UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: 

Subj ect: 

From: 

Through: 

To: 

l 7-November-2015 

Carfentr azone-Ethyl: 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. 

PC Codes: 128712 DP Barcode: 0425574 

Decision No.: 498511 Re istration No.: 279-3194; 279-3241 ; 279-3242 

Petition No.: 4E8337 Regulatory Action: Section 3 

Case No.: 7422 

CAS No.: 128639-02-1 

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 

application of carfentrazone-ethyl (ethyl a,2-dichloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl5-oxo-l!-l-1 ,2,4-triazol-1-yl)-4-fluorobenzenepropanoic acid) to globe artichoke, asparagus, mint, 

psyllium, quinoa, and teff and updates to several CG or CSG designations. The aggregate risk 

assessment, dietary risk assessment, and residue chemistry review were provided by Tom Bloem 

(RAB I), the hazard characterization was provided by Sarah Gallagher (RAB 1 ), the 

occupational/residential exposure (ORE) and risk assessment were provided by Lata 

Venkateshwara (RAB 1 ), and the drinking water assessment was provided by Richard Shamblen of 

the Environmental Fate and Effects Division (EFED). 

Page 1 of38 
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D425574

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Table of Contents

1.0 Executive Summary................................................................................................................................................................... 3

2.0 Recommendations...................................................................................................................................................................... 6

2.1 Data 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 Chemical 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 Toxicity 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..................................................... 38
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D425574

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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. Carfentrazone-ethyl is currently registered for application to numerous crops with 

tolerances for the combined residues of carfentrazone-ethyl and its metabolite 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 Project 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 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 13-07F); 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 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 the target organs 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 

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-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 red fluorescent granules consistent with porphyrin deposits. 

There 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 dose

and only on the treatment day. There 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 wavy 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 throughout 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.
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D425574

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Food Quality Protection Act (FQPA) Safety Factor (SF) Decision: The RAB1 risk assessment 

team recommends that the FQPA SF be reduced to 1X for all exposure scenarios based on the 

following considerations: (1) the 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 Exposure 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 toxicological 

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 

chronic 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 

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. These 

exposure scenarios were assessed using the most recent standard operating proceudres (SOPs). The 

resulting residential 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: HED aggregates 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-/intermediateterm 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 risk assessment combined chronic dietary exposure with incidental 

oral exposure from the turf use (hand-to-mouth). The resulting aggregate MOEs are ≥2,100 and, 

therefore, do not exceed HED’s LOC. The exposure estimates and populations included in the shortterm aggregate assessment are protective of all potential short-term exposures.

Chronic Aggregate Risk: Chronic 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 D425574

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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 exposures are not expected.

All occupational handler scenarios for the proposed uses 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, therefore, 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 shoes 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 Agency 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 does not involve changes 

to the registered application scenarios. Based on this and since there is no difference between the 

occupational scenarios and the agronomics/practices already assessed for the revised crop 

group/subgroup definitions, the additional crops are already covered by an existing risk assessment 

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 Worker 

Protection Standard (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 accordance 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 with 

applicable ethics requirements. For certain studies, the ethics review may have included review 

by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their 

use, can be found at the Agency website1

. 

 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-exposure
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D425574

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2.0 Recommendations

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 analyze 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 tolerances 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 been 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 suitable 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 tolerances 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 removed; 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, forage; 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, straw; 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 D425574

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Table 2.2.2.1: Tolerance Summary.

