Document ID: EPA-HQ-OPP-2020-0065-0007
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2021-07-23T04:00Z

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

EPA Registration Division contact: Marietta Echeverria, 703-305-8578

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:

E.I. du Pont de Nemours and Company

PP No. 9F8795

	EPA has received a pesticide petition (PP No. 9F8795) from E.I. du Pont de Nemours & Company ("DuPont"), Chestnut Run Plaza, 974 Centre Road, Wilmington, DE 19805, 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 fluazaindolizine, including its metabolites and their conjugates, expressed as the stoichiometric equivalent of fluazaindolizine, in or on the raw agricultural commodities: Carrots at 0.05 parts per million (ppm); Cucurbit Vegetables (Crop Group 9) at 0.15 ppm; Fruiting Vegetables (Crop Group 8-10) at 0.07 ppm; Tomato, dried at 0.4 ppm; Tuberous and Corm Vegetables (Crop Subgroup 1C) at 0.2 ppm; and establishing tolerances for residues of fluazaindolizine including its metabolites and degradates, in the animal commodities: Cattle, fat at 0.01 ppm; Cattle, meat at 0.01 ppm;  Cattle, meat byproducts at 0.01 ppm; Eggs at 0.01 ppm;  Goat, fat at 0.01 ppm; Goat, meat at 0.01 ppm;  Goat, meat byproducts at 0.01 ppm; Hog, fat at 0.01 ppm; Hog, meat at 0.01 ppm;  Hog, meat byproducts at 0.01 ppm; Horse, fat at 0.01 ppm; Horse, fat at 0.01 ppm;  Horse, meat at 0.01 ppm; Horse, meat byproducts at 0.01 ppm; Milk at 0.01 ppm; Poultry, fat at 0.01 ppm; Poultry, meat at 0.01 ppm; Poultry, meat byproducts at 0.01 ppm; Sheep, fat at 0.01 ppm; Sheep, meat at 0.01 ppm;  Sheep, byproducts at 0.01 ppm. 

In addition, DuPont is proposing pursuant to section 408(d) of the Federal Food, Drug and cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR part 180 to establish indirect or inadvertent tolerances for residues of fluazaindolizine, including its metabolites and their conjugates, expressed as the stoichiometric equivalent of fluazaindolizine, in or on the following commodities: Animal feed, nongrass, group 18, forage at 0.01 ppm; Animal feed, nongrass, group 18, hay at 0.015 ppm; Animal feed, nongrass, group 18, straw at 0.15 ppm; Berry, Low Growing (Crop Subgroup 13-07G) at 0.01 ppm; Grain, cereal, forage, fodder, and straw, group 16, forage at 0.01 ppm; Grain, cereal, forage, fodder, and straw, group 16, hay at 0.015 ppm; Grain, cereal, forage, fodder, and straw, group 16, stover at 0.15 ppm; Grain, cereal, forage, fodder, and straw, group 16, straw at 0.15 ppm; Grain, cereal, group 15 at 0.01 ppm; Grass, forage, fodder and hay, group 17, forage at 0.01 ppm; Grass, forage, fodder and hay, group 17, hay at 0.015 ppm; Grass, forage, fodder and hay, group 17, straw at 0.15 ppm; Oilseed, group 20 at 0.8 ppm; Rapeseed, forage at 0.09 ppm; Stalk, stem and leaf petiole vegetables group 22 at 0.03 ppm; Vegetable, Brassica, head and stem, group 5-16 at 0.015 ppm; Vegetable, bulb, group 3-07 at 0.03 ppm; Vegetable, foliage of legume, group 7, forage at 0.09 ppm; Vegetable, foliage of legume, group 7, hay at 0.4 ppm; Vegetable, leafy, group 4-16 at 0.015 ppm; Vegetable, leaves of root and tuber, group 2 at 0.015 ppm; Vegetable, legume, group 6 at 0.8 ppm; Vegetable, root (except sugar beet), subgroup 1B at 0.02 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

 Plant metabolism. 
The metabolism of fluazaindolizine is adequately understood to support the proposed tolerances. Studies in cucurbits (cucumbers, melons, squash), fruiting vegetables (tomatoes, peppers), carrots and potatoes were treated with two different application scenarios. Plant metabolism and rotational crop studies conducted with [14]C-fluazaindolizine demonstrated that the parent compound was typically not the most prevalent residue but that a mixture of metabolites comprised the majority of the residue in the various crop commodities. The metabolites were mostly highly conjugated derivatives of IN-F4106 and IN-QEK31. The behavior and major pathways were consistent among the various crop groups in both the primary and rotational crops with any differences attributed to the degree and complexity of conjugation of metabolites measured in analytical methods. 

