Document ID: EPA-HQ-OPP-2012-0926-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2013-01-16T05:00Z

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

EPA Registration Division contact: Ms. Kathryn Montague, 703-305-1243

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:

Syngenta Crop Protection, LLC

Insert petition number

	EPA has received a pesticide petition ([insert petition number]) from Syngenta Crop Protection, LLC, P.O. Box 18300, Greensboro, NC 27419 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 amending a tolerance for residues of S-metolachlor in or on the raw agricultural commodities corn, field, forage; corn, sweet, forage; and corn, stover at 20, 40 and 40 parts per million (ppm), respectively.  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 S-metolachlor residues in plants is adequately understood for the purpose of the proposed tolerances, based upon acceptable corn, potato and soybean metabolism studies.  The metabolism of S-metolachlor involves conjugation with glutathione, breakage of this bond to form the mercaptan, conjugation of the mercaptan with glucuronic acid, hydrolysis of the methyl ether, and conjugation of the resultant alcohol with a neutral sugar.  EPA has determined that, for S-metolachlor, residues of concern in plants include parent and metabolites, determined as the derivatives CGA-37913 and CGA-49751.]

	2. Analytical method. [Syngenta has developed and validated analytical methodology for enforcement purposes.  A gas chromatography-nitrogen phosphorus detection (GC/NPD) method has been submitted to the Agency for determining residues in/on crop commodities and is published in PAM Vol. II, Method I.  A gas chromatography-mass selective detection (GC/MSD) method has been submitted to the Agency for determining residues in livestock commodities and is published in PAM Vol. II, Method II.  These methods determine residues of S-metolachlor and its metabolites as either CGA-37913 or CGA-49751 following acid hydrolysis.  An extensive database of method validation data using these methods on various crop commodities is available.]

	3. Magnitude of residues. [Complete residue data to support the requested tolerances are submitted with this petition.  The residue studies were conducted per EPA Test Guidelines 860.1000 and 860.1500.]

B. Toxicological Profile

	1. Acute toxicity.  [The database for acute toxicity of S-metolachlor is considered to be complete.  S-metolachlor is moderately acutely toxic (toxicity category III) by the oral and dermal routes of exposure and relatively non-toxic (toxicity category IV) by the inhalation route of exposure.  It causes slight eye irritation (toxicity category III) and is non-irritating dermally (toxicity category IV).  The active ingredient was found to be positive in a dermal sensitization test but this effect is mitigated in end-use product formulations.]

	2. Genotoxicty. [Gene mutation (Guideline 870.5100), micronucleus (Guideline 870.5395) and unscheduled DNA synthesis (Guideline 870.5550) studies conducted with S-metolachlor have been reviewed and approved by EPA.  There is no evidence of a mutagenic or cytogenetic effect in vivo or in vitro with S-metolachlor.]

	3. Reproductive and developmental toxicity. [Prenatal developmental studies in the rat and rabbit with S-metolachlor revealed no evidence of a qualitative or quantitative susceptibility in fetal animals.  No significant developmental toxicity was observed in most studies even at the highest dose tested.  In a two-generation reproduction study, there was no evidence of parental or reproductive toxicity at the highest dose tested (80 mg/kg/day).  The results indicate that S-metolachlor is not embryotoxic or teratogenic in either species at maternally toxic doses.]

	4. Subchronic toxicity. [In a 90-day dietary study in rats with S-metolachlor, no effects were observed in males or females at 209 and 236 mg/kg/day, respectively.  In another 90-day dietary study in rats, decreased body weight, reduced food consumption and food efficiency in both sexes and increased kidney weight gain in males was observed at 150 mg/kg/day; the NOAEL was 15 mg/kg/day.  A 90-day dog study with S-metolachlor has been accepted by EPA; no effects were observed in males and females at 62 mg/kg/day and 74 mg/kg/day, respectively, which were the highest doses tested.]

