designated Reviewe Y:l_ \: Risk Assessment Review Committee '--.)'{) Health Effects Division (7509P)

TO: Thoma s Harris / John Hebert, RM # 07 Insecticide Rodenticide Branch (IRB) Registration Division (7505P)

Page I of85

### Cyantranilipro l e Human Health Risk Assessment DP No. 404762

Table of Contents



### 1.0 Executive Summary

.............................. . ... . ...... . ... . ... . .......................................... . ....... . .... . ... 4 2.0 HED Recommendations

....................................................... . ........ . ... . ... . ... . ... . ... .. ... . .... . ... . .... 6 2.1 Data Deficiencies

. .. .. .. . .. .. .. . ... . .. .. .. .. .. . .. .. .. .. .. .. .. .. . ... . ... .. . ... . .. ... . .. .. .. .. .. .. .. .. ... .. .. .. ... .. .. .. .. ... .. . 6 2.2 Tolerance Cons i dera t i ons

.. ...... . .............. . .............................................. . ............... . ........... 6 2.2.1 Enforcement Analytical Method

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

. 2.2 Recommended Tolerances

............................................ . .. .. .. .. .. . .... .. .. . ... . ... .. ... . .... . ... .. 6 2.2.3 Revisions to Petitioned

- For Tolerances

......................... . ... . ... . ... . ... .. ....... . ............. . . 10 2.2.4 International Harmonization

..... . ... . ... . ... . .. . ... . ... . ... . ... . ... . ... . ... . ... . ... . ... . ... .. ... . ... .. .... . ... 11 2.3 Recommendations

.... . ...... . .......... . ................................................................................... 11 2.3

. 1 Recommendations from Residue Rev i ews

. . ... . ... .. .. . .. .. .. ... .. .. .. . .. .. ... . ... .. .. .. .. .. ... ... .. .. 1 1 2.3.2 Recommendations from Occupational Assessment

................................................ 1 1 2

. 3.3 Recommendations from Residential Assessment..

....................... . ......................... 12 3

. 0 Introduction

. ... . .. . ... . ... . .. . ... . .. . ... . ... . .. . ... . ... . ... . ...... . ... . ... . ... . ... . ... . ...... . ....... . .... . ... . ... . ........ . ... . ... 12 3.1 Chemical I dentity

.......... . ... . ...... . ... . ....................................................... . ......................... 1 2 3.2 Physical/Chemical Characteristics

................................................. . ..... . ..... . ................... 1 2 3.3 Pestic i de Use Pattern

....... . .............. . .. . ...................... . ........................... . ......... . ........ . ...... 13 3.4 Anticipated Exposure Pathways

.... . ... . .......... . ... . ... . ... . .......... . ... . ... .. ...... .. ........... .. ........ . ... 14 3.5 Considerat i on of Environmental Justice

....... . ............. . ........ . .. . ... . ... . ... . ....... .. ... . ... .. ... .. ... 15 4.0 Hazard Characterization and Dose

- Response Assessment

... . ....... . ....... . .. .. ........ . ... . ......... . . 15 4. 1 Toxicology Studies Ava i lab l e for Analysis

. . ... . ... . ... . .. . ... . ... . ... . ... . ... . ... . ........ . ... . ... .. ... . .... 16 4.2 Absorption, Distribution, Metabo l ism, & Elimina t ion (ADME)

................................... 16 4.3

· Toxicological Effects

................ . ....... . .......... . .. . .... . .. . .. . ... .. ... . .. .. ....... .. ... . ............ . ............ 17 4.4 Safety Factor for I nfants and Children (FQPA Safety Factor)

. ... . .. . ... . ... . ........ . .............. 19 4.4

. 1 Completeness of the T oxicology Database

................................... . ................. . ....... 20 4.4.2 Evidence ofNeurotox i c i ty

.... . ... . ...... . ... . ... . ... . ... . .. .. .. . ... . ... . ... . ... . ... . ... . .... . ... . ... .. ... . .... . 20 4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

......... 20 4.4.4 Residual U ncertainty in the Exposure Database

..... . ....................... . ....... . ... .. ... . ..... . 20 4.5 T oxicity Endpo i nt and Point of Departure Se l ec t io n s

.......................................... . ......... 20 4.5.1 Dose-Response Assessment.

................................................................................... 20 4

. 5.2 Recommendation fo r Combining Routes of Exposures for Risk Assessment

. .. .. . .. 22 4.5.3 Cancer Classification and Risk Assessment Recommendation

. . ...... .. ... . .... . ... . .... . .. 22 4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in 

### H uman Risk Assessment

....... . ....................................................................................... . .. . ......................... 22 5

. 0 D i etary Exposure and Risk Assessment

. . .. .. .. .. .. .. .. . ... .. . ... . ... .. . ... . ... . ... .. .. .. . ... . ... .. .. .. ... .. .. .. ... 25 5.1 Metabolite/Degradate Residue Profile

................................................. . ......................... 25 5.1.1 Summary ofP l ant and Anima l Metabolism Studies

........ .. ....... . ... . ........ . ... . ........ . ... 25 5 .1.2 Summary of Environmental Degradation

.............. . ... . .................. . ......... . ........ . .... . . 25 5 .1.3 Comparison of Metabolic Pathways

........ . ........ . ................... . ................... . ............. 26 5. 1 .4 Res i dues of Concern Summary and Rationa l e .

. ... . ... . ... . ... . ... . ... . ... . ... . ... . ... .. ... . ... .. ... . 27 5.2 Food Residue Profile

...................................................................................................... 28 5.3 Wa t er Residue Profile

..... . ..................... . ... . .................. . ....................... . ......................... 29 5.4 Dietary Risk Assessment

.. . ............................................................................. . .............. . 30 

## 5.4

. 1 Description of Residue Data Used in Dietary Assessment

..................................... 30 5.4.2 Acute Dietary R i sk Assessment

... . ......... .. .. . ... .. . . . . ............. . ....... . ... . ..... . ................... 31

Page 2 of85

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 3 of 85 5.4.3 Chronic Dietary Risk Assessment

................................ ................................ .......... 31 5.4.4 Summary Table

................................ ................................ ................................ ....... 31 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

................................ .... 31 6.1 Residential Handler Exposure

................................ ................................ ........................ 32 6.2 Post

- Application Exposure

................................ ................................ ............................. 34 6.3 Residential Risk Estimates for Use in Aggregate Assessment

................................ ...... 36 6.4 Residential Bystander Post

- Application Inhalation Exposure

................................ ....... 37 6.5 Spray Drift

................................ ................................ ................................ ...................... 38 7.0 Aggregate Ex posure/Risk Characterization

................................ ................................ ....... 38 7.1 Acute Aggregate Risk

................................ ................................ ................................ .... 38 7.2 Short

- Term Aggregate Risk

................................ ................................ ........................... 39 7. 3 Intermediate

- Term Aggregate Risk

................................ ................................ ................ 39 7.4 Chronic Aggregate Risk

................................ ................................ ................................ . 39 7.5 Cancer Aggregate Risk

................................ ................................ ................................ ... 39 8.0 Cumulative Exposure/Risk Characterization

................................ ................................ ..... 39 9.0 Occupational Exposure/Risk Characterization

................................ ................................ .. 40 9.1 Short

- and Intermediate

- Term Handler Risk

................................ ................................ .. 40 9.2 Short

- and Intermediate

- Term Post

- Application Risk

................................ ................... 42 9.2.1 Dermal Post

- Application Risk

................................ ................................ ................ 42 9.2.2 Restricted Entry Interval

................................ ................................ ......................... 42 9.2.3 Inhalation Post

- Application Risk

................................ ................................ ............ 43 10.0 References

................................ ................................ ................................ .......................... 44 Appendix A. Deta iled Use Profile Summary

................................ ................................ ............ 47 Appendix B. Toxicology Profile and Executive Summaries

................................ .................... 55 B.1 Toxicology Data Requirements

................................ ................................ ...................... 55 B.2 Toxicity Profiles

................................ ................................ ................................ ............. 56 B.3 Hazard Identification and Endpoint Selection

................................ ............................... 67 B.3.1 Acute Reference Dose (aRfD)

- General Population

................................ .............. 67 B.3.2 Chronic Reference Dose (cRfD)

................................ ................................ ............. 67 B.3.3 Incidental Oral Exposure (Short

- and Intermediate

- Term)

................................ ..... 67 B.3.4 Dermal Exposure (Short

- , Intermediate

- and Long

- Term)

................................ ..... 68 B.3.5 Inhalation Exposure (Short

- and Intermediate

- Term)

................................ ............. 68 B.4 Human Equivalent Concentrations (HEC) and Human Equivalent Dose Calculations

. 69 Appendix C. Metabolism Summary Table

................................ ................................ ............... 72 Appendix D. Physical/Chemical Properties

................................ ................................ .............. 79 Appendix E. Review of Human Research

................................ ................................ ................ 79 Appendix F. Occupational Exposure/Risk Summary Tables

................................ ................... 80

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 4 of 85 1.0 Executive Summary

Cyantraniliprole is a new second

- generation ryanodine receptor (RyR) insecticide currently undergoing global joint review. It is a systemic insecticide that is mobile in both the xylem and phloem of plants. Cyantraniliprole belong s to the diamide class of chemistry whose pesticidal mode of action (MOA) is through unregula ted activation of insect RyR channels

. This then leads to inter n al calcium store depletion and impair ed regulation of muscle contraction, causing paralysis and eventual death of the insect.

Proposed Use Profile Cyantraniliprole has been jointly developed by DuPont an d Syngenta, with a proposal for one technical product and 14 U.S. end

- use product (EP) registratio ns, including agricultural food

uses (PP# 1F7894 ) . The agricultural uses include foliar, soil, and seed treatment to various crops including cotton, fruits, oilseeds, and v egetables. The residential use sites include turfgrass, ornamentals, and structural buildings (including indoor crack/crevice and outdoor broadcast).

Exposure Profile Non

- occupational e xposures to cyantraniliprole a re expec ted for short

- and intermediate

- term durations. Exposure pathways include dietary (food and drinking water), and residential
exposure sources. Dietary exposures are also expected for chronic duration. Occupational exposures are expected for short

- and i ntermediate

- term durations only. The dermal route of
exposure is not assessed because there is no dermal hazard. The proposed residential u se s ( turf, ornamentals, and indoor crack/crevice ) result in inhalation exposures for adults ( handlers ) and post

- application incidental oral exposure s for children (1 to <2 years old)

.
Toxicity/Hazard The risk assessment for cyantraniliprole is based on a well

- characterized an d complete toxicology database. While unregulated activation of RyR channels lead s to insect death, the insect RyR are shown to be 350 to >2500 times more sensitive than those of mammals. In general, cyantraniliprole administration produce s both adverse and adaptive changes in the liver, thyroid gland, and adrenal cortex

. With repeated dosing, consistent finding s of mild to moderate increases in liver weights across multiple species (rats, mice, dogs) a re observed

. Dogs appear to be more sensitive than rats and mice; cyantraniliprole produces adverse liver effects (increases in alkaline phosphatase, decreases in cholesterol

, and decreases in albumin) in dogs at lower dose levels than in rats. In addition, the liver effects in the dog show progressive severity with increased duration of exposure. The available dat a also show thyroid hormone homeostasis i s altered in rats following exposure to cyantraniliprole after 28 or 90 days. However,

c yantraniliprole i s not a direct thyroid toxicant.

Cyantraniliprole is classified as “ Not L ikely to be Carcinogenic to Humans” based on the absence of increased tumor incidence in acceptable/guideline carcinogenicity studies in rats and mice. In addition, there are no genotoxicity, mutagenicity, neurotoxicity, or immunotoxicity

concerns. There are also no developmental or reproductive toxicity concerns. Therefore, the data support a reduction of the Food Quality Protection Act ( FQPA ) safety factor to 1X. There i s

no evidence of an adverse effect attributable to a single dose . The toxici ty endpoint and points of departure (PODs) for chronic dietary and short

- /intermediate

- term incidental oral exposure a re

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 5 of 85 based on the 1

- year and 90

- day dog oral toxicity studies, respectively. The toxicity endpoint and POD for inhalation exposure a re base d on the results of a 28

- day rat inhalation toxicity study.

Dietary Exposure (Food and Water) and Risk Estimates An acute dietary assessment was not conducted because t here was no indication of an adverse effect attributable to a single dose

. A somewhat refined chronic (food and drinking water) dietary assessment was conducted assuming average field trial residues for all proposed crops (except crop subgroup 1A) and that 100% of crops are treated (CT). Tolerance

- level residues were adequate to cover residues in all livestock commodities except liver and meat byproducts for which higher anticipated residue calculations were used

. The e stimated drinking water concentration (EDWC) of 24.45 μ g/L derived from the 1

- in

- 10 year annual mean from s urface
wat er estimates was incorporated directl y into the chronic dietary assessment

. The results of the chronic dietary (food and drinking water) analysis are below the Agency’s level of concern (LOC) for the general U.S. population and all population subgroups. T he dietary (food and drinking water) exposure is estimated at 22 % of the c hronic Population Adjusted Dose (cPAD) for the general U.S. population and 50 % of the cPAD for children 1

- 2 y ea rs old , the population subgroup with the highest estimated chronic die tary exposure to cyantraniliprole

.
Residential Exposure and Risk Estimates Residential exposure may occur by the dermal, oral, and inhalation routes of exposures. As previously noted, cyantraniliprole does not pose a dermal hazard; therefore, only inhalation (handler exposure for adults) and oral (post

- application incidental ora l for children) require
assessment. The proposed uses do not result in residential handler inhalation (adults) or post

application incidental oral (children) risk estimates o f concern. For the proposed residential uses (turf, ornamentals , and crack/crevi ce) , the s hort

- term residential handler inhalation margins of exposure ( MOEs ) range from 2 2 ,0 00 to 22 0 ,000,000

. Short

- term incidental oral p ost

- application risk estimates (which are protective of intermediate

- term risk estimates) for all scenarios are not of concern to HED ( MOEs range from 290 to 1,000 ,000)

.
Residential Aggregate Exposure Risk Estimates There is potential for short

- term aggregate exposure to cyantraniliprole via the dietary and residential pathways

. For adults, the oral and inhalation ro utes of exposure should not be aggregated since the endpoints of concern are not common. For children, the short

- term aggregate risk estimate is not of concern ; the MOE is 190 which is greater than the LOC of 100.

Occupational Exposure and Risk Estimates Occupational handler and post

- application exposure may occur by the dermal and inhalation routes of exposure only. Since there is no dermal hazard, only inhalation exposures were quantitatively assessed. The results of the occupational handler exposure and risk assessment indicate that short

- and intermediate

- term inhalation risk estimate s are not of concern at baseline (long

- sleeved shirt, long pants, shoes plus socks) without mitigation from any personal protective equipment ( PPE)

. In general, the l ab els require PPE of chemical

- resistant gloves. The proposed level of clothing and PPE are adequate for protection of workers. Short

- and interme diate

- term inhalation MOEs range from 370 to 3,900,000

. Based on the Agency's current practices, a quantitative non

- cancer occupational post

- application inhalation exposure assessment was not performed for cyantraniliprole at this time. The technical form of cyantraniliprole meets the

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 6 of 85 criteria for a 4

- hour REI. However, two of the proposed EPs (EPA Re g. No. 352

- ILT and EPA Reg. No. 352

- ILI) have been identified as dermal sensitizers, so a 12

- hour REI is required to protect agricultural workers from post

- application exposures to cyantraniliprole. Aside from these two products, a 4

- hour REI is adequate to protect agricultural workers from post

application exposures to cyantraniliprole

.

Environmental Justice Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment. Dietary and non

- di etary exposures were considered.

2.0 HED Recommendations

HED has examined the toxicology and residue chemistry database s for cyantraniliprole . Pending submission of a revised Section B (label) , a revised Section F (tolerances) , and submission of analytical reference standards

, there are no toxicology or residue chemistry issues that would preclude granting Section 3 registration for the requested crop commodity uses of cyantraniliprole (exce pt food/feed establishment uses), or establishment of tol erances for residues of cyantraniliprole. The spec ific tolerance recommendation s are discussed in Section 2.2, and label modifications are discussed in Section 2.3.

2.1 Data Deficiencies

There are no data deficiencies to prohibit tolerance establishments or product registrations

.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

The submitted residue analytical method data are adequate. V alidation data have been provided for the proposed enforcement methods. M ethods for measuring cyantraniliprole include the European Union ( EU ) multi

- residue method DFG S19 (LC/MS/MS module, Dupont

- 21328) and the North American Free Trade Association ( NAFTA ) LC/MS/MS 1187 & 1552 methods. These methods utilize two ma ss ion transitions so confirmatory methods are not required. EU Method DFG S19 has bee n independently validated with a limit of quantification ( LOQ ) of 0.01
ppm for parent cyantraniliprole in cereals and dry products, matrices with high water content, aci dic matrices

, and fatty product s

. NAFTA method 1187 has been independently valida ted with

an LOQ of 0.0 1 ppm for parent cyantraniliprole in almond s , onion s , tomato paste
, and sun dried
tomatoes. NAFTA m ethod 1552 has been independently validated with an LOQ of 0.01 ppm for parent cyantraniliprole in milk, muscle

, and kidney. Note that c yantraniliprole is not recovered using the FDA multi

- residue method s

.

2.2. 2 Recommended Tolerances

It is recommended that tolerances be established for residues of the insecticide cyantraniliprole (3

- bromo

- 1

- (3

- chloro

- 2

- pyridinyl)

- N

- [4

- cyano

- 2

- methyl

- 6

- [(methylamino)carbonyl]phenyl]

- 1 H

-

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 7 of 85 pyrazole

- 5

- carboxamide), including its metabolites and degradates, in or on the plant commodities and livestock specified below in Table 2.2.2

.

It is recommended that indirect or inadvertent tolerances be established for residues of the insecticide cyantraniliprole (3

- bromo

- 1

- (3

- chloro

- 2

- pyridinyl)

- N

- [4

- cyano

- 2

- methyl

- 6

- [(methylamino )carbonyl]phenyl]

- 1 H

- pyrazole

- 5

- carboxamide), including its metabolites and degradates, in or on the commodities specified below in Table 2.2.2

. Compliance with the tolerance levels specified below is to be determined by measuring only cyantraniliprole in or on the commodity.

Table 2.2.2 Tolerance Summary for Cyantraniliprole

Commodity Proposed Tolerance Recommended Tolerance Comments

Correct Commodity Definition ppm ppm 40CFR §180 Part (a) General: It is recommended that tolerances be established for residues of the insect icide cyantraniliprole ( 3

- b romo

- 1

- (3

- chloro

- 2

- pyridinyl)

- N

- [4

- cyano

- 2

- methyl

- 6

- [(methylamino)carbonyl]phenyl]

- 1 H

pyrazole

- 5

- carboxamide ), including its metabolites and degradates, i n or on the commodities below. Compliance with the tolerance levels specified below is to be determined by measuring only cyantraniliprole in or on the commodity.

Almond, hulls 30 8.0 A revised Section F must be submitted to propose a tolerance
at 8 .0 ppm

. Berries and small fruits, bushberries (crop subgroup 13

- 07B ) 4 4.0 Bushberry subgroup 13

- 07B

Brassica ( Cole ) leafy vegetables, head and stem Brassica (crop subgroup 5A) 2 3.0 Brassica , head and stem, subgroup 5A A revised Section F must be submitted to propose a tolerance
at 3.0 ppm

. Brassica ( Cole ) leafy vegetables, leafy Brassica greens (crop subgroup 5B) 30 30 Brassica , leafy greens, subgroup 5 B
Bulb vegetables, onion, bulb (crop subgroup 3

- 07A) 0.04 0.04 Onion, bulb, subgroup 3

- 07A

Bulb vegetables, onion, green (crop subgroup 3

- 07B) 8 8.0 Onion, green, subgroup 3

- 07B

Cattle, fat 0.01 0.01 Cattle, liver 0.04 None Included under meat byproducts

. Cattle, meat 0.01 0.01 Cattle, meat byproducts, except liver 0.01 0.01 Cattle, meat byproducts

Cherries 6 6.0 Cherry subgroup 12

- 12A Citrus fruits (crop group 10

- 10) 0.7 0.7 0 Fruit, citrus, group 10

- 10

Citrus, oil 4 2.4 A revised Section F must be submitted to propose a tolerance
at 2.4 ppm

.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 8 of 85 Table 2.2.2 Tolerance Summary for Cyantraniliprole

Commodity Proposed Tolerance Recommended Tolerance Comments

Correct Commodity Definition ppm ppm Citrus, raw peel 0.9 None Cotton, gin byproduct 10 10 Cotton, gin byproducts

Cucurbit vegetables (crop group 9) 0.3 0.4 0 A revised Section F must be submitted to propose a tolerance
at 0.4 ppm

. Vegetable, cucurbit, group 9 Fruiting vegetables (crop group 8

- 10) 2 2.0 Vegetable, fruiting , group 8

- 10

Goat, fat 0.01 0.01 Goat, liver 0.04 None Included under meat byproducts. Goat, meat 0.01 0.01 Goat, meat byproducts, except liver 0.01 0.01 Goat, meat byproducts
Hog, fat 0.01 None 40CFR§180(a)(3) Hog, liver 0.04 None 40CFR§180(a)(3) Hog, meat 0.01 None 40CFR§180(a)(3) Hog, meat byproducts, except liver 0.01 None 40CFR§180(a)(3)

Horse, fat 0.01 0.01 Horse, liver 0.04 None Included under meat byproducts. Horse, meat 0.01 0.01 Horse, meat byproducts, except liver 0.01 0.01 Horse, meat byproducts.

Leafy vegetables (except Brassica vegetables) (crop group 4) 15 20 A revised Section F must be submitted to propose a tolerance
at 20 ppm

. Vegetable, leafy, except Brassica , group 4
Milk 0.01 0.01
Milk fat 0.04 None Covered by milk tolerance.

Oilseeds, except cotton byproduct (crop group 20) 1 1.5 A revised Section F must be submitted to propose a tolerance
at 1.5 ppm

. Oilseed group 20

Pome fruits (crop group 11

- 10) 0.8 1.5 A revised Section F must be submitted to propose a tolerance
at 1.5 ppm

. Fruit, pome, group 11

- 10 Potato, wet peel 0.3 None Root and tuber vegetables, tuberous and corm vegetables (crop subgroup 1C) 0.15 0.15 Vegetable, tuberous and corm, subgroup 1C
Sheep, fat 0.01 0.01 Sheep, liver 0.04 None Included under meat byproducts. Sheep, meat 0.01 0.01

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 9 of 85 Table 2.2.2 Tolerance Summary for Cyantraniliprole

Commodity Proposed Tolerance Recommended Tolerance Comments

Correct Commodity Definition ppm ppm Sheep, meat byproducts, except liver 0.01 0.01 Sheep meat byproducts

Stone fruits, except cherries (crop group 12) 1.5 1.5 Peach subgroup 12

- 12B
0.5 0 Plum subgroup 12

- 12C

Tree nuts, except almond hulls (crop group 14) 0.06 0.04 A revised Section F must be submitted to propose a tolerance
at 0.04 ppm

. Nut, tree, group 14 40CFR §180 Part (d) Indirect or inadvertent residues: It is recommended that indirect or inadvertent tolerances be established for residues of the insect icide cyantraniliprole ( 3

- b romo

- 1

- (3

- chloro

- 2

- pyridinyl)

- N

- [4

- cyano

- 2

- methyl

- 6

- [(methylamino)carbonyl]phenyl]

- 1 H

- pyrazole

- 5

- carboxamide ), including its metabolites and degradates, in or on the commodities below. Compliance with the tolerance levels specified below is to be determined by measuring only cyantraniliprole in or on the commodity. Foliage of legume vegetables (crop group 7), forage 0.15 None Only one tolerance per crop
group.

Foliage of legume vegetables (crop group 7), hay 0.6 0.7 0 A revised Section F must be submitted to propose a tolerance
at 0.7 ppm

. Vegetable, foliage of legume, group 7 Forage, fodder and straw of cereal grains (crop group 16), forage 0.06 None Only one tolerance per crop
group.

Forage, fodder and straw of cereal grains (crop group 16), hay and straw 0.15 0.5 A revised Section F must be submitted to propose a tolerance
at 0.5 ppm

. Gr ai n, cereal, forage, fodder and straw, group 16 Grass forage, fodder, and hay (crop group 17), forage 0.06 None Only one tolerance per crop
group.

Grass forage, fodder, and hay (crop group 17), hay 0.15 0.50 A revised Section F must be submitted to propose a tolerance
at 0.5 ppm

. Grass , forage, fodder and hay

, group 1 7
Leaves of root and tuber vegetables (human food or animal feed) (crop group 2) 0.04 0.04 Vegetable, leaves of root and tuber, group 2
Nongrass animal feeds (forage, fodder, straw, and hay) (crop group 18), forage 0.06 None Only one tolerance per crop
group.

Nongrass animal feeds (forage, fodder, straw, and hay) (crop group 18), hay 0.15 0.20 A revised Section F must be submitted to propose a tolerance
at 0.2 ppm

. Animal feed, nongrass, group 18

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 10 of 85 Table 2.2.2 Tolerance Summary for Cyantraniliprole

Commodity Proposed Tolerance Recommended Tolerance Comments

Correct Commodity Definition ppm ppm

Peanut, hay 0.03 0.01 A revised Section F must be submitted to propose a tolerance
at 0.01 ppm

. Peanut, hay

Root and tuber vegetables, root vegetables (crop subgroup 1A) 0.03 0.02 A revised Section F must be submitted to propose a tolerance
at 0.02 ppm

. Vegetable, root, subgroup 1A



### 2.2. 3 Revisions to Petitioned

- For Tolerances

The proposed tolerances must be modified for the following plant commodities : almond hulls, Brassica vegetables (crop subgroup 5A), cucurbit vegetables (crop group 9), leafy vegetables except Brassica (crop group 4), oilseeds (crop group 20), pome fruits (cr op group 11

- 10) , stone fru its except cherry (crop group 12

- 12 ) , and tree nuts (crop group 14) . The recommended primary plant commodity tolerances are derived from use of the Organization of Economic Cooperation and Development ( OECD ) statistical calculation procedure s

. The proposed tolerances for processed commodities are not appropriate for citrus raw peel and potato wet peel. The processing studies do not show a concentration of residue in these commodities relative to the raw agricultural commodities ( RAC ) . The proposed tolerance for citru s oil needs to be lowered from 4 ppm to 2.4 ppm, consistent with the results from application of the median processing factor to the highest average f ield trials ( HAFT ) for

o range s

. The proposed tolerances for livestock commodities are acceptable, except for liver of cattle, goat, horse, and sheep; hog fat, liver, meat, and meat byproducts; and milk fat. The livestock commodity tolerances are derived from consideration of the maximum reasonably balanced livestock diets and the livestock feeding studies. A tolerance value of 0.01 ppm is appropriate for liver (of cattle, goat, horse, and sheep)

, which would be covered by the meat byproducts tolerance. The dietary exposures of hogs and poultry do not indicate a need for tolerances ( residue s are not anticipated), and there is no indication of significant concentration of cyantraniliprole in milk fat relative to milk.

With the exception of the proposed to lerance for leaves of root and tuber vegetables, all of the proposed tolerances for inadvertent residues ( with a plantback interval ( PB I ) of 30 days ) need to be revised . The revisions must reflect the recommended tolerances based on the use of the OECD statistical calculation procedure s

. For some crop g r oups, more than one tolerance was proposed for various components of the group (e.g. crop group 16 which includes forage, fodder

, and straw of cereal grains); h owever, only one tolerance is possible per group, and the tolerance is based on the member commodity with the highest residue levels.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 11 of 85 2.2. 4 International Harmonization

Currently there are no Codex Maximum Residue Limits ( MRLs ) /tolerances for cyantraniliprole. Therefore, there are no issues with harmonization of tolerances. Canadian MRLs are being proposed concurrently with US tolerances and are harmonize d for primary crop and livestock commodities except for fruiting vegetables. The US fruiting vegetables tolerance is harmonized with the Europe an Union.

