Document ID: EPA-HQ-OPP-2020-0004-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2020-03-03T05:00Z

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

EPA Registration Division contact: [insert name and telephone number with area code]

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 Linden Hill Rd., Suite 501,
Wilmington, DE 19808 

	EPA has received a pesticide petition (9F8809) from Nichino America, Inc., 4550 Linden Hill Rd., Suite 501, Wilmington, DE 19808 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

(Options (pick one))
   
   	1. by establishing a tolerance for residues of

	[Pyraclonil 1-(3-chloro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)-5-[methyl(prop-2-ynyl)amino]pyrazole-4-carbonitrile] in or on the raw agricultural commodity Rice, grain at 0.01 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. [A metabolism study was conducted with [3-pyrazole-[14]C]pyraclonil (P-label) and [3a-pyrazolyl-[14]C]pyraclonil (PP-label) to determine the nature and amount of residue uptake in rice after application to the paddy water at the 2.5 leaf stage.  The test substance was prepared to mimic a granular formulation application at a target rate of 0.18 lb a.i./A (200 g a.i./ha) and applied to the two treated plots (one for each label).  Two harvests, one at an immature stage (day 42) and the other at final harvest (day 113), were conducted.  The radioactive residue at the immature forage harvest was 0.326 and 0.366 mg eq/kg and increased approximately 5X to 1.39 and 1.61 mg eq/kg by the final harvest.  The radioactive residue in brown rice was very low (0.007 mg eq/kg).  In addition, most of the radioactive residue in brown rice (60.8% and 62.2%) and approximately half of the residue in straw (52.7% and 52.1%) was unextractable and was determined to be incorporated into proteins and starch.  No single compound exceeded 10% formation in any of the plant matrices (at immature or mature harvest).  The minor metabolites, PM-5 and PM-7, and other hydroxides of pyraclonil were identified.]

	2. Analytical method. [A method validation was performed to validate the method of analysis for pyraclonil and the metabolites M-1, PM-5, and PM-7 in the raw agricultural commodity (RAC) rice grain.  The LOQ for pyraclonil and each of the metabolites was 0.01 mg/kg (0.01 ppm).  Independent laboratory validation was performed of the methodology for the determination of residues of pyraclonil and the metabolites M-1, PM-5, and PM-7 in rice grain.  An LOQ of 0.01 mg/kg was achieved for each analyte and the validation was successful for pyraclonil, M-1, PM-5, and PM-7, monitoring two ion mass transitions per analyte. The independent laboratory validation met the criteria detailed in EPA OCSPP 860.1340.]

	3. Magnitude of residues. [Magnitude of the residue field trials for rice were conducted with one granular application of pyraclonil at a rate of 0.268 lb ai/A (equivalent to 0.3 kg ai/ha) to the flooded paddy immediately after seeding.  Plots treated at 3X or 5X rate were also included in case processing was needed.  At 99-152 days after the application, all rice residues were found to be non-detect (ND) or less than the limit of detection (<LOD) for pyraclonil, M-1, PM-5, and PM-7 on all samples except for one sample where residues of PM-5 were between the LOD and limit of quantitation (LOQ).  The duplicate treated sample from this same trial had ND residues for all analytes, including PM-5.  The results also show that after one application of pyraclonil at a 5X rate of 1.34 lb ai/A (1.50 kg ai/ha), residues of pyraclonil, M-1, PM-5, and PM-7 in the rice grain RAC collected for processing were ND and therefore the processing phase was not required.  In the decline trials all residues were similarly ND for all analytes in all samples at all time intervals.]

B. Toxicological Profile

	1. Acute toxicity.  [Pyraclonil demonstrates low oral, dermal, and inhalation toxicity. The acute oral LD50 values in the rat were 3,053 mg/kg bw for both sexes combined, 4,979 mg/kg for males and 1,127 mg/kg for females.  The acute dermal LD50 value was greater than 2,000 mg/kg bw.  The acute inhalation LC50 value in the rat was greater than 4.97 mg/L (4-hr).  Pyraclonil is not irritating to the eyes or skin.  Pyraclonil did not demonstrate any potential for skin sensitization.  For the acute neurotoxicity study, mortality and clinical signs were reported at 1,500 mg/kg bw for males and 400 mg/kg/day for females.  There were no test substance-related effects on brain weights or brain dimensions for perfused animals.  In addition, no test substance-related neuropathological lesions were observed.  Based on mortality and clinical observations following a single oral dose of pyraclonil, the no observed adverse effect level (NOAEL) of a single oral dose of pyraclonil to rats in this study was 400 mg/kg bw for males and 150 mg/kg bw females.]

