Document ID: EPA-HQ-OPP-2014-0590-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2014-12-17T05:00Z

Interregional Research Project #4 (IR-4)
 Petition #4E8302

 EPA has received a pesticide petition (4E8302) from IR-4, IR-4 Project Headquarters, Rutgers, The State University of NJ, 500 College Road East, Suite 201 W, Princeton, NJ 08540 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 pyrimethanil (4,6-dimethyl-N- phenyl-2-pyrimidinamine) in or on the raw agricultural commodities cucumber at 1.5 ppm, Orange subgroup 10-10A at 10 ppm, Lemon subgroup 10-10B at 11 ppm, Grapefruit subgroup 10-10C at 10 ppm, Fruit, pome, group 11-10 at 14 ppm, Fruit, stone, group 12-12 at 10 ppm, and Tomato subgroup 8-10A at 0.5 ppm. The petitioner also requests that upon approval of the above tolerances, that the tolerances for fruit, citrus, group 10 except lemon, postharvest; lemon, preharvest and postharvest; fruit, pome, group 11 (pre-harvest and post-harvest); fruit, stone, group 12; and tomato be removed as unnecessary and also requests that the existing tolerance for "Onion, bulb, subgroup 3-07A" be changed from 2.0 ppm to 0.20 ppm..  EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of the 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 metabolic profile of pyrimethanil has been investigated following application to five different crops (apple, carrots, grapes, lettuce and tomatoes) and is well understood. In plants, pyrimethanil is the only significant residue ranging from essentially all of the Total Radioactive Residues (TRR) in carrots and tomatoes to 44% in lettuce.  Limited metabolism of pyrimethanil occurs with minor amounts (less than 10%) of the phenyl and pyrimidyl hydroxylated metabolites (AE C614276, AE C614277, AE C614278, and AE C621312) being released after acid hydrolysis. Analysis of the foliage from apples and carrots confirmed that the metabolism of pyrimethanil in plants proceeded primarily via hydroxylation of the aromatic ring structures as well as the methyl groups.

 2. Analytical method. The plant metabolism studies demonstrated that analysis for the parent compound, pyrimethanil is sufficient to enable the assessment of the relevant residues in crop commodities. Pyrimethanil was extracted from cucmbers by homogenization with acetone.  After clean-up, an aliquot of the extract was diluted with a mixture of acetonitrile and water with subsequent residue determination by HPLC-MS/MS.  The method allows the detection and measurement of residues in or on agricultural commodities at or above the proposed tolerance level.

 3. Magnitude of residues. Magnitude of residue trials were conducted for pyrimethanil on cucumbers grown in the greenhouse. Trials were conducted in various regions across the United States and Canada in accordance with EPA guidance for crop field trials under OPPTS 860.1500.

 B. Toxicological Profile

 1. Acute toxicity. Pyrimethanil shows low toxicity by the oral (toxicity category III), inhalation (toxicity category III), and dermal (toxicity category IV) routes. It is slightly irritating to the eyes and non-irritating to the skin in rabbit studies. Pyrimethanil is not a dermal sensitizer.  Acute neurotoxicity of pyrimethanil in the rat was assessed, the NOAEL was 100 mg/kg due to reduced body temperature in males, and transient behavioral effects observed at the high dose tested (HDT).

 2. Genotoxicty. Pyrimethanil is not mutagenic or genotoxic in any assay in either the presence or absence of metabolic activation.

 3. Reproductive and developmental toxicity. Pyrimethanil is not a developmental or reproductive toxicant.  An oral developmental toxicity study in the Sprague Dawley rat did not reveal any evidence of teratogenic potential. The maternal and developmental NOAEL was 85 mg/kg/day.  An oral developmental toxicity study in New Zealand rabbits did not reveal any evidence of teratogenic potential and the NOAEL was 45 mg/kg/day. The maternal and developmental LOAEL was 300 mg/kg/day due to reduced body weights, reduced fecal production, and food consumption in the dams and decreased mean body weight, body weight gain, food consumption, and an increased incidence of fetuses with 13 thoracic vertebrae and ribs. A two-generation reproduction study in the Sprague-Dawley rats did not indicate any disruption of reproductive function.  The NOAEL for maternal and developmental toxicity was 20.9 mg/kg/day due to reduced body weights at higher dose levels, and the reproductive NOAEL was 266.7 mg/kg/day, the HDT.

