Page 1 of 38 **UNITED STA TES ENVIRONMENTA**  **L PROTECTION A GENCY** 

WA SHINGTON, D.C. 20460 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION **Date:** January

1 7 , 201 2 **MEMORANDUM SUBJECT:**  **S -**  **Metolachlor .**  Human Health Risk Assessment for the Section 3 Requests

for Use on Coriander (Cilantro) and Garden Beet Leaves . **PC Code:** 108800 **DP Barcode:** D 396452 **Decision No.:** 451816 **Registration No. :**  100 - 816 **Petition No.:** 1 E7898 **Regulatory Action:** Section 3 **Risk Assessment Type:** Single Chemical **Case No.:** 0001 **T XR No.:**  NA **CAS No.:** 87392 - 12 - 9 **MRID No.:** NA **40 CFR:** 180.368 FROM: W. Cutchin, Chemist

Alternative Risk Integration Assessment Team (ARIA) In ert Ingredients Assessment Branch ( IIAB ) Registration Division (RD; 7505P) THROUGH: S. Hummel , Senior Scientist

Regis tration Action Branch 4 (RAB4) Health Effects Division ( HED; 7509P) TO: B. Madden, Risk Manager

Minor Use and Emergency Response Branch RD (7 5 05P) RD of the Office of Pesticide Programs (OPP) has requested that ARIA evaluate the Section 3 request fo r the use of the herbicide S - metolachlor to control weeds on coriander (cilantro) and beet, garden, leaves . **I NTRODUCTION**  Section 3 request s has been received from the Interregional Research Project No.4 (IR - 4), on behalf of the Agricultural Experiment St ation of IR - 4 and the Agricultural Experiment Stations of New York, North Carolina and South Carolina (coriander (cilantro)); and California, Oklahoma, Texas and Tennessee (beet, garden, leaves), for use of the herbicide S - metolachlor formulated as Dual Ma gnum® (EPA Reg. No. 100 - 816).Page 2 of 38 **Table of Contents 1.0 EXECUTIVE SUMMA** **RY ................................**  **................................ ...............................**  **4 2.0 DETAIL DISCUSSI**  **ON ................................**  **................................ ................................**  **.. 10**  **2.1 PROPOSED NEW US ES**  **................................ ................................**  **............................... 10**  **2.2 PHYSICAL/CHEMIC AL PROPERTIES**  **................................ ................................**  **. 10**  **3.0 HAZARD ASSESSME NT**  **................................ ................................**  **.............................. 12**  **3.1 HAZARD PROFILE ................................**  **................................ ................................**  **....... 12**  **3.2 FQPA Hazard Considerations ................................**  **................................ ................................**  **....... 13**  **3.2.1 Dev**  **elopmental Toxicity ................................**  **................................ ................................**  **........... 13**  **3.2.1.1 Rat Developm ental Study**  **– Metolochlor**  **................................ ................................**  **........ 14**  **3.2.1.1 Rabbit Developm ental Study**  **- Metolochlor**  **................................ ................................**  **... 14**  **3.2.1.3 Rat Developm ental Study**  **– S**  **- Metolochlor**  **................................ ................................**  **..... 15**  **3.2.1.4 Rabbit Developm ental Study**  **– S**  **- Metolochlor**  **................................ ...............................**  **15 3.2.2 Reproductive Toxicity**  **................................ ................................**  **................................ ............**  **16 3.2.3 Pre**  **- and/or Postnatal Toxicity**  **................................ ................................**  **................................ 17**  **3.2.4 Immunoto xicity**  **................................ ................................**  **................................ .......................**  **17 3.2.5 Neurotoxicity**  **................................ ................................**  **................................ ..........................**  **17 3.2.6 FQPA Safety Factor**  **................................ ................................**  **................................ ...............**  **17 3**  **.3 Toxicity Endpoint Selection ................................**  **................................ ................................**  **........... 18**  **3.3.1 Acute Reference Dose (aRfD)**  **- General Population**  ................................ ................................ . 18 **3.3.4 Derm al Exposure (Short**  **- Term** **)** ................................ ................................ ................................ . 20 **3.3.5 Inhalation Exposure (Short -**  **Term)** ................................ ................................ ............................ 20 **3.3.6 Inhalation Exposure (Intermediate -**  **Term)** ................................ ................................ ................ 20 **3.3.7 Classification of Carcinogenic Potential** ................................ ................................ .................... 21 **3.4 Margins of Exposure ................................**  **................................ ................................**  **........................ 21**  **3.5 Recommenda tion for Aggregate Exposure Risk Assessments**  **................................ ......................**  **21 3.6 Summary of Endpoints Selected for Risk Assessment**  **................................ ................................**  **.. 21**  **3.7 Endocrine Disrupt ion**  **................................ ................................**  **................................ .....................**  **23 4.0 RESIDUE CHEMIST**  **RY CONSIDERATIONS ................................**  **...................... 23**  **4.1 Metabolism in Plants/Livestock**  **................................ ................................**  **................................ .....**  **23 4.2 Metabolism** **in Rotational Crops ................................**  **................................ ................................**  **.... 24**  **4.3 Residue Analytical Methods ................................**  **................................ ................................**  **.......... 25** Page 3 of 38

