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

EPA Registration Division contact: 
Hope Johnson (703) 305-5410

OAT AGRIO CO., LTD.
EPA Company No. 11581
 
PP 5F8408

	EPA has received a pesticide petition 5F8408 from OAT AGRIO CO., LTD., 1-3-1 Kanda Ogawa-machi, Chiyoda-ku, Tokyo 101-0052, Japan 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 by establishing a tolerance for residues of Flutianil, (Z)-2-[2-fluoro-5-(trifluoromethyl)phenylthio]-2-[3-(2-methoxyphenyl)-1,3-thiazolidin-2-ylidene]acetonitrile, including its metabolites and degradates, in or on apple at 0.15 ppm, apple, wet pomace at 0.30 ppm, cantaloupe at 0.07 ppm, cherry at 0.40 ppm, cucumber at 0.20 ppm, grape at 0.70 ppm, squash at 0.05 ppm, and strawberry at 0.50 ppm and to establish an exemption from the requirement of a tolerance for indirect or inadvertent residues of flutianil, including its metabolites and degradates, in or on all food commodities that do not have tolerances. 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                                        

 Plant metabolism.   

The plant metabolism of flutianil is adequately understood in four diverse crops: apple, cucumber, grape and lettuce. The parent compound, flutianil, accounted for the majority of residues extracted in all crops. The metabolism of flutianil in plants is understood for the purposes of the proposed tolerances. 


 Analytical method.
   
The following analytical method was used for apple, cantaloupe, cherry, cucumber, squash and strawberry samples:  residues were extracted with acetonitrile/water solution and the aqueous sample was cleaned up by liquid/liquid partition with hexane. The organic phase was concentrated and further cleaned up using a silica gel column. Quantitation was achieved by GC/MSD in selective ion monitoring mode. 

The lowest level of method validation (LLMV) in the apple study was 0.01 ppm. Based on recoveries of samples fortified at the LLMV, the limit of detection (LOD) and limit of quantitation (LOQ) were calculated as 0.001 ppm and 0.0037 ppm, respectively for the apple RAC, 0.002 ppm and 0.0046 ppm for apple juice, and as 0.0003 ppm and 0.00076 ppm, respectively, for apple wet pomace.

The LLMV in the cantaloupe study was 0.010 ppm. Based on recoveries of samples fortified at the LLMV, the LOD and LOQ were calculated as 0.001 ppm and 0.0038 ppm, respectively. 

For the cherry study, the LLMV was 0.010 ppm. 

Based on recoveries of samples fortified at the LLMV, the LOD and LOQ were calculated as 0.0009 ppm and 0.0027 ppm, respectively in the cucumber study. The LLMV in the cucumber study was 0.01 ppm.

In the squash study, the LLMV in this study was 0.01 ppm. Based on recoveries of samples fortified at the LLMV, LOD and LOQ were calculated as 0.001 ppm and 0.0030 ppm, respectively.

The LOD was determined to be 0.0025 ppm for strawberry, and the LOQ was 0.0076 ppm. The LLMV was 0.010 ppm for strawberry. 

In the grape RAC and PC study, the analytical method was as follows:  flutianil residues were analyzed and quantified in grapes, grape juice and raisins by gas chromatography after extraction and cleanup. Flutianil metabolite OC-56635 residues were analyzed and quantified in grapes, grape juice and raisins by high performance liquid chromatography with tandem mass spectral detection (LCMS/MS). A LOQ of 0.01 mg/kg was determined for flutianil and OC-56635 in grapes and grape juice. A LOQ of 0.10 mg/kg was determined for flutianil and OC-56635 in raisins. The limit of detection was set at 30% of the LOQ.

 Magnitude of residues.
   
Apple

Foliar applications of flutianil (V-10118, a 5EC formulation) at a rate of approximately 0.04 lb ai/A each were made 4 times (~7 day retreatment interval), for a total of approximately 0.16 lb ai/A in the apple magnitude of residues study. The results from the trials show that the maximum residues in/on apple were 0.095 ppm. V-10118 was also applied at 5X the application rate (approximately 0.2 lb ai/A) at three sites to provide apples for processing into juice and wet pomace. The results from the trials show that the maximum residues in/on apple juice to be 0.016 ppm and wet pomace to be 1 ppm.	

Cantaloupe

For cantaloupes, foliar applications of V-10118 at a rate of approximately 0.04 lb ai/A each were made 5 times (~7 day retreatment interval), for a total of approximately 0.20 lb ai/A.  The results from the trials show that the maximum residues in/on cantaloupe were 0.042 ppm. 


