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**EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER**  **EPA Registration**  **Division contact: Laura Nollen, (703) 305**  **- 7390**  Interregional Research Project No. 4 (IR - 4) I n cooperation with Sy

ngenta Crop Protection, LLC Pesticide Petition (PP#) 2E8052 EPA has received a pesticide petition , PP# 2E8052 from Interregional Research Project No. 4 (IR - 4) , 500 College Road East, Suite 201 W, Princeton, NJ 08540 request ing, 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 .222 by establishing a tolerance for residues of prometry

n , (2,4 - bis(isopropylamino) - 6 - methy lthio - s - triazine), in or o n the raw agricultural commodities bean, snap, succulent at 0.05 parts per million (ppm) ; bean, forage at 0.09 ppm ; dill, leaves at 0.3 ppm ; dill, dried leaves at 1.1 ppm ; and dill, oil at 1.3 ppm . EPA has determined that the petition contains data or information r egarding 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 o n the petition. A. Residue Chemistry 1. Plant metabolism. The qualitative nature of prometry n residues in plants has been characterized based upon EPA approved cotton and celery me tabolism studies. A rice metabolism study

has b een submitted and is currentl y being reviewed by EPA . The metabolism of prometry

n in cotton, celery

and rice is extensive, involving N - dealk yl ation and hy droly sis, leading to multiple minor products. Characterization of the residues indicates the biotransformation of prome try n is qualitatively

similar in all three crops. 2. Analytical method. Syngenta has developed and v alidated a gas chromatograph y anal yt ical method for enforcement purposes. The method determines residues of prometry

n in/on plants using a microcoulometr ic sulfur detection sy stem. This method has been submitted to the EPA and is in the Pesticide Analy tical Manual (PAM). 3. Magnitude of residues. Complete residue data to supp ort the requested tolerances have been submitted with thi s petition.2

B. Toxicological Profile 1. Acute toxicity. The data base for acute toxicity

of prometry

n is considered complete . Prometry

n technical is slightly

to practically

non - toxic (Toxicity

Category III) by the oral, dermal and inhalation route s . It causes mild ey e irritation (Toxicity Category III) and slight dermal irritation (Toxicity Category IV). Prometry n is not considered a skin sensitizer. 2. Genotoxicty. In four mutagenicity studies (Ames salmonella test, chromosomal aberration, bacterial DNA repair, and unscheduled DNA s ynthesis test) prometryn was found to be negative. There is no evidence of a mutagenic or cy togenetic effect in vivo or in vitro with prometryn . 3. Reproductive and developmental toxicity. In developmental toxicity studies with rats and rabbits, maternal and developmental toxicity was observed only at the highest doses tested (rats 250 mg/kg/day , rabbits 72 mg/kd/day) . The developmental NOEL was 50 mg/kg/day in rats and 12 mg/kg/day in rabbits. A 2 - generation reproduction stud y with rats showed effects at the highest dose (1500 ppm; 105.6 mg/kg/day), with a reproductive NOEL of 750 ppm or approximately 50 mg/kg/day . Th e results indicate that prometry n is not embry otoxic or teratogenic in the species tested at maternall y toxic doses. 4. Subchronic toxicity. In a subchronic 28 - day feeding study

in mice at the highest dose tested (4500 mg/kg/day), there were pathological findings limited to the G.I. tract along with decreased body weights. The NOAEL was 450 mg/kg/day. In a 21 - day dermal toxicity

study in rabbits, no local or sy stemic toxicity was observed at all dose levels with a NOAEL of > 1,000 mg/kg/day . 5. Chronic toxicity. Studies with prometry n have shown n o signifi cant chronic toxicity in either rats, mice or dogs. In a chronic toxicity study /oncogenicity

study in mice the NOAEL in females was 1,000 ppm and the LOAEL was 3,000 ppm based upon decreased bod y weig ht gain. There were no effects observed in males. Prometry n was not oncogenic under the conditions of the study . The lowest chronic toxicity endpoints were observed in the chronic toxicity study in dogs , with a NOAEL of 3.75 mg/kg/day and a LOAEL of 37.5 mg/kg/day . The EPA has determined that, for prometry n, there is “no evidence of human carcinogenic potential”. 6. Animal metabolism. The metabolism of prometry n in rats is adequately understood. Data indicate that the distribution of p rometry n is greatest in the blood, followed b y the spleen and the lungs. Prometryn is predominantly excreted in the urine and feces with slightl y higher concentrations in the urine. 7. Metabolite toxicology . For risk assessment and enforcement purposes, EPA has determined that residues of concern include parent prometry n only . 8. Endocrine disruption . There is no indication from the mammalian toxicology3

database for an y endocrine disrupting effect of prometry n. C. Aggregate Exposure 1. Dietary exposure. Tier Iacute and chronic dietary exposure evaluations were made for prometry

n using the Dietary

Exposure Evaluation Model (DEEM - FCIDTM), version 2.16 from Exponent. In addition to current uses, these aggregate assessments included estimated prom etry n tolerances for a proposed I R - 4 use on succulent snap beans as well as a proposed use on dill. Percent of crop treated (%CT) values were conservativel y estimated to be 100% for all registered and proposed uses. Drinking water estimates were incorpor ated directl y into the dietary exposure assessment using the higher of the estimated drinking water concentrations (EDWCs) for surface and ground water. All consumption data for these assessments was taken from the USDA’s Continuing Survey

of Food Intake by

I ndividuals (CSFII) with the 1994 - 96 consumption database and the Supplemental CSFII children’s survey (1998) consumption database . i. Food. Acute Exposure. An acute reference dose of 0.12 mg/kg/ day for females 13 - 49 y ears old was based on a no observed adverse effect level (NOAEL) of 12 mg/kg/day

from a developmental toxicity study in rabbits and an uncertainly factor of 100X. No additional FQPA safet y factor was applied. For the purpose of the aggregate risk assessment, the exposure value was expressed in terms of margin of exposure (MOE), which was calculated by dividing the NOAELby

the exposure for each subpopulation. In addition, exposure was expressed as a percent of the acute reference dose (aRfD). Acute (food only) exposure to females 13 - 49 y ears old resulted in an MOE of 23,391 or 0.4% of the aRfD (Benchmark MOE = 100; aRfD = 0.12 mg/kg/day) . Chronic Exposure. The prometry n chronic dietary