Commodity

Proposed 

Tolerance 

(ppm)

HEDRecommended 

Tolerance (ppm)

Comments

Current Requests

artichoke, globe 0.10 0.10 --

asparagus 0.25 0.10

field trials resulted in < limit of quantitation (LOQ) residues 

(LOQ = 0.05) peppermint, tops 0.25 0.10

spearmint, 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

vegetable, bulb, group 3-07 0.10 0.10 --

vegetable, fruiting, 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

13-07F, except fuzzy kiwifruit 0.10 0.10 --

berry, low growing, subgroup 13-07G 0.10 0.10 --

nut, tree, group 14-12 -- 0.10 --

oilseed group 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 recommended as part of the Scoping Assessment conducted in support of Registration Review.

banana -- 0.10

D382666, K. Lowe et al., 9-Feb-2011

grain, cereal, group 16, forage -- 1.0

grain, cereal, group 16, hay -- 0.30

grain, cereal, group 16, stover -- 0.80

grain, cereal, group 16, straw -- 3.0

2.2.3 Revisions to Petitioned-For Tolerances

A revised Section F is requested 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 equal to that recommended herein 

(tolerance expressions are identical). Therefore, harmonization is not an issue for this petition.
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D425574

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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 should 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 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: 

citrus (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 Appendix 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

Cl F

N

N

O

CHF2

CH3

Et

O

Cl

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-1H-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-1H-1,2,4-triazol-1-yl]-4-

fluorobenzenepropanoic acid

CAS # 128639-02-1

3.2 Proposed Use Pattern

The petitioner is proposing application of Aim® Herbicide (EPA Reg. No. 279-3194), Aim® EC 

Herbicide (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 13-07F); 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; the 

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 D425574

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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 

should 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 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: 

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%

waterdispersible 

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); 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); tree nuts (CG 14-12); and oilseed (CG 

20)

broadleaf 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); postemergence (hooded)

WDG; EC; 

EW 0.031 not specified

0.096 (preplant 

= 0.031 lb 

ai/acre; postemergence = 

0.065 lb 

ai/acre)

0

-post-emergence application made 

with hooded sprayer to row 

middles

-spray vol. ≥20 GPA for postemergent applications

teff, quinoa, psyllium

preplant burndown; 

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 D425574

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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; postemergence = 

0.065 lb 

ai/acre)

0

-post-emergence application made 

with hooded sprayer to row 

middles

-spray vol. ≥20 GPA for postemergent 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 

applications are made with hooded 

sprayers 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. Aquatic 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 occupational (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 (D382665, 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 Actions 

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 assessment, OPP considers a large variety of consumer subgroups according to 

well-established procedures. In line with OPP policy, HED estimates risks to population 

subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water 

consumption, and activities in and around the home that involve pesticide use in a residential 

setting. Extensive data on food consumption patterns are compiled by the USDA under 

NHANES/WWEIA (2003-2008) and are used in pesticide risk assessments for all registered food 

uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season 

of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary 

exposure to smaller, specialized subgroups and exposure assessments are performed when 

conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on 

home use of pesticide products and associated risks for adult applicators and for toddlers, youths, 

and adults entering or playing on treated areas post-application are evaluated. Further 

considerations are currently in development as OPP has committed resources and expertise to the 

development of specialized software and models that consider exposure to bystanders and farm 

workers as well as lifestyle and traditional dietary patterns among specific subgroups.
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D425574

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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 for hazard characterization, 

toxicity endpoint selection, and FQPA SF consideration. The 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 incorporated 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) Developmental 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, metabolism, excretion (ADME) studies in rats.

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME)

Absorption of orally administered carfentrazone-ethyl in rats 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 extensively metabolized in the rat since only a small amount of the parent 

(0.06 to 2.78%) was found in the feces by 48 hours and no 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 carcasses assayed was very low (males: 0.09%; females: 0.08%). The major 

metabolites 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 metabolic reactions generate a number of minor 

metabolites. There were no differences in the male and female rate metabolic profiles.

4.2.1 Dermal Absorption

There are no dermal penetration studies available for carfentrazone-ethyl. There was no 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-Health Risk Assessment D425574

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4.3 Toxicological Effects

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 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 repeated 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 hematopoietic system (decreased 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 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 red fluorescent granules 

consistent with porphyrin deposits. There were no indicators of targeted effects on the immune 

system. The results of the acute neurotoxicity study indicated 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. Fetal effects in the rat 

developmental study (increase in litter incidence of wavy 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 risk assessment team recommends that the FQPA SF be reduced to 1X for all exposure 

scenarios based on the following considerations: (1) the 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. 

