Carfentrazone - ethyl (128712) Human - Health Risk Assessment D 389083

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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 human health risk assess ment for carfentrazone - ethyl w as 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 carfe ntrazone - ethyl and CR - 75 ( α ,2 - dichloro - 5 - [4 - (difluoromethyl) - 4,5 - dihydro - 3 - methyl - 5 - oxo - 1 H - 1,2,4 - triazol - 1 - yl] - 4 - fluorobenzenepropanoic acid): 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 evaluatio n. 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 ra t. 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 excr etion, 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 increase d urinary porph yrin 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 ra ts and mice. There was no evidence of increased susceptibility in prenatal developmental toxicity studies (rats and rabbits) or the multigeneration al 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 th e highest dose tested (300 mg/kg/day). The offspring effects from the 2 - generation reproduction study consisted of decreased pup bodyCarfentrazone - ethyl (128712) Human - Health Risk Assessment D 389083

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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 ob served in the form of decreased body - weight gain s, increased liver weights, liver and bile duct histopathology, and reductions in the mean cell volume (F 0 

### and F 1 

### males, F 1 

### females), mean cell hemoglobin (F 0 

### and F 1 

### males, F 1 

### females), hematocrit (F 1 

### males), and hemoglobin (F 1 

### 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 sho wed 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 , ” b ased on the lack of evidence for carcinogenicity in the mouse and rat ; t herefore, 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 sho rt - /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 - /interme diate term inhalation and incidental oral exposure, exposure via these routes can be aggregated. For the following reasons, t he risk assessment team recommends that the FQPA SF may be reduced to 1x for all exposure scenarios: (1) B ased on the results of the rat / rabbit prenatal developmental toxicity studies and the rat 2 - generation reproductive toxicity study , t here is no evidence of increased pre - and/or postnatal susceptibility and t here are no residual uncertainties with respect to pre - or postnatal susceptibility ; (2) A lthough an immunotoxicity study is currently lacking in the toxicity database for ca r fentrazone - ethyl, there is no evidence in the current database that the immune system organs are directly affected followi ng carfentrazone - ethyl expo sure; (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 underestim ate 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 cr op 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 forCarfentrazone - ethyl (128712) Human - Health Risk Assessment D 389083

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### the residues of concern for risk assessment, 100% crop treated, and modeled drinking water estimates. Sinc e 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) defau lt 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 population adjusted 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 Procedure s ( SOP s ; 2012) and residential exposure resulting from the a quatic use were assess ed 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 f r om the turf use and short - term incidental oral and inhalation exposure from the aquatic use (adult and children; post application) . Dermal risk assessments w ere 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 r isk assessment is protective of intermediate - term exposure. The resulting combined margins of exposure ( M OE s ) were ≥ 84,000 and are not of concer n 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 sho rt - 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). TheCarfentrazone - ethyl (128712) Human - Health Risk Assessment D 389083

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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 exposure s are expected to be short - term ( only one application per season ) . However, i t 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 expe cted. 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 assessment s were conducted using generic handler data as a surrogate . The “baseline” ( long - sleeved shirt, long pants, shoes plus socks , and no protective gloves) MOE s 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 E ntry 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 Pr otection 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 Low Income 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 pat terns 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 todd lers, 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 consi der 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 b ioaccumulative toxic (PBT) compound , it is registered for aquatic application with f ish/shellfish tolerances established (0.30 ppm) . For the following reasons, HED concludes that exposure to car fentrazone - ethyl as a result of s ubs istence fishing is not of concern : (1) dietary analyses assumed tolerance level res idues a ndCarfentrazone - ethyl (128712) Human - Health Risk Assessment D 389083

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### 100% crop treated with the resulting exposure estimates less than HED’s LOC (≤1% aPAD (95 th 

### percentile ) ; ≤69% cPAD) ; (2) acute exposure at the 99.9 th 

### 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 Agricul tural 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 (Spart an 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 database s support a n un conditional Section 3 registration and establishment of the tolerance s 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 nongra ss 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 th an 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 d atabase s . The o nly toxicological database deficiency i s 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 requiremen t for carfentrazone - ethyl.Carfentrazone - ethyl (128712) Human - Health Risk Assessment D 389083

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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 H

armonization: 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 tolerance s 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 tolerance s 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 li sted 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 - 1 H - 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 - 1 H - 1,2,4 - triazol - 1 - yl] - 4 - fluorobenzenepropanoic acid), calculated as the stoichiometric equivalent of carfentrazone - ethyl , in or on th e 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 toleran ces were appropriate. The HED - r ecommended 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 conclude s that crop group tolerances ar e 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.Carfentrazone - ethyl (128712) Human - Health Risk Assessment D 389083

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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 plan t 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 app lication scenario. Based on the available field tr i al 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 gr own 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 Form ulation 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 s uspension c oncentrate and c oncentrated a queous e mulsion ; 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 a i /acre) Max. Seasonal App.

