Interregional Research Project Number 4 (IR - 4)

Petition #4E8248 EPA has received a pesticide petition ( 4E8248 ) 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 by establishing a tolerance for residues of S - metolachlor in or on the raw agricultural commodity lettuce at 1.5 parts per million (ppm) , cucurbit vegetabl e crop group 9 at 0.50 ppm, vegetable, fruiting, group 8 - 10, except tabasco pepper , low growing berry subgroup 13 - 07G excluding cranberry at 0.40 ppm, and sunflower subgroup 20B at 0.50 ppm and the concurrent deletion of the existing tolerance for okra. E PA 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 adequatel y understood for the purpose of the proposed tolerances, b ased upon acceptable corn, potato and so ybean 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, hydroly sis of the methylether, 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 metho d. Syngenta has developed and validated anal yt ical methodology

for enforcement purposes. A gas chromatograph y - nitrogen phosphorus detection (GC/NPD) method has been submitted to the Agency for determining residues in/on crop commodities and is published i n PAM Vol. II, Method I. A gas chromatograph y - 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 - me tolachlor and its metabolites as either CGA - 37913 or CGA - 49751 following acid hydrol ys is. An extensive database of method validation data using these methods on various crop commodities is available . 3. Magnitude of residues. Complete residue data to su pport the requested tolerances are submitted or referenced 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 - metolachl or is considered to be complete. S - metolachlor is moderatel y acutely toxic (toxicity category III) b y the oral2

and dermal routes of exposure and relativel y non - toxic (toxicity category IV) by the inhalation route of exposure. It causes slight eye irritat ion (toxicity category I II) and is non - irritating dermall y (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 s ynthesis (Guideline 870.5550) studies conducted with S - metolachlor have been reviewed and approved by EPA. There is no evidence of a mutagenic or cy

togenetic 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 developm ental 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 - metolac hlor is not embryotoxic or teratogenic in either species at maternally toxic doses . 4. Subchronic toxicity. Ina 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 ano ther 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 , respectivel y, which were the highest doses tested . 5. Chronic toxicity. Chronic studies in both the rat and dog with S - metolachlor revealed no sign ificant 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. An imal 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 primaril y 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 st andard FIFRA metabolism studies. S - metolachlor does not readily undergo dealkyl ation 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 readil y undergo dealkyl ation, producing a common toxic metabolite (quinone imine). EPA has reviewed toxicology

data submitted by

S yn genta demonstrating that the S - metolachlor metabolite s ethane sulfonic acid (CGA 354743) and oxanilic acid (CGA 51202) are not3

absorbed b y 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 cla ss of chemicals known or suspected of having adverse effects on the endocrine s ys tem. There is no evidence that S - metolachlor has an y 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 s ys tem is targeted by S - metolachlor, even at maximally tolerated doses administered for a lifetime. There is no evidence that S - metolachlor bioaccumulates in the envi ronment . **C. Aggregate Exposure 1.**  **Dietary exposure.** Acute (Tier I) and chronic (Tier II) dietary exposure evaluations were made for S - metolachlor using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM - FCIDTM, v ersion 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. These aggregate human health assessments include all current and pending uses as well as proposed new IR - 4 uses on head lettuce, leaf lettuce, low - growing berries (Subgroup 13 - 07G), cucurbits (Crop Group 9), and revised crop groupings for fruiting vegetables (Group 8 - 10, except tabasco peppers), and sunf lowers (Subgroup 20B). The acute exposure assessments were based on established or proposed tolerances for S - metolachlor. The chronic exposure assessments were based on average field trial residues, established tolerances, or market basket survey data (p otato and tomato). The percent of crop treated (%CT) was assumed to be 100% for all commodities. Secondary residues in animal commodities were estimated based on “maximum reasonably

balanced dietary

burdens” and transfer information from metabolism and f

eeding 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 dev elopmental 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 - FCIDTM software using establi shed 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 b y dividing the NOAEL b y 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 60,235 or 0.2% of the aRfD (Benchmark MOE =100; aRfD = 3.0 mg/kg bw/day). Acut e food exposure to the most sensitive subpopulation (children 1 to 2 y ears old) resulted in a MOE of 26,373 or 0.4% of the aRfD (Benchmark MOE =100; 3.0 mg/kg - bw/day). Chronic Risk. The chronic assessments were run using DEEM - FCIDTM software using4