4.4.1 Completeness of the Toxicology Database

The existing toxicology database is adequate for characterizing carfentrazone-ethyl toxicity and 

quantifying hazard for dietary and occupational exposures. Developmental 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-Health Risk Assessment D425574

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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 carfentrazoneethyl 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 analysis is unlikely to underestimate exposure as they 

incorporated tolerance-level residues or tolerance-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 considered 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; D389083), 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 lowest-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 than 

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 carfentrazone-ethyl. 

Table 4.5.3 summarizes the toxicological doses 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 rats was used to evaluate acute dietary exposures; 

however, effects (salivation 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-ethyl (128712) Human-Health Risk Assessment D425574

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Chronic dietary (all populations): A rat chronic toxicity/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 following 

chronic exposure to carfentrazone-ethyl. The 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 mg/kg 

bw/day). The 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. The 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 limit 

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. The LOC for inhalation oral exposures is 100 (10X for 

interspecies extrapolation, 10X for intraspecies extrapolation, and 1X for FQPA SF). For this 

endpoint, inhalation exposure is assumed to be equivalent to toxicity by the oral route of 

exposure.

Cancer: Carfentrazone-ethyl has been classified as “not likely to be carcinogenic” based on the 

lack of evidence for carcinogenicity in mice and rats; therefore, a quantitative cancer risk 

assessment is not necessary. 

4.5.2 Recommendation for Combining 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 selected. 
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D425574

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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 carcinogenic 

potential of carfentrazone-ethyl. In addition, the mutagenic test battery demonstrated that 

carfentrazone-ethyl is not mutagenic. Based on these findings and in accordance with the Draft 

Proposed Guidelines for Carcinogen Risk Assessment (April, 1999), the Agency classified 

carfentrazone-ethyl as “not likely to be a carcinogenic to humans”; therefore, a quantitative

cancer risk assessment is not required.

4.5.4 Summary of PODs 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

UFA = 10X

UFH =10X

FQPA SF = 1X

cRfD = 0.03 mg/kg/day

cPAD = 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 increased 

urinary porphyrin levels in both 

sexes

Incidental Oral 

(short- and 

intermediate-term)

NOEL = 

50 mg/kg/day

UFA = 10X 

UFH =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 offspring; therefore, a quantitative dermal assessment is not needed.

Inhalation

(short- and 

intermediate-term)

Oral NOEL = 

50 mg/kg/day

UFA = 10X 

UFH =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 mice.

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

UFA = 10X 

UFH =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 = noobserved-effect level. LOEL = lowest-observed-effect level. UF = uncertainty factor. UFA = extrapolation from animal to 

human (interspecies). UFH = 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 

exposure. LOC = level of concern. 
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D425574

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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, reproductive, 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 rates, 

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 decision 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), carfentrazoneethyl is subject to the 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 effect 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 first 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 chemicals 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 or 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-Health Risk Assessment D425574

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5.0 Dietary Exposure and Risk Assessment 

D427527, T. Bloem, 17-Nov-2015 (residue chemistry summary); D428859, 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 submitted 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 concluded 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 studies; 

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 on 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-OHF8426-BAc, F8426-BAc, and Me-3-OH-F8426-BAc were included for the following reasons: (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 goats, 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 risk assessment purposes, are carfentrazone-ethyl 

and CR-75 (TXR 0012659, J. Stokes, 19-Jun-1998). 
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D425574

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Nature of the Residue - Fish/Shellfish: The petitioner has submitted and EFED has reviewed a 

fish metabolism/bioconcentration study (MRID 44165042). Rainbow trout were exposed 

continuously to [C-phenyl-U14C]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 metabolite 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 eliminated. 

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 carfentrazone-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 metabolite. 