2.3 Recommendations

2.3.1 Recommendations from Residue Reviews

860.1200 Directions for Use The use in fo od/feed handling establishments is not supported by the required studies of OCSPP Guideline 860.1460. Therefore, all uses related to treat ment of food and feed handling/storage/ transportation are not allowed. This applies specifically to DuPont TM HGW86 SC Insect Control (EPA Reg. No. 352

- I AI )

. The rotational crop restrictions must be amended, as follows: Cereal grains (crop group 15) may not be planted immediately after use of cyantraniliprole. Cereal grain s (crop group 15) must have a 30

- day PBI . This is to be consistent with the 30

- day PBI for crop group 16 (forage, fodder, and straw of cereal grains). Legume vegetables (crop group 6) may not be planted immediately after use of cyantraniliprole. Legume vegetable s (crop group 6) must have a 30

- day PBI. This is to be consistent with the 30 day PBI for crop group 7 (foliage of legume vegetables). Tuberous and corm vegetabl es (subgroup 1C) may not be planted immediately afte r use of cyantraniliprole. Subgroup 1C must have a 30

- day PBI . This is to be consistent with the 30

- day PBI for crop group 2 (leaves of root and tuber vegetables).

860.1650 Submittal of Analytical Refe rence Standards A nalytical reference standards for cyantraniliprole must be submitted to the Analytical Chemistry Lab, which is located at Fort Meade, to the attention of either Theresa Cole or Thuy Nguyen at the following address: USEPA National Pesticide Standards Repository/Analytical Chemistry Branch/OPP 701 Mapes Road Fort George G. Meade, MD 20755

- 5350

2.3.2 Recommendations from Occupational Assessment

The labeled use pattern for EPA Reg. No. 352

- IAG must be clarified. The proposed label states bo th: “For vegetable transplants in and around greenhouses,” as well as “Do not apply to greenhouse or field grown vegetables, only apply to vegetable transplants g rown in enclosed structures.” Note that both use patterns have been considered in this risk a ssessment and neither would result in occupational risk estimates of concern.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 12 of 85 2.3.3 Recommendations f rom Residential Assessment

There are no recommendations based on the residential exposure and risk assessment.

3.0 In troduction

Cyantraniliprole is a new second

- generation RyR insecticide currently undergoing global joint review. It is a systemic insecticide that is mobile in both the xylem and phloem of plants. Cyantraniliprole belongs to the diamide class of chemistry whose pes ticidal MOA is through unregulated activation of insect RyR channels. This then leads to internal calcium store depletion and impaired regulation of muscle contraction, causing paralysis and eventual death of the insect.

Cyantraniliprole has been jointly developed by DuPon t and Syngenta, with a proposal for one technical product and 14 U.S. end

- use product (EP) registrations, including several agricultural food

- uses (PP# 1F7894 ) and various residential use sites.

3.1 Chemical Identity

Table 3.1 Test Com pound Nomenclature

Chemical Structure

Empirical Formula C 19 H 14 BrClN 6 O 2 Common Name c yantraniliprole Company experimental name DPX

- HGW86; SYN545377

IUPAC name 3

- b romo

- 1

- (3

- chloro

- 2

- pyrid yl)

- 4 ’

- cyano

- 2 ’

- methyl

- 6 ’

- (methyl carb am o yl)

- pyrazole

- 5

- carboxanil ide

CAS Name 3

- b romo

- 1

- (3

- chloro

- 2

- pyridinyl)

- N

- [4

- cyano

- 2

- methyl

- 6

- [(methylamino)carbonyl]phenyl]

- 1 H

- pyrazole

- 5

- carboxamide CAS Registry Number 736994

- 63

- 1

End

- use product/EP 352

- IAG, 18.66% SX; 352

- IAI, 18.66% SC; 352

- IAN, 18.66% SC; 352

- IAT, 50% FS; 352

- ILT, 50% FS; 352

- ILD, 10.2% SE; 352

- ILT, 10.26% OD. Chemical Class Anthranilic diamide Known Impurities of Concern None



### 3.2 Physical/Chemical Characteristics

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 13 of 85 The physicochemical properties of the technical grade of cyantraniliprole are summarized in A ppendix D , Table D .1 . The log of the oc tanol/wat er partition coefficient is 1.9, which indicates a lack of fat solubility and

, therefore

, low propensity to bioaccumulate i n fatty tissue or milk. The low coefficient also suggests low potential for dermal absorption. A t 20°C , t he Henry’s Law con stant was calculated to be 1.7× 10 - 13 

### Pa/m 3 

### /mol (1.7× 10 - 18 

### atm· m 3 

### /mol) based on vapo r pressure and water solubility. Thus, c yantraniliprole is unlikely to volatilize significa ntly

. Cyantraniliprole is hydrolytically stable under acid and neutral conditions

, and has so me water solubility (0.014 g/L) which suggests persistence in ground water. However, this is counterbalanced by lack of photolytic stability, which would impact surface waters.

3.3 Pesticide Use Pattern

Cyantraniliprole has been jointly developed by DuPont an d Syngenta, with a proposal for one
t echnical product and 14 U.S. EP registrations, including agricultural food

- uses. The agricultural uses include foliar, soil, and seed treatment to various crops including cotton, fruits, oilseeds, and vegetables. The residential uses include turfgrass, ornamentals, and structural buil dings (including indoor crack/crevice and outdoor broadcast). The proposed formulations include the 

### following : flowable suspension (FS), granular (G), oil dispersion (OD) , suspension concentrate (SC) , suspoemulsion (SE)

, and water dispersible gran ular (WG ). A summary of all proposed EPs is summarized in Table 3.3 , and a detailed use pattern is summarized in Appendix A, Table A.1

.

Table 3.3 Summary of Proposed Cyantraniliprole Products (DuPont and Syngenta Labels)

Trade Name EPA Reg.

File Symbol Number % A ctive

I ngredient Formulation

Type a Target Crop/Use Site

DuPont

DuPontTM HGW86 fly control bait 352

- IAE 0.5% G (ready

- to

- use) residential, commercial, and agricultural

structures (including hotels, kennels, schools, food/beverage processing plants, poultry/livestock housing, horse stables, and food/feed handling establishments)

DuPontTM HGW86 GH & N insect control 352

- IAG 18.66 % (1.67 lb ai/gallon) SC ornamental plants/shrubs/tree s and vegetable transplants in and around greenhouses, nurseries, interior plantscapes, lath and shadehouses (trees (including non

- fruit bearing and nut trees), shrubs, evergreens, bedding plants, flowering plants, flowers, foliage plants, ground covers, v ines (non

bearing), interior plantscape plants, and vegetable transplants (including fruiting, leafy, and tuberous/corm))

DuPontTM HGW86 SC insect control 352

- IAI 18.66% (1.67 lb ai/gallon) SC single and multi

- family residential buildings, schools, institutional, commercial, agricultural and industrial facilities (including warehouses, apartments, supermarkets, restaurants, motels, hotels, hospitals, daycares, and food handling/storage/processing establishments, animal production facilities, feedlots , broiler houses, livestock barns, pet kennels) and transportation equipment such as aircraft, trains, ships, boats and buses

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 14 of 85 Table 3.3 Summary of Proposed Cyantraniliprole Products (DuPont and Syngenta Labels)

Trade Name EPA Reg.

File Symbol Number % A ctive

I ngredient Formulation

Type a Target Crop/Use Site

DuPontTM HGW86 T&O insect control 352

- IAL 18.66% (1.67 lb ai/gallon) SC landscape and recreational turfgrass (including golf cours es), sod farms, ornamental plants and interior plantscapes DuPontTM VerimarkTM insect control powered by CyazypyrTM 352

- IAN 18.66 (1.67 lb ai/gallon) SC Brassica vegetables, cucurbit vegetables

, f ruiting vegetables, leafy vegetables, tuberous and corm vegetables, citrus, potato seed pieces DuPontTM CyazypyrTM Technical 352

- ILA 96.7% white fine powder solid all proposed uses

DuPontTM Dermacor® Z

- 103 insecticide seed
treatment 352

- ILI 50.0% (5.21 lb ai/gallon) FS rapeseed (canola), mustard seed

DuPontTM ExirelTM insect control powered by CyazypyrTM 352

- ILO 10.20 % (0.83 lb ai/gallon) SE Brassica vegetables, bulb vegetables, cucurbit vegetables, fruiting vegetables, leafy vegetables, bushberries (subgroup 13

- 7B), citrus fruit, pome fruit, stone fruit , tree nuts, commercial greenhouse grown (to harvest: eggplant, pepper, tomato ) DuPontTM BeneviaTM insect control powered by CyazypyrTM 352

- ILT 10.26% (0.83 lb ai/gallon) OD bulb vegetables, cotton, oil seed crops, tuberous and corm vegetables, tree nuts

Syngenta

Mainspring Insecticide (MAI with thiamethoxam) 100

- RUEE 20.0% (3.2 oz ai/lb) WG o rnamental plants, fruit and nut trees (non

bearing), and forest seedlings grown in greenhouses, lath and shade houses, containers, field nurseries and interiorscapes

, vegetable plants grown for transplant and re

sale to consumers (fruiting vegetables, cucurbit vegetables, B rassica vegetables) A16901B Residential Insecticide 100

- RUEG 20.0% (3.2 oz ai/lb) WG residential landscape plants

A17960A ST Insecticide 100

- RUEN 48.8% (600 g ai/L) FS potato seed pieces, sunflower seeds

A16901B CP Insecticide (MAI with thiamethoxam) 100

- RUER 20.0% (3.2 lb ai/oz) WG Brassica vegetables, cucurbit vegetables, fruiting vegetables, leafy vegetables, tuberous and corm vegetables

A16901B Turf Insecticide 100

- RUEU 20.0% (3.2 lb ai/oz) WG turfgrass including golf courses, institutional, commercial and residential lawns, sod farms, sports fields, parks, municipal grounds and cemeteries A17960B ST Insecticide 100

- RURI 48.8% (600 g ai/L) FS potato seed pieces, sunflower seeds

a Formulation codes: G = granular

, SC = suspension concentrate, SE = suspoemulsion, WG = water dispersible granules, OD = oil dispe rsion, FS = flowable suspension

.



### 3.4 Anticipated Exposure Pathways

H umans may be exposed to cyantraniliprole in food and drinking water, since cyantraniliprole may be applied directly to growing crops and application may result in cyantraniliprole reaching surface and ground sources of drinking water. There are also resid ential uses of cyantraniliprole,

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 1 5 of 85 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 also a potential for post

- application exposure for workers re

entering treated fields.

This is the first aggregate risk assessment prepared for the proposed uses of cyantraniliprole. This risk assessment considers all of the exposure pathways based on the proposed new uses of cyantraniliprole.

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 O rder 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.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 tha t 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 co nsumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individu als (CSFII) and /or the CDC under the 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, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess di etary 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 applicator s 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 mod els 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

C yantraniliprole belong s to the anthranilic diamide class o f pesticides. Anthranilic diamide s are potent activators of RyR s ; they control insects through unregulated activation of RyR channels leading to internal calcium store depletion that impairs regulation of muscle contraction. Insects exposed to a nthranili c diamide s exhibit general lethargy and muscle paralysis , ultimately followed by death (Cordova et al., 2006).

RyR s are present across species and their rol e is similar across species. However, primary sequence diversity indicates differences between the isoforms within and across species. I nsects possess a single form of RyR which is distributed in muscle a nd neuronal tissue . Whereas

m ammals possess three forms of RyR : (1) RyR1 which is di stributed primarily in skeletal, (2) RyR2 which is distributed p rimarily in cardiac muscle, and (3) RyR3 which is heterogeneously

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 16 of 85 distributed. M ammalian RyRs are substantially less sensitive to the effects of anthranilic diamide s than the insect RyR, ranging from 350 to >25 00 times less sensitive (Satelle et al., 2008; Lahm et al., 2009)

. This selectivity indicates relatively low mammalian toxicity in comparison to other pesticides that act on neuronal receptors. As seen in the cyantraniliprole toxicity studies relevant for human health, lethargy or effe cts on muscle control were not observed, su pporting the concept that RyRs may not be the primary target in mammals . Instead, effects on the liver and thyr oid are the most sensitive and are being used to derive PODs

.

4.1 Toxicology Studies Available for A nalysis

All of the required toxicity studies have been submitted to support the proposed food

- use registrations for cyantraniliprole and the potential exposure scenarios associated with this action

. Furthermore, subchronic toxicity studies i n rats, mice, and dogs contain additional data on liver enzymes, thyroid hormones, and metabolite measurements (beyond what is typically required by Agency guidelines)

.

The toxicology database is acceptable for characterizing cyantraniliprole hazard . It includes the following toxicity studies: 14

- day oral, 28

- day oral, 90

- day oral, 28

- day dermal

, 28

- day inhalation , 2

- year dietary c ombined c hronic/ c arcinogenicity , 2

- generation r eproduction study, acute/subchronic neurotoxicity , and m etabolism and p harmacokinetic in r ats; 28

- day oral, 90

- d ay oral , and carcinogenicity in mice; 28

- d ay

- oral, 90

- day oral , and 1

- year dietary in dogs; developmental studies in rats and ra bbits; m utagenicity and g enotoxicity studies in b acterial &

m ammalian m odel s ystems ; 28

- day dietary immunotoxicity studies in r ats and m ice ; and in vivo and in vitro dermal absorption factor studies on the SC, SE

, and OD formulations.

Several metabolites which were not identified in the rat metabolism studies (IN

- JSE

- 76, IN

PLT97, IN

- F6 L99, and IN

- N5M09) were tested fo r mutagenic potential, and a 28

- day oral toxicity study was conducted with IN

- JSE

- 76. Mechanistic studies on the adrenal and thyroid glands , and an in vit r o thyroid peroxidase inhibition study are also available. Summarie s of all toxicology studies are presented in the Toxicology Disciplinary Chapter ( DP 408479

, W. Phang, 11/21/2012 )

.

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

ADME was evaluated in male and female rats following single and repeated low

- dose (10 mg/kg) administration , as well as a single high

- dose (150 mg/kg) administration. A bile cannul ation study was conducted with both single low

- and single high

- dose administration. All of the metabolism studies were conducted with bo th [Cyano

14 

### C]

- and [pyrazo

- carbonyl

14 

### C]

- cy antraniliprole. The data do not show an appreciable difference in ADME between the two labeled compounds. Therefore, the following discussion does not reference specific radiolabel s

. The data also do not show a significant difference in ADME between single (at the low dose level of 10 mg/kg/day) and multiple (at 10 mg/kg/day) dosing and the results following single dosing are typical of what was seen following multiple dosing.

Cyantraniliprole i s readily absorb ed , and the absorption patterns are similar at low and high doses

. The majority of the absorpti on occurs during the first 24 hours (85% of the absorbed

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 17 of 85 radioactivity), and the peak plasma concentration i s reached approximately 2 hour after dosing, regardl ess of the sex or dose level . The values of C max 

### and area

- under

- the

- curve (AUC) demonstrate a greater internal dose in female rats than in male rats . With dose

- normalized AUC, the data suggest a decrease in percent absorption at the high dose in comparison to the low dose.

Following oral dosing, the majority of the dose i s initially associated with the gastrointestinal ( GI ) tract contents followed by uptake and distribution to all tissues. The tissue concentration data show the skin, liver, G I content
, and muscle to have a higher percent of the admi nistered dose. However, each of the four tissues had less than 0.5 % of the administered dose at 168 hours. The mean half lives in plasma a re shorter in males than in females (≈ 42 hours and 129 ho ur in males and females, respectively). As expected, f emale rats contained a greater proportion of 14 

### C residues than male rats

. The absorbed cyantraniliprole was readily and extensively metabolized ; IN

- N7B69 and IN

MYX98 were initially formed due to resp ective hydroxylations of methylphenyl and N

- methyl carbon

. During the initial step, cyantraniliprole also underwent nitrogen

- to

- carbon ring closure to yield IN

- J9Z38

. Further metabolism of the hydroxylated metabolites includes N

- methylation, nitrogen

- to

- carbon cyclization with loss of water mole cule, oxidation of alcohols to c arboxylic acids, amide bridge cleavage, amine hydrolysis, and O

- glucuronidation. The bile was found to be very rich in metabolites, and m ost of the metabolites were found in both ur ine and feces.

Rats given a single 10 mg/kg dose eliminated a greater percentage of the dose in urine ( 22.0 to 34.6% ) than rats dosed with 150 mg/kg ( 11.8 to 14.8% of the dose ). For both dose levels, the majority was e liminated by 24 t o 48 hours after administration with the feces as the major route of elimination. By seven days after dosing, t he mean pe rcentage for total recovery ranged from 88.3 to 96.5% of the administered dose

. Furthermore, t here was no appreciable tendency for bioaccumulation to occur.

4.3 Toxicological Effects

In general, cyantraniliprole adminis tration produces both adverse and adaptive changes in the liver, thyroid gland, and adrenal c ortex . With repeated dosing, consistent finding s of mild to moderate increases in liver wei ghts a re observed across multiple species (rats, mice, dogs). The increases in liver weights a re accompanied by hepatocellular hypertrophy along with increase s in metaboli c liver enzymes (cytochrome P4 50) and UDP

- glucuronyltransferase activity. In rats, the liver effects tend to be more pronounced in females than in males , which is consistent with the pharmacokinetic data that show s a greater internal dose in female rats than in male rats

. M ost of the liver effects seen in the subchronic rat toxicity studies consist of increases in liver weights and hepatocellular hypertrophy . These effects a re considered adaptive, whereas the liver effects in the chronic/carcinogenicity study are considered adverse based on conditions such as foci of cellul ar alteration and focal vacuolation. The data also show that dogs a re more sensitive to liver effects than rats and mice. The adverse liver effects in rats occur at approximately 85 mg/kg with 2

- year treat ment while comparable effects a re seen at 6 mg/kg w ith 1

- year treatment in dogs; a dverse liver effects in mice occur at even higher dose levels (769 mg/kg with 18

- month treatment).

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 18 of 85 The available data also show thyroid hormone homeostasis i s altered in rats following exposure to cyantraniliprole after 28 or 90 days. The findings include decreases in T4 ( and in some cases

, T3 ) and increases in TSH. Thyroid follicular cell hy pertrophy (graded as minimal) i s evident in both the 28

- d ay and 90

- day studies with rats. However, it d oes not persist with longer term dosing because it i s neither present at the one year interim sacrifice nor following the two years of exposure in the 2

- year chronic toxicity/carcinogenicity study in rats

.

A dose

- related increase in the incidence of thyroid follicular epithelial cel l hypertrophy/ hyperplasia occurred in the P 1 

### and F 1 

### adult parental animals of a reproduction study

. Based on the submitted mechanistic data, HED proposes an adverse outcome pathway (AOP) by which cyantraniliprole disrupts thyroid homeostasis via inductio n of hepatic metabolizing enzymes including UDP glucuronyltransferase (Wolf et al., 2006). However, at this time, HED has not conducted a Mode of Action Analysis using the MOA Framework. The PODs selected for risk assessment are derived from liver effect s in the dog. As such, the limited mechanistic data do not inform the PODs. The submitted data do support a conclusion that the effects on the thyroid are secondary to effects on the liver. Specifically, t he available data in the rats is consistent with increases in hepatic cytochrome P450 content and UDP

- glucuronyltransferase activity , which lead to decreases in plasma T4 thyroid hormone level and alteration of thyroid hormone homeostasis , resulting in increases in TSH

. Increased plasma TSH th en stimulates the thyroid gland, which results in the thyroid follicular epithelial cell hypertrophy/hyperplasia.

Effects in the dog studies provide lower NOAELs for use in deriving PODs compared to the rat studies. In the 28

- day, 90

- day, and 1

- year dog s tudies , consistent finding s in clinical chemistry parameters includ e: increases in alkaline phosphatase, alanine aminotransferase

, and gamma glutamyltransferase ; and decreases in total protein, albumin, and cholesterol

. The liver effects in the dog also s how progressive severity with increased duration of exposure. For example, in the 28

- day and 90

- day dog studies, clinical chemistry parameters indicate liver toxicity; while, in the 1

- year dog study, similar clinical chemistry changes a re observed but a r e associated with hepatocellular histopathological changes. When considered in combination with altered enzyme levels, s ignificant increases in abso lute and relative liver weights ar e indicative of adverse liver effects

. Microscopic observations in the l iver include hepatocellular degeneration, inflammation of the portal regions with increased fibrous connective tissues and pigment deposition, and/or bile du ct hyperplasia.

Although it i s not observed in dogs, an i ncreased incidence of adrenal cortical microvesiculation i s mainly seen in males i n both the 90

- day rat and mouse studies

, and in the 2

- generation reproduction rat study

. The microve siculation in affected groups i s predominantly graded as minimal with a few incidences graded as mild . These microvesiculations a re not associated with changes in gross appearance, adrenal cortical cytotoxicity, hypertrophy

, or atrophy. E ffect s on cortical cell function a re not associated with the microvesiculation changes as demonstrated by studies evaluating c orticosterone concentrations in serum and urine with ACTH stimulation. In addition, treatme nt

- related neoplastic changes a re not observed in the adrenal cortex of rats following chronic dietary administration of c y antraniliprole. Rats exposed to c y antran iliprole do show a slight increase in lipid storage in the adrenal cortex. However, t he study report indicates that the adrenal cortex normally shows a microvesiculation appearance under light microscope s resulting from the storage of lipid to be used as precursors for steroid hormone synthesis.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 19 of 85 Although clearly treatment

- related, the slight microvesiculation of the adrenal cortex noted following exposure to cyantraniliprole i s not considered toxicologica lly relevant

.

T he results of the chronic/carcinogenicity in rats and the carcinogenicity study in mice do not show compound

- related increase in tumor incidence. G enotoxic potential i s not found in the mutagenicity study battery.

Cyantraniliprole does not produce developmental toxicity in either rats or rabbits. In rats

, there

a re no m aternal or fetal effects up to the limit dose of 1000 mg/kg/day. In rabbits, reduced pup weight and late gestation aborti ons or early deliveries occur as a result of se vere maternal toxicity. The 2

- generation reproduction study in rats shows that c yantraniliprole has no adverse effect on any reproductive parameter s

. In offspring, reduction s in body weight and organ weight s ( thymus and spleen )

, as well as clinical signs such as dehydration

, a re noted at dietary

conce ntrations where there i s evidence of maternal toxicity. A significant increase in the thyroid weights (absolute and relative) i s seen in P 1 

### and F 1 

### parental animals at 14 mg/kg or above with a corresponding d ose

- related increase in the incidence of the thyroid follicular epithelial cell hypertrophy /hyperplasia in the P 1 

### males and females at 136 mg/kg/day or above and in F1 parental males and fe males at 14 mg/kg/day or above . In the F 1 

### parental males and femal es, the increased incidence of thyroid follicular epithelial cell hypertrophy/hyperplasia occur at lower dose level (14 mg/kg/day) relative to that of the P 1 

### parental males and females (136 mg/kg/day). However, a clear NOAEL (1.4 mg/kg/day) i s demonstrate d for thyroid follicular cell hypertrophy/hyperplasia in the F 1 

### parental animals, which were dosed prenatally and postnatally. Furthermore, the POD s selected for risk assessment (1 or 3 mg/kg/day) are protective of the effects seen in the F 1 

### parental anim als.

Acute and subchroni c neurotoxicity studies reveal no evidence of neurotoxicity. Similarly, cyantraniliprole does not adversely impact the immune system in rats and mice . T he decrease in thymus and spleen weights seen in the 2

- generation reproduction study weights a re not observed in rat or mice. Based on the results of a 28

- day dermal study in rats (as well as the dermal LD 50 

### study), cyantraniliprole d oes not demonstrate a ny appreciable toxicity via dermal exposure. The 28

- day inhal ation toxicity study in rats does not show any adverse systemic or portal of entry effect at the highest concentration tested (100 mg/ m 3 

### , equivalent to 18 mg/kg/day). However, an increase in th e incidence of minimal laryngeal squamous metaplasia i s seen at the highest tested concentration. This finding i s considered to be treatment related but not adverse because the effect i s graded as minimal

. With longer duration of treatment and higher con centrations, the effects seen in the larynx could potentially progress and become adverse.

Cyantraniliprole has no significant acute toxicity via the oral, dermal, and inhalation routes of
exposure (Toxicity Category IV)

. Cyantraniliprole is not an eye o r skin irritant and does not cause skin sensiti z ation.

4.4 Safety F actor for Infants and Children (FQPA Safety Factor)

Based on the currently available toxicity and exposure data, the risk assessment team recommend s that the FQPA Safety Factor be reduce d to 1X for the following reasons: there is a complete toxicological data base

, there is no evidence of neurotoxicity, the POD s based on liver

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 20 of 85 toxicity selected for risk assessment are protective of effects on the thyroid observed in the reproductive toxicity study , and there is no uncertainty in the exposure data. The details for reducing the FQPA safety factor to 1X are detail ed below.

4.4 .1 Completeness o f the Toxicology Database

The toxicology database is complete for cyantraniliprole.

4.4.2 Ev idence of N eurotoxicity

There are no indications in any of the available studies that the nervous system is a target for cyantraniliprole. Effects indicative of neurotoxicity a re not seen in the neurotoxicity screening battery at or above the limit dose levels in acute (2

, 000 mg/kg) and 90

- day (1

, 000 mg/kg) neurotoxicity studies.

4.4.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

There is no evidence of susceptibility in developmental toxicity studies in rats and rabbits. Th e developmental toxicity study in rats is tested up to the limit dose (1

, 000 mg/kg/day). In the rabbit developmental toxicity study decrease in fetal body weight i s seen at a dose higher than that resulting in maternal effect s

. In the reproductive toxicity study, inc reased incidence of thyroid follicul ar epithelium hypertrophy/ hyperplasia occur s in fetal 1 ( F 1 

### ) p arental animals at a dose lower than that for the parental (P) generation. A clear NOAEL (1.4 mg/kg/day) i s established for F 1 

### parental an imals, and the PODs selected for risk assessment from the d og studies (1 or 3 mg/kg/day) are protective of the effect (thyroid effect) seen in the F 1 

### parental animals. In addition the submitted data support the conclusion that the effects on the thyroid a re secondary to effects on the liver. As such, a comparative thyroid study is not required. T he FQPA safety factor can be reduced to 1X

.

4.4.4 Residual Uncertainty in the Exposure Database

The exposure databases are complete or are estimated based on data that reasonably account for potential exposures. The chronic dietary food exposure assessment was conservatively based on 100 % crop treated (CT) assumptions

, and conservative ground and su rface drinking water modeling estimates. New 2012 Residential SOPs a re used to assess post

- application exposure to children including incide ntal oral exposure. The residential post

- application assessment assumes that maximum application rates are applied and that ha nd

- to

- mouth activities occur on the day of application . All of the exposure esti mates are based on conservative, health

- protective assumptions and are not likely to underestimate risk.

4.5 Toxicity Endpoint and Point of D eparture Selections

4.5.1 Dose

- Response Assessment

As discussed in Section 4.3, the thyroid effects in treated animals are a consequence of a series of effects in the liver leading to disturbance in thyroid hormone homeostasis and thyroid effects.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 21 of 85 Therefore, the liver effec ts are the most appropriate in selecting the toxicity endpoints and PODs for risk assessment. The liver effect seen in the 1

- year dog study provide s the most solid basis for a toxicity endpoint and for the POD for chronic dietary exposure risk assessment. In addition, the POD is also protective of the thyroid effects seen in all toxicity studies in rats. For dermal and inhalation exposure risks, route specific studies are considered.

A dermal POD i s not chos en because systemic toxicity i s not seen in the 28

- day dermal toxicity study in rats up to the limit dose (1000 mg/kg/day). The short

- and intermediate

- term incidental oral POD is based on two co

- critical studies: the 28

- day and 90

- day oral toxicity studi es in dogs (NOAEL = 3.0 mg/kg/day). In the special 28

- day study (MRID 48119942) in dog, liver effects were observed at the LOAEL of 35 mg/kg/day. As such, the liver findings in the dog are relevant for the short

- term duration of 1

- 30 days.