	2. Genotoxicity. [Pyraclonil was tested in a standard battery of genotoxicity and mutagenicity tests in vitro and in vivo.  There was no indication of gene mutation either in the presence or absence of metabolic activation in both the bacterial reverse mutation and mammalian gene cell mutation tests.  The in vitro chromosome aberration in both Chinese Hamster Lung (CHL) cells and human lymphocytes demonstrated positive results, although the latest study CHL study conducted in 2018 was negative with and without metabolic activation.  The in vivo mouse bone marrow chromosome aberration and mouse erythrocyte micronucleus tests were negative.  These studies demonstrate that pyraclonil has no mutagenic or genotoxic potential in vivo.]

	3. Reproductive and developmental toxicity. [Pyraclonil is not considered to be a reproductive or a developmental toxicant.  In the rat two-generation reproduction study, the NOAEL for parental systemic and offspring parameters was 7.3 mg/kg bw/day for males and 11.1 mg/kg bw/day for females.  Parental effects included increased incidences of thyroid follicular cell hypertrophy in both sexes of the P and F1 generations, and offspring effects included decreased pup body weights.  Decreases in implantation sites and the number of pups born in F1 females were not treatment-related effects.  All offspring effects occurred in the presence of overt parental toxicity and were considered to be secondary to parental toxicity.    

In the rat developmental toxicity study, the NOAEL for maternal and prenatal developmental toxicity was 26 mg/kg bw/day.  At dose levels of 225 mg/kg bw/day both maternal animals and fetuses had reduced body weights, additionally fetuses had decreased cervical ossification.  In the rabbit developmental toxicity study, the NOAEL for maternal and prenatal developmental toxicity was 24 mg/kg bw/day.  At dose levels of 200 mg/kg bw/day, increased post-implantation loss, increased early intrauterine deaths, and decreased number of implantations were observed and attributed to both maternal and developmental toxicity. Additionally, fetuses had increased skeletal variations of the skull and sternebrae.  All developmental effects occurred in the presence of overt maternal toxicity.]   

	4. Subchronic toxicity. [The subchronic toxicity studies with pyraclonil include 28-day oral toxicity studies with rats, mice, and dogs and 90-day feeding studies with rats, mice, and dogs.  The most sensitive subchronic endpoint was observed following 90-days of administration to rats.  In this study, the NOAEL was 2.2 mg/kg bw/day in males and 2.44 mg/kg bw/day in females based on increased absolute and relative thyroid weights and thyroid follicular cell hypertrophy in both sexes observed at LOAELs of 108 and 120 mg/kg bw/day in males and females, respectively.]

	5. Chronic toxicity. [The oncogenic potential of pyraclonil was assessed in both the rat and the mouse.  In the rat combined chronic toxicity and carcinogenicity study, the NOAEL over a 24-month period of dietary administration with pyraclonil to the rats was 44 mg/kg kg/day for males and 58 mg/kg kg/day for females based on increased TSH in both sexes, non-statistically significant, but slight dose-dependent increases thyroid weights in both sexes, and thyroid follicular cell hypertrophy in females at 52 weeks.  The incidence of the thyroid follicular cell tumors is within historical controls.  In the mouse carcinogenicity study, the NOAEL was 210 mg/kg bw/day for males and 87 mg/kg bw/day for females based on based on increased incidence of foci of cellular alteration (eosinophilic) in the liver of female rats.  An increase in liver tumors were observed in female mice.  The NOAEL for the dog 1-year study was 5 mg/kg bw/day based on decreased body weight at 50 mg/kg bw/day in both sexes.] 

	6. Animal metabolism. [The metabolism of pyraclonil in animals is adequately understood. Pyraclonil was extensively metabolized and readily eliminated following oral administration to rodent (rat), poultry (laying hen), and ruminant (lactating goat) via excreta.  All three animals exhibited a similar pathway.  The parent chemical (pyraclonil) was metabolized or conjugated to many metabolites.  Since residues were not detected in the feed items, no methods were developed for the metabolites observed in the livestock metabolism studies.] 