	5. Chronic toxicity. [Chronic studies in both the rat and dog with S-metolachlor revealed no significant chronic toxicity.  In the rat, a decrease in body weight was observed at the highest dose tested.  In the dog, the only adverse effect was decreased body weight gain in females at 33 mg/kg/day; the NOAEL was 10 mg/kg/day.]

	6. Animal metabolism. [Animal metabolism studies have shown that S-metolachlor is extensively absorbed, rapidly metabolized and almost totally eliminated following oral administration in rats, goats and poultry.  S-metolachlor was primarily absorbed from the gastrointestinal tract and ultimately eliminated in the excreta of the species tested.  Metabolism in animals proceeds through common Phase 1 intermediates and glutathione conjugation.]

	7. Metabolite toxicology. [The metabolism of S-metolachlor has been well characterized in standard FIFRA metabolism studies.  S-metolachlor does not readily undergo dealkylation to form an aniline or quinone imine as has been reported for other members of the chloroacetanilide class of chemicals.  Therefore, as EPA has agreed, it is not appropriate to include S-metolachlor with the group of chloroacetanilides that readily undergo dealkylation, producing a common toxic metabolite (quinone imine).  EPA has reviewed toxicology data submitted by Syngenta demonstrating that the S-metolachlor metabolites ethane sulfonic acid (CGA 354743) and oxanilic acid (CGA 51202) are not absorbed by mammalian systems and/or have a significantly lower level of mammalian toxicity when compared to parent.]

	8. Endocrine disruption. [S-metolachlor does not belong to a class of chemicals known or suspected of having adverse effects on the endocrine system.  There is no evidence that S-metolachlor has any effect on endocrine function in developmental or reproduction studies.  Furthermore, histological investigation of endocrine organs in the chronic dog, rat and mouse studies did not indicate that the endocrine system is targeted by S-metolachlor, even at maximally tolerated doses administered for a lifetime.  There is no evidence that S-metolachlor bioaccumulates in the environment.]

C. Aggregate Exposure

	1. Dietary exposure. [Acute (Tier I) and chronic (Tier III/IV) dietary exposure evaluations were made for S-metolachlor using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID(TM), version 3.15).  DEEM-FCID software incorporates food consumption data from the National Health and Nutrition Examination Survey "What We Eat in America" (NHANES/WWEIA) dietary survey conducted in 2003-2008.  The acute exposure assessments were based on established tolerances for S-metolachlor and the percent of crop treated was assumed to be 100% for all commodities. The chronic exposure assessments were based on established tolerances for S-metolachlor, average field trial residues, market basket surveys and adjustments for percent crop treated.  Percent of crop treated values were estimated based upon economic, pest and competitive pressures.  Secondary residues in animal commodities were estimated based on "maximum reasonably balanced diets" diets and transfer information from metabolism and feeding studies.]

	i. Food. [Acute Risk.  The acute dietary risk assessments were performed for all population subgroups with an acute reference dose of 3.0 mg/kg-bw/day based on an acute no observed adverse effect level (NOAEL) of 300 mg/kg/day prenatal developmental toxicity study in rats and an uncertainly factor of 100X.  The 100X safety factor includes intra- and interspecies variations.  No additional FQPA safety factor was applied.  The acute assessments were run using DEEM-FCID(TM) software using established tolerances for S-metolachlor and 100% crop treated values.  For the purpose of the aggregate risk assessments, the exposure values were expressed in terms of margin of exposure (MOE), which was calculated by dividing the NOAEL by the exposure for each population subgroup.  In addition, exposures were expressed as a percent of the acute reference dose (% aRfD).  Acute food exposure to the U.S. population resulted in a MOE of 71,788 or 0.1% of the aRfD (Benchmark MOE =100; aRfD = 3.0 mg/kg-bw/day).  Acute food exposure to the most sensitive subpopulation (children 1 to 2 years old) resulted in a MOE of 33,845 or 0.3% of the aRfD (Benchmark MOE =100; 3.0 mg/kg-bw/day).  

