Document ID: EPA-HQ-OPP-2012-0303-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-07-25T04:00Z

EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING FOR PESTICIDE PETITION  
EPA Registration Division Contact: Sidney Jackson (703) 305-7610
Docket ID Number: EPA-HQ-OPP-2012-0303
Interregional Research Project Number 4 (IR-4)
Pesticide Petition Number (PP#): 2E8007
	EPA has received a pesticide petition (PP 2E8007) from Interregional Research Project Number 4 (IR-4), 500 College Road East, Suite 201W., 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 the herbicide ethalfluralin in or on the raw agricultural commodity rapeseed subgroup 20A and sunflower subgroup 20B at 0.05 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  FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data support granting of the petition. Additional data may be needed before EPA rules on the petition.
A. Residue Chemistry
	1. Plant metabolism. Nature of residue studies with 14C-ethalfluralin have demonstrated very low terminal residues and that ethalfluralin per se is the residue of concern in plants grown in soil treated with this compound and that there are no significant metabolic products.  These studies indicate that it is appropriate to base a tolerance on residues of the parent compound, ethalfluralin.
	2. Analytical method. Rapeseed/Canola - A residue method has been developed and validated at a limit of quantitation (LOQ) of 0.02 μg/g for the determination of ethalfluralin in rapeseed seed which utilizes capillary gas chromatography with mass selective detection (GC/MSD).  Validation data were generated using this method during the analysis of the canola seed field samples from the magnitude of residue studies.
Safflower - Adequate residue analytical methods are available for purposes of registration based upon the analytical method for sunflower.  A GC method, Method I, with electron capture detection is listed in the Pesticide Analytical Manual (PAM, Vol. II, Section 180.416) for tolerance enforcement.  Method I is applicable for analysis of ethalfluralin residues in/on sunflower seed.  The LOQ is 0.01 ppm.

	3. Magnitude of residues. Canola - In the magnitude of residue field studies, herbicides containing the active ingredient ethalfluralin N-ethyl-N-(2-methyl-2-propenyl)-2,6-dinitro-4-(trifluoromethyl) benzenamine were applied in 1996 at eight sites as a preplant incorporated application.  Sonalan* 10G herbicide was applied directly to the soil surface and Sonalan* HFP herbicide was diluted in water and applied in a spray volume of 16 - 23 gal/A.  The applications were made to field plots of canola at the rate of 1.25 lb a.i./A at all sites except Georgia and Washington, and at the rate of 0.75 lb a.i./A (Georgia and Washington).  Three to five days after application, a second incorporation was done and canola seeds were planted.  Samples of canola seed were collected at normal harvest, 87 - 216 days after the last application.  Residues in canola seed collected at normal harvest were non detectable based on a method limit of detection of 0.006 ppm and limit of quantification of 0.02 ppm. Residues in processed fractions after application of up to 3X maximum recommended rate showed non-detectable residues, and therefore there is no magnification of residues through processing.
Safflower - The magnitude of residue data from sunflower are surrogate data for safflower.  The registered uses of ethalfluralin on sunflowers along with the established tolerances on these commodities are supported by acceptable field residue data from trials reflecting the maximum registered use patterns.  In all cases, the residues were < LOQ = 0.01ppm.  The re-registration requirements for processing studies were fulfilled.  Adequate processing studies have been conducted on sunflower seed.  Field residue data resulting from up to 5X label rates showed non-detectable (<LOQ = 0.01ppm) residues of ethalfluralin in sunflower seed.
B. Toxicological Profile
	1. Acute toxicity.  Ethalfluralin is of relatively low toxicity.  The rat oral LD50 is >5,000 mg/kg.  The acute dermal lethal dose (LD)50 in rabbits is >5,000 mg/kg and the acute rat inhalation lethal concentration (LC)50 is >0.94 mg/l air.  Ethalfluralin produced slight to moderate eye irritation and moderate to severe dermal irritation in rabbits.  A guinea pig dermal sensitization study conducted by the modified Buehler method found no sensitization, whereas a study conducted by the Magnusson and Kligman maximization method showed a positive sensitization reaction.  The signal word for the technical grade active ingredient is Caution.
	2. Genotoxicty. Ethalfluralin was weakly mutagenic in activated strains TA1535 and TA100 of Salmonella typhimurium, but not in strains TA1537, TA1538, and TA98 in an Ames assay.  In a modified Ames assay with Salmonella typhimurium and Escherichia coli, ethalfluralin was weakly mutagenic in strains TA1535 and TA100, with and without activation, and in strain TA98 without activation, at the highest dose.  No mutagenicity was found in the mouse lymphoma assay for forward mutation.  Ethalfluralin did not induce unscheduled DNA synthesis in rat hepatocytes.  In Chinese hamster ovary cells, ethalfluralin was negative without S9 activation, but it was clastogenic with activation.