Rate (lb a i /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)Carfentrazone - ethyl (128712) Human - Health Risk Assessment D 389083

Page 10 of 33 Table 3.1.2 : Summary of Proposed Application Scenario for Carfentrazone - ethyl. Formulation (EPA Reg. No.) App. Timing App. Rate (lb a i /acre) Max. Seasonal App.

Rate (lb a i /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 AI M 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

Common name carfentrazone - ethyl Company experimental name F8426 IUPAC name ethyl ( RS ) - 2 - chloro - 3 - {2 - chloro - 5 - [4 - (difluoromethyl) - 4,5 - dihydro - 3 - methyl - 5 - oxo - 1 H - 1,2,4 - triazol - 1 - yl] - 4 - fluorophenyl}propionic acid CAS name ethyl α,2 - dichloro - 5 - [4 - (difluoromethyl) - 4,5 - dihydro - 3 - methyl - 5 - oxo - 1 H - 1,2,4 - triazol - 1 - yl] - 4 - fluorobenzenepropanoic acid CAS # 128639 - 02 - 1 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 (pK a ) no dissociation constant Octanol/water partition coefficient Log(K OW ) log K ow = 3.36 UV/visible absorption spectrum not availableCarfentrazone - ethyl (128712) Human - Health Risk Assessment D 389083

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### 4 .0 Hazard Characterization/Assessment T he 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 carfentra zone - ethyl are consistent with PPO inhibition. 4. 1 Toxicity Studies Available for Analys is 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 human health assessment scoping document submitted i n 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 ev aluate 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 ca rfentrazone - 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 de termine 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 fo r 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 toxicol ogical 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 u rine 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 metabolite s 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 appe ared 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 D 389083

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### Dechlorination of CR - 75 formed F8426 - PAc, and hy droxylation 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 [MC H] 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 . Si milarly, chronic toxicity studies in rats and dogs demonstrated increase d urinary porphyrin excretion and liver histopathology findings in rats and mice consisting of liver pigmentation and increases in red fluorescence. Fluorescence microscopy on liver s ections 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 multigeneration al reproductive toxi city 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 tes ted (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 for m of decreased body - weight gain s, increased liver weights, liver and bile duct histopathology, and reductions in the mean cell volume (F 0 

### and F 1 

### males, F 1 

### females), mean cell hemoglobin (F 0 

### and F 1 

### males, F 1 

### females), hematocrit (F 1 

### males), and hemoglobin (F 1 

### 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 neurotoxi city 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 100 0 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 withCarfentrazone - ethyl (128712) Human - Health Risk Assessment D 389083

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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 ; t herefore, a qua ntitative 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 carfentrazone ethyl is adequate for evaluation . Although an immunotoxicity study is currently lacking, it is u nlikely 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) d evelopmental toxicity study in rats and rabbits ; (2) t wo generation reproduction study in rats ; and (3) a cute 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 neurotoxi city 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 t oxicity study . A significant increase in litter incidences of wavy and thickened ribs was observed in rats a t 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 interfere nce 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 reprod uctive 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 Database s : The exposure databases are sufficient to determine the nature/magnitude of the residue in food and water. The d ietary exposure analyses are unlikely to underestimate exposure as they incorporated t olerance - level residues or tolerance level residues adjusted to account for the residues of concern for risk assessment, 100% crop treated, and modeled drinking water estimates . The residential exposure assessm ent uses HED’s Residential SOPs, assumes maximum application rates, and is considered health - protective.Carfentrazone - ethyl (128712) Human - Health Risk Assessment D 389083