Cherry

Foliar applications of V-10118 at a rate of approximately 0.04 lb ai/A each were made 4 times (~7 day retreatment interval), for a total of approximately 0.16 lb ai/A for cherry.  Five applications were made at the Washington site for a total of approximately 0.20 lb ai/A due to a delay in crop maturity. The results from the trials show that the maximum residues in/on cherry were 0.26 ppm.

Cucumber

For cucumbers, six trials were conducted in the field and two trials were conducted in the greenhouse.  Foliar applications of V-10118 at a rate of approximately 0.04 lb ai/A each were made 5 times (~7 day retreatment interval), for a total of approximately 0.20 lb ai/A. The maximum residues in/on cucumber were 0.014 ppm.

Grape

Foliar applications of flutianil at a rate of approximately 0.09 lb ai/ha each were made 5 times (~7 day retreatment interval), for a total of approximately 0.49 lb ai/ha in the grape residue study.  Flutianil residues in treated grape samples ranged from <LOQ to 0.4977 ppm. OC-56635 residues in treated grape samples ranged from <LOQ to 0.0536 ppm.  For grape raisins and juice, flutianil was also applied at 5X the application rate (approximately 0.49 lb ai/ha per application) at one site to provide grapes for processing into juice and raisins.    Flutianil residues in grape juice were found with a maximum residue of 0.2059 ppm. Flutianil residues in raisins were found with a maximum residue of 0.2993 ppm.   OC-56635 residues in grape juice were found with a maximum residue of 0.0187 ppm.  OC-56635 residues in raisins were found with a maximum residue of <LOQ.  

Squash

For squash (summer), the trials were conducted foliar applications of V-10118 at a rate of approximately 0.04 lb ai/A each were made 5 times (~7 day retreatment interval), for a total of approximately 0.20 lb ai/A.  The results from the trials show that the maximum residue in/on summer squash is 0.021 ppm.

Strawberry

For strawberries, trials foliar applications of V-10118 at a rate of approximately 0.04 lb ai/A each were made 5 times (~7 day retreatment interval), for a total of approximately 0.20 lb ai/A.  
At the Florida trial, one additional application was needed to allow the fruit to ripen for a total of approximately 0.24 lb ai/A.  At the Colorado trial, two additional applications were needed to obtain fruit for harvest for a total of approximately 0.28 lb ai/A. The results from the trials show that the maximum residues in/on strawberry were 0.24 ppm. 

B. Toxicological Profile

      1. Acute toxicity. 

Technical flutianil shows low acute toxicity (Toxicity Category IV) via the oral, dermal and inhalation routes of exposure. Flutianil has a very low acute oral (LD50: >5,000 mg/kg bw), dermal (LD50: >5,000 mg/kg bw) and inhalation toxicity (LC50: >5.17 mg/L air) in male and female rats. Flutianil shows no irritation to the eye or skin and shows no skin sensitization potential under the conditions of the guinea pig maximization test. There were no acute neurotoxicity concerns. 

      2. Genotoxicity. 

Flutianil was tested for its genotoxic potential in a battery of four in vitro or in vivo studies covering all required end-points (gene mutations, chromosomal aberrations). There was no evidence of genotoxicity.

      3. Reproductive and developmental toxicity. 

Flutianil shows no evidence of primary developmental or reproductive effects. In the prenatal developmental toxicity studies in rats and rabbits and in the two-generation reproduction study in rats, neither fetal toxicity nor maternal toxicity was present. There was no evidence to suggest that Flutianil possessed a teratogenic potential in either species. 

      4. Subchronic toxicity. 

The subchronic toxicity of Flutianil was investigated in 90-day toxicity studies via the oral route in mouse, rat and dog and via inhalation and dermal routes in 28-day toxicity studies in the rat. Rats, dogs, and mice tolerated the chemical in excess of the limit dose without mortalities or clinical signs.  The NOAEL for oral studies were 10000 ppm (1387 mg/kg), 20000 ppm (1271 mg/kg/ bw for males and 1500 mg/kg/bw for females), and 1000 mg/kg in the mouse, rat and dog respectively.  A LOAEL was not established for mice, rats or dogs. The NOAEL in the rat for dermal exposure was >1000 mg/kg/day (highest dose tested). The NOAEL for inhalation was 14.4 mg/kg (100 mg/m[3]).
 
