EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: [Bethany Benbow (703) 347-8072]

FMC Corporation, 1735 Market Street, Philadelphia, PA 19103

[1F7839]

EPA has received a pesticide petition (1F7839) from FMC Corporation,1735 

Market street, Philadelphia, PA 19103, proposing, pursuant to section 408(d) of the 

Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR 

part 180.515 by establishing a tolerance for residues of carfentrazone-ethyl (ethyl- -2-

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

fluorobenzene-propanoate) and the metabolite carfentrazone-ethyl chloropropionic acid 

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

4-fluorobenzenepropanoic acid)] in or on the raw agricultural commodity [Crop Group 

18 Non-grass animal feed (forage, fodder, straw and hay): alfalfa, forage at 5 ppm; 

alfalfa, hay at 18 ppm; alfalfa, seed at 10 ppm; clover, forage at 5 ppm; clover, hay at 18 

ppm; clover, seed at 10 ppm parts per million (ppm). EPA has determined that the 

petition contains data or information regarding the elements set forth in section 408 (d)(2) 

of the FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted 

data at this time or whether the data supports granting of the petition. Additional data 

may be needed before EPA rules on the petition.
A. Residue Chemistry

1. Plant metabolism. [The metabolism of carfentrazone-ethyl in plants is 

adequately understood. Corn, wheat, radish and soybean metabolism studies with 

carfentrazone-ethyl have shown uptake of material into plant tissue with no significant 

movement into grain, root or seeds. All four plants extensively metabolized 

carfentrazone-ethyl and exhibited a similar metabolic pathway. The residues of concern 

are the combined residues of carfentrazone-ethyl and carfentrazone-ethylchloropropionic acid.

2. Analytical method. There is a practical analytical method for detecting and 

measuring levels of carfentrazone-ethyl and its metabolite in or on food with a limit of 

quantitation that allows monitoring of food with residues at or above the levels set or 

proposed in the tolerances. The analytical enforcement method for carfentrazone-ethyl

was used with minor modification that eliminated several clean-up and derivatization 

steps that was required for GC/MSD but not for LC/MS/MS. The analytical method for 

carfentrazone-ethyl involves separate analyses for parent and its metabolite. The parent 

is analyzed by evaporation and reconstitution of the sample prior to analysis by

LC/MS/MS GC/ECD. The metabolite samples were refluxed in the presence of acid and 

cleaned up with solid phase extraction prior to analysis by LC/MS/MS.

3. Magnitude of residues. The magnitude of the residue of carfentrazone-ethyl and 

its major metabolites in/on Crop Group 18 (non-grass animal feed) representative crops 

alfalfa and clover treated with Spartan Charge Herbicide were determined. Forage/hay

plots were treated with one or two applications of carfentrazone-ethyl for a cumulative 

application of 0.04 lbs ai/A. Applications to each treated plot in this study were made 

using a spray solution of approximately 10 GPA. Each field trial followed one of three 

treatment types: single dormant application, single stubble application or split dormant 

and stubble applications. Seed plots were treated with one application of carfentrazoneethyl at a rate of 0.04 lbs ai/A. At maturity, seed plots were treated with carfentrazoneethyl at a rate of 0.06 lbs ai/A as a harvest aid for seed samples. RAC for each crop were 

harvested at the appropriate time and subsequent analyses determined that the residues of 

carfentrazone-ethyl and its metabolites would not exceed the proposed tolerances.

B. Toxicological Profile

1. Acute toxicity. Carfentrazone-ethyl demonstrates low oral, dermal and 

inhalation toxicity. The acute oral LD50 value in the rat was greater than 5000 mg/kg, the 

acute dermal LD50 value in the rat was greater than 4000 mg/kg and the acute inhalation 

LC50 value in the rat was greater than 5.09 mg/L/4h. Carfentrazone-ethyl is non-irritating 

to rabbit skin and minimally irritating to rabbit eyes. It did not cause skin sensitization in 

guinea pigs. An acute neurotoxicity study in the rat had a systemic NOAEL of 500 

mg/kg based on clinical signs and decreased motor activity levels; the NOAEL for 

neurotoxicity was greater than 2000 mg/kg (highest dose tested) based on the lack of 

neurotoxic clinical signs or effects on neuropathology.
2. Genotoxicty. Carfentrazone-ethyl did not cause mutations in the Ames assay

with or without metabolic activation. There was a positive response in the Chromosome 

Aberration assay without activation but a negative response with activation. The Mouse 

Micronucleus assay (an in vivo test which also measures chromosome damage), the 

CHO/HGPRT forward mutation assay and the Unscheduled DNA Synthesis assay were 

negative. The overwhelming weight of the evidence supports the conclusion that 

Carfentrazone-ethyl is not genotoxic.

