Carfentrazone-ethyl (128712) Human-Health Risk Assessment D389083

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1.0 Executive Summary

Background: Carfentrazone-ethyl is a postemergence herbicide of the phenyl triazolinone group 

used for control of broad leaf weeds. It acts as an inhibitor of protoporphyrinogen oxidase (PPO),

which results in disruption of the cell membrane and desiccation of susceptible plant species. 

Carfentrazone-ethyl is registered for use on numerous agricultural crops, turf (including golf 

courses and residential lawns), and in aquatic areas. As a result of the agricultural uses, plant and 

livestock tolerances are established at 0.05-10 ppm (40 CFR 180.515). The most recent humanhealth risk assessment for carfentrazone-ethyl was completed on 14-July-2006 (D328332, T. Bloem 

et al.); a scoping document in support of Registration Review was completed on 19-Jan-2011 

(D382666, K. Lowe et al.). 

FMC Corporation is proposing application of carfentrazone-ethyl to the nongrass animal feed crop 

group 18. In conjunction with this request, the petitioner proposed the establishment of the 

following permanent tolerances for the combined residues of carfentrazone-ethyl and CR-75 (α,2-

dichloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]-4-

fluorobenzenepropanoic acid): alfalfa, forage - 5 ppm; alfalfa, hay - 18 ppm; alfalfa, seed - 10 ppm; 

clover, forage - 5 ppm; clover, hay - 18 ppm; and clover, seed - 10 ppm.

Hazard Characterization and Dose Response Assessment: The toxicological database for 

carfentrazone-ethyl is adequate for hazard evaluation, toxicity endpoint and point of departure 

(POD) dose selection, and FQPA evaluation. Carfentrazone-ethyl was ranked low (Category III or 

IV) for inducing acute lethality 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.

As indicated above, the carfentrazone-ethyl’s proposed herbicidal mode of action is through 

inhibition of PPO. In mammals, PPO is also an important enzyme in heme biosynthesis and its 

inhibition can lead to toxic effects where heme is utilized (e.g., red blood cells). The effects 

observed following repeated oral exposures to carfentrazone-ethyl are consistent with those 

expected from PPO inhibition. The target tissues/organs identified are the blood and liver, with the 

most sensitive species being the rat. Subchronic toxicity studies in rats, mice, and dogs demonstrated 

that the primary effects were on hematological parameters (decreased mean corpuscular 

hemoglobin [MCH] and mean corpuscular volume [MCV]). There was also increased urinary 

porphyrin excretion, increased liver weights, and liver histopathology findings 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 and liver 

histopathology findings in rats and mice consisting of liver pigmentation and increases in red 

fluorescence. Fluorescence microscopy on liver sections also revealed red fluorescent granules 

consistent with porphyrin deposits in rats and mice. 

There was no evidence of increased susceptibility in prenatal developmental toxicity studies (rats 

and rabbits) or the multigenerational reproductive toxicity study in rats. Carfentrazone-ethyl 

induced a significant increase in litter incidences of wavy and thickened ribs in rats at a dose (1250 

mg/kg/day) much higher than the dose (600 mg/kg/day) that caused maternal toxicity consistent 

with interference with porphyrin metabolism (i.e., staining of the abdominogenital area and of the 

cage pan liner). The rabbit prenatal developmental toxicity study did not yield any evidence of 

treatment-related prenatal developmental toxicity even at the highest dose tested (300 mg/kg/day). 

The offspring effects from the 2-generation reproduction study consisted of decreased pup body 
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weight in both sexes of the F2 generation at the highest dose tested (343 mg/kg/day) and at which 

maternal toxicity was observed in the form of 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).

There is no concern for neurotoxicity. The results of the acute neurotoxicity study indicate clinical 

signs (i.e., salivation) and mild decreases in motor activity only on the treatment day and the 

subchronic neurotoxicity showed no signs of neurotoxicity up to the limit dose (1178 mg/kg/day for 

males and 1434 mg/kg/day for females).

In a 21-day dermal toxicity study, carfentrazone-ethyl did not induce any type of dermal or 

systemic toxicity up to the limit dose of 1000 mg/kg/day. The mutagenic test battery demonstrated 

that carfentrazone-ethyl is not mutagenic. In accordance with the Draft Proposed Guidelines for 

Carcinogen Risk Assessment (April, 1999), carfentrazone-ethyl is classified as a “not likely human 

carcinogen,” based on the lack of evidence for carcinogenicity in the mouse and rat; therefore, a 

quantitative cancer risk assessment is not necessary. 

Toxicity Endpoint and Points of Departure (PODs) Selection; Food Quality Protection Act 

(FQPA) Safety Factor (SF): Table 4.6.1 is a summary of the toxicological doses and endpoints for 

carfentrazone-ethyl risk assessment. Short-/intermediate-term dermal assessments were not 

conducted because no hazard was identified via the dermal route for these durations. The short-

/intermediate term inhalation endpoint is based on an oral study with assessments conducted 

assuming toxicity by the inhalation route is equivalent to toxicity by the oral route. Since the same 

study/effect was selected for assessment of short-/intermediate term inhalation and incidental oral 

exposure, exposure via these routes can be aggregated. 

For the following reasons, the risk assessment team recommends that the FQPA SF may be reduced 

to 1x for all exposure scenarios: (1) Based on the results of the rat/rabbit prenatal developmental 

toxicity studies and the rat 2-generation reproductive toxicity study, there is no evidence of 

increased pre- and/or postnatal susceptibility and there are no residual uncertainties with respect to 

pre- or postnatal susceptibility; (2) Although an immunotoxicity study is currently lacking in the 

toxicity database for carfentrazone-ethyl, there is no evidence in the current database that the 

immune system organs are directly affected following carfentrazone-ethyl exposure; (3) There is no 

evidence of neurotoxicity based on the results of acute and subchronic neurotoxicity studies in rats 

or any other study in the database; and (4) The dietary and residential exposure analyses are 

conservative and unlikely to underestimate exposure. 

Residue Chemistry: Provided revised Sections B (see Section 2.1) and F (see Section 2.2) are 

submitted, HED concludes that the residue chemistry database is sufficient to support registration 

for application to the nongrass animal feed crop group 18. 

Dietary (Food + Drinking Water) Risk Assessment: Acute and chronic dietary (food and drinking 

water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model 

- Food Consumption Intake Database (DEEM-FCIDTM, ver. 2.03) which incorporates the food 

consumption data from the United States Department of Agriculture (USDA) Continuing Surveys 

of Food Intakes by Individuals (CSFII; 1994-1996 and 1998). The acute and chronic analyses 

assumed tolerance-level residues or, if necessary, tolerance-level residues adjusted to account for 
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the residues of concern for risk assessment, 100% crop treated, and modeled drinking water 

estimates. 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 acute (≤1% acute populationadjusted dose (aPAD); all infants (<1 year old) were the most highly exposed subgroup) and 

chronic (≤69% cPAD; children 1-2 years old were the most highly exposed subgroup) exposure 

estimates do not exceed HED’s level of concern (LOC). 

Residential Risk Assessment: The proposed application scenario to the nongrass animal feed crop 

group 18 will not result in residential exposure. However, carfentrazone-ethyl is currently 

registered for application to turf (including golf courses and residential lawns) and for aquatic 

application. It is the policy of HED to use the best available data to assess residential exposure; 

therefore, residential exposure resulting from the turf use were assessed using HED’s Residential 

Standard Operating Procedures (SOPs; 2012) and residential exposure resulting from the aquatic 

use were assessed using HED’s SOP for Residential Exposure Assessments (Draft; 17-Dec-1997; 

pages 52 -57) and modified in HED’s SWIMODEL V 1.0 (W. Dang et al., 27-Mar-1999).

Based on the turf and aquatic application scenarios, HED assessed short-term inhalation (adult 

handler) and incidental oral (children; post-application) exposure from the turf use and short-term 

incidental oral and inhalation exposure from the aquatic use (adult and children; post application). 

