### UNITED STATES ENVIRONMENTAL PROTECTION AGENC Y WASHINGTON , D
. C
. 20460 OFFICE OF CHEMICAL SAFETY AND PO L LUTION PREVE N TIO N



### MEM O RAN D UM Date: S ubj e c t:

F r o m:

T hrou g h :

T o: l 7-November-2015 Ca rf e n t r azone - Et h y l : Human Health Risk Assessment in Support of Application to Globe Artichoke, Asparagus , Mint , Psyllium , Quinoa , and Teff and Updates to Several Crop Group (CG) or Subgroup ( CSG) Designations. P C Co d es: 128712 DP Ba r code: 04 2 5574 D ec i s i o n No.: 498511 Re i stration No.: 279-3194; 2 79- 3 241 ; 279-3242 P etit i o n No.: 4E8 3 37 Reg ul ato r y Act i o n: Section 3 Case No.: 742 2 CAS No.: 1 2 8639-02-1 40 CFR: 180.515



### Barbara Madden/Andrew Ettman , RM05 Registration Division (7505P) This document provides the HED's human health risk assessment conducted in support of app l ication of carfentrazone

- ethyl (ethyl a , 2

- dichloro

- 5

- [4-(difluorom e thy l )-4 , 5-d i hydro

- 3

- methyl5

- oxo-l!-l-1 , 2 , 4-triazol-1-yl)-4-fluorobenzenepropanoic acid) to globe art i choke , asparagus , mint , psyllium , quinoa , and teff and updates to several CG or CSG designations. The aggregate risk ass e ssment , dietary risk assessment , and residue chemistry r e view were prov i ded by Tom Bloem (RAB I) , th e hazard characterization was provided by Sarah Gallagher (RAB 1 ) , the occupational/residential exposur e (ORE) and r i sk assessment were provided by Lata Venkateshwara (RAB 1 ) , and the dr i nking water assessment was provided by Richard Shamblen of the Environmental Fate and Effects Division (EFED).

Page 1 of38Carfentrazone

- ethyl (128712) Human

- Health Risk Assessment D 42557 4

Page 2 of 38 Table of Contents 1.0 Executive Summary
................................ ................................ ................................ ................................ ................................ ... 3 2.0 Recommendations
................................ ................................ ................................ ................................ ................................ ...... 6 2.1 Dat a Deficiencies/Data Needs
................................ ................................ ................................ ................................ ............. 6 2.2 Tolerance Considerations
................................ ................................ ................................ ................................ .................... 6 2.2.1 Enforcement Analytical Method
................................ ................................ ................................ ................................ 6 2.2.2 Recommended Tolerances
................................ ................................ ................................ ................................ ......... 6 2.2.3 Revisions to Petitioned

- For Tolerances
................................ ................................ ................................ ...................... 7 2.2.4 International Harmonization
................................ ................................ ................................ ................................ ....... 7 2.3 Label Recommendations
................................ ................................ ................................ ................................ ..................... 8 3.0 Ingredient Profile
................................ ................................ ................................ ................................ ................................ ....... 8 3.1 C hemical Identity
................................ ................................ ................................ ................................ ................................ 8 3.2 Proposed Use Pattern
................................ ................................ ................................ ................................ ........................... 8 3.3 Anticipated Exposure Pathways
................................ ................................ ................................ ................................ ........ 10 3.4 Consideration of Environmental Justice
................................ ................................ ................................ ............................ 10 4.0 Hazard Characterization and Dose

- Response Assessment
................................ ................................ ................................ ....... 11 4.1 Toxicology Studies Available for Analysis
................................ ................................ ................................ ....................... 11 4.2 Absorption, Distribution, Metabolism, and Excretion (ADME)
................................ ................................ ........................ 11 4.2.1 Dermal Absorption
................................ ................................ ................................ ................................ ................... 11 4.3 Toxicological Effects
................................ ................................ ................................ ................................ ......................... 12 4.4 Safety Factor for Infants and Children (FQPA SF)
................................ ................................ ................................ ........... 12 4.4.1 Completeness of the Toxicology Database
................................ ................................ ................................ ............... 12 4.4.2 Evidence of Neurotoxicity
................................ ................................ ................................ ................................ ........ 13 4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal
................................ ............................ 13 4.4.4 Residual Uncertainty in the Exposure Database
................................ ................................ ................................ ....... 13 4.5 Toxicity Endpoint and Point of Departure Selections
................................ ................................ ................................ ........ 13 4.5.1 Dose

- Response Assessment
................................ ................................ ................................ ................................ ..... 13 4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment
................................ .......................... 14 4.5.3 Cancer Classification and Risk Assessment Recommendation
................................ ................................ ................ 15 4.5.4 Summary of PODs and Toxic ity Endpoints Used in Human Risk Assessment
................................ ........................ 15 4.6 Endocrine Disruption
................................ ................................ ................................ ................................ ......................... 16 5.0 Dietary Exposure and Risk Assessment
................................ ................................ ................................ ................................ ... 17 5.1 Metabolite/Degradate Residue Profile
................................ ................................ ................................ ............................... 17 5.1.1 Comparison of Metabolic Profiles
................................ ................................ ................................ ............................ 18 5.1.2 Residues of Concern Summary
................................ ................................ ................................ ................................ 19 5.2 Food Residue Profile
................................ ................................ ................................ ................................ ......................... 19 5.3 Water Residue Profile
................................ ................................ ................................ ................................ ........................ 20 5.4 Dietary Risk Assessment
................................ ................................ ................................ ................................ ................... 20 6.0 Residential Exposure and Risk Estimates
................................ ................................ ................................ ................................ 21 6.1 Residential Handler Exposure/Risk
................................ ................................ ................................ ................................ ... 21 6.2 Residential Post

- application Exposure and Risk
................................ ................................ ................................ ............... 22 6.3 Residential Risk Estimates for Use in Aggregate Assessment
................................ ................................ ........................... 23 6.4 Non

- Occupational Spray Drift Exposure and Risk Estimates
................................ ................................ ............................ 24 6.5 Non

- Occupational Bystander Post

- Application Inhalation Exposure and Risk Estimates
................................ ................. 24 7.0 Aggregate Exposure/Risk Characterization
................................ ................................ ................................ ............................. 25 7.1 Short

- Term Aggregate Risk
................................ ................................ ................................ ................................ ............... 25 7.2 Chronic Aggregate Risk
................................ ................................ ................................ ................................ .................... 25 8.0 Cumulative Exposure/Risk Characterization
................................ ................................ ................................ ........................... 26 9.0 Occupational Exposure and Risk Estimates
................................ ................................ ................................ ............................. 26 9.1 Occupational Handler Exposure/ Risk Estimates
................................ ................................ ................................ .............. 26 9.2 Occupational Post

- application Exposure/Risk Estimates
................................ ................................ ................................ .. 29 9.2.1 Occupational Post

- application Inhalation Exposure/Risk Estimates
................................ ................................ ........ 29 9.2.2 Occupational Post

- application Dermal Exposure/Risk Estimates
................................ ................................ ............ 29 9.2.3 REI
................................ ................................ ................................ ................................ ................................ ........... 30 Appendix A. Toxicology Profile
................................ ................................ ................................ ................................ .................... 31 Appendix B: Chemical Structures
................................ ................................ ................................ ................................ .................. 36 Appendix C: Physicochemical Properties of Carfentrazone

- Ethyl
................................ ................................ ................................ 37 Appendix D: HED Recommended Teff, 13

- 07B, 13

- 07F, and 13

- 07G Application Scenarios
................................ ..................... 38Carfentrazone

- ethyl (128712) Human

- Health Risk Assessment D 42557 4

Page 3 of 38 

### 1.0 Executive Summary Carfentrazone

- ethyl is a postemergence herbicide of the phenyl triazolinone group used for control of broad leaf weeds. It acts as an inhibitor of the enzyme protoporphyrinogen oxidase (PPO), which results in disruption of the cell membrane and desiccation of susceptible plant species. C arfentrazone

- ethyl is currently registered for application to numerous crops with tolerances for the combined residues of carfentrazone

- ethyl and its metabolit e CR

- 75 ranging from 0.10

- 15 ppm (40 CFR 180.515 ; see Appendix B for structures) . Tolerances have also been established for these same compounds in/on ruminant/poultry tissues, eggs , and milk ranging from 0.02

- 0.10 ppm. The Interregional Research Proje ct No. 4 (IR

- 4) is proposing Section 3 Registrations for application of carfentrazone

- ethyl to globe artichoke, asparagus, peppermint, spearmint, teff, quinoa, and psyllium and updates to the CG or CSG designations for bulb vegetables (CG 3

- 07); fruiting v egetables (CG 8

- 10); citrus (CG 10

- 10); pome fruit (CG 11

- 10); stone fruit (CG 12

- 12); caneberry (CSG 13

- 07A); bushberry (CSG 13

- 07B); fruit, small vine climbing, except fuzzy kiwifruit (CSG 13

- 07F); berry, low growing (CSG 13

- 07G); and tree nuts (CG 14

- 12 ). Hazard Assessment: The proposed herbicidal mode of action for carfentrazone

- ethyl is inhibition of the enzyme PPO. In plants, inhibition of PPO results in the disruption of chlorophyll biosynthesis and ultimately in the desiccation of susceptible p lant species. In mammals, PPO is an important enzyme in heme biosynthesis and its inhibition can lead to toxic effects where heme is utilized (e.g., red blood cells). The mammalian toxicity database for carfentrazone

- ethyl indicates that the target organ s are the hematopoietic system and liver, which is consistent with those expected from PPO inhibition. Subchronic oral toxicity studies in rats, mice, and dogs demonstrated that the primary effects were on the hematopoietic system (decreased mean corpuscu lar hemoglobin and mean corpuscular volume). There was also increased urinary porphyrin excretion, increased liver weights, and alterations in liver histopathology consisting of : hepatic pigment deposition, hepatocytomegaly, single

- cell necrosis, and cell mitosis . Similarly, chronic toxicity studies in rats and dogs demonstrated increased urinary porphyrin excretion. Chronic studies in rats and mice found liver histopathology (pigment deposits) and fluorescence microscopy of liver sections revealed r ed fluorescent granules consistent with porphyrin deposits. T here were no effects observed on the immune system. The results of the acute neurotoxicity study indicated clinical signs (i.e., salivation) and mild decreases in motor activity at the limit do se and only on the treatment day. T here were no additional signs of neurotoxicity in the rest of the database. There was no evidence of increased susceptibility in prenatal developmental toxicity studies (rats and rabbits) or the multigenerational reproductive toxicity study in rats. Fetal effects in the rat developmental study (increase in litter incidence of wav y and thickened ribs) and offspring effects in the rat reproduction toxicity study (decreased pup body weights) were seen at or above doses eliciting blood and liver effects in maternal/parental animals, effects that are consistent with those observed thro ughout the hazard database. No developmental effects were seen in the rabbits. Carfentrazone

- ethyl was classified as having low (Category III or IV) acute toxicity in rats via the oral, dermal, and inhalation routes of exposure. It was minimally irrit ating to eyes, non

- irritating to skin, and not a skin sensitizer.Carfentrazone

- ethyl (128712) Human

- Health Risk Assessment D 42557 4

Page 4 of 38 

### Food Quality Protection Act (FQPA) Safety Factor (SF) Decision: The RAB1 r isk assessment team recommends that the F QPA SF be reduced to 1X for all exposure scenarios based on the following considerations: (1) t he toxicological database is adequate for FQPA consideration; (2) there is low concern for neurotoxicity ; (3) there is no evidence of offspring susceptibility/ sensitivity ; and (4) the assumptions incorporated in the dietary and ORE assessments are unlikely to underestimate exposure. Dietary Risk Estimates (Food + Drinking Water ): Dietary (food and drinking water) exposure and risk assessments were conducted using the Dietary Exposu re Evaluation Model

- Food Consumption Intake Database (DEEM

- FCID, ver. 3.16) which incorporates food consumption data from the United States Department of Agriculture (USDA) National Health and Nutrition Examination Survey, What We Eat in America (NHANES/ WWEIA; 2003

- 2008). The chronic analysis assumed tolerance

- level residues or, if necessary, tolerance

- level residues adjusted to account for the residues of concern for risk assessment, 100% crop treated, and modeled drinking water estimates (based on toxi cological considerations, acute and cancer analyses are unnecessary). Since adequate processing studies have been submitted which indicate that tolerances in/on apple juice, citrus juice, grape juice, grape raisin, dried potato, dried prune, prune juice, tomato paste, and tomato puree are unnecessary, the DEEM (ver
. 7.81) default processing factors for these commodities were reduced to 1. The DEEM (ver
. 7.81) default processing factors were retained for the remaining relevant commodities. The resulting c hronic exposure estimates are not of concern to HED (≤78% chronic population

- adjusted dose (cPAD); children 1

- 2 years old were the most highly exposed subgroup). Residential (Non - Occupational) Exposure and Risk Assessment: Residential exposure is not a nticipated from the proposed uses. However, carfentrazone

- ethyl is currently registered for application to turf (including golf courses and residential lawns) and for aquatic application. These exposure scenarios were assessed using the most recent stand ard operating proceudres (SOPs). The resulting r esidential handler and post

