Document ID: EPA-HQ-OPP-2009-0553-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-09-08T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  
EPA Registration Division contact: Shaja Joyner, Registration Support Branch
(703) 308-3194
INSTRUCTIONS:  Please utilize this outline in preparing the pesticide petition.  In cases where the outline element does not apply, please insert "NA-Remove" and maintain the outline. Please do not change the margins, font, or format in your pesticide petition. Simply replace the instructions that appear in green, i.e., "[insert company name]," with the information specific to your action.
TEMPLATE:
Nichino America, Inc.
4550 New Linden Hill Rd., Suite 501
Wilmington, DE 19808

Pesticide Petition xxxxxx
	EPA has received a pesticide petition (PP xxxxxx) from Nichino America, Inc., 4550 New Linden Hill Rd., Suite 501, Wilmington, DE 19808, 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 180.484 by establishing a tolerance for residues of flutolanil [N-(3-(1-methylethoxy) phenyl) -2- (trifluoromethyl) benzamide] and its metabolite, M-4, desisopropylflutolanil [N-(3-hydroxyphenyl)-2-(trifluromethyl) benzamide], expressed as 2-trifluoromethyl benzoic acid and calculated as flutolanil in or on the raw agricultural commodities cotton, seed and soybean, seed 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 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 flutolanil in plants is adequately understood for the purposes of the petition.  Plant metabolism studies have been conducted in rice, cucumber, and peanuts.  The metabolic profile for flutolanil was similar in all three crops.  The major route of degradation was 4-0-dealkylation to desisopropylflutolanil, followed by conjugation.  Other metabolites may occur at very low levels due to hydroxylation and oxidation of the side chain, hydroxylation of the aniline ring, and methylation of the hydroxyl groups.  These minor metabolites were also subject to conjugation.  The residues of concern in plants are the parent, flutolanil, and desisopropylflutolanil.
   2. Analytical method.  A previously submitted analytical method designated AU-95R-04 (MRID 45104001), a gas chromatography, mass spectrometry detection method has been independently validated and is adequate for enforcement purposes for flutolanil residue detection in soybean and wheat raw agricultural commodities.  A multi-residue method for flutolanil has been previously submitted.  The method is for use only by experienced chemists who have demonstrated knowledge of the principals of trace organic analysis and have proven skills and abilities to run a complex residue analytical method obtaining accurate results at the part per billion level.  Users of this method are expected to perform additional method validation prior to using the method for either monitoring or enforcement.  The method can detect gross misuse.
   3. Magnitude of residues.  Sugarbeet, cotton and soybean seeds were treated with radiolabled and formulated flutolanil at 1.64 mg a.i./gram seed, 1.22 mg/g and 1.09 mg/g respectively.  The label and target rate was 1.25 mg/g.  Specimens were harvested and total radioactive residues (TRR) were determined for sugarbeet roots and tops, cotton gin trash and seed and soybean forage, hay and seed.  TRR values determined were less than 0.01 ppb for all specimens except treated cotton gin trash (0.013 ppb treated soybean forage (0.075 ppb) and treated soybean hay (0.057 ppb).  Extraction and analysis of soybean forage and hay specimens resulted in no detection of the parent flutolanil and a metabolite profile where no single metabolite exceeded 0.035 ppm.  For cotton gin trash, very low residue of flutolanil was detected (0.001 ppm) and a metabolite profile where no single metabolite exceeded 0.004 ppm.
B. Toxicological Profile
   An extensive battery of toxicology studies has been conducted with flutolanil.  EPA has evaluated the available toxicity data and considered its validity, completeness, and reliability as well as the relationship of the results of the studies to human risk.  The nature of the toxic effects caused by flutolanil is discussed in the document "Flutolanil, Human Health Risk Assessment. Requests for Inadvertent or Indirect Tolerances for use on soybean, wheat, corn and cotton, November 27, 2007" beginning on page 7 in docket ID number EPA-HQ-OPP-2007-1021.
      1.       Acute Toxicity.  [NA-Remove]
      2.       Genotoxicity.   [NA-Remove]
      3.       Reproductive and developmental toxicity.   [NA-Remove]
      4.       Subchronic toxicity.   [NA-Remove]	
      5.       Chronic toxicity.  [NA-Remove]
      6.       Animal metabolism.  The metabolism of flutolanil has been extensively studied in various species of mammals. Studies in rats, ruminants and poultry suggest that flutolanil is not well absorbed following oral administration.  Once absorbed, however, it is rapidly metabolized, primarily to desisopropylflutolanil and its conjugates, and rapidly excreted via urine and feces.  The proposed metabolic pathway and corresponding chemical structures were provided previously in MRIDs 42606602 and 43452301.