       4. Subchronic toxicity. A 28 - day dietary toxicity study was conducted in CD-
 1 mice established a NOAEL of 202 mg/kg/day.  A 90-day dietary toxicity study in Sprague-Dawley rats showed a NOAEL of 54.5 and 66.7, in males and females, respectively. A 90-day dietary toxicity study was conducted in CD-1 mice and demonstrated a NOAEL of 139 and 203 mg/kg/day in males and females, respectively, based on changes found in the kidney, liver, thyroid, and urinary bladder at higher dose levels.  A 90-day oral toxicity study in dogs showed a NOAEL of 80 mg/kg/day due to decreased body weight and food consumption and changes in clinical chemistry endpoints at 800 mg/kg/day.  A subchronic neurotoxicity study in Sprague-Dawley rats indicated no treatment-related findings in behavioral assessments, neuropathology or brain morphometrics. The NOAEL was 44.3 mg/kg/day in females based upon decreased mean body weight, body weight gain and food consumption at 429.9 mg/kg/day. There were no treatment related effects in males at any dose level up to 391.9 mg/kg/day.  A 28-day immunotoxicity study conducted in female Sprague-Dawley rats revealed no evidence of immune suppression at dose levels up to and including 652 mg/kg/day, the HDT.

 5. Chronic toxicity A 12-month chronic toxicity study in the dog demonstrated a NOAEL of 30 mg/kg/day due to a decrease in mean body weight gain and mean consumption of food and water at higher dose levels. Two oncogenicity studies were conducted using CD-1 mice continually exposed to pyrimethanil by administration in the diet. These lifetime feeding studies demonstrated no evidence of oncogenic potential at dose levels up to, and including 984 mg/kg/day (males) and 1217 mg/kg/day (females), the HDT. A 2-year combined chronic toxicity/oncogenicity study conducted in the Sprague-Dawley rat showed a NOAEL of 17 mg/kg/day (males) and 22 mg/kg/day (females) due to decreased body weight gain and food consumption, and effects on the liver and thyroid at 221 mg/kg/day (males) and 291 mg/kg/day (females).  The results of mechanistic studies, demonstrate that the thyroid effects are likely secondary due to induction of enzymes in the liver involved in metabolism of thyroid hormones, a well characterized, threshold-mediated mechanism. 

 6. Animal metabolism. Metabolism and pharmacokinetic studies in the rat show rapid absorption and elimination within 24-hours of pyrimethanil administration. The major routes of elimination were the urine (approximately 72% of the administered dose), and the feces (17-18% of the administered dose). The main pathways of metabolism involved oxidation to phenols in either or both
 aromatic rings. The minor pathway of metabolism involved oxidation of the methyl group to the corresponding alcohol.

 7. Metabolite toxicology. Not applicable. The primary residue of concern in both crop and animal commodities is pyrimethanil.

 8. Endocrine disruption. There is no evidence to suggest that pyrimethanil has any potential primary endocrine disruption.  Chronic, life span, and multi- generational bioassays in mammals and acute and subchronic studies on aquatic organisms and wildlife did not reveal any potential endocrine effects. Changes in the thyroid are secondary to induction of metabolic enzymes in the liver, and not due to a direct effect on endocrine mediated functions.

 C. Aggregate Exposure

       1. Dietary exposure. For dietary analysis, an acute reference dose (aRfD) of
 0.45 mg/kg/day was derived for females 13 - 50 from an NOAEL of 45 mg/kg/day in the rabbit developmental study, based on an increased incidence of fetuses with 13 thoracic vertebrae and ribs, and an uncertainty factor of 100. For the general population including infants and children, the acute reference dose is 1 mg/kg/day from on an NOAEL of 100 mg/kg/day in the acute rat neurotoxicity study, based on transient behavioral effects, and an uncertainty factor of 100.  A chronic reference dose (cRfD) of 0.17 mg/kg/day for all populations was derived from the chronic toxicity study in the rat,  based on decreased body weight gain and food consumption, increased liver weights and histopathological changes, and an uncertainty factor of 100.  EPA has evaluated the potential for increased susceptibility of infants and children from exposure to pyrimethanil and has determined there was no quantitative or qualitative evidence of increased susceptibility following prenatal exposure (in rats and rabbits), or postnatal exposure (in rats). There were no effects on fertility or reproduction in the two- generation reproduction study in rats. The special FQPA SF has been reduced to 1X based on toxicological considerations, the nature of the assumptions used
 in the dietary exposure risk assessments, the completeness of the residue chemistry and environmental fate databases, and the lack of the potential for residential exposures.  Acute and chronic Population Adjusted Doses (aPAD and cPAD) are, therefore, the same as the reference doses for the populations and subpopulations of interest.