- application margins of exposure (MOEs) for all relevant scenarios were ≥84,000 and, therefore, do not exceed HED’s level of concern (LOC). Aggregate - Risk Estimates: H ED aggre gate s pesticide exposures and risks from food, drinking water, and residential exposures. Based on the proposed/registered uses, short

- term (food, water, inhalation, and/or incidental oral) and chronic (food and water) aggregate risk assessments are required. Although intermediate

- term residential exposures are not anticipated, the relevant short

- /intermediate

term points of departure (PODs) are the same and, therefore, the short

- term risk assessment is protective of intermediate

- term exposure. Short

- Term Aggregate Risk: For adults, the short

- term aggregate risk assessment combined chronic dietary exposure with residential incidental oral and inhalation exposure from the aquatic use. For children, the short

- term aggregate ris k assessment combined chronic dietary exposure with incidental oral exposure from the turf use (hand

- to
- mouth). The resulting aggregate MOEs are ≥ 2,1 00 and, therefore, do not exceed HED’s L OC. The exposure estimates and populations included in the short

term aggregate assessment are protective of all potential short

- term exposures. Chronic Aggregate Risk: C hronic aggregate risk concerns only dietary exposure (food and water). The chronic (≤69% cPAD) dietary exposure estimates do not exceed HED’s LOC.Carfentrazone

- ethyl (128712) Human

- Health Risk Assessment D 42557 4

Page 5 of 38 

### Occupational Exposure and Risk Assessment: It is anticipated that there will be occupational handler and post

- application short

- and intermediate

- term exposure from the proposed uses. Chronic exposure s are not expected
. All occupational handler scenarios for the proposed use s on teff, quinoa, psyllium, globe artichoke, asparagus , and mint resulted in MOEs greater than 100 at baseline (i.e., baseline attire with no respirator; engineering control for aerial applications (enclosed cockpits)) and, t herefore , do not exceed HED’s LOC
. No additional personal

- protective equipment (PPE) will be required for the proposed label. All three proposed labels require handlers and applicators to wear long

- sleeved shirt and long pants, waterproof gloves , and sho es plus socks. Based on the Agency's current practices, a quantitative non

- cancer occupational post

- application inhalation exposure assessment was not performed for carfentrazone

- ethyl at this time. If new policies or procedures are put into place, the A gency may revisit the need for a quantitative occupational post

- application inhalation exposure assessment for carfentrazone

- ethyl
. The proposed updates to the crop group/subgroup commodity definitions do es not involve changes to the registered applicat ion scenarios . Based on this and since t here is no difference between the occupational scenarios and the agronomics/practices already assessed for the revised crop group /subgroup definitions, t he additional crops are already covered by an existing risk a s sessment where no risks of concern were identified ( D364236, L. Venkateshwara, 11

- May

- 2009)
. Restricted - Entry Interval (REI): Carfentrazone

- ethyl is classified as Toxicity Category 3 for acute dermal and Toxicity Category 4 for acute inhalation and primary skin irritation . It is non

- irritating to skin and minimally irritating to eyes. It is not a skin sensitizer. Therefore, the interim W orker P rotection S tandard (WPS) REI of 12 hours is adequate to protect agricultural workers. The product labels list an REI of 12 hours. Environmental Justice Considerations: Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in acco rdance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations.” Review of Human 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 PHED 1.1; AHETF database; and the ORETF database are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant w ith 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 1



### .

1 http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/occupational

- pesticide

- handler

- exposure - data ; http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/occupational

- pesticide

- post
- application

- exposureCarfentrazone

- ethyl (128712) Human

- Health Risk Assessment D 42557 4

Page 6 of 38 

### 2.0 Recommen dations Provided the petitioner submits revised Sections B and F, HED concludes that the human health risk assessment supports the establishment of the permanent tolerances listed in Section 2.2.2. 2.1 Data Deficiencies/Data Needs None 2.2 Tolerance Considerations 2.2.1 Enforcement Analytical Method Enforcement Method

- Plants: A method for determining carfentrazone

- ethyl and CR

- 75 in/on wheat forage, straw, and grain has been validated by the Analytical Chemistry Branch (ACB; D245908, J . Stokes, 20

- May

- 1998) and forwarded to Food and Drug Administration (FDA) for inclusion in the Pesticide Analytical Manual (PAM) II (D260428, T. Bloem, 23

- Nov

- 1999). The procedures used in the enforcement method are similar to the procedures used to anal yze the samples collected from the field trial studies. Since the procedures are similar and since the field trial studies included adequate method validation data, HED concludes that the current enforcement method is appropriate for enforcement of the to lerances associated with the current review. Enforcement Method

- Livestock: The livestock method P

- 3151M is available for collecting data on residues of carfentrazone

- ethyl, CR

- 75, and F8426

- PAc in livestock commodities (D233587, J. Stokes, 18

- Jun

- 1998). This method has be en radiovalidated and undergone a successful independent laboratory validation trial using milk. HED has reviewed method P

- 3151M using the ACB SOP No. 019 (revision 1.0) and determined that the method is suitab le for tolerance enforcement. 2.2.2 Recommended Tolerances Table 2.2.2.1 is a summary of the proposed and HED

- recommended tolerances for the combined residues of carfentrazone

- ethyl and CR

- 75 (expressed in parent equivalents). HED notes that proposed changes to the banana and cereal grain tolerances are based on recommendations made as part of scoping assessment submitted in support of registration review (D382666, K. Lowe et al. , 9

- Feb

- 2011). With the establishment of the tole rances listed in Table 2.2.2.1, the following tolerances should be deleted: barley, bran; barley, flour; berry group 13; borage; caneberry subgroup 13A; canola; coconut; corn, field, forage; corn, sweet, forage; corn, sweet, kernel plus cob with husk remo ved; cotton, undelinted seed; cotton, hulls; cotton, meal; cotton, refined oil; crambe, seed; flax, seed; fruit, citrus, group 10; fruit, pome, group 11; fruit, stone, group 12; grain, cereal, forage, fodder and straw group 16, except corn and sorghum, for age; grain, cereal, forage, fodder and straw, group 16, hay; grain, cereal, forage, fodder and straw, group 16, stover; grain, cereal, forage, fodder and straw, group 16, except rice, straw; grain, cereal, group 15; grain, cereal, stover; grain cereal, str aw; grape; juneberry; lingonberry; millet, flour; mustard, seed; nut, tree, group 14; oat, flour; okra; pistachio; pummelo; rapeseed, seed; rice, hulls; rice, straw; rye, bran; rye, flour; safflower, seed; salal; sorghum, forage; sorghum, sweet; strawberry ; sunflower, seed; vegetable, bulb, group 3; vegetable, fruiting, group 8; wheat, bran; wheat, flour; wheat, germ; wheat, middlings; and wheat, shorts.Carfentrazone

- ethyl (128712) Human

- Health Risk Assessment D 42557 4

Page 7 of 38 Table 2.2.2.1: Tolerance Summary . Commodity Proposed Tolerance

(ppm) HED

Recommended Tolerance (ppm) Comments Current Requests a rtichoke, globe 0.10 0.10

-- a sparagus 0.25 0.10 field trials resulted in < limit of quantitation (LOQ) residues (LOQ = 0.05) p eppermint, tops 0.25 0.10 s pearmint, tops 0.25 0.10 teff, grain 0.25 0.25

-- teff, forage 1.00 1.0 significant figures teff, hay 0.30 0.30

-- teff, straw 0.10 3.0 see 3.0 ppm cereal grain straw tolerance recommended below v egetable, b ulb, group 3

- 07 0.10 0.10

-- v egetable, f ruiting, group 8

- 10 0.10 0.10

-- fruit, citrus, group 10

- 10 0.10 0.10

-- fruit, pome, group 11

- 10 0.10 0.10

-- fruit, stone, group 12

- 12 0.10 0.10

-- caneberry subgroup 13

- 07A 0.10 0.10

-- bushberry subgroup 13

- 07B 0.10 0.10

-- fruit, small vine climbing, subgroup 1 3

- 07F , except f uzzy kiwifruit 0.10 0.10

-- berry, low growing, subgroup 13

- 07G 0.10 0.10

-- n ut, tree, g roup 14

- 12

-- 0.10

-- o ilseed g roup 20 0.20

-- To maintain harmonization with the Canadian canola (0.1 ppm) , mustard seed (0.1 ppm) , safflower seed (0.1 ppm) , and sunflower seed (0.1 ppm) MRLs, subgroup tolerances are recommended. rapeseed subgroup 20A

-- 0.10 sunflower subgroup 20B

-- 0.10 cottonseed subgroup 20C

-- 0.20 quinoa, grain 0.10 0.10

-- psyllium, seed 0.10 0.10

-- Tolerances changes r e commended as part of the Scoping Assessment conducted in support of Registration Review. banana

-- 0.10 D382666, K. Lowe et al. , 9

- Feb

- 2011 g rain, cereal, group 16, forage

-- 1.0 g rain, cereal, group 16, hay

-- 0.30 g rain, cereal, group 16, stover
-- 0.80 g rain, cereal, group 16, straw
-- 3.0 

### 2.2.3 Revisions to Petitioned - For Tolerances A revised Section F is reques ted which specifies the commodity definitions and tolerance values specified in Table 2.2.2.1. The comments column of Table 2.2.2.1 provides a rationale for the requested changes. 2.2.4 International Harmonization Mexican and Codex carfentrazone

- ethyl MRLs are not established in/on the relevant crops
. Canadian MRLs are established in/on several of the relevant crops at levels eq ual to that recommended herein (tolerance expressions are identical). T herefore , harmonization is not an issue for this petition
.Carfentrazone

- ethyl (128712) Human

- Health Risk Assessment D 42557 4

Page 8 of 38 

### 2.3 Label Recommendations A revised Section B which specifies the following is requested:
● Based on the HED Chemistry Science Advisory Council (ChemSAC) conclusions (minutes 14

- Sep

- 2011), the teff application scenario shoul d be identical to the currently

- registered grain sorghum scenario (see Attachment 4). ● The use directions for subgroups 13

- 07B, 13

- 07F, and 13

- 07G shoul d be identical to the currently

- registered 13B, grape (representative crop for 13

- 07F), and strawberry (13

- 07G) scenarios, respectively (see Attachment 4). ● The crops listed for the following CGs should be altered to conform with 40 CFR 180.41: ci trus (CG 10

- 10); pome fruit (CG 11

- 10); stone fruit (CG 12

- 12); tree nut (CG 14

- 12); and oil seeds (CG 20, except cotton )
. 3.0 Ingredient Profile 3.1 Chemical Identity Table 3.1.1 is a summary of carfentrazone

- ethyl structure and nomenclature. See A ppendix B and C for structures of the metabolites and the physiochemical properties of technical grade carfentrazone

- ethyl, respectively.

Table 3.1. 1: Carfentrazone - Ethyl Nomenclature.

Chemical Structure N F C l

N N O

C H F 2

C H 3 E t O C l

O
Common name carfentrazone

- ethyl Company experimental name F8426 IUPAC name ethyl ( RS )

- 2

- chloro

- 3

- {2

- chloro

- 5

- [4

- (difluoromethyl)

- 4,5

- dihydro

- 3

- methyl

- 5

- oxo - 1 H

- 1,2,4

- triazol

- 1

- yl]

- 4

- fluorophenyl}propionic acid CAS name ethyl α,2

- dichloro

- 5

- [4

- (difluoromethyl)

- 4,5

- dihydro

- 3

- methyl

- 5

- oxo - 1 H

- 1,2,4

- triazol

- 1

- yl]

- 4

- fluorobenzenepropanoic acid CAS # 128639

- 02

- 1 

### 3.2 Proposed Use Pattern The petitioner is proposing application of A im® Herbicide (EPA Reg. No. 279

- 3194), Aim® EC He rbicide (EPA Reg. No. 279

- 3241), and Aim® EW Herbicide (EPA Reg. No. 279

- 3242) to globe artichoke, asparagus, peppermint, spearmint, teff, quinoa, and psyllium. The petitioner is also proposing establishing an oilseed (CG 20) tolerance and updating the CG or CSG designation for bulb vegetables (CG 3

- 07); fruiting vegetables (CG 8

- 10); citrus (CG 10

- 10); pome fruit (CG 11

- 10); stone fruit (CG 12

- 12); caneberry (CSG 13

- 07A); bushberry (CSG 13

- 07B); fruit, small vine climbing, except fuzzy kiwifruit (CSG 13

- 0 7F); berry, low growing (CSG 13

- 07G); and tree nuts (CG 14

- 12). The labels indicated that a treated field may be rotated to a labeled crop at any time and may be rotated to any other crop 12 months after application ; t he listed REI is 12 hours. Table 3.3 .1 is a summary of the proposed end

- use products and Table 3.3.2 is a summary of the proposed application instructions.Carfentrazone

- ethyl (128712) Human

- Health Risk Assessment D 42557 4

Page 9 of 38 

### The use directions for globe artichoke, asparagus, mint, quinoa, and psyllium are adequate. A revised Section B which specifies the following is requested: ●Based on the ChemSAC conclusions (minutes 14