Chronic Risk.  The chronic assessments were run using DEEM-FCID(TM) software using average field trial residue values, USDA-PDP residues, SMBS data and percent crop treated adjustments for all current and proposed crop registrations.  The chronic dietary risk assessments were performed for all population subgroups with a chronic reference dose of 0.1 mg/kg-bw/day based on a one-year feeding study in dogs with a NOAEL of 9.7 mg/kg/day and an uncertainly factor of 100X.  The 100-fold safety factor includes intra- and interspecies variations.  No additional FQPA safety factor was applied.  For the purpose of the aggregate risk assessments, the exposure values were expressed in terms of margin of exposure (MOE), which was calculated by dividing the NOAEL by the exposure for each population subgroup.  In addition, exposures were expressed as a percent of the reference dose (% cRfD).  Chronic food exposure to the U.S. population resulted in a MOE of 27,067 or 0.4% of the cRfD (Benchmark MOE = 100; cRfD = 0.1 mg/kg-bw/day).  Chronic food exposure to the most exposed sub-population (children, 1-2 years old) resulted in a MOE of 10,180 or 1.0% of the cRfD (Benchmark MOE = 100; cRfD = 0.1 mg/kg-bw/day).  

Cancer.  S-metolachlor has been classified as a Group C, possible human carcinogen based on the occurrence of liver tumors in rats.  The NOAEL that was established based on tumors in rats (15 mg/kg/day) is comparable to the NOAEL of 9.7 mg/kg/day selected for the chronic reference dose.  Therefore the chronic dietary end point is protective for cancer dietary exposure.]

	ii. Drinking water. [The estimated drinking water concentrations (EDWCs) for surface water and groundwater were taken from monitoring data from two National Water Quality Assessment (NAWQA) programs.  The maximum concentration of parent metolachlor / S-metolachlor detected in a nationwide NAWQA surface water monitoring program (that did not analyze for the degradates) was used as the peak surface water EDWC for the acute assessment; the maximum time-weighted mean from the same database was used as the chronic surface water EDWC.  For the metolachlor ethanesulfonic acid (ESA) and metolachlor oxanilic acid (OA) metabolites, maximum surface water concentrations from a NAWQA monitoring program (that collected both surface and groundwater data on parent metolachlor / S-metolachlor and the ESA and OA degradates) in the mid-west corn belt states of Iowa and Illinois were used as peak surface water EDWCs for the acute assessment; maximum time weighted means were used as the chronic surface water EDWCs.  All groundwater EDWCs were taken from the nationwide and Iowa / Illinois NAWQA groundwater monitoring programs.  Maximum (upper bound) detections of parent metolachlor / S-metolachlor and the ESA and OA metabolites were used for both acute and chronic groundwater EDWCs since time weighted means were not available.

For surface water, the EDWCs of parent metolachlor / S-metolachlor and its degradates were estimated to 96.75 ppb (parent: 77.6 ppb, ESA: 12.4 ppb, and OA: 6.75 ppb) for acute exposure and 13.87 ppb (parent: 4.3 ppb, ESA: 7.3 ppb, and OA: 2.27 ppb) for chronic exposure.  For ground water the EDWCs of parent metolachlor / S-metolachlor and its degradates were estimated to be 109.9 ppb (parent: 32.8 ppb, ESA: 63.7 ppb, and OA: 13.4 ppb) for both acute and chronic exposure.

Acute Exposure from Drinking Water.  The acute EDWC of 109.9 ppb for ground water was used in the DEEM-FCID(TM) software as "water, direct and indirect, all sources" to model the acute drinking water exposures.  The acute drinking water exposure contributions at the 95%-ile of exposures were determined by taking the difference between the aggregate (food + drinking water) exposures and the food exposures for each population subgroup.  Acute drinking water exposure to the U.S. population resulted in an MOE of 64,502 or 0.2% of the aRfD (Benchmark MOE = 100; aRfD = 3.0 mg/kg-bw/day).  Acute drinking water exposure to the most exposed sub-population (infants, <1 year old) resulted in an MOE of 20,597 or 0.5% of the aRfD (Benchmark MOE = 100; aRfD = 3.0 mg/kg-bw/day).  