	3. Reproductive and developmental toxicity. The maternal NOAEL and LOAEL of ethalfluralin in rats was 50 mg/kg/day and 250 mg/kg/day, respectively, based on decreased body weight gain and dark urine.  In this rat study, there was no observable developmental toxicity.  The developmental NOAEL in rats was 1000 mg/kg/day, the highest dose tested.  In rabbits the NOAELs for maternal and developmental toxicity were 75 mg/kg/day.  The maternal LOAEL of 150 mg/kg/day was based on abortions and decreased food consumption.  These effects as well as decreased weight gain, enlarged liver, and orange urine were found at 300 mg/kg/day.  In this study developmental toxicity was observed.  The developmental LOAEL in rabbits was 150 mg/kg/day, based on slightly increased resorptions, abnormal cranial development, and increased sternal variants.  In a three-generation rat reproduction study, the parental NOAEL was 12.5 mg/kg/day.  The parental LOAEL was 37.5 mg/kg/day, based on depressed mean body weight gains in males in all generations.  No treatment-related effects were noted on reproductive parameters and the NOAEL was 37.5 mg/kg/day or greater.  A seven-month multigeneration bridging study was conducted with doses equivalent to 0, 8, 20, or 61 mg/kg/day in the diet of Fischer 344 rats.  The parental NOAEL was 20 mg/kg/day.  The parental LOAEL was 61 mg/kg/day based on increased liver weights.  No treatment-related effects were noted on reproductive parameters and the reproductive NOAEL was equal to or greater than 61 mg/kg/day.
	4. Subchronic toxicity. Ethalfluralin was evaluated in five subchronic dietary studies which showed NOAELs of 560 ppm in a three-month mouse study, 12 mg/kg/day in a one-year mouse study, 29 mg/kg/day in a three-month rat study, 3.9 mg/kg/day in male rats and 4.9 mg/kg/day in female rats in a one-year study, and 27.5 mg/kg/day in a three-month dog study.  A 21-day dermal study in rabbits showed no systemic toxicity, while slight to severe dermal irritation was observed.
	5. Chronic toxicity. Ethalfluralin was administered to Fisher 344 rats in the diet for two years in combined chronic toxicity and carcinogenicity replicate studies.  The doses were equivalent to 0, 4.2, 10.7, or 32.3 mg/kg/day.  The NOAEL for systemic effects was 32.3 mg/kg/day.  Mammary gland fibroadenomas were found in dosed female rats at statistically significant incidences in the mid and high doses.  Ethalfluralin was administered to B6C3F1 mice in the diet for two years in combined chronic toxicity and carcinogenicity replicate studies.  The doses were equivalent to 0, 10.3, 41.9, or 163.3 mg/kg/day.  No increased incidence of neoplasms was attributed to the treatment.  The NOAEL was 10.3 mg/kg/day. The mid dose (LOAEL) and high dose showed focal hepatocellular hyperplasia in both sexes.  There were increased relative liver, kidney, and heart weights in females.  Some blood changes were found also, including decreased hematocrit, hemoglobin, and erythrocyte count accompanied by increased mean corpuscular hemoglobin concentration in high dose females.  Alkaline phosphatase values were increased at the high dose in both sexes.  Body weight gain decreased at the high dose.  
Beagle dogs were given 0, 4, 20, or 80 mg/kg/day orally, by capsule, for one year.  The NOAEL was 4 mg/kg/day.  The LOAEL was 20 mg/kg/day, based on increased urinary bilirubin, variations in erythrocyte morphology, increased thrombocyte count, and increased erythroid series of the bone marrow.  Elevated alkaline phosphatase levels were found at the two higher doses and siderosis of the liver at the high dose.
The EPA Office of Pesticide Program's Carcinogenicity Peer Review Committee concluded that ethalfluralin should be classified as Group C, a possible human carcinogen, based on increased mammary gland fibroadenomas and adenomas/fibroadenomas combined in female rats.  The tumor incidences were statistically significant at both the mid and high dose, and exceeded the upper range of historical controls.  Based on a low dose extrapolation, the Q1* of 8.9 x 10-2 (mg/kg/day)-1 has been calculated.
	6. Animal metabolism. Fischer 344 rats were treated orally with a single low dose, a single high dose, or repeated low doses of radiolabeled ethalfluralin.  Absorption of ethalfluralin was estimated at 79 - 87% of the dose for all dose levels.  Ethalfluralin was rapidly and extensively metabolized, and 95% of the chemical was excreted in urine and feces by seven days.  The major route of elimination for the radiolabel was in the feces, 50.9 - 63.2%, and the levels remaining in the tissues after 72 hours were negligible.  The major metabolites in urine and feces were identified.