Dermal risk assessments were not conducted because no hazard was identified via the dermal route 

for the relevant exposure durations. Although intermediate-term exposures are not anticipated, the 

relevant short-/intermediate-term PODs are the same and, therefore, the short-term risk assessment 

is protective of intermediate-term exposure. The resulting combined margins of exposure (MOEs)

were ≥84,000 and are not of concern to HED. Note that 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 Assessment: In accordance with the FQPA, HED must consider and aggregate 

(add) pesticide exposures and risks from three major sources: food, drinking water, and residential 

exposures. Based on the proposed/registered uses, aggregate acute (food and water), short-term 

(food, water, inhalation, and/or incidental oral) and chronic (food and water) risk assessments are 

required. Although intermediate-term residential exposures are not anticipated, the relevant short-

/intermediate-term PODs are the same and, therefore, the short-term risk assessment is protective of 

intermediate-term exposure. The following paragraphs are summaries of the acute, short-term, and 

chronic aggregate exposure assessments. 

Acute and Chronic Aggregate Risk: Acute and chronic aggregate risk concerns only dietary 

exposure (food and water). The acute (≤1% aPAD) and chronic (≤69% cPAD) dietary exposure 

estimates do not exceed HED’s LOC. 

Short-Term Aggregate Risk: For adults and the general U.S. population, 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 
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exposure estimates and populations included in the short-term aggregate assessment are protective 

of all potential short-term exposures. The resulting aggregate MOEs are ≥2,300 and, therefore, do 

not exceed HED’s LOC. 

Occupational Risk Assessment: Based on the proposed nongrass animal feed crop group 18 

application scenario, occupational handler exposures are expected to be short-term (only one 

application per season). However, it is noted that the relevant short-/intermediate-term PODs are 

the same and assessing short-term exposure is protective of intermediate-term exposure. Long-term 

exposures are not expected. It is the policy of HED to use the best available data to assess 

occupational exposure. Since no chemical-specific data were available for carfentrazone-ethyl, the 

occupational handler assessments were conducted using generic handler data as a surrogate. The 

“baseline” (long-sleeved shirt, long pants, shoes plus socks, and no protective gloves) MOEs for 

occupational handlers are ≥21,000 and, therefore, do not exceed HED’s LOC. Post-application 

occupational assessments were not conducted as no hazard was identified via the dermal route for 

the relevant exposure durations and it is the Agency’s current practice to not conduct quantitative 

occupational post-application inhalation exposure.

Restricted Entry Interval (REI): Carfentrazone-ethyl is classified as Toxicity Category 3 for acute 

dermal and Toxicity Category 4 for 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 

a REI of 12 hours. 

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 LowIncome Populations” (http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf).

As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups 

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

population subgroups from pesticide exposures that are based on patterns of 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 

the CSFII 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 (see below). 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.

Although carfentrazone-ethyl is not considered a persistent bioaccumulative toxic (PBT) 

compound, it is registered for aquatic application with fish/shellfish tolerances established (0.30 

ppm). For the following reasons, HED concludes that exposure to carfentrazone-ethyl as a result of 

subsistence fishing is not of concern: (1) dietary analyses assumed tolerance level residues and 
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100% crop treated with the resulting exposure estimates less than HED’s LOC (≤1% aPAD (95th

percentile); ≤69% cPAD); (2) acute exposure at the 99.9th percentile were ≤2% aPAD; (3) screening 

level usage analysis (SLUA) yielded average percent crop treated estimates of <1-10% for all 

except caneberry which was at 30%. 

Human Studies: 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 

studies from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural 

Handler Exposure Task Force (AHETF) database; the Outdoor Residential Exposure Task Force 

(ORETF) database; and the Agricultural Re-entry Task Force (ARTF) database, are subject to 

ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable 

ethics requirements. For certain studies that 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 http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html.

2.0 HED Recommendations

HED notes that one of the proposed products contains sulfentrazone and carfentrazone-ethyl 

(Spartan Charge; EPA Reg. No. 279-3337). The following recommendation is in reference to only 

the carfentrazone-ethyl toxicological, residue chemistry, and occupational/residential exposure 

databases. 

Provided revised Sections B and F are submitted, HED concludes that the toxicological, residue 

chemistry, and occupational/residential databases support an unconditional Section 3 registration 

and establishment of the tolerances listed in Section 2.2. 

2.1 Data Deficiencies/Conditions of Registration

Prior to Registration: Revised Section F - See Section 2.2; Revised Section B - HED requests that 

the labels be revised to conform with the following: (1) all labels - following application to the 

nongrass animal feed crop group, only a labeled primary-crop may be rotated; (2) AIM® EW, 

AIM® EC, and AIM® Herbicide labels - maximum application rate of 0.04 lb ai/acre and a 

preharvest interval (PHI) of 21 days for stands grown for forage and hay and a maximum 

application rate of 0.06 lb ai/acre and a PHI of 3 days for stands grown for seed; and (3) AIM® EW

label - harvest-aid application instructions should indicate a rate of 0.06 lb ai/acre rather than 0.6 lb 

ai/acre. 

As a Condition of Registration: None.

Data Deficiencies: Provided revised Sections B and F are submitted as described above, there are 

no data deficiencies associated with the residue chemistry and occupation/residential exposure 

databases. The only toxicological database deficiency is the lack of an immunotoxicity study 

conducted as specified in the new 40 CFR Part 158 requirements. This study has yet to be 

submitted to the Agency and represents a pending toxicity data requirement for 

carfentrazone-ethyl.
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2.2 Tolerance Considerations

Enforcement Analytical Method: HED previously forwarded an analytical enforcement method to 

the Food and Drug Administration (FDA) for inclusion in the Pesticide Analytical Manual II (PAM 

II; D260428, T. Bloem, 23-Nov-1999). HED concludes that this method is sufficient to enforce the 

tolerances associate with the current petition. 

International Harmonization: There are no Codex, Canadian, or Mexican maximum residue limits 

(MRLs) in/on the requested crops (see Attachment 3). Therefore, harmonization is not an issue for 

this petition. 

Recommended Tolerances: Table 2.2.1 is a summary of the proposed and HED-recommended 

tolerances for residues of carfentrazone-ethyl and CR-75. In accordance with the most recent 

guidance, HED recommends that the tolerance expression for 180.515(a) be changed as indicated 

below. A revised Section F specifying the new tolerance expression and the HED-recommended 

tolerances should be submitted. 

180.515(a) General. Tolerances are established for residues of the herbicide carfentrazone-ethyl, 

including its metabolites and degradates, in or on the commodities listed below. Compliance with the 

following tolerance levels is to be determined by measuring only the sum of carfentrazone-ethyl 

(ethyl-alpha-2-dichloro-5-[-4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H -1,2,4-triazol-1-yl]-4-

fluorobenzenepropanoate) and its metabolite carfentrazone-chloropropionic acid (alpha, 2-dichloro-5-

[-4-difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl]-4-fluorobenzenepropanoic 

acid), calculated as the stoichiometric equivalent of carfentrazone-ethyl, in or on the following 

commodities:

Table 2.2.1: Tolerance Summary for Carfentrazone-ethyl.

Commodity Proposed Tolerance 

(ppm)

HED-Recommended 

Tolerance (ppm) Comments

alfalfa, forage 5 --

Based on the proposed uses and the 

submitted data, HED concluded that 

crop group tolerances were appropriate. 

The HED-recommended tolerances are 

based on the submitted field trial data 

and the OECD tolerance calculation 

procedure. 

alfalfa, hay 18 --

alfalfa, seed 10 --

clover, forage 5 --

clover, hay 18 --

clover, seed 10 --

animal feed, nongrass, crop group 18, forage -- 2.0

animal feed, nongrass, crop group 18, hay -- 5.0

animal feed, nongrass, crop group 18, seed -- 15

Revisions to Petition-For Tolerances: Based on the proposed uses and the submitted data, HED 

concludes that crop group tolerances are appropriate. The HED recommended tolerances are 

based on the submitted field trial data and the Organization for Economic Co-operation and 

Development (OECD) tolerance calculation procedure. 
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3.0 Ingredient Profile

Carfentrazone-ethyl is a postemergence herbicide of the phenyl triazolinone group used for 

control of broad leaf weeds. It acts as an inhibitor of PPO which results in disruption of the cell 

membrane and desiccation of susceptible plant species. 

3.1 Summary of Registered/Proposed Uses

Registered: Carfentrazone-ethyl is registered for use on numerous agricultural crops, turf 

(including golf courses and residential lawns), and in aquatic areas. 

