Interregional Research Project Number 4 (IR-4)

Petition 4E8337

EPA has received a pesticide petition (4E8337) from Interregional Research 

Project No. 4 (IR-4), 500 College Road East, Suite 201 W, Princeton, NJ 08540

requesting, 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 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 Quinoa, grain at 0.10 ppm, and Psyllium, seed at 0.10 

ppm.

EPA has determined that the petition contains data or information regarding the 

elements set forth in section 408 (d)(2) of 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 asparagus treated with 2 broadcast application to the soil 

(after clean harvest) at an interval of 20 (± 2) days with the last application 5 days before 

harvesting emergent spears. Carfentrazone-ethyl formulated as Aim EC or Aim EW 

Herbicide was applied at 0.03 lbs ai/A per application using a spray solution of 
2

approximately 10 to 40 gallons of water per acre.

The magnitude of the residue of carfentrazone-ethyl and its major metabolites in/on mint 

treated with one broadcast application to emerged weeds before mint break dormancy. 

Carfentrazone-ethyl formulated as Aim EC or Aim EW Herbicide was applied at 0.015 

lbs ai/A to 0.03 lbs ai/A using a spray solution of approximately 10 to 40 gallons of water 

per acre.

RAC for each crop, crop group or subgroup 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 toxicant. 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 
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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 - Remove.

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 subchronic, 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 

an acute Reference Dose (RfD) for carfentrazone-ethyl of 5 mg/kg/day. The acute RfD is 

based on acute neurotoxicity study in rats with a threshold NOEL of 500 mg/kg/day and 

an uncertainty factor of 100. A chronic RfD for carfentrazone-ethyl was established at 

0.03 mg/kg/day. This is based on a 2-year chronic toxicity/carcinogenicity study in rats 
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with a threshold No-Observed 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 using DEEM-FCID, ver 3.16 which 

incorporates consumption data from the USDA NHANES/WWEIA; 2003-2008. For 

both analysis 100% crop-treated, DEEM default processing factors and modeled drinking 

water estimates resulting from the highest registered proposed application rate of 0.46 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 <49% respectively for the most sensitive 

sub-population (non-nursing infants <1 year old).

i. Food. The registered tolerances (40CFR 180.515) and the tolerances proposed 

by IR-4 Project subject to this petition (AMENDS 40CFT180.515) were used as dietary 

exposure. 

Acute dietary exposure: The most conservative acute exposure estimate was for the 

population subgroup of non-nursing infants (< 1 year old), which utilized <1% of the 

aPAD at the 95th percentile for carfentrazone-ethyl. The acute drinking water residue of 

160 ppb (using groundwater as the most conservative estimate) was used in the 

assessment. The results show that for all populations, the estimated exposures are below 

the Agency's level of concern (< 100% aPAD).

Chronic dietary exposure: The highest chronic exposure estimate was for the population 

subgroup of non-nursing infants (<1 year old), which utilized 49% of the cPAD for 

carfentrazone-ethyl. The chronic drinking water residue of 128 ppb (using groundwater 

as the most conservative estimate) was used in the assessment. The results show that for 

all populations, the exposures are below the Agency’s level of concern (< 100% cPAD).

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 49% or less of the cPAD in subpopulations (including infants 

and children).

ii. Drinking water. Groundwater estimates of 160 ppb (highest daily value) and 

128 ppb (post-breakthrough average) using the Tier I/II ground water exposure model, 

PRZM-GW, exceeded the surface water estimates (DP Barcode 389083) of 126 ppb 

(peak exposure) and 48 ppb (annual average). Therefore, groundwater estimates from 

PRZM-GW were incorporated directly into the acute and chronic dietary risk assessment

to provide a conservative estimate.

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 
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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 17% of the cPAD for the

general US population. 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 cRfD of 0.03 

mg/kg/day is appropriate (cRfD = cPAD) for assessing aggregate risk to infants and 

children.

Using the conservative exposure assumptions described above (Tier I dietary 

assessment), the percent of the PAD that will be utilized by aggregate exposure to 
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residues of carfentrazone-ethyl for non-nursing infants (<1 year old) would be <1% 

(aPAD) and 49% (cPAD), which represent the most conservative exposure in all 

subpopulations. 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.