      7.       Metabolite toxicology. [NA-Remove]
      8.       Endocrine disruption.  No special studies have been conducted to investigate the potential of flutolanil to induce estrogenic or other endocrine effects. The standard battery of required toxicity studies has been completed. These studies include an evaluation of the potential effects on reproduction and development and an evaluation of the pathology of the endocrine organs following repeated or long-term exposure. These studies are generally con- sidered to be sufficient to detect any endocrine effects.   However, no evidence of such effects has been observed in the subchronic, chronic or reproductive studies previously discussed.  Thus, the potential for flutolanil to cause endocrine effects is considered to be minimal.
      9.       Toxicity  endpoint selection.   Flutolanil is of low acute toxicity via all routes
      of administration and did not induce significant maternal or developmental toxicity in either rats or rabbits, even at the limit dose of 1000 mg/kg/day.  Furthermore, no evidence of toxicity was noted following repeated dosing at 1000 mg/kg/day in a 21-day dermal toxicity study.  Thus acute dietary, occupational and residential risk assessments are not considered necessary.  The Agency has identified the 2-year chronic dog as a more appropriate endpoint for the chronic RfD.  This is based on clinical signs (emesis, salivation and soft stool) at 250 mg/kg/day following 65 weeks of exposure. The flutolanil risk assessment team selected a chronic RfD of 0.5 mg/kg/day (NOAEL of 50 mg/kg/day; 10x interspecies factor; 10x intraspecies factor, 1X FQPA SF).  The Agency has also determined that the cancer classification for flutolanil should be "not likely to be carcinogenic to humans," based on the absence of significant tumor increases in two adequate rodent carcinogencity studies.
C. Aggregate Exposure
      1. Dietary exposure. Chronic dietary risk analyses were conducted to
         estimate the potential flutolanil residues in/on the following crops:  rice, peanuts, potato, wheat, corn, cottonseed (undelinted), and soybeans.    Meat, milk, poultry, and egg residues were included.  Analyses were performed using the Lifeline TM Version 3.0 which incorporates data as reported by respondents in the USDA 1994-1996 and 1998 Nationwide Continuing Surveys of Food Intake by Individuals (CSFII) and accumulated exposure to the chemical for each commodity.  The number of individuals simulated was 3000.  Chronic exposure estimates to food were based on tolerance levels and assumed 100% crop treatment, yielding the worst case chronic dietary exposure estimates.
         The chronic Population Adjusted Dose (cPAD) was determined to be 0.5 mg/kg/day based on an oral NOAEL of 50 mg/kg/day in the dog chronic study and an uncertainty factor of 100X for inter- and intra-species variations and an FQPA children's safety factor of 1X.
         i. Food.  An acute dietary assessment is not required as there is no acute toxicity associated with flutolanil exposure.
         The chronic dietary exposure estimated food exposure to be 0.0026 mg/kg/day for the U.S. population, which was less than 1% of the cPAD.  The highest exposure group was infants, less than 1 year old, with exposures of .006 mg/kg/day, which represented 1.2 % of the cPAD.  These are considered conservative values as all exposure was based on tolerance levels and assumed all crops were treated with flutolanil. 
         ii. Drinking water.  The potential for flutolanil to leach into groundwater has been assessed in two terrestrial field dissipation studies, a long-term terrestrial field dissipation study, and an aquatic field dissipation study.  Under field conditions, the half-life of flutolanil varied from 101 to 123 days in the long-term study, which was consistent with the other field studies, and was approximately 180 days in the aquatic environment.  Flutolanil strongly adsorbs to soil following application and did not exhibit mobility under either terrestrial or aquatic conditions.  Based on these observations, the Agency concluded that the most important means of dissipation in surface water and also in ground water will most likely be dilution.  Due to the lack sufficient monitoring exposure data to complete a dietary risk assessment for flutolanil in drinking water, models that best accounted for the application of flutolanil to rice paddies were used to simulate exposure to flutolanil in drinking water.  Based on the First Approximation Rice Model and Screening Concentrations in Ground Water (SCI-GROW) model, the estimated environmental concentrations (EECs) of flutolanil for acute exposures are 3.8 parts per billion (ppb) for surface water and 0.34 ppb for ground water.  The EECs for chronic exposures are 3.8 ppb for surface water and 0.34 ppb for ground water.
