


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)

In cooperation with Syngenta 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 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 180.222 by establishing a tolerance for residues of prometryn, (2,4-bis(isopropylamino)-6-methylthio- s -triazine), in or on 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 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. The qualitative nature of prometryn residues in plants has been characterized based upon EPA approved cotton and celery metabolism studies.  A rice metabolism study has been submitted and is currently being reviewed by EPA.  The metabolism of prometryn in cotton, celery and rice is extensive, involving N-dealkylation and hydrolysis, leading to multiple minor products.    Characterization of the residues indicates the biotransformation of prometryn is qualitatively similar in all three crops.

	2. Analytical method. Syngenta has developed and validated a gas chromatography analytical method for enforcement purposes.  The method determines residues of prometryn in/on plants using a microcoulometric sulfur detection system.  This method has been submitted to the EPA and is in the Pesticide Analytical Manual (PAM).

	3. Magnitude of residues. Complete residue data to support the requested tolerances have been submitted with this petition.


B. Toxicological Profile

	1. Acute toxicity.  The database for acute toxicity of prometryn is considered complete.  Prometryn technical is slightly to practically non-toxic (Toxicity Category III) by the oral, dermal and inhalation routes.  It causes mild eye irritation (Toxicity Category III) and slight dermal irritation (Toxicity Category IV).  Prometryn is not considered a skin sensitizer.

	2. Genotoxicty. In four mutagenicity studies (Ames salmonella test, chromosomal aberration, bacterial DNA repair, and unscheduled DNA synthesis test) prometryn was found to be negative.  There is no evidence of a mutagenic or cytogenetic 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 study 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.  The results indicate that prometryn is not embryotoxic or teratogenic in the species tested at maternally 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 systemic toxicity was observed at all dose levels with a NOAEL of >1,000 mg/kg/day.

	5. Chronic toxicity. Studies with prometryn have shown no significant 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 body weight gain.  There were no effects observed in males.  Prometryn 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 prometryn, there is "no evidence of human carcinogenic potential".

	6. Animal metabolism. The metabolism of prometryn in rats is adequately understood.  Data indicate that the distribution of prometryn is greatest in the blood, followed by the spleen and the lungs.  Prometryn is predominantly excreted in the urine and feces with slightly higher concentrations in the urine.

	7. Metabolite toxicology. For risk assessment and enforcement purposes, EPA has determined that residues of concern include parent prometryn only.

	8. Endocrine disruption. There is no indication from the mammalian toxicology database for any endocrine disrupting effect of prometryn.

C. Aggregate Exposure

	1. Dietary exposure. Tier I acute and chronic dietary exposure evaluations were made for prometryn using the Dietary Exposure Evaluation Model (DEEM-FCIDTM), version 2.16 from Exponent.  In addition to current uses, these aggregate assessments included estimated prometryn tolerances for a proposed IR-4 use on succulent snap beans as well as a proposed use on dill.  Percent of crop treated (%CT) values were conservatively estimated to be 100% for all registered and proposed uses.  Drinking water estimates were incorporated directly 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 Individuals (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 years 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 safety 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 NOAEL by 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 years 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 prometryn chronic dietary (food only) risk assessment was performed for all subpopulations with a chronic 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 uncertainty factor of 100X.  The 100X safety factor includes intra- and inter-species variations.  No additional FQPA safety factor was applied.  For the purpose of aggregate risk assessment, the exposure values were expressed in terms of margin of exposure (MOE), which was calculated by dividing the NOAEL by the exposure for each subpopulation.  In addition, exposure was expressed as a percent 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 year old, with an MOE of 7,094 or 1.3% of the cRfD (Benchmark MOE = 100; cRfD = 0.04 mg/kg/day).  

Cancer.  Prometryn has been classified as a Group E chemical (no evidence of human carcinogenic potential).  Therefore, a cancer risk assessment was not performed for prometryn.

	ii. Drinking water. The Estimated Drinking Water Concentrations (EDWCs) of prometryn were determined using Tier l screening models, SCI-GROW which estimates pesticide concentration in ground water and FIRST which estimates pesticide concentration in surface water.  EDWCs of prometryn from the currently registered uses plus the proposed snap bean and dill uses were determined.   Based on the SCI-GROW modeling, the highest groundwater EDWC for prometryn is 15.5 ppb (acute and chronic) based on the currently 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 water 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-FCID(TM) 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 concern was females 13-49 years 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 directly into the DEEM-FCID(TM) 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 MOE 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 year 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 prometryn 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.  Prometryn is a member of the triazine class of pesticides.  Other members of this class include atrazine, simazine, cyanazine, prometron, propazine, metribuzin, hexazinone, ametryn, terbutryn, dipropetryn and ethiozin.  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 does not have, at this time, available data to determine whether prometryn 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 prometryn has a common mechanism of toxicity with other substances.

E. Safety Determination

	1. U.S. population. An acute dietary exposure analysis was not required for the general U.S. population, however exposure from all current and proposed prometryn 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 analysis (food plus water) showed that exposure from all current and proposed prometryn 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 prometryn for infants and children.  The chronic dietary exposure analysis (food plus water) showed that exposure from all current and proposed prometryn uses for infants <1 year 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 MRLs established for residues of prometryn in plant or animal commodities.