- Sep

- 2011), the teff application scenario shoul d be identical to the currently

- registered grain sorghum scenario (see Attachment 4). ●The use directions for subgroups 13

- 07B, 13

- 07F, and 13

- 07G should be iden tical to the currently

- registered 13B, grape (representative crop for 13

- 07F), and strawberry (13

- 07G) scenarios, respectively (see Attachment 4). ●The crops listed for the following CGs should be altered to conform with 40 CFR 180.41: citrus (CG 10

- 10), pome fruit (CG 11

- 10), stone fruit (CG 12

- 12), tree nut (CG 14

- 12), and oil seeds (CG 20). Table 3.3.1: Summary of End - Use Products. Trade Name (EPA Reg. No.) Conc. Formulation Label Date Target Crops Target Pests Aim® Herbicide (279

- 3194) 40% water
dispersible

granule (WDG)
not indicated globe artichoke, asparagus, mint, teff, quinoa, psyllium and updating the crop group (CG) or subgroup (CSG) designations for bulb vegetables (CG 3

- 07); fruiting vegetables (CG 8

- 10); ci trus (CG 10

- 10); pome fruit (CG 11

- 10); stone fruit (CG 12

- 12); caneberry (CSG 13

- 07A); bushberry (CSG 13

- 07B); fruit, small vine climbing, except fuzzy kiwifruit (CSG 13

- 07F); berry, low growing (CSG 13

- 07G); tree nuts (CG 14

- 12); and oilseed (CG 20) bro adleaf weeds Aim® EC Herbicide (279

- 3241) 2.0 lbs ai/gallon emulsifiable concentrate
Aim® EW Herbicide (279

- 3242) 1.9 lbs ai/gallon emulsion in water
Table 3.3.2: Summary of Proposed Directions . 1 App. Timing; Type Formulation App. Rate (lb ai/acre) Max. No. App. per Year Max. Yearly/ Seasonal Rate

(lb ai/acre) PHI (days) Use Directions and Limitations asparagus post
- emergence; broadcast spray WDG; EC; EW 0.007

- 0.030 2 0.060 5 - RTI = 20 days

- spray vol. ≥10 GPA (ground) 5 GPA (aerial) mint dormancy; broadcast spray WDG; EC; EW 0.007

- 0.030 1 0.030 not indicated - do not apply to actively growing crop

- spray vol. ≥10 GPA (ground); ≥ 5 GPA (aerial) globe artichoke preplant burndown (broadcast); post

emergence (hooded) WDG; EC; EW 0.031 not specified 0.096 (preplant = 0.031 lb ai/acre; post

emergence =

0.065 lb ai/acre ) 0 - post
- emergence application made with hooded sprayer to row middles

- spray vol. ≥20 GPA for post

emergent applications teff, quinoa, psyllium preplant burndo wn; post
- emergence; harvest aid; broadcast spray WDG; EC; EW preplant

- 0.031 postemergence
-

0.007

- 0.031 harvest aid

- 0.015

- 0.031 not specified 0.031 3 (7 days for forage ) - post
- emergence application can be made up to the jointing stage

- spray vol. ≥10 GPA (ground); 3 GPA (aerial)Carfentrazone

- ethyl (128712) Human

- Health Risk Assessment D 42557 4

Page 10 of 38 Table 3.3.2: Summary of Proposed Directions . 1 App. Timing; Type Formulation App. Rate (lb ai/acre) Max. No. App. per Year Max. Yearly/ Seasonal Rate

(lb ai/acre) PHI (days) Use Directions and Limitations oilseed CG 20 preplant burndown; post
- emergence (hooded) WDG; EC; EW 0.031 not specified 0.096 (preplant = 0.031 lb ai/acre; post

emergence =

0.065 lb ai/acre ) 0 - post
- emergence application made with hooded sprayer to row middles

- spray vol. ≥20 GPA for post

emergent applications cotton preplant burndown; post
- emergence (hooded) ; harvest aid WDG; EC; EW preplant and postemergence
- 0.031 harvest aid

- 0.025 not specified 0.124 (do not apply more than 0.050 as a

harvest aid) 7 - non - harvest aid post
- emergence application s are made with hooded sprayer s to row middles

- spray vol. ≥10 GPA (ground); ≥5 GPA (aerial) 1 RTI = retreatment interval; GPA = gallons per acre. 

### 3.3 Anticipated Exposure Pathways Carfentrazone

- ethyl is registered for application to numerous crops with LOQ

- level tolerances established for the majority of the relevant food commodities . A quatic application and application to turf (including residential lawns and golf courses) is also registered. Livestock tolerances have been established based on the potential for secondary residues from the consumption of treated feed. As a result of these and the proposed uses , dietary ( food and water) , residential (dermal, inhalation, and incidental oral) , and occupati onal (dermal and inhalation) exposure to carfentrazone

- ethyl are possible. It is noted that EFED concluded that carfentrazone

- ethyl is not likely to bioaccumulate in the aquatic environment (D3 82665 , G
. Orrick , 8

- Mar

- 2011). 3.4 Consideration of Environmental Justice Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Ac tions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://www.archives.gov/federal

- register/executive

- orders/pdf/12898.pdf ). As a part of every pesticide risk assessme nt, 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 t hat subgroup’s food and water co nsumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under NHANES/WWEIA ( 2003

- 2008 ) and are used in pesticide risk assessments for all re gistered 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 ab le to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or pl aying on treated areas post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm wor kers as well as lifestyle and traditional dietary patterns among specific subgroups.Carfentrazone

- ethyl (128712) Human

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### 4.0 Hazard Characterization and Dose - Response Assessment 4.1 Toxicology Studies Available for Analysis The toxicological database for carfentrazone

- ethyl is adequate f or hazard characterization, toxicity endpoint selection, and FQPA SF consideration
. T he HED Hazard and Science Policy Council (HASPOC) concluded using a weight

- of

- evidence approach that the subchronic inhalation study is not required at this time (Memo, D . Smegal, 21

- FEB

- 2012, TXR# 0051142 ). Since the last risk assessment, an immunotoxicity study has been submitted and the results of the study incorpora ted into the current assessment
. Appendix A includes a summary of the carfentrazone

- ethyl toxicological database. Carfentrazone

- ethyl was evaluated for the following: (1) Subchronic and chronic oral toxicity in rats, mice, and dogs; (2) Subchronic dermal toxicity in rats; (3) Developmen tal toxicity in rats and rabbits; (4) Reproductive and postnatal toxicity in rats; (5) Carcinogenicity in mice and rats; (6) Neurotoxicity in rats; (7) Immunotoxicity in rats ; (8) Genotoxicity and mutagenicity studies; and (9) Absorption, distribution, me tabolism, excretion (ADME) studies in rats. 4.2 Absorption, Distribution, Metabolism, and Excretion (ADME) Absorption of oral ly administered carfentrazone

- ethyl in rat s was rapid in both sexes as measured indirectly by the rapid excretion of radioactivity in urine within the first 24 hours
. The majority of the administered dose was excreted in urine (72.4% to 87.0%), followed by feces (10.47% to 25.68%). Carfentrazone

- ethyl was e xtensive ly metabolized in the rat since only a small amount of the parent (0.0 6 to 2.78%) was found in the feces by 48 hours and n o parent was found in the urine
. There was no evidence suggestive of bioaccumulation; the total mean percentage of the administered dose found in all tissues and carcas ses assayed was very low (males: 0.09% ; female s: 0.08%). The major metabolite s in both the urine and feces are CR

- 75 (49

- 66%) and CR

- 48 (18

- 34%)
. The proposed metabolic pathway of carfentrazone

- ethyl begins with hydrolysis to generate CR

- 75 followed by either hydroxylation to generate CR

- 48 . Additional metaboli c reactions generate a number of minor metabolites. There were n o differences in the male and female rate metabolic profile s . 4.2.1 Dermal Absorption There are no dermal penetratio n studies available for carfentrazone

- ethyl. There was n o dermal hazard identified in the toxicological database . As a result, a dermal absorption factor is not needed because a quantitative dermal assessment was not performed.Carfentrazone

- ethyl (128712) Human

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Page 12 of 38 

### 4.3 Toxicological Effects The proposed herbicidal mode of action for carfentrazone

- ethyl is inhibition of the enzyme PPO. In plants, i nhibition of PPO results in the disruption of chlorophyll biosynthesis and ultimately in the desiccation of susceptible plant species. In mammals, PPO is an important enzyme in heme biosynthesis and its inhibition can lead to toxic effects where heme is utilized (e.g., red blood cells). The mammalian toxicity database for carfentrazone

- ethyl indicates that effects observed following repeat ed oral exposures that are consistent with those expected from PPO inhibition , toxicity of the hematopoietic system and liver. Subchronic oral toxicity studies in rats, mice, and dogs demonstrated that the primary effects were on hemato poietic system (dec reased mean corpuscular hemoglobin and mean corpuscular volume). There was also increased urinary porphyrin excretion, increased liver weights, and alterations in liver histopathology consisting : of hepatic pigment deposition, hepatocytomegaly, single ce ll necrosis, and cell mitosis . Similarly, chronic toxicity studies in rats and dogs demonstrated increased urinary porphyrin excretion
. Chronic studies in rats and mice found liver histopathology (pigment deposits) and fluorescence microscopy of liver se ctions revealed red fluorescent granules consistent with porphyrin deposits. T here were no indicators of targeted effects on the immune system. The results of the acute neurotoxicity study indicate d clinical signs (i.e., salivation) and mild decreases in motor activity but only at the limit dose and only on the treatment day. However, there were no other signs of neurotoxicity in the rest of the database. There was no evidence of increased susceptibility in prenatal developmental toxicity studies (rats and rabbits) or the multigenerational reproductive toxicity study in rats. F etal effects in the rat developmental study (increase in litter incidence of wav y and thickened ribs) and offspring effects in the rat reproduction toxicity study (decreased pup body weights) were seen at or above doses eliciting blood and liver effects in maternal/parental animals , effects that are consistent with the observed in the hazard database. No developmental effects were seen in the rabbits
. Carfentrazone

- ethyl was classified as having low (Category III or IV) acute toxicity in rats via the oral, dermal, and inhalation routes of exposure. It was minimally irritating to eyes, non

- irritating to skin, and not a skin sensitizer. 4.4 Safety Factor for Infants and Children (FQPA SF) The RAB1 r isk assessment team recommends that the F QPA SF be reduced to 1X for all exposure scenarios based on the following considerations: (1) t he toxicological database is adequate for FQPA consideration; (2) there is low concern for neurotoxicity ; (3) there is no evidence of offspring susceptibil ity/sensitivity ; and (4) the assumptions incorporated in the dietary and ORE assessments are unlikely to underestimate exposure. 4.4.1 Completeness of the Toxicology Database The e xisting toxicology database is adequate for characterizing carfentrazon e - ethyl toxicity and quantifying hazard for dietary and occupational exposures. D evelopmental toxicity studies in rats and rabbits and a two
- generation reproduction study in rats are available to evaluate in utero and pre - /postnatal sensitivity
. Acute and subchronic neurotoxicity studies in rats are available to assess potential neurotoxicity due to carfentrazone

- ethyl exposure
.Carfentrazone

- ethyl (128712) Human

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### 4.4.2 Evidence of Neurotoxicity Although effects were seen in the acute neurotoxicity study (clinical signs and mild decreases in motor activity), concern is low since : 1) the effects are minimal; 2) the effects were seen at the highest doses tested (≥1000 mg/kg); and 3) there is no evidence of neurotoxicity in the rest of the carfentrazone

- ethyl database, including the subchronic neurotoxicity study. 4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal There is no evidence of increased pre

- and/or postnatal susceptibility following carfentrazone

ethyl exposure. 4.4.4 Residual Uncertainty in the Exposure Database The exposure databases are sufficient to determine the nature/magnitude of the residue in food and water. The dietary exposure analys is is unlikely to underestimate exposure as they incorporated tolerance

- level residues or toler ance - level residues adjusted to account for the residues of concern for risk assessment, 100% crop treated, and modeled drinking water estimates. The residential exposure assessment uses HED’s Residential SOPs, assumes maximum application rates, and is co nsidered health

- protective. 4.5 Toxicity Endpoint and Point of Departure Selections 4.5.1 Dose - Response Assessment Since the last risk assessment ( T
. Bloem et al .; 01

- MAR

- 2012 ; D 389083 ), the PODs have not been changed except the acute dietary endpoint has been removed
. It is recognized that the studies in the carfentrazone

- ethyl database, including those used for endpoint selection, have not been updated to reflect current approaches in hazard characterization
. No

- observed

- effect levels (NOELs) and l owest
- observed

- effect levels (LOELs) have not been updated to no

- observed adverse

- effect levels (NOAELs) and lowest

- observed adverse

- effect levels (LOAELs), respectively. Several studies have NOEL/LOEL or NOAEL/LOAEL values based on effects that are not considered adverse according to current practices (e.g., decreased body

- weight gain without a corresponding decrease in absolute body weight). These studies are considered protective since updates would result in higher NOEL/LOEL or NOAEL/LOAEL values tha n those currently established
. The currently selected PODs address all of the effects observed in the carfentrazone