3. Reproductive and developmental toxicity. Carfentrazone-ethyl is not considered 

to be a reproductive or a developmental toxin. In the 2-generation reproduction study, 

the NOEL for reproductive toxicity was greater than 4000 ppm (greater than 323 to 

greater than 409 mg/kg/day). In the developmental toxicity studies, the rat and rabbit 

maternal NOELs were 100 mg/kg/day and 150 mg/kg/day, respectively. The 

developmental NOEL for the rabbit was greater than 300 mg/kg/day, which were the 

highest dose tested and for the rat the NOEL was 600 mg/kg/day based on increased litter 

incidences of thickened and wavy ribs at 1250 mg/kg/day. These two findings (thickened 

and wavy ribs) are not considered adverse effects of treatment but related delays in rib 

development which are generally believed to be reversible.

4. Subchronic toxicity. Ninety-day feeding studies were conducted in mice, rats 

and dogs with Carfentrazone-ethyl. The NOEL for the mouse study was 4000 ppm (571 

mg/kg/day), for the rat study was 1000 ppm (57.9 mg/kg/day for males; 72.4 mg/kg/day

for females) and for dogs was 150 mg/kg/day. A 90-day subchronic neurotoxicity study

in the rat had a systemic NOEL of 1000 ppm (59.0 mg/kg/day for males; 70.7 mg/kg/day

for females) based on decreases in body weights, body weight gains and food 

consumption at 10,000 ppm; the neurotoxicity NOEL was greater than 20,000 ppm 

(1178.3 mg/kg/day for males; 1433.5 mg/kg/day for females) which was the highest dose 

tested.

5. Chronic toxicity. Carfentrazone-ethyl is not carcinogenic to rats or mice. A 2-

Year Combined Chronic Toxicity/Oncogenicity study in the rat was negative for

carcinogenicity and had a chronic toxicity NOEL of 200 ppm (9 mg/kg/day) for males 

and 50 ppm (3 mg/kg/day) for females based on red fluorescent granules consistent with 

porphyrin deposits in the liver at the 500 and 200 ppm levels, respectively. An 18 Month 

Oncogenicity study in the mouse had a carcinogenic NOEL that was greater than 7000 

ppm (>1090 mg/kg/day for males; >1296 mg/kg/day for females) based on no evidence 

of carcinogenicity at the highest dose tested. A 1-Year Oral Toxicity study in the dog 

had a NOEL of 50 mg/kg/day based on isolated increases in urine porphyrins in the 150 

mg/kg/day group (this finding was not considered adverse).

Using the Guidelines for Carcinogen Risk Assessment, carfentrazone-ethyl should be 

classified as Group AE@ for carcinogenicity -- no evidence of carcinogenicity -- based on 

the results of carcinogenicity studies in two species. There was no evidence of 

carcinogenicity in an 18-month feeding study in mice and a 2-year feeding study in rats at 

the dosage levels tested. The doses tested are adequate for identifying a cancer risk. 

Thus, a cancer risk assessment is not necessary.
6. Animal metabolism. The metabolism of carfentrazone-ethyl in animals is 

adequately understood. Carfentrazone-ethyl was extensively metabolized and readily 

eliminated following oral administration to rats, goats, and poultry via excreta. All three 

animals exhibited a similar metabolic pathway. As in plants, the parent chemical was 

metabolized by hydrolytic mechanisms to predominantly form carfentrazone-ethylchloropropionic acid, which was readily excreted.

7. Metabolite toxicology. [NA ]

8. Endocrine disruption. An evaluation of the potential effects on the endocrine 

systems of mammals has not been determined; however, no evidence of such effects was 

reported in the chronic or reproductive toxicology studies described above. There was no 

observed pathology of the endocrine organs in these studies. There is no evidence at this 

time that carfentrazone-ethyl causes endocrine effect.

C. Aggregate Exposure

1. Dietary exposure. Based on the available toxicity data, the EPA has established 

a Reference Dose (RfD) and cPAD for carfentrazone-ethyl of 0.03 mg/kg/day. This is 

based on a 2-year chronic toxicity/carcinogenicity study in rats with a threshold NoObserved Effect Level (NOEL) of 3 mg/kg/day and an uncertainty factor of 100. In 

support of the proposed harvest-aid application the Agency conducted acute and chronic 

dietary risk assessments. For both analysis 100% crop-treated, default processing factors 

and modeled drinking water estimates resulting from the highest registered proposed 

application rate of 0.4 lbs ai/acre, tolerance- level residues for livestock, fish, shellfish, 

cereal grains and cotton commodities were made. Using the above assumptions, the 

resulting acute and chronic exposure estimates were aPAD <1% and cPAD <89% 

respectively.

i. Food. Dietary exposure from the proposed harvest-aid application accounts for 

1.0% or less of the aPAD in subpopulations (including infants and children). Dietary

exposure from all uses would accounts for 89% or less of the cPAD in subpopulations 

(including infants and children).

ii. Drinking water. Ground water estimate of 13.4 ppb, surface water estimates of 

34.3 ppb (peak concentration) and 19.0 ppb (annual average) were incorporated directly

into the acute and chronic dietary assessment by the Agency.