The short

- an d intermediate

- term inhalation PODs are based on the results of a 28

- day inhalation toxicity study in rats (NOAEL = 10.08 mg/kg/day for occupational exposure, NOAEL = 7

. 2 mg/kg/day for residential exposure). To determine the inhalation PODs for residentia l and occupational exposure, the Agency’s Reference Concentration (RfC) methodology was used to calculate human equivalent concentrations (HECs). These calculations are detailed in Appendix B, Section B.4. The HECs are based on a 28

- day r at inhalation st udy which show no systemic or port of entry effects at the highest concentration (NOAEL = 0.1 mg/ L ). Because the 28

- day study was conducted 6 hours per day, 5 days per week, the HECs a re adjusted to represent both residential and occupational exposure sce narios. For residential exposure, the HEC i s adjusted to represent continual exposure for 24 hours per day, 7 days per week. For occupational exposure, the HEC was adjusted to represent an average work week for 8 hours per day, 5 days per week. The shor t

- term inhalation HEC of 0.21 mg/L calculated for residential exposures i s then

conver ted to a human equivalent dose NOAEL of 7

. 2 mg/kg/day to allow for comparison to estimated residential inhalation doses (which are in units mg/kg/day). The short

- and in termediate

- term inhalation HEC of 0.05 mg/L calculated for occupational expos ures was also converted to a human equivalent dose NOAEL of 10.08 mg/kg/day to allow for comparison to estimated occupational inhalation doses (which are in units mg/kg/day).

Alt hough a route specific 28

- day inhalation study is use d to establish the intermediate

- term POD,

s ome of the t oxicity data indicate a progression in toxicity with time. The data indicate an approximate three

- fold difference in the LOAEL between a 28

- day oral toxicity stud y in rats (53 mg/kg/day) and a reproduction study in rats (14 mg/kg/day). Theref ore, an uncertainty factor of 3X i s selected to account for using a POD from a short

- term 28

- day day inhalation study to

assess intermediate

- term exposure (1

- 6 months)

. Given that the 28

- day inhalation study does not show any adverse effects at the highest concentration, HED acknowledges that the application of 3X is a conservative approach. However, given the progression of liver effects seen in oral studi es, HED cannot rule out the potential for adverse port of entry or systemic effects given longer exposures.

The toxicity e ndpoints and PODs are summarized in Tables 4. 5.4a and 4 .5.4b , and detailed rationale for the selections is presented in Appendix B , Section B .3

.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 22 of 85 4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

In accordance with the requirements of the FQPA (1996), HED has considered the potential for
concurrent cyantraniliprole exposure via oral, dermal, and inhalation r outes. HED aggregates exposure from different routes for each population if the same toxic effects are seen for that duration of exposure by each route. The dermal route of exposure does not need to be combined with another route of exposure or included in the aggregate risk assessment because there i s no identified dermal hazard

. For adults, the oral and inhalation routes of exposure should not be aggregated since the endpoints of concern are not common.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Cyantraniliprole is classified as “ Not L ikely to be Carcinogenic to Humans” based on the absence of increased tumor incidence in acceptable/guideline carcinogenicity studies in rats and mice. For cancer risk assessment, a non

- linear approa ch is recommended and adequately
account s for all chronic toxicity.

4. 5

. 4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment

Table 4.5.4a Summary of Toxicological Do ses and Endpoints for C yantraniliprole for Use in Non

Occupational /Residential Human Health Risk Assessments a

Exposure/ Scenario Point of

Departure Uncertainty/

FQPA Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects

Acute Dietary (General Population, including Infants and Children and Females 13

- 49 years of age) An effect attributed to a single dose was not identified in the toxicology database



### .

Chronic Dietary (All Populations) NOAEL =

1 mg/kg/day UF A = 10 x

UF H =10 x FQPA SF = 1 x c RfD =

0.01 mg/kg/day cPAD = 0.01 mg/kg/day 1

- year oral study in dogs

.

LOAEL = 6 mg/kg/day based on effects indicative of liver toxicity (increased liver weights and alkaline phosphatase activity), and significant decreases in albumin level.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 23 of 85 Table 4.5.4a Summary of Toxicological Do ses and Endpoints for C yantraniliprole for Use in Non

Occupational /Residential Human Health Risk Assessments a

Exposure/ Scenario Point of

Departure Uncertainty/

FQPA Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects

Incidental Oral Short

- T erm (1

- 30 days) and I ntermediate

- T erms (1

- 6 months) NOAEL =

3 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X LOC = 100 28

- day and 90

- day oral study in dogs. 28

- day LOAEL = 35 mg/kg/day (lowest dose tested) based on decreases in body weight, food consumption, food effic iency, and changes in clinical chemistry (↑ALP, ↓ cholesterol and ↓ albumin). 90

- day LOAEL = 32 mg/kg/day based on a collection of treatment

- related effects indicative of liver toxicity. The effects included decreases in total protein, albumin, and cholesterol in males and females; increases in alkaline p hosphatase in males and females; increases in alan ine aminotransferase in females; and increase s in liver weights in males and females. Dermal Short

- Term (1

- 30 days) A toxicity endpoint was not identified

.

S ystemic toxicity was not seen in 28

- day dermal toxicity in rats at the limit dose (1000 mg/kg/day) . T here are no concerns for developmental or reproductive toxicity or neurotoxicity.

Inhalation Short

- Term (1

- 30 days) NOAEL =

0.1 mg/L UF A = 3X b

UF H = 10X FQPA SF = 1X LOC = 30 28

- day in halation toxicity study in rats. A LOAEL was not established because the highest concentration tested (0.1 mg/L) did not demonstrate any adverse portal of entry or systemic effects. HEC = 0

. 05 mg/L HED = 7. 2 mg/kg/day Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on data showing lack of

trea tment

- related increase in tumor incidence in the rat and mouse carcinogenicity studies. M utagenic concern was not reported in the mutagenicity studies.

a 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. HED = human equivalent dose. HEC = human equivalent concentration. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety F actor. LOC = level of concern. b T he magnitude of the UFs applied is dependent on the methodology used to calculate risk. The RfC methodol ogy takes into consideration the pharmacokinetic (PK) differences, but not the pharmacodynamic (PD) differences . Consequently, the UF for interspecies extrapolation may be reduced to 3X (to account for the PD differences).

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 24 of 85 Table 4.5.4b Summary of Tox icological Do ses and Endpoints for C yantraniliprole for Use in Occupational Human Health Risk Assessments a

Exposure/ Scenario Point of

Departure Uncertainty/

Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects

Dermal Short

- Term (1

- 30 days) and I ntermediate

- T erms (1

- 6 months) A toxicity endpoint was not identified

.

S ystemic toxicity was not seen in 28

- day dermal toxicity in rats at the limit dose (1000 mg/kg/day) . T here are no concerns for developmental or repr oductive toxicity or neurotoxicity.

Inhalation Short

- Term (1

- 30 days) NOAEL =

0.1 mg/L

UF A = 3X b

UF H = 10X LOC = 30 28

- day inhalation toxicity study in rats

. A LOAEL was not established because the highest concentration tested (0.1 mg/L) did not demonstrate any adverse portal of entry or systemic effects. HEC = 0. 05 mg/L HED = 10.08 mg/kg/day

Inhalation Intermediate

- Term (1

- 6 months) NOAEL =

0.1 mg/L UF A = 3X

UF H = 10X UF DB = 3X c LOC = 100 28

- day in halation toxicity study in rats. A LOAEL was not established because the highest concentration tested (0.1 mg/L) did not demonstrate any adverse portal of entry or systemic effects. HEC = 0

. 05 mg/L HED = 10.08 mg/kg/day Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on data showing lack of

trea tment

- related increase in tumor incidence in the rat and mouse carcinogenicity studies. M utagenic concern was not reported in the mutagenicity studies.

a 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 observed adverse effect level. LOAEL = lowest observed adverse effect level. HED = human equivalent dose. HEC = human equivalent concentration. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF DB = database uncertainty factor: use of a short

- term study for intermediate

- term risk assessment. FQPA SF = FQPA Safety F actor. LOC = level of

concern. b T he ma gnitude of the UFs applied is dependent on the methodology used to calculate risk. The RfC methodology takes into consideration the pharmacokinetic (PK) differences, but not the pharmacodynamic (PD) differences . Consequently, the UF for interspecies extr apolation may be reduced to 3X (to account for the PD differences).

c A route specific 28

- day inhalation study is used to establish the intermediate term exposure toxicity endpoint and point of departure. Some of the toxicity da ta on cyantraniliprole indic ate that there was a progression in toxicity with time. The data indicate a ~three

- fold difference in the LOAEL between a 28

- day oral toxicity stud y in rats (53 mg/kg/day) and a reproduction study in rats (14 mg/kg/day)

. Therefore, an uncertainty factor of 3X was selected to account for using a POD from a short

- term 28

- day day inhalation study to assess intermediate

- term exposure (1

- 6 months).

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 25 of 85 5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The plant metabolism studies are adequate

. Studies indicate that metabolism of cyantraniliprole is similar following foliar and soil application to the following crops: rice, lettuce, cotton, and tomato (respectively representing cereal , leafy vegetables , oilseeds, and fruit groups )

. The metabolic fate of this insecticide is complex with the formation of many low level metabolites. However, cyantraniliprole is the major component in ric e, lettuce, cotton, and tomato; r esults in crop field trials confirm that the parent compound is the predominant residue in all crop fractions at various sampling points up to crop maturity. Numerous metabolites were detected in various crop matrices.

In plants, m etabolism of cyantran iliprole appears to proceed via loss of water leading to the formation of the quinazolinone ring, oxidation of the cyano group, and hydroxylation of the N

methyl and/or tolyl methyl group. I mmature and mature samples taken of four different crop
groups co vering a wide range of agro

- climatic conditions show very similar metabolic pathways. The formation of a new metabolite soon after application would be very unlikely

. The chemical names and structures of each metabolite are summarized in Appendix C

, Tabl e C .1.

The nature of the residue s in livestock is adequately understood. The metabolism of cyantraniliprole in poultry and ruminants was found to be similar. The metabolism in livestock is extensive and the amount of unchanged parent present in milk, eggs, and tissues is matrix

dependent. The major components present in various tissues include a combination of the parent compound , IN

- N7B69, IN

- J9Z38, IN

- MLA

- 84, and/or IN

- MYX98.

In rotational crops, the parent compound is the major residue present in soybean, wheat grain, lettuce, and beet root. As in primary crops, many minor metabolites exist

. In livestock feed stuffs such as wheat (forage, hay, and straw) and soybean (foliage) , parent plus a few metabolites (IN

- J9Z38, IN

- JSE76, and/or IN

- MLA84) are present as major residues.

5.1.2 Summary of Environmental Degradation

Since c yantraniliprole is soluble in water (14.2 mg/L at 20oC) , it may move from the tre ated field s t o surface water through run

- off occurring shortly after app lication (i.e. rainfall events). Mobility and p ersistence of cyantraniliprole degradates may be of concern. Due to the stability and mobility of the degradates, some compounds may move from the treated field t o groundwater through leaching. Batch equilibrium studies on cyantr aniliprole and its degradates characterize cyantraniliprole as being moderately mobile (K oc 

### = 157 to 376 mL/g oc 

### ) in test soils. Cyantraniliprole degradates ha ve measured K oc 

### values ranging from 14 to 32,152 mL/g

, indicating that some degradates are more mobile than the parent and some are less mobile than the parent

.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 26 of 85 M ajor routes of dissipation include alkaline

- based hydrolysis, photodegradation in aqueous a nd moist soil environments, and aerobic and anaerobic biotransformation in terrestrial and aquatic environments. Co nsidering abiotic degradation, hydrolytic degradation appears to be pH dependent, with degradation increasing with increasing pH. Photodegr adation appears to be a major degradation pathway in aqueous and moist soil environments. The aqueous photolysis study shows a phototransformation half

- life of about 7.9 hours or 0.33 days

. Biodegradation is an effective dissipation pathway for cyantrani liprole, with anaerobic biotransformation occurring at a faster rate than aerobic biotransformation in terrestrial and aquatic environ ments. It is important to note that all aerob ic soil metabolism degradat ion half

- life values are significantly longer tha n that of the parent cyantraniliprole

. Based on laboratory studies, the major environmental degradates of cyantraniliprole include IN

J9Z38, IN

- NXX69, IN

- QKV54, IN

- RNU71, IN

- JSE76, IN

- JCZ38, IN

- PLT97, and IN

- K5A78

, IN

- K5A78 and IN

- PLT97 . The majority of these degrada tes formed under both microbial

mediated and abiotic processes. Major degradates that continued to increase over time to the study termination in various fate studies include IN

- J9Z3 8, IN

- RNU71, IN

- JSE76, IN

- JCZ38, IN

- K5A78 and IN

- PLT97 . In addition, IN

- K5A77, IN

- K5A79, and IN

- PLT97 were also detected in the terrestrial field studies.

5.1.3 Comparison of Metabolic Pathways

The metabolism/degradation in plant, livestock, rat, rotational crops, and proc essed commodities is similar. The c yantraniliprole parent compound along with the same minor metabolites is the common theme (see Appendix C

, Table C .1).

The nature of the residues in p rocessing studies indicate s that cyantraniliprole degra des under simulated conditions of pasteurization a nd sterilization. Further degrad ation of cyantraniliprole

occur s under hydrolytic conditions representative of baking, brewing, or boiling at 100 C for 60 min utes in a pH 5 solution . In actual processing studies, the formation of these degradates was

ver y minor, except for a few processed commodi ties (such as cooked spinach, tomato puree/paste, and apple sauce).

Rotational crop metabolism i s similar to primary crop metabolism. Cyantraniliprole was the major component of the residue at all PBIs ( 30, 120, 365 days). Transfer of cyantraniliprole and its metabolites to animal feed items was higher than observed in the comm odities for human consumption . Inadvertent tolerances for various livestock feed items were necessary and were established based on a PBI of 30 days. Residues are not anticipated in food commodities from a 30

- day PBI or are covered by primary crop commodity tolerances (w ith the exceptions of root and tuber vegetables subgroup 1A and leaves of root a nd tuber vegetables g roup 2 )

.

M etabolism in la ctating goats and laying hens i s similar. Transfer of residue s to poultry commodities was low, and cyantraniliprole was generally the major component of the total radioactive residue approach ( TRR ) in all consumable matrices. The available feedstuffs with cyantraniliprole residues produced a relatively low die tary burden for livestock. Residues a re expected in poultry and hog commodities; low levels a re anticipated in ruminant commodities

.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 27 of 85 In the feeding studies, there was no indication o f significant concentration of cyantraniliprole in milk fat or fat tissue.

5.1.4 Residues of Concern Summary and Rationale

Parent cyantraniliprole was detected as a main residue in the metabolism studies, crop field trials

, and livestock feeding studies. Based on this

, it is considered an appropriate marker for primary crops, rotational crops

, and livestock commodities . Thus, parent cyantraniliprole is recommended as the residue of concern ( ROC) for tolerance enforcement. Due to structural similarity a nd lack of toxicity data for the associate metabolites, hazard is expected to be similar.

Primary Crops: Metabolism studies show parent cyantraniliprole as a major residue in rice, lettuce, cotton , and tomato; and IN

- J9Z38 as a major residue in rice and lettuce. However, in lettuce field trials, IN

- J9Z38 was generally absent. The crop field trials show the presence of several metabolites at levels below the LOQ or at significantly lower amounts than parent cyantraniliprole.

Rotational Crops: Parent cyantraniliprole was the main residue in all the commodities for human consumption. Other metabolites were present at similar or lower levels than parent cyantraniliprole in feedstuff commodities only

. Since the metabolites will not be significant contri butors to the overall livestock dietary burden

, inclusion of the metabolites in the residue of concern will not significantly affect the dietary risk assessment.

Processed Commodities: Although metabolites IN

- J9Z38, IN

- N5M09, and IN

- F6L99 were formed un der conditions of heat and/or hydrolysis, only IN

- J9Z38 was generally observed at significant concentrations in a few processed commodities (e.g. cooked spinach, apple sauce). IN

- N5M09 and IN

- F6L99 were found at low levels in apple sauce and cooked spinac h, but were absent (<LOQ) in a variety of other processed commodities

. In addition to parent cyantraniliprole, metabolite IN

- J9Z38 is included as a residue of concern for risk assessment.

Livestock: Feeding studies show that parent cyantraniliprole, IN

- N7B69, IN

- MLA84, IN

MYX98, and/or IN

- J9Z38 are likely to be present in significant amount s in some commodities. These metabolites are assumed to have similar toxic ity to parent cyantraniliprole. In addition to parent cyantraniliprole, metabolites IN

- N7B6 9, IN

- MLA84, IN

- MYX98, and IN

- J9Z38 are included as residues of concern for risk assessment.

Water: Cyantraniliprole is likely to extensively degrade in the environment through several degradation routes to form IN

- J9Z38, IN

- NXX69, IN

- QKV54, IN

- RNU71, IN

- JSE76, IN

JCZ38, IN

- K5A78, IN

- K5A77, IN

- K5A79, and IN

- PLT97. These degradates were major degradates in relevant laboratory studies, formed in the field, or both. In the absence of toxicity data and similar analogs, these degradates are considered no mor e toxic than the parent compound

.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 28 of 85 Table 5.1.4 Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression

Matrix Residues included in Risk Assessment a Residues included in Tolerance Expression

Plants Primary Crop Cyantraniliprole Cyantraniliprole

Rotational Crop Cyantraniliprole Cyantraniliprole Processed Commodities Cyantraniliprole and IN

J9Z38 Cyantraniliprole

Livestock Ruminant Cyantraniliprole , IN

- N7B69, IN

- MLA84, IN

- MYX98

, and/or IN

- J9Z38 b Cyantraniliprole

Poultry Cyantraniliprole

Drinking Water Cyantraniliprole and the degradates listed below c Not Applicable

a Cyantraniliprole is 3

- b romo

- 1

- (3

- chloro

- 2

- pyridinyl)

- N

- [4

- cyano

- 2

- methyl

- 6

- [(methylamino)carbonyl]phenyl]

- 1 H

- pyrazole

- 5

- carboxamide. The names and chemical structures of the metabolites can be found in A ppendix C , Table C .1

. b Parent cyantraniliprole is recommended as residue of concern in all commodities along with the metabolites that are at significant amount s in the commodity under consideration.

c IN

- J9Z38, IN

- NXX69, IN

- QKV54, IN

- RNU71, IN

- JSE76, IN

- JCZ38, IN

- K5A78, IN

- K5A77, IN

- K5A79, and IN

- PLT97.



### 5 .2 Food Residue Profile

Quantifiable residues of cyantraniliprole from foliar application or a com bination of seed
treatment or at

- plant applications and foliar applications were consistently found. The residue from foliar applications was primarily a surface residue, as evidenced by distribution of residue in peel and pulp.

Adequate field trial dat a are available to support the proposed uses on Brassica ve getables (Group 5), b ulb v egetables (Group 3

- 07), b ushberries (Group 13

- 07B), o ilseed s (Group 20),

c itrus f ruit s (Group 10

- 10), c ucurbit vegetables (Group 9), f ruiting v egetables (Group 8

- 10), l eafy v egetables (non

- Brassica ) (Group 4), pome f ruit s (Group 11

- 10), stone f ruit s (Group 12

- 12 ), tree nuts (Group 14), and tuberous and corm v egetables (Subgroup 1C). However, there are no data to support use in food/feed handling, storage, and transport facilities.

Processing studies have been submitted for several crops including potato, tomato, orange, apple, plum, and cottonseed. Tolerances are not needed for most processed commodities, as parent cyantraniliprole did not increase from the RAC to the processed commodity. Cyantraniliprole did concentrate in tomato dry pomace, sundried tomatoes, orange oil, apple puree, apple dry pomace (but not wet), and dried plums. C itrus oil is recognized as a processed commodity for tolerance purposes

. Storage stability data have been submitted for residues of cyantraniliprole and various metabolites in five categories of plant commodity matrices

, in milk

, and in eggs. The storage stability intervals cover th e actual intervals of frozen storage of plant and livestock commodity samples from the crop field trials, processing studies, and livestock feeding studies. C orrections for loss during storage are not needed for any plant or livestock commodity for purpos es of tolerance considerations.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 29 of 85 Based on the livestock metabolism studies , HED concludes that storage stability data for the livestock matrices are unnecessary. This is mainly due to the fact that there was no change in the metabolic profile after 10 months of frozen storage for eggs, muscle

, and fat of hens nor after 6 months of frozen storage for milk, fat, kidney and liver of goats. Furthermore, the egg, milk, and tissue samples from the livestock feeding s tudies were stored frozen and analyzed within 30 days of collection

. Adequate cattle and poultry feeding studies have been submitted. The data indicate that tolerances for milk and the fat, meat, and meat byproducts of cattle, goat, horse, and sheep are needed to support the proposed cyantraniliprole uses , but tolerances are not required for hog and poultry commodities

. The confined rotational crop studies are adequate. A dequate limited and extended field rotational crop studies have been submitted. The studies indicate the presence of non

quantifiable levels of parent residues in/on cereal grains, soybean seed, and legumes, and quantifiable levels in leafy vegetables, foliage of legume vegetables, and some root commodities, at a PBI of 30 days. The studies also indicate the presence of quantifiable levels of parent residues in livestock feed stuffs such as alfalfa, grass hay, and soybean hay. Inadvertent or indirect tolerances for these rotational crops are needed at a PBI of 30 days.

5.3 Water Re sidue Profile

Since cyantraniliprole is a new chemical, there is no monitoring data regarding the concentrations of the parent cyantraniliprole in surface or ground water. The drinking water residues used in the dietary risk assessment were provided by E FED (DP 403747, C. Koper, 11/21/2012 ). This drinking w ater assessment was conducted on the parent cyantraniliprole and numerous degradates. The degradates include d in the drinking water assessment are the following: IN

- J9Z38, IN

- NXX69, IN

- QKV54, IN

- RNU71, IN

- JSE76, IN

- JCZ38, IN

- K5A78, I N

- K5A77, IN

- K5A79, and IN

- PLT97. In the absence of toxicity data and similar analogs, these degradates are considered no more toxic than the parent compound and the TR R was recommended for risk assessment purposes.

The EDW Cs for use in the human health risk assessment are based on the maximum proposed application rates specified in the product labels. EDWCs for the chronic assessments were estimated using two EFED Tier I screening models. For surface water, the FIRST ( F QP A I ndex R eservoir S creening T ool) Version1.1.1 model was used to estimate drinking water concentrations. For ground water, the SCI

- GROW ( Sc reening Concentration in Ground Water) Version 2.3 model was used to predict the maximum acute concentrations presen t in shallow ground water. The model and its description are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/

. Based on FIRST and SCI

- GROW modeling, the surface and ground water EDWCs for the parent cyantraniliprole for various uses are presented in Table 5.3.

F or drinking water derived from surface water, the FIRST model estimated the acute and chronic (annual average) EDWC at 43.14 μ g/L and 24.45 μ g/L, respectively . F or dri nking water derived from ground water
, the SCI

- GROW model estimated the ground water EDWC at 6.33 μ g/L. The

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 30 of 85 EDWC chosen for chronic dietary assessment i s the 1

- in

- 10 year annual mean of 24.45 μ g/L from surface water estimates.

Table 5.3 Maximum Estimated Drinking Water Concentrations (EDWCs) Resulting from Applications of Cyantraniliprole for Various Uses a

Drinking Water Source (Model) Label Use Method Application Rate (interval between applications) b PCA

Adjustment Factor c Peak Day

(ac ute) Conc. Annual

Average (chronic) Conc. μg/L μg/L

Surface Water (FIRST) 352

- ILT

352

- ILO Various

Crops Aerial 3 app @ 0.133 ai /acre (5 days)

1 40.77 23.11

352

- IAN Citrus

Vegetables Chemigation 1 app @ 0.4 ai/acre (NA) 40.75 23.09

352

- ILI Canola

Mustard Seed

Treatment 1 app @ 0.4

a i/acre (NA) 40.75 23.09

352

- IAE Fly Control Bait Broadcast 5 app @ 0.087

a i/acre (7 days) 43.14 24.45

100

- RUEN 100

- RURI Potato Seed Treatment 1 app @ 0.468

ai/acre (NA) 23.84 13.51

Ground Water (SCI

- GROW) 352

- ILT

352

- ILO Various

Crops Aerial 3 app @ 0.133 ai/acre (5 days) --- 5.40 5.40

100

- RUEN 100

- RURI Potato Seed Treatment 1 app @ 0.468

ai/acre (NA) --- 6.33 6.33

a Bold values denote maximum EDWCs. b NA = Not Applicable

. c Percent Cropped Area (PCA) Adjustment Factor = 1 following updated PCA guidance document (2012).



### 5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

A somewhat refined chronic (food and drinking water) dietary assessment was conducted assuming average field trial residues for all proposed crops (except crop subgroup 1A) and that 100% CT. Tolerance

- level residues were adequate to cover residues in all livestock commodities except liver and meat byproducts for which a higher anticipated residue calculations were used. For processed commodities, input values included combined average residues of parent and the metabolite with relevant processing factors. The chronic assessment incorporated empir ical processing factors if available or (Dietary Exposure Evaluation Model) DEEM V ersion 7.81 default processing factors as appropriate. Empirical processing factors were used for potato flakes and chips, tomatoes (paste, puree, dried, and juice), orange juice, apple juice, cottonseed oil, citrus oil, and dried plums. The processing factors for these commodities were set at 1 because the input values included combined residues of the parent and the metabolite with relevant processing factors. Crop field trial data depic ting residues in/on citrus fruit peel s (lemon and orange) w ere available and included into the assessment

. The EDWC of 24.45 μ g/L was incorporated directly into the dietary assessment

.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 31 of 85 5.4. 2 Acute Dietary Risk Assessment

An acute dietary endpoint was not selected for quantitative risk assessment because acute hazard attributable to a single dose was not identified.

5.4.3 Chronic Dietary Risk Assessment

The results indicate that chronic dietary (food and drinking water) exposure and risk estimates do not exceed HED’s LOC for the U.S. population and all population subgroups. T he risk estimate s are not underestimated at 22 % of the cPAD for the general U.S. population and 50 % of the cPAD for children (1

- 2 years old), the mo st highly exposed subgroup. Table 5.4. 4 summarizes the dietary exposure and risk estimates for cyantraniliprole.

The dietary exposure and risk estimates are somewhat refined since they assume average residues for most crops and include empirical processi ng factors. Additional refinements may be implemented such as the incorporation of %CT data.

5.4. 4 Summary Table

Table 5.4. 4 Summary of Dietary (Food and Drinking Water) Exposure and Risk for Cyantraniliprole a

Population Subgroup cPAD Chronic Dietary Dietary Exposure cPAD mg/kg/day mg/kg/day % General U.S. Population

0.010 0.002223 22 All Infants (< 1 year old) 0.004378 44 Children 1

- 2 years old 0.005027 50 Children 3

- 5 years old 0.003738 37 Children 6

- 12 years old 0.002205 22 Youth 13

- 19 years old 0.001484 15 Adults 20

- 49 years old 0.001977 20 Adults 50+ years old 0.002244 22 Females 13

- 49 years old 0.002053 21

a The values for the highest exposed p opulation is bolded

.



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

Residential exposure may occur by the dermal, oral, and inhalation routes of exposures. H owever, since dermal hazard has not been identified for cyantraniliprole, the only exposures of concern are handler inhalation ( for adults ) , and pos t

- application incidental oral ( for children )

. These exposures have been assessed with current policies which include updates to HED’s 2012 Residential SOPs 1 

### along with policy change s for body weight assumptions (N. Tsaur, DP 407964

, 02/26/2013)

.

The end u se products that may lead to residential exposures (handler and/or post

- application
exposure s ) include the following EPs: 1. EPA Reg. No. 352

- IAE (fly bait for use in and around residential structures);

1 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 32 of 85 2. EPA Reg. No. 352

- IAG (foliar and systemic insect control on ornamental plants/shrubs/trees, and interior plantscapes); 3. EPA Reg. No. 352

- IAI (for indoor use as a crack/crevice and for outdoor broadcast in single and multi

- family residential buildings, scho o ls, apartments, and daycares); 4. EPA Reg. No. 352

- IAL (foliar and systemic insect control in landscape and recreational turfgrass, including golf courses and interior plantscapes); 5. EPA Reg. No. 100

- RUEG (outdoor applications to residential landscape plants); and 6. EPA Reg. No. 100

- RUEU (foliar and systemic insect control in turfgrass including golf courses, residential lawns, and recreational turfgrass).