      2.  Non-Dietary Exposure.  As a professional use turf and ornamental fungicide flutolanil is used primarily (>95%) on golf courses for control of brown patch disease (Rhizoctonia solani) as Prostar 50WP (EPA Reg No. 45639-153.  Very limited use of Prostar 50WP may occur on commercial ornamental turf by professional lawn care applicators or on sod farms.  The risk of flutolanil to these non-occupational handlers were assessed for inhalation risk.  The MOE's for these scenarios range from 1.4x10[3] to 4.4 x 10[4] for handlers.  
      Post-application inhalation exposure following turfgrass treatment is considered negligible and was not assessed.  Because certain flutolanil products are registered for use on residential lawns, postapplication exposure to infants may result in their hand-to-mouth activities on treated turf.  The MOE's for these scenarios ranged from 6.7 x 10[2] to 1.4 x 10[3].  These MOEs are greater than the LOC of 100 and above the Agency's level of concern.  
D. Cumulative Effects
      Cumulative effects from substances with a common mechanism of toxicity. Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider ``available information'' concerning the cumulative effects of a particular pesticide's residues and ``other substances that have a common mechanism of toxicity.'' Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to flutolanil and any other substances and flutolanil does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that flutolanil has a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's OPP concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's web site at  http://www.epa.gov/ pesticides/cumulative/. 
      Flutolanil has demonstrated only minimal toxicity in animal studies.  The mechanism of this toxicity is not known.  Furthermore, there are no available data to indicate that flutolanil has a common mechanism of toxicity with other substances.  Thus, only the potential risks from flutolanil are being considered in this document.
E. Safety Determination
      1.       U.S. Population.  The (cPAD) was determined to be 0.5 mg/kg/day based on an oral NOAEL of 50 mg/kg/day in the dog chronic study and an uncertainty factor of 100X for inter- and intra-species variations and an FQPA children's safety factor of 1X.  Based on the existing tolerances in rice, peanuts and secondary commodities plus the proposed tolerances in soybean and cotton  commodities, the chronic food exposure is estimated to be 0.0026 mg/kg/day for the U.S. population in general.  There is generally no concern for exposures below 100% of the cPAD since the cPAD represents the exposure level at or below which daily exposure over a lifetime will not pose any appreciable risks to human health.  Therefore, there is a reasonable certainty that no harm will result to the U.S. population in general from aggregate exposure to flutolanil.
      i. Acute Risk.  An acute risk assessment is not required as there is no acute toxicity associated with flutolanil exposure.
      ii.Chronic Risk.  Based on the toxicology data base and available information on anticipated residues, the chronic dietary exposure to the U.S. Population (total) was estimated to be 0.0026 mg/kg/day, which was less than 1% of the cPAD. In addition, there is potential for chronic dietary exposure to flutolanil in drinking water.  The DWLOC for the general population is 3 x 104 and for infants less than one year old 8.6 x 10[3].  Based on the use pattern, chronic residential exposure to residues of flutolanil in not expected.  In addition there is potential for chronic dietary exposure to flutolanil in drinking water.  After calculation DWLOCs and comparing them to the EECs for surface and ground water, the EPA concluded that the aggregate exposure to not exceed 100% of the cPAD.   The MOE's scenarios for the non-dietary exposure ranged from 6.7 x 10[2] to 1.4 x 10[3].  These MOEs are greater than the LOC of 100 and are above the Agency's level of concern.  Therefore, these three routes of exposure, when aggregated, present a certainty of no harm to the population.
      2.        Infants and children.  Chronic exposure to infants, less than 1 year old, the highest exposed population subgroup, was 0.006 mg/kg/day, which represented 1.2 % of the cPAD.  Data from reproductive and developmental toxicity studies are generally used to assess the potential for increased sensitivity of infants and children.  No evidence of developmental toxicity was evident.  Therefore, there is no reason to believe there is an increased sensitivity in infants and children. The FQPA safety factor was determined to be 1x. 
      3.        Short-term risk.  Short-term aggregate exposure takes into account residential exposure plus chronic exposure to food and water (considered to be a background exposure level).   EPA has determined that although residential exposure could occur with the use of flutolanil, no toxicological effects have been identified for short-term dermal toxicity. Incidental oral exposure to adult residential handlers is expected to be insignificant and is therefore not assessed. Incidental oral exposure to infants eating treated turf is assessed below under intermediate-term aggregate risk.
F. International Tolerances.
      Canada, Codex, and Mexico do not have maximum residue limits (MRLs) for flutolanil or desisopropyl-flutolanil residues on soybean, seed or cotton, seed.