**4.5 Residues in Processed Comm odities**  **................................ ................................**  **.............................. 27**  **4.6 Residues in Rotational Crops ................................**  **................................ ................................**  **......... 27**  **4.7 Drinking Water Profile ................................**  **................................ ................................**  **.................. 27**  **4.8 Dietary Exposure Analysis and Risk Estimates ................................**  **................................ .............**  **28 5.0 NON**  **- DIETARY, NON**  **- OCCUPATIONAL EXPOSUR** **E ................................**  **..... 29**  **6.0 AGGREGAT E RISK**  **................................ ................................**  **................................ ......**  **30 6.1 Acute Aggregate Risk**  **................................ ................................**  **................................ ....................**  **30 6.2 Short**  **- & Interm**  **ediate -**  **Term Aggregate Risk ................................**  **................................ ...............**  **30 6.3 Chronic Aggregate Risk**  **................................ ................................**  **................................ .................**  **31 6.4 Cancer Aggregate Risk**  **................................ ................................**  **................................ ..................**  **31 7.0 OCCUPATIONAL EX**  **POSURE AND RISK ................................**  **............................ 31**  **9.0 CONCLUSION ................................**  **................................ ................................**  **................. 35**  **10.0 DATA NEEDS ................................**  **................................ ................................**  **................ 35**  **10.1 Toxicology Data Requir em**  **ents ................................**  **................................ ................................**  **.... 35**  **10.2 Residue Chemistry Data Requirements ................................**  **................................ .......................**  **36 10.3 Occupational/Residential Requirements**  **................................ ................................**  **..................... 36**  **REFERENCES ................................**  **................................ ................................**  **......................... 36** Page 4 of 38

**1.0 EXECUTIVE SUMMARY**  **General Information** Metolachlor (PC Code 108801) is a racemic herbicide that consists of 50% each of the R enantiomer and the S- enantiomer which is the herbicidally active isomer. S - metolachlor (PC Code 108800) is an isomer enriched formula comprised of 88% S- isomer and 12% R - isomer. Permanent tolerances are established at 40 CFR §180.638(a)(2) for S metolachlor in/on a variety of crop commoditie s, at levels ranging from 0.02 in/on meat and dairy products to 20 ppm in/on peanut hay and includes Brassica, leafy greens, subgroup 5A at 1.8 ppm and spinach at 0.5 ppm . Compliance with the tolerance levels is determined b y measuring only the sum of fre e and bound S - metolachlor, S - 2 - chloro -N - (2 - eth yl - 6 - methylphenyl ) -N - (2 - methoxy- 1 - methylethyl)acetamide, its R - enantiomer, and its metabolites, determined as the derivatives, 2 - [(2 - eth yl - 6 - methylphenyl )amino] - 1 - propanol ( CGA - 37913) and 4 - (2 - eth yl - 6 - methylp henyl) - 2 - hydrox y- 5 - methyl - 3 - morpholinone ( CGA - 49751 ) calculated as the stoichiometric equivalent of S - metolachlor. S - metolachlor is a selective, chloroacetanilide herbicide used primaril y for grass y weed control in many