2. Non-dietary exposure. Non-occupational exposures to carfentrazone-ethyl are 

anticipated from the lawn, turf and aquatic applications. The resulting MOEs were 

calculated to be >500,000.

D. Cumulative Effects

EPA is also required to consider the potential for cumulative effects of 

carfentrazone-ethyl and other substances that have a common mechanism of toxicity. 
EPA consideration of a common mechanism of toxicity is not appropriate at this time 

since EPA does not have information to indicate that toxic effects produced by

carfentrazone-ethyl would be cumulative with those of any other chemical compounds; 

thus only the potential risks of carfentrazone-ethyl are considered in this exposure 

assessment.

E. Safety Determination

1. U.S. population. Using the conservative exposure assumptions described and 

based on the completeness and reliability of the toxicity data, the aggregate exposure to 

carfentrazone-ethyl will utilize less than 1% of the aPAD and less than 32% of the cPAD 

for the US subpopulations. EPA generally has no concern for exposures below 100 

percent of the aPAD or cPAD. Therefore, based on the completeness and reliability of 

the toxicity data and the conservative exposure assessment, there is a reasonable certainty

that no harm will result from aggregate exposure to residues of carfentrazone-ethyl, 

including all anticipated dietary exposure and all other non-occupational exposures.

2. Infants and children. In assessing the potential for additional sensitivity of 

infants and children to residues of carfentrazone-ethyl, EPA considers data from 

developmental toxicity studies in the rat and rabbit and the two-generation reproduction 

study in the rat. The developmental toxicity studies are designed to evaluate adverse 

effects on the developing organism resulting from pesticide exposure during prenatal 

development. Reproduction studies provide information relating to effects on the 

reproductive capacity of males and females exposed to the pesticide. Developmental 

toxicity was not observed in developmental toxicity studies using rats and rabbits. In 

these studies, the rat and rabbit maternal NOELs were 100 mg/kg/day and 150 

mg/kg/day, respectively. The developmental NOEL for the rabbit was greater than 300 

mg/kg/day, which was the highest dose, tested and for the rat was 600 mg/kg/day based 

on increased litter incidences of thickened and wavy ribs. These two findings are not 

considered adverse effects of treatment but related delays in rib development, which are 

generally believed to be reversible.

In a two-generation reproduction study in rats, no reproductive toxicity was observed 

under the conditions of the study at 4000 ppm, which was the highest dose tested.

FFDCA section 408 provides that EPA may apply an additional safety factor for infants 

and children in the case of threshold effects to account for pre- and post-natal toxicity and 

the completeness of the database. Based on the current toxicological data requirements, 

the database relative to pre- and post-natal effects for children is complete and an 

additional uncertainty factor is not warranted. Therefore at this time, the RfD of 0.03 

mg/kg/day is appropriate for assessing aggregate risk to infants and children.

Population Adjusted Dose (aPAD and cPAD)

Using the conservative exposure assumptions described above, the percent of the aPAD 

that will be utilized by aggregate exposure to residues of carfentrazone-ethyl for non-
nursing infants (<1 year old) would be < 1% (aPAD) and < 53% (cPAD); for children 1-6 

years of age would be < 1% (aPAD) and < 89% (cPAD), (the most highly exposed 

group). Based on the completeness and reliability of the toxicity data and the 

conservative exposure assessment, there is a reasonable certainty that no harm will result 

to infants and children from aggregate exposure to the residues of carfentrazone-ethyl

including all anticipated dietary exposure.

F. International Tolerances

Canadian MRLs are established for root and tuber vegetables (Crop Group 1), 

bulb vegetables (Crop Group 3), leafy vegetables (Crop Groups 4 and 5), legume 

vegetables (Crop Group 6), fruiting vegetables (Crop Group 8), cucurbit vegetables (Crop 

Group 9), pome fruits (Crop Group 11), stone fruits (Crop Group 12), berries (Crop 

Group 13), cereal grains (Crop Group 15), oilseeds (Crop Group 20), grapes and 

strawberries. There are no established Codex Alimentarius Commission (Codex) 

Maximum Residue Levels (MRLs) for carfentrazone-ethyl, in/on the proposed 

commodities.