avera ge field trial residue values, USDA - PDP residues, SMBS data, and 100% crop treated values. 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 stud y in dogs with a NOAEL of 9.7 mg/kg/day and an uncertainl y 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 b y dividing the NOAEL b y 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 13,860 or 0.7% 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 5,829 or 1.7% of the cRfD (Be nchmark 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 co mparable 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 the First Index Reservoir Screening Tool (FIRST), Pesticide Root Zone Model/Exposure Analy sis Modeling Sy stem (PRZM/EXAMS) and Screening Concentration in Ground Water (SCI - GROW) models; as well as monitoring data from two N ational Water Qualit y Assessment (NAWQA) programs. The maximum concentration of parent metolachlor / S - metolachlor detected in a nationwide NAWQA surface water monitoring program (that did not analy ze for the degradates) was used as the peak surface water EDWC for the acute assessment; the one in - ten - year maximum annual average PRZM/EXAMS concentration was used as the chronic surface water EDWC. For the metolachlor ethanesulfonic acid (ESA) and metolachlor oxanilic acid (OA) metabolites, the one - in - ten - ye ar maximum FIRST concentrations were used as peak surface water EDWCs for the acute assessment; one - in ten - ye ar annual averages were used as the chronic surface water EDWCs. Groundwater EDWCs for parent metolachlor / S - metolachlor and the ESA metabolite w ere taken from the nationwide and Iowa / I llinois NAWQA groundwater monitoring programs; maximum (upper bound) detections were used for both acute and chronic groundwater EDWCs, since time weighted means were not available. For the OA metabolite, the SCI GROW concentration was used. For surface water, the EDWCs of parent metolachlor / S - metolachlor and its degradates were estimated to be 218.78 ppb (parent: 77.60 ppb, ESA: 47.61 ppb, and OA: 93.57 ppb) for acute exposure and 118.81 ppb (parent: 18.15 ppb, ESA: 34.04 ppb, and OA: 66.62 ppb) for chronic exposure. For ground water the EDWCs of parent metolachlor / S - metolachlor and its degradates were estimated to be 126.2 ppb (parent: 32.8 ppb, ESA: 63.7 ppb, and OA: 29.7 ppb) for both acute and chronic exp osure.5

Acute Exposure from Drinking Water. The acute EDWC of 218.78 ppb for surface water was used in the DEEM - FCIDTM 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 b y 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 29,101 or 0.3% 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 ye ar old) resulted in an MOE of 9,465 or 1.1% 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 126.2 ppb was input directly into the DEEM - FCIDTM 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 3,677 or 2.6% of the cRfD (Benchmark MOE = 100; cRfD = 0.1 mg/kg - bw/day). Chronic drinking water exposure to the most exposed subpopulation (infants, <1 ye ar old) resulted in an MOE of 1, 426 or 6.8% 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 professionall y - 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 onl y parameter o f 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** 6 **1. U.S. population.**  Using the conservative assumptions described above, and based on the completeness and reliability of the toxicity

data, the a cute aggregate exposure calculation for all current, pending, and proposed uses of S - metolachlor provided an MOE of 19,621 or 0.5% of the aRfD (Benchmark MOE = 100; aRfD = 3.0 mg/kg - bw/day) for the U.S. population. The chronic aggregate exposure calculati on for all current, pending, and proposed uses of S - metolachlor provided an MOE of 2,906 or 3.3% 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 all current, pending, and proposed uses of S - metolachlor provided an MOE of 7,357 or 1.4% of the aRfD (Benchmark MO E = 100; aRfD = 3.0 mg/kg - bw/day) for infants < 1 y ear old (the most sensitive subpopulation for the acute assessment). The short - term aggregate assessment resulted in an MOE of 1,149 for the children (1 - 2 years old) population subgroup (Benchmark MOE = 1 00). The chronic aggregate exposure calculation for all current, pending, and proposed uses of S - metolachlor provided an MOE of 1,220 or 7.9% of the cRfD (Benchmark MOE = 100; cRfD = 0.1 mg/kg - bw/day) for infants <1 ye ar old (the most sensitive subpopulat ion for the chronic assessment). **F. International Tolerances** There are currently

no Maximum Residue L imits (MRL s) set for S - metolachlor for crops b y the Codex Alimentarius Commission. International MRLs for the herbicide S - metolachlor have been establi shed for various agricultural commodities in a number of countries including Argentina, Australia, Austria, Belarus, Belgium, Brazil, Canada, Czech Republic, France, Georgia, German y, Greece, Hungary , India, It aly , Japan, Korea (South), Luxembourg, Malay si a, Moldova, Morocco, Netherlands, New Zealand, Russia, Serbia and Montenegro, Slovak Republic, Slovenia, Spain, Switzerland, Taiwan, and Ukraine **.**