      5. Chronic toxicity. 

The chronic toxicity of Flutianil was evaluated in the dog, rat, and mouse. Oncogenic potential was evaluated in rats and mice. The NOAEL from the one-year feeding study in the dog was 1000 mg/kg bw/day, the highest dose tested. In a combined chronic/carcinogenicity rat study, the NOAEL in males rats was 6000 ppm (249 mg/kg), the highest dose evaluated.  The NOAEL in female rats in the combined study was 20000 ppm (1130 mg/kg/day), the highest dose tested. The LOAEL was not established for either sex. The NOAEL in the oncogenic mouse study was 10000 ppm (1084 mg/kg/day for males and 1063 mg/kg bw/day for females), the highest dose tested.  No flutianil induced carcinogenicity was observed. Flutianil is not likely to be carcinogenic, based on rat and mouse bioassays as well as negative in vivo and in vitro mutagenic effects.

      6. Animal metabolism.  

The elimination of flutianil was very rapid with over 90% being eliminated in the first 24 hours with little absorbed material.  Absorption of [[14]C]-flutianil was low and biotransformation of absorbed radioactivity was rapid, giving rise to an extensive range and number of metabolites. The number and nature of metabolites and difference in radio-profiles for animals dosed with [trifluoromethyl-[14]C] and [2-methoxyphenyl-U-[14]C] labelled flutianil suggested that cleavage of the molecule was a significant process in the metabolic pathway.  This was observed in both the rat and goat metabolism studies.

      7. Metabolite toxicology.  

One major soil metabolite was evaluated in a 28-day study which showed a NOAEL of 1380 mg/kg, which was similar to parent flutianil.  Mutagenicity testing (in vitro bacterial reverse mutation and mouse lymphoma gene mutation and in vivo mouse micronucleus) was conducted with three major metabolites and all were negative. None of the studies or assessments showed any toxicity of the metabolite greater than the parent, flutianil. 

      
      8. Endocrine disruption. 

The toxicology database for Flutianil is current and complete. There is no evidence that flutianil has any effect on endocrine organs or function in subchronic, chronic, carcinogenicity, developmental, reproductive or developmental neurotoxicity studies.  Furthermore, histological investigation of endocrine organs in chronic dog, rat and mouse studies did not indicate that the endocrine system is targeted by flutianil.

      9. Immunotoxicity. 

Flutianil was evaluated in a 28-day dietary immunotoxicity study.  The NOAEL was greater than 13000 ppm (1251 mg/kg/day).  There was no effect on immune function.

B.	Toxicological Endpoints 

The toxicological database for flutianil is complete for risk assessment. No single or repeated dose study conducted by any route of exposure (oral, dermal or inhalation) produced an adverse effect following flutianil exposure below, at, or above the limit dose (1000 mg/kg/day).  In addition, there was no evidence that flutianil produced susceptibility in fetuses or pups with prenatal or postnatal exposures. Flutianil is not carcinogenic based on the carcinogenicity studies in rats and mice and does not cause genotoxicity. Based on the toxicological studies for flutianil, no toxicological endpoints of concern or points of departure were selected for dietary (acute or chronic) or non-dietary (oral, dermal or inhalation route for any duration of exposure (short, intermediate or long term)) risk assessment. As a result, no dietary, occupational, residential, or aggregate quantitative risk assessments were conducted. Therefore, the Food Quality Protection Act (FQPA) safety factor to protect children is not needed. 

C.	Exposure Assessment

	1. 	Dietary Exposure
There is a potential for exposure to flutianil via food and drinking water based on the proposed uses; however, no adverse effects were observed in the toxicological studies for flutianil based on the route of exposure. No dietary exposure assessments are needed for the EPA to conclude with reasonable certainty that dietary exposures to flutianil do not pose a significant human health risk. 

	a.	Acute exposure

Acute dietary risk assessments are performed for a food-use pesticide if a toxicological study has indicated the possibility of an effect of concern occurring as a result of a one day or single exposure. No toxicological endpoint attributable to a single (acute) dietary exposure was identified; therefore, an acute risk assessment was not performed.

	b.	Chronic exposure

Chronic dietary risk assessments are performed for a food-use pesticide if a toxicological study has indicated the possibility of an effect of concern occurring as a result of prolonged or repeated exposure. Since no repeated dose study conducted by any route of exposure (oral, dermal or inhalation) produced an adverse effect following flutianil exposure below, at, or above the limit dose (1000 mg/kg/day), a chronic risk assessment was not performed. No toxicological endpoints of concern or points of departure were selected for chronic dietary assessment. 	