6.1 Residential Handler Exposure

Of all proposed residential uses, only one WG product is intended for hom eowner use: A16901B Residential (EPA Reg. No. 100

- RUEG: outdoor applications to residential landscape plants). However, since the other labels include residential use sites, use by homeowners is possible, and prohibition of use by homeowners is not enforc eable. Thus, residential handler exposure and risk estimates have been calculated for all possible residential exposure scenarios. Including all possible residential exposure scenarios provides a conservative and health protective assessment for the potential for homeowners to use the professionally labeled products on residential use sites. The formulations for the other labels include G and SC.

Residential handler exposure is expecte d to be short

- term in duration. The turf an d ornamental labels indicate that a maximum of two applications are allowed per season. Thus, i ntermediate

term exposures are not likely because of the intermittent nature of applications by homeowners

. Unit ex posure values and estimates for area treated or amount handled were taken from HED’s 2012 Residential SOPs 2 

### (Lawns/Turf; Gardens and Trees; Indoor Environments). The algorithms used to estimate exposure and dose for residential handlers can be found in th e 2012 Residential SOPs 2 

### (Lawns/Turf; Gardens an d Trees; Indoor Environments).

Handler risk estimates were assessed for all possible residential handler scenarios in which homeowners may be exposed to cyantraniliprole. Risk estimates of a ll possible scen arios are not of concern. Short

- term inhalation MOEs range from 2 2

, 0 00 to 22 0 ,000,000 as summarized in Table 6.1

. Furthermore, these calculated risk estimates are highly conservative because the inhalation exposure POD is based on a n exposure duration of 24 hours per day.

2 Available: http://www.ep a.gov/pesticides/science/residential

- exposure

- sop.html

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 33 of 85 Table 6.1 Residential Handler Non

- C ancer Exposure and Risk Estimates for Cyantraniliprole

Application Equipment Crop or Target Inhalation Unit Exposure Maximum

Application Rate a Amount Handled Daily b Inhalation

Dose c MOE d mg/lb ai mg/kg/day
Mixer/Loader/Applicator for Granular Formulations
Push

- Type Rotary Spreader Outdoor areas used for storage of

waste around commercial establishments, commercial operations, and agricultural animal production facilities 0.0026 0.0871 lb ai/A 0.5

acres 0.000 0 0142 5

, 10 0, 000

Belly Grinder 0.039

0.00000200 lb ai/sq ft 1200

sq ft 0.00000117 6

, 20 0, 000
Spoon 0.08 7 100 sq ft 0.000000218 33,000, 000 Cup 0.013 0.0000000325 220, 000

, 000 Hand Dispersal 0.38 0.000 0 00950 7

, 6 0 0,000 Shaker Can 0.013 0.0000000325 22 0 ,000,000

Bait Station/Trap Indoor areas of residential,

institutional, public, agricultural buildings/structures, or food/feed handling establishments (including restaurants, warehouses, supermarkets, hospitals, nursing homes, motels, hotels, schools, daycares, laboratories, computer facilities, aircraft, buses, boats/ships, trains, pet shops and zoos) E xposure is considered negligible

.

Mixer/Loader/Applicator for Liquid Formulations

Manually

Pressurized H andwan d Indoor Spot and Crack / Crevice 1.1 0.00887 lb ai/gal 0.5

gal 0.0 0 00610 12 0 ,000

Outdoor Broadcast: Gardens/Trees 0.018 0.00000719 lb ai/sq ft 1200

sq ft 0.0 0 000194 3

, 70 0 ,000

0.00418 lb ai/gal 5

gal 0.0 0 000470 1

, 50 0 ,000 Outdoor Broadcast: Lawns/Turf

Hose

- End S prayer Outdoor Broadcast: Gardens/Trees 0.0014 0.00000719 lb ai/sq ft 1200

sq ft 0.0 0 0000151 4 8

, 0 00,000

0.00418 lb ai/gal 11

gal 0.0 0 0000804 9 ,0 00,000

Outdoor Broadcast: Lawns/Turf 0.022 0.313 lb ai/A 0.5

acres 0. 0 000431 17 0 ,000

Backpack Outdoor Broadcast: Gardens/Trees 0.14 0.00000719 lb ai/sq ft 1200

sq ft 0. 0 000151 48 0 ,000

0.00418 lb ai/gal 5

gal 0. 0 000365 20 0 ,000 Outdoor Broadcast: Lawns/Turf

Sprinkler C an Outdoor Broadcast: Gardens/Trees 0.0014 0.00000719 lb ai/sq ft 1200

sq ft 0.0 0 0000151 4 8

, 0 00,000

0.0014 0.00418

lb ai/gal 5

gal 0.00 0 000365 2 0 ,000,000

Outdoor Broadcast: Lawns/Turf 0.022 0.00000719 lb ai/sq ft 1000

sq ft 0.00 0 00198 3

, 6 0 0,000

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 34 of 85 Table 6.1 Residential Handler Non

- C ancer Exposure and Risk Estimates for Cyantraniliprole

Application Equipment Crop or Target Inhalation Unit Exposure Maximum

Application Rate a Amount Handled Daily b Inhalation

Dose c MOE d mg/lb ai mg/kg/day

Mixer/Loader/Applicator for Dry Flowable Formulations

Manually

Pressurized H andwand Outdoor Broadcast: Gardens/Trees 1.1 0.00000301 lb ai/sq ft 1200

sq ft 0.0 0 0 0497 14 0 ,000

0.00203 lb ai/gal 5

gal 0.0 0 0 139 5 2 ,0 00 Outdoor Broadcast: Lawns/Turf

Hose

- End S prayer Outdoor Broadcast: Gardens/Trees 0.0014 0.00000301 lb ai/sq ft 1200

sq ft 0.000 0 0 00633 11 0 ,000,000

0.00475 lb ai/gal 11

gal 0.00 000 0 914 7

, 9 0 0,000

Outdoor Broadcast: Lawns/Turf 0.022 0.133 lb ai/A 0.5

acres 0.0 0 0 0182 4 0 0,000

Backpack Outdoor Broadcast: Gardens/Trees 1.1 0.00000301 lb ai/sq ft 1200

sq ft 0.00 0 0497 14 0 ,000

0.00475 lb ai/gal 5

gal 0.0 0 0 327 22 ,0 00

Outdoor Broadcast: Lawns/Turf 0.00203 lb ai/gal 5

gal 0.0 0 0 139 5 2 ,0 00

Sprinkler C an Outdoor Broadcast: Gardens/Trees 0.0014 0.00000301 lb ai/sq ft 1200

sq ft 0.000 0 0 00633 11 0 ,000,000

0.00475 lb ai/gal 5

gal 0.00 000 0 416 1 7

, 0 00,000

Outdoor Broadcast: Lawns/Turf 0.022 0.00000 304 lb ai/sq ft 1000

sq ft 0.00 00 0 0 836 8

, 60 0 ,000

a Based on maximum application rate s on proposed labels: EPA Reg. No. 352

- IAE for granular application to indoor and outdoor areas, EPA Reg. No. 352

- IAI for liquid applications to indoor crack and crevices, EPA Reg. No. 352

- IAL for liquid applications to ornamentals and turf, EPA Reg. No. 100

- RUEE for dry flowable applications to ornamentals , and EPA Reg. No. 100

- RUEU for dry flowable applications to turf. b Based on HED’s 2012 Residential SOPs: Lawns/Turf; Gardens and Trees; Indoor Environments ( http://www.epa .gov/pesticides/science/residential

- exposure

- sop.html ).

c Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or lb ai/ gal) × Amount Handled ( A/day or gallons/day) ÷ BW ( 80 kg adult ). d Inhalation MOE = Inhalation NOAEL (mg /kg/day) ÷ Inhalation Dose (mg/kg/day). Short

- Term Inhalation NOAEL = 7.2 mg/kg/day

. Level of concern = 30.



### 6.2 Post

- Application Exposure

Although residential dermal exposure is expected following the treatment of turf or cracks/crevices, a quantitative post

- application dermal risk assessment was not conducted because a dermal hazard was not identified for cyantraniliprole. Furthermore, a r isk assessment for incidental oral ingestion of granules has not been conducted based on a lack of hazard via the acute dietary route of exposure; and an indoor inhalation risk assessment has not been conducted because the acute inhalation toxicity is low (Toxicity Cate g ory IV)

, and exposure is expected to be negligible based on the low vapor pressure of cyantraniliprole (3.85×10 - 17 

### mm Hg at 20oC) and the low proposed application rate (0.391 lb ai/A)

. Short

- term incidental oral p ost

- application

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 35 of 85 risk estima tes for all scenarios are not of concern to HED ( MOEs range from 290 to 1,000 ,000)

. Furthermore, short

- term incidental oral post

- application risk estimates are protective of intermediate

- term because the POD is the same.

The lifestage (children 1 to < 2 years old) selected for each post

- application scenario is based on an analysis provided as an Appendix in the 2012 Residential SOPs 3 

### . This lifestag e is not the only lifestage that could be potentially exposed for these post

- application scenarios; howeve r, the assessment of these lifestages is health protective for the exposures and risk estimates for any other potentially exposed lifestages.

The end use products that may lead to residential post

- application exposures include the following EPs: 1. EPA Reg. No. 352

- IAE (G fly bait for use in and around residential structures); 2. EPA Reg. No. 352

- IAI (SC crack and crevice use in single and multi

- family residential buildings, schools, apartments, and daycares); 3. EPA Reg. No. 352

- IAL (foliar and systemic insect con trol in landscape and recreational turfgrass, including golf courses and interior plantscapes); and 4. EPA Reg. No. 100

- RUEU (foliar and systemic insect control in turfgrass including golf courses, residential lawns, and recreational turfgrass).

A series of assumptions and exposure factors served as the basis for completing the residential post

- application risk assessment. Each assumption and factor is detailed in the 2012 Residential SOPs 4 

### (Lawns/Turf; Indoor Environments). The algorithms used to estimate residential post

application exposure and dose can be found in the 2012 Residential SOPs 5 

### (Lawns/Turf; Indoor Environments). Based on the SOPs, the deposited residue value for liquid application to indoor cracks/crevices was calculated to be 1.74 μg/cm 2



### . In addition to the SOPs, the registrant has submitted chemical

- specific turf transferrable residue (TTR) data (DP407965, N. Tsaur, 01/ 22 /2013

, Cyantraniliprole. Determination of Transferable Residues of Cyantraniliprole from Turf Treated with Water

- Dispe rsible Granule (WG) and Granule (GR) Formulations of Cyantraniliprole ). The high

- end TTR value chosen to be protective of all exposure scenarios (regardless of formulation applied), is the predicted Day 0 residue from the California site of 0.0282 μg/cm 2



### . This value is based on a target application rate of 0.20 lb ai/A and must be adjusted for the proposed application rates in quantitative post

application risk estimate calculations.

Table 6 .2 presents the post

- application incidental oral MOE values calculated from the following application scenarios: 1. liquid application of cyantraniliprole to turf, 2. granular application to cyantraniliprole to turf, and 3. liquid application of cyantraniliprole to indoor cracks/crevices.

3 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html
4 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html
5 Available: http://www.epa.gov/pesticides/scienc e/residential

- exposure

- sop.html

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 36 of 85 Post

- application risk estimates fo r all scenarios are not of concern to HED (MOEs range from 290 to 1,000,000). The incidental oral scenarios (i.e., hand

- to

- mouth and object

- to

- mouth) should be considered inter

- related and it is likely that they occur interspersed amongst each other

acros s time. However, combining these scenarios would be overly

- conservative because of the conservative nature of each individual assessment. Therefore, the hand

- to

- mouth post

application exposure scenario for children 1 < 2 years old should be considered a protective estimate of children’s exposure to pesticides used indoors. Furthermore, incidental oral risk estimates are highly conservative because the short

- and intermediate

- term incidental oral POD is based on a 90

- day exposure duration.

Table 6. 2 Res idential Post

- Application Non

- Cancer Exposure and Risk Estimates for Cyantraniliprole

Lifestage Post

- Application Exposure Scenario Application Rate a Dose b MOEs c Use Site Route of Exposure mg/kg/day

Children 1 to <2 years old Liquid Application

to Turf ST Hand to Mouth 0.313 lb ai/A 0.00604 500

ST Object to Mouth 0.000184 16,000

ST/IT Incidental Soil Ingestion 0.0000106 280,000

Granular Application

to Turf ST Hand to Mouth 0.0871 lb ai/A 0.000834 3,600

ST Object to Mouth 0.0000511 59,000

ST/IT Incidental Soil Ingestion 0.00000295 1,000,000
Incidental Granular Ingestion Acute dietary hazard not identified. Liquid Application to Cracks/Crevices (Carpet) ST /IT Hand to Mouth

0.0000355 lb ai/sq ft 0.0103 290

ST /IT Object to Mouth 0.00137 2,200 Liquid Application to Cracks/Crevices (Hard Surfaces) ST /IT Hand to Mouth 0.00342 880

ST /IT Object to Mouth 0.000910 3,300

a Based on registered or proposed label (Reg. No s

. 352

- IAE

, 352

- IAI, 352

- IAL ). EPA Reg. No. 352

- IAE for granular application to indoor and outdoor areas, EPA Reg. No. 352

- IAI for liquid applications to indoor crack and crevices, and EPA Reg. No. 352

- IAL for liquid applications to turf. b Dose (mg/kg/day) equations: Hand

- to

- Mouth Dose = hand residue loading ( μ g/cm 2 ) × fraction of hand mouthed (0.127) × surface area of 1 hand (150 cm 2 ) × exposure time (1.5 hrs/day) × # of replenishment intervals/hr (4 int/hr) × (1

- ((1

- saliva extraction factor (0.5))^(Number of hand

- to

- mouth events per h our (13.9 events/hr) ÷ # of replenishment intervals/hr)) ÷ body weight (11 kg). Object

- to

- Mouth Dose = object residue loading ( μ g/cm 2 ) × un it conversion factor (0.001 mg/ μ g) × object surface area mouthed / event (10 cm 2 /event) × exposure time (1.5 hrs/day ) × # replenishment intervals/hr (4 int/hr) × (1

- ((1

- saliva extraction factor (0.50))^(# Object

- to

- Mouth Events/hr (8.8 events/hr) ÷ # replenishment intervals/hr)) ÷ body weight (11 kg). Soil Ingestion = soil residue (μg/g) × ingestion rate (50 mg/day) × conversion factor (0.000001 g/μg) ÷ body weight (11 kg). TTR for liquid application rate of 0.313 lb ai/A = 0.0282 μg/cm 2 × (0.313 lb ai/A ÷ 0.20 lb ai/A) = 0.0441 μg/cm 2

. TTR for granular application rate of 0.0871 lb ai/A = 0.0282 μg/cm 2 × (0.0871 lb ai/A ÷ 0.20 lb ai/A) = 0.0123 μg/cm 2

. Deposited residue for liquid application to cracks/crevices = 1.74 μg/cm 2

. c MOE = NOAEL ÷ Daily Dose (mg/kg/day). ST/IT Incidental Oral NOAEL = 3.0 mg/kg/day. Level of concern = 100.



### 6.3 Residential Risk Estimates for Use in Aggregate Assessment

For the purpose of the cyantraniliprole aggregate human health risk assessment, a summary of the most protective residential exposure risk estimates for all proposed residential uses are provided in Table 6. 3

. Based on the residential use profile

, and the 2012 Revised Residential

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 37 of 85 SOPs, only short

- term inhalation residential handler exposures (for adults) and short

- term incidental oral post

- application exposures (for children) should be included in the aggregate risk

assessm ent

. It is noted that intermediate

- term incidental oral post

- application exposures are possible (i.e. from indoor applications and form soil ingestion due to the persistence of cyantraniliprole); however, the short

- term incidental oral exposures are protectiv e of the possible intermediate

- term incidental oral exposures because the POD for both durations is the same.

Although it is possible for residential handlers to have combined exposures from concurrent turf and ornamental applications (based on the propos ed label for EPA Reg. No. 352

- IAL which would result in an MOE of 9 0

, 0 00 ) 6 

### , the suggested exposure contribution for aggregate risk estimate is based on the most protective risk estimate from dry flowable application to ornamentals only (based on the propos ed label for EPA Reg. No. 100

- RUEE which results in an MOE of 2 2

, 0 00). The most protective risk estimate for children’s post

- application incidental oral exposure s is based on indoor liquid crack/crevice application to carpets which results in an MOE of 29 0.

Table 6. 3 Scenarios Recommended for Aggregate Risk Assessment of Cyantraniliprole

Scenario Daily Dose a MOE b mg/kg/day Adults Residential Handler Inhalation Exposure (Applying Dry Flowables to Ornamentals with a Backpack Sprayer) 0.00032 7 2 2

, 0 00

Children (1 to <2 Years Old)
Post

- Application Incidental Oral Exposure : Hand

- to

- Mouth (After Liquid Application to Cracks/Crevices on Carpet) 0.010 3 29 0

a D aily Dose = See Table 6 .1 for a dult h andler s cenarios and Table 6.2 for post

- application incidental oral scenarios. Adults based on EPA Reg. No. 100

- RUEE (WG). Children based on EPA Reg. No. 352

- IAI (SC). b MOE = NOAEL/ Daily Dose (mg/kg/day)

. ST Inhalation NOAEL = 7

. 2 mg/kg/day. ST Inhalation LOC = 30. ST /IT Incidental Oral = 3 .0 mg/kg/day. ST /IT Incidental Oral LOC = 100.



### 6.4 Residential Bystander Post

- A pplication Inhalation Exposure

Based on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for cyantraniliprole at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure (3.85×10 - 17 

### mm Hg at 20oC), and the low proposed use rate (0. 391 lb ai/A). However, volatilization of pesticides may be a source of post

- applic ation 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 7 

### . The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify

6 EPA Reg. No. 352

- IAL (SC) may lead to concurrent turf and ornamental exposures. A conservative health

protective calculation of these two exposures results in a daily dose of 0.0000431 mg/kg/day (liquid application to law ns/turf) + 0.0000365 mg/kg/day (liquid application to gardens/trees) = 0.0000796 mg/kg/day; thus resulting in a combined MOE of 90,000 (NOAEL of 7.2 mg/kg/day ÷ 0.0000796 mg/kg/day).
7 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 38 of 85 the need for and, subsequently, the way to incorporat e 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 inh alation exposure assessment for

c yantraniliprole

.

6.5 Spray Dri ft

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 method employed for cyantraniliprole

. 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 Agenc y’s Spray Drift website for more information ) 8 

### . 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 d ata 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 with significant risk estimates associated with drift.

Although a quantitative residential post

- application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated a gricultural fields, an inhalation exposure assessment was performed for flaggers. This exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post

- applic ation inhalation exposure scenarios

.

It is noted that the 0.313 lb ai/acre application rate for turf was modeled to estimate post

application residential exposure of children. As this rate is equal to or higher than many of the agricultural applicatio n rates, this scenario is protective of any incidental inhalation exposure of farm children vi a spray drift from agricultural cyantraniliprole applications.

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 quantit ative 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.

7.1 Acute Aggregate Risk

An ac ute aggregate risk assessment was not conducted s ince adverse effect s a ttributable to a single dose were not identified

.

8 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 39 of 85 7.2 Short

- Term Aggregate Risk

There is potential short

- term exposure to cyantranili p r ole via the dietary (which is considered background exposure) and residential (which is consider ed primary exposure ) pathways. For adults, the oral and inhalation routes of exposure should not be aggregated since the endpoints of
concern are not common. For children, the pathways lead to exposure via the dietary oral (backg round) and incidental oral (primary) routes. The children short

- term aggregate risk estimate ( dietary and residential ) is not of concern (as presented in Table 7.2)

. The MOE is 190 which is greater than the LOC of 100.

Table 7.2 Short

- Te rm Aggregate Ri sk Calculations

Population Short

- Term Scenario

NOAEL mg/kg/day LOC a Max

Allowable Exposure b mg/kg/day Average

Food and Water Exposure mg/kg/day Residential

Exposure mg/kg/day c Total

Exposure mg/kg/day d Aggregate

MOE (food, water, and residential) e

Children 1

- 2 years old 3.0 100 0.030 0.005027 0.0107 0.0157 19 0

a Children LOC = 100 (based on inter

- and intra

- species uncertainty factors, each at 10X). b Maximum Allowable Exposure (mg/kg/day) = NOAEL ÷ LOC.

c Re sidential Exposure = Incidental Oral Only for children (See Table 6.3). d T otal Exposure = Average Food and Water Exposure + Residential Exposure.

e Aggregate MOE = NOAEL ÷ Total Exposure. ST Children NOAEL = 3 mg/kg/day. LOC = 100.



### 7.3 Intermediate

- Term Aggregate Risk

For adults, i ntermediate

- term exposure is not expe cted for the residential exposure pathway. Therefore, the intermediate

- term aggregate risk would be equivalent to the chronic dietary exposure estimate. Refer to Section 5.4.3. For children, the incidental oral POD is the same for both short

- and intermediate

- term durations. Thus, the short

- term aggregate risk estimate is protective of potential intermediate

- term exposures and risks. Refer to section 7.2.

7.4 Chronic Aggregate Risk

There are no chronic residential exposure scenarios; therefore , the chronic aggregate risk would be equivalent to the chronic dietary (food and drinking water) risk estimate . Refer to Section 5.4. 3.

7.5 Cancer Aggregate Risk

Cyantraniliprole is classified as “not like ly to be carcinogenic to humans. ” T herefore, an aggregate cancer assessment was not conducted.

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

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 40 of 85 to cyantraniliprole and any other substances and cyantraniliprole does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, there fore, EPA has not assumed that cyantraniliprole has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxic ity 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 m echanism on EPA’s website at http://www.epa.gov/pesticides/cumulative.

9.0 Occupational Exposure/Risk Characterization

Occupational handler and post

- application exposure may occur by the dermal and inhalation routes of exposure only. Since there is no dermal hazard, only inhalation exposures were quantitatively assessed. The results of the occupational handler exposure and risk assessment indicate that short

- and intermediate

- term inhalation risk estimate s are not of concern (N. Tsaur, DP 407964 , 02/26/2013). Appendix F, Tab les F.1 and F .2 summarize all assessed occupational exposure and risk estimates including those fr om proposed seed treatment uses

.

9.1 Short

- and Intermediate

- Term Handler Risk

Agricultural Field Uses Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposu re is expected from the proposed agricultural uses. The quantitative exposure/risk assessment developed for occupational handlers is ba sed on several scenarios which include mixing/loading/applying various formulations of cyantraniliprole, including liqui ds, dry flowables, and granules. The use sites are sum marized in Section 3 .0. Methods of application include aerial, airblast, chemigation, groundboom, seed treatment, and handheld equipment (refer to Appendix F for a detailed list of each scenario )

.

HE D classifies exposures from 1 to 30 days as short

- term and exposures 30 days to six months as intermediate

- term. Exposure duration is determined by many things, including the exposed population, the use site, the pest pressure triggering the use of the pe sticide, and the cultural practices surrounding that use site. For most agricultural uses, it is reasonable to believe that occupational handlers will not apply the same chemical every day for more than a one

- month time frame; however, there may be a larg e agribusiness and/or commercial applicators who may apply a product over a period of weeks (e.g., completing multiple applications for mult iple clients within a region). The area treated or amount handled is b ased on HED Exp oSAC Policy No. 9.1 (refer to Appendix F for these assumptions for each scenario).

It is the policy of HED to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical

- specific data, include PHED 1.1, the AHETF database, the Outdoor Residential Exposure Tas k Force (ORETF) database, or other registrant

- submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting ha ndler exposure that are used in this assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 41 of 85 Exposure Surrogate Reference Table 9 

### ”, which, along with additional information on HED policy on use of surrogate data, incl uding descriptions of the various sources, can be found at the Agency website 10



### . In general, the labels require the chemical

- resistant gloves as PPE

. The results of the occupational handler exposure and risk assessment indicate that short

- and intermediat e

- term inhalation risks do not exceed HED’s LOC (i.e. an MOE < 3 0 for short

- term exposures and an MOE < 100 for intermediate

- term exposures ) at baseline mitigation (no PPE)

. Since the short

and intermediate

- term PODs are the same, the inhalation MOEs are also the same, ranging from 1,200 to 3,900,000

. Note that o nly engineering control (enclosed cockpit) data are available to assess risks to handlers operating aircrafts.

The Agency matches quantitative occupational exposure assessment with appropriate

c haracterization of exposure potential. While HED presents quantitative risk estimates for human flaggers whe n appropriate, agricultural aviation has changed dramatically over the past two decades. According to the 2012 National Agricultural Aviation Asso ciation (NAAA) survey of their membership, the use of GPS for swath guidance in agricultural aviation has grown steadily from the mid 1990’s. Over the same time period, the use of human flaggers for aerial pesticide applications has decreased steadily from ~15% in the late 1990’s to only 1% in the most recent (2012) NAAA survey. The Agency will continue to monitor all available information sources to best assess and characterize the exposure potential for human flaggers in agricultural aerial applications.

HED has no data to assess exposures to pilots using open cockpits. The only data available is for exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the engineering control (enclosed cockpits) and baseline attire (lon g

- sleeve shirt, long pants, shoes, and socks); per the Agency’s Worker Protection Standard stipulations for engineering controls, pilots are not required to wear protective gloves for the duration of the application. With this level of protection, there a re no risk estimates of concern for applicators.

Agricultural Seed Treatment Uses Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from th e proposed seed
treatment uses. The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenarios: 1. Mixing/loading liquids for potato seed piece treatment, 2. Planting potato seed pieces, 3. Mixing/loading liquids for commercial seed treatment, and 4. Planting treated seed.

Occupational seed treatment handlers may experience short

- and intermediate

- term exposure to cyantraniliprole while performing seed treatment activities in commercial settings. In addition,
occup ational secondary handlers may experience short

- and intermediate

- term exposure while planting cyantraniliprole

- treated seeds. No chemical

- specific handler exposure data were

9 Available: http://www.epa.gov/opp00001/science/handler

- exposure

- table.pdf
10 Available: http://www.epa.gov/pesticides/science/handler

- ex posure

- data.html

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 42 of 85 submitted in support of this use pattern. For assessing commercial seed treatme nt and seed planting activities, unit exposure data were taken from HED ExpoSAC Policy 14: SOPs for Seed Treatment. The amount of active ingredient handled depends on the application rate (lb ai/lb seed) and the pounds of seed treated in a day (or the pou nds of seed that can be planted in a day), all of which vary depending upon the seed type. Values for the amount of seed treated and planted per day were obtained from HED ExpoSAC Policy 15.

The results of the occupational handler exposure and risk asse s sment indicate that short

- term inhalation risk estimate s do not exceed HED’s LOC (i.e. an MOE < 3 0 for short

- term exposures) at baseline , without mitigation from PPE. Short

- term exposure risk estimates are protective of intermediate

- term exposure risk est imates because the throughput (amount of seed treated) is greater than, or equal to, the throughput of intermed i ate

- term exposure. The calculated inhalation risk estimates do not exceed HED’s LOC for intermediate

- term exposures (i.e. an MOE < 100 ) at base line, without mitigation from PPE

. The inhalation MOEs range from 370 to 4,000 for primary handlers (treaters) and 2,200 to 190,000 for secondary handlers (planters).

9.2 Short

- and Intermediate

- Term Post

- Application Risk

HED uses the term post

- application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re

entry exposure). Such exposures may occur when workers enter previ ously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Post

- app lication exposure levels vary over time and depend on such things as the type of activity, the nature of the c rop or target that was treated, the type of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post

- application exposure

.

9.2.1 Dermal Post

- A pplication Risk

An occupational post

- application exposure and risk assessment was not conducted because a dermal hazard was not identified for cyantraniliprole.