- ethyl database and any updates would not impact the overall findings of the risk assessment given the current risk profile for carfentrazon e - ethyl. Table 4.5.3 summarizes the toxicological d oses and endpoints selected for dietary, as well as occupational/residential risk assessments . The rationale for the dose/endpoint selection is also described below. Acute dietary (all populations): An endpoint was not selected to evaluate acute dietary exposures
. Previously, the acute neurotoxicity study in rat s was used to evaluate acute dietary exposures; however, effects (salivatio n and decreased motor activity) were only seen at the LOAEL of 1000 mg/kg/day (NOAEL=500 mg/kg/day), which is not considered relevant for human health risk assessment. There were no other effects seen in the database attributable to a single dose.Carfentrazone

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### Chronic dietary (all populations): A rat chronic t oxicity/carcinogenicity study was selected for this exposure scenario since the endpoints of concern were seen following long

- term dietary exposure , and the rat is the most sensitive species following chronic exposure . The LOEL of 12 mg/kg bw/day (NOEL = 3.0 mg/kg bw/day) was based on liver histopathology (increases in red fluorescence and pigmentation) and increased urinary excretion of porphyrins. This study is appropriate for the route and duration of exposure and is protective of all effects seen foll owing chronic exposure to carfentrazone

- ethyl. T he cPAD of 0.03 mg/kg/day is based on the NOAEL of 3 mg/kg/day and a 100

- fold uncertainty factor (10X for interspecies extrapolation, 10X for intraspecies extrapolation, and 1X for FQPA SF). Short - and intermediate - term incidental oral: The incidental oral endpoint was established based on decreased body

- weight gain and increased urinary excretion of porphyrins reported in a subchronic oral dog toxicity study at the LOEL of 150 mg/kg bw/day (NOEL = 50 m g/kg bw/day). T he study is appropriate for the route and duration of exposure and is protective of all effects seen following subchronic exposure as well as offspring effects seen in the reproduction toxicity study. T he LOC for incidental oral exposures is 100 (10X for interspecies extrapolation, 10X for intraspecies extrapolation, and 1X for FQPA SF)
. Short - and intermediate - term dermal: A dermal endpoint was not selected. There is no concern for increased pre

- or postnatal sensitivity/susceptibility to offspring from carfentrazone

- ethyl exposure ; therefore , the effects of concern in adults and offspring are adequately assessed in the dermal toxicity study where no adverse dermal or systemic effects were observed up to the l imit dose (1000 mg/kg/day)
. Short - and intermediate - term inhalation: The inhalation endpoint was established based on decreased body

- weight gain and increased urinary excretion of porphyrins reported in a subchronic oral dog toxicity study at the LOEL of 150 mg/kg bw/day (NOEL = 50 mg/kg bw/day). This study is appropriate for the duration of exposure and is protective of all effects seen following subchronic exposure to carfentrazone

- ethyl as well as developmental and offspring effects observed in the database . T he LOC for inhalation oral exposures is 100 (10X for interspecies extrapolation, 10X for intraspecies extrapolation, and 1X for FQPA SF)
. For this endpoint, i nhalation exposure is assumed to be equivalent to toxicity by the oral route of expos ure. Cancer: Carfentrazone

- ethyl has been classified as “n ot likely to be carcinogenic” based on the lack of evidence for carcinogenicity in mice and rats ; t herefore, a quantitative cancer risk assessment is not necessary
. 4.5.2 Recommendation for Com bining Routes of Exposures for Risk Assessment When there are potential occupational and residential exposures to a pesticide, the risk assessment must address exposures from three major sources (oral, dermal, and inhalation) and determine whether the individual exposures can be combined if they have the same toxicological effects. Incidental oral and inhalation exposures can be combined for carfentrazone

- ethyl since the same study and endpoint were chosen for both routes. No dermal endpoint was selec ted.Carfentrazone

- ethyl (128712) Human

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Page 15 of 38 

### 4.5.3 Cancer Classification and Risk Assessment Recommendation There was no evidence of carcinogenicity in male or female CD

- 1 mice and Sprague

- Dawley rats following dietary administration at doses that were adequate for assessing the carcinogeni c potential of carfentrazone

- ethyl
. In addition, t he mutagenic test battery demonstrated that carfentrazone

- ethyl is not mutagenic. Based on these findings and i n accordance with the Draft Proposed Guidelines for Carcinogen Risk Assessment (April, 1999), the Agency classified carfentrazone

- ethyl as “not likely to be a carcinogen ic to humans ”; t herefore, a quantitative cancer risk assessment is not required
. 4.5.4 Summary of P O D s and Toxicity Endpoints Used in Human Risk Assessment

Table 4.5. 4 .1. Summary of Toxicological Doses and Endpoints for Carfentrazone - ethyl for Use in Dietary and Non - Occupational Human Health Risk Assessments. Exposure/ Scenario POD Uncertainty/ FQPA SFs RfD, PAD, LOC for Risk Assessment Study and Toxicological Effects Dietary and Non

- Occupational Acute Dietary (All Populations) No appropriate toxicological effects attributable to a single dose was observed. Therefore, a dose and endpoint were not identified for this risk assessment.
Chronic Dietary (All Populations) NOEL= 3.0 mg/kg/day UF A = 10X UF H = 10X FQPA SF = 1X cRfD = 0.03 mg/kg/day c PAD = 0.03 mg/kg/day Chronic toxicity

- rats: LOEL = 12 mg/kg/day based on liver histopathology (increases in microscopic red fluorescence and pigmentation) and inc reased urinary porphyrin levels in both sexes Incidental Oral (short

- and intermediate

- term) NOEL = 50 mg/kg/day UF A = 10X UF H =10X FQPA SF = 1X Residential LOC for MOE <100 Subchronic toxicity

- dogs: LOEL = 150 mg/kg bw/day based on decreased body

- weight gain increased urinary excretion of porphyrins. Dermal (short

- and intermediate

- term) No hazard was identified for dermal exposure and there is no evidence of enhanced sensitivity/susceptibility to o ffspring; therefore, a quantitative dermal assessment is not needed. Inhalation (short

- and intermediate

- term) Oral NOEL = 50 mg/kg/day UF A = 10X UF H =10X FQPA SF = 1X Residential LOC for MOE <100 Subchronic toxicity

- dogs: LOEL = 150 mg/kg bw/day based on decreased body

- weight gain increased urinary excretion of porphyrins. Cancer (oral, dermal, inhalation) Classified as “not likely to be carcinogenic to humans” based upon lack of evidence of carcinogenicity in rats and mi ce. Occupational Dermal (short

- and intermediate

- term) No hazard was identified for dermal exposure and there is no evidence of enhanced sensitivity/susceptibility to offspring; therefore, a quantitative dermal assessment is not needed Inhalation (short

- and intermediate

- term) Oral NOEL = 50 mg/kg/day UF A = 10X UF H =10X Occupational LOC for MOE <100 Subchronic toxicity

- dogs: LOEL = 150 mg/kg bw/day based on decreased body

- weight gain increased urinary excretion of porphyrins. Cancer (oral, dermal, inhalation) Classified as “not likely to be carcinogenic to humans” based upon lack of evidence of carcinogenicity in rats and mice. 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. NOEL = no

observed

- effect level. LOEL = lowest

- observed

- effect level. UF = uncertainty factor. UF A = extrapolation from anima l to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population

- adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of ex posure. LOC = level of concern.Carfentrazone

- ethyl (128712) Human

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### 4.6 Endocrine Disruption As required by the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal Food, Drug, and Cosmetic Act (FFDCA) , EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic , and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproducti ve, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rat es, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its reregistration d ecision for carfentrazone

- ethyl, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), carfentrazone

ethyl is subject to th e endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an ef fect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance , and establish a dose

- response relationship between the dose and the E, A, or T effect. Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the firs t group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 and includes some pesticides scheduled for registration review and che micals found in water ( http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0074 )
. Neither of these lists should be construed as a list of known o r likely endocrine disruptors. For further information on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website ( http://www.epa.gov/endo/ )
.Carfentrazone

- ethyl (128712) Human

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### 5.0 Dietary Exposure and Risk Assessment D427527, T. Bloem, 17

- Nov

- 2015 (residue chemistry summary) ; D 428859, T. Bloem, 17

- Nov

- 2015 (dietary exposure) 

### 5 .1 Metabolite/Degradate Residue Profile Primary Crops: Based on corn, wheat, and soybean metabolism studies (foliar application), the HED Metabolism Assessment Review Committee (MARC) determined that residues of concern in these crops, for tolerance expression and risk assessment, are carfentrazone

- ethyl and CR

- 75 (MARC decision memoranda, J. Stokes, 19

- Jun

- 1998). The MARC also determined that residues of CR

- 48 should be monitored in future field trials , as it was a significant residue in soybean forage and hay. Subsequent to this decision, the petitioner s ubmitted a radish metabolism study (foliar application; 46046716.der.wpd) which resulted in the identification of significant residues of CR

- 75, CR

- 48, 3

- OH

- F8426

- BAc, and F8426

- BAc. The compounds identified in the radish metabolism study were identified in the previous metabolism studies but not at significant concentrations. Since no unique compounds were identified in the radish metabolism study, HED conclude d that the metabolic pathway in radish is similar to that for wheat, corn, and soybean. Table 5.1.2.1 and the following paragraph are a summary of the residues of concern for tolerance enforcement and risk assessment in the registered/proposed crops; for further information concerning these decisions see the following documents: D271468 (T. Bloem, 9

- Jan

- 2001); D303030 (T. Bloem, 30

- Jan

- 2004); D293779 (T. Bloem, 14

- Jul

- 2004) ; and D3899976 (T. Bloem, 29

- Feb

- 2012)
. Based on the primary crop metabolism studies, HED concluded that the residue of concern for the registered/proposed crops for tolerance enforcement are carfentrazone

- ethyl and CR

- 75. Based on the registered/proposed foliar application scenario for cereal grain, cotton, grass, nongrass animal feed, asparagus, mint, teff, quinoa, and psyllium; the soybean, wheat, and corn metabolism studie s; and the field trial data; HED concluded that the residues of concern in these crops for risk assessment are carfentrazone

- ethyl and CR

- 75 for all except nongrass animal feed where the residues of concern are carfentrazone

- ethyl, CR

- 75, and CR

- 48. Based o n the soil

- directed application scenario for the remaining proposed crops and the soybean, wheat, corn, and radish metabolism data, HED concluded that the residues of concern in these crops for risk assessment are carfentrazone

- ethyl, CR

- 75, CR

- 48, 3

- OH

- F8426

- BAc, F8426

- BAc, and Me

- 3

- OH

- F8426

- BAc. Residues of CR

- 48 were included as it was a significant residue in the soybean metabolism study (forage and hay). Residues of 3

- OH

F8426

- BAc, F8426

- BAc, and Me

- 3

- OH

- F8426

- BAc were included for the following re asons: (1) soil

- directed applications are proposed; (2) these compounds were identified in significant concentrations in the radish metabolism study and/or confined rotational crop study; and (3) detectable residues of 3

- OH

- F8426

- BAc were found in those field trials in which it was monitored (sugarcane and field pea hay; monitored in pea and bean but not detected). Livestock: Adequate ruminant (50

- ppm dietary burden) and poultry (10

- ppm dietary burden) metabolism studies are available (D233587, J. Stokes, 18

- June

- 1998). In both goats and hens, carfentrazone

- ethyl is initially hydrolyzed to CR

- 75, the major metabolite. In go ats, CR

- 75 is dehalogenated to F8426

- PAc and de

- hydro/halogenated to F8426

- CAc. In poultry, CR

- 75 undergoes oxidation of the allylic 3

- methyl group to yield CR

- 48. The MARC determined that residues of concern in livestock, for tolerance enforcement and r isk assessment purposes, are carfentrazone

- ethyl and CR

- 75 (TXR 0012659, J. Stokes, 19

- Jun

- 1998).Carfentrazone

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### Nature of the Residue - Fish/Shellfish: The petitioner has submitted and EFED has reviewed a fish metabolism/bioconcentration stud y (MRID 44165042). Rainbow trout were exposed continuously to [C

- phenyl

- U

14 

### C]carfentrazone

- ethyl at 16 ppb (41 days) or 160 ppb (28 days). CR

- 75 was the major compound identified in the viscera (92% TRR) and edible tissue (80% TRR). The conjugated meta bolite CR

- 48 was also identified in edible tissue and the viscera at ≤4% TRR (polar unknowns were at ≤8% TRR). Carfentrazone

- ethyl was not identified. The depuration portion of the study indicated that by 14 days after exposure, 98

- 99% of the TRR was eli minated. Based on these data, HED concluded that the residues of concern in fish/shellfish, for purposes of tolerance enforcement and risk assessment, are carfentrazone

- ethyl and CR

- 75 (D303030, T. Bloem, 15

- Jul

- 2004). Rotational Crops: The existing c arfentrazone

- ethyl confined rotational study (lettuce, radish, and wheat) employed a bare

- soil application at 0.031 lb ai/acre (D233587, J. Stokes, 18

- Jun

- 1998; 0.3x for globe artichoke; 1x for remaining proposed crops). The metabolic profile was similar in all the rotated crop commodities analyzed. The major metabolites identified were 3