Proposed: The petitioner submitted several proposed labels which include instructions for 

application to nongrass animal feed (crop group 18; REI = 12 hours). Table 3.1.1 is a summary 

of the proposed end-use products and Table 3.1.2 is a summary of the proposed application 

scenario. 

Based on the available field trial and rotational crop data, HED requests that the labels be revised 

to conform with the following: (1) all labels - following application to the nongrass animal feed 

crop group, only a labeled primary-crop may be rotated; (2) AIM® EW, AIM® EC, and AIM®

Herbicide labels - maximum application rate of 0.04 lb ai/acre and a PHI of 21 days for stands 

grown for forage and hay and a maximum application rate of 0.06 lb ai/acre and a PHI of 3 days 

for stands grown for seed; and (3) AIM EW label - harvest aid application instructions should 

indicate a rate of 0.06 lb ai/acre rather than 0.6 lb ai/acre. 

Table 3.1.1: Summary of Proposed End-Use Products.

Trade Name EPA Reg. No. concentration Formulation Label Date Target Pests

Crop Group 18 (established stands only): nongrass animal feed (includes alfalfa, velvet bean, clover, kudzu, 

lespedeza, lupin, sainfoin, trefoil, vetch, and crown/milk vetch)

Spartan Charge 279-3337 carfentrazone-ethyl - 0.35 lbs ai/gallon

sulfentrazone - 3.15 lbs ai/gallon suspoemulsion (SE)1

not indicated

broadleaf, 

grass, and 

sedge weeds

AIM® EW 279-3242 1.9 lbs ai/gallon oil emulsion in water (EW) not indicated

AIM® EC 279-3241 2.0 lbs ai/gallon emulsifiable concentrate (EC) not indicated

AIM® Herbicide 279-3194 40% water-dispersible granule 

(WDG) not indicated

1

 suspoemulsion = combination of a suspension concentrate and concentrated aqueous emulsion; allows two active ingredients 

with different physical properties to be combined into one formulation.

Table 3.1.2: Summary of Proposed Application Scenario for Carfentrazone-ethyl.

Formulation

(EPA Reg. No.) App. Timing App. Rate(lb ai/acre)

Max. Seasonal App. 

Rate (lb ai/acre) Use Directions and Limitations

Crop Group 18 (established stands only): nongrass animal feed (includes alfalfa, velvet bean, clover, kudzu, 

lespedeza, lupin, sainfoin, trefoil, vetch, and crown/milk vetch)

Spartan Charge (279-3337) 

AIM® EW (279-3242); 

AIM® EC (279-3241); 

AIM® Herbicide (279-3194)

dormant season

(fall and winter 

application)

0.01-0.04 0.04

-Apply to the dormant stubble of established stands.

-Apply in-season between cuttings to established 

stands. Applications may be made from hay removal 

up to 6 inches of new growth. 

-Harvest-aid instructions apply to crops grown for 

forage, hay, or seed. 

-Max. app. rate per season is 0.04 lb ai/acre for 

dormant and in-season application and 0.06 lb ai/acre 

per season for harvest aid application.

between cuttings 

(in-season 

application)
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Table 3.1.2: Summary of Proposed Application Scenario for Carfentrazone-ethyl.

Formulation

(EPA Reg. No.) App. Timing App. Rate(lb ai/acre)

Max. Seasonal App. 

Rate (lb ai/acre) Use Directions and Limitations

AIM® EW (279-3242); 

AIM® EC (279-3241); 

AIM® Herbicide (279-3194)

harvest aid 

application 0.03-0.06 0.06

-The AIM EW, AIM EC, and AIM Herbicide labels 

indicate a 3-day PHI.

-The Spartan Charge label indicates the following 

PHIs following dormant and in-season application: 

21 days for forage/hay and 41 days for crops grown 

for seed. 

-Minimum of 10 GPA for ground applications and 3-5 

GPA for aerial applications.

-Addition of COC, MSO, or NIS to the spray solution 

is recommended. Fertilizers may also be included 

with the spray solution.

-PBIs of anytime to 12 months for several labeled 

crops and 12 months for all other crops.

-App. through irrigation equipment is prohibited. 

3.2 Structure and Nomenclature

Table 3.2.1 is a summary of carfentrazone-ethyl nomenclature; Table 3.2.2 is a summary of the 

physiochemical properties of technical grade carfentrazone-ethyl. 

Table 3.2.1: 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

Table 3.2.2: Physicochemical Properties of the Technical Grade Test Compound.

Melting point -22.1 C 

EPA Fact Sheet

pH not available

Density 1.46 at 20 C

Water solubility (20°C) 12 g/ml

Solvent solubility ( g/L at 20°C)

acetone - >2000; toluene - 900; 

dichloromethane - >2000; hexane - 30; 

ethanol - >2000; ethyl acetate - >2000

Vapor pressure 1.2 x 10-7 mm Hg (25 C); 5.4 x 10-8

mm Hg (20 C)

Dissociation constant (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 D389083

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4.0 Hazard Characterization/Assessment

The proposed herbicidal mode of action for carfentrazone-ethyl is PPO inhibition. Inhibition of 

PPO in plants results in disruption of chlorophyll biosynthesis and ultimately in 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). Some of the toxic 

effects reported for carfentrazone-ethyl are consistent with PPO inhibition. 

4.1 Toxicity Studies Available for Analysis

The toxicological database for carfentrazone-ethyl is adequate for evaluation of hazard (see 

Attachment 2 for a summary of the carfentrazone-ethyl toxicological database). In the humanhealth assessment scoping document submitted in support of registration review (D382666, K. 

Lowe et al., 17-Dec-2010), the only toxicological database deficiency was the lack of an 

immunotoxicity study as specified in the new 40 CFR Part 158 requirements. The immunotoxicity 

test (OPPTS 870.7800) is designed to evaluate the potential of repeated exposures to a chemical on 

the function of the immune system. This study has yet to be submitted to the Agency and 

represents a pending toxicity data requirement for carfentrazone-ethyl.

There is no animal toxicity study with carfentrazone ethyl based on repeated inhalation exposures; 

inhalation risk assessments are being conducted using an oral study (toxicity by the inhalation 

route is considered equivalent to toxicity by the oral route). The HED Hazard and Science Policy 

Council (HASPOC) met on February 21, 2012 to determine if a 28-day rat inhalation study is 

needed to support the requested use. The HASPOC concluded, based on a weight of evidence 

approach, that a 28-day inhalation toxicity study is not required for the proposed use for the 

following reasons: (1) the use of an oral POD results in occupational inhalation MOEs from the 

proposed use of greater than 21,000; (2) the physical/chemical properties and low volatility of 

carfentrazone- ethyl; (3) the toxicological profile of carfentrazone-ethyl being consistent with PPO 

inhibition; and (4) its low acute inhalation toxicity (TXR# 0051142). However, an inhalation 

study may be required as part of future petitions and/or Registration review. 

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

Following oral administration in the rat, carfentrazone-ethyl was rapidly absorbed and excreted in 

both sexes as measured indirectly by the rapid excretion of radioactivity in urine within the first 24 

hours. The urine contained the majority of the administered dose (72.4% to 87.0%), followed by 

feces (10.47% to 25.68%). Extensive metabolism was indicated by only a small amount of the parent 

(0.06 to 2.78%) found in the feces while no parent was found in the urine by 48 hours. 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 (male - 0.09%, female - 0.08%). 

The major metabolites in both the urine and feces were CR-75 (49-66% total radioactive residue 

(TRR)) and to a lesser extent CR-48 (18-34% TRR) followed by 3-OH-F8426-PAc (2-6% TRR) 

and F8426-CAc (<2% TRR). In addition, minute quantities of 3-OH-F8426-CAc and F8426-PAc 

were found in the urine, but the levels were too low to quantify. 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 conversion of the 

parent compound by hydrolysis of the ester moiety to form CR-75, followed by oxidative 

hydroxylation of the methyl group to form CR-48, or dehydrochlorination to form F8426-CAc. 
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D389083

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Dechlorination of CR-75 formed F8426-PAc, and hydroxylation of the methyl group of F8426-

PAc formed 3-OH-F8426-PAc. 

4.3 Toxicological Effects

Carfentrazone-ethyl was ranked low (Category III or IV) for inducing acute lethality 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.