	7. Metabolite toxicology. [The acute oral toxicity study, bacterial reverse mutation assay, and qualitative structure-activity-relationship ((Q)SAR) modeling are available for the environmental degradates M-1 (1-(3-chloro-4,5,6,7-tetrahydropyrazolo[1,5-α]pyridin-2-yl)-5-(methylamino)pyrazole-4-carbonitrile) and M-11 ((1-(3-chloro-4,5,6,7-tetrahydropyrazolo[1,5-α]pyridin-2-yl)-5-[methyl(prop-2-enyl)amino]pyrazole-4-carbonitrile).  In the acute oral toxicity studies in female rats, the oral LD50s were >300 and <2,000 mg/kg for both M-1 and M-11.  The results of the bacterial reverse mutation assay were negative with and without metabolic activation for both M-1 and M-11.  Derek Nexus (Q)SAR modeling was conducted using Derek Nexus v6.0.1 from Lhasa Limited for parent pyraclonil and both M-1 and M-11.  Based on the Derek modeling results, the degradates M-1 and M-11 contain no unique toxicity alerts when compared to the parent compound.  Based on the available acute oral toxicity studies, bacterial reverse mutation assays, Derek (Q)SAR modeling, and structural similarity of M-1 and M-11 to pyraclonil, the environmental degradates M-1 and M-11 are of equal toxicity to pyraclonil.]

	8. Endocrine disruption. [An evaluation of the potential effects on the endocrine systems of mammals has not been determined; however, no evidence of such effects was reported in the subchronic, chronic, or reproductive toxicology studies described above.  Thyroid effects were reported only in rats in the toxicological database and were secondary to liver effects.  Based on dietary and occupational risk assessments, the available points of departure (PODs) for chronic dietary and occupational exposure are protective of any potential thyroid effects.  .  There is no evidence that pyraclonil causes endocrine effects.]

C. Aggregate Exposure

	1. Dietary exposure. [Tier 1 acute and chronic aggregate exposure assessments were conducted for pyraclonil using Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID[TM], version 4.02; DEEM). A tolerance has been proposed for residues of pyraclonil on rice, grain. No adjustments were made for "percent crop treated" (i.e. 100% CT was assumed). The drinking water estimates selected for use in the dietary exposure assessment were the higher of the estimated drinking water concentrations (EDWCs) for surface and ground water. All consumption data for these assessments were taken from USDA NHANES 2-day Food Consumption Data for 2005-2010. Using the above assumptions, the resulting acute and chronic exposure estimates were 0.90% of the aPAD and 0.2% of the cPAD, respectively, for the most highly exposed sub-population (all infants).  At the 95th percentile, acute (food + drinking water) exposure to females 13-49 resulted in 1.62% of the aPAD.]

	i. Food. Acute Dietary Exposure [The pyraclonil acute dietary (food + drinking water) risk assessment for the general population was performed using an acute reference dose (aRfDGenPop) of 1.5 mg/kg bw based upon mortality and clinical effects in the acute neurotoxicity study in rats with a No Observable Adverse Effect Level (NOAEL) of 150 mg/kg bw and an uncertainty factor of 100X.  The 100X safety factor includes intra- and inter- species variability; no additional FQPA safety factor was required.  The pyraclonil acute dietary (food + drinking water) risk assessment for the females 13+ was performed using an acute reference dose (aRfDFemales 13+) of 0.24 mg/kg bw/day based on increased post-implantation loss, increased early intrauterine deaths, and decreased number of implantations in a rabbit developmental toxicity study (early intrauterine deaths may be the result a single dose effect).  The NOAEL for the aRfDfemales 13+ is 24 mg/kg bw/day with an uncertainty factor of 100X.  The 100X safety factor includes 10X intra- and 10X inter- species variability; no additional FQPA safety factor was required.  At the 95th percentile, acute (food + drinking water) exposure to the U.S. population resulted in 0.003929 mg/kg/day which accounts for 0.26% of the aRfD of 1.5 mg/kg bw/day.  At the 95th percentile, acute (food + drinking water) exposure to all infants (the most highly exposed subpopulation) resulted in 0.013444 mg/kg/day which accounts for 0.90% of the aRfD of 1.5 mg/kg bw/day. At the 95th percentile, acute (food + drinking water) exposure to females 13-49 resulted in 0.003880 mg/kg/day which accounts for 1.62% of the aRfD of 0.24 mg/kg/day.  Since the EPA generally has no concern for exposures below 100% of the aRfD, there is a reasonable certainty that no harm will result from dietary (food + drinking water) exposure to residues arising from the proposed uses for pyraclonil.]