9.2.2 Restricted Entry Interval

Cyantraniliprole is classified as Toxi city Category IV via the dermal route. It is not irritating to the skin and it is not a skin sensitizer. Typically, the REI specified on the proposed label is based on the acute toxicity of the active ingredient. Under 40 CFR 156.208 (c) (2) (iii), acti ve ingredients classified as Acute III or IV for acute dermal, eye irritation and primary skin irrigation are assigned a 12

- hour REI. However , REIs may be further reduced from 12 hours if certain criteria are met for both the technical material and the di fferent end

- use products in accordance with the Pesticide Registration (PR) Notice 95

- 3 [Red uction of Worker P rotection Standard (WPS) Interim Restricted Entry Intervals (REIs) for Certain Low Risk Pesticides]. 11



### The criteria for reducing REIs include the following: (1) The active ingredient is in Toxicity Category III or IV based upon data for acute dermal

11 Available: http://www.epa.gov/PR_Notices/pr95

- 3.html

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 43 of 85 toxicity, acute inhalation toxicity, primary skin irritation, and primary eye irritation. (2) The active ingredient is not a dermal sensitizer. (3) The active ingredient is not a cholinesterase inhibitor. (4) The active ingredient is not associated with known reproductive, developmental, carcinogenic, or neurotoxic effects. (5) EPA does not possess incident information that are “definitely” or “probably” related to the post

- application exposures to the active ingredient.

With respect to the active ingredient, cyantraniliprole, t hese criteria have been met for the technical and all but two of the proposed EPs

. Since the two products, EPA Reg. No. 352

- ILT and EPA Reg. No . 352

- ILI , have been identified as dermal sen si tizer s , a 12

- hour REI is required to protect agricultural workers from post

- application exposures to cyantraniliprole. Aside from these two products, the 4

- hour REIs listed on all other proposed labels are ad equate

. Table 9.2.2 shows the acute toxicity results for each proposed label and formulation.

Table 9.2.2 Acute Toxicity Results of All Proposed U.S. Registrations for Cyantraniliprole
Reg . No. Formulation Oral Dermal Inhalation Skin Irrit ation Eye Irrit ation Sens itiz ation

352

- ILA 96.7% technical IV IV IV IV IV

- ve

352

- ILT 100 g/l OD IV IV IV IV III +ve

352

- ILO 100 g/l SE IV IV IV III III +ve

352

- IAN 200 g/l SC IV IV IV IV IV

- ve

352

- ILI 625 g/l FS IV IV IV IV IV

- ve

352

- IAE 0.5% RB IV IV w aived a IV IV

- ve

352

- IAI 200 g/l SC IV IV IV IV IV

- ve

352

- IAL 200 g/l SC IV IV IV IV IV

- ve

352

- IAG 200 g/l SC IV IV IV IV IV

- ve

100

- RUER 200 +200 g/kg WG IV IV IV IV III

- ve

100

- RUEE 200 +200 g/kg WG IV IV IV IV III

- ve

100

- RUEG 200 +200 g/kg WG IV IV IV IV III

- ve

100

- RUEU 200 +200 g/kg WG IV IV IV IV III

- ve

100

- RUEN 600 g/l FS IV IV IV IV IV

- ve

100

- RURI 600 g/l FS IV IV IV IV III

- ve

a Waiver request granted (Technical = Tox Cat IV; Bait station, no potential for inhalation exposure, etc.)



### 9.2.3 Inhalation Post

- A pplication Risk

Agricultural/Commercial Outdoor Uses Based on the Agency's current practices, a quantitative post

- application inhalation exposure

a ssessment was not performed for cyantraniliprole at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure ( 3.85×10 - 17 

### mm Hg at 20oC ), and

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 44 of 85 the low proposed use rate (0. 391 lb ai/A). However, there are multiple potential sources of post

application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. 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 12 

### . The Agency is in the process of evaluating the SAP report as well as available post

- application inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occu pational post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post

- application inh alation exposure assessment for cyantra niliprole

. Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pestic ides outdoors is likely to result in higher exposure than post

- application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post

- application inhalation exposure scenarios.

Green house Uses The Worker Protection Standard for Agricultural Pesticides contains requirements for protecting workers from inhalation exposures during and after greenhouse applications through the use of ventilation requirements. 13



### Indoor Commercial Uses Comm ercial applicators do not typically return to the treated areas after an indoor commercial pesticide application (sites such as warehouses, food handling establishments, and hotels, etc.) and thus an occupational post

- application inhalation exposure assess ment was not performed for commercial applicators.

Seed Treatment Uses A post

- application inhalation exposure assessment is not required as exposure is expected to be negligible. Seed treatment assessments provide quantitative inhalation exposure assessm ents for seed treaters and secondary handlers (i.e. planters). It is expected that these exposure estimates would be protective of most post

- application inhalation exposure scenarios.

10.0 References

D. Cordova, E.A. Benner, M.D. Sacher, J.J. Rauh, J.S. Spoa, G.P. Lahm, T.P. Selby, T.M. Stevenson, L. Flexner, S. Gutteridge, D.F. Rhoades, L. Wu, R.M. Smith, Y. Tao. (2006)

. anthranilic diamides: a new class of insecticides with a novel mode of action, ryanodine receptor activation. Pesticide Biochemistry and physiology 84 (2006) 196

- 214

.

12 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
13 40 CFR 170.110, (3) (Restrictions associat ed with pesticide applications)

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 45 of 85 I. Encarnacion, 09/25/2012, DP404411, “ Cyantraniliprole: Report of the Residues of Concern Knowledgebase Subcommittee (ROCKS). ”

S. Funk, 01/25 /2013, DP407961

, “ Cyantraniliprole. Petition for the Establishment of Permanent Tolerances and Registration for Use on Brassica ( Cole ) Leafy Vegetables (Group 5), Bulb Vegetables (Group 3

- 07), Bushberries (Group 13

- 07B), Oilseed (Group 20), Citrus Fruit (Group 10

- 10), Cucu rbit Vegetables (Group 9), Fruiting Vegetables (Group 8

- 10), Leafy Vegetables (non

- Brassica ) (Group 4), Pome Fruit (Group 11

- 10), Stone Fruit (Group 12), Tree Nuts (Group 14), Tuberous and Corm Vegetables (Subgroup 1C), and Food/Feed Handling Establishmen ts. Summary of Analytical Chemistry and Residue Data.”

S. Funk, 01/25/ 2013, DP40796 2 , “ Cyantraniliprole. Application (Syngenta) for Section 3 Registration for Use of WG Formulation on Brassica (C ole) Leafy Vegetables (Group 5), Cucurbit Vegetables (Group 9), Fruiting Vegetables (Group 8

- 10), Leafy Vegetables (non

Brassica ) (Group 4), and for Use of FS Formulation on Sunflower and Tuberous and Corm Vegetables (Subgroup 1C). Summary of Analytical Chemistry and Residue Data. ”

J. Kidwell, 09/27/2012, ToxSAC Report PC Code 090098 , “Cyantraniliprole

- Summary of Toxicology Science Advisory Council (ToxSAC) Meeting of July 19, 2012.”

C. Koper, 11/21/2012, DP403747, “Tier I Drinking Water Exposure Assessment for Cyantraniliprole in Support of New Chemical Registration on Various Crops.”

G.P. Lahm, D. Cordova, J.D. Barry. (2009). New and selective ryanodine receptor activators for insect control. Bioorganic & Medicinal Chemistry (2009) 17 (12): 4127

- 4133.

M. Negussie, 01/29/ 2013, DP407963, “ Cyantranilip role: Chronic Aggregate Dietary (Food plus Drinking Water) Exposure and Risk Assessments for the First Food Uses in Support of a Section 3 Registration Action on Brassica ( Cole ) Leafy Vegetables (Group 5), Bulb Vegetables (Group 3

- 07), Bushberries (Group 1 3

- 07B), Canola (Rapeseed), Citrus Fruit (Group 10

- 10), Cotton, Cucurbit Vegetables (Group 9), Fruiting Vegetables (Group 8

- 10), Leafy Vegetables (non

- Brassica ) (Group 4), Mustard Seed, Oil Seed Crops (Group 20), Pome Fruit (Group 11

- 10), Stone Fruits (Grou p 12), Tree Nuts (Group 14) and Pistachio, and Tuberous and Corm Vegetables (Subgroup 1C).”

D.B. Sattelle, D. Cordova, T.R Cheek. (2008). Insect ryanodine receptors: molecular targets for novel pest control chemical. Invert Neurosci (2008) 8:107

- 119.

P.W. Snyder, E.A. Kazacos, J.C. Scott

- Moncrieff, H. HogenEsch, W.W. Carlton, L.T. Glickman, P.J. Felsburg. (1995). Pathologic features of naturally occurring Juvenile polyarteritis in Beagle dogs. Vet Path (1995) 32:337

- 345.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 46 of 85 N. Tsaur, 0 2 / 28 /2013, DP40 7964, “Cyantraniliprole. Occupational and Residential Exposure and Risk Assessment for the Proposed New Uses of the New Active Insecticide, including Agricultural Uses on Brassica (Cole) Leafy Vegetables (Group 5), Bulb Vegetables (Group 3

- 07), Bushberrie s (Group 13

- 07B), Citrus Fruit (Group 10

- 10), Cotton, Cucurbit Vegetables (Group 9), Fruiting Vegetables (Group 8

- 10), Leafy Vegetables (non

- Brassica ) (Group 4), Oilseeds (Group 20), Pome Fruits (Group 11

- 10), Stone Fruits (Group 12), Tree Nuts (Group 14), Tuberous and Corm Vegetables (Subgroup 1C); Seed Treatment Uses on Canola, Mustard Seed, Sunflowers, and Potatoes; and Residential, Commercial, and Agricultural Uses on Ornamentals, Turfgrass (including Sod Farms), and Structural Buildings (including Indo or Crack/Crevice and Outdoor Broadcast).”

D.C. Wolf, J.W. Allen, M.H. George, et al. (2006). Toxicity Profiles in Rats Treated with Tumorigenic and Nontumorigenic Triazole Conazole Fungicides: Propiconazole, Triadimefon, and Myclobutanil. Toxicologic Pathology ( 2006) 34:895

– 902.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 47 of 85 Appendix A

. Detailed Use Profile Summar y

Table A.1 Summary of Proposed Directions for Use of Cyantraniliprole (DuPont and Syngenta Labels)

Application Timing, Type, and Equipment Formulation

[EPA Reg. No.] Trade Name a Maximum

Application Rate Max. No.

of Apps per Season Max.

Seasonal Application Rate RTI Use Directions and Limitations

days

Brassica (Cole) Leafy Vegetables (Group 5)

Soil at Planting (in

- furrow spray, transplant water treatment, hill drench, surface band, soil shank injection) 18.66% SC

[352

- IAN] VerimarkTM 0.176

lb ai/A

0.00202 lb ai/gal 1 0.176 lb ai/A N/A Only to be applied to the soil by ground or drip

chemigation application equipment. Must be applied uniformly in the root zone. Do not make aerial or airblast applications

. Do not treat plants being grown for transplanting in nurseries. Use this product only in commercial and farm plantings. May be used on crops grown for seed production.

Foliar (ground, aerial) 10.20% SE

[352

- ILO] ExirelTM 0.133

lb ai/A

0.00443 lb ai/gal N/S

0.4 lb ai/A 5 Do not treat plants grown for transplanting. Do

not apply to the soil or through drip irrigation systems. Use this product only in commercial and farm plantings. May be used on crops grown for seed production. Adjuvants may be used (methylated seed oil s; petroleum oil
concentrates ; non

- ionics; organosilicones/ organosilicates). Use a minimum of 10 gallons per acre for all vegetable crops.

Soil ( i n

- furrow spray at seeding or transplanting; post seeding, post transplant, hill drench; drip (trickle) chemigation; shanked into root zone) 20.0% WG

[100

- RUER] A16901B CP 0.175

lb ai/A

0.0175 lb ai/gal 1 NA Use this product only in commercial and farm plantings. Do not use in greenhouses. Do not treat plants grown for transplanting. Apply within 21 days of planting or transplanting. Make only one soil application per growing

season.

Foliar (ground, aerial, chemigation) 20.0% WG

[100

- RUER] A16901B CP 0.0875

lb ai/A

0.00875 lb ai/gal N/S 7 Use this product only in commercial and farm plantings. Do not use in greenhouses. Do not treat plants grown for transplanting. Apply within 21 days of planting or transplanting. Use

a m inimum of 10 gal water per acre for ground application

. Bulb Vegetables (Group 3

- 07)

Foliar (ground, aerial) 10.20% SE

[352

- ILO] ExirelTM 0.133

lb ai/A

0.00443 lb ai/gal N/S 0.4 lb ai/A 5 Do not treat plants grown for transplanting. Do

not apply to the soil or through drip irrigation systems. Use this product only in commercial and farm plantings. May be used on crops grown for seed production. Adjuvants may be used (methylated seed oil s; petroleum oil

con centrates; non

- ionics; organosilicones/ organosilicates). Use a minimum of 10 gallons per acre for all vegetable crops.

Foliar (ground, aerial

, chemigation ) 10.26% OD

[352

- ILT] BeneviaTM 0.133

lb ai/A

0.0133 lb ai/gal N/S 0.4 lb ai/A 5 Do not treat plants grown for transplanting. Do

not apply to the soil or through drip irrigation systems. Use this product only in commercial and farm plantings. May be used on crops grown for seed production. Adjuvants may be used (methylated seed o ils; petroleum oil concentrates; non

- ionics; organosilicones/ organosilicates). Use a minimum of 10 gallons per acre for bulb vegetables.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 48 of 85 Table A.1 Summary of Proposed Directions for Use of Cyantraniliprole (DuPont and Syngenta Labels)

Application Timing, Type, and Equipment Formulation

[EPA Reg. No.] Trade Name a Maximum

Application Rate Max. No.

of Apps per Season Max.

Seasonal Application Rate RTI Use Directions and Limitations

days
Bushberries (Group 13

- 07B)

Foliar (ground, aerial) 10.20% SE

[352

- ILO] ExirelTM 0.133

lb ai/A

0.00443 lb ai/gal N/S 0.4 lb ai/A 5 Do not treat plants grown for transplanting. Do

not apply to the soil or through drip irrigation systems. Use this product only in commercial and farm plantings. May be used on crops grown for seed production. Adjuvants may be used (m ethylated seed oi ls; petroleum oil concentrates; non

- ionics; organosilicones/ organosilicates). Use a minimum of 30 gallons per acre for all fruit and nut crops.

Citrus Fruits (Group 10

- 10)

Soil drench or microsprinkler chemigation 18.66% SC

[352

- IAN] VerimarkTM 0.391

lb ai/A

0.00449 lb ai/gal 1 0.4 lb ai/A N/A For use on citrus nursery stock (trees less than 4

years old). Only to be applied to the soil by ground or drip chemigation application equipment. Must be applied uniformly in the
root zone. Do not make aerial or airblast applications

. Do not treat plants being grown for transplanting in nurseries. Use this product only in commercial and farm plantings. May be used on crops grown for seed production.

Foliar (ground, aerial) 10.20% SE

[352

- ILO] ExirelTM 0.133

lb ai/A

0.00443 lb ai/gal N/S 0.4 lb ai/A 7 Do not treat plants grown for transplanting. Do

not apply to the soil or through drip irrigation systems. Use this product only in commercial and farm plantings. May be used on crops
g rown for seed production. Adjuvants may be used (methylated seed o ils; petroleum oil concentrates; non

- ionics; organosilicones/ organosilicates). Use a minimum of 30 gallons per acre for all fruit and nut crops.

Cotton

Foliar (ground, aerial) 10.26% OD

[352

- ILT] BeneviaTM 0.133

lb ai/A

0.0133 lb ai/gal N/S 0.4 lb ai/A 7 Do not treat plants grown for transplanting. Do

not apply to the soil or through drip irrigation systems. Use this product only in commercial and farm plantings. May be used on crops grown for seed production. Adjuvants may be used (methylated seed oil s; petroleum oil
concentrates ; non

- ionics; organosilicones/ organosilicates). Use a minimum of 10 gallons per acre for cotton. Cucurbit Vegetables (Group 9)
Soil at Planting (in

- furrow spray, transplant water treatment, hill drench, surface band, soil shank injection) 18.66% SC

[352

- IAN] VerimarkTM 0.176

lb ai/A

0.00202 lb ai/gal 1 0.176 lb ai/A N/A Only to be applied to the soil by ground or drip

chemigation application equipment. Must be applied uniformly in the root zone. Do not make aerial or airblast applications

. Do not treat plants being grown for transplanting in nurseries. Use this product only in commercial and farm plantings. May be used on crops grown for seed production. Drip chemigation 18.66% SC

[352

- IAN] VerimarkTM 0.130

lb ai/A

0.00149 lb ai/gal 2

(1 if at

plant app is made) 0.26 0

lb ai/A 10

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 49 of 85 Table A.1 Summary of Proposed Directions for Use of Cyantraniliprole (DuPont and Syngenta Labels)

Application Timing, Type, and Equipment Formulation

[EPA Reg. No.] Trade Name a Maximum

Application Rate Max. No.

of Apps per Season Max.

Seasonal Application Rate RTI Use Directions and Limitations

days

Foliar (ground, aerial) 10.20% SE

[352

- ILO] ExirelTM 0.133

lb ai/A

0.00443 lb ai/gal N/S 0.4 lb ai/A 1 Do not treat plants grown for transplanting. Do

not apply to the soil or through drip irrigation systems. Use this product only in commercial and farm plantings. May be used on crops grown for seed production. Adjuvants may be used (methylated seed oil s; petroleum oil concentrates; non

- ionics; organosilicones/ organosilicates). Use a minimum of 10 gallons per acre for all vegetable crops. Soil (i n

- furrow spray at seeding or transplanting; post seeding, post transplant, hill drench; drip (trickle) chemigation; shanked into root zone) 20.0% WG

[100

- RUER] A16901B CP 0.175

lb ai/A

0.0175 lb ai/gal 1 0.4 lb ai/A NA Use this product only in commercial and farm

plantings. Do not use in greenhouses. Do not treat plants grown for transplanting. Apply within 21 days of planting or transplanting. Make only one soil application per growing

season.

Foliar (ground, aerial, chemigation) 20.0% WG

[100

- RUER] A16901B CP 0.0875

lb ai/A

0.00875 lb ai/gal N/S 0.4 lb ai/A 7 Use this product only in commercial and farm

plantings. Do not use in greenhouses. Do not treat plants grown for transplanting. Apply within 21 days of planting or transplanting. Use a m inimum of 10 gal water per acre for ground application

. Fruiting Vegetables (Group 8

- 10)

Soil at Planting (in

furrow spray, transplant water treatment, hill drench, surface band, soil shank injection) 18.66% SC

[352

- IAN] VerimarkTM 0.176

lb ai/A

0.00202 lb ai/gal 1 0.176 lb ai/A N/A Only to be applied to the soil by ground or drip

chemigation application equipment. Must be applied uniformly in the root zone. Do not make aerial or airblast applications

. Do not treat plants being grown for transplanting in nurseries. Use this product only in commercial and farm plantings. May be used on crops grown for seed production. Drip chemigation 18.66% SC

[352

- IAN] VerimarkTM 0.130

lb ai/A

0.00149 lb ai/gal 2

(1 if at

plant app is made) 0.26 0

lb ai/A 10

Foliar (ground, aerial)

Foliar (greenhouse) 10.20% SE

[352

- ILO] ExirelTM 0.133

lb ai/A

0.00443 lb ai/gal N/S 0.4 lb ai/A 1 Do not treat plants grown for transplanting. Do

not apply to the soil or through drip irrigation systems. Use this product only in commercial and farm plantings. May be used on crops grown for seed production. Adjuvants may be used (methylated seed oil s; petroleum oil
concentrates: non

- ionics; organosilicones/ organosilicates). Use a minimum of 10 gallons per acre for all vegetable crops.
Soil (i n

- furrow spray at seeding or transplanting; post seeding, post transplant, hill drench; drip (trickle) chem igation; shanked into root zone) 20.0% WG

[100

- RUER] A16901B CP 0.175

lb ai/A

0.0175 lb ai/gal 1 0.4 lb ai/A NA Use this product only in commercial and farm

plantings. Do not use in greenhouses. Do not treat plants grown for transplanting. Apply within 21 days of planting or transplanting. Make only one soil application per growing

season.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 50 of 85 Table A.1 Summary of Proposed Directions for Use of Cyantraniliprole (DuPont and Syngenta Labels)

Application Timing, Type, and Equipment Formulation

[EPA Reg. No.] Trade Name a Maximum

Application Rate Max. No.

of Apps per Season Max.

Seasonal Application Rate RTI Use Directions and Limitations

days

Foliar (ground, aerial, chemigation) 20.0% WG

[100

- RUER] A16901B CP 0.0875

lb ai/A

0.00875 lb ai/gal N/S 0.4 lb ai/A 7 Use this product only in commercial and farm

plantings. Do not use in greenhouses. Do not treat plants grown for transplanting. Apply within 21 days of planting or transplanting. Use a m inimum of 10 gal water per acre for ground application

. Leafy Vegetables (non

- Brassica ) (Group 4)

Soil at Planting (in

- furrow spray, transplant water treatment, hill drench, surface band, soil shank injection) 18.66% SC

[352

- IAN] VerimarkTM 0.176

lb ai/A

0.00202 lb ai/gal 1 0.176 lb ai/A N/A Only to be applied to the soil by ground or drip

chemigation application equipment. Must be applied uniformly in the root zone. Do not make aerial or airblast applications

. Do not treat plants being grown for transplanting in nurseries. Use this product only in commercial and farm plantings. May be used on crops grown for seed production.

Foliar (ground, aerial) 10.20% SE

[352

- ILO] ExirelTM 0.133

lb ai/A

0.00443 lb ai/gal N/S 0.4 lb ai/A 1 Do not treat plants grown for transplanting. Do

not apply to the soil or through drip irrigation systems. Use this product only in commercial and farm plantings. May be used on crops grown for seed production. Adjuvants may be used (methylated seed oil s; petroleum oil
concentrates: non

- ionics; organosilicones/ organosilicates). Use a minimum of 10 gallons per acre for all vegetable crops. Soil (i n

- furrow spray at seeding or transplanting; post seeding, post transplant, hill drench; drip (trickle) chemigation; shanked into root zone) 20.0% WG

[100

- RUER] A16901B CP 0.175

lb ai/A

0.0175 lb ai/gal 1 0.4 lb ai/A NA Use this product only in commercial and farm

plantings. Do not use in greenhouses. Do not treat plants grown for transplanting. Apply within 21 days of planting or transplanting. Make only one soil application per growing

season.

Foliar (ground, aerial, chemigation) 20.0% WG

[100

- RUER] A16901B CP 0.0875

lb ai/A

0.00875 lb ai/gal N/S 0.4 lb ai/A 7 Use this product only in commercial and farm

plantings. Do not use in greenhouses. Do not treat plants grown for transplanting. Apply within 21 days of planting or transplanting. Use a m inimum of 10 gal water per acre for ground application

. Mustard Seed

Seed treatment b 50% FS

[352

- ILI] Dermacor® Z

- 103 1.0

lb ai/cwt 1 0.4 lb ai/A 7 Apply as a water

- based slurry prior to planting.

May be applied with other registered seed treatment fungicides and insecticides. Use EPA

approved dye or colorant to ensure that seed pieces are dyed an unnatural color.
Oilseed Crops (Group 20) (see also rapeseed)

Foliar (ground, aerial ) 10.26% OD

[352

- ILT] BeneviaTM 0.133

lb ai/A

0.0133 lb ai/gal N/S 0.4 lb ai/A 7 Do not treat plants grown for transplanting. Do

not apply to the soil or through drip irrigation systems. Use this product only in commercial and farm plantings. May be used on crops grown for seed production. Adjuvants may be used (methylated seed oil s; petroleum oil
concentrates: non

- ionics; organosilicones/ organosilicates). Use a minimum of 10 gallons per acre for oilseed crops.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 51 of 85 Table A.1 Summary of Proposed Directions for Use of Cyantraniliprole (DuPont and Syngenta Labels)

Application Timing, Type, and Equipment Formulation

[EPA Reg. No.] Trade Name a Maximum

Application Rate Max. No.

of Apps per Season Max.

Seasonal Application Rate RTI Use Directions and Limitations

days

Pome Fruits (Group 11

- 10)

Foliar (ground, aerial) 10.20% SE

[352

- ILO] ExirelTM 0.133

lb ai/A

0.00443 lb ai/gal N/S 0.4 lb ai/A 7 Do not treat plants grown for transplanting. Do

not apply to the soil or through drip irrigation systems. Use this product only in commercial and farm plantings. May be used on crops grown for seed production. Adjuvants may be used (methylate d seed oils; petroleum oil
concentrates: non

- ionics; organosilicones/ organosilicates). Use a minimum of 30 gallons per acre for all fruit and nut crops.

Potato

Seed piece
treatment b 18.66% SC

[352

- IAN] VerimarkTM 0.176

lb ai/A

0.010 lb ai/ cwt 1 0.176 lb ai/A N/A Apply as a water

- based slurry prior to planting.

May be applied with other registered seed treatment fungicides and insecticides. Use EPA

- approved dye or colorant to ensure that seed pieces are dyed an unnatural color. Treat seed pieces as c lose to planting as possible. If planting is delayed, do not cover seed pieces as rotting can be accelerated. Best results are obtained if treated potatoes are allowed to dry during transit and planted the same day of
treatment. Seed piece
treatment b 48.8% FS

[100

- RUEN] A17960A ST 0.000135 lb

ai/lb seed 1 0.000135 lb ai/lb seed N/A

Seed piece
treatment b 48.8% FS

[100

- RURI] A17960B ST 0.000135 lb

ai/lb seed 1 0.000135 lb ai/lb seed N/A

Rapeseed (Canola)

Seed treatment b 50% FS

[352

- ILI] Dermacor® Z

- 103 1.0

lb ai/cwt 1 0.4 lb ai/A N/A Apply as a water

- based slurry prior to planting.

May be applied with other registered seed treatment fungicides and insecticides. Use EPA

approved dye or colorant to ensure that seed pieces are dyed an unnatural color.

Stone Fruits (Group 12)

Foliar (ground, aerial) 10.20% SE

[352

- ILO] ExirelTM 0.133

lb ai/A

0.00443 lb ai/gal N/S 0.4 lb ai/A 7 Do not treat plants grown for transplanting. Do

not apply to the soil or through drip irrigation systems. Use this product only in commercial and farm plantings. May be used on crops grown for seed production. Adjuvants may be used (methylated seed oil s; petroleum oil
concentrates: non

- ionics; organosilicones/ organosilicates). Use a minimum of 30 gallons per acre for all fruit and nut crops.

Sunflower

Seed treatment b 48.8% FS

[100

- RUEN] A17960 A ST 0.2

mg a i/ seed

0.00397 lb ai/lb seed 1 0.2 mg ai/ seed

0.00397 lb ai/lb seed N/A Apply as a water

- based slurry prior to planting.

May be applied with other registered seed treatment fungicides and insecticides. Use EPA

approved dye or colorant to ensure that seed pieces are dyed an unnatural color. Seed treatment b 48.8% FS

[100

- RURI] A17960 B ST 1 N/A

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 52 of 85 Table A.1 Summary of Proposed Directions for Use of Cyantraniliprole (DuPont and Syngenta Labels)

Application Timing, Type, and Equipment Formulation

[EPA Reg. No.] Trade Name a Maximum

Application Rate Max. No.

of Apps per Season Max.

Seasonal Application Rate RTI Use Directions and Limitations

days

Tree Nuts (Group 14) and Pistachio

Foliar (ground, aerial) 10.20% SE

[352

- ILO] ExirelTM 0.133

lb ai/A

0.00443 lb ai/gal N/S 0.4 lb ai/A 7 Do not treat plants grown for transplanting. Do

not apply to the soil or through drip irrigation systems. Use this product only in commercial and farm plantings. May be used on crops grown for seed production. Adjuvants may be used (methylated seed oil s; petroleum oil
concentrates: non

- ionics; organosilicones/ organosilicates). Use a minimum of 30 gallons per acre for all fruit and nut crops.