The effects observed following repeated oral exposures to carfentrazone-ethyl are consistent with 

those expected from PPO inhibition. The target tissues/organs identified are the blood and liver, 

with the most sensitive species being the rat. Subchronic toxicity studies in rats, mice, and dogs 

demonstrated that the primary effects were on hematological parameters (decreased mean 

corpuscular hemoglobin [MCH] and mean corpuscular volume [MCV]). There was also increased 

urinary porphyrin excretion, increased liver weights, and liver histopathology findings 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 and 

liver histopathology findings in rats and mice consisting of liver pigmentation and increases in red 

fluorescence. Fluorescence microscopy on liver sections also revealed red fluorescent granules 

consistent with porphyrin deposits in rats and mice. 

There was no evidence of increased susceptibility in prenatal developmental toxicity studies (rats 

and rabbits) or the multigenerational reproductive toxicity study in rats. Carfentrazone-ethyl 

induced a significant increase in litter incidences of wavy and thickened ribs in rats at a dose (1250 

mg/kg/day) much higher than the dose (600 mg/kg/day) that caused maternal toxicity consistent 

with interference with porphyrin metabolism (i.e., staining of the abdominogenital area and of the 

cage pan liner). The rabbit prenatal developmental toxicity study did not yield any evidence of 

treatment-related prenatal developmental toxicity even at the highest dose tested (300 mg/kg/day). 

The offspring effects from the 2-generation reproduction study consisted of decreased pup body 

weight in both sexes of the F2 generation at the highest dose tested (343 mg/kg/day) and at which 

maternal toxicity was observed in the form of 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).

There is no concern for neurotoxicity. The results of the acute neurotoxicity study indicate clinical 

signs (i.e., salivation) and mild decreases in motor activity only on the treatment day and the 

subchronic neurotoxicity showed no signs of neurotoxicity up to the limit dose (1178 mg/kg/day 

for males and 1434 mg/kg/day for females).

In a 21-day dermal toxicity study, carfentrazone-ethyl did not induce any type of dermal or 

systemic toxicity up to the limit dose of 1000 mg/kg/day. There are no toxicity studies based on 

repeated inhalation exposures to carfentrazone-ethyl. A waiver of a 28-day inhalation toxicity 

study was previously accepted by HED based on its relatively low volatility, low acute inhalation 

lethality (Category 4), and the large inhalation MOEs associated with the requested applications.

An immunotoxicity study is currently the only toxicity database deficiency for carfentrazone-ethyl. 

However, the current toxicity database is consistent with a mode of action involving PPO 

inhibition and there is no indication that the immune system organs may be a target. The 

mutagenic test battery demonstrated that carfentrazone-ethyl is not mutagenic. In accordance with 
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D389083

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the Draft Proposed Guidelines for Carcinogen Risk Assessment (April, 1999), Carfentrazone-ethyl 

is classified as a “not likely human carcinogen,” based on the lack of evidence for carcinogenicity 

in the mouse and rat; therefore, a quantitative cancer risk assessment is not necessary. 

4.4 Dermal Absorption

There are no dermal penetration studies available for carfentrazone-ethyl. In a rat dermal toxicity 

study, however, there was no dermal or systemic toxicity reported up to the limit dose tested of 

1000 mg/kg bw/day, probably indicative of very low dermal absorption.

4.5 Safety Factor for Infants and Children (FQPA Safety Factor)

The carfentrazone-ethyl risk assessment team recommends that the FQPA SF be reduced from 10X 

to 1x for all exposure scenarios. The rationale is described below. 

Completeness of the Toxicology Database: The existing toxicology database for carfentrazoneethyl is adequate for evaluation. Although an immunotoxicity study is currently lacking, it is 

unlikely that the results of such a study would yield a lower POD than those being used for risk 

assessment since there is no evidence in the current database that the immune system organs are 

directly affected following carfentrazone-ethyl exposure. The following acceptable studies are 

available for FQPA consideration: (1) developmental toxicity study in rats and rabbits; (2) twogeneration reproduction study in rats; and (3) acute and subchronic neurotoxicity studies.

Evidence of Neurotoxicity: There is no evidence of neurotoxicity based on the results of acute 

and subchronic neurotoxicity studies in rats. Clinical signs (i.e., salivation) and mild decreases in 

motor activity were noted only on the day of treatment and there were no signs of neurotoxicity in 

a subchronic neurotoxicity study at the highest dose tested (>1000 mg/kg bw/day). Furthermore, 

there is no evidence in the toxicity database that carfentrazone-ethyl may directly target the 

developing nervous system. 

Evidence of Sensitivity/Susceptibility in the Developing or Young Animal: There is no evidence 

of increased pre- and/or postnatal susceptibility based on the results of the rat and rabbit prenatal 

developmental toxicity studies and the rat 2-generation reproductive toxicity study. A significant 

increase in litter incidences of wavy and thickened ribs was observed in rats at a relatively high 

dose (1250 mg/kg bw/day) that was also much higher than the dose (600 mg/kg/day) for maternal 

effects consistent with interference with porphyrin metabolism (i.e., staining of the abdominogenital 

area and of the cage pan liner). There was no evidence of developmental toxicity in the rabbit 

prenatal developmental toxicity at the highest dose tested. In the rat 2-generation reproductive 

toxicity study, the offspring effects (i.e., body weight deficits in both sexes of the F2 generation) 

occurred at the same dose as parental effects that were consistent with interference with porphyrin 

metabolism (i.e., liver histopathology findings and reductions in hemoglobin parameters).

Residual Uncertainty in the Exposure Databases: The exposure databases are sufficient to 

determine the nature/magnitude of the residue in food and water. The dietary exposure analyses 

are unlikely to underestimate exposure as they incorporated tolerance-level residues or tolerancelevel 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.
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D389083

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4.6 Toxicity Endpoint Selection and PODs Selection

Table 4.6.1 summarizes the toxicological doses and endpoints selected for residential dietary and

occupational risk assessment. The rationale for the dose/endpoint selection is also described 

below. Since the inhalation and incidental oral short-/intermediate-term PODs are based on the 

same effects, exposure via these routes may be aggregated (dermal assessment as been determined 

to be unnecessary; see below). 

Acute dietary (all populations): The acute neurotoxicity (ACN) study in rats was selected for 

this endpoint on the basis that the observed effects (salivation and decreased motor activity) at the 

LOAEL of 1000 mg/kg bw (NOAEL = 500 mg/kg bw) were due to a single orally administered 

dose of carfentrazone-ethyl. Other studies evaluated for this endpoint include the rat prenatal 

developmental study for which the developmental effects of increased incidence of wavy and 

thickened ribs could also be attributed to a single dose of carfentrazone-ethyl. However, the 

developmental effects were reported at a much higher dose of carfentrazone-ethyl and, thus, the 

NOAEL for the ACN study can be expected to be protective of all acute effects and for all 

populations. The standard combined uncertainty factor (UF) of 100x is being applied to account 

for interspecies (10x) and intraspecies (10x) extrapolation. The FQPA SF was reduced to 1x (see 

above). Thus, the acute reference dose (aRfD) and population adjusted dose (aPAD) are 

equivalent and estimated at 5.0 mg/kg bw.

Chronic dietary (all populations): A rat chronic toxicity/carcinogenicity study was selected for 

this exposure scenario since the endpoints of concern were seen in the most sensitive species 

following long-term dietary exposure. The LOAEL of 12 mg/kg bw/day (NOAEL = 3.0 mg/kg 

bw/day) was based on liver histopathology (increases in red fluorescence and pigmentation) and 

increased urinary excretion of porphyrins which are consistent effects associated with PPO 

inhibition. The standard combined UF of 100x is being applied to account for interspecies (10x) 

and intraspecies (10x) extrapolation. The FQPA SF was reduced to 1x (see above). Thus, the 

cRfD and cPAD are equivalent and estimated at 0.03 mg/kg bw/day.