agricultural food and feed crops, residential lawns, commercial turf (including golf courses, sports fields, recreation areas, and sod farms), ornamentals and horticultural nurseries. S - metolachlor formulations include emulsifiable and flowable concentrates, granular, and ready- to - use pro ducts. Application methods for agricultural uses include ground, aerial, irrigation and chemigation. Applications of S - metolachlor to residential lawns or turf are limited to professional applicators using backpack, hose - end, or handgun sprayers. IR - 4 has proposed the use of the herbicide S - metolachlor formulated as Dual Magnum® (EPA Reg. No. 100 - 816) on coriander (cilantro) as a broadcast, foliar application (0.64 - 0.96 lbs ai/A) at 30 day s before the leaf harvest and 70 day s before seed and on beets grown for leaves as a broadcast, pre - emergence soil surface treatment at 0.63 - 1.26 lbs ai/A after the crop has been planted but before the crop and weeds emerge. A second application of S - metolachlor to beets may be made as one post emergence, broadcast treatment at 0.63 - 1.26 lbs ai/A when plants are at 1 to 2 true leaf stage. **Toxicology** The existing toxicological database is primaril y comprised of studies conducted with metolachlor. However, bridging studies indicate that the metolachlor toxicology database can be used to assess toxicity for S - metolachlor. The toxicology database for S metolachlor, when combined with the metolachlor database, is complete for risk assessment purposes. However, neurotoxicity (870.6200 a and b) and immunotoxicity stu dies (870.7800) are required in accordance with the revised 40 CFR Part 158 Toxicology

Data Requirements. S - Metolachlor exhibits low acute toxicity via the oral (Toxicity

Category I II), inhalation (Toxicity Category IV), and dermal (Toxicity Category I II) routes of exposure. It causes slight eye irritation, and is non - irritating dermall y but is a dermal sensitizer. InPage 5 of 38

subchronic (metolachlor and S - metolachlor) and chronic (metolachlor) toxicity studies in dogs and rats decreased body weight and body

weight gain were the most commonly observed effects. No s ys temic toxicity was observed when metolachlor was administered dermally . No neurotoxicity studies with metolachlor or S - metolachlor are available. How ever, there was no evidence of neurotoxic effects in the available toxicity studies. Prenatal developmental studies in the rat and rabbit with both metolachlor and S metolachlor revealed no evidence of a qualitative or quantitative susceptibility in fetal animals. A two - generation reproduction study wi th metolachlor in rats showed no evidence of parental or reproductive toxicity . The FQPA safety factor was reduced to 1X because there are no residual uncertainties with regard to pre - and/or postnatal toxicity . There was no evidence of mutagenic or cy to genetic effects in vivo or in vitro . Metolachlor has been classified as a Group C, possible human carcinogen based on liver tumors in rats at the highest dose tested. No cancer potency factor has been established, as risks established based on the chronic reference dose are protective of cancer effects. **Dose Response Assessment** Toxicological endpoints were selected for dietary /drinking water, occupational and residential exposure scenarios. An acute reference dose (RfD) for assessment of food and drinki ng water exposures was selected from a developmental toxicity study in rats. A chronic RfD was selected from a chronic toxicity study in dogs. A point of departure (POD) for dermal exposure was not selected because no dermal or s ys temic toxicity was seen in rabbits following repeated dermal application at the highest dose tested for 21 day s. An inhalation exposure POD was selected from a developmental toxicity study in rats. An uncertainty

factor of 100X was applied to endpoints selected for exposure ro utes (10x for interspecies extrapolation, 10x for intraspecies variation). Ac ute Dietary aPAD = 3.0 mg/kg/day (General Population) Chronic Dietary cPAD = 0.97mg/kg/day (All Populations) Cancer (all routes) Group C carcinogen Incidental Or al Short - term NOAEL= 50 mg/kg/day (1 - 30 days) Inhalation Short - Term NOAEL= 50 mg/kg/day (1 - 30 days) Inhalation Short - Term NOAEL= 8.8 mg/kg/day (1 - 30 days) **Residue Chemistry** The qualitative nature of metolachlor residues in plants is adequatel y unde rstood. Residues of concern in plants, livestock, and rotational crops include metolachlor and its metabolites, determined as the derivatives CGA - 37913 and CGA - 49751. The Agency previously