Foliar (ground, aerial) 10.26% OD

[352

- ILT] BeneviaTM 0.133

lb ai/A

0.000443 lb ai/gal N/S 0.4 lb ai/A 7 Do not treat plants grown for transplanting. Do

not apply to the soil or through drip irrigation systems. Use this product only in commercial and farm plantings. May be used on crops grown for seed production. Adjuvants may be used (methylated seed oil s; petroleum oil
concentrates: non

- ionics; organosilicones/ organosilicates). Use a minimum of 30 gallons per acre for tree nuts.

Tuberous and Corm Vegetables (Subgroup 1C)

Soil at Planting (in

- furrow spray, transplant water treatment, hill drench, surface band, soil shank injection) 18.66% SC

[352

- IAN] VerimarkTM 0.176

lb ai/A

0.010 lb ai/ cwt 1 0.176 lb ai/A N/A Only to be applied to the soil by ground or drip

chemigation application equipment. Must be applied uniformly in the root zone. Do not make aerial or airblast applications

. Do not treat plants being grown for transplanting in nurseries. Use this product only in commercial and farm plantings. May be used on crops grown for seed production.

Foliar ( ground, aerial) Chemigation (overhead only) 10.26% OD

[352

- ILT] BeneviaTM 0.133

lb ai/A

0.0133 lb ai/gal N/S 0.4 lb ai/A 5 Do not treat plants grown for transplanting. Do

not apply to the soil or through drip irrigation systems. Use this product only in commercial and farm plantings. May be used on crops grown for seed production. Adjuvants may be used (methylated seed oil s; petroleum oil
concentrates: non

- ionics; organosilicones/ organosilicates). Use a minimum of 10 gallons per acre for tuberous and corm vegetables.

Soil (in

- furrow spray during planting; apply impregnated on dry granula r fertilizer before or during planting; at plant emergence by direct spray to the soil near base of plant and incorporate with irrigation; at plant emergence with overhead chemigation after hilling) 20.0% WG

[100

- RUER] A16901B CP 0.12 5

lb ai/A

0.0125 lb ai/gal 1 0.4 lb ai/A NA Use this product only in commercial and farm

plantings. Do not use in greenhouses. Do not treat plants grown for transplanting. Apply within 21 days of planting or transplanting. Make only one soil application per growing

season

.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 53 of 85 Table A.1 Summary of Proposed Directions for Use of Cyantraniliprole (DuPont and Syngenta Labels)

Application Timing, Type, and Equipment Formulation

[EPA Reg. No.] Trade Name a Maximum

Application Rate Max. No.

of Apps per Season Max.

Seasonal Application Rate RTI Use Directions and Limitations

days
Residential, Commercial, Agricultural Structures (Single and multi

- family residential buildings, schools, institutional, commercial, agricultural and industrial facilities (including warehouse s, apartments, supermarkets, restaurants, motels, hotels, hospitals, daycares, and food handling/storage/processing establishments, animal production facilities, feedlots,

broiler houses, livestock barns, pet kennels) and transportation equipment such as aircraft, trains, ships, boats and buses).

Broadcast or bait station 0.5 % G

[352

- IAE ] HGW86 Fly Control Bait 0.0871

lb ai/A

0.00000200 lb ai/sq ft As

needed Not

specified 7 INTENDED FOR USE BY COMMERCIAL

APPLICATORS ONLY. Broadcast or scatter HGW86 fly control bait using suitable granular spreader equipment or directly from the container evenly to the target areas. Use in indoor areas at all the above described use sites only if HGW86 fly control bait is placed in bait stations. U se commercially available bait stations that are designed to hold granular baits. When bait stations are being used, place them where the stations are inaccessible to children or pets.

Outdoor: broadcast

Indoor: c rack and crevice, including indoor areas with exposed food/feed present 18.66% SC

[352

- IAI] HGW86 SC Insect Control 0.0355

lb ai/1000 sq ft

0.00887 lb ai/gallon As

needed Not

specified 7 INTENDED FOR USE BY COMMERCIAL

APPLICATORS ONLY. Avoid spraying food and feed handling equipment. Do not apply to areas that are routinely washed such as cracks and crevices in tops o f tables, food/feed preparation and prepared food holding surfaces. Do not apply a broadcast or general surface application to interior surfaces of residential or commercial
structures. Do not apply this product to pets, edible crops, or sources of elect ricity. Do not make applications to structures while occupied by livestock, poultry or companion animals. Do not apply to milk rooms or feed rooms. Do not make applications to any animal f eedstuffs, water, or watering equipment. Do not contaminate any animal food, feed, or w ater in and around livestock, poultry, or c ompanion animal housing when making applications.

Ornamentals (Ornamental plants/shrubs/trees and vegetable transplants in and around greenhouses, nurseries, interior plantscapes, lath an d shadehouses (grassy, weedy, mulched, bare soil areas in and around), trees (including non

- fruit bearing and nut trees), shrubs, evergreens, bedding plants, flowering plants, flowers, foliage plants, ground covers, vines (non

- bearing), interior plantscape p lants, vegetable transplants (including fruiting, leafy, and tuberous/corm)).

Foliar spray, soil broadcast spray, soil drench, soil injection, or chemigation 18.66% SC

[352

- IAG] HGW86 GH&N Insect Control 0.261

lb ai/A

0.00326 lb ai/gal 2 0.418 lb ai/A 7 Do not apply this product with aerial application

equipment. Do not apply to greenhouse or field grown vegetables, only apply to vegetable transplants grown in enclosed structures.

Foliar 18.66% SC

[352

- IAL] HGW86 T&O Insect Control 0.313

lb ai/A

0.00418 lb ai/gal 2 0.418 lb ai/A 7 Do not apply this product through any type of

irrigation system. Do not apply this product with aerial application equipment. Do not use on plants being grown for sale or other commercial use; or for commercial seed
pr oduction. Do not apply this product in commercial nurseries and greenhouses.

Foliar, soil, chemigation, or handheld equipment 20% WG [100

- RUEE] Mainspring Insecticide 0.131

lb ai/A

0.00131 lb ai/gal 2 0.263 lb ai/A 14 Do not apply with aerial equipment.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 54 of 85 Table A.1 Summary of Proposed Directions for Use of Cyantraniliprole (DuPont and Syngenta Labels)

Application Timing, Type, and Equipment Formulation

[EPA Reg. No.] Trade Name a Maximum

Application Rate Max. No.

of Apps per Season Max.

Seasonal Application Rate RTI Use Directions and Limitations

days

Soil (individual fire ant mound treatment) 20% WG [100

- RUEE] Mainspring Insecticide 0.00475

lb ai/gal NA NA NA For small mounds (<6 inch in diameter) apply 1 gal of water per m ound and for larger mounds apply 2

- 3 gal of dilute solution per mound for optimum control. Direct the application to the center of the mound, including a 6

- inch diameter circle.

Foliar 20% WG

[100

- RUEG] A16901B Residential 0.000781

lb ai/gal 2 0.00156 lb ai/gal 7 Mix 1 teaspoon in 1 gallon of water.

Apply as a thorough cover spray. 1 gallon treats plants in a 400 square feet area.

Turfgrass (including golf courses, institutional, commercial and residential lawns, landscape, recreational, sod farms, sports fields, parks, municipal grounds and cemeteries).

Foliar 18.66% SC

[352

- IAL] HGW86 T&O Insect Control 0.313

lb ai/A

0.00418 lb ai/gal 2 0.418 lb ai/A 7 Do not apply this product through any type of

irrigation system. Do not apply this product with aerial application equipment. Do not use on plants being grown for sale or other commercial use; or for commercial seed production. Do not apply this product in commercial nurseries and greenhouses.

Foliar 20% WG

[100

- RUEU] A16901B Turf Insecticide 0.133

lb ai/A

0.00203 lb ai/gal 2 0.265 lb ai/A 30 Do not apply this product through any type of

irrigation system.

a Formulation codes: G = granular, SC = suspension concentrate, SE = suspoemulsion, WG = water dispersible granules, OD = oil dispersion, FS = flowable suspension. b cwt = hundredweight (100 lb seed). Seed treatment rate calculations are based on the following assumptions: Mustard seed: 90,000 to 115,000 seeds per lb (assumed to be equivalent to rapeseed/canola). Potato seed pieces: 5 to 11 seed pieces per lb. Rapeseed (canola): 90,000 to 115,000 seeds pe r lb. Sunflowers: 2,000 to 9,000 seeds per lb.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 55 of 85 A ppendix B

. Toxicology Profile and Executive Summaries

B .1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food and non food uses for cyantraniliprole are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table B .1 Summary of Toxicology Data Requirements

Study 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 870.3050 28

- Day Oral (rodent)

................................ ..................... 870.3100 Oral Subchronic (rodent)

................................ ............... 870.3150 Oral Subchronic (nonrodent)

................................ ......... 870.3200 21

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 90

- Day Inhalation (28

- Day Inhalation)

......................... no yes yes CR b
CR b

yes yes

yes yes yes

- yes 870.3700a Developmental Toxicity (rodent)

................................ ... 870.3700b Developmental Toxicity (nonrodent)

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

................................ ................................ . yes yes yes yes

yes yes 870.4100b Chronic Toxicity (nonrodent

- dog )

................................ . 870.4200b Carcinogenicit y (mouse)

................................ ................ 870.4300 Chronic Toxicity /Oncogenicity (rodent

- rat)

.................. no yes yes yes

yes yes 870.5100 Mutagenicity

— Gene Mutation

- bacterial

..................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

................ 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations

... 870.5xxx Mutagenicity

— Other Genotoxic Effects

....................... yes yes yes yes yes

yes yes yes 870.6100a Acute Delayed Neurotoxicity (hen)

............................... 870.6100b 90

- Day Neurotoxicity (hen)

................................ ........... 870.6200a Acute Neurotoxicity Screening Battery (rat)

................. 870.6200b 90

- Day Neurotoxicity Screening Battery (rat)

............... 870.6300 Develop. Neurotoxicity

................................ ................. no

no yes yes CR b -

- yes yes

- 870.7485 General Metabolism

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

................................ ........................ 870.7800 Immunotoxicity

................................ ............................. yes CR b

yes yes

- a
yes

a A d ermal penetration study on the technical grade is not available; however , both in

- vivo and in

- vitro dermal penetration studies on four formulations are available. A human dermal absorption factor was calculated based on these studies. b CR = conditionally required.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 56 of 85 B .2 Toxicity Profile s

Table B .2.1 Acute Toxicity Profile

– Technical Cyantraniliprole

Guideline No. Study Type MRID Results Toxicity Category

870.1100 Acute oral (mouse) 48119957 LD 50 >5000 mg/kg IV

Acute oral (rat) 48119952 LD 50 >5000 mg/kg IV 870.1200 Acute dermal (rat) 48119953 LD 50 >5000 mg/kg IV 870.1300 Acute inhalation

— 4 hour (rat) 48119958 LC 50 >5.2 mg/L IV 870.2400 Acute oral (mouse) 48119957 LD 50 >5000 mg/kg IV

870.2500 Skin irritatio n ( rabbit ) 48119954 Not irritating

NA

Eye irritation ( rabbit ) 48119955 Slightly irritating; clearing by 72 hours Eye irritation ( rabbit ) 48208421 Not irritating

870.2600 Skin sensitization ( mouse )

local lymph node assay 48208422 Not sensitizing

Skin sensitiz ation ( mouse ) local lymph node assay 48208423 Not sensitizing

Skin sensitiz ation ( guinea pig ) maximiz ation test 48119984 Not Sensitizing

Table B .2.2 Acute Toxicity Profile

– Cyantraniliprole Metabolites

Test Substance Study Type MRID Results Toxicity Category

IN

- JSE76

- 005 Acute oral ( rat ) 48119978 LD 50 >5000 mg/kg IV

IN

- PLT97

- 003 Acute oral ( mouse ) 48122579 LD 50 >5000 mg/kg IV

IN

- F6L99

- 004 Acute oral ( mouse ) 46979929 LD 50 >2000 mg/kg IV

IN

- N5M09

- 003 Acute oral ( mouse ) 48119939 LD 50 >5000 mg/kg IV

Table B .2.3 Subchronic, Chronic , and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

Sub chronic Toxicity Studies

870.3050 2

- Week oral

study

— gavage with metabolism information (rats) 48119938 (2010)

Acceptable /non

- guideline

25, 300, and 1

, 000 mg/kg/day NOAEL =1

, 000 mg/kg/day (HDT). T reatment related effects were not found at any dose levels.

Supplemental data: The kinetic data indicate that the plasma T 1/2 = 3.84, 6.41, and 5.44 hours fo r the 25, 300, and 1

, 000 mg/kg /day

, respective ly. T max = 2.00, 2.33, and 1.67 hours i n the 25, 300, and 1

, 000 mg/kg /day groups, respectively. The tissue concentration in peripheral fat was <0.1% at 24 hrs after dosing. Total cytochrome P

- 450 content in male or female rats was minimally elevated. I n male rats, cyantraniliprole i s an inducer of cytochrome P

- 450 isozyme CYP1A1 and CYP2B1. In female rats, cyantraniliprole i s an inducer of cytochrome P

- 450 isozyme CYP2B1.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 57 of 85 Table B .2.3 Subchronic, Chronic , and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.3050 28

- Day feeding

study (mice) 48119940 (2009)

Acceptable/guideline

0, 300, 1

, 000, 3 ,000, and 7

, 000 ppm

M: 0, 53, 175, 528, and 1

, 261 mg/kg/day

F: 0, 63, 212, 664, and 1

, 476 mg/kg/day NOAEL = 528/664 (M/F)

. LOAEL = 1

, 261/1

, 476 mg/kg/day (M/F) (highest dose tested). A dverse effects were not found at any dietary concentration s

. Supplemental data: Cyantraniliprole does not induce hepatic

- oxidation in male or female mice. In male mice, the total cytochrome P

- 450 content significantly increased at dietary concentrations of 3

, 000 and 7

, 000 ppm. In female mice, total cytochrome P

- 450 content significantly increased at d ietary concentrations of 300, 1

, 000, 3

, 000, and 7

, 000 ppm. At 3

, 000 and 7

, 000 ppm

, both male and female mice show adaptive liver responses such as increased liver weight and liver enzyme.

870.3050 28

- Day feeding

study (rats) 48119941 (2009)

Acceptable/g uideline

0, 600, 2000, 6000, and 20

, 000 ppm

M: 0, 53, 175, 528, and 1 ,776 mg/kg /day

F: 0, 62, 188, 595, and 1

, 953 mg/kg/day NOAEL for males can not be established due to treated

- related increase in the incidence of thyroid follicular hypertrophy at 53 mg/kg/day (LOAEL) (lowest dose tested).

For females: NOAEL = 62 mg/kg/ day. LOAEL = 188 mg/kg/day based on thyroid follicular cell hypertrophy.

Supplemental data: In male rats, cyantraniliprole i s a mild inducer of hepatic UDP

- glucuronyltransferase acti vity (range from ↑39% at low dose to ↑132% at high dose) while inducing only a minimal effect on cytochrome P

- 450 content. In female rats, cyantraniliprole cause s a slight increase in total hepatic cytochrome P

- 450 content while inducing a somewhat lesser e ffect on hepatic UDP

- glucuronyl transferase activity. Cyantraniliprole does not induce hepatic

- oxidation, a measure of peroxisome proliferation, in male or female rats.

870.3050 28

- Day palatability

study

— dietary (dogs) 48119942 (2007)

Acceptable/non

- guideline

0, 1000, 10,000, and 40

, 000 ppm

M: 0, 35, 311, and 1

, 043 mg/kg/day

F: 0, 35, 335, and 1

, 240 mg/kg /day) NOAEL for male and female dogs could not be determined. LOAEL = 35 mg/kg/day (lowest dose tested) based on decreases in body weight, food consumption, food efficiency, and changes in clinical chemistry (↑ALP, ↓ cholesterol and ↓ albumin).

Supplemental data: Increases in hepatic cytochrome P

- 450 (total and 2B1, 3A2, a nd 4A1/2/3 isozymes) were observed in all male and female dose groups but the increase did not demonstrate a dose related response.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 58 of 85 Table B .2.3 Subchronic, Chronic , and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.3100 90

- Day feeding

toxicity study (mice) 48119943 (2007)

Acceptable/ guideline

48119944 (2007) supplement to 48119943 Provide information about metabolites

0, 50, 300, 1,000, and 7

, 000
ppm

M: 0, 7, 47, 150, and 1

, 092 mg/kg /day.

F: 0, 10, 58, 204, & 1

, 344 mg/kg /day. NOAEL = 150/204 (M/F) LOAEL =1

, 092/1

, 344 (M/F) based on increase d incidence of focal necrosis o f the liver

, and liver weight increase.

Supplemental data: Metabolite analyses showed that IN

- MLA84 was the most prev alent analyte present in male and female mice, followed by cyantraniliprole. Plasma values for all the evaluated metabolites were similar between males and females at comparable dose levels.

870.3100 90

- D ay feeding

study (r ats )

[Interim sacrifice was also conducted on 5/sex/dose on 29 th (♂) day and 30 th day(♀) ] 48119945 (2007)

Acceptable/ guideline

48119946 (2007) Supplement to 48119945

0, 100, 400, 3 ,000, and 20

, 000 ppm

M: 0, 6, 22, 168, and 1

, 147 mg/kg /day

F: 0, 7, 27, 202, or 1 ,346 mg/kg/day Females: NOAEL = 7 mg/kg/day

. LOAEL = 27 mg/kg /day) based on thyroid follicular cell hypertrophy, increased thyroid weights, and alterations in thyroid hormone homeostasis.

Males: NOAEL =168 mg/kg/day

. LOAEL= 1

, 147 mg/kg /day) based on thyroid follicular cell hypertrophy, increased thyroid weights, and alterations in thyroid hormone homeostasis in male rats.

Supplemental data: IN

- M LA84 was the major metabolite present in the plasma of male and female rats followed by parent cyantraniliprole and IN

- J9Z38.

870.3150 90

- Day oral study

—

d ietary (dogs)

[ T3, T4, TSH, and cytochrome P450 were also measured ] 48119948 (2007)

Acceptable/guideline

48119947 (2007) Supplement to 48119948

0, 30, 100, 1

, 000, and 10

, 000
ppm

M: 0, 1, 3, 32, and 281 mg/kg /day

F: 0, 1, 3. 34, and 294 mg/kg/day) NOAEL = 3 mg/kg/day

. LOAEL = 32 mg/kg/day based on based on a collection of treatment

- rel ated effects indicative of hepatotoxicity. The effects included decreases in total protein, albumin, and cholesterol in males and females; increases in alkaline phosphatase in males and females, and increases in alanine aminotransferase in females, and inc rease liver weights in males and females. Supplemental data indicated the major analyte in the plasma was the parent cyantraniliprole. Thyroid hormone levels were not consistently changed.

870.3200 28

- Day d ermal

study (r ats ) 48119970 (2009)

Acceptable/guideline

0, 100, 300, and 1 ,000 mg/kg /day (6 hours /day) NOAEL ≥ 1

, 000 mg/kg/day (highest dose tested). Systemic toxicity was not found.

870.3465 28

- Day i nhalation

study (rats) 48663602 (2011)

Acceptable non guideline

0, 1, 10, and 100 mg/m 3 NOAEL = 100 mg/m 3 (0.1 mg/L) . S ystemic or portal of entry effects were not seen at the highest concentration. However, at 100 mg/m 3 , an increase in the incidence of minimal laryngeal squamous metaplasia was found; it was considered to be
treatment

- related and non adverse.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 59 of 85 Table B .2.3 Subchronic, Chronic , and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

Developmental and Reproductive Toxicity Studies

870.3700a Prenatal

d evelopmental study

— g avage (r ats ) 48119968 (2009)

Acceptable/guideline

0, 20, 100, 300, and 1

, 000 mg/kg/day ( GD 6 to 20 ) Both maternal and developmental NOAELs = 1

, 000 mg/kg/day, the highest dosage tested. LOAELs were not established.

870.3700b Prenatal

d evelopmental study

— g avage (rabbits ) 48119969 (2009)

Acceptable/guideline

0, 2 5, 100, 250, and 500 mg/kg /day ( GD 7

- 28 ) Maternal: NOAEL = 25 mg/kg/day

. LOAEL = 100 mg/kg/day based on increased mortality, increased incidences of diarrhea and reduced and/or absent of feces, decreased body weights, and reduced food consumption. Developmental: NOAEL=100 mg/kg /day. LOAEL was 250 mg/kg/day based on reductions in me an fetal body weights.

870.3800 2

- Generation

r eproduction study

— diet ary ( rats) 48119967 (2011)

Acceptable/guideline

0, 20, 200, 2

, 000, and 20

, 000
ppm

0, 1.4, 14, 136, and 1

, 344 mg/kg/day based on premating compound intake in P 1 females Parental NOAEL = 1.4 mg/kg/day. LOAEL= 14 mg/kg/day based on thyroid weight increase and corresponding dose

- related increase in the incidence of thyroid follicular epithelial cell hypertrophy/ hyperplasia.

Reproductive: NOAEL = 1344 mg/kg/day (the highest dose tested) based on the lack of adverse test substance

- related effects on fertility and reproductive parameters at any dose levels in the study. Offspring: NOAEL = 14 mg/kg/day. LOAEL=136 mg/kg/day based on dose

- related decreases in organ weights (thymus and spleen), and pup body weight in the F2 generation pups. Chronic Toxicity Studies

870.4100 Com

bined chronic/ carcinogenicity study ( rats ) 48122577 (2011)

Acceptable/guideline

0, 20, 200, 2

, 000, and 20

, 000 ppm

M: 0, 0.8 , 8.3, 84.8, and 906.6 mg/kg /day

F: 0, 1.1, 10.5, 106.6, and 1

, 160.8 mg/kg/day N OAEL = 8.3 mg/kg /day LOAEL = 84.8 mg/kg/day based on microscopic liver pathology characterized by foci of cellular alteration (clear, eosinophilic, and basophilic) and focal vacuolation.

Cyantraniliprole did not pr oduce compound

- related or dose

- related increase in tumor incidence.

870.4100b 1

- Year o ral study

—

diet art with active ingredient (dogs )

[ a recovery period was also included ] 48119960 (2010)

Acceptable/guideline

48208427 ( 2010) Supplement to 48119960.

0, 40, 200, 1

, 000, and 5

, 000
ppm

M: 0, 1, 6, 27, and 144 mg/kg/day

F: 0, 1, 6, 27, an d 133 mg/kg /day NOAEL = 1 mg/kg/day LOAEL = 6 mg/kg/day based on decreases in albumin levels, statistically significant increases in liver weight and alkaline phosphata se. At the next dose level (1

, 000 ppm, or 27 mg/kg bw/day) histopathological changes characterized by hepatocellular degeneration and inflammatory process with associated increases in alkaline phosphatase (ALP) and alanine aminotransferase (ALT), and decre ases in total protein and albumin were found.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 60 of 85 Table B .2.3 Subchronic, Chronic , and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.4200b 18

- Month

carcinogenicity study ( mice ) 48122578 (2011)

Acceptable/guideline

0, 20, 150, 1,000, and 7

, 000 ppm

M: 0, 2, 16, 104, and 769 mg/kg/day

F: 0, 2, 19, 131, and 904 mg/kg/day NOAEL = 104/131 (M/F) LOAEL = 769/904 (M/F) Based on the finding that cyantraniliprole induced a statistically significant increase in food consumption and a decrease in food efficiency with very little changes in body weights. These changes suggest that the high dose ani mals were unable to adequately utilize food, and it was a compound

- related effect and was considered to be adverse.

Cyantraniliprole did not produce compound

- related increase in tumor incidence. Genotoxicity Toxicity Studies

870.5100 Bacterial reverse

mutation t est ( S

. t yphimurium and E. coli) 48122587 (2010)

Acceptable/guideline Negative. 0, 50, 150, 500, 1

, 500, and 5

, 000 g/plate were tested (+/

- S9). Precipitate was observed at 5

, 000 g/plate.

48119980 (2009) Acceptable/guideline Negative. The dose levels tested were 0, 50, 150, 500, 1

, 500, and 5

, 000 μg/plate (+/

- S9); precipitate was observed at 5

, 000 g/plate.

48208424 (2009) Acceptable/guideline Negative. The dose levels tested were 0, 50, 150, 500, 1

, 500, and 5

, 000 μg/plate. (+/

- S9). Precipitation was observed at 5

, 000μg/ plate.

870.5300 In v itro

mammalian cell gene mutation test (CHO/HGPRT

a ssay) 48122589 (2010)

Acceptable/guideline Negative. of 0, 50.0, 100, 150, 250, and 500 μg/ml (+/

- S9). Ethyl methanesulfonate (EMS) and benzo( a)pyrene (BaP) were used as positive controls.

870.5300 In vitro

CHO/HPRT forward mutation

a ssay 48208443 (2011)

Acceptable/guideline Negative. 0, 10.0, 25.0, 50.0, 100, 250, 500, 750, and 1

, 000 μg/mL were tested. Ethyl methanesulfonate (EMS) and methylch olanthrene (MCA) were used as positive controls. Compound precipitation was observed at concentrations in treatment medium ≥250 g/mL.

870.5375 In v itro

Mammalian chromosome aberration t est with human lymphocytes 48208425 (2009)

Acceptable/guideline Negative. 0, 62.5, 125, 250, 500, 600, 700, 800, and 900 g/mL for the 4

- hour non

- activated and activated treatment conditions, and 0, 31.3, 62.5, 125, 250, 400, 500, 600, 700, and 800 g/mL for the 20

- hour

non

- activated treatment condition.

870.5375 In v itro

Mammalian chromosome aberration t est with human lymphocytes 48208426 (2009)

Acceptable/guideline Negative

. Doses ranged from 125 to 3

, 500 μg/mL for the non

activate d and S9

- activated 4

- hour exposure groups, and from 15.7 to 1

, 500 μg/mL for the non

- activated 20

- hour exposure group. Compound precipitation was recorded at ≥1

, 000 μg/mL.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 61 of 85 Table B .2.3 Subchronic, Chronic , and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.5375 In v itro

Mammalian chromosome aberration t est with human peripheral blood lymphocytes (HPBL) 48122588 (2010)

Acceptable/guideline Negative

. 0, 62.5, 125, 250, 500, 600, 700, 800, and 1

, 000 g/mL for non

- activated 4

- hour; 0, 62.5, 125, 250, 500, 600, 700, 800, and 900 g/mL for activated 4

- hour; and 0, 7.8, 15.6, 31.3, 62.5, 125, 250, 500, and 1

, 000 g/mL for non

- activated 20

- hour. Visible precipitate was ob served in treatment medium at 500 g/mL.

870.5395 (Other Genotoxic

Effects) In vivo Mouse bone marrow micronucleus

— gavage 48208444 (2011)

Acceptable/guideline Negative. Doses were 0, 500, 1 ,000 and 2

, 000 mg/kg by single

dose oral gavage (10 Crl:CD1(ICR) mice/sex/dose)

.

Neurotoxicity Studies

870.6200a Acute n eurotoxicity

study

— g avage (rats) 48119950 (2006)

Acceptable/guideline

0, 250, 1

, 000, and 2

, 000 mg/kg NOAEL = 2

, 000 mg/kg (HDT). A dverse effects

were not observed at any tested dose levels

.