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### 4.6 Toxicity Endpoint Selection and P OD s 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 vi a 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 (sal ivation 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 whi ch the developmental effects of increase d 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 N OAEL 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 (10 x ) and intraspecies (10 x ) extrapolation . The FQPA SF was reduced to 1x (see above). T hus, 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 selec ted 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 fluores cence 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 (10 x ) and intraspecies (10 x ) extrapolation . T he FQPA SF was reduced to 1x (see above). Thus, the cRfD and c PAD 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, urinar y 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 (10 x ) and intraspecies (10 x ) 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 w ere not selected for assessing potential risks from exposure via this route. No dermal or systemic toxicity was seen at the l imit d ose (1000 mg/kg/day) following repeated dermal applications to rats for 21 days. There is no concern for developmental or repr oductive 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/ k g/ d ay) caused no adverse effects on reproduction and only decreases in body - weight gain in the offspring.Carfentrazone - ethyl (128712) Human - Health Risk Assessment D 389083

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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 (10 x ) and intraspecies (10 x ) 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 “n ot likely to be carcinogenic” based on the lack of evidence for c arcinogenicity in mice and rats ; t herefore, a quantitative cancer risk assessment is not necessary . Table 4 .6.1 : Summary of Toxicological Doses and Endpoints for Carfentr a zone - Ethyl for Use in Dietary , Non Occupational , and Occupational Human Health Risk Assessments . Exposure/ Scenario P OD Uncertainty Factors / FQPA SF RfD, PAD, L OC for Risk

Assessment Study and Toxicological Effects Acute Dietary (all populations) NOAEL= 500

mg/kg bw UF A = 10x

UF H =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 UF A = 10x

UF H =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 UF A = 10x

UF H =10x FQPA SF= 1x Residential /Occupational

LOC for MOE ≤ 100 Subchronic t oxicity - d ogs : 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 (short and i ntermediate t erm Oral NOAEL= 50

mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x Residential /Occupational

LOC for MOE ≤ 100 Subchronic Toxicity Study - dogs: LOAEL = 50 mg/kg bw/day based on decreased body weight gain increased urinary excretion of porphyrins . Cancer (oral, dermal, inhalation) Classification: “n ot likely to be carcinogen ; ” t herefore, 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 releva nt human exposures. NOAEL = no - observed adverse - effect level. LOAEL = lowest - observed adverse - effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA S afety 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 D 389083

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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 carfen trazone - 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 conclude d that the metabolic pathway in radish is similar to that for wheat, corn, and soybean. The following paragraph s 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 residue s of concern for the registered crops for tolerance enforcement are carfentrazone - ethyl and CR - 75. Based on the regi stered 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 registere d soil directed 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 Me 3 - OH - F8426 - BAc were included for th e following reasons: (1) soil - directed applications are proposed; (2) these compounds were identified in significant concentrations in the radish metabolism study and/or confined rotational crop study; and (3) detectable residues of 3 - OH F8426 - BAc were found in those field trials in which it was monitored (sugarcane and field pea hay; monitored in pea and bean but not detected). 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 propose d 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 carfentrazone ethyl, CR - 75, and CR - 48. Nature of t

he 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 wa s similar in all the rotated crop commodities analyzed. The major metabolites identified were 3 - OH - F8426 - BAc, F8426 -Carfentrazone - ethyl (128712) Human - Health Risk Assessment D 389083

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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. Sto kes, 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 all ylic 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 - U 14 

### C]carfentrazone - ethyl at 1 6 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 purpo ses 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 CR 75 which subsequently breaks down to F8426 - CAc , F8426 - PAc , F8426 - BAc , and 3 - OH - F8426 - BAc at slower rates than the parent compound. No aerobic or anaerobic aquatic laboratory data were available to evaluate the degradation of carfentrazone - ethyl in water. However , an aquatic field dissipation stu dy 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 an a erobic 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 rap id 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 F84 26 - CAc (MARC decision document, TXR 0012659, J. Stokes, 19 - Jun - 1998). 5. 1.1 Comparison of M etabolic Profiles Section 4.2 includes a sum mary of the metabolism of carfentrazone - ethyl in the rat ; Section 5.1 inc l udes a discussion of the metab olism of carfentrazone - ethyl in plants, livestock, and fish as well as the environmental degradation of carfentrazone - ethyl. Based on the se data, the metaboli sm/ degradation of carfentrazone - ethyl in rats, primary crops, rotational crops, livestock, fish, andCarfentrazone - ethyl (128712) Human - Health Risk Assessment D 389083