concluded that the residues of concern for S - metolachlor are the same as for metolachlor. The residues of concern for S - metolachlor in drinking water include thePage 6 of 38

parent, CGA - 354743 (metolachlor ethanesulfonic acid (ESA)) and CGA - 51202 (metolachlor oxanilic acid (OA)) . Adequate methodology

is available for enforcing th e established and recommended tolerances. PAM Vol. II, Pesticide Regulation Section 180.368, lists a gas chromatograph y with nitrogen - phosphorus detector (GC/NPD) method (Method I) for determining residues in/on plant commodities and a gas chromatography with mass selective detector (GC/MSD) method (Method II) for determining residues in livestock commodities. These methods determine residues of metolachlor and its metabolites as either CGA - 37913 or CGA - 49751 following acid hydrol ys is. Adequate data are also available on the recovery of metolachlor through FDA’s Multiresidue Method Testing Protocols which indicat e that metolachlor is completely recovered through Method 302. IR - 4 and Sy

ngenta have proposed a high pressure liquid chromatography with mass s pectroscop y/mass spectroscopy (HPL C/MS/MS) enantiomer - specific method for the enforcement of the proposed tolerances, Method 1848 - 01. The method uses a chiral HPL C column to separate out the S - enantiomers (SYN506357 and SYN508500) of the hydrol ys is produc ts CGA - 37913 and CGA - 49751. This method has been determined to be adequate for enforcement purposes. Coriander (cilantro) fresh, dried and seed samples were anal yz ed using “Working Method for PR 09595: Analy sis of s - Metolachlor in Cilantro as Metabolites s - CGA - 37913 (SYN 506357 ) and s - CGA - 49751 (SYN - 508500) ,” a modification of Sy ngenta Method No. 1848 - 01. Samples of the raw agricultural commodities, leaves and stems, and seed were refluxed in acid and partitioned into dichloromethane (DCM). An aliquot w as purified with column chromatography and concentrated into aqueous acetonitrile. The lower limit of method validation (LLMV) for residues of SYN 506357 and SYN 508500 was 0.05 ppm in all matrices. Based on the LLMV, the calculated limits of detection ( LOD) ranged from 0.0132 - 0.0175 ppm for SYN 506357 and SYN 508500 in coriander (cilantro) fresh, dried and seed samples. The calculated limits of quantitation (LOQ) ranged from 0.0359 - 0.0526 ppm for SYN 506357 and SYN 508500 in coriander (cilantro) fresh, dried and seed samples, respectively . The method is adequate for data collection. Previously

submitted storage stability data indicates that the residues of metolachlor are stable on a variety

of commodities for up to 2 y rs. Coriander (cilantro) fresh l eaves and stems, dried leaves and stems and seed samples were stored frozen for a maximum of 708 day s, 702 day s, and 416 day s, respectively . The results of the storage stability study with coriander (cilantro) samples and previousl y submitted storage stab ility data are adequate to show that residues of S - metolachlor were stable for the duration of this study . There are no coriander (cilantro) or garden beet leaf livestock feed items of regulatory interest; therefore, a discussion of S - metolachlor residues on livestock food items is not germane to this petition. The submitted c oriander (cilantro) study is adequate in number and geographic location of the residue field trials. At all sites, two plots received a single broadcast application ofPage 7 of 38

S - metolachlor at the approximate rate of 0.64 lb ai/A or 0.96 lb ai/A. Coriander (cilantro) fresh leaf and stem samples were harvested approximately 30 (27 - 34) day s pre - harvest interval (PHI), after the application and placed into frozen storage shortl y after harvest. At one site, additional treated plots received a single broadcast application of S metolachlor at the approximate rate of 0.64 lb ai/A or 0.96 lb ai/A, where coriander (cilantro) seed were collected. At another site, additional treated plots received a single broadcast application of S - metolachlor at the approximate rate of 0.64 lb ai/A or 0.96 lb ai/A, and coriander (cilantro) leaves and stems were collected at 27 day s and dried in an oven. No spray

adjuvant was used at the trials. No residue decline studies were submitted. The anal ytical results show that after a single foliar broadcast application of S metolachlor at the approximate rate of 0.64 lb ai/A and 0.96 lb ai/A with a 27 to 34 - days PHI , the maximum total S - metolachlor residues as parent equivalents were approximately 3.7 ppm and 4.1 ppm in coriander (cilantro) fresh leaves and stems, respectively . The maximum total S - metolachlor residues as parent equivalents were increased from approximately