- OH

- F8426

- BAc, F8426

- BAc, 3

- DM

- F8426

- BAc, 3

- DM

- F8426

- PAc, and 3

- DM

- F8426

- ClPAc. The MARC determined that parent and CR

- 75 are the residues of concern in rotational crops for purposes of tolerance expression and risk assessment (TXR 0012659, J. Stokes, 19

- Jun

- 1998). The MARC also expressed concern for the residues of the benzoic acid compounds if the levels found are similar to or greater than the parent and the metabolit e. Environmental Degradation: Carfentrazone

- ethyl breaks down rapidly in the environment to CR

75 which subsequently breaks down to F8426

- CAc, F8426

- PAc, F8426

- BAc, and 3

- OH

- F8426

- BAc at slower rates than the parent compound. No aerobic or anaerobic aquatic laboratory data were availa ble to evaluate the degradation of carfentrazone

- ethyl in water. However, an aquatic field dissipation study was available in which the combined residues of parent, F8426

- BAc, F8426

- PAc, CR

- 75, and F8426

- CAc had a half

- life of 4

- 10 days in surface water. In an anaerobic soil metabolism study, degradation was much slower. For example, the slowest degradation was observed for F8426

- BAc, which had an average half

- life in three soil types of 1878 days. These data suggest that residues in the subsurface may be longer lived than residues in surface water. Hydrolysis of carfentrazone

- ethyl is pH

- dependent with rapid hydrolysis occurring at alkaline pH (3.6 hours), moderate hydrolysis at neutral pH (8.6 days), and at acidic pH the compound is stable to hydrolys is. CR

- 75 is stable to hydrolysis at neutral and alkaline pHs. Hydrolysis data are not available for the other degradates. The MARC determined that the residues of concern in water are carfentrazone

- ethyl, CR

- 75 , and F84 26

- CAc (MARC decision document, T XR 0012659, J. Stokes, 19

- Jun

- 1998). 5.1.1 Comparison of Metabolic Profiles Section 4.2 includes a summary of the metabolism of carfentrazone

- ethyl in the rat; Section 5.1 includes a discussion of the metabolism of carfentrazone

- ethyl in plants , fish/shellfish, and livestock as well as the environmental degradation of carfentrazone

- ethyl. Based on these data, the metabolism/ degradation of carfentrazone

- ethyl in rats, primary crops, rotational crops, livestock, fish, and drinking water are simila r. C arfentrazone

- ethyl is initially hydrolyzed to CR

- 75 which is then dehalogenated to F8426

- PAc or de

- hydro/halogenated to F8426

- CAc. F8426

- CAc may be further oxidized to form F8426

- BAc. Oxidative hydroxylation of the triazolinone ring yields the 3

- OH form of some of these metabolites.Carfentrazone

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### 5.1.2 Residues of Concern Summary Table 5.1.2.1 is a summary of the residues of concern for tolerance enforcement and risk assessment in plants, livestock, fish, and water. These decisions are based on the available metabolism, fate, and magnitude of the residue data. Table 5.1.2.1 : Summary of Residues to be Included in the Risk Assessment and Tolerance Expression. Matrix Residues of Concern for Risk Assessment Residues of Concern for Tolerance Assessment

plants Primary Crops (cereal grain, cotton, grass, mint, asparagus, teff, quinoa, psyllium) carfentrazone

- ethyl and CR

- 75

carfentrazone

- ethyl and CR

- 75 Primary Crop (nongrass animal feed) carfentrazone

- ethyl, CR

- 75, and CR

- 48 Primary Crops (remaining proposed/ registered crops) carfentrazone

- ethyl, CR

- 75, CR

- 48, 3

- OH

- F8426

- BAc, F8426

- BAc, and Me

- 3

- OH

- F8426

- BAc Rotational Crops carfentrazone

- ethyl and CR

- 75; the MARC also expressed concern for the residues of the benzoic acid compounds if the levels found are similar to

or greater than the parent and the metabolite livestock (ruminant poultry) carfentrazone

- ethyl and CR

- 75 fish/shellfish carfentrazone

- ethyl and CR

- 75 water carfentrazone

- ethyl, CR

- 75, and F8426

- CAc not applicable 

### 5.2 Food Residue Profile As indicated below, HED concludes that provided a revised Section B is submitted, adequate residue data are available to support the tolerances recommend in Table 2.2.2.1 (revised Section F is requested) . No additional residue data are required (D427527, T. Bloem, 17

- Nov

- 2015). ●Adequate data are available for CSGs 13

- 07B, 13

- 07F, and 13

- 07G provided the uses direction are altered as indicated in Appendix D. The recommended application scenarios for each CSG were derived from the re gistered scenarios for the representative crops. ●Adequate residue data are available to support the proposed application scenarios for globe artichoke, quinoa, psyllium, asparagus, and mint. Based on the available data, HED is recommending for deletion of the currently

- established cereal grain processed commodity tolerances ( D382666, K. Lowe et al. , 9

- Feb

- 2011) . T herefore, tolerances in/on the grain processed commodities for quinoa and psylli um are unnecessary. ●Adequate residue data are available for citrus (CG 10

- 10); pome fruit (CG 11

- 10); stone fruit (CG 12

- 12); tree nut (CG 14

- 12); oil seeds (CG 20). However HED requests that the labels be altered so that the crops listed for these CGs conform with 40 CFR 180.41. HED notes that cottonseed processed commodity tolerances were initially established due to the lack of a processing study. The petitioner has subsequently submitted adequate data which indicate that these tolerances are unnec essary and should be deleted (D303274, T. Bloem, 19

- May

- 2004). Therefore, tolerances in/on the processed commodities for the other oilseeds are unnecessary. ● For teff , t he ChemSAC noted that teff flower heads are more similar to grain sorghum than wheat grain. Based on this and since the tolerances and application scenarios for wheat and grain sorghum differ with grain sorghum having a lower harvest aid rate than wheat (0.016 lb ai/acre

- vs - 0.031 lb ai/acre) but a higher tolerance (0.25 ppm

- vs - 0.10 ppm), the ChemSAC concluded that the teff tolerances and application scenario should be the same as that for grain sorghum (ChemSAC minutes 14

- Sep

- 2011)
. Therefore, HED requests a revised label specifying a teff application scenario identical to that curr ently registered for grain sorghum (see A ppendix D ) . As indicated above, HED is recommending for deletion of the currently

- established cereal grain processed commodity tolerances ( D382666, K. Lowe et al. , 9

- Feb

- 2011) . T herefore, tolerances in/on the grai n processed commodities for teff are unnecessary.Carfentrazone

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### 5.3 Water Residue Profile The rice and caneberry application scenarios yield the highest surface water and ground water estimated drinking water concentrations (EDWCs) , respectively, for all proposed/re gistered uses (D 425572 , R. Shamblen, 16

- Sep

- 2015); the EDWCs for these uses are summarized in Table 4. The surface water EDWCs resulting from the rice use were generated using the Tier I Rice Model . The groundw ater EDWCs from the caneber ry use was genera ted using Pesticide Root Zone Model for Ground Water (PRZM

- GW)
. Additional information concerning these m odels are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/ . Th e EDWCs from the rice use are the highest and were incorporated into the chronic dietary exposure analys i s ( “water, direct, all sources” and “water, indirect, all sources”). Table 4: EWDCs. Drinking Water Source (Model) Application Rate Value for Chronic Assessment (μg/L) s urface water (Tier I Rice Model) r ice, wild rice (0.20 lbs ai/ acre ) 86 g round water ( PRZM

- GW ) c aneberries (0.4 lbs ai/ acre ) 43.9 

### 5.4 Dietary Risk Assessment D ietary (food and drinking water) exposure and risk assessments were conducted using DEEM

FCID ( ver. 3.16) which incorporates food consumption data from USDA NHANES/WWEIA ( 2003

- 2008). The chronic analysi s assumed tolerance

- level residues or, if necessary, tolerance

- level residues adjusted to account for the residues of concern for risk assessment, 100% crop treated, and modeled drinking water estimates (based on toxicological considerations, acute and cancer analyses are unnecessary) . Since adequate proces sing studies have been submitted which indicate that tolerances in/on apple juice, citrus juice, grape juice, grape raisin, dried potato, dried prune, prune juice, tomato paste, and tomato puree are unnecessary, the DEEMTM (ver 7.81) default processing fact ors for these commodities were reduced to 1. The DEEMTM (ver 7.81) default processing factors were retained for the remaining relevant commodities. The resulting chronic exposure estimates are not of concern to HED ( ≤ 7 8 % c hronic population adjusted dose ( c PAD ) ; children 1

- 2 years old were the most highly exposed subgroup ). Table 5.4.1 provides a summary of the exposure estimates. Table 5.4.1 : Summary of the Chronic Dietary Exposure s and Risk s . Population cPAD (mg/kg/day) Exposure (mg/kg/day) %cPAD General U.S. Population

0.03 0.007972 27 All Infants (< 1 year old) 0.017437 58 Children 1 - 2 years old 0.023432 78 Children 3

- 5 years old 0.017502 58 Children 6

- 12 years old 0.010253 3 4 Youth 13

- 19 years old 0.006020 20 Adults 20

- 49 years old 0.006616 22 Adults 50

- 99 years old 0.006598 22 Females 13

- 49 years old 0.006453 22Carfentrazone

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### 6.0 Residential Exposure and Risk Estimates D 3 89978, L. Venkateshwara, 29

- Feb

- 2012 ; D428858 

### , L Venkateshwara, 17

- Nov

- 2015 

### Residential exposure is not anticipated from the proposed uses. However, carfentrazone

- ethyl is currently registered for application to turf (including golf courses and residential lawns) and for aquatic application and residential exposure is anticipated form these uses. The following sections are summaries of the residential handler and post

- application exposures from these uses. Details concering the turf assessment are provided in D389978 ( L. Venkateshwara, 29

- Feb

- 2012) . Details concering the aqauti c assessment are provided in D428858 ( L. Venkateshwara, 17

- Nov

- 201 5 )
. As part of the current assessment t he swimmer exposure estimates were updated to reflect the November 2015 Draft Aquatic Use SOP. 6.1 Residential Handler Exposure/Risk Aquatic Application Scenario: According to the registered label (EPA Reg. No. 279

- 3279), application is limited to the following: (1) Corps of Engineers; (2) Federal or State Public Agencies (i.e., Water Management District personnel, municipal officials); and ( 3) applicators and/or licenses (certified for aquatic pest control) that are authorized by the State or local governments. Therefore, assessment of residential handler exposure from the aquatic application scenario is unnecessary. Turf Application Scen ario: Homeowner application to turf is permitted (EC and DF formulations; 0.03

- 0.04 lb ai/acre). Due to the infrequent use patterns associated with homeowner products, residential handler exposure scenarios are considered to be short

- term only. T he hand ler assessments were conducted using HED’s Residential SOPs (2012). Homeowner handlers assessments are based on the assumption that all tasks associated with the use of the product are performed by the same individual (mixing, loading, and application) wi th that individual wearing shorts, short

- sleeved shirts, socks, and shoes. The currently registered turf labels indicate the following personal protective equipment (PPE): long

- sleeeved shirt, long pants, waterproof gloves, and shoes plus socks. Short

- term inhalation MOEs to residential handlers are ≥5,300,000 and, therefore, do not exceed HED’s LOC (see Table 6.1.1). Dermal risk assessments were not conducted because no hazard was identified via the dermal route for the relevant exposure duration. T able 6.1.1 : Residential Handler Exposure / Risk Estimates for Carfentrazone - Ethyl Applications to Turfgrass. Exposure Scenario Application Rate ( lb ai/ acre ) 1 Area Treated Daily (acres) 2 Baseline Unit Exposures 3 (mg/lb ai) Baseline Exposure 4 (mg/kg/day) Baseline MOE 5 Inhalation Inhalation Inhalation Mixer/Loader/Applicator Mixing/Loading/Applying DF with Manually

- pressurized Handwand 0.03 0.023 1.1 9.5E

- 06 5,300,000 Mixing/Loading/Applying DF with Backpack Sprayer 0.03 0.023 1.1 9.5E

- 06 5,300,000 Mixing/Loading/Applying DF with Hose end sprayer 0.03 0.5 0.022 4.2E

- 06 12,000,000 Mixing/Loading/Applying DF with Sprinkler Can 0.03 0.023 0.022 1.9E

- 07 260,000,000 Mixing/Loading/Applying EC with Manually

- pressurized Handwand 0.04 0.023 0.018 2.1E

- 07 240,000,000 Mixing/Loading/Applying EC with Backpack Sprayer 0.04 0.023 0.14 1.6E

- 06 31,000,000Carfentrazone

- ethyl (128712) Human

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Page 22 of 38 T able 6.1.1 : Residential Handler Exposure / Risk Estimates for Carfentrazone - Ethyl Applications to Turfgrass. Exposure Scenario Application Rate ( lb ai/ acre ) 1 Area Treated Daily (acres) 2 Baseline Unit Exposures 3 (mg/lb ai) Baseline Exposure 4 (mg/kg/day) Baseline MOE 5 Inhalation Inhalation Inhalation Mixing/Loading/Applying EC with Hose end sprayer 0.04 0.5 0.022 5.5E

- 06 9,100,000 Mixing/Loading/Applying EC with Sprinkler Can 0.04 0.023 0.022 2.5E

- 07 200,000,000 1 Application rates are from the Human Health Assessment Scoping Document in Support of the Registration Review (K. Lowe, et al., D382666)
. 2 Based on HED’s S OP s for Residential Pesticide Exposure Assessment; Lawns/Turf (January 2012). 3 Baseline Inhalation: no respirator. 4 Dose (mg/kg/day) = daily unit exposure (mg/lb ai) x application rate (lb ai/ acre ) x acres treated ÷ body weight (80 kg). 5 MOE = NOAEL (50 mg/kg/day) ÷ daily dose (mg/kg/day). LOC for MOEs < 100. 