Environmental Degradation: Carfentrazone-ethyl breaks down rapidly in the environment to CR75 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 available 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 hydrolysis. 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 F8426-CAc (MARC decision document, TXR 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 similar. Carfentrazone-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-ethyl (128712) Human-Health Risk Assessment D425574

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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 registered 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). Therefore, tolerances in/on the grain processed commodities for quinoa and 

psyllium 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 

unnecessary 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, the 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 currently registered for grain sorghum (see Appendix 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). Therefore, tolerances in/on the grain processed commodities 

for teff are unnecessary. 
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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/registered uses 

(D425572, 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 groundwater EDWCs from the caneberry use was generated using Pesticide Root 

Zone Model for Ground Water (PRZM-GW). Additional information concerning these models 

are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/. The EDWCs 

from the rice use are the highest and were incorporated into the chronic dietary exposure analysis 

(“water, direct, all sources” and “water, indirect, all sources”). 

Table 4: EWDCs.

Drinking Water Source (Model) Application Rate Value for Chronic Assessment (μg/L)

surface water (Tier I Rice Model) rice, wild rice (0.20 lbs ai/acre) 86

ground water (PRZM-GW) caneberries (0.4 lbs ai/acre) 43.9

5.4 Dietary Risk Assessment

Dietary (food and drinking water) exposure and risk assessments were conducted using DEEMFCID (ver. 3.16) which incorporates food consumption data from USDA 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 toxicological 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 DEEMTM (ver 7.81) default processing 

factors 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 (≤78% chronic population adjusted dose (cPAD); 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 Exposures and Risks.

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 34

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 22
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6.0 Residential Exposure and Risk Estimates

D389978, 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 aqautic assessment are provided in D428858 (L. Venkateshwara, 17-Nov-2015). As 

part of the current assessment the 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 Scenario: 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. The handler 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) with 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.

Table 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 

Exposures3 (mg/lb ai)

Baseline Exposure4

(mg/kg/day) 

Baseline 

MOE5

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 31,000,000
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D425574

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Table 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 

Exposures3 (mg/lb ai)

Baseline Exposure4

(mg/kg/day) 

Baseline 

MOE5

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 SOPs 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 conducted 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 

toxicological 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-application 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 the lifestages selected for assessment are protective of any other potentially exposed 

lifestages. In addition, although HED does not anticipate intermediate-term post-application 

exposure from the aquatic application scenario, the short-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 LOC Max. Conc. in 

Water 1 (mg/L)

Exposure (mg/kg/day) Short-term MOE2

Incidental 

Oral1 Inhalation1 Combined Incidental Oral Inhalation Combined

Adult MOEs <100 0.018 1.125E-06 4.50E-10 1.125E-06 4.4E7 1.1E11 4.4E7

Child 3 to <6 years 1.1842E-05 3.78E-09 1.1842E-05 4.2E6 1.3E10 4.2E6 1 Maximum concentration in water = 0.018 mg/L based on maximum application rate for aquatic 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-ethyl (128712) Human-Health Risk Assessment D425574

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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 hazard 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). 

The incidental oral assessments were conducted 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 other 

potentially exposed lifestages. In addition, although HED does not anticipate intermediate-term postapplication exposure from the turf application scenario, the short-term risk assessment is protective of 

intermediate-term exposure as the relevant short-/intermediate-term PODs are the same. 

Table 6.2.2: Short-Term Residential Post-application Exposure and Risk Estimates for Carfentrazone-Ethyl.