Short- and intermediate-term incidental oral: This toxicity 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 LOAEL of 150 mg/kg bw/day (NOAEL = 50 mg/kg 

bw/day). The offspring effects from the 2-generation toxicity study were also evaluated for this 

endpoint. However, urinary porphyrin levels were not assessed for offspring so it is uncertain if 

such an effect accompanied the reported body weight deficits of the offspring at the LOAEL of 

387 mg/kg bw/day (NOAEL = 142 mg/kg bw/day) as in the selected dog study. A MOE of >100 

which includes interspecies (10x) and intraspecies (10x) extrapolation and FQPA SF (1x; see 

above) is adequate for this scenario. 

Short-and intermediate-term dermal: Quantification of dermal risk is not required and,

therefore, a dose and endpoint were not selected for assessing potential risks from exposure via 

this route. No dermal or systemic toxicity was seen at the limit dose (1000 mg/kg/day) following 

repeated dermal applications to rats for 21 days. There is no concern for developmental or 

reproductive toxicity. In the developmental toxicity study in rats, skeletal variations (not 

malformation, which are of concern) were seen at a very high dose (1250 mg/kg/day). No 

developmental toxicity was seen at the highest dose tested (300 mg/kg/day) in the rabbits. In the 

two generation reproduction study, the highest dose tested (384 mg/kg/day) caused no adverse 

effects on reproduction and only decreases in body-weight gain in the offspring. 
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D389083

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Short- and intermediate-term inhalation: Due to the lack of a repeated dose inhalation study, an 

oral study was selected for assessing risks via the inhalation route. This toxicity 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 LOAEL of 150 mg/kg bw/day (NOAEL = 

50 mg/kg bw/day). A MOE of >100 which includes interspecies (10x) and intraspecies (10x) 

extrapolation and the FQPA SF (1x; see above) is adequate for this scenario. Since no inhalation 

toxicity data are available, toxicity by the inhalation route is considered 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. 

Table 4.6.1: Summary of Toxicological Doses and Endpoints for Carfentrazone-Ethyl for Use in Dietary, NonOccupational, and Occupational Human Health Risk Assessments.

Exposure/ 

Scenario POD Uncertainty Factors/FQPA SF

RfD, PAD, LOC for Risk 

Assessment Study and Toxicological Effects

Acute Dietary (all 

populations)

NOAEL= 500 

mg/kg bw

UFA= 10x

UFH=10x

FQPA SF= 1x

aRfD = 5 mg/kg/day

aPAD = 5 mg/kg/day

Acute neurotoxicity - rat: LOAEL = 1000 

mg/kg bw based on clinical observations 

(salivation) and decreased motor activity.

Chronic Dietary 

(all populations)

NOAEL= 3.0

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

cRfD = 0.03 mg/kg/day

aPAD = 0.03 mg/kg/day

Chronic toxicity - rats: LOAEL = 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)

NOAEL = 50 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Residential/Occupational

LOC for MOE ≤ 100

Subchronic toxicity - dogs: LOAEL = 50 

mg/kg bw/day based on decreased body-weight 

gain increased urinary excretion of porphyrins.

Dermal (short- and 

intermediate-term)

Dermal risk assessment is not required - No toxicity seen at the limit-dose (1000 mg/kg/day) in a 21-day rat dermal 

toxicity study and low level of concern for developmental effects.

Inhalation (shortand intermediateterm

Oral NOAEL= 50 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Residential/Occupational

LOC for MOE ≤ 100

Subchronic Toxicity Study - dogs: LOAEL = 

50 mg/kg bw/day based on decreased bodyweight gain increased urinary excretion of 

porphyrins.

Cancer (oral, 

dermal, inhalation)Classification: “not likely to be carcinogen;” therefore, a quantitative cancer risk assessment is not necessary. 

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and used to 

mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL 

= no-observed adverse-effect level. LOAEL = lowest-observed adverse-effect level. 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 D389083

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5.0 Dietary Exposure and Risk Assessment

D389976, T. Bloem, 29-Feb-2012 (residue chemistry summary); D389977, T. Bloem, 29-Feb-2012 (dietary exposure)

5.1 Metabolite/Degradate Residue Profile

Nature of the Residue - 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. The following paragraphs are a summary of the residues of concern 

in/on 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); and 

D293779 (T. Bloem, 14-Jul-2004). 

Based on the soybean, wheat, corn, and radish metabolism studies, HED concluded that the 

residues of concern for the registered crops for tolerance enforcement are carfentrazone-ethyl and 

CR-75. Based on the registered foliar application to cereal grain, cotton, and grass and the 

soybean, wheat, and corn metabolism studies, HED concluded that the residues of concern in these 

crops for risk assessment are carfentrazone-ethyl and F8426-ClPAc. Based on the registered soildirected or soil-directed/foliar application for the remaining registered crops and the soybean, 

wheat, corn, and radish metabolism studies, HED concludes that the residues of concern in these 

crops for risk assessment are carfentrazone-ethyl, CR-75, CR-48, 3-OH-F8426-BAc, F8426-BAc, 

and Me-3-OH-F8426-BAc. Residues of CR-48 were included as it was a significant residue in the 

soybean metabolism study (forage and hay). Residues of 3-OH-F8426-BAc, F8426-BAc, and Me3-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-OHF8426-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). 

HED concludes that the available wheat, corn, and soybean metabolism data are sufficient to 

support registration for application to the nongrass animal feed crop group. Based on these data, 

the alfalfa/clover magnitude of the residue data, and the proposed foliar application scenario, the 

residues of concern in the nongrass animal feed crop group for tolerance enforcement are 

carfentrazone-ethyl and CR-75; the residues of concern for risk assessment are carfentrazoneethyl, CR-75, and CR-48. 

Nature of the Residue - Rotational Crops: The existing carfentrazone-ethyl confined rotational 

study (lettuce, radish, and wheat) employed a bare soil application of carfentrazone-ethyl at 0.031 

lb ai/acre (D233587, J. Stokes, 18-Jun-1998). The metabolic profile was similar in all the rotated 

crop commodities analyzed. The major metabolites identified were 3-OH-F8426-BAc, F8426-
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BAc, 3-DM-F8426-BAc, 3-DM-F8426-PAc, and 3-DM-F8426-ClPAc (petitioner indicated that 

demethylation may be a byproduct of sample work-up). 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 concentrations are similar to or greater than the parent 

and the metabolite. 

Nature of the Residue - 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). 

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). 

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, livestock, and fish 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 
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D389083

Page 18 of 33

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. 

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 Metabolites and Degradates to be included in the Risk Assessment/ and Tolerance 

Expression.

1

Matrix Residues of Concern for 

Tolerance Expression

Residues of Concern for 

Risk Assessment

plants

Primary Crop 

(cereal grain, grass, and cotton)

carfentrazone-ethyl and CR-75

carfentrazone-ethyl and CR-75

Primary Crop 

(nongrass animal feed) carfentrazone-ethyl, CR-75, and CR-48

Primary Crop 

(remaining 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 (poultry and ruminant) carfentrazone-ethyl and CR-75 carfentrazone-ethyl and CR-75

fish/shellfish carfentrazone-ethyl and CR-75 carfentrazone-ethyl and CR-75

drinking water carfentrazone-ethyl, CR-75, and 

F8426-CAc --

1 TXR 0012659, J. Stokes, 19-Jun-1998; D303030, T. Bloem, 30-Jun-2004; D389976, T. Bloem, 29-Feb-2012.

5.2 Food Residue Profile

Magnitude of the Residue - Primary Crops: The submitted clover (n=9) and alfalfa (n=9) 

magnitude of the residue trials consisted of separate treated plots for forage/hay and seed. The 

forage and hay treated plots received either a single dormant application, single stubble 

application (application after cutting), or split application (dormant and stubble application). The 

seed plots received a split application (dormant/stubble application and harvest-aid application). 

The forage and hay samples were harvested at several PHIs; all of the seed samples had a PHI of 

3 days. 

Harvest-aid application is proposed for forage, hay, and seed, and based on the application rate 

and PHI, is likely to yield the highest residues (0.06 lb ai/acre, 3-day PHI). However, only the 

seed plots employed both the harvest-aid application rate and PHI. Some of the clover forage/hay 

samples (n=2) were harvested 3 days after application but employed an application rate of 0.04 lb 

ai/acre rather than the proposed 0.06 lb ai/acre rate. The bulk of the clover (n=6) and alfalfa 

(n=9) forage/hay data employed applications at ~0.04 lb ai/acre and PHIs of 20-23 days. 