	c.	Cancer
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Flutianil is not carcinogenic based on the carcinogenicity studies in rats and mice and does not cause genotoxicity.
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      	2.	Non-dietary exposure
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	a.	Occupational exposure

Flutianil is formulated a 5% emulsifiable concentrate to be applied to strawberry, cantaloupe, cucumber, summer squash, apple, cherry, and grape using groundboom or airblast spray equipment. Based on the toxicological studies for flutianil, no toxicological endpoints of concern or points of departure were selected for non-dietary [oral, dermal or inhalation route for any duration of exposure (short, intermediate or long term)] risk assessment. As a result, no occupational risk assessments were conducted.

	b.	Residential (Non-occupational) exposure and risk

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Based on the toxicological studies for flutianil, no toxicological endpoints of concern or points of departure were selected for non-dietary [oral, dermal or inhalation route for any duration of exposure (short, intermediate or long term)] risk assessment. As a result, no residential risk assessments were conducted.
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D.  	Cumulative Effects
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Cumulative effects from substances with a common mechanism of toxicity: Section 408(b)(2)(D)(v) of the 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 flutianil and any other substances, and flutianil does not appear to produce a toxic metabolite produced by other substances. Therefore for the purposes of this tolerance action, EPA has not assumed that flutianil has a common mechanism of toxicity with other substances.

E. 	Safety Factor for Infants and Children
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In general, Section 408 of the FFDCA provides that EPA shall apply an additional ten-fold margin of safety for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity and the completeness of the database on toxicity and exposure unless EPA determines that a different margin of safety will be safe for infants and children. Margins of safety are incorporated into EPA risk assessments either directly through use of a MOE analysis or through using uncertainty (safety) factors in calculating a dose level that poses no appreciable risk to humans.

Prenatal developmental toxicity studies in rabbits and rats showed no qualitative/qualitative evidence of increased susceptibility in offspring.  The 2-generation reproduction study in rats did not show evidence of qualitative/qualitative evidence of increased susceptibility in offspring.

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The toxicological database for flutianil is complete for risk assessment. No single or repeated dose study conducted by any route of exposure (oral, dermal or inhalation) produced an adverse effect following flutianil exposure below, at, or above the limit dose (1000 mg/kg/day).  In addition, there was no evidence that flutianil produced susceptibility in fetuses or pups with prenatal or postnatal exposures. Based on the toxicological studies for flutianil, no toxicological endpoints of concern or points of departure were selected for risk assessment. A quantitative human health risk assessment was not conducted. Therefore, the Food Quality Protection Act (FQPA) safety factor to protect children is not needed.
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F. 	Aggregate Risks and Determination of Safety
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The proposed uses are the first uses proposed for flutianil in the United States. 
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 Acute risk
An acute risk assessment was not performed. No toxicological endpoint attributable to a single (acute) dietary exposure was identified. Therefore, acute risk from flutianil exposure to is not expected.

 Chronic risk
         
A chronic risk assessment was not performed. No toxicological endpoint attributable to a prolonged or repeated dietary exposure was identified. Therefore, chronic risk from flutianil exposure to is not expected.

 Short-term risk
         
Based on the toxicological studies for flutianil, no toxicological endpoints of concern or points of departure were selected for non-dietary (oral, dermal or inhalation route) for short-term risk assessment.

 Intermediate-term risk
         
Based on the toxicological studies for flutianil, no toxicological endpoints of concern or points of departure were selected for non-dietary (oral, dermal or inhalation route) for intermediate-term risk assessment.

Cancer risk 

Flutianil is not expected to pose a cancer risk.
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      Determination of safety 
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Since no toxicological endpoints of concern or points of departure were selected for risk assessment. A quantitative human health risk assessment was not conducted. Therefore, the Food Quality Protection Act (FQPA) safety factor to protect children is not needed.
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G.	 International Tolerances

Tolerances have been established in Japan for the following crops:  eggplant (0.2 ppm), cucumber (including gherkin (0.2 ppm)), pumpkin (including squash (0.05 ppm)), watermelon (0.05 ppm), melons (0.05 ppm) and strawberry (0.5 ppm).  Tolerances have been established in Korea for the following crops:  green and red pepper (0.5 ppm), strawberry (0.3 ppm), melon (0.05 ppm), watermelon (0.05 ppm), cucumber (0.05 ppm), Korean melon (0.05 ppm) and sweet pepper (0.5 ppm). 