Chronic Dietary Exposure:  The pyraclonil chronic dietary (food + drinking water) risk assessment was performed for all population subgroups using a cRfD of 0.243 mg/kg bw/day based increased incidences of thyroid follicular cell hypertrophy in a 2-generation rat reproduction study.  The NOAEL for the cRfD is 7.3 mg/kg bw/day with an uncertainty factor of 30X.  The 30X safety factor includes 3X intra- and 10X inter-species variability based on effects being limit to thyroid effects in rats only; no additional FQPA safety factor was required.  Chronic (food + drinking water) exposure to the U.S. population resulted in 0.000137 mg/kg/day which accounts for 0.1% of the RfD of 0.243 mg/kg/day. The most highly exposed sub-population was all infants with 0.000511 mg/kg/day which accounts for 0.2% of the RfD of 0.243 mg/kg/day.  Since the EPA generally has no concern for exposures below 100% of the RfD, there is a reasonable certainty that no harm will result from dietary (food + drinking water) exposure to residues arising from the proposed uses for pyraclonil.]

	ii. Drinking water. [Exponent modeled the estimated drinking water concentrations (EDWCs) for the proposed uses of pyraclonil according to EPA standard methods using EPA's latest PWC model (v 1.52).  Of all the EDWCs predicted for surface water and ground water screening, the highest daily value (peak) EDWC of 73.7 ppb and the highest post breakthrough average EDWC of 6.66 ppb were used in the acute and chronic dietary risk assessments, respectively.  The acute and chronic EDWCs were input directly into the DEEM-FCID(TM) software as "water, direct, all sources" and "water, indirect, all sources" to model the acute and chronic drinking water exposures. Acute and chronic exposure from drinking water are included in the dietary risk assessments described above.] 

	2. Non-dietary exposure. [Occupational exposure and risk assessments were conducted for all proposed agricultural uses of pyraclonil in the current petition.  Pyraclonil is applied as a granule to rice via aerial application. Applications to rice will be made at a maximum single application rate of 0.268 lb a.i./A with one application per year.  A dermal assessment was not conducted because no toxicity was observed in the 28-day dermal toxicity study with rats and there were no developmental effects or pup effects in the reproductive or developmental toxicity studies with the exception of pup body weight reduction which occurred in the presence of maternal toxicity.  The inhalation assessment was conducted at baseline (no respirator). The point of departure (POD) for occupational inhalation exposure is 7.3 mg/kg/day based on increased incidences of thyroid follicular cell hypertrophy in a 2-generation rat reproduction study.  The level of concern (LOC) for inhalation risk estimate is a MOE of 30 and includes 3X intra- and 10X inter-species variability based on effects being limit to thyroid effects in rats only. Baseline inhalation MOEs ranged from 1,400 to 12,000. Since the EPA generally has no concern for MOEs above the LOC, at there is a reasonable certainty that no harm will result from short- and intermediate-term occupational exposures arising from all proposed uses for pyraclonil.]

D. Cumulative Effects

	[Cumulative Exposure to Substances with a Common Mechanism of Toxicity: Section 408(b)(2)(D)(v) 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". EPA consideration of a common mechanism of toxicity is not appropriate at this time since EPA does not have information to indicate that toxic effects produced by pyraclonil would be cumulative with those of any other chemical compounds; thus, only the potential risks of pyraclonil are considered in this exposure assessment.] 

E. Safety Determination

	1. U.S. population. [Using the conservative exposure assumptions described above and based on the completeness and reliability of the toxicity data, the aggregate exposure (food + drinking water) to pyraclonil will utilize 0.26% of the aPAD and 0.1% of the cPAD for the general US population.  The aggregate exposure (food + drinking water) to pyraclonil will utilize 1.62% of the aPAD for females 13-49.  EPA generally has no concern for exposures below 100% of the aPAD or cPAD. Therefore, based on the completeness and reliability of the toxicity database and the conservative exposure assessment, there is a reasonable certainty that no harm will result from aggregate exposure to residues of pyraclonil.]

	2. Infants and children. [Using the conservative assumptions described above and based on the completeness and reliability of the toxicity database, the acute aggregate (food plus water) exposure calculation for all proposed uses of pyraclonil is equivalent to 0.90% (aPAD) and 0.2% (cPAD) for all infants. Since the EPA generally has no concern for exposures below 100% of the cRfD or aRfD, there is a reasonable certainty that no harm will occur to infants and children from aggregate exposures arising from all proposed uses for pyraclonil.]

F. International Tolerances [International tolerances have been established in Japan in brown rice and other cereal grains at an MRL of 0.05 ppm.  In Korea, an MRL is established at 0.05 mg/kg in rice grain.  A draft MRL in China at 0.3 mg/kg for paddy rice and brown rice has been established as a temporary limit.]