(food only) risk assessment was performed for all subpopulations with a c hronic reference dose of 0.04 mg/kg/day based on a chronic feeding study in dogs with a NOAEL of 3.75 mg/kg/day and an uncertaint y factor of 100X. The 100X safet y factor includes intra - and inter - species variations. No additional FQPA safety

factor was a

pplied. For the purpose of aggregate risk assessment, the exposure values were expressed in terms of margin of exposure (MOE), which was calculated b y dividing the NOAEL b y the exposure for each subpopulation. In addition, exposure was expressed as a per cent of the chronic reference dose (cRfD). Chronic (food only) exposure to the U.S. population resulted in an MOE of 27,217 or 0.3% of the cRfD (Benchmark MOE = 100; cRfD = 0.04 mg/kg/day). The most exposed subpopulation was infants <1 ye ar old, with an MOE of 7,094 or 1.3% of the cRfD (Benchmark MOE = 100; cRfD = 0.04 mg/kg/day). Cancer . Prometry

n has been classified as a Group E chemical (no evidence of human carcinogenic potential). Therefore, a cancer risk assessment was not performed for prometr yn . ii. Drinking water . The Estimated Drinking Water Concentrations (EDWCs) of prometry n were determined using Tier l screening models, SCI - GROW which estimates pesticide concentration in ground water and FI RST which estimates pesticide4

concentration in surface water. EDWCs of prometry n from the currentl y registered uses plus the proposed snap bean and dill uses were determined. Based on the SCI - GROW modeling, the highest groundwater EDWC for prometry n is 15.5 ppb (acute and chronic) b ased on the currentl y registered use on carrot. Based on the FIRST modeling, the carrot use provided the highest surface water EDWCs of 97.1 ppb for acute and 32.3 ppb for chronic. Since the surface water EDWCs exceed the ground water EDWC, the surface w ater values were used for risk assessment purposes and will be considered protective for any ground water exposure concerns. Acute Exposure from Drinking Water: The acute surface water EDWC of 97.1 ppb was input directly

into the DEEM - FCIDTM software as “water, direct and indirect, all sources” to model the acute drinking water exposures. Exposure contributions at the 95.0th % - ile of exposures were determined by taking the difference between the aggregate (food + drinking water) exposures and the food ( alone) exposures for each population subgroup. Acute drinking water exposure to the U.S. population resulted in an MOE of 2,542 (3.9% of the acute RfD of 0.12 mg/kg - bw/day). The subpopulation of conc ern was females 13 - 49 y ears old with an MOE of 2,721 (3 .7% of the aRfD of 0.12 mg/kg/day ). Chronic Exposure from Drinking Water. The chronic surface water EDWC of 32.3 ppb was input directl y into the DEEM - FCIDTM software as “water, direct and indirect, all sources” to model the chronic drinking water exposures. Chronic drinking water exposure to the U.S. population resulted in an MO E of 5,508 (1.8% of the chronic RfD of 0.04 mg/kg - bw/day). Chronic drinking water exposure to the most exposed subpopulation (infants, <1 y ear old) resulted in an MOE of 1,680 (6.0% of the chronic RfD of 0.04 mg/kg - bw/day). 2. Non
- dietary exposure . There are currently no registered or planned uses for prometry n that would result in residential handler (mixer/loader/applicator) or post application exposure . D. Cumulative Effects . Cumulative Exposure to Substances with a Common Mechanism of Toxicity . Prometry

n is a member of the triazine class of pesticides. Other members of this class include atrazine, simazine, cy anazine, prometron, propazine, metribuzin, hexazinone, ametry

n, terbutry

n, dipropetry

n and ethiozin. Section 408(b)(2)(D)(v) requires th at, 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”. E PA does not have, at this time, available data to determine whether prometry n has a common mechanism of toxicity with other substances or how to include this pesticide in a cumulative risk assessment. For the purposes of this tolerance action, the EPA has not assumed that prometry n has a common mechanism of toxicity with other substances . E. Safety Determination 1. U.S. population. An acute dietary exposure analy sis was not required for the5

general U.S. population, however exposure from all current and proposed prometry n uses would result in an MOE of 2,437 or 4.1% of the aRfD for females 13 - 49 years old (Benchmark MOE = 100; aRfD = 0.12 mg/kg/day). The chronic dietary exposure anal ys is (food plus water) showed that exposure from all current and propose d prometry n uses for the general U.S. population would result in an MOE of 4,581 or 2.1% of the cRfD (Benchmark MOE = 100; cRfD = 0.04 mg/kg/day ). 2. Infants and children . There are no acute dietary exposure concerns from prometry n for infants and children. The chronic dietary exposure anal ys is (food plus water) showed that exposure from all current and proposed prometry n uses f or infants <1 ye ar old would result in an MOE of 1,358 or 7.3% of the cRfD (Benchmark MOE = 100; cRfD = 0.04 mg/kg/day) . F. International Tolerances . There are no Codex MRL s established for residues of prometry n in plant or animal commodities .