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### drinking water are similar . C arfentrazone - ethyl is initially hydrolyzed to CR - 75 which is then dehalogenated to F8426 - PAc o r 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 r egistered 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 a nd 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 y ield 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 r ate 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 application s 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 D 389083

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### The ha rvested 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, fora ge - 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 R esidue - 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. P rovided the labels are revised to indicate that following application to the nongrass animal feed cr op 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 liv estock 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 curr ently - 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 G ro und Water (SCI - GROW) models, respectively ( D240937, J. Carleton, 2 - Nov - 1999) . Additional information concerning these m odels 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 D 389083

Page 20 of 33 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 - FCID TM 

### 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., a pple 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 chro nic 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, chil dren 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% a PAD; 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 dieta ry 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 95 th percentile (tier 1 analysis)Carfentrazone - ethyl (128712) Human - Health Risk Assessment D 389083

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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 Handle r 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) a pplicators and/or licenses (certified for aquatic pest control) that are authorized by the State or local governments. Therefore, assessment of residential handler exposure fr om the aquatic application scenario is unnecessar y . Turf Application Scenario: Homeowner application to turf is permitted (EC and DF formulations; 0.03 - 0.04 lb ai/acre). D ue to the infrequent use patterns associated with homeowner products , r esidential 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 SOP s (2012) . Homeowner handlers assessments a re based on the assumption tha t all task s 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 follo wing 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) . D ermal ris k 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

Exposures 3 (mg/lb ai) Baseline Dose 4 (mg/kg/day) Baseline

MOE 5 Inhalation Inhalation Inhalation Mixer/Loader/Applicator Mixing/Loading/Applying DF with Manually - pressurized Handwand 0.03 0.023 1.1 9.5E - 06 5,300,000 Mixing/Loading/Applying DF with Backpack Sprayer 0.03 0.023 1.1 9.5E - 06 5,300,000 Mixing/Loading/Applying DF with Hose end sprayer 0.03 0.5 0.022 4.2E - 06 12,000,000 Mixing/Loading/Applying DF with Sprinkler Can 0.03 0.023 0.022 1.9E - 07 260,000,000 Mixing/Loading/Applying EC with Manually - pressurized Handwand 0.04 0.023 0.018 2.1E - 07 240,000,000Carfentrazone - ethyl (128712) Human - Health Risk Assessment D 389083

Page 22 of 33 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

Exposures 3 (mg/lb ai) Baseline Dose 4 (mg/kg/day) Baseline

MOE 5 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 S OP s for Residential Pesticide Exposure Assessment; Lawns/Turf (January 2012). 3 Baseline Inhalation: no respirator. 4 Dose (mg/kg/day) = daily unit exposure (mg/lb ai) x application rate (lb ai/ acre ) x acres treated ÷ body weight (80 kg). 5 MOE = NOAEL (50 mg/kg/day) ÷ daily dose (mg/kg/day). LOC for MOEs < 100. 

### 6 .2 Residential Post - application Exposure and Risk Aquatic Application: While HED believes it is improbable that swimmers would recreationally utilize water where large amounts of floating aquatic vegetation occurs, there is no restriction on the label prohibiting recreational use of treated water bodies. Therefore, HED conducted a swimmer exposure assessment (short - term incidental oral and inhalation ) based on HED’s SOP for R esidential Exposure Assessments ( Draft ; 17 - Dec - 1997 ; pages 52 - 57 ) and modified in HED’s SWIMODEL V 1.0 ( W. D ang 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 liter s/hour. Short - term incidental - oral and inhalation MOEs are ≥100,000 and, therefore, do not e xceed 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, a lthough 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 re levant short - /intermediate - term PODs are the same. Table 6.2.1 : Short - Term Residential Post - app . Risk Estimates for Carfentrazone - Ethyl for Swimmers 1 Lifestage Aquatic Dose (mg/kg/day) Incidental Oral MOEs 2 Inhalation MOEs 2

Incidental Oral 1 Inhalation 1 Child 3 <6 year old 0.0004905 1.36 x 10 - 13 10 0 ,000 3.67 x 10 14 Child (6 year) 0.0002539 7.06 x 10 - 13 200 , 0 00 7.08x 10 13 Adult 0.0001051 4.14 x 10 - 13 4 80 , 0 00 1.2 x 10 14 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). L OC for MOEs ≤100.Carfentrazone - ethyl (128712) Human - Health Risk Assessment D 389083