	7. Metabolite toxicology. The residue of concern is ethalfluralin per se, as specified in 40 CFR 180.416.  Thus, there is no need to address metabolite toxicity.
	8. Endocrine disruption. There is no evidence to suggest that ethalfluralin has an effect on any endocrine system.
C. Aggregate Exposure
	1. Dietary exposure. Acute dietary risk assessments are performed for a food-use pesticide if a toxicological study has indicated the possibility of an acute effect of concern occurring as a result of a 1-day or single exposure.  An acute dietary endpoint (i.e., single dose endpoint) for risk assessment was not identified in the toxicity database for the general US population.  For females 13-49, the acute assessment was somewhat refined with the use of anticipated residues for existing commodities.  However, the risk estimate is considered conservative because anticipated residues were only used for blended commodities, but tolerance-level and proposed tolerance-level residues were used for all others.  In addition, an assumption of 100% crop treated (CT) was used. EPA has previously used a NOAEL of 75 mg/kg/day from a rabbit developmental toxicity study as the toxicity endpoint for assessing acute dietary risk in females 13 - 49 years of age.  An acute RfD of 0.75 mg/kg/day was calculated, based on a NOAEL of 75 mg/kg/day and an uncertainty factor of 100 (10 for interspecies extrapolation and 10 for intraspecies variation).  
Chronic dietary exposure to ethalfluralin is possible due to the potential presence of ethalfluralin residue in certain foods.  Chronic dietary risk was evaluated using a chronic RfD of 0.04 mg/kg/day, which is based on a NOAEL of 4 mg/kg/day from a chronic dog study along with an uncertainty factor of 100.  EPA previously concluded that an FQPA Safety Factor of 1X is appropriate for assessing chronic dietary risk.
EPA has concluded that ethalfluralin should be classified as group C, a possible human carcinogen, based on increased mammary gland fibroadenomas and adenomas/fibroadenomas combined in female rats.  Therefore, a cancer risk assessment was included.  Based on a low dose extrapolation, the Q1* of 8.9 x 10-2 (mg/kg/day)-[1] has been calculated and was used in this cancer risk assessment.
	i. Food. The latest dietary exposure assessment was based on all commodities with tolerances for ethalfluralin established at 40 CFR 180.416 together with the tolerances of 0.05 ppm for rapeseed, and 0.05 ppm for canola and safflower.  The Dietary Exposure Evaluation Model (DEEM), which is produced by Exponent, Inc. and licensed to Dow AgroSciences, was used to estimate dietary exposure.  This software used the food consumption data for the 1994-1996, 1998 USDA Continuing Surveys of Food Intake by Individuals (CSFII 1994-1996, 1998).
a.  Acute:  An acute dietary risk assessment was conducted with the conservative assumptions of 100% CT and tolerance level residues for all crops.  These assumptions result in a very conservative estimate of human exposure and risk.  Acute dietary risk for females 13-49 years old was assessed using an acute population adjusted (aPAD) of 0.75 mg/kg/day.  Even with conservative assumptions used in this analysis acute dietary exposure was estimated to occupy only <1% of the aPAD for females 13-49 years old.  Adverse effects are not expected for exposures occupying 100% or less of the aPAD.  Therefore, acute exposure and risk from food is well within acceptable levels.
b.  Chronic:  Chronic dietary exposure and risk was estimated with the conservative assumptions of 100% crop treated and tolerance level residues for all crops.  The estimate of potential chronic exposure and risk is very conservative and estimated risk would be substantially reduced with further refinement to the exposure estimate.  Even with the conservative assumptions used in this analysis, chronic exposure is estimated to occupy only <1% of the RfD for the general U.S. population.  Chronic dietary exposure is estimated to occupy 0.4% of the RfD for non-nursing infants, the population subgroup estimated to have highest potential exposure.  Therefore, chronic exposure and risk from food is well within acceptable levels.
c.  Cancer:  The cancer dietary analysis for ethalfluralin, although more refined than the chronic non-cancer assessment, is also conservative because 100% CT was assumed.  The risk estimate for chronic cancer dietary exposure (0.000022 mg/kg/day) to ethalfluralin for the U.S. population yields a cancer risk estimate of 2 x 10[-6].  EPA generally considers cancer risks of 10[-6] or less to be below the level of concern. Based on registered product uses, exposure to ethalfluralin from food plus water is estimated to not exceed a lifetime cancer risk of 2 x 10-[6] . Additional refinement with %CT estimates would lead to a lower estimate of dietary cancer risk.  EPA generally considers cancer risks of 10[-6] or less to be below the level of concern.