870.6200b 90

- Da y

n eurotoxicity study

— dietary ( rats ) 48119966 (2009)

Acceptable/guideline

0, 200, 2,000, and 20

, 000 ppm

M: 0, 11, 116, and 1 ,195 mg/kg/day

F: 0, 14, 137, and 1,404 mg/kg /day NOAEL = 1

, 195/1

, 404 mg/kg/day (M/F) (HDT). A dverse effects were not observed at any tested dose levels.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 62 of 85 Table B.2.3 Subchronic, Chronic, and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

Metabolism Studies

870.7485 Metabolism s tud y

— ADME ( r at s ) 48119949 (2010)

Acceptable/guideline

Single g avage dose of 10 or 150 mg/kg /day (low

- and high

- dose, respectively) of either [CN

14 C]

- cyantraniliprole or [PC

14 C]

- cyantraniliprole Cyantraniliprole was absorbed re adily either at low (10 mg/kg /day ) or high (150 mg/kg /day) dose with oral dosing (62

- 80% of the administered dose was absorbed). The majority of the absorption occurred during the first 48 hours, and the peak plasma concentration was reached at approximately 2 hour after dosing irrespective of the position of label, sex of the test animal, and dose level. Male low dose half

- lives: CN T 1/2 = 42 hrs; PC T 1/2 = 54 hrs; Female low dose half

- lives: CN T 1/2 = 129 hrs; PC T 1/2 = 117 hrs; Male high dose half

- lives: CN T 1/2 = 62 hrs; PC T 1/2 = 55 hrs; Fem ales high dose half

- lives: CN T 1/2 = 65 hrs; PC T 1/2 = 80 hrs. The distribution data showed that the majority of the dose was initially associated with the GI tract contents and subsequently showed uptake and distribution to all tissues. Female rats reta ined a greater proportion of 14 C residues than male rats. Cyantraniliprole was readily hydroxylated to form IN

- N7B69 and IN

- MYX98. IN

- N7B69 was further metabolized to a glucuronide. Cyantraniliprole also underwent ring closure to generate IN

- J9Z38. The

m etabolites which were found to be greater than 5% of the administered dose were bis

- hy d roxy

cyantraniliprole, IN

- N7B69, IN

- MYX98, INDBC80, and the parent compound. There was very little difference in elimination between rats administered [CN

14 C]

- cyantrani liprole or [PC

14 C]

- cyantraniliprole. Majority of the administered dose was eliminated during the first 24 to 48 hour after administration. The major route of elimination was via feces (approximately 80% of the administered dose). The data show no bioaccu mulation).

870.7485 Disposition during

and after multiple dosing

— kinetics and metabolism study (male and female rats) 48119951 (2009)

Acceptable/non

- guideline

A mixture of [CN

14 C]

- cyantraniliprole and [PC

14 C]

- cyantraniliprole at a 1:1 mg ratio: 10 m g/kg /day multiple doses by gavage The data on the tissue concentrations and the tissue percent recovery showed that tissue concentration fell rapidly following the end of dosing. The tissue concentration half

- lives ranged from 2.6 days in fat
to approximately 6 days in whole blood. Very little tissue accumulation was found. The total percent of the administered dose eliminated via urine was 29% in males and 20% in females and that eliminated via feces was approximately 60% in males and females. Me tabolites found in this study were similar to those in the single dose study (MRID 48119949). Dermal Absorption Toxicity Studies

870.7600 Dermal p enetration No dermal penetration study on technical grade is available, but several in vivo and in vitro dermal penetration studies on three formulations are available.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 63 of 85 Table B.2.3 Subchronic, Chronic, and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

In vivo dermal absorption

— SC formulation (rats) 48120313 (2009)

Acceptable

200 g/L and 1 g/L Maximum absorption 200 g/L = 0.34% at 498 hrs 1 g/L = 0.93% at 498 hrs DAF 200 g/L = 0.02% 1 g/L = 0.43%

Nearly all the applied dose was readily removed from the skin surface with gentle skin washing. In vitro dermal penetration study

— SC formu lation (rat and human skin) 48120314 (2009)

Acceptable

200 g/L & 1g/L Maximum Dermal penetration at 24 hrs:

Human skin: 200 g/L = 0.24% 1 g/L = 5.28%

Rat skin: 200 g/L = 3.69% 1 g/L = 11.5%

In vivo dermal absorption

— SE formulation (rats) 48120413 (2009)

Acceptable

100 g/L and 1 g/L Maximum absorption : 100 g/L = 1.25% at 498 hrs 1 g/L = 1.47% at 498 hrs DAF 100 g/L = 0.25% 1 g/L = 0.83%

Nearly all the applied dose was readily removed from the skin surface with gentle skin washing. In vitro dermal penetration study

— SE formu lation (rat and human skin) 48120412 (2009)

Acceptable

100 g/L and 1 g/L Maximum Dermal penetration at 24 hrs:

Human skin: 100 g/L = 2.7 % 1 g/L = 6.1 %

Rat skin: 100 g/L =13.4 % 1 g/L = 10.7 % In vivo dermal absorption

— OD formulation (rats) 48120209 (2008)

Acceptable

100 g/L and 1 g/L Maximum absorption 100 g/L = 1.36% at 498 hrs 1g/L = 0.74% at 498 hrs DAF 100 g/L = 0.06% 1 g/L = 0.03%

Nearly all the applied dose was readily removed from the skin surface with gentle skin washing. In vitro dermal penetration study

— OD formu lation (rat and human skin) 48120210 (2008)

Acceptable

100 g/L and 1 g/L Maximum Dermal penetration at 24 hrs:

Human skin: 100 g/L = 0.25 % 1 g/L = 0.86%

Rat skin : 100 g/L = 10.5% 1 g/L = 20.2 % In vivo dermal absorption

—
c yantraniliprole/ thiamethoxam WG formulation (A16901B) formulation (rat

s kin ) 48432611 (2011)

Acceptable

Slurry concentrate, 1/20 and 1/267 dilution , correspond to 10.0, 1.0, and 0.75 mg/rat respective ly At 24 hours after dosing: 0.08%, 0.92%, and 1.23% of the applied dose were absorbed with s l urry concentrate, 1/20 dilution and 1/267 dilution, respectively. DAF for WG formulation:

Slurry concentrate 1/20 dilution = 0 .005%

Slurry concentrate 1/267 dilution = 0 .07%

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 64 of 85 Table B.2.3 Subchronic, Chronic, and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

In vitro dermal penetration study

—
c yantraniliprole/ thiamethoxam WG formulation (A16901B) formu lation ( rat skin ) 48432513 (2011)

Acceptable

Slurry concentrate, 1/20 di lution and 1/267 dilution At 24 hours after dosing, the total absorbable dose were 0.133%, 2.57%

, and 15.78% of the applied dose for s lu rry concentrate, 1/20 dilution and 1/267 dilution, respectively. Nearly all the applied dose was readily removed from the skin surface with gentle skin washing.

In vivo dermal absorption

—
c yantraniliprole/ thiamethoxam WG formulation (A16901B) formulation (human skin) 48432512 (2011)

Acceptable

Sl urry concentrate, 1/20 dilution and 1/267 dilution At 24 hours after dosing, the total absorbable dose were 0.008%, 0.128% and 0.92% of the applied dose for s lur ry concentrate, 1/20 dilution and 1/267 dilution, respectively.

In vitro dermal penetration study

—
c yantraniliprole/ thiamethoxam WG formulation (A16901B) formu lation (human skin) 48432412 (2011)

Acceptable

Slurry concentrate, 1/534 dilution and 1/1

, 600 dilution The total absorbable dose expressed as percent of the applied dose over 24 hours was 0.010, 1.597

, and 0.561% for concentrate slurry, 1/534 w/w dilution, and 1/167 w/w dilution, respectively. Irrespective of the applied dose, greater than 97% of the applied d ose remained on the skin surface after a 24 hour exposure period and was readily removed by gentle skin washing. Very low proportions of the dose were associated with the stratum corneum and the remaining epidermal membrane. Immunotoxicity Toxicity Studi es

870.7800 28

- Day

immunotoxicity study

— d ietary (rats)

[ assess primary humoral response to sheep red blood cells (sRBC) ] 48119971 (2009)

Acceptable/guideline

0, 20, 200, 2 ,000, and 20

, 000 ppm

M: 0, 1.7 , 17, 166, and 1

, 699 mg/kg/day

F: 0, 1.8 , 18, 172, and 1

, 703 mg/kg/day Systemic toxicity NOAEL = 1

, 699/1

, 703 mg/kg/day (M/F) (highest dose tested). A LOAEL was not established.

The SRBC

- specific IgM ELISA results did not indicate any treatment

- related immunosuppressive effects. Therefore, the immunotoxicity NOAEL = 1

, 699/1

, 703 mg/kg/day (M/F).

870.7800 28

- Day

immunotoxicity study

— d ietary (mice )

[ assess primary humoral response to sheep red blood cells (sRBC) ] 48119972 (2009)

Acceptable/guideline

0, 20, 150, 1

, 000, or 7

, 000 ppm

M: 0, 3.0, 23, 154, or 1

, 065 mg/kg/day

F: 0, 4.1, 32, 224, or 1

, 386 mg/kg/day The systemic toxicity NOAEL = 1

, 065/1

, 386 mg/kg/day (M/F) (highest dose tested). The LOAEL was not established.

The SRBC

- specific IgM ELISA results did not indicate any treatment

- re lated immunosuppressive effects. There were no statistical differences in quantity of SRBC

- specific IgM in any treatment group when compared with the vehicle controls. Evaluation of individual animal data did not show any trend or distribution that would demonstrate significant suppression of SRBC

- specific antibody
response. Therefore, the immunotoxicity NOAEL = 1

, 065/1

, 386 mg/kg/day (M/F) (highest dose tested).

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 65 of 85 Table B.2.3 Subchronic, Chronic, and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

Metabolite: IN

- JSE76 Toxicity Studies

870.3050 28

- Day feeding

study with IN

JSE76 (up to 20,000ppm) 48119983 (2010)

Acceptable/guideline

48208474 (2010) Supplemental study to 48119983

0, 100, 400, 3

, 000, and 20

, 000ppm

M: 0, 7, 29, 212, and 1

, 445 mg/kg/day

F: 0, 8, 31, 232, and 1

, 471 mg/kg/day NOAEL = 1

, 445/1

, 471 mg/kg /day (M/F) ( h ighest dose tested)

.

A LOAEL was not established because toxicity was not seen at any tested dose level.

870.5100 Bacterial reverse

mutation t est ( S

. t yphimurium & E. coli) 48119976 (2009)

Acceptable/guideline Negative

. Toxicity test: 1.5, 5.0, 15, 50, 150, 500, 1

, 500, and 5

, 000 g/plate. Confirmatory assay, 50, 150, 500, 1

, 500, and 5

, 000 g/plate

.

870.5300 In vitro

m ammalian cell gene mutation test (CHO/HGPRT

a ssay) 48119974 (2009)

Acceptable/guideline Negative

. Test concentrations: 0, 100, 150, 500, 1

, 000, and 1

, 500 g/mL

.

870.5375 In v itro

m ammalian

c hromosome aberration t est with human lymphocytes 48119975 (2009)

Acceptable/guideline Negative

.

- S9: 0, 313, 625,1

, 250, and 2

, 500 g/mL

- 4

- hr
exposure;

- S9 156, 313, 625, 1

, 000, 1

, 500, and 2

, 000 g/mL 20

- hr exposure; and +S9: 156, 313, 625, 1

, 250, and 2

, 500 g/mL

- 4

- hr
exposure

.
Metabolite: IN

- PLT97 Toxicity Studies

870.5100 Bacterial reverse

mutation t est ( S

. t yphimurium & E. coli) 48122580 (2009)

Acceptable/guideline Negative

. 0, 50, 150, 500, 1

, 500, and 5

, 000 g/plate were tested in the confirmatory test. The test substance was administered as a workable suspension in DMSO

.

870.5300 In v itro

mammalian c ell
g ene m utation test (CHO/HGPRT

a ssay) 48122582 (2010)

Acceptable/guideline Negative

. Test con centrations: 10, 25, 50, 100, and 150 μg/ml. Exposure time = 5 hour s. Precipitation occurred at ≥ 150 μg/ml.

870.5375 In v itro

mammalian chromosome aberration t est with human lymphocytes 48122581 (2011)

Acceptable/guideline Negative

.

- S9 &+S9: 50, 100, 200, 400, 800, and 1

, 550 g/mL

- 4 hr exposure.

- S9: 25, 50, 100, 200, 500, 1000, and 1

, 550 g/mL

- 20

- hr exposure

.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 66 of 85 Table B.2.3 Subchronic, Chronic, and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

Metabolite: IN

- F6L99 Toxicity Studies

870.5100 Bacterial reverse

mutation t est ( S

. t yphimurium & E. coli) 46979931 (2006)

Acceptable/guideline Negative

. Initial toxicity (Trial I): 33.3, 66.7, 100, 333, 667, 1

, 000, 3

, 333, and 5

, 000 g/plate. Confirmatory test (Trail II): 333, 667, 1

, 000, 3

, 333, and 50

, 00 g/plate

. Metabolite: IN

- N5M09 Toxicity Studies

870.5100 Bacterial reverse

mutation t est ( S

. t yphimurium & E. coli) 48119982 (2009)

Acceptable/guideline Negative

. Toxicity test (Trial I):1.5, 5.0, 15, 50, 150, 500 1

, 500, and 5

, 000 g/plate. Confirmatory assay(Trial II): 50, 150, 500, 1

, 500

, and 5

, 000 g/plate

. Other (Non

- Guideline) Studies (Mechanistic Studies)

Adrenal and t hyroid

m echanistic study (rats) 48119973 (2010)

Acceptable/non

- guideline

For thyroid effect (female rats): 20,000 ppm (1 ,903 mg/kg/day) for 29 days

For adrenal effect (male rats): 20 ,000 ppm (1,230 mg/kg /day) for 93 days In 20

, 000 ppm females, increased liver and thyroid weights and minimal thyroid follicular cell hypertrophy were seen. These effects were associated with increased hepatic UDP

glucuron yltransferase (UDPGT) activity and reduced serum T 4 and increased TSH levels.

90

- Day adrenal

m echanistic study

— feeding (male mice) 48119985 (2010)

Acceptable/non

- guideline

7

, 000 ppm (1

, 120 mg/kg/day) for 93 days Cyantraniliprole at 1

, 120 mg/kg/day did not adversely affect the following parameters: survival, clinical signs of toxicity, body weight, food consumption, or food efficiency. No gross or microscopic pathology effects were attributed to test substance exposure. No adverse effects on adrenal

co rtical structure or function were found. Basal urinary corticosterone was comparable between the control and treated groups. The electron microscopy results showed that cyantraniliprole did not affect adrenal cortical cell structure. The finding of the mi crovesiculation of the adrenal cortex in male mice at ≥ 50 ppm in the 90

- day study (MRID 48119943) was not duplicated in this study where male mice were fed dietary concentration of 7

, 000 ppm (1

, 120 mg/kg/day) of cyantraniliprole for 93 days. In vitro th yroid peroxidase inhibition

[ thyroid preparation derived from Yuca tan pig, microswine] 48119979 (2010)

Acceptable/non

- guideline

2, 5, 10, 20, 50, 100, 200, and 400 M

Positive control: Propylthiouracil (PTU) Cyantraniliprole did not cause inhibition of thyroid peroxidase at any concentration tested; therefore, an IC 50 value for cyantraniliprole was unable to be determined. The positive control, PTU at 7.2 M caused a 50% reduction in enzyme activity.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 67 of 85 B .3 Hazard Identification and Endpoint Selection

B .3. 1 Acute Reference Dose (aRfD)

- General Population

Not established. An endpoint attributable to a single dose was not seen in the database (including the pre

- natal toxicity studies in rats and rabbits).

B .3. 2 Chronic Reference Dose (cRfD )

Study Selected One

- Y ear Oral Toxicity Study in Dogs

MRID No. 48119960

Dose and Endpoint for Establishing cRfD NOAEL = 1 mg/kg/day. LOAEL = 6 mg/kg/day based on effects indicative of liver toxicity (increased liver weights an d alkaline phosphatase activity , an d significant decreases in albumin level s )

. Uncertainty Factor (UF) 100X (10X intraspecies, 10X interspecies , 1X FQPA )

. Comments about Study/Endpoint/Uncertainty Factor The one

- year dog study is appropriate for both the duration and population of concern. The dogs
appear to be more sensitive to the liver effects th an rats. The results of the one

- year dog study provide the most sensitive LOAEL (6 mg/kg/day) for liver effects. T he POD i s also protective of the thyroid effects seen in all toxicity studies in rats , including the 2

- generation reproduction study (LOAEL = 14 mg/kg/day)

.

cRfD = 1 mg/kg/day = 0.01 mg/kg/day

100 cPAD = 0.01 mg/kg/day = 0.01 mg/kg/day

1

B .3.3 Incidental Oral Exposure (Short

- and Intermediate

- Term)

Selected Study 90

- Day Oral Toxicity Study in Dogs

MRID No. 48119947, 48119948

Dose and Endpoint for Risk Assessment NOAEL = 3 mg/kg/day. LOAEL = 32 mg/kg/day based on a collection of treatment

- related effects indicative of liver toxicity. The effects include decreases in total protein, albumin, and cholesterol in males and females; increases in alkaline p hosphatase in males and females;

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 68 of 85 increases in alani ne aminotransferase in females; and increase d liver weights in males and females.

Uncertainty Factor (UF) 100X (10X intraspecies, 10X interspecies, 1X FQPA).

Comments about Study/Endpoint/Margins of Exposure This study is appropriate for the duratio n of exposure. While the population of concern is for children engaged in hand

- to

- mouth behavior, t he POD ( NOAEL of 3 mg/kg/day) selected from the 90

- day study is protective of the effects seen in the 2

- generation reproduction study in rats.

B .3.4 Derma l Exposure (Short

- , Intermediate

- and Long

- Term )

S ystemic toxicity was not seen in the 28

- day dermal toxicity in rats up to the limit dose (1000 mg/kg/day)

. The target organs of toxicity were looked at in this study. In addition, there are no

concerns for developmental, reproductive

, or neurotoxicity. The lack of effects in the dermal study is consistent with the low dermal absorption factor of 1%.

B .3. 5 Inhalation Exposure (Short

- and Intermediate

- Term)

Selected Study 28

- Day Inhalation Toxicity Study

- Rats

MRID No. 48663602

Dose and Endpoint for Risk Assessment NOAEL =0.1 mg /L. A LOAEL was not established since the highest concentration (0.1 mg/L) tested did not demonstrate any adverse effects.

Uncertainty Factor (UF) Short

- term = 30X (10X intraspecies, 3X interspecies, 1X FQPA for residential only ). Intermediate

- term = 100X (10X intraspecies, 3X interspecies, 3X database uncertainty).

The UF is reduced from the default 100X because the RfC methodology was used to calculate inhalation risk. The RfC methodology accounts for the pharmacokinetic (PK) differences between rats and humans, but does not account for the pharmacodynamic (PD) differences

. Consequently, the UF for interspecies extrapolation may be reduced to 3X (to account for the PD differences) while the UF for intraspecies variation is retained at 10X. Thus, the UF when using the RfC methodology is customarily 30X. For i ntermediate

- term exposures, the occupational and residential LOC for MOE = 100. An additional 3X UF was added to the intermediate

- term exposure scenarios

. This was based on a number of factors: The database indicates a progression in the severity of toxicity with time; The chemical has a low vapor pressure, and; The 28

- day inhalation study is protective of c ritical effects.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 69 of 85 Although a 10X UF is typically applied for extrapolating for durations of expo sure, a 3X UF is sufficient for cyantraniliprole . This conclusion is supported by the observation that the LOAEL for the multigeneration reproduction toxicity study in rats (a long

- term study) is ≈3X lower than the LOAEL for the 28

- day oral toxicity study in rats (14 versus 53 mg/kg/day , based on thyroid toxicity). In addition, the lack of toxicity in the acute inhalation toxicity study a t a dose 50 X higher than the 28

- day inhalation study supports that a 3X UF for duration of exposure extrapolat ion is sufficiently protective.

Comments about Study/Endpoint/Margins of Exposure The route

- specific 28

- day inhalation toxicity study is appropri ate to use for this assessment

. Although this 28

- day inhalation toxicity study in rats could be tested 14 

### at higher concentrations and adverse effect s were not identified in the study, it is appropriate for risk assessment. Th is conclusion is based on a we ight of evidence (WOE) approach that takes into consideration the overall toxicity profile for this chemical. Liver and thyroid toxicity are the critical effects identified in the cya n traniliprole database, with thyroid toxicity being most likely the resu lt of liver enzyme activation. Although the inhalation study did not measure thyroid hormones, it does provide his topathology data on the thyroid; clinical chemistry observations for liver
enzymes; liver histopathology ; and liver weights (all of the endpo ints of concern ) . Since the thyroid effect is secondary to liver effect and the liver is not affected in this study, the inhalation study provides a conservati ve NOAEL. While the POD selected for the inhalation risk
assessment may be artificially low ( i. e. resulting in an overestimation of risk) due to dose selection, the inhalation study i s selected because it is route

- specific and protective of the effects seen throughout the database.

B .4 H uman Equivalent Concentrations (H EC ) and Human Equivalent Dose Calculations

The HEC and human equivalent dose calculations were based on the results of a 28

- day rat inhalation study in rats (MRID 48 697401 ) . In this study, cyantraniliprole was administered (as

an aerosol) to Crl:CD(SD) rat s (10/sex/dose) for 6 hours/day, 5 days/week, for 4

- weeks. The test animals were exposed nose

- only to target concentrations of 0 (air control), 1, 10, or 100 mg/m3 of cyantraniliprole (equivalent to 0.001, 0.01, and 0.1 mg/L, respectively). A dverse effec ts were
not seen at any concentration tested, although laryngeal metaplasia was considered treatment related but not adverse at 0.1 mg/L. The NOAEL was 0.1 mg/L.

RDDR for Cyantraniliprole Calculations used to estimate the inhalation risk to humans from a erosols are dependent not on the regional gas dose ratio (RGDR) as for gases, but on the regional deposited dose ratio (RDDR). Inhalation studies using aerosols characterize particulate exposure by defining the particulate diameter [mass median aerodynami c diameter (MMAD)] and the geometric standard deviation (σ g 

### ), which is then used to determine the RDDR. The RDDR is a multiplicative factor used to adjust an observed inhalation particulate exposure concentration of an animal (A) to the predicted inhalati on particulate exposure concentration for a human (H) that would be associated with the same dose delivered to the affected region (r) or target tissue.

14 An acute inhalation toxicity study tested concentrations 50

- fold higher than the highest concentration in the 28

- day inhalation study.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 70 of 85 RDDR r 

### = (RDD r



### /Normalizing Factor) A / 

### (RDD r 

### /Normalizing Factor) H


### As with calculations for gases, the affected regions and potential target tissues are the three respiratory regions (extrathoracic, tracheobronchial, and pulmonary). The RDDR is easily calculated by using a software program designed specifically for computing the RDDR from the MMAD and σ g 

### defined from an aerosol inhalation study. The values for the species

- specific parameters used to calculate the RDDR are provided in the EPA document “Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry.” The magnitude of the UFs applied is dependent on the methodology used to calculate risk. The RfC methodology takes into consideration the PK differences, but not the PD differences

. Consequently, the UF for interspecies extrapolation may be reduced to 3X (to account for the PD differences) while the UF for intraspecies variation is retained at 10X. Thus, the UF when using the RfC methodology is customarily 30X.

Regional Deposited Dose Ratio (RDDR) MMAD = 3

. 00 Sigma g = 2. 30

SPECIES Body Weight ( g) Minute Ventilation (VE, ml) deposited fraction
rat 236 1 71

. 5 0.587 human 70000 13800.0 0.759 RATIO 0.7 34

RDDR = (VE/ SA ) animal 

### ÷ (VE/ SA ) human 

### × deposited fraction animal 

### ÷ d eposited fraction human 

### = ( 171.5 / 236 ) animal 

### ÷ (13800/ 70000 ) human 

### × 0. 587 ÷ 0. 759

= 2.8

Example for HEC calculations for short

- term occupational exposure: Assume workers will be in the greenhouse for 8 hrs/day and 5 days/week:

HEC = NOAEL study × (daily duration of exposure animal ÷ daily duration of exposure human ) × (days/week of
exposure animal ÷ days/week of exposure human ) × RDDR



### HEC = 0.1 mg/ L × (6 ÷ 8) × (5 ÷ 5) × 2.8 = 0.21 mg/L

T able B .4. HEC Array for Non

- Occupational and Occupational Risk Assessment

Relevant Study LOAEL (mg/L) NOAEL

(mg/L) Da Dh Wa Wh RDDR HEC (mg/L) inter intra UF

Short

- & Intermediate

- Term Occupational Exposure

Inhalation

– Rat (MRID 48697401 ) 28

- day Not Obs. 0.1 6 8 5 5 2.8 0.21 3 10 NA

Short

- & Intermediate

- Term Non

- Occupational (Residential) Exposure

Inhalation

– Rat (MRID 48697401 ) 28

- day Not Obs. 0.1 6 24 5 7 2.8 0.05 3 10 NA

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 71 of 85 T able B .4. HEC Array for Non

- Occupational and Occupational Risk Assessment
Long Term Exposure: Not A ppropriate Key: LOAEL : Lowest observed adverse effect level Da : Daily animal exposure (hrs/day) Wa : Weekly animal exposure (days/week) RRDR : Regional Deposited Dose Ratio inter : interspecies extrapolation uncertainty factor Dh : Anticipated daily human exposure (hrs/day) Wh : Anticipated weekly human exposure (days/week) HC: Human Concentration HEC : Human Equival ent Concentration intra : intraspecies variation uncertainty factor UF : Other uncertainty factor(s)



### Summary of Human Equivalent Concentrations Occupational Short

- T erm

Study NOAEL ( m/L)

systemic RDDR Daily Duration ( 6 hrs rat/8 hrs human) Weekly (days/week)

Duration (rat 5 days/human 5 days) HEC (mg/L) UF

28

- day rat 0.1 2.8 0.75 1 0.21 30 Non

- Occupational Short

- T erm

Study NOAEL (m/L)

systemic RDDR Daily Duration (6 hrs rat/24 hrs human) Weekly (days/week)

Duration (rat 5 days/human 7 days) HEC (mg/L) UF

28

- day rat 0.1 2.8 0.25 0.714 0.05 30


### Human Equivalent Doses The HEC is in mg/L but exposure data are in mg/kg/day. Therefore, conversion of the human mg/L value to human mg/kg/day was conducted as follows:

Inhalation to Oral Equation: dose (systemic HEC value) mg/L × A × CF (L/hr/kg) × D (hours) × AF = mg/kg;

Occupational: (0.21 mg/L) × 1 × 6 × 8 × 1 = 10.08 mg/kg/day

Residential : (0.05 mg/L) × 1 × 6 × 24 × 1 = 7.2 mg /kg/day

Where:
A absorption: ratio of deposition and absorption in r espiratory tract compared to absorption by the oral route. A default A of 1 was used.
CF Conversion Factor: A L/hr/kg factor which accounts for respiratory volume and body weight for a given species and strain ( A human conversion factor of 6 for ages 10

- 3 0 yrs was used for both occupational and non

occupational calculations ).
D Duration: Duration of daily animal or human exposure (hours). The default assumption for occupational is 8 hrs while non

- occupational could potentially be 24 hrs.
AF Activity Factor: The default human activity factor is 1.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 72 of 85 A ppendix C

. Metabolism Summary Table

Table C .1 Tabular Summary of Metabolites and Degradates

Chemical Name (other names in parenthesis) and Structure Matrix Percent TRR ( ppm )

Matrices

- Major Residue (>10%TRR) Matrices

- Minor

Residue (<10%TRR)
Cyantraniliprole DPX

- HGW86 SYN545377

CAS Name: 3

- Bromo

- 1

- (3

- chloro

- 2

- pyridinyl)

- N

- [4

- cyano

- 2

- methyl

- 6 [(methylamino)carbonyl]phenyl]

- 1 H

pyrazole

- 5

- carboxamide Rice Foliage: 57.4 (0.232) [CN] 48.7 (0.205) [PC] Grain: 62.7 (0.007) [CN]

46.2 (0.014) [PC] Straw: 44.9 (0.125) [CN]

42.1 (0.125) [PC]

Lettuce Leaves: 37.1 (0.004) [CN] 69.0 (0.039) [PC]

Cotton Gin byproducts: 25.6 (0.025) [CN] 46.8 (0.011) [PC]

Tomato Leaves: 43.4 (0.562) [CN/PC]

Rotational Crops

Ruminant Milk: 39.5 (0.030) [CN] 49.6 (0.070) [PC] Liver: 17.1 (0.073) [CN]

27.3 (0.136) [PC] Kidney: 12.7 (0.017) [CN]

18.9 (0.0.040) [PC] Muscle: 30.3 (0.009) [CN]

15.3 (0.006) [PC] Fat: 30.8 (0.016) [CN]

