Document ID: EPA-HQ-OPP-2019-0135-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2019-05-16T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

  EPA Registration Division contact: Mindy Ondish, PM/23 (703-605-0723)

  Gowan Company LLC 
  PP8F8721
  EPA has received a pesticide petition (PP8F8721) from Gowan Company LLC., 370 S Main Street, Yuma, AZ85364 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

        1. by establishing a tolerance for residues of

  ethalfluralin in or on the raw agricultural commodity potato at 0.01 parts per million (ppm). Upon approval of the petition Gowan Company has requested EPA to remove the existing tolerance for potatoes at 0.05 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.

 Residue Chemistry

 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.

   Analytical method. Potato - A residue method has been developed and validated at a limit of quantitation (LOQ) of 0.01 ppm for the determination of ethalfluralin in potato which utilizes capillary gas chromatography with mass selective detection (GC/MSD). Validation data were generated using this method during the analysis of the potato field samples from the magnitude of residue and processing studies.

   Magnitude of residues. For the Magnitude of Residue (MOR) trials, 12 sites located in 7 regions (1, 2, 3, 5, 9, 10, and 11) representative of the major potato growing areas of the United States were selected. The processing field trial was conducted at one (1) site located in Idaho (region 11). The decline field trials were conducted at two (2) sites, one field site located

  in New York-2 (region 1) and the second site selected was in Iowa (region 5). All trial sites included a control plot (UTC) and a treated plot (TRT#1) that received a single application of
  1.125 lb ai/A (3 pt/A) Sonalan HFP containing the active ingredient ethalfluralin N-ethyl-N- (2-methyl-2-propenyl)-2,6-dinitro-4-(trifluoromethyl) benzenamine were applied in 2017 as a preplant incorporated application. One trial site (ID) included an additional treated plot (TRT#2) treated at a 5X rate of 5.625 lb ai/A (15 pt/A) Sonalan HFP pre-emergence incorporated.
  Potato tuber samples were collected at commercial maturity from the UTC and TRT#1 plots. At two trial sites (NY-2 & IA), potato tuber samples were collected at 8+-1 & 4+-1 days before commercial maturity, at commercial maturity, and 8+-1 days after commercial maturity to evaluate residue decline. Residues of ethalfluralin in all the treatments and the processed commodities following an exaggerated 5X rate were <LOQ.

 Toxicological Profile

 Acute toxicity. Ethalfluralin is of relatively low toxicity. The rat oral LD50 is >5,000 mg/kg. The acute dermal LD50 in rabbits is >5,000 mg/kg and the acute rat inhalation LC50 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.

 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.

 Reproductive and developmental toxicity. The maternal NOEL and LOEL 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 NOEL in rats was 1000 mg/kg/day, the highest dose tested. In rabbits the NOELs for maternal and developmental toxicity were 75 mg/kg/day. The maternal LOEL 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 LOEL 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 NOEL was 12.5 mg/kg/day. The parental LOEL 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 NOEL 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 NOEL was 20 mg/kg/day. The parental LOEL was 61 mg/kg/day based on increased liver weights. No treatment-related effects were noted on reproductive parameters and the reproductive NOEL was equal to or greater than 61 mg/kg/day.

 Subchronic toxicity. Ethalfluralin was evaluated in five subchronic dietary studies which showed NOELs 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.

 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 NOEL 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 NOEL was 10.3 mg/kg/day. The mid dose (LOEL) 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 NOEL was 4 mg/kg/day. The LOEL 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.

 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.

 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.

 Endocrine disruption. There is no evidence to suggest that ethalfluralin has an effect on any endocrine system.

   Aggregate Exposure

 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 (100% CT) was used. EPA has previously used a NOEL 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 NOEL 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 NOEL 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.

 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 potato, rapeseed, and 0.05 ppm for canola and safflower. To support the Registration Review of Ethalfluralin EPA in 2016 has conducted the acute, chronic non-cancer and chronic cancer dietary (food and drinking water) exposure assessments using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM- FCID) Version 3.18, which uses food consumption data from the U.S. Department of Agriculture's (USDA's) National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/W WEIA) from 2003 through 2008).

 Acute: An acute dietary risk assessment was conducted with the conservative assumptions of 100% crop treated and tolerance level residues for all crops. A modeled estimated drinking water concentration (EDWC) of 0.02612 ppm was included directly in the dietary analysis. 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 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.

 Chronic: Chronic dietary exposure and risk was estimated with the conservative assumptions of 100% crop treated and tolerance level residues for all crops. A modeled EDWC of 0.00057 ppm was included directly in the dietary analysis. 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 and risk estimates are <1% of the chronic population-adjusted dose (cPAD) for all populations subgroups and are below Health Effects Division's (HED) Level of Concern (LOC) is estimated to occupy only <1% of the RfD for the general U.S. population. The most highly exposed population subgroup are children 1 to 2 years old who have the highest potential exposure. Therefore, chronic exposure and risk from food is well within acceptable levels.

 Cancer: The cancer dietary analysis for ethalfluralin, although more refined than the chronic non-cancer assessment, is also conservative because 100% CT was assumed. A modeled EDWC of 0.00036 ppm was included in the dietary analysis. The most highly exposed adult population subgroups were adults 20-49 years old and females 13-49 years old, with a cancer dietary (food and drinking water) exposure of 0.000009 mg/kg/day resulting in a risk estimates of 8.4x10-7. 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 8.4 x 10[-7]. 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.

 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. The drinking water used in the dietary risk assessment for the registration review of 2016 was provided by EFED using the Surface Water Concentration Calculator (SWCC) and the Pesticide Root Zone Model for GroundWater (PRZM-GW) models. The surface water EDWCs were much higher than the groundwater EDWCs which reflects the low leaching potential for the strongly adsorbed ethalfluralin molecule. The surface water EDWCs were used in the acute, chronic and cancer dietary (food and drinking water assessments. The acute EDWC's were modeled using the FL cucumber scenario with a single and seasonal application rate of 1.7 lb ai/A applied annually and the chronic and cancer EDWCs were modeled using the MS corn scenario as a surrogate for soybeans using a maximum single and seasonal application rate of 1.31 lb ai/A applied annually. The acute and chronic EDWC's from the PRZM-GW was 0.000437 ppb based on a 100-year simulation with maximum rate

  applied each year. The EDWC's from the SWCC for the acute, chronic (annual) and chronic/cancer (30+years) were 26.1, 0.57 and 0.36 00b, respectively. These estimated water values were entered directly in to the DEEM-FCID model for water, direct and indirect, all sources, for dietary exposure estimation. (US EPA OPPTS Ethalfluralin: Acute, Chronic Non- Cancer Chronic, and Cancer Dietary (Food and Drinking Water) Exposure and Risk Assessments to Support Registration Review. PC Code: 113101, Decision Number: 510535, March 18, 2016).

 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.

   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.

 Safety Determination

 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 <1% of the 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.

 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 be <1% of the cPAD 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.

   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.