<0.131 ppm (fresh samples) to 0.834 ppm (dried s amples) in the 0.64 lb ai/A treated plot. The maximum total S - metolachlor residues as parent equivalents were increased from approximately 0.170 ppm (fresh samples) to 2.031 ppm (dried samples) in the 0.96 lb ai/A treated plot. The maximum total S - metola chlor residues as parent equivalents were <0.131 ppm in coriander (cilantro) seed at both application rates. Based on the results of these trials, the appropriate tolerance for residues of S - metolachlor in/on coriander (cilantro) leaves is 8.0 ppm. Howev er, the Agency uses the preferred name coriander not cilantro for this raw agricultural commodity and, in addition, does not differentiate between dry and fresh leaves for coriander (cilantro). Therefore, a revised Section F should be submitted to indicat e a request for coriander, leaves at 8.0 ppm and the cilantro dried and fresh leaves should be removed. The study data indicates that the requested tolerance on coriander, seed at 0.13 ppm is adequate. No new data have been submitted in support of the requested tolerance on beet, garden, leaves. The request is based on the currently established tolerance for residues of S metolachlor on Brassica leafy vegetables (Sub - group 5B), of 1.8 ppm. The Chemistry Science Advisory

Council (ChemSAC) has considere d the issue and determined that since the use pattern for beet greens is the same as that for leafy Brassica (sub group 5B), and beet greens are similar to the commodities in the leafy Brassica subgroup 5B, it is appropriate to translate this tolerance of 1.8 ppm to beet greens. Based on the CHEMSAC determination and that the proposed use pattern for beet, garden, leaves is the same as leafy Brassica greens, subgroup 5B, ARIA recommends for the proposed tolerance of 1.8 ppm on beet, garden, leaves. There is no crop associated with this petition which requires residue data for processed fractions. The rotational crop restrictions listed on the label are appropriate for these proposed uses. **Drinking Water**Page 8 of 38

Environmental fate data in dicate that parent met olachlor/S - metolachlor is moderatel y persistent to persistent. It is mobile to highly mobile in different soils and has been detected extensively

in surface water and groundwater. Major degradates identified in groundwater include metolachlor ethanesulfo nic acid (ESA) and metolachlor oxanilic acid (OA) in both groundwater and surface water. Environmental Fate and Effects Division ( EFED ) calculated conservative, Tier I Estimated Drinking Water Concentrations (EDWCs) of metolachlor and S - metolachlor in gro und water and surface water for use in the last human health risk assessment. Since there are existing uses of S metolachlor with higher application rates than the proposed S ection 3 use s , those EDWCs will not increase. EDWCs for metolachlor and S - metola chlor were calculat ed for both the parent compound, metolachlor ESA and metolachlor OA degradates (see metabolites table, Appendix 1). EDWCs were calculated using drinking water models PRZM/EXAMS and FIRST for surface water and SCI GROW for ground water. Current NAWQA monitoring data was also used to determine EDWCs. Based on monitoring and modeling data, total EDWCs for peak and average surface water respectively are 219 ppb and 119 ppb. Recommended groundwater EDWCs (peak and average) are 126 ppb. **Die tary Exposure**  For acute and non - cancer chronic exposures, ARIA is concerned when estimated dietary risk exceeds 100% of the population adjusted dose (PAD). S - metolachlor is classified as a Group C carcinogen, so no separate dietary assessment was perform ed for cancer. For acute and chronic di etary exposures an unrefined assessment w as conducted, assuming 100% crop treated, and tolerance level residues. T he acute and chronic dietary risk estimates are below the Agency ’s level of concern for the general U .S. population and all population subgroups with the most highly exposed subgroups being all infants (<1 year old) at 1.5 % of the a cute PAD (aPAD) and 11 .6 % of the chronic PAD ( cPAD ) . **Non -**  **Dietary, Non -**  **Occupational Exposure** There are no residential user exposures for the proposed new use of S - metolachlor for this Section 3 assessment. However, there is potential for residential exposure to S metolachlor from use of other registered products which are applied to residential lawns or turf b y professional a