Life Stage Scenario Post-application Exposure Scenario Dose (mg/kg/day) Short-term MOEs1

Child 1 < 2 year old Turf - sprays

Hand to Mouth 0.0006 84,000

Object to Mouth 0.00002 2,700,000

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 pesticide on the same day. Therefore, 

aggregate risk assessments for adults will be conducted using the handler exposure from 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, objectto-mouth, and soil ingestion) are inter-related and it is likely that they occur interspersed 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 estimate 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 exposure 

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 the 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 - turf1 9.5 x 10-6 5,300,000 not applicable

Child 1<2 years old - turf2 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).
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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 working with the Spray Drift Task Force 

(a task force composed of various registrants which was developed as a result of a Data Call-In 

issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other 

parties to develop the best spray drift management practices (see the agency’s Spray Drift website 

for more information; 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 Registration 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 Standard 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

Volatilization of pesticides may be a source of post-application inhalation exposure to individuals 

nearby pesticide applications. The agency sought expert advice and input on issues related to 

volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific 

Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The agency 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-OPP2014-0219). 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.
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7.0 Aggregate Exposure/Risk Characterization

HED considers 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 aggregate 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 the same and, therefore, the shortterm risk assessment is protective of intermediate-term exposure. 

7.1 Short-Term Aggregate Risk

For adults, the short-term aggregate risk assessment combined chronic dietary exposure with 

handler inhalation exposure from 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 ≥2,100 and, therefore, do 

not exceed 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) MOE2

Dietary1 Inhalation1 Incidental-oral1

Adults

MOE <100

0.006616 0.0000095 not applicable 7,500

Children (1-2 years old) 0.023432 not applicable 0.0006 2,100

1 See Tables 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). 
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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, see the policy 

statements released by EPA’s Office of Pesticide Programs concerning common mechanism 

determinations and procedures for cumulating effects from substances found to have a common 

mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure and Risk Estimates

9.1 Occupational 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 task. 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 occupational 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 the best available data to assess handler exposure. 

Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, 

include PHED 1.1, the AHETF database, or other registrant-submitted occupational exposure 

studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection 

provisions of FIFRA. The standard values recommended for use in predicting handler exposure that 

are used in this assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide 

Handler Unit Exposure Surrogate Reference Table” (http://www.epa.gov/opp00001/science/handlerexposure-table.pdf), which, along with additional information on HED policy on use of surrogate 
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D425574

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data, including descriptions of the various sources, can be found at the Agency website

(http://www.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 applicators 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 uses, 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, 

loaders, 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 handlers. 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 Occupational 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 over 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 assessed 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 gloves for the duration of the application. With this level of protection, 

there are no risk estimates of concern for applicators.
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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 

(μg/lb ai)1 Maximum

Application Rate2

Area Treated or 

Amount 

Handled Daily3

Inhalation

Mitigation Level (Baseline, 

No Respirator)

Dose 

(mg/kg/day)4 MOE5

Mixer/Loader

M/L, 

EC, Groundboom Applications

High acreage crops6

0.219

0.031 lb ai/A 200 0.000017 2,900,000

Typical acreage crops7 0.065 lb ai/A 80 0.0000143 3,500,000

M/L, 

WDG, Groundboom Applications

High acreage crops 8.960.031 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 0.2190.031 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 8.960.031 lb ai/A 1,200 0.00416 12,000

Typical acreage crops 0.065 lb ai/A 350 0.00255 20,000

Applicator

applicator, Spray, Groundboom 

Open Cab

High acreage crops 0.340.031 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)

0.031 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

0.031 lb ai/A 350 0.0000264 1,900,000

Typical acreage crops 0.065 lb ai/A 350 0.0000995 500,000
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D425547

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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 reentry 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 nature 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-application exposure. Also 

post-application exposures are anticipated based on the proposed new uses of carfentrazoneethyl.

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 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 Volatilization Screening Tool and a subsequent 

Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQOPP-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 to 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 that 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 postapplication risk assessment was not conducted due to the lack of dermal hazard and because no 

systemic hazard was identified. 
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D425547

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9.2.3 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 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 Recommended Teff, 13-07B, 13-07F, and 13-07G Application Scenarios
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D425547

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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

no1

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

yes2

yes

yes2

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-ethyl (128712) Human-Health Risk Assessment D425547

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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 LD50 > 5000 mg/kg IV

870.1200 Acute dermal 43189209 LD50 > 4000 mg/kg III

870.1300 Acute inhalation 43189211 LC50 > 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 

histopathological 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/day
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D425547