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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 potenti ally exposed lifestages. In addition, a lthough HED does not anticipate intermediate - term post application exposure from the turf application scenario, the short - term risk assessment is protective of intermediate - term exposure as the relevant short - /interm ediate - term PODs are the same. Table 6. 2. 2 : Short - Term Residential Post - application Exposure and Risk Estimates for Carfentrazone - Ethyl. Life S tage Scenario Post - application Exposure Scenario Dose (mg/kg/day) Short - term MOEs 1 Child 1 < 2 year old Turf - sprays Hand to Mouth 0.0 006 84,000 Object to Mouth 0.000 02 2,70 0,000 Incidental Soil Ingestion 1.3 x 10 - 6 38,000 ,000 1 MOE = NOAEL/ d ose; 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 w hen 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 combine d 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 - applicati on exposures to children from the use on turf and in aquatic areas. Although the incidental oral exposures from the turf application scenario (i.e., hand - to - mouth, object to - mouth, and soil ingestion) are inter - related and it is likely that they occur int erspersed 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 ex posure 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 ex posure (see Table 6.3.1)Carfentrazone - ethyl (128712) Human - Health Risk Assessment D 389083

Page 24 of 33 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 - 4 480,000 Child 1<2 years old - turf N/A N/A 0.0 006 0.0 006 84,0 00 Child - aquatic N/A N/A 7.06 x 10 - 13 2.54 x 10 - 4 2.54 x 10 - 4 200,000 1 B olded 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 B ased 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 p otential 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 A ct 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 appr opriate, 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 carfentrazone ethyl. 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. pes ticide 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 A gency 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 w as 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 con sidered protective of most outdoor agricultural and commercial post - application inhalation exposure scenarios .Carfentrazone - ethyl (128712) Human - Health Risk Assessment D 389083

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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 f rom 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 b e 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 incidenta l oral) and chronic (food and water) risk assessment s 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 exposure s from the aquatic use. For children, the short - term aggregate risk assessment combine d chronic dietary exposure with po st - 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 ≥ 2,30 0 and, therefore, do not exceed HED’s LOC (see Table 7.2.1) . Table 7 .2.1: Short - Term Aggregate Risk Estimates . Population LOC E xposure (mg/kg/day) Total MOE 3 Dietary 1 Inhalation 2 Incidental - oral 2 General U.S. P opulation MOE <100 0.007467 4.14 x 10 - 13 1.05 x 10 - 4 6 , 600 Children (1 - 2 years old) 0.020687 N/A 0.0006 2,3 00 1 See Table 5.4.1 for exposures. 2 See Table 6.3.1 for exposures. 3 Total MOE = 50 mg/kg/day (NOAEL) ÷ ( d ietary 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 D 389083

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### 8.0 Cumulative Exposure/Risk Characteriz ation 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 n ot 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 E PA’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 D 3 89978, L. Venkateshwara, 29 - Feb - 2012 

### 9.1 Occupational Ha ndler 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) aeri al 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). E xposure s 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 expos ure. 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 p redicting 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, al ong 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/hand ler - exposure - data.html . For pesticide handler s, it is HED’s standard practice to present exposure estimated for “baseline” that is, for workers wearing a single layer of wor k 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 p ersonal - p rotective e quipment (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 D 389083

Page 27 of 33 Table 9.1.1 : Short - /Intermediate - term Ex posure & Risk to Occupational Handlers f rom Appl ication of Carfentrazone ethyl to the Nongrass Animal Feed Crop Group 18. Crop or Target Unit Exposure 1

mg ai/lb handled App . Rate 2

lb ai/A Units Treated 3

A/day Avg. Daily Dose 4

mg ai/kg bw/day MOEs 5 Short - and Intermediate term 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: 3,80 0,000 Mixer/Loader - W ater - dispersible Granules - Groundboom Applications Nongrass animal feed Inhal.

Baseline: 0.0 0896 0.06 80 Inhal: Baseline: 0.00 05 Inhal. Baseline: 9 3 ,000 Mixer/Loader - W ater - dispersible Granules - Aerial Applications Nongrass animal feed Inhal.