pplicators. Therefore, the only potential short - term residential risk scenario anticipated is post - application exposure of children playing on treated lawns. S - metolachlor incidental oral exposure is assumed to include hand - to - mouth exposure, object - to - m outh exposure and exposure through incidental ingestion of soil. The residential exposure to toddlers for this scenario was calculated to be 0.046 mg/kg/day

resulting in an MOE of 1100. Based on this analy sis, the short - term oral MOEs are not of concern. **Aggregate Risk** The aggregate acute and chronic risk estimates include exposure to residues of S metolachlor in food and drinking water, and does not include dermal, inhalation orPage 9 of 38

incidental oral exposure. Since the dietary exposure assessment already i ncludes the highest acute and chronic exposure s from the drinking water modeling data, no further calculations are necessary. The acute and chronic risk estimate s for all populations, resulting from aggregate exposure to S - metolachlor in food and drinking water is below ARIA’s l evel of concern. The food and drinking water exposure estimates for the most highl y exposed subgroup, all i nfants (< 1 ye ar old) , is 1.5 % of the aPAD and 11 .6 % of the cPAD. There are no residential user exposures for the proposed new use of S - metolachlor for this Section 3 assessment. No intermediate - term risk scenarios are anticipated for the existing and proposed uses of S - metolachlor. However, there is potential for short - term residential exposure to S - metolachlor from use of other registered products which are applied to residential lawns or turf b y professional applicators via post - application exposure to children playing on treated lawns including hand - to - mouth exposure, object to - mouth exposure and exposure through incidental ingestion of soil. Results from that assessment have been used to assess aggregate risk from exposure to food, drinking water, and residential lawns. Based on this anal ysis, short - term aggregate MOE of 860 for toddlers is not of concern. As estimate d risks are calculated based on the chronic reference dose are protective of cancer effects, no separate cancer risk assessment is necessary . **Occupational Exposure** The occupational exposure scenario of mixing, loading, and appl yi ng S - metolachlor as an herbicide on crops has been assessed . The proposed uses may result in short - /intermediate - term (i.e., 1 - 30 day s or up to 6 months) dermal and inhalation exposures during mixing, loading, applying, and postapplication activities. L ong - term exposures (i.e. , 6 months of continuous exposure) are not expected to occur based on the proposed use pattern. Dermal toxicological endpoints of concern were not identified (i.e., no sy stemic toxicity

was seen following dermal exposure at the limit dose) therefore, no d ermal exposures were calculated. Short - and intermediate - term exposures from inhalation exposure routes were assessed for all exposure scenarios. Occupational and residential exposure and risk estimates were conducted using maximum application rates and surrogate exposure data. Based on the Agency's current practices, a quantitative postapplication inhalation exposure was also not assessed. Data from Occupational Pesticide Handler Unit Expo sure Surrogate Reference Table, which summarizes data from the Pesticide Handlers Exposure Database (PHED) was used to assess handler and post - application exposures in the absence of chemical - specific data. At the baseline level, all inhalation MOEs are above the target MOE of 100, thus, risks are not of concern. The handler exposure estimates in this assessment are based on a central tendency

estimate of unit exposure and an upper - percentile assumption for the application rate, and thus assumed to represent high - end exposures. The uncertainties associated with thi s assessment stem from the use of surrogate exposure data (e.g., differences in use scenario and data confidence), and assumptions regarding the amountPage 10 of 38

