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 request ing, 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 a cid ( 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 petit ion 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 dat a 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 carf entrazone - ethyl and carfentrazone - ethyl chloropropionic 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 allow s 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 requ ired 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. Th e 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 t reated 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 . C arfentrazone - ethyl formulated as Aim EC or Aim EW Herbicide was applied at 0.03 lb s ai/A per application using a spray solution of2

approximately 1 0 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 b reak 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 harveste d at the appropriate time and subsequent analys es 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, d ermal and inhalation toxicity. The acute oral LD 50 value in the rat was greater than 5000 mg/kg, the acute dermal LD 50 value in the rat was greater than 4000 mg/kg and the acute inhalation LC 50 value in the rat was greater than 5.09 mg/L/4h. Carfentrazon e - 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 ac tivity 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 o r 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/HGP RT 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 i s 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 studie s, 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 increas ed 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. Subch ronic 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/day3

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 To xicity/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, car fentrazone - ethyl should be classified as Group A E @ 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 adequatel y 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 met abolized by hydrolytic mechanisms to predominantly form carfentrazone - ethyl chloropropionic acid, which was readily excreted . 7. Metabolite toxicology . NA - Remove. 8. Endocrine disruption . An evaluation of the potential effects on the endocrine system s 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 e vidence 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 acu te 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/carcinogenici ty study in rats4

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 0.4 6 l bs 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 sen sitive 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 95 th percentile for carfentrazone - ethyl. The acute drinking water residue of 160 ppb (using groundw ater 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 chil dren). Dietary exposure from all uses would accounts for 49 % or less of the cPAD in subpopulations (including infants and children). ii. Drinking water . Groundwater estimate s of 160 ppb (highest daily value) and 128 ppb (post - breakthrough average) using the Tier I/II ground water exposure model, PRZM - GW, exceed ed 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 a cute 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 of5

carfentrazone - ethyl and other substances that have a common mechanism of toxicity. EPA consideration of a common mechanism of toxi city 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 c onservative 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 chil dren . 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 dev elopmental 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 t reatment 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 toxicologic al 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 c RfD of 0.03 mg/kg/day is appropriate ( c RfD = c PAD) for assessing aggre gate 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 to6

residues of carfentrazone - ethyl for non - nursing infants (<1 y ear 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 tha t 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 G roup 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.