 Livestock Metabolism 
The metabolism of fluazaindolizine in ruminants and poultry is adequately understood to support the proposed tolerances. Metabolism studies in animals (rats, mice, goats and poultry) were conducted with [[14]C]fluazaindolizine.  In addition, supplementary metabolism studies have also been conducted with major plant metabolites including [[14]C]IN-QEK31 in the goat and hen and with [[14]C]IN-QZY47 and [[14]C]IN-TMQ01 in the goat. In addition, supplementary metabolism studies in the goat, hen and rat have also been conducted with the major plant metabolites. These studies show metabolic pathways for fluazaindolizine in ruminants and poultry is consistent with rat and mouse metabolism. 

Livestock metabolism studies with fluazaindolizine demonstrated low transfer potential to tissues and milk or eggs.

 Analytical method. 
An analytical method was developed and independently validated for the detection and quantification of fluazaindolizine degradants/metabolites in various crop matrices. The method was validated at 0.010 and 0.10 ppm in all matrices using an LC/MS/MS system operating with an electrospray interface (ESI) operating in both positive and negative polarities. The analytical method is suitable for enforcement/monitoring and data generation for regulatory studies.

 Magnitude of residues. 
An extensive program of residue trials was conducted on primary treated crops, rotational crops, and processed commodities. The results of the field trials show that there are significant levels of quantifiable residues for seven post-hydrolysis metabolites with no strong patterns of distribution between commodities or sampling timeframes. 

For commodities of animal origin, there was very little transfer of residues to milk or edible commodities. Cattle feeding studies conducted with fluazaindolizine demonstrated very little transfer of residues to milk or edible commodities. Goat metabolism studies with two metabolites indicated very little transfer of residues to milk and meat. Tolerances are proposed for animal commodities based upon the results of the cattle feeding study. A poultry feeding study was not required, therefore no poultry commodity tolerances are necessary.

B. Toxicological Profile

 		1. Acute toxicity.  According to EPA criteria, technical fluazaindolizine is classified as acute toxicology category III based on overall results from several studies. This compound is considered acute toxicology category III for acute oral toxicity and eye irritation, and category IV for dermal and inhalation toxicity and skin irritation. Technical fluazaindolizine is not a dermal sensitizer. 
 
 No evidence of neurotoxicity was observed in studies conducted with fluazaindolizine in rats. The NOAEL for neurotoxicity was 1750 mg/kg bw based on the absence of primary neurotoxic effects at the highest dose level evaluated. The NOAEL for systemic toxicity was 125 mg/kg bw based on reductions in body weight in males at 450 and 1750 mg/kg bw doses.

 	2. Genotoxicty. Fluazaindolizine was evaluated in a battery of in vitro and in vivo genetic toxicology studies. Negative results were obtained in most studies. It was negative in the bacterial mutagenicity test, as well as in the mammalian gene mutation test. It was positive in the in vitro chromosome aberration test, but negative the higher tier in vivo mouse micronucleus test. The weight of evidence shows that fluazaindolizine does not pose a mutagenic hazard.

  	3. Reproductive and developmental toxicity. Based on the results of reproduction studies in rats and developmental toxicity studies in rats and rabbits, fluazaindolizine does not pose a specific concern for effects on reproduction or development. 

  4. Subacute/Subchronic toxicity. The primary toxicological findings in short-term, repeated-dose feeding toxicity studies included marked liver toxicity at doses in dogs that also caused adverse effects on body weight and nutritional status. The NOAEL in the 90-day dog study was 50 ppm (20.4 mg/kg bw/day in males and 20.9 mg/kg bw/day in females). 
  
  Dermal application of fluazaindolizine to rats for 28 days did not result in any treatment-related findings up to and including a maximum dose of 1000 mg/kg bw/day.
  
  Fluazaindolizine showed no evidence of immunotoxicity in a 28-day feeding study in rats and no evidence of neurotoxicity in a 90-day feeding study in rats. 
  
  No treatment-related clinical signs indicative of potential neurotoxicity were observed in short-term and long-term exposure studies in rats, mice or dogs. 
 
  		5. Chronic toxicity. Based on the results of chronic feeding studies in rats and mice, fluazaindolizine is not a carcinogen. The lowest NOAEL following chronic, long-term feeding is 1000 ppm (35.8 and 36.6 mg/kg bw/day for males and females, respectively) and is based on liver enzyme changes, liver histopathology and effects on red blood cell mass parameters in the one-year dog study at 2000 ppm.   