of chemical handled. The estimated exposures are believed to be reasonable high - end estimates based on observations from field studies and professional judgment. **Use of Human Studies** This risk assessment relies in part on data from studies in which adult human subjects were intentionall y exposed to a pesticide or other chemical. These studies have been determined to require a review of their ethical conduct . S ome of these studies are also subject to review b y the Human Studies Review Board. All of the studies used have received the appropriate review. **Environmental Justice** Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow In come Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ). **Conclusion** Pending resolution of the toxicology and residue chemistry concerns outlined in Section 10 below, ARIA has no concerns regarding human health exposure and risk from the proposed Section 3 use of S - metolachlor on coriander and garden beet leaves. **2.0 DETAIL DISCUSSION**  **2.1 Proposed New Uses**  S - metolachlor is to be applied to coriander (cilantro) formulated as Dual MAGNUM (EPA Reg. No.: 100 - 816) as a broadcast, foliar application (0.64 - 0.96 lbs ai/A) at 30 day s before the leaf harvest and 70 day s before seed. Use the lower end of S - metolachlor rate range for soils that are relatively coarse textured and the higher rates on fine textured soils. Apply

S - metolachlor to beets grown for leaves as a broadcast, pre - emergence soil surface treatment at 0.63 - 1.26 lbs ai/A after the crop has been planted but before the crop and weeds emerge. A second application of S - metolachlor to beets may be made as one post emergence, broadcast treatment at 0.63 - 1.26 lbs ai/A when plants are at 1 to 2 true leaf stage. Use the lower end of S - metolachlor rate range for soils that are relatively coarse textured and the higher rates on fine textured soils. **2.2 P**  **hysical/Chemical Properties T**  **able 2.2.a**  **Nom enclature of S**  **- Metolachlor and its Regulated Hydrolytic Derivatives.** Page 11 of 38

**T able**  **2.2.a Nom**  **enclature of S -**  **Metolachlor and its Regulated Hydrolytic Derivatives.** Com pound S - metolachlor

Common name S- metolachlor Com pany experimental name CGA - 77102 IUPAC name 2 - Chloro -N - (2 - ethyl - 6 - me thylphenyl) - N - {S(2 - methoxy - 1 - methylethyl)}acetamide CAS name Chloro -N - (2 - ethyl - 6 - methylphenyl) -N - (2 - methoxy - 1 - methylethyl)acetamide CAS # 87392 - 12 - 9 End - use product/(EP) Dual Magnum® Herbicide (7.62 lb/gal EC; EPA Reg. No. 100 - 816) Regulated resi due - CGA - 37913 Common name None Com pany experimental names SYN506357 (S - enantiomer of CGA 37913) Chemical name 2 - [(2 - ethyl - 6 - methylphenyl) amino] - 1 - propanol CAS registry number 61520 - 53 - 4 82508 - 08 - 5 (S - enantiomer) Regulated residue - CGA - 49751 Common name None Com pany experimental names CGA - 49751 SYN508500 (S - enantiomer of CGA 49751) Chemical name 4 - (2 - ethyl - 6 - methylphenyl) - 2 - hydroxy - 5 - methyl - 3 - mo rpholine CAS registry number 61520 - 54 - 5 **Table 2**  **. 2.b**  **Physicochemical Properties of the Technical Grade Test Compound**  **Parameter Value**  **Reference** Melting point/

boiling point N/A Registration Division: Phy sical and Chemical Characteristics (DP Num: 225258) pH 7.8 at 25°C (1% aqueous dispersion) Density 1.117 g/cm3 at 20°C Water solubility (25°C) 0 .48 g/LPage 12 of 38

**Table 2**  **. 2.b**  **Physicochemical Properties of the Technical Grade Test Compound**  **Parameter Value**  **Reference** Solvent solubility (mg/L at 25°C) Miscible with methanol, acetone, toluene, n octanol, n - hexane, ethyl acetate, dichloromethane Vapor pressure at 25°C 2.8 x 10 - 5 mm Hg Dissociation constant (pKa) No dissociation constant in pH range 2 - 12 Oc tanol/water partition coefficient Log(KOW) 3.0 at 25°C UV/visible absorption spectrum λmax Neutral: 534 L/mol•cm @ 266.4 nm 443 L/mol•cm @ 274.4 nm Acidic: 534 L/mol•cm @ 266.4 nm 444 L/mol•cm @ 274.4 nm Basic: 531 L/mol•cm @ 266.4 nm 411 L/mol•cm @ 274.4 nm **3.0 HAZARD ASSESSMENT**  **3.1 Hazard Profile** Th e existing toxicological database is comprised primarily of studies conducted with metolachlor. Metabolism studies were inadequate for comparing the metabolic pathway s of metolachlor and S - metolachlor. However, based on a comparison of the findings in to xicity studies with both chemicals, S - metolachlor is considered to be of comparable toxicity to metolachlor and data can be bridged between the two compounds. The metolachlor toxicology