Therefore, HED concludes that the submitted field trial data support a maximum application rate 

of 0.04 lb ai/acre and a PHI of 21 days for stands grown for forage and hay and a maximum 

application rate of 0.06 lb ai/acre and a PHI of 3 days for stands grown for seed (revised Section 

B is requested). 
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D389083

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The harvested samples were analyzed for residues of carfentrazone-ethyl, CR-75, and CR-48 

using an adequately validated method (storage intervals have also been validated). The clover 

residue-decline data indicated that combined residues of carfentrazone-ethyl, CR-75, and CR-48 

were consistent as the PHI increased from 0 to 7 days. The multiple cutting alfalfa forage/hay 

data indicated that only the first cutting is likely to have quantifiable residues. 

Provided a revised Section B is submitted and based on the existing data and the OECD tolerance 

calculation procedure, HED concludes that the following tolerances are appropriate (revised Section 

F is requested): animal feed, nongrass, crop group 18, forage - 2.0 ppm; animal feed, nongrass, 

crop group 18, hay - 5.0 ppm; and animal feed, nongrass, crop group 18, seed - 15 ppm. The 

current carfentrazone-ethyl enforcement method is appropriate for enforcement of these tolerances. 

Nature/Magnitude of the Residue - Rotational Crops: The proposed labels indicate PBIs of 

anytime to 12 months for several labeled crops and 12 months for all other crops. A field rotational 

crop study has not been submitted. The existing carfentrazone-ethyl confined rotational study 

(lettuce, radish, and wheat) employed a bar-soil application of carfentrazone-ethyl at 0.031 lb 

ai/acre (D233587, J. Stokes, 18-Jun-1998; 0.8x the proposed dormant and in-season rate; 0.5x the 

proposed harvest-aid rate). Combined residues of concern were ≤0.051 ppm for all commodities/

PBIs except wheat straw. In wheat straw, combined residues of concern were ≤0.274 ppm. 

Provided the labels are revised to indicate that following application to the nongrass animal feed 

crop group, only a labeled primary-crop may be planted, HED concludes that the existing rotational 

crop data are sufficient. 

Magnitude of the Residue - Livestock: HED previously recommended for the establishment of 

the following livestock tolerances for the combined residues of carfentrazone-ethyl and CR-75 

(D297216, T. Bloem, 25-May-2004; D328830, T. Bloem, 26-April-2006): meat (cattle, goat, 

horse, sheep, and hog) - 0.10 ppm; meat byproducts (cattle, goat, horse, sheep, and hog) - 0.10 

ppm; fat (cattle, goat, horse, sheep, and hog) - 0.10 ppm; poultry meat byproducts - 0.10 ppm; and 

milk - 0.05 ppm. Based on the current livestock maximum reasonable dietary burdens (MRDBs) 

and the available residue data, HED concludes that the currently-established tolerances are 

appropriate; establishment of additional livestock tolerances is unnecessary. 

5.3 Water Residue Profile

The rice and caneberry application scenarios yield the highest surface water and ground water 

estimated drinking water concentrations (EDWCs) for all proposed/registered uses (including 

cranberry) and are summarized in Table 5.3.1. The surface water EDWCs resulting from the rice 

use were generated using the provisionally modified Tier I Rice Model (D384371, N. Thurman, 

16-Feb-2011); the surface water and ground water EDWCs from the caneberry use were 

generated using the FQPA Index Reservoir Screening Tool (FIRST) and Screening Concentration 

In Ground Water (SCI-GROW) models, respectively (D240937, J. Carleton, 2-Nov-1999). 

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 acute and chronic 

dietary exposure analyses (“water, direct, all sources” and “water, indirect, all sources”). The rice 

EDWCs were generated using regional percent cropped area figures but do not account for 

dissipation processes such as dilution or adsorption to downstream sediments and are considered 

highly conservative. 
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D389083

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Table 5.3.1: EWDCs for Carfentrazon-ethyl.

Drinking Water Source (Model) Application Scenario (Max. Rate; lb ai/acre) Peak (μg/L) Annual Mean (μg/L)

Surface water (Tier I Rice Model) Rice, wild rice (0.20 lbs ai/acre) 126 48

Surface water (FIRST) Caneberries (0.46 lbs ai/acre) 34 19

Ground water (SCI-GROW) Caneberries (0.46 lbs ai/acre) ≤13

5.4 Dietary Assessment

Acute and chronic dietary exposure assessments were conducted using the DEEM-FCIDTM

model, Version 2.03, which incorporates consumption data from USDA’s CSFII, 1994-1996 and 

1998. The 1994-96, 98 data are based on the reported consumption of more than 20,000 

individuals over two non-consecutive survey days. Foods “as consumed” (e.g., apple pie) are 

linked to EPA-defined food commodities (e.g., apples, peeled fruit - cooked; fresh or N/S; baked; 

or wheat flour - cooked; fresh or N/S, baked) using publicly available recipe translation files 

developed jointly by USDA/ARS and EPA. For chronic exposure assessment, consumption data 

are averaged for the entire U.S. population and within population subgroups, but for acute 

exposure assessment are retained as individual consumption events. Based on analysis of the 

1994-96, 98 CSFII consumption data, which took into account dietary patterns and survey 

respondents, HED concluded that it is most appropriate to report risk for the following 

population subgroups: the general U.S. population, all infants (<1 year old), children 1-2, 

children 3-5, children 6-12, youth 13-19, adults 20-49, females 13-49, and adults 50+ years old.

The acute and chronic analyses 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. 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 acute (≤1% aPAD; all infants (<1 year old) were the most highly exposed subgroup) 

and chronic (≤69% cPAD; children 1-2 years old were the most highly exposed subgroup) 

exposure estimates do not exceed HED’s LOC. Table 5.4.1 is a summary of the acute and 

chronic dietary exposure and risk estimates. 

Table 5.4.1: Summary of the Acute and Chronic Dietary Exposure and Risk.

Population aPAD 

(mg/kg/day)

Exposure 

(mg/kg/day)1 %aPAD cPAD (mg/kg/day)

Exposure 

(mg/kg/day) %cPAD

General U.S. Population

5

0.021373 <1

0.03

0.007467 25

All Infants (< 1 year old) 0.046931 1 0.016039 54

Children 1-2 years old 0.045058 1 0.020687 69

Children 3-5 years old 0.036002 1 0.016403 55

Children 6-12 years old 0.023444 <1 0.010107 34

Youth 13-19 years old 0.015886 <1 0.006123 20

Adults 20-49 years old 0.014991 <1 0.005893 20

Adults 50+ years old 0.014329 <1 0.005926 20

Females 13-49 years old 0.014848 <1 0.005778 19

1

 95th percentile (tier 1 analysis)
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D389083

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6.0 Residential (Non-occupational) Exposure/Risk Characterization

D89978, L. Venkateshwara, 29-Feb-2012 (turf); D296322, T. Bloem et al., 21-Jul-2004 (aquatic use)

The proposed application scenario to the nongrass animal feed crop group 18 will not result in 

residential exposure. However, an EC (EPA Reg. No. 279-3279) carfentrazone-ethyl formulation is 

currently registered for aquatic application (0.2 lb ai/surface acre) and EC (EPA. Reg. No. 279-8383)

and dry flowable (DF; EPA. Reg. No. 2217-832) formulations are currently registered for 

application to turf (including golf courses and residential lawns; 0.03-0.04 lb ai/acre). The 

paragraphs below are summaries of the residential handler and post-application exposure/risk from 

these uses. 

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. It is the policy of HED to use the best available data to assess residential exposure; 

therefore, 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 Dose4

(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
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D389083

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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 Dose4

(mg/kg/day) 

Baseline 

MOE5

Inhalation Inhalation Inhalation

Mixing/Loading/Applying EC 

with Backpack Sprayer 0.04 0.023 0.14 1.6E-06 31,000,000

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 SOP 

for Residential Exposure Assessments (Draft; 17-Dec-1997; pages 52 -57) and modified in 

HED’s SWIMODEL V 1.0 (W. Dang et al., 27-Mar-1999). Dermal risk assessments were not 

conducted because no hazard was identified via the dermal route for the relevant exposure 

durations. The assessment assumed an exposure duration of 2 hours/day and an ingestion rate of 

0.05 liters/hour. 