### 6.2 Residential Post - application Exposure and Risk Aquatic Application: While HED believes it is improbable that swimmers would recreationally utilize water where large amounts of floating aquatic vegetation occurs, there is no restriction on the label prohibiting recreational use of treated water bodies. Therefore, HED con ducted a swimmer exposure assessment (short

- term incidental oral and inhalation) based on HED’s November 2015 Draft Aquatic Use SOP
. Dermal risk assessments were not conducted because no hazard was identified via the dermal route for the relevant exposure durations. A body weight of 80 kg is used for assessing incidental oral ingestion and inhalation for adults since the toxic ological endpoint is not based on developmental and/or fetal effects
. The assessment assumed an exposure duration of 0.1 hours/day for adults and 0.25 hours/day for children and an ingestion rate of 0.05 liters/hour. Since the incidental oral and inhalation POD are based on the same study, the exposures from these routes were combined. Table 6.2.1 presents the post

- appli cation incidental oral , inhalation , and combined MOEs for adults and children 3 to <6 years old after aquatic applications of carfentrazone

- ethyl. Post

- application risk estimates range from 4,200,000 to 44,000,000 and do not exceed HED’s level of concern. Ity is noted that t he lifestages selected for assessment are protective of any other potentially exposed lifestages. In addition, a lthough HED does not anticipate intermediate

- term post
- application exposure from the aquatic application scenario, the sho rt
- term risk assessment is protective of intermediate

- term exposure as the relevant short

- /intermediate

- term PODs are the same. Table 6.2.1 : Swimmer Residential Post - application Exposure and Risk Estimates Lifestage L OC Max
. Conc
. in Water 1 (mg/L) Exposure (mg/kg/day) Short

- term MOE 2 Incidental

Oral 1 Inhalation 1 Combined Incidental Oral Inhalation Combined Adult MOEs < 100 0.018 1.125E

- 06 4.50E

- 10 1.125E

- 06 4
. 4 E7 1 .1E11 4
. 4 E7 Child 3 to <6 years 1.1842E

- 05 3.78E

- 09 1.1842E

- 05 4
. 2 E6 1
. 3 E10 4
. 2 E6 1 Maximum concentration in water = 0.018 mg/L based on maximum application rate for aqua tic weed control: 0.2 lb ai/acre from EPA Reg No. 279

- 8383 2 MOE = NOAEL/Exposure dose. The level of concern for adults and children (3< 6 years old) is MOEs < 100.Carfentrazone

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Page 23 of 38 

### Turf application Scenario: Short

- term incidental oral post

- application exposure to children (1

- <2 years old) from physical activities on turf are expected. Dermal risk assessments (including the golfer scenario ) were not conducted because no ha zard was identified via the dermal route for the relevant exposure durations. Quantitative inhalation post

- application risk assessments were not conducted based on the Agency’s current practices (see Section 6.4). T he incidental oral assessments were c onducted using HED’s Residential SOPs (2012). Short

- term incidental

- oral MOEs are ≥84,000 and, therefore, do not exceed HED’s LOC (see Table 6.2.2). The lifestages selected for assessment are based on the aforementioned SOP and are protective of any othe r potentially exposed lifestages. In addition, a lthough HED does not anticipate intermediate

- term post
application exposure from the turf application scenario, the short

- term risk assessment is protective of intermediate

- term exposure as the relevant shor t
- /intermediate

- term PODs are the same. Table 6. 2.2 : Short - Term Residential Post - application Exposure and Risk Estimates for Carfentrazone - Ethyl. Life S tage Scenario Post

- application Exposure Scenario Dose (mg/kg/day) Short

- term MOEs 1 Child 1 < 2 year old Turf

- sprays Hand to Mouth 0.0 006 84,000 Object to Mouth 0.000 02 2,70 0,000 Incidental Soil Ingestion 1.3 x 10 - 6 38,000 ,000 1 MOE = NOAEL/dose; short

- term incidental oral NOAEL = 50 mg/kg/day; LOC is for MOEs ≤100. 

### 6.3 Residential Risk Estimates for Use in Aggregate Assessment HED assessed adult handler exposure for the turf application scenario and adult post

- application exposure for the aquatic exposure scenario. It is unlikely that a homeowner would treat their lawn and then also swim in a water

- body treated with the same pe sticide on the same day. Therefore, aggregate risk assessments for adults will be conducted using the handler exposure f rom the turf scenario as it yielded the highest residential exposure for adults (see Table 6. 1 .1). HED also assessed post

- application exposures to children from the use on turf and in aquatic areas. Although the incidental oral exposures from the turf application scenario (i.e., hand

- to
- mouth, object

to
- mouth, and soil ingestion) are inter

- related and it is likely that they occur inters persed amongst each other across time, combining all three of these scenarios would be overly

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

- to
- mouth scenario was chosen as the health protective est imate of children’s exposure to pesticides used on turf. HED did not combine exposures from the turf and aquatic uses due to the conservative nature of each of these assessments and since it is considered unlikely that an individual would experience expos ure from both of these uses on the same day. Aggregate risk assessments for children will be conducted using the hand

- to
- mouth exposure estimate from the turf application scenario as it yielded the highest residential exposure for children (see Table 6.3. 1)
. HED notes that t he selected lifestages are protective of any other potentially exposed lifestages
. Table 6.3.1: Short

- Term Residential Exposures for Carfentrazone

- ethyl

- Combined Residential Risk Calculations. Population Handler Post

- Application Exposure (mg/kg/day) MOE Exposure (mg/kg/day) MOE Adult

- turf 1 9.5 x 10 - 6 5,300,000 not applicable Child 1<2 years old

- turf 2 not applicable 0.0006 84,000 1 Handler exposure represents high

- end estimate (see Tables 6.1.1 and 6.2.1)
. 2 Post

- application exposure from the turf use represents high

- end estimate (see Table 6.2.1 and 6.2.2)
.Carfentrazone

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### 6. 4 Non - Occupational Spray Drift Exposure and Risk Estimates Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for carfentrazone

- ethyl . The agency has been workin g with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call

- In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best sp ray drift management practices (see the agency’s Spray Drift website for more information ; http://www.epa.gov/opp00001/factsheets/spraydrift.htm ). The agency has also developed a policy on how to appropriately consider spray drift as a potential source of exposure in risk assessments for pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during the Registra tion Review process which ensures that all uses for that pesticide will be considered concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs)

- Residential Exposure Assessment Stand ard Operating Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification of indirect non

- occupational exposure to drift. 6. 5 Non - Occupational Bystander Post - Application Inhalation Exposure and Risk Estimates Volatil ization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide , and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The agency has evaluated the SAP report and has developed a Vol atilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

2014

- 0219). During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, r oute
- specific inhalation toxicological studies) or further analysis is required for carfentrazone

- ethyl.Carfentrazone

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Page 25 of 38 

### 7.0 Aggregate Exposure/Risk Characterization HED consider s pesticide exposures and risks from food, drinking water, and residential exposures when conducting aggregate assessment. Based on the proposed/registered uses and toxicological considerations , short

- term (food, water, inhalation, and/or incidental oral) and chronic (food and water) aggregate risk assessments are required. The aggregat e assessments do not include dermal exposure because no hazard was identified via the dermal route for the relevant exposure durations. Although intermediate

- term residential exposures are not anticipated, the relevant short

- /intermediate

- term PODs are th e same and, therefore, the short

term risk assessment is protective of intermediate

- term exposure. 7. 1 Short - Term Aggregate Risk For adults, t he short

- term aggregate risk assessment combined chronic dietary exposure with handler inhalation exposure fr om the turf use . For children, the short

- term aggregate risk assessment combined chronic dietary exposure with post

- application incidental oral exposure from the turf use (hand

- to
- mouth). The resulting aggregate MOEs are ≥2, 1 00 and, therefore, do not exc eed HED’s LOC (see Table 7.2.1). The exposure estimates and populations included in the short

- term aggregate assessment are protective of all potential short

- term exposures. Table 7.2.1: Short - Term Aggregate Risk Estimates. Population LOC Exposure (mg/kg/day) MOE 2 Dietary 1 Inhalation 1 Incidental

- oral 1 Adults MOE <100 0.00 6616 0.0000095 not applicable 7, 5 00 Children (1

- 2 years old) 0.02 3432 not applicable 0.0006 2, 1 00 1 See Table s 5.4.1 and 6.3.1. For the adult and child lifestages, the dietary exposure estimates for the adult (20

- 49 years old) and children (1

- 2 years old) subpopulations yielded the highest exposures and were used in the aggregate assessment. 2 MOE = 50 mg/kg/day (NOAEL) ÷ (dietary exposure + inhalation exposure + incidental

- oral exposure). 

### 7. 2 Chronic Aggregate Risk Chronic aggregate risk concerns only dietary exposure (food and water). The chronic dietary risk estimates are ≤ 78 % cPAD and, therefore, do not exceed HED’s LOC (see Section 5.4).Carfentrazone

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Page 26 of 38 

### 8.0 Cumulative Exposure/Risk Characterization Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to carfentrazone

- ethyl and any other substances and carfentrazone

- ethyl does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that carfentrazone

- ethyl has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, s ee the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/. 9.0 Occupational Exposure and Risk Estimates 9.1 O ccupational Handler Exposure/ Risk Estimates HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each t ask. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application event. 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 the proposed uses. The quantitative exposure/risk assessment developed for occupat ional handlers is based on the following scenarios: (1) Mixing/loading liquids for groundboom application; (2) Mixing/loading WDG for groundboom applications; (3) Mixing/loading liquids for aerial applications; (4) Mixing/loading WDG for aerial applications; (5) Applying sprays via groundboom applications; (6) Applying sprays via aerial applications; and (7) Flagging to support aerial applications. Occupational Handler Exposure Data and Assumptions A series of assumptions and exposure factors served as the basis for completing the occupational handler risk assessments. Each assumption and factor is detailed below on an individual basis. Application Rate : A summary of the proposed application rates is provided in Table 3.3.2
. Unit Exposures: It is the policy of HED to use t he 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, or other registrant

- submitted occupational exposure studies. Some o f 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 handler exposure that are used in this assessment, known as “unit exposures”, are outlined in th e “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( http://www.epa.gov/opp00001/science/handler

exposure - table.pdf ) , which, along with additional information on HED policy on use of surrogateCarfentrazone

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Page 27 of 38 

### data, including descriptions of the various sources, can be found at the Agency website ( http://ww w.epa.gov/pesticides/science/handler

- exposure - data.html )
. Area Treated or Amount Handled : The acres treated or amount handled per day are based on ExpoSAC Policy 9.1 and outlined in Table 9 .1.1. Exposure Duration: HED 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 pesticide, 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 large agribusiness and/or commercial ap plicators who may apply a product over a period of weeks (e.g., completing multiple applications for multiple clients within a region). For carfentrazone

- ethyl , based on the proposed use s , both short

- and intermediate

- term exposures are expected (i.e., up to 2 pre

- or post
- emergence directed applications). Mitigation/Personal Protective Equipment: Estimates of inhalation exposure were calculated for “baseline” PPE, defined as no respirator. The carfentrazone

- ethyl product labels direct mixers, loade rs, applicators and other handlers to wear long pants, long sleeved shirts, waterproof gloves, shoes, and socks. Under the WPS, the acute toxicity of the formulated end

- use product dictates the default personal protective equipment worn by occupational ha ndlers . The formulated products are Toxicity Category IV via the dermal route and there is no systemic dermal hazard identified for carfentrazone

- ethyl; therefore additional PPE (i.e., gloves) are not currently required at this time. Summary of Occupa tional Handler Non

- Cancer Exposure and Risk Estimates There are no risk estimates of concern for carfentrazone

- ethyl at baseline (no PPE). For the proposed uses of carfentrazone

- ethyl, the short and intermediate

- term occupational handler inhalation MOEs ranged from 12,000 to 36,000,000 at baseline (no respirator). The Agency matches quantitative occupational exposure assessment with appropriate characterization of exposure potential. While HED presents quantitative risk estimates for human flaggers where appropriate, agricultural aviation has changed dramatically ov er the past two decades. According the 2012 National Agricultural Aviation Association (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 ass essed using the engineering control (enclosed cockpits) and baseline attire (long