  	6. Animal metabolism. The metabolism of [[14]C]fluazaindolizine was extensively investigated in rats (low and high dose and repeated low dose administration). Greater than 90% of the administered dose was eliminated in urine and feces over 48 hours. There was essentially no elimination of radioactivity via expired air. In rats, the portion of the dose eliminated in urine was comparable to that eliminated in feces. The excretion pattern following multiple oral administrations was similar to that following a single oral administration indicating there were no changes to the elimination or metabolic pathway.
  Absorption appeared to be proportional to the dose administered as the AUCs (0-T) increased approximately 16 to 22.6-fold relative to the 20-fold increase in dose (10 to 200 mg/kg).  While the time to reach mean peak concentration (Tmax) was prolonged in the high dose rats (ca 3-6 h), as compared to the low dose rats (ca 0.25 to 0.625 h), plasma half-lives were similar and relatively short in all dose groups ranging from 8 to 11.4 h in low dose rats and 8.4 to 13.4 h in the high dose groups. Tissue clearance was rapid with less than 1% remaining in tissues after 168 hours. There is no indication of bioaccumulation as tissue to plasma ratios are close to unity. 
  
  Fluazaindolizine was readily absorbed with bile cannulation experiments in rats, indicating that between 47.6 to 59.1% of the dose was absorbed at the 10 mg/kg dose and between 44.1 to 49.5% absorbed from the 200 mg/kg dose. Fluazaindolizine is mostly eliminated intact due to its chemical characteristics of being ionized at physiological pH with high aqueous solubility with between 23 to 55% of the dose being eliminated directly in the urine when considering the cage wash being urinary in nature. Unmetabolized fluazaindolizine in urine and feces accounted for 68.1 to 86.4% of the dose.
   
  The primary biotransformation pathways of fluazaindolizine involved O-demethylation, hydroxylation of the phenyl ring, and hydrolysis of the amide bond.  Direct hydroxylation of the phenyl ring of fluazaindolizine resulted in the formation of the metabolite IN-UHD20 (up to 7.2% of the dose).  Fluazaindolizine and the metabolite IN-UHD20 undergo O-demethylation to form metabolites IN-REG72 (0.1 to 5.2% dose) and IN-UHD21 (0-0.6% dose).  Direct hydrolysis of fluazaindolizine or IN-REG72, produced metabolites IN-F4106 and IN-A5760, respectively, which contained only the phenyl ring and were found at a low level (<0.8 % dose).  IN-F4106 appeared to be rapidly O-demethylated to IN-A5760, which is mostly found as a sulfate conjugate (up to 7.3% of the dose), and to a lesser extent as a glucuronide conjugate in the urine (<0.8% dose).  IN-QEK31, which contains the imidazopyridine rings from the hydrolysis reaction, was found in up to 9.7% of the dose.  IN-QEK31 does not appear to undergo further metabolism and is readily excreted.  A glucuronide conjugate of IN-UHD20 and its glucuronide-containing bridge hydrolysis product, hydroxylated IN-A5760, and sulfate conjugates of IN-REG72, were found eliminated in minor amounts in the bile (<0.3% dose).  IN-RYC33, a minor metabolite, was also found in the bile and the urine of female rats (high dose only <0.2% dose). The major metabolic pathways of fluazaindolizine in rats, mice and goats were consistent across these species. Analysis of plasma from rats, mice and beagle dogs treated with fluazaindolizine also confirmed similar biotransformation pathways in rodents and dogs.
 
  	7. Metabolite toxicology. Toxicology studies are available for the major metabolites of fluazaindolizine. These metabolites are of similar or lower toxicity than the parent. One minor metabolite (IN-VM862) that occurs at very low levels showed greater toxicity than parent, but based on the negligible exposure to that metabolite, it is not of concern.  

  	8. Endocrine disruption. No relevant effects were observed on any endocrine tissue in short and long-term studies in rats, mice and dogs to suggest any adverse impact on thyroid hormone homeostasis, estrogen or androgen pathways, or on steroid biosynthesis. Initial findings of decreased accessory sex organ weights in an intact male assay in rats were not confirmed in other rat studies, and were interpreted to be the result of excessive toxicity causing secondary effects at high doses, and the current control group having a higher than expected weight based on historical control data. 

C. Aggregate Exposure. The following reference doses are proposed based on the extensive toxicology database of fluazaindolizine. An Acute RfD of 1.25 mg/kg bw/day, is based on the NOAEL of 125 mg/kg from the acute neurotoxicity study in rats with standard uncertainty factors of 10x for intraspecies and 10x for interspecies extrapolation. 