Short-term incidental-oral and inhalation MOEs are ≥100,000 and, therefore, do not exceed 

HED’s LOC (see Table 6.2.1). 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 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: Short-Term Residential Post-app. Risk Estimates for Carfentrazone-Ethyl for Swimmers1

Lifestage

Aquatic Dose (mg/kg/day)

Incidental Oral MOEs2Inhalation MOEs2

Incidental Oral1Inhalation1

Child 3 <6 year old 0.0004905 1.36 x 10-13 100,000 3.67 x 1014

Child (6 year) 0.0002539 7.06 x 10-13 200,000 7.08x 1013

Adult 0.0001051 4.14 x 10-13 480,000 1.2 x 1014

1 Source: July 2006 Risk Assessment (D296322, T. Bloem et al., 21-Jul-2004)

2 Calculated MOE = NOAEL (50 mg/kg/day) ÷ daily dose (mg/kg/day). LOC for MOEs ≤100.
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D389083

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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 

sceanrio) 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). 

It is the policy of HED to use the best available data to assess residential exposure; therefore, 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 Combined Exposure Risk Assessments

HED combines exposure/risk estimates from the different pathways (dermal, inhalation, incidental 

oral) when it is likely they can occur simultaneously based on the use pattern and the behavior 

associated with the exposed population and when the toxicological effects are similar. HED reviewed 

all residential sources of exposure to determine which residential exposure scenarios would be 

appropriate to combine.

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, HED 

selected the most conservative combined adult residential scenario, post-application exposure for the 

aquatic exposure scenario (combined incidental oral and inhalation MOE = 480,000), as the 

contributing source of adult residential exposure (see Table 6.3.1).

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. Therefore, HED selected the most conservative combined 

child residential scenario, post-application exposure to treated turf (incidental oral MOE = 84,000), as 

the contributing source of child residential exposure (see Table 6.3.1)
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D389083

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Table 6.3.1: Short-Term Residential Exposures for Carfentrazone-ethyl - Combined Residential Risk Calculations.1

Population

Handler Exposure 

(mg/kg/day)2

Handler Total 

Exposure 

(mg/kg/day)

Handler 

Total MOE

Post-application Exposure 

(mg/kg/day)3

Post-app. Total 

Exposure 

(mg/kg/day)

Post-app.

Total MOE

Dermal Inhalation Dermal Inhalation Oral

Adult -turf N/A 9.5 x 10-6 9.5 x 10-6

5,300,000 N/A

Adult - aquatic N/A N/A 4.14 x 10-13 1.05 x 10-4

1.05 x 10-4480,000

Child 1<2 years old -turf N/A N/A 0.0006 0.0006 84,000

Child- aquatic N/A N/A 7.06 x 10-13 2.54 x 10-4

2.54 x 10-4200,000

1 Bolded values chosen as contributing source of residential exposure for aggregate assessment (see Section 7.0).

2 Handler exposure represents high-end inhalation handler exposure, where the exposure duration is appropriate to assess.

3

Postapplication exposure represents high-end incidental oral exposure for the relevant exposure duration.

6.4 Residential Bystander/Post-application Inhalation Exposure

Based on the Agency's current practices, a quantitative residential bystander post-application 

inhalation exposure assessment was not performed for carfentrazone-ethyl. However, 

volatilization of pesticides may be a potential source of post-application inhalation exposure to 

individuals nearby to 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. The Agency received the SAP’s final report 

on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The 

Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate post-application 

inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into 

place, the Agency may revisit the need for a quantitative post-application inhalation exposure 

assessment for carfentrazone-ethyl.

6.5 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for carfentrazoneethyl. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices 

and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices (see the Agency’s Spray Drift website for more information at 

http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical-by-chemical basis, the 

Agency is now requiring interim mitigation measures for aerial applications that must be placed 

on product labels/labeling. The Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is 

developing a policy on how to appropriately apply the data and the AgDRIFT® computer model 

to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic 

methods. After the policy is in place, the Agency may impose further refinements in spray drift 

management practices to reduce off-target drift with specific products with significant risks 

associated with drift.

Although a quantitative residential post-application inhalation exposure assessment was not 

performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation 

exposure assessment was performed for flaggers. This exposure scenario is representative of a 

worse case inhalation (drift) exposure and may be considered protective of most outdoor 

agricultural and commercial post-application inhalation exposure scenarios.
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D389083

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7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

risks from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure.

Based on the proposed/registered uses, aggregate acute (food and water), short-term (food, water, 

inhalation, and/or incidental oral) and chronic (food and water) 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 short-term risk assessment is protective of intermediate-term exposure. 

7.1 Acute Aggregate Risk

Acute aggregate risk concerns only dietary exposure (food and water). The acute dietary risk 

estimates are ≤1% aPAD and, therefore, do not exceed HED’s LOC (see Section 5.4). 

7.2 Short-Term Aggregate Risk

For adults and the general U.S. population, the short-term aggregate risk assessment combined 

chronic dietary exposure with residential post-application incidental oral and post-application 

inhalation exposures from the aquatic 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 exposure estimates and populations included in the 

short-term aggregate assessment are protective of all potential short-term exposures. The 

resulting aggregate MOEs are ≥2,300 and, therefore, do not exceed HED’s LOC (see Table 

7.2.1). 

Table 7.2.1: Short-Term Aggregate Risk Estimates. 

Population LOC

Exposure (mg/kg/day)

Total MOE3

Dietary1Inhalation2Incidental-oral2

General U.S. Population

MOE <100

0.007467 4.14 x 10-13 1.05 x 10-46,600

Children (1-2 years old) 0.020687 N/A 0.0006 2,300

1

 See Table 5.4.1 for exposures.

2

 See Table 6.3.1 for exposures.

3

 Total MOE = 50 mg/kg/day (NOAEL) ÷ (dietary exposure + inhalation exposure + incidental-oral exposure).

7.3 Chronic Aggregate Risk

Chronic aggregate risk concerns only dietary exposure (food and water). The chronic dietary 

risk estimates are ≤69% cPAD and, therefore, do not exceed HED’s LOC (see Section 5.4). 
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D389083

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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/Risk Characterization

D389978, L. Venkateshwara, 29-Feb-2012

9.1 Occupational Handler Exposure/Risk

Potential occupational exposure scenarios include: 1) mixing/loading liquids in support of aerial 

and groundboom applications; 2) mixing/loading water-dispersible granules (WDG) in support 

of aerial and groundboom applications; 3) aerial applicators; 4) applicators using open-cab 

ground boom equipment; and 5) flaggers. Only inhalation risk assessments were conducted as 

no hazard was identified via the dermal route for the relevant exposure durations (assessment 

assumed 80-kg body weight). Exposures are expected to be short-term since there is only one 

application per season. It is noted that the short-/intermediate-term inhalation PODs are the 

same and assessing short-term exposure is protective of intermediate-term exposure. Long-term 

exposures are not expected.

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 the 

PHED (Version 1.1), AHETF database, ORETF database, or other registrant-submitted 

occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject 

to the data protection provisions of FIFRA. The standard values recommended for use in 

predicting 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/handler-exposure-table.pdf), which, along with additional 

information on HED policy on use of surrogate data, including descriptions of the various sources, 

can be found at http://www.epa.gov/pesticides/science/handler-exposure-data.html.

For pesticide handlers, it is HED’s standard practice to present exposure estimated for “baseline” 

that is, for workers wearing a single layer of work clothing consisting of a long-sleeved shirt, 

long pants, shoes plus socks and no protective gloves, as well as for “baseline” and the use of

protective gloves or other personal-protective equipment (PPE) as might be necessary. All four 

labels require long-sleeved shirt and long pants, waterproof gloves, and shoes plus socks. Table 

9.1.1 provides a summary of the estimated exposures and risks to occupational pesticide 

handlers. All inhalation MOEs with baseline protection (no respirator) are >100 and are,

therefore, not of concern to HED. 
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D389083

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Table 9.1.1: Short-/Intermediate-term Exposure & Risk to Occupational Handlers from Application of Carfentrazoneethyl to the Nongrass Animal Feed Crop Group 18.