- 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 glo ves for the duration of the application. With this level of protection, there are no risk estimates of concern for applicators.Carfentrazone

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Page 28 of 38 1 Based on “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( March 2013 ) ; includes data from PHED/ORETF/AHETF (level of mitigation: Baseline, PPE, Eng. Controls). 2 Based on labels
. Aim ® (279

- 3194), Aim ® EC (279

- 3241), and Aim ® EW Herbicide (279

- 3242 )
. 3 Exposure Science Advisory Council Policy #9.1. 4 Inhalation Dose =Inhalation Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/ μg ) x Application Rate (lb ai/gallon) x Amount Handled Daily (gallons/day) /BW ( 80 kg). 5 Inhalation MOE = Inhalation NOAEL (50 mg/kg/day)/ Inhalation Dose (mg/kg/day). 6 High acreage crops include teff, quinoa, psyllium, and mint. 7 Typical acreage crops include globe artichoke and asparagus. Table 9.1.1. Short - and Intermediate - Term Occupational Exposure and Risk Estimates for Carfentrazone - Ethyl
. All Estimates are at Baseline Mitigation (i.e., Without Respirator, Unless Specified). Exposure Scenario Crop or Target Inhalation Unit Exposure (μ g/lb ai) 1 Maximum Application Rate 2 Area Treated or Amount Handled Daily 3 Inhalation Mitigation Level (Baseline, No Respirator) Dose (mg/kg/day) 4 MOE 5 Mixer/Loader M/L, EC, Groundboom Applications High acreage crops 6 0.219 0. 0 31 lb ai/A 200 0.000017 2,900,000 Typical acreage crops 7 0.065 lb ai/A 80 0.0000143 3,500,000 M/L, WDG, Groundboom Applications High acreage crops 8.96 0. 0 31 lb ai/A 200 0.000583 72,000 Typical acreage crops 0.065 lb ai/A 80 0.000583 86,000 M/L, EC, Aerial Applications High acreage crops 0.219 0. 0 31 lb ai/A 1,200 0.000102 490,000 Typical acreage crops 0.065 lb ai/A 350 0.0000623 800,000 M/L, WDG, Aerial Applications High acreage crops 8.96 0. 0 31 lb ai/A 1,200 0.00416 12,000 Typical acreage crops 0.065 lb ai/A 350 0.00255 20,000 Applicator
a pplicator, Spray, Groundboom Open Cab High acreage crops 0.34 0. 0 31 lb ai/A 200 0.0000264 1,900,000 Typical acreage crops 0.065 lb ai/A 80 0.0000221 2,300,000 Applicator, Spray, Aerial, Broadcast High acreage crops 0.0049 (engineering control

- enclosed cockpit) 0. 0 31 lb ai/A 1,200 0.00000228 22,000,000 Typical acreage crops 0.065 lb ai/A 350 0.00000139 36,000,000 Flagger Flagger, Liquids High acreage crops 0.035 0. 0 31 lb ai/A 350 0.0000264 1,900,000 Typical acreage crops 0.065 lb ai/A 350 0.0000995 500,000Carfentrazone

- ethyl (128712) Human

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Page 29 of 3 8 

### 9 .2 Occupational Post - application Exposure/Risk Estimates 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 previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Post

- application exposure levels vary over time and depend on such things as the type of activity, the natu re of the crop 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

- applicati on exposure. Also post
- application exposures are anticipated based on the proposed new uses of carfentrazone

ethyl. 9 .2.1 Occupational Post - application Inhalation Exposure/Risk Estimates 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 e xpert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov /scipoly/SAP/meetings/2009/120109meeting.html ). The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

OPP

- 2014

- 0219 ). During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is required for carfentrazone

- ethyl
. In addition, the Agency is continuing to evaluate the available post

- application inhalation exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the Agency will continue t o identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the agency's risk assessments. 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 pesticides outdoors is likely to result in higher exposure than post

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

- application inhalation exposure scenarios. 9 .2.2 Occupational Post - application Dermal Exposure/Risk Estimates Although there is potential for dermal post

- application exposure, a quantitative dermal post

application risk assessment was not conducted due to the lack of dermal hazard and because no systemic hazard was identified.Carfentrazone

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Page 30 of 38 

### 9.2.3 R EI Carfentrazone

- ethyl is classified as Toxicity Category 3 for acute dermal and Toxicity Category 4 for acute inhalation and primary skin irritation . It is non

- irritating to skin and minimally irritating to eyes. It is not a skin sensitizer. Therefore, the interim WPS REI of 12 hours is adequate to protect agricultural workers. The product labels list an REI of 12 hours. Appendix A. Toxicology Profile Appendix B: Chemical Structures Appendix C: Physiochemical Properties of Carfentrazone

- Ethyl Appendix D: HED Recommen ded Teff, 13

- 07B, 13

- 07F, and 13

- 07G Application ScenariosCarfentrazone

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Page 31 of 38 

### Appendix A. Toxicology Profile A.1 Toxicology Data Requirements for Carfentrazone - ethyl Study requirements (40 CFR 158.340) for use of carfentrazone

- ethyl are in Table A.1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used. Study Technical Required Satisfied 870.1100 Acute Oral Toxicity
................................ ................................ .. 870.1200 Acute Dermal Toxicity
................................ ............................. 870.1300 Acute Inhalation Toxicity
................................ ......................... 870.2400 Acute Eye Irritation
................................ ................................ .. 870.2500 Acute Dermal Irritation
................................ ............................. 870.2600 Skin Sensitization
................................ ................................ ..... yes yes yes yes yes yes yes yes yes yes yes yes 870.3100 90

- Day Oral Toxicity in Rodents
................................ .............. 870.3150 90

- Day Oral Toxicity in Nonrodents
................................ ........ 870.3200 21/28

- Day Dermal Toxicity
................................ ...................... 870.3250 90

- Day Dermal Toxicity
................................ ........................... 870.3465 90

- Day Inhalation Toxicity
................................ ....................... yes yes yes no no 1 yes yes yes

--

-- 870.3700a Prenatal Developmental Toxicity (rodent)
................................ 870.3700b Prenatal Developmental Toxicity (nonrodent)
.......................... 870.3800 Reproduction and Fertility Effects
................................ ............ yes yes yes yes yes yes 870.4100a Chronic Toxicity (rodent)
................................ ......................... 870.4100b Chronic Toxicity (nonrodent)
................................ ................... 870.4200a Carcinogenicity (rat)
................................ ................................ . 870.4200b Carcinogenicity (mouse)
................................ ........................... 870.4300 Combined Chronic Toxicity/Carcinogenicity
........................... yes yes yes yes yes yes 2 yes yes 2 yes yes 870.5100 Mutagenicity

— Bacterial Reverse Mutation Test
...................... 870.5300 Mutagenicity

— Mammalian Cell Gene Mutation Test
.............. . 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations
.............. . 870.5xxx Mutagenicity

— Other Genotoxic Effects
................................ .. yes yes yes yes yes yes yes yes 870.6200a Acute Neurotoxicity Screening Battery (rat)
............................. 870.6200b 90

- Day Neurotoxicity Screening Battery (rat)
.......................... 870.6300 Developmental Neurotoxicity
................................ ................... yes yes no yes yes

-- 870.7485 Metabolism and Pharmacokinetics
................................ ........... 870.7600 Dermal Penetration
................................ ................................ ... 870.7800 Immunotoxicity
................................ ................................ ........ yes no yes yes

-- yes 1 HED HASPOC concluded that the subchronic inhalation study was not required at this time (D. Smegal, 21

- FEB

- 2012, TXR# 0051142). 2 The combined chronic toxicity/carcinogenicity study satisfies the requirement of the study.Carfentrazone

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Page 32 of 38 

### A.2 Toxicity Profiles

Table A.2.1. Acute Toxicity Profile

– Carfentrazone - ethyl .

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

870.1100 Acute oral 43189027 LD 50 > 5000 mg/kg IV 870.1200 Acute dermal 43189209 LD 50 > 4000 mg/kg III 870.1300 Acute inhalation 43189211 LC 50 > 5.09 mg/L IV 870.2400 Acute eye irritation 43189213 Minimum eye irritant IV 870.2500 Acute dermal irritation 43189215 Non

- irritant IV 870.2600 Skin sensitization 43189217 Not a skin sensitizer N/A Note: The studies in the carfentrazone

- ethyl database, including those used for endpoint selection, have not been updated to reflect current approaches in hazard characterization . These studies are considered protective since, for several of the studies, updates would result in higher NOAEL/LOAEL values than those currently established
.

Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile

– Carfentrazone - ethyl .

Guideline No. Study Type MRID No. (year)/ Classification/Doses Results

870.3050 28

- Day oral toxicity (rats) 43189219 (1994) Not Classified 0, 1000, 4000, 8000, 14000, 20000 ppm M: 0, 75, 293, 584, 982, 1292 mg/kg/day F: 0, 85, 330, 660, 1140, 1587 mg/kg/day NOAEL = 75/85 mg/kg/day (M/F) LOAEL = 293/330 mg/kg/day (M/F) based on histopatholog ical lesions in the liver and kidneys of both sexes of rats.

870.3100 90

- Day Oral Toxicity in Rodents (rat) 43189220 (1994) Guideline 0, 1000, 4000, 8000, 14000, 20000 ppm M: 0, 56, 226, 470, 831, 1197 mg/kg/day F: 0, 72, 284, 578, 1008, 1427 mg/kg/day NOAEL = 226/284 mg/kg/day (M/F) LOAEL = 470/578 mg/kg/day (M/F) based on clinical signs, decreases in bodyweight and/or body

- weight gain, reductions in food consumption, alterations in clinical chemistry parameters, and histopathological lesions
.

870.3100 90

- Day Oral Toxicity in Rodents (mouse) 43829706 (1993) 44165019 (1996) Acceptable 0, 1000, 4000, 8000, 14000, 20000 ppm M: 0, 95, 762, 1589, 2930, 4990 mg/kg/day F: 0, 344, 1500, 2613, 5500, 8915 mg/kg/day NOAEL = 762/1500 mg/kg/day (M/F) LOAEL = 1589/2313 mg/kg/day (M/F) based on liver pathology

870.3150 90

- Day Oral Toxicity in Non

- Rodent (dog) 43869201 (1995) Acceptable 0, 50, 150, 500, 1000 mg/kg/day NOEL = 50 mg/kg/day LOEL = 150 mg/kg/day based on systemic toxicity (decrease in the rate of weight gain in females and an increase in porphyrin levels in both sexes).

870.3200 21/28

- Day Dermal Toxicity (rat) 44165020 (1996) Acceptable/Guideline 0, 100, 500, 1000 mg/kg/day NOEL = 1000 mg/kg/day LOEL is >1000 mg/kg/dayCarfentrazone

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Page 33 of 38 Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile

– Carfentrazone - ethyl .

Guideline No. Study Type MRID No. (year)/ Classification/Doses Results

870.3700a Prenatal Developmental in Rodent (rat) 43829710 (1993) 43829711 (1994) Acceptable 0, 100, 650, 1000 mg/kg/day Maternal NOEL = 100 mg/kg/day LOEL = 600 mg/kg/day based on staining of the abdominogenital area and of the cage pan liner. Developmental NOEL = 600 mg/kg/day LOEL = 1250 mg/kg/day based on significant increase in the litter incidences of wavy and thickened ribs.

870.3700b Prenatal Developmental in Non

- Rodent (rabbit) 43829707 (1994) 43829708 (1994) 43829709 (1995) Acceptable 0, 10, 40, 150, 300 mg/kg/day Maternal NOEL = 150 mg/kg/day LOEL = 300 mg/kg/day based on unthriftiness and emaciation Developmental NOEL = 300 mg/kg/day LOEL is >300 mg/kg/day

870.3800 Reproduction and Fertility Effects (rat) 44165026 (1994) 44165027 (1995) Acceptable 0, 100, 500, 1500, 4000 ppm M:0, 8.6, 42.4, 127, 343 mg/kg/day F:0, 9.5, 47.8, 142, 387 mg/kg/day Parental/Systemic NOEL = 127/142 mg/kg/day (M/F) LOEL = 347/387 mg/kg/day (M/F) based on decreased body

- weight gains, increas ed liver weights, liver and bile duct histopathology, and reductions in the mean cell volume (F0 and F1 males, F1 females), mean cell hemoglobin (F0 and F1 males, F1 females), hematocrit (F1 males), and hemoglobin (F1 males). Reproductive NOEL = 387 mg/k g/day LOEL is >387 mg/kg/day Offspring NOEL = 142 mg/kg/day LOEL = 387 mg/kg/day based on decreased pup weights in both sexes of the F2 generation.

870.4100b Chronic Toxicity (dog) 44165022 (1996) Acceptable 0, 50, 150, 500, 1000 mg/kg/day NOEL = 50 mg/kg/day LOEL = 150 mg/kg/day based on an increase in absolute mean total urinary porphyrins.

870.4200b Carcinogenicity (mouse) 44165023 (1995) Acceptable 0, 70, 700, 7000 ppm M: 0, 10, 110, 1090 mg/kg/day F: 0, 12, 119, 1296 mg/kg/day NOEL = 10/12 mg/kg/day (M/F) LOEL = 110/119 mg/kg/day (M/F) based on increased mortality and microscopic signs of hepatotoxicity. No evidence of carcinogenicity.