	ii. Drinking water. There are no established Maximum Contaminant Levels (MCLs) for residues of ethalfluralin in drinking water and Health Advisory Levels (HALs) for ethalfluralin have not been established.  EPA has previously used modeling for a screening level assessment of potential ethalfluralin exposure through drinking water.  The Agency has used PRZM/EXAMS and SCI-GRO to provide a screening level assessment for surface water and groundwater, respectively.  Modeled estimated drinking water concentrations (EDWCs) were higher for surface water sources of drinking water obtained from the PRZM-EXAMs model than ground water concentrations generated using the SciGrow model. Based on these models EPA has indicated the estimated environmental concentrations (EECs) for acute exposures are 11 parts per billion (ppb) for surface water and 0.02 ppb for groundwater.  The maximum simulation, the 1-in-10 year peak value, used for acute dietary exposure, was calculated for the use on canola using a maximum application rate of 1.15 lb ai/A.  The estimated drinking water concentration (EDWC) from this simulation was 11 ppb.  The maximum simulation for chronic exposures, or the 1-in-10 probability yearly, was calculated for the use on dill, with a maximum application rate of 1.5 lb ai/A.  The EDWC from this simulation was 0.4 ppb.  For cancer risk assessment, the average of yearly means was estimated to be 0.2 ppb. These estimated water values were entered directly in to the DEEM-FCID model (as 0.011ppm acute, 0.0004 ppm chronic and 0.2 ppm cancer) for water, direct and indirect, all sources, for dietary exposure estimation. (US EPA OPPTS Ethalfluralin: Acute, Chronic Non-Cancer, and Chronic Cancer Dietary Risk Assessment. PC Code: 113101, Decision Number: 336469, November 2, 2007)
a.   Acute:  In the dietary analyses, the peak value of 11 ppb was used for acute dietary assessment .  
b.   Chronic:  for chronic dietary assessment, the 1-in 10-year average of 0.4 ppb was used. 
c. Cancer:  For cancer risk assessment, the average of yearly means was estimated to be 0.2 ppb.
	2. Non-dietary exposure. Ethalfluralin is not currently registered for use on any residential non-food sites, and thus, it is not expected that non-occupational, non-dietary exposures will occur.
D. Cumulative Effects. EPA at this time has not established methodologies to resolve the complex issues concerning common mechanism of toxicity in a meaningful way.  Although ethalfluralin is a member of the dinitroaniline class of herbicides, there is no information available at this time to determine whether ethalfluralin has a common mechanism of toxicity with other substances or how to include this pesticide in a cumulative risk assessment.  Based on the metabolic profile, ethalfluralin does not appear to produce a toxic metabolite produced by other substances.  Therefore, only aggregate exposure and risk were considered.
E. Safety Determination
	1. U.S. population. Using conservative exposure assumptions previously described, chronic dietary exposure to residues of ethalfluralin from current uses including drinking water, was estimated to occupy only 0.2% of the chronic population adjusted dose (cPAD) for the general U.S. population.  EPA generally has no concern for exposures below 100% of the cPAD since the cPAD represents the level at or below which daily exposure over a lifetime will not pose appreciable risks to human health.    Cancer risk resulting from potential exposure to ethalfluralin through food and drinking water was estimated.  Cancer risk from potential dietary and drinking water exposure for the general U.S. population was found to be within a range that EPA has generally considered negligible.  Thus, based on the completeness and reliability of the toxicity data and the conservative exposure assessment, it is concluded that there is a reasonable certainty that no harm will result to the general U.S. population from aggregate exposure to ethalfluralin residues from current and proposed uses.
	2. Infants and children. Risk for developmental toxicity from acute exposure to ethalfluralin was evaluated only for females 13-49 years old.  Risk from aggregate acute exposure to ethalfluralin through food and drinking water is well within acceptable levels.  It can be concluded that there is a reasonable certainty that no harm will result for both females 13-49 years old and for the pre-natal development of infants from aggregate acute exposure to ethalfluralin.
Chronic aggregate exposure and risk was evaluated for children 1-2 years old, the population subgroup predicted to be most highly exposed, and was estimated to occupy only 0.3% of the cRfD for the general U.S. population .  Risk from aggregate chronic exposure through food and drinking water is well within acceptable levels.  Thus, based on the completeness and reliability of the toxicity data and the conservative exposure assessment, it can be concluded with reasonable certainty that no harm will result to infants and children from chronic aggregate exposure to ethalfluralin based on current and proposed uses.
F. International Tolerances	There are no Codex, Canadian or Mexican Maximum Residue Limits established for ethalfluralin, therefore there are no international harmonization issues associated with this action.