Crop or Target Unit Exposure1

mg ai/lb handled

App. Rate2

lb ai/A

Units Treated3

A/day

Avg. Daily Dose4

mg ai/kg bw/day

MOEs5Short- and Intermediateterm

Mixer/Loader - Liquids - Aerial Applications

Nongrass animal feed Inhal.

Baseline: 0.00022 0.06 350 Inhal.Baseline: 0.000057

Inhal. Baseline:

870,000

Mixer/Loader - Liquids - Groundboom Applications

Nongrass animal feed Inhal.

Baseline: 0.00022 0.06 80 Inhal:Baseline: 0.000013

Inhal. Baseline:

3,800,000

Mixer/Loader - Water-dispersible Granules - Groundboom Applications

Nongrass animal feed Inhal.

Baseline: 0.00896 0.06 80 Inhal:Baseline: 0.0005

Inhal. Baseline:

93,000

Mixer/Loader - Water-dispersible Granules - Aerial Applications

Nongrass animal feed Inhal.

Baseline: 0.00896 0.06 350 Inhal.Baseline: 0.0024

Inhal. Baseline:

21,000

Applying Sprays via Aerial Equipment

Nongrass animal feed Inhal.

Eng. Cont: 0.000068 0.06 350 Inhal.Eng. Cont: 0.000018

Inhal. Eng. Cont:

280,000

Applying Sprays via Groundboom Equipment

Nongrass animal feed Inhal.

Baseline: 0.00034 0.06 80 Inhal.Baseline: 0.0000026

Inhal. Baseline:

2,500,000

Flagger

Nongrass animal feed Inhal.

Baseline: 0.00035 0.06 350 Inhal.Baseline: 0.0000018

Inhal. Baseline:

81,000

1

 Unit Exposures are taken from “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” September 26, 2011. 

Inhal. = Inhalation. 

2

 App. Rate. = Taken from Aim, Aim EC, Aim EW, and Spartan Charge labels. 

3

 Amount handled per day values are HED estimates of acres treated per day based on Exposure SAC SOP #9 “Standard Values for 

Daily Acres Treated in Agriculture,” industry sources, and HED estimates.

4

 Average Daily Dose = Unit Exposure * Application Rate * Units Treated 80 kg Body Weight. 

5

 MOE = Margin of Exposure = NOAEL ADD. NOAEL = 50 mg/kg/day (short-/intermediate-term inhalation).

6 Baseline = no respirator (inhalation)

9.2 Post-application Exposure/Risk

Dermal: Dermal risk assessments were not conducted because no hazard was identified via the 

dermal route for the relevant exposure durations.

Inhalation: Based on the Agency's current practices, a quantitative occupational postapplication inhalation exposure assessment has not been performed for carfentrazone-ethyl. 

However, there are multiple potential sources of post-application inhalation exposure to 

individuals performing post-application activities in previously treated fields. These potential 

sources include volatilization of pesticides and resuspension of dusts and/or particulates that 

contain pesticides. The Agency sought expert advice and input on issues related to volatilization 

of pesticides from its FIFRA SAP in December 2009. The Agency received the SAP’s final 

report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). 

The Agency is in the process of evaluating the SAP report as well as available postapplication 

inhalation exposure data generated by the Agricultural Reentry Task Force and may, as 

appropriate, develop policies and procedures, to identify the need for and, subsequently, the way 

to incorporate occupational post-application inhalation exposure into the Agency's risk 

assessments. If new policies or procedures are put into place, the Agency may revisit the need 

for a quantitative occupational post-application inhalation exposure assessment for 

carfentrazone-ethyl.
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D389083

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REI: Carfentrazone-ethyl is classified as Toxicity Category 3 for acute dermal and Toxicity 

Category 4 for 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 a REI of 12 hours. 

10.0 References

●occupational/residential exposure: D389978, L. Venkateshwara, 29-Feb-2012; D296322, T. 

Bloem et al., 21-Jul-2004

●dietary exposure: D389977, T. Bloem, 29-Feb-2012

●residue chemistry: D389976, T. Bloem, 29-Feb-2012

●residue chemistry: D271468, T. Bloem, 9-Jan-2001

●residue chemistry: D303030, T. Bloem, 30-Jan-2004

●residue chemistry: D293779, T. Bloem, 14-Jul-2004

●human-health scoping document: D382666, K. Lowe et al., 17-Dec-2010

Attachment 1: Chemical Names and Structures.

Attachment 2: Spirodiclofen Toxicity Profile.

RDI: RAB1 (22-Feb-2012)

T. Bloem:S10945:Potomac Yard 1: 703-605-0217:7509P:RAB1
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D389083

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Attachment 1: Chemical Structures

Common name /code Chemical name Chemical structure

carfentrazone-ethyl

F8426

ethyl- ,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

,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; CR-48

,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

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 D389083

Page 30 of 33

Attachment 2: Spirodiclofen Toxicity Profile.

Acute Toxicity Profile for Carfentrazone-Ethyl.

Guideline Study Type MRID Results Toxicity Category

81-1 Acute Oral-Rat 43189027 LD50 >5000 mg/kg 4

81-2 Acute Dermal-Rat 43189209 LD50 >4000 mg/kg 3

81-3 Acute Inhalation- Rat 43189211 LC50 >5.09 mg/L 4

81-4 Primary Eye Irritation-Rabbit 43189213 Minimum eye irritant 4

81-5 Primary Skin Irritation-Rabbit 43189215 Non-irritant 4

81-6 Dermal Sensitization-Guinea pig 43189217 Not a skin sensitizer N/A

Subchronic, Chronic and Other Toxicity Profile

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 

(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 

(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 

(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

870.3700a Prenatal developmental 

in (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.
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D389083

Page 31 of 33

Subchronic, Chronic and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ 

Classification /Doses Results

870.3700b Prenatal developmental 

in (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 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 hepatoxicity.

no evidence of carcinogenicity

870.4300

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

Mutagenicity, Gene 

Mutation-Microbial 

System

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.

870.5100

Mutagenicity, Gene 

Mutation-Microbial 

System

43829712 (1995)

Acceptable

No indication that the test material induced a 

mutagenic effect at any dose with or without S9 

activation.

870.5100

Mutagenicity, Gene 

Mutation-Microbial 

System

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 induced a mutagenic effect at any 

dose with or without S9 activation. 

870.5100

Mutagenicity, Gene 

Mutation-Microbial 

System

44165028 (1995)

Acceptable

[Formulation Tested]

There was no indication that the test material induced a 

mutagenic effect at any dose with or without S9 

activation.
Carfentrazone-ethyl (128712) Human-Health Risk Assessment D389083

Page 32 of 33

Subchronic, Chronic and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ 

Classification /Doses Results

870.5100

Mutagenicity, Gene 

Mutation-Microbial 

System

44165029 (1996)

Acceptable

[Formulation Tested]

There was no indication that the test material induced a 

mutagenic effect at any dose with or without activation.

870.5100

Mutagenicity, Gene 

Mutation-Microbial 

System

44165030 (1996)

Acceptable

[Formulation Tested]

There was no indication that the test material induced a 

mutagenic effect at any dose with or without activation.

870.5300

Mutagenicity, Gene 

Mutation-Mammalian 

Cells

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

Mutagenicity, 

Chromosomal 

Aberration-In vitro

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.

Gene Mutation

870.5395

Mutagenicity, 

Chromosomal 

Aberration – In Vivo

43189224

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.

Non-Guideline

Mutagenicity, Other 

Mutagenic Mechanisms 

- In Vivo/In Vitro

43829713 (1994)

Acceptable

There was no evidence that the test material induced a 

genotoxic response at any dose or sacrifice time.

870.6200a Acute neurotoxicity 

screening battery

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

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 D389083

Page 33 of 33

Subchronic, Chronic and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ 

Classification /Doses Results

870.7485

Metabolism and 

pharmacokinetics

(rat)

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-

hydroxymethyl-F8426-propionic acid [1.73 to 5.83%] 

and F8426-cinnamic acid [0.34 to 1.50%]. In addition,

minute quantities of 3-hydroxy-F8426-cinnamic acid 

and F8426-propionic acid were found in the urine, but 

the levels were too low to quantify. Extensive 

metabolism was indicated by only a small amount of 

the parent (0.06 to 2.78%) found in the feces; no parent 

was found in the urine by 48 hours. A variety of polar 

and non-polar 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.