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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, increased 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/kg/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 solubility limit.
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D425547

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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 conditions 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 D425547

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 majority 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 carcasses 

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-hydroxymethylF8426-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 metabolites 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 recovery 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-Health Risk Assessment D425547

Page 36 of 38

Appendix B: Chemical Structures

Table A1.1: 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-1H-1,2,4-

triazol-1-yl)-4-fluorobenzenepropanoate

N

Cl F

N

N

O

CHF2

CH3

Et

O

Cl

O

carfentrazonechloropropionic acid

F8426-ClPAc; CR-75

α,2-dichloro-5-[4-(difluoromethyl)-4,5-

dihydro-3-methyl-5-oxo-1H-1,2,4-triazol1-yl]-4-fluorobenzenepropanoic acid

N

Cl F

N

N

O

CHF2

CH3

HO

Cl

O

3-hydroxymethylcarfentrazonechloropropionic acid

3-OH-F8426-ClPAc; HMF8426-ClPAc; 3-HM-F8426-

ClPAc; CR-48

α,2-dichloro-5-[4-(difluoromethyl)-4,5-

dihydro-3-hydroxymethyl-5-oxo-1H1,2,4-triazol-1-yl]-4-

fluorobenzenepropanoic acid

N

Cl F

N

N

O

CHF2

CH2OH

HO

Cl

O

3-hydroxymethylcarfentrazone-benzoic acid 

3-OH-F8426-BAc; 3-HMF8426-BAc; HM-F8426-BAc

2-chloro-5-[4-(difluoromethyl)-4,5-

dihydro-3-hydroxymethyl-5-oxo-1H1,2,4-triazol-1-yl]-4-fluorobenzoic acid

Cl

N

N

N

F

CHF2

CH2OH

O

O

HO

3-desmethyl-carfentrazonechloropropionic acid

3-DM-F8426-ClPAc

2-dichloro-5-[4-(difluoromethyl)-4,5-

dihydro-5-oxo-1H-1,2,4-triazol-1-yl]-4-

fluorobenzenepropanoic acid

Cl

N

N

N

F

CHF2

O Cl

HO

O

F8426-propionic acid; 

F8426-PAc

2-chloro-5-[4-(difluoromethyl)-4,5-

dihydro-3-methyl-5-oxo-1H-1,2,4-triazol1-yl]-4-fluorobenzenepropanoic acid

Cl

N

N

N

F

CHF2

O

HO

O

CH3

F8426-cinnamic acid; F8426-

CAc

2-chloro-5-[4-(difluoromethyl)-4,5-

dihydro-3-methyl-5-oxo-1H-1,2,4-triazol1-yl]-4-fluorobenzenepropenoic acid

Cl

N

N

N

F

CHF2

O

HO

O

CH3

F8426-benzoic acid; F8426-

BAc

2-chloro-5-[4-(difluoromethyl)-4,5-

dihydro-3-methyl-5-oxo-1H-1,2,4-triazol1-yl]-4-fluorobenzoic acid

Cl

N

N

N

F

CHF2

O

CH3

O

HO
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D425574

Page 37 of 38

Appendix C: Physicochemical 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 μg/ml

Solvent solubility (μg/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 (pKa) no dissociation constant

Octanol/water partition coefficient Log(KOW) log Kow = 3.36

UV/visible absorption spectrum not available
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D425574

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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

teff1

preplant ( 1 day before 

seeding); postemergence (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 postemergent application (not including 

harvest aid).

-do not apply more than 0.016 lb 

ai/acre as a harvest aid treatment. 

13-07B2

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

13-07F3

preplant (1-day before 

transplanting); postemergence (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

-do not allow spray solution to 

contact green stem tissue, leaves, 

fruit, or blooms

-RTI = 14 days

-spray volume ≥10 GPA

13-07G2

preplant (1-day before 

translating); postemergence (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 D303030 (T. Bloem, 30-Jun-2004) and currently-registered labels.