A Chronic RfD of 0.36 mg/kg bw/day is based on the NOAEL of 36 mg/kg for liver toxicity in the one-year dog toxicity study and using standard uncertainty factors.

 Dietary exposure.
         i. Food.
Acute Dietary Risk: Estimates of the US acute exposure from food were determined with Dietary Exposure Evaluation Model-Food Commodity Intake Database (DEEM-FCID(TM), Version 4.02, 05-10-c) based on the National Health and Nutrition Examination Survey (NHANES) 2-day food consumption data for 2005-2010. The acute dietary assessment used high total Parent Equivalent (tPEQ) residues for the 7 post-hydrolysis analytes from supervised field trials for primary treated crops and rotational crops, experimentally determined average processing factors, calculated high residues in livestock commodities, and the conservative assumption of 100% crop treated. For crops which are both primary treated crops and rotational crops, the sum of high residues was used for the estimate.  Residues for primary treated crops were translated between crops based on US EPA HED SOP 2000.1 ("Crop Group/Subgroup Field Trial Data Translation", Sept 12, 2000). Residues for rotational crops were translated between crops based on the OECD Guidance Document on Residues in Rotational Crops, ENV/JM/MONO(2018)9. 
The 95th percentile acute exposure of the US population from food commodities was determined to be 0.044755 mg/kg bw/day, 3.6% of the proposed acute reference dose of 1.25 mg/kg bw. The calculated acute exposures of all US subpopulations were <10% of the proposed acute reference dose indicating there are no short-term consumer intake concerns. 
Chronic Dietary Risk: Estimates of the US chronic exposure from food were determined using the same model and inputs as for the US acute exposure.  The chronic dietary assessment used median total Parent Equivalent (tPEQ) residues for the 7 post-hydrolysis analytes from supervised field trials for primary treated crops and rotational crops.
The chronic exposure of the US population from food commodities was determined to be 0.001622 mg/kg bw/day, <1% of the proposed chronic reference dose of 0.36 mg/kg bw/day. The calculated chronic exposures of all US subpopulations were <2% of the proposed chronic reference dose indicating there are no long-term consumer intake concerns. 

ii. Drinking water. Estimates of fluazaindolizine concentrations in groundwater and surface water from the proposed uses of fluazaindolizine were evaluated with current US EPA modeling tools and guidance.  The aerobic soil DT50 from each soil was calculated by combining the metabolism study residues of parent and all metabolites (i.e. the TTR approach which represents the worst-case for each soil for generation of DT50). The highest chronic and peak concentrations were modelled following applications evaluated using groundwater exposure modeling tool (Pesticide Water Calculator (PWC), Version 1.52).  Based on the modeling inputs following US EPA guidance, the highest peak and chronic concentrations are 1248 and 1015 ppb, respectively, across all the crops and use rates on the proposed label (2 applications at 2 lb/acre).  These concentrations are carried forward in the acute and chronic dietary risk assessments.   
When the groundwater concentrations were included for drinking water in the acute and chronic aggregate assessments to evaluate acute and chronic exposure and risk from food and drinking water, no population including the general U.S. population and all subpopulations had an exposure greater than 21% of the acute or greater than 25% of the chronic reference dose, indicating a significant margin of safety.  These results indicate that a reasonable certainty exists that fluazaindolizine residues in drinking water will not contribute significantly to the aggregate human risk.

        2. Non-dietary exposure. Since there are currently no registered residential uses for fluazaindolizine, non-dietary residential exposure is not expected. Based on the proposed conditions of usage, coupled with its low volatility and low inhalation toxicity, residential exposure to fluazaindolizine through drift is not anticipated to occur. Therefore, residential non-dietary exposure is not a concern. 

D. Cumulative Effects A determination has not been made that fluazaindolizine has a common mechanism of toxicity with other substances. Fluazaindolizine does not appear to produce a common toxic metabolite with other substances. A cumulative risk assessment was, therefore, not performed for this analysis.

E. Safety Determination 

	1. U.S. population.  Based on risk assessments performed using worst-case exposure assumptions there is a reasonable certainty that no harm will result to the general population from the aggregate exposure to fluazaindolizine. No additional safety factors are warranted.

	2. Infants and children.  Based on the risk assessments performed using worst-case exposure assumptions there is a reasonable certainty that no harm will result to the infants and children from the aggregate exposure to fluazaindolizine. No additional safety factors are warranted.

F. International Tolerances

	No tolerances have been established to date for fluazaindolizine.