Chronic Exposure from Drinking Water.  The predicted chronic ground water value of 109.9 ppb was input directly into the DEEM-FCID(TM) software as water, direct and indirect, all sources to model the chronic drinking water exposure.  Chronic drinking water exposure to the U.S. population resulted in an MOE of 4,215 or 2.3% of the cRfD (Benchmark MOE = 100; cRfD = 0.1 mg/kg-bw/day).  Chronic drinking water exposure to the most exposed subpopulation (infants, <1 year old) resulted in an MOE of 1,635 or 5.9% of the cRfD (Benchmark MOE = 100; cRfD = 0.1 mg/kg-bw/day).]

	2. Non-dietary exposure. [There is a potential for post-application exposure to adults and children resulting from professionally-applied treatments of S-metolachlor on residential lawns.  Post-application exposure is considered to be short-term based on label directions limiting application to one time per season.  Since toxicity was not observed in a dermal toxicity study, up to a dose level of 1,000 mg/kg/day, the only parameter of short-term residential risk that needs to be addressed is the possible oral exposure of toddlers and children from treated turf or soil.  Using these exposure assumptions, the short-term residential exposures from metolachlor/S-metolachlor resulted in an aggregate MOE of 1,314 for children, 1-2 years.  Note that there are no non-dietary contributions to the aggregate MOE for adults or infants (<1 year) from turf uses since none of the oral exposure scenarios (hand-to-mouth, object-to-mouth, soil ingestion) would be applicable to these subpopulations.]

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".  The EPA has examined the common mechanism potential for S-metolachlor and has concluded that S-metolachlor should not be included with the chloroacetanilide pesticides designated as a "Common Mechanism Group."  The Agency's position is that only some chloroacetanilides, namely acetochlor, alachlor and butachlor should be considered as a "Common Mechanism Group" due to their ability to cause nasal turbinate tumors.]

E. Safety Determination

	1. U.S. population. [Using the conservative assumptions described above, and based on the completeness and reliability of the toxicity data, the acute aggregate exposure calculation for current and proposed uses of S-metolachlor provided an MOE of 33,976 or 0.3% of the aRfD (Benchmark MOE = 100; aRfD = 3.0 mg/kg-bw/day) for the U.S. population.  The chronic aggregate exposure calculation for current and proposed uses of S-metolachlor provided an MOE of 3,647 or 2.7% of the cRfD (Benchmark MOE = 100; cRfD = 0.1 mg/kg-bw/day) for the U.S. population.]

	2. Infants and children. [Using the conservative assumptions described in the exposure section above, and based on the completeness and reliability of the toxicity data, the acute aggregate exposure calculation for current and proposed uses of S-metolachlor provided an MOE of 13,534 or 0.7% of the aRfD (Benchmark MOE = 100; aRfD = 3.0 mg/kg-bw/day) for infants < 1 year old (the most sensitive subpopulation for the acute assessment).  The short-term aggregate assessment resulted in an MOE of 1,181 for the children (1-2 years old) population subgroup (Benchmark MOE = 100).  The chronic aggregate exposure calculation for current and proposed uses of S-metolachlor provided an MOE of 1,499 or 6.4% of the cRfD (Benchmark MOE = 100; cRfD = 0.1 mg/kg-bw/day) for infants < 1 year old (the most sensitive subpopulation for the chronic assessment).]

F. International Tolerances

	[There are currently no Maximum Residue Limits (MRLs) set for S-metolachlor for crops by the Codex Alimentarius Commission.  International MRLs for the herbicide S-metolachlor have been established for various agricultural commodities in a number of countries including Argentina, Australia, Austria, Belarus, Belgium, Brazil, Canada, Czech Republic, France, Georgia, Germany, Greece, Hungary, India, Italy, Japan, Korea (South), Luxembourg, Malaysia, Moldova, Morocco, Netherlands, New Zealand, Russia, Serbia and Montenegro, Slovak Republic, Slovenia, Spain, Switzerland, Taiwan, and Ukraine.]