Baseline: 0.0 0896 0.06 350 Inhal. Baseline: 0.0 024 Inhal. Baseline: 21 , 0 00 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: 2,50 0,000 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 Ave rage Daily Dose = Unit Exposure * Applic ation Rate * Units Treated 8 0 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 : D ermal 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 post application 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 pre viously 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 i ts 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 i nhalation 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 D 389083

Page 28 of 33 

### 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 ● o ccupational /

r esidential e xposure : D389978, L. Venkateshwara, 29 - Feb - 2012 ; D296322, T. Bloem et al. , 21 - Jul - 2004 ● d ietary e xposure: D389977, T. Bloem, 29 - Feb - 2012 ● r esidue c hemistry: D389976, T. Bloem, 29 - Feb - 2012 ● r esidue c hemistry: D271468 , T. Bloem, 9 - Jan - 2001 ● r esidue c hemistry: D303030 , T. Bloem, 30 - Jan - 2004 ● r esidue c hemistry: D293779 , T. Bloem, 14 - Jul - 2004 ●human - h ealth 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:RAB1Carfentrazone - ethyl (128712) Human - Health Risk Assessment D 389083

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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

carfentrazone chloropropionic acid F8426 - ClPAc ; CR - 75 ,2 - dichloro - 5 - [4 - (difluoromethyl) - 4,5 - dihydro - 3 - methyl - 5 - oxo - 1H - 1,2,4 - triazol 1 - yl] - 4 - fluorobenzenepropanoic acid

3 - hydroxymethyl carfentrazone chloropropionic acid 3 - OH - F8426 - ClPAc ; HM F8426 - ClPAc ; CR - 48 ,2 - dichloro - 5 - [4 - (difluoromethyl) - 4,5 - dihydro - 3 - hydroxymethyl - 5 - oxo - 1H 1,2,4 - triazol - 1 - yl] - 4 - fluorobenzenepropanoic acid
3 - hydroxymethyl carfentrazone - benzoic acid 3 - OH - F8426 - BAc HM - F8426 - BAc 2 - chloro - 5 - [4 - (difluoromethyl) - 4,5 - dihydro - 3 - hydroxymethyl - 5 - oxo - 1H 1,2,4 - triazol - 1 - yl] - 4 - fluorobenzoic acid

3 - desmethyl - carfentrazone chloropropionic acid 3 - DM - F8426 - ClPAc 2 - di chloro - 5 - [4 - (difluoromethyl) - 4,5 - dihydro - 5 - oxo - 1H - 1,2,4 - triazol - 1 - yl] - 4 - fluorobenzenepropanoic acid F8426 - propionic acid; F8426 - PAc 2 - chloro - 5 - [4 - (difluoromethyl) - 4,5 - dihydro - 3 - methyl - 5 - oxo - 1H - 1,2,4 - triazol 1 - yl] - 4 - fluorobenzenepropanoic acid
F8426 - cinnamic acid; F8426 - CAc 2 - chloro - 5 - [4 - (difluoromethyl) - 4,5 - dihydro - 3 - methyl - 5 - oxo - 1H - 1,2,4 - triazol 1 - yl ] - 4 - fluorobenzenepropenoic acid
F8426 - benzoic acid; F8426 - BAc 2 - chloro - 5 - [4 - (difluoromethyl) - 4,5 - dihydro - 3 - methyl - 5 - oxo - 1H - 1,2,4 - triazol 1 - yl] - 4 - fluorobenzoic acidCarfentrazone - ethyl (128712) Human - Health Risk Assessment D 389083

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### Attachment 2: Spirodiclofen Toxicity Profile. Acute Toxicity Profile for Carfentrazone - Ethyl . Guideline Study Type MRID Results Toxicity Category 81 - 1 Acute Oral - Rat 43189027 LD 50 >5000 mg/kg 4 81 - 2 Acute Dermal - Rat 43189209 LD 50 >4000 mg/kg 3 81 - 3 Acute Inhalation - Rat 43189211 LC 50 >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, 14 000, 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)

Guid eline 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 D 389083

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 Materna l NOEL = 150 mg/kg/day LOEL = 300 mg/kg/day based on unthriftiness and emaciation Developmenta l 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 gain s, increased liver w eights, 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. 87 0.5100 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 in dication 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 D 389083

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 un der 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 D 389083

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 - chloropropioni c 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 le vels 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 o xidative 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.