45.4 (0.054) [PC]

Poultry Egg white: 32.5 (0.084) [CN] 41.7 (0.085) [PC] Egg yolk: 10.3 (0.009) [CN]

9.3 (0.008) [PC]

Rat

Water

IN

- J9Z38

CAS Name: 2

- [3

- Bromo

- 1

- (3

- chloro

- 2

- pyridinyl)

- 1 H

- pyrazol

- 5

- yl]

- 3,4

- dihydro

- 3,8

- dimethyl

- 4

- oxo

- 6

- quinazolinecarbonitrile Rice Foliage: 16.2 (0.066) [CN] 22.1 (0.093) [PC] Grain: 10.2 (0.001) [CN] Straw: 18.4 (0.051) [CN]

14.3 (0.042) [PC]

Lettuce Leaves: 10.0 (0.005) [PC]

Cotton Gin byproducts

Tomato Leaves Rotational Crops

Ruminant

Poultry Egg white: 29.2 (0.075) [CN] 17.1 (0.034) [PC] Egg yolk: 13.1 (0.011) [PC] Liver

Rat

Water
IN

- JCZ38 Rice Foliage, grain, straw

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 73 of 85 Table C .1 Tabular Summary of Metabolites and Degradates

Chemical Name (other names in parenthesis) and Structure Matrix Percent TRR ( ppm )

Matrices

- Major Residue (>10%TRR) Matrices

- Minor

Residue (<10%TRR)

CAS Name: 4

- [[[3

- Bromo

- 1

- (3

- chloro

- 2

- pyridinyl)

- 1 H

- pyrazol

- 5

- yl]carbonyl]amino]

- N’3’,5

- dimethyl

- 1,3

- benzenedicarboxamide Cotton Gin byproducts

Tomato Leaves

Rotational Crops

Ruminant Milk, liver

Poultry

Rat

Water

IN

- JSE76

CAS Name: 3

- (Methylaminocarbonyl)

- 4

- [[[3

- bromo

- 1

- (3

- chloro

- 2

- pyridinyl)

- 1 H

pyrazol

- 5

- yl]carbonyl]amino]

- 5

- methyl benzoic acid Rice Foliage, grain, straw

Cotton Gin byproducts

Tomato

Rotational Crops

Ruminant

Poultry Egg yolk

Rat

Water

IN

- K7H19

CAS Name: 4

- [[[3

- Bromo

- 1

- (3

- chloro

- 2

- pyridinyl)

- 1 H

- pyrazol

- 5

- yl]carbonyl]amino]

- 5

- methyl

- 1,3

- benzenedicarboxamide Rice Straw

Cotton Gin byproducts

Tomato Leaves

Rotational Crops

Ruminant Milk, liver, kidney, muscle, fat

Poultry

Rat

Water

IN

- MLA84

CAS Name: 2

- [3

- Bromo

- 1

- (3

- chloro

- 2

- Rice Foliage, straw

Lettuce Leaves (+ IN

- NXX70)

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 74 of 85 Table C .1 Tabular Summary of Metabolites and Degradates

Chemical Name (other names in parenthesis) and Structure Matrix Percent TRR ( ppm )

Matrices

- Major Residue (>10%TRR) Matrices

- Minor

Residue (<10%TRR)
pyridinyl)

- 1 H

- pyrazol

- 5

- yl]

- 1,4

- dihydro

- 8

- methyl

- 4

- oxo

- 6

- quinazolinecarbonitrile Cotton Gin byproducts

Tomato Leaves (+ IN

- NXX70)

Rotational Crops

Ruminant

Poultry Egg white: 18.7 (0.049) [CN] 18.2 (0.037) [PC] Egg yolk: 11.6 (0.011) [CN]

16.8 (0.015) [PC] Liver

Rat

Water

IN

- DBC80

CAS Name: 3

- Bromo

- 1

- (3

- chloro

- 2

- pyridinyl)

- 1 H

- pyrazole

- 5

- carboxylic acid Rice Foliage, grain, straw

Cotton

Tomato Leaves

Rotational Crops

Ruminant

Poultry

Rat

Water

IN

- N7B69

CAS Name: 3

- Bromo

- 1

- (3

- chloro

- 2

- pyridinyl)

- N

- [4

- cyano

- 2

- (hydroxymethyl)

- 6

- [(methylamino)carbonyl]phenyl]

- 1 H

pyrazole

- 5

- carbonitrile Rice Foliage, grain

Cotton Gin byproducts

Tomato Leaves

Rotational Crops

Ruminant Milk: 11.8 (0.008) [CN]

Poultry Liver

Rat

Water

IN

- K5A77

CAS Name: 2

- [3

- Bromo

- 1

- (3

- chloro

- 2

- pyridinyl)

- 1 H

- pyrazol

- 5

- yl]

- 3,4

- dihydro

- 3,8

- Rice Foliage, straw

Cotton

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 75 of 85 Table C .1 Tabular Summary of Metabolites and Degradates

Chemical Name (other names in parenthesis) and Structure Matrix Percent TRR ( ppm )

Matrices

- Major Residue (>10%TRR) Matrices

- Minor

Residue (<10%TRR)
dimethyl

- 4

- oxo

- 6

- quinazolinecarboxamide Tomato

Rotational Crops

Ruminant

Poultry

Rat

Water

IN

- K5A78

CAS Name: 2

- [3

- Bromo

- 1

- (3

- chloro

- 2

- pyridinyl)

- 1 H

- pyrazol

- 5

- yl]

- 3,4

- dihydro

- 3,8

- dimethyl

- 4

- oxo

- 6

- quinazolinecarboxylic acid Rice Foliage, grain, straw

Cotton

Tomato

Rotational Crops

Ruminant

Poultry Liver

Rat

Water

IN

- K5A79

CAS Name: 3

- (Aminocarbonyl)

- 4

- [[[3

- bromo

- 1

- (3

- chloro

- 2

- pyridinyl)

- 1 H

- pyrazol

5

- yl]carbonyl]amino]

- 5

- methyl benzoic acid Rice

Cotton

Tomato

Rotational Crops

Ruminant

Poultry Egg white, yolk, liver

Rat

Water

IN

- HGW87 Rice

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 76 of 85 Table C .1 Tabular Summary of Metabolites and Degradates

Chemical Name (other names in parenthesis) and Structure Matrix Percent TRR ( ppm )

Matrices

- Major Residue (>10%TRR) Matrices

- Minor

Residue (<10%TRR)

CAS Name: N

- [2

- (Aminocarbonyl)

- 4

- cyano

6

- methylphenyl]

- 3

- bromo

- 1

- (3

- chloro

- 2

- pyridinyl)

- 1 H

- pyrazole

- 5

- carboxamide Lettuce Leaves

Cotton

Tomato

Rotational Crops

Ruminant

Poultry Egg yolk: 12.0 (0.011) [CN] Egg white

Rat

Water

IN

- QKV54

CAS Name: 2

- [3

- Bromo

- 1 H

- pyrazol

- 5

- yl]

- 3,4

- dihydro

- 3,8

- dimethyl

- 4

- oxo

- 6

- quinazolinecarbonitrile Rice

Lettuce Leaves

Cotton Gin byproducts

Tomato Leaves

Rotational Crops

Ruminant

Poultry

Rat

Water

IN

- MYX98 Rice

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 77 of 85 Table C .1 Tabular Summary of Metabolites and Degradates

Chemical Name (other names in parenthesis) and Structure Matrix Percent TRR ( ppm )

Matrices

- Major Residue (>10%TRR) Matrices

- Minor

Residue (<10%TRR)

CAS Name: 3

- Bromo

- 1

- (3

- chloro

- 2

- pyridinyl)

- N

- [4

- cyano

- 2

- [[(hydroxymethyl) amino]carbonyl]

- 6

- [(methylphenyl]

- 1 H

pyrazole

- 5

- carboxamide Cotton

Tomato Leaves

Rotational Crops

Ruminant Milk: 15.1 (0.011) [CN] 18.3 (0.026) [PC] Liver, kidney

Poultry Egg white, yolk, liver

Rat

Water

IN

- NBC94

CAS Name: 2

- [3

- Bromo

- 1

- (3

- chloro

- 2

- pyridinyl)

- 1 H

- pyrazol

- 5

- yl]

- 3,4

- dihydro

- 3

- methyl

- 4

- oxo

- 8

- hydroxymethyl

- 6

- quinazolinecarbonitrile Rice

Cotton

Tomato

Rotational Crops

Ruminant Fat

Poultry Egg white, yolk, liver

Rat

Water

IN

- N5M09

Processing Conditions

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 78 of 85 Table C .1 Tabular Summary of Metabolites and Degradates

Chemical Name (other names in parenthesis) and Structure Matrix Percent TRR ( ppm )

Matrices

- Major Residue (>10%TRR) Matrices

- Minor

Residue (<10%TRR)

IN

- F6L99

Processing Conditions

a Cyantraniliprole is lab e led with carbon

- 14 either in the cyano group [CN] or in the carbonyl next to the pyrazole ring [PC]. The label positions are depicted below.

1. [CN

14 C]

- cyantraniliprole 2. [PC

14 C]

- cyantraniliprole

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 7 9 of 85 Appendix D

. Physical/Chemical Properties

Table D

. 1 Physicoc hemical Properties of the Technical Grade of Cyantraniliprole

Parameter Value Reference Molecular Weight 473.72 g/mol

MRID 48208438 Physical state White fine powder solid Melting point 224 oC Density 1.4965 g/cm 3 at 20 oC
pH pH 4: Stable pH 7: Stable Water solubility (20°C) 14.24 mg/L

Solvent solubility ( g/L at 20°C) Acetone 6.54 Ethyl acetate 1.96 Dichloromethane 5.05 Toluene 0.576

n

- Octanol 0.79 Methanol 4.73

o

- Xylene 0.29 Acetonitrile 2.45
Vapor pressure (20 °C) 5.13 x 10 - 15 Pa 3.85×10 - 17 mm Hg Henry’s Law Constant ( 20 °C ) at pH7 = 1.7 x 10 - 18 atmosphere.m 3 /mole Dissociation constant, pKa ( 2 0 °C) 8.80 + 1.38 Octanol/water partition coefficient, log K OW (2 0 °C) Log Kow = 1.94 + 0.11

Hydrolysis and photolysis pH 9: Hydrolyzed very rapidly with a half

- life of <1 day. On e major metabolite was observed: IN

- J9Z38. Photolysis: 0.233 days at 40 o latitude in the summer to 4.12 days at 60 o latitude in the winter.



### Appendix E

. Review of Hum an Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agr icultural Handler Exposure Task Force (AHETF) database; the Outdoor Residential Exposure Task Force (ORETF) database ; ExpoSAC Policy 14 and 15.1 (SOPs for Seed Treatment); and the Residential SOPs ( Lawns/Turf; Gardens and Trees; Indoor Environments ), are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 15



### .

15 http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http ://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 80 of 85 Appendix F

. Occupational Exposure/Risk Summary Tables

Table F .1 Occupational Handler Non

- Cancer E xposure and Risk Estimates for Cyantraniliprole

Exposure Scenario Crop or Target a Baseline Inhalation Unit Exposure b Maximum

Application Rate c Area

Treated or Amount Handled Daily d Baseline Inhalation

Dose e MOE f

μg/lb ai lb ai/A Acres mg/kg/day ST LOC = 30 IT LOC = 100

Mixer/Loader
Mixing/Loadi ng Dry Flowables for Aerial Application Sod Farms

8.96 0.133 350 0.0 0520 1,900

Typical Field Crops 0.175 0.00686 1,500 Mixing/Loading Dry Flowables for Airblast Application Nursery Plants 0.131 20 0.000 294 34 ,000

Mixing/Loading Dry Flowables for Chemigation Application Only Typical Field Crops 0.175 350 0.00686 1,500
Greenhouse Plants 0.131 60 0.00 0883 11, 00 0 Nursery Plants

Mixing/Loading Dry Flowables for Groundboom Application Golf Courses

(tees and greens only) 0.133 5 0.0000743 140,000

Golf Courses (fairways, tees, and greens) 0.133 40 0.000594 17,000

Field

- Grown Ornamentals 0.131 40 0.000588 17,000 Nursery Plants 0.131 60 0.000883 11,000 Greenhouse Plants Sod Farms 0.133 8 0 0.00119 8,500 Typical Field Crops 0.175 80 0.00156 6,500

Mixing/Loading Liquids for Aerial Application Orchard Crops

0.219 0.133 350 0.000128 79,000 Sod Farms 0.313 350 0.000300 34,000 Typical Field Crops 0.133 350 0.000128 79,000 High

- Acreage Field Crops 0.133 1200 0.000436 23,000 Mixing/Loading Liquids for Airblast Application Nursery Plants 0.261 20 0.0000143 700,000
Orchard Crops 0.133 40 0.0000145 700,000

Mixing/Loading Liquids for Chemigation Orchard Crops 0.391 350 0.000375 27,000 Sod Farms 0.313 350 0.000300 34,000 Typical Field Crops 0.133 350 0.000128 79,000 High

- Acreage Field Crops 0.133 350 0.000128 79,000 Greenhouse Plants 0.261 60 0.0000429 230,000 Nursery Plants 0.391 60 0.0000643 160,000

Mixing/Loading Liquids for Groundboom Application Golf Courses

(tees and greens only) 0.313 5 0.00000429 2,300,000

Golf Courses (fairways, tees, and greens) 0.313 40 0.0000343 290,000

Field

- Grown Ornamentals 0.261 40 0.0000286 350,000 Nursery Plants 0.391 60 0.0000643 160,000 Greenhouse Plants 0.261 60 0.0000429 230,000 Sod Farms 0.313 80 0.0000686 150,000 Typical Field Crops 0.133 80 0.0000291 350,000 High

- Acreage Field Crops 0.133 200 0.0000728 140,000 Applicator

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 81 of 85 Table F .1 Occupational Handler Non

- Cancer E xposure and Risk Estimates for Cyantraniliprole

Exposure Scenario Crop or Target a Baseline Inhalation Unit Exposure b Maximum

Application Rate c Area

Treated or Amount Handled Daily d Baseline Inhalation

Dose e MOE f

μg/lb ai lb ai/A Acres mg/kg/day ST LOC = 30 IT LOC = 100

Applying Sprays for Aerial Application Orchard Crops

0.068 0.133 350 0.0000395 260,000 Sod Farms 0.133 350 0.0000394 260,000 Typical Field Crops 0.175 350 0.0000521 190,000 High

- Acreage Field Crops 0.133 1200 0.000135 75,000 Applying Sprays for Airblast Application Nursery Plants 4.71 0.131 20 0.000155 65,000 Orchard Crops 0.133 40 0.000313 32,000

Applying Sprays for Groundboom Application Golf Courses

(tees and greens only)

0.34 0.133 5 0.00000281 3,600,000

Golf Courses (fairways, tees, and greens) 0.133 40 0.0000225 450,000

Field

- Grown Ornamentals 0.131 40 0.0000224 450,000 Nursery Plants 0.131 60 0.0000335 300,000 Greenhouse Plants Sod Farms 0.133 80 0.0000450 220,000 Typical Field Crops 0.175 80 0.0000595 170,000 High

- Acreage Field Crops 0.133 200 0.000113 89,000 Applying Granules via Hand Dispersal Poultry/Li vestock

Houses/Horse Barns/Feedl ots 470 0.0871 1 0.000511 20,000

Flagger

Flagging for Aerial Applications Orchard Crops

0.35 0.133 350 0.000204 49,000 Sod Farms 0.133 350 0.000203 50,000 Typical Field Crops 0.175 350 0.000268 38,000 High

- Acreage Field Crops 0.133 350 0.000204 49,000

Mixer/Loader/Applicator

M/L/A Dry Flowables for Backpack Sprayers Greenhouse Plants (Foliar) 140 0.00131 lb ai/gal

40

gallons 0.0000919 110,000 Nursery Plants (Foliar)
Nursery Plants (Ground/Soil) 2.58 0.00475 lb ai/gal 0.00000613 1,600,000
Landscaping (trees/shrubs/bushes) 140 0.00131 lb ai/gal 0.0000919 110,000 Landscaping (plants/flowers) Landscaping (turf, lawns, athletic fields, parks, etc) 2.58 0.00203 lb ai/gal 0.00000261 3,900,000

M/L/A Dry Flowables for Manually

Pressurized Handwand Sprayers Greenhouse Plants (Foliar)

30 0.00131 lb ai/gal 40

gallons 0.0000198 510,000 Nursery Plants (Foliar) Landscaping (trees/shrubs/bushes) Landscaping (plants/flowers) Interior Landscaping Landscaping (turf, lawns, athletic fields, parks, etc) 30 0.00203 lb ai/gal 0.0000304 330,000

M/L/A Dry Flowables for Mechanically

Greenhouse Plants (Foliar) 120 0.00131 lb ai/gal 1000

gallons 0.00198 5,100

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 82 of 85 Table F .1 Occupational Handler Non

- Cancer E xposure and Risk Estimates for Cyantraniliprole

Exposure Scenario Crop or Target a Baseline Inhalation Unit Exposure b Maximum

Application Rate c Area

Treated or Amount Handled Daily d Baseline Inhalation

Dose e MOE f

μg/lb ai lb ai/A Acres mg/kg/day ST LOC = 30 IT LOC = 100 Pressurized Handgun Sprayers Greenhouse Plants (Ground/Soil) 0.00475 lb ai/gal 0.00713 1,400

Nursery Plants (Foliar)

3.9 0.00131 lb ai/gal 0.0000640 160,000

Nursery Plants (Ground/Soil) 0.00475 lb ai/gal 0.000231 44,000
Landscaping (trees/shrubs/bushes) 0.00131 lb ai/gal 0.0000640 160,000

Typical Field Crops (Foliar) 3.9 0.00875 lb ai/gal 0.000426 24,000
Typical Field Crops (Ground/Soil) 3.9 0.0175 lb ai/gal 0.000854 12,000

Golf Courses (tees and greens only)

42 0.133 5

acres 0.000348 29,000 Golf Courses (fairways, tees, and greens) Landscaping (turf, lawns, athletic fields, parks, etc)

M/L/A Liquids for Backpack Sprayers Orchard (Ground/Soil) 2.58 0.00443 lb ai/gal

40

gallons 0.00000571 1,800,000

Greenhouse Plants (Foliar) 140 0.00326 lb ai/gal 0.000229 44,000 Nursery Plants (Foliar) Nursery Plants (Ground/Soil) 2.58 0.00000421 2,400,000 Landscaping (trees/shrubs/bushes) 140 0.00418 lb ai/gal 0.000293 34,000 Landscaping (plants/flowers) Landscaping (turf, lawns, athletic fields, parks, etc) 2.58 0.00000539 1,900,000

Industrial/Commercial Areas (tires, rail yards, junk yards,

etc) 30 0.00887 lb ai/gal 0.000133 76,000 Poultry/Livestock Houses/Horse Barns/Feed

Lots
Foundations/Perimeters 2.58 0.0000115 880,000

M/L/A Liquids for Manually

- Pressurized Handwand Sprayers Greenhouse Plants (Foliar)

30 0.00326 lb ai/gal

40

gallons 0.0000489 210,000 Nursery Plants (Foliar) Landscaping (trees/shrubs/bushes) 0.00418 lb ai/gal 0.0000626 160,000 Landscaping (plants/flowers) Landscaping (turf, lawns, athletic fields, parks, etc) 30 0.00418 lb ai/gal 0.0000626 160,000
Interior Landscaping

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 83 of 85 Table F .1 Occupational Handler Non

- Cancer E xposure and Risk Estimates for Cyantraniliprole

Exposure Scenario Crop or Target a Baseline Inhalation Unit Exposure b Maximum

Application Rate c Area

Treated or Amount Handled Daily d Baseline Inhalation

Dose e MOE f

μg/lb ai lb ai/A Acres mg/kg/day ST LOC = 30 IT LOC = 100

Industrial/Commercial Areas (tires, rail yards, junk yards,

etc)

30

0.00887 lb ai/gal 0.000133 76,000 Poultry/Li vestock Houses/Horse Barns/Feedl ots Foundations/Perimeters Structural Areas (bridges, shipyards, home decks, foundations)
Warehouses

110 0 0.00448 2,100 Residential Living Spaces (homes, apartments) Childcare Center/Schools/Institutions

M/L/A Liquids for Mechanically

Pressurized Handgun Sprayers Orchard Crops (Foliar) 3.9 0.00443 lb ai/gal

1000

gallons 0.000216 47,000

Orchard Crops (Ground/Soil) 3.9 0.00449 lb ai/gal 0.000219 46,000

Greenhouse Plants (Foliar) 120 0.00326 lb ai/gal 0.00489 2,100 Greenhouse Plants (Ground/Soil) Nursery Plants (Foliar) 3.9 0.000159 63,000 Nursery Plants (Ground/Soil) Landscaping (trees/shrubs/bushes) 3.9 0.00418 lb ai/ga l 0.0000626 160,000

Industrial/Commercial Areas (tires, rail yards, junk yards,

etc) 3.9

0.00887 lb ai/gal 0.000433 23,000

Warehouses

79 0.00876 1,200 Poultry/Li vestock Houses/Horse Barns/Feedl ots Structural (bridges, shipyards, home decks, foundations, etc) Typical Field Crops (Foliar) 3.9 0.00202 lb ai/gal 0.0000985 100,000 Typical Field Crops (Ground/Soil) Golf Courses (tees and greens only)

1.9 0.313 5

acres 0.0000371 270,000 Golf Courses (fairways, tees, and greens) Landscaping (turf, lawns, athletic fields, parks, etc)
Loader/Applicator

L/A Granules for Belly Grinders Orchard Crops 62 0.0871 1

acre 0.0000675 150,000 Greenhouse Plants Nursery Plants

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 84 of 85 Table F .1 Occupational Handler Non

- Cancer E xposure and Risk Estimates for Cyantraniliprole

Exposure Scenario Crop or Target a Baseline Inhalation Unit Exposure b Maximum

Application Rate c Area

Treated or Amount Handled Daily d Baseline Inhalation

Dose e MOE f

μg/lb ai lb ai/A Acres mg/kg/day ST LOC = 30 IT LOC = 100 Landscaping (trees/shrubs/bushes) Landscaping (plants/flowers) Landscaping (turf, lawns, athletic fields, parks, etc) Industrial/Commercial Areas (tires, rail yards, junk yards,

etc) Poultry/Li vestock Houses/Horse Barns/Feedl ots Foundations/Perimeters

L/A Granules for Rotary Spreaders Orchard Crops

10 0.0871 5

acres 0.0000545 180,000 Greenhouse Plants Nursery Plants Golf Courses (tees and greens only) Golf Courses (fairways, tees, and greens) Landscaping (turf, lawns, athletic fields, parks, etc) Industrial/Commercial Areas (tires, rail yards, junk yards,

etc) Poultry/Livestock Houses/Horse Barns/Feed

Lots 10 0.0871 1

acre 0.0000109 920,000

L/A Granules for Backpack Sprayers Nursery Plants

23.8 0.0871 1

acre 0.0000 259 390,000 Industrial/Commercial Areas (tires, rail yards, junk yards,

etc)

L/A Granules for Cups Poultry/Livestock Houses/Horse Barns/Feed

Lots 12.5 0.0871 1

acre 0.0000136 740,000

L/A Granules for Spoons Poultry/Livestock

Houses/Horse Barns/Feed

Lots 121 0.0871 1

acre 0.000131 77,000

Hand Dispersal of Granules Poultry/Livestock

Houses/Horse Barns/Feed

Lots 470 0.0871 1

acre 0.000511 20 ,000

a “Typical Field Crops” include Brassica (Cole) leafy vegetables (Group 5), bulb vegetables (Group 3

- 07), bushberries (Group 13

- 07B), citrus fruits (Group 10

- 10), cotton, cucurbit vegetables (Group 9), fruiting vegetables (Group 8

- 10), leafy vegetables (non

- Brassica ) (Group 4), oilseeds (Group 2 0), pome fruits (Group 11

- 10), potatoes, stone fruits (Group 12), sunflowers, tree nuts (Group 14), tuberous and corm vegetables (Subgroup 1C). “High

- Acreage Field Crops” includes cotton. “Nursery Plants” include ornamentals, vegetables, trees, container stock. “Greenhouse Plants” include ornamentals, roses, cut flowers, container stock, vegetables grown for re

- sale to consumers. b Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( March 2012 ); Level of mitigatio n = Base line.

### Cyantraniliprole Human Health Risk Assessment DP No. 404762

Page 85 of 85 c Based on the maximum application rates on the proposed label s (Reg. No s

. 352

- IAE, 352

- IAG, 352

- IAI, 352

- IAL, 253

- IAN, 352

- ILA, 352

- ILI, 352

- ILO, 352

- ILT, 100

- RUEE, 100

- RUEG, 100

- RUEN, 100

- RUER, 100

- RUEU, and 100

- RURI ). d Exposure Science Advisory C ouncil Policy #9.1.

e Inhalation Dose = Dermal Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW ( 80 kg adult ). f Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

Table F .2 Summary of Short

- Term Handler Exposures and Risks for Cyantraniliprole (Seed Treatment Only) a

Seed Type Max

Application Rate b Inhalation

UE c Amount of

Seed Treated or Planted Per Day d Inhalation

Dose e Inhalation

MOE f

lb ai/lb seed mg/lb lb seed/day mg/kg/day ST LOC = 30

Loader/Applicator
Potato Seed Pieces 0.000135 0.0064 * 800,000 0.00864002 1,200 Rapeseed/Canola 0.0100 0.00034 125,000 0.00531939 1,900 Mustard Seed 0.0100 125,000 0.00531939 1,900 Sunflowers 0.00397 339,500 0.00572580 1,800 Sewer Rapeseed/Canola 0.0100 0.00023 125,000 0.00359841 2,800 Mustard Seed 0.0100 125,000 0.00359841 2,800 Sunflowers 0.00397 339,500 0.00387333 2,600 Bagger Rapeseed/Canola 0.0100 0.00016 125,000 0.00250324 4,000 Mustard Seed 0.0100 125,000 0.00250324 4,000 Sunflowers 0.00397 339,500 0.00269449 3,700 Multiple Activities Rapeseed/Canola 0.0100 0.0016 125,000 0.02503242 400 Mustard Seed 0.0100 125,000 0.02503242 400 Sunflowers 0.00397 339,500 0.02694492 370
Planter
Potato Seed Pieces 0.000135

0.0034 800,000 0.0045900 2,200 Rapeseed/Canola 0.0100 400 0.0001702 59,000 Mustard Seed 0.0100 560 0.0002383 42,000 Sunflowers 0.00397 320 0.0000540 190,000

a Seed treatment rate calculations are based on the following assumptions: Mustard seed: 90,000 to 115,000 seeds per lb; 7 lbs of seed planted per day, 80 acres planted per day. Potato seed pieces: 5 to 11 seed pieces per lb; 800,000 seed pieces planted per day. Rapeseed (ca nola): 90,000 to 115,000 seeds per lb; 5 lbs of seed planted per day, 80 acres planted per day. Sunflowers: 2,000 to 9,000 seeds per lb; 4 lbs of seed planted per day, 80 acres planted per day. b Application Rates based on proposed label uses for cyantran iliprole (EPA Reg. Nos. 352

- IAN, 100

- RUEN, and 100

- RURI).

c Unit Exposures from HED Exposure Science Advisory Council Policy 14: Standard Operating Procedures for Seed Treatment (baseline inhalation = no respirator). * The inhalation unit exposure for pot ato seed pieces comes from D378750. d HED default for lb seed treated/planted per day from HED Exposure Science Advisory Council Interim Policy 15.1 and the BEAD m emo “Acres Planted Per Day and Seeding Rates of Crops Grown in the United States” (J. Becker, March 2011).

e Daily Inhalation Dose (mg/kg/day) = daily inhalation unit exposure (mg/ lb ai) × application rate (lb ai/lb seed) × amount planted (lb seed/day)

÷ body weight (80 kg adult). f Inhalation MOE = NOAEL (10.08 mg/kg/ day for short

- term exposure ) ÷ Inhalation Dose (mg/kg/day). Short

- term level of concern = 30.