870.4300 Combined Chronic Toxicity/ Carcinogenicity (rat) 44076501 (1995) Acceptable 50, 200, 800, 4000 ppm M: 2, 9, 37, 188 mg/kg/day F: 3, 12, 49, 242 mg/kg/day NOEL = 9/3 mg/kg/day (M/F) LOEL = 37/12 mg/kg/day (M/F) based on liver histopathology (increases in microscopic red fluorescence of the liver, liver pigment) and total mean urinary porphyrin in both sexes. No evidence of carcinogenicity.

870.5100 Bacterial reverse mutation 43189221 (1993) Acceptable Although there was a consistent increase in numbers of revertants in strain TA1538 in the presence of S9 at 1000 μg/plate, in only 1 of 3 assays was there >2X the number of revertants observed in the solvent control, and the occurrence of oily droplets in the medium at doses greater than or equal to 3333 μg/plate indicates that this increase occurred beyond the test material’s s olubility limit.Carfentrazone

- ethyl (128712) Human

- Health Risk Assessment D 425547

Page 34 of 38 Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile

– Carfentrazone - ethyl .

Guideline No. Study Type MRID No. (year)/ Classification/Doses Results
870.5100 Bacterial reverse mutation 43829712 (1995) Acceptable No indication that the test material induced a mutagenic effect at any dose with or without S9 activation.

870.5100 Bacterial reverse mutation 43849602 (1994) Acceptable [F97083 Tested degradation product] Cytotoxicity (i.e., slightly reduced background lawn of growth) was observed at 5000 μg/plate

- S9. All strains responded in the expected manner to the appropriate positive control. There was, however, no indication that the test material degredation product induced a mutagenic effect at any dose with or without S9 activation. 870.5100 Bacterial reverse mutation 44165028 (1995) Acceptable [Formulation Tested] There was no indication that the formulated test material induced a mutagenic effect at any dose with or without S9 activation.
870.5100 Bacterial reverse mutation 44165029 (1996) Acceptable [Formulation Tested] There was no indication that the formulated test material induced a mutagenic effect at any dose with or without activation.
870.5100 Bacterial reverse mutation 44165030 (1996) Acceptable [Formulation Tested] There was no indication that the formulated test material induced a mutagenic effect at any dose with or without activation.
870.5300 In vitro mammalian cell gene mutation 43189222 (1993) Acceptable Under the experimental conditions, there was no indication of an increased incidence of gene mutation at the HGPRT locus as a result of exposure to F8426. F8426 is negative under the conditi ons of this assay. 870.5375 In vitro mammalian cytogenetics assay 43189223 (1993) Guideline There was no indication of any effect in the presence of S9 at doses of up to 1250 μg/ml, considerably above the partial insolubility noted at doses ≥375 μg/ml. F8426 is positive under nonactivated conditions in this assay.
870.5395 Bone marrow micronucleus (mouse) 43189224 (year) Acceptable There was no indication of an increased incidence in micronucleated polychromatic erythrocytes associated with exposure to the test material. F8426 is negative for clastogenic and/or aneugenic activity under the conditions of this assay.
870.6200a Acute Neurotoxicity Screening Battery (rat) 44165024 (1996) Acceptable/Guideline 0, 500, 1000, 2000 mg/kg NOAEL = 500 mg/kg/day LOAEL = 1000 mg/kg/day based on clinical observations (i.e., salivation) and motor activity testing.

870.6200b Subchronic Neurotoxicity Screening Battery (rat) 44165021 (1995) 44165025 (1996) 0, 1000, 10000, 20000 ppm M: 0, 59, 603, 1178 mg/kg/day F: 0, 71, 718, 1434 kg/mg/day Systemic NOEL = 59/71 mg/kg/day (M/F) LOEL = 603/718 mg/kg/day (M/F) based on body weight decrease. Neurotoxicity NOEL = 1178/1434 mg/kg/day (M/F) LOEL is > 1178/1434 mg/kg/day (M/F)Carfentrazone

- ethyl (128712) Human

- Health Risk Assessment D 425547

Page 35 of 38 Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile

– Carfentrazone - ethyl .

Guideline No. Study Type MRID No. (year)/ Classification/Doses Results

870.7485 Metabolism and Pharmacokinetics 43829714 (1995) Acceptable F8426 was rapidly absorbed as measured indirectly by the rapid excretion in both sexes of radioactivity [>85%] generally within the first 24 hours after dosing. The urine contained the ma jority of the administered dose (72.4 to 87.0%); feces contained a lesser amount (10.47 to 25.68%). The blood contained the highest concentration [M 0.002 ppm, F 0.001 ppm]. The total mean percentage of the administered dose found in all tissues and carcas ses assayed was very low [M 0.09%, F 0.08%] with the highest concentration found in the residual carcasses [0.08%] of both sexes. The major metabolites in both the urine and feces were F8426

- chloropropionic acid [48.84 to 66.06%] and to a lesser extent 3

- hydroxymethyl

- F8426

- chloropropionic acid [17.97 to 34.03%] followed by 3

- hydroxymethyl

F8426

- propionic acid [1.73 to 5.83%] and F8426

- cinnamic acid [0.34 to 1.50%]. In addition, minute quantities of 3

- hydroxy

- F8426

- cinnamic acid and F8426

- propionic acid were found in the urine, but the levels were too low to quantify. Extensive metabolism was indicated by only a small amount of the parent (0.06 to 2.78%) found in the feces; no parent was found in the urine by 48 hours. A variety of polar and non

- polar met abolites were found in both urine and feces (1.83%). No differences in the metabolic profile existed between the sexes. The proposed metabolic pathway appeared to be the conversion of the parent compound by hydrolysis of the ester moiety to form F8426

- chloropropionic acid, followed by oxidative hydroxylation of the methyl group to form 3

- hydroxymethyl

- F8426

- chloropropionic acid, or dehydrochlorination to form F8426

- cinnamic acid. Dechlorination of F8426

- chloropropionic acid formed F8426

- propionic acid, hydroxyla

- tion of the methyl group of F8426

- propionic acid formed 3

- hydroxymethyl

- F8426

- propionic acid. The overall recove ry of the administered dose was >96% in both sexes.

870.7800 Immunotoxicity 49397613 (2013) Acceptable/guideline 0, 90, 369, or 741 mg/kg/day Systemic NOAEL = 369 mg/kg/day. LOAEL = 741 mg/kg/day based on increased liver weights. Immunotoxicity NOAEL = 741 mg/kg/day. LOAEL = Not established.Carfentrazone

- ethyl (128712) Human

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Page 36 of 38 

### A ppendix B : Chemical Structures Table A 1.1: Chemical Structures. Common name/code Chemical name Chemical structure
carfentrazone

- ethyl F8426 ethyl

- α ,2

- dichloro

- 5

- [4

- (difluoromethyl)

- 4,5

- dihydro

- 3

- methyl

- 5

- oxo - 1 H

- 1,2,4

- triazol

- 1

- yl)

- 4

- fluorobenzenepropanoate N F C l

N N O

C H F 2

C H 3 E t O C l

O

carfentrazone

chloropropionic acid F8426

- ClPAc ; CR

- 75 α ,2

- dichloro

- 5

- [4

- (difluoromethyl)

- 4,5

- dihydro

- 3

- methyl

- 5

- oxo - 1 H

- 1,2,4

- triazol

1

- yl]

- 4

- fluorobenzenepropanoic acid N F C l

N N O

C H F 2

C H 3 H O C l

O
3

- hydroxymethyl

carfentrazone

chloropropionic acid 3

- OH

- F8426

- ClPAc ; HM

F8426

- ClPAc ; 3

- HM

- F8426

- ClPAc ; CR

- 48 α ,2

- dichloro

- 5

- [4

- (difluoromethyl)

- 4,5

- dihydro

- 3

- hydroxymethyl

- 5

- oxo - 1 H

1,2,4

- triazol

- 1

- yl]

- 4

- fluorobenzenepropanoic acid N F C l

N N O

C H F 2

C H 2 O H H O C l

O

3

- hydroxymethyl

carfentrazone

- benzoic acid 3

- OH

- F8426

- BAc ; 3

- HM

F8426

- BAc; HM

- F8426

- BAc 2

- chloro

- 5

- [4

- (difluoromethyl)

- 4,5

- dihydro

- 3

- hydroxymethyl

- 5

- oxo - 1 H

1,2,4

- triazol

- 1

- yl]

- 4

- fluorobenzoic acid C l

N N N F

C H F 2

C H 2 O H O

O H O

3

- desmethyl

- carfentrazone

chloropropionic acid 3

- DM

- F8426

- ClPAc 2

- di chloro

- 5

- [4

- (difluoromethyl)

- 4,5

- dihydro

- 5

- oxo - 1 H

- 1,2,4

- triazol

- 1

- yl]

- 4

- fluorobenzenepropanoic acid C l

N N N F

C H F 2 O C l H O
O

F8426

- propionic acid; F8426

- PAc 2

- chloro

- 5

- [4

- (difluoromethyl)

- 4,5

- dihydro

- 3

- methyl

- 5

- oxo - 1 H

- 1,2,4

- triazol

1

- yl]

- 4

- fluorobenzenepropanoic acid C l

N N N F

C H F 2 O H O
O C H 3
F8426

- cinnamic acid; F8426

- CAc 2

- chloro

- 5

- [4

- (difluoromethyl)

- 4,5

- dihydro

- 3

- methyl

- 5

- oxo - 1 H

- 1,2,4

- triazol

1

- yl]

- 4

- fluorobenzenepropenoic acid C l

N N N F

C H F 2 O H O
O C H 3 F8426

- benzoic acid; F8426

- BAc 2

- chloro

- 5

- [4

- (difluoromethyl)

- 4,5

- dihydro

- 3

- methyl

- 5

- oxo - 1 H

- 1,2,4

- triazol

1

- yl]

- 4

- fluorobenzoic acid C l

N N N F

C H F 2 O

C H 3 O H OCarfentrazone

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Page 37 of 38 

### A ppendix C : Physi c ochemical Properties of Carfentrazone - Ethyl

Table C.1 : Physicochemical Properties of the Technical Grade Carfentrazone - Ethyl Melting point

- 22.1 ° C

EPA Fact Sheet pH not available Density 1.46 at 20 ° C Water solubility (20°C) 12 μ g/ml Solvent solubility ( μ g/L at 20°C) acetone
- >2000; toluene

- 900; dichloromethane

- >2000; hexane

- 30; ethanol

- >2000; ethyl acetate

- >2000 Vapor pressure 1.2 x 10 - 7 mm Hg (25 ° C); 5.4 x 10 - 8 mm Hg (20 ° C) Dissociation constant (pK a ) no dissociation constant Octanol/water partition coefficient Log(K OW ) log K ow = 3.36 UV/visible absorption spectrum not availableCarfentrazone

- ethyl (128712) Human

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Page 38 of 38 

### Appendix D: HED Recommended Teff, 13 - 07B, 13 - 07F, and 13 - 07G Application Scenarios Table D.1: HED Recommended Teff, 13 - 07B, 13 - 07F, and 13 - 07G Application Scenarios. App. Timing; Type Formulation App. Rate (lb ai/acre) Max. No. App. per Year Max. Seasonal Rate (lb ai/acre) PHI (days) Use Directions and Limitations teff 1
preplant ( 1 day before seeding); post

emergence (hooded or directed); harvest aid EDG, EC, EW 0.008

- 0.016 not specified 0.032 3 - in

- season application may be made from 4

- inches tall to just prior to the boot stage

- do not apply more than 0.016 lb ai/acre including preplant and post

emergent application (not including harvest aid).

- do not apply more than 0.016 lb ai/acre as a harvest aid treatment. 13 - 07B 2 Dormant application directed to the base of plant and a banded application between rows up to 1

- day prior to harvest. WDG, EC, EW 0.031 not specified 0.096 0 - avoid contact of the berry plant with the spray solution

- do not apply more than 0.031 lb ai/acre during dormancy

- spray volume ≥20 GPA 13 - 07F 3 preplant (1

- day before transplanting); post

emergence (hooded) or directed to the base of vine trunks or root sprouts for control of suckers WDG, EC, EW 0.031 not specified 0.124 3 - do not apply more than 0.031 lb ai/acre preplant

- d o not allow spray solut ion to contact green stem tissue, leaves, fruit , or blooms

- RTI = 14 days

- spray volume ≥10 GPA 13 - 07G 2 preplant (1

- day before translating); post

emergence (hooded or banded) WDG, EC, EW 0.031 not specified 0.096 0 - do not apply more than 0.031 lb ai/acre preplant

- do not apply more than 0.065 lb ai/acre post

- emergence 1 Based on grain sorghum application scenario (ChemSAC minutes; 14

- Sep

- 2011). 2 Based on D293779 (T. Bloem, 26

- Aug

- 2004) and currently

- registered labels
. 3 Based on D 303030 (T. Bloem, 30

- Jun

- 2004) and currently

- registered labels
.