 i. Food. Dietary exposure to pyrimethanil was estimated from potential residues on food using CARES Version 3.0 software for dietary analyses. The acute Tier One assessments used 100% crop treated and tolerance level residue values. The chronic Tier 2 assessment is based on tolerances, average residue values for key crops and percent crop treated values for key crops from the 2004 EPA assessment. All registered uses, pending uses; and the proposed use on cucumbers were included in the assessment.  Acute exposure utilizes 22.7% of the aPAD for Females 13-49 and 44.7% and 90.7% of the aPAD for the US Population and Children 1-2 respectively.  Chronic exposure utilizes 12.5% for the US Population and 65.4% for Children 1-2, the most highly exposed subpopulation. These are conservative estimates and actual exposures are likely to be much less.
 ii. Drinking Water. EPA drinking water values (2004) were used in the assessment.  EDWCs were calculated for use on strawberries (the scenario resulting in the highest drinking water exposure), and included pyrimethanil and its major metabolite (2-amino-4,6-dimethylpyrimidine). The surface water estimated drinking water concentrations (EDWCs) were determined using PRZM/EXAMS (Pesticide Root Zone Model/Exposure Analysis Modeling System).  Ground water EDWCs, calculated using SCI-GROW (Screening Concentration in Ground Water), model were lower than the surface water EDWCs. For surface water, the maximum estimated peak acute concentration of the combined residues is 37.8 g/L. The maximum estimated annual mean non-cancer chronic exposure concentration for the combined residues (adjusted for regional percent cropped area) is 5.1 g/L. These estimates are well below the Drinking Water Levels of Comparison (DWLOC) for all subpopulations.  The aDWLOC is 22608, 31413 and 6851 g/L for Females 13-49, the US Population and Children 1-2 (the most highly exposed subpopulation), respectively. The cDWLOC is 5899 and 1624 g/L for the US Population and Children 1-2 (the most highly exposed subpopulation), respectively.

 These conservative estimates indicate there is no concern for dietary exposures from potential residues of pyrimethanil in food and drinking water.

 2. Non-dietary exposure. Pyrimethanil is not registered for use on any sites that would result in residential exposure. Therefore, the aggregate risk is the sum of the risk from food and water.

 D. Cumulative Effects

 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 has not made a common mechanism of toxicity finding as to pyrimethanil and any other substances and pyrimethanil does not appear to produce a toxic metabolite produced by other substances.

 E. Safety Determination

 1. U.S. population. Risk assessments for pyrimethanil are based on a complete and reliable toxicity data package and highly conservative assumptions. Chronic dietary (food) exposure will utilize 12.5% of the cPAD for the US Population. The chronic EDWC is more than 1000 fold lower than the cDWLOC. EPA generally has no concern for exposures below 100% of the cPAD because the cPAD represents the level at or below which daily aggregate exposure over a lifetime will not pose appreciable risk to human health.  Acute dietary (food) exposure for females 13-49, representing the most sensitive subpopulation of the overall U.S. adult population, utilizes only 5.42% of the aPAD using highly conservative assumptions and the aEDWC is more than 500 fold lower than the aDWLOC.  Therefore, there is a reasonable certainty that no harm will occur to the US Population from aggregate exposure (food, drinking water and non-dietary) to residues of pyrimethanil.

 2. Infants and children. EPA has determined that the toxicology database for pyrimethanil regarding potential pre- and post-natal effects in children is complete and does not indicate any particular developmental or reproductive concerns. The special FQPA SF has been reduced to 1X. Using the conservative assumptions described in the exposure section above, chronic dietary exposure to residues of pyrimethanil in food for Children 1-2 (the most highly exposed sub group) is 65.4% of the cPAD. The chronic EDWC is more than 300 fold lower than the cDWLOC. Acute dietary exposure to residues of pyrimethanil in food for Children 1-2 (the most highly exposed sub group) is 33.7% of the aPAD. The chronic EDWC is more than 180 fold lower than the cDWLOC. There are no non-dietary concerns for infants and children. Therefore, there is a reasonable certainty that no harm will occur to infants and children from aggregate exposure to residues of pyrimethanil.

 F. International Tolerances

 EU and Codex MRLs have not been established for pyrimethanil in cucumbers.