database is complete. The combined metolachlor and S metolachlor tox icity

data bases are adequate to characterize the toxicity of S - metolachlor for risk assessment purposes. In subchronic oral studies on metolachlor, the only evidence of toxicity was decreased body weight/body

weight gain in rats and dogs in both sexes . There was no evidence of sy stemic toxicity

at the limit dose in a 21 day dermal toxicity

metolachlor study

in rabbits, however dermal irritatio n was observed at lower doses. In the chronic dog study on metolachlor, the onl y adverse effect was decreased body weight gain in females. In the mouse carcinogenicity study , possible treatment - related deaths in females and decreased body weight/body weight gain in both sexes were observed. In the rat combined chronic toxicity / carcinogenicity

study , decrease d body

weight gain and food consumption were observed. There was no evidence of carcinogenicity in mice; however, there were statistically significant increases in liver adenomas and combined adenomas/carcinomas in female rats. In male rats, there was a statistically significant trend but no pair - wise significance for liver tumors. There was no evidence of a mutagenic or cy

togenetic effect in vivo or in vitro in studies with either metolachlor or S metolachlor. Metolachlor has been classified as a Group C carcinogen with risk quantitated using a non - linear (Margin of Exposure (MOE) ) approach.Page 13 of 38

There was no evidence of increased quantitative or qualitative fetal susceptibility in the prenatal developmental studies in rats and rabb its with either metolac hlor or S metolachlor. In general, significant developmental toxicity was not seen in rats or rabbits with either compound. In the metolachlor rabbit prenatal developmental toxicity study , maternal animals had persistent anorexia and decreased body weight gain. There were no developmental effects. In the rat prenatal developmental toxicity study on metolachlor, death, clinical signs (clonic and/or tonic convulsions, excessive salivation, urine - stained abdominal fur and/or excessive salivation) and decre ased body weight gain was observed at the limit dose in maternal animals. Developmental effects at the limit dose included slightly decreased number of implantations per dam, decreased number of live fetuses/dam, increased number of resorptions/dam and si gnificant decrease in mean fetal body weight. In the S - metolachlor rat study , maternal toxicity, including increased clinical signs (pushing head through bedding), and decreased body weight/weight gain, food consumption and food efficiency , was observed at the mid - dose. There were no developmental effects at the highest dose tested. In the rabbit, clinical signs of toxicity (little/none/soft stool) were observed at the mid - dose in maternal animals tested with S metolachlor. No developmental effects were observed at the highest dose tested. In the two - generation reproduction study in rats conducted with metolachlor, there was no evidence of parental or reproductive toxicity at the highest dose tested (80 mg/kg/day). At this dose, there was a minor decrea se in fetal body weight beginning at lactation day 4. Since a similar body

weight decrease was not seen on lactation day 0, the cause of the effect on later lactation day s is most likely due to exposure of the pups to metolachlor in the diet and/or milk and therefore is not evidence of an increased quantitative susceptibility

in post - natal animals. Both compounds are extensively absorbed and metabolized following oral administration. Elimination is via the urine and feces. Tissue residues were highest in red blood cells. Neurotoxicity

battery (870.6200 a and b) and immunotoxicity studies (870.7800) are required in accordance with the revised 40 CFR Part 158 Toxicology Data Requirements. **3.2 FQ**  **PA Hazard Considerations** The toxicity

database for S - meto lachlor/metolachlor is sufficient for a full hazard evaluation and is considered adequate to evaluate risks to infants and children. Acceptable developmental toxicity studies in the rat and rabbit and an acceptable reproduction study in the rat are availa ble. Based on the results of the available toxicity studies, there is no evidence for neurotoxicity or immunotoxicity . However, in accordance with the revised 40 CFR Part 158 Toxicology Data Requirements, n eurotoxicity b attery

(870.6200) and i mmunotoxici ty (870.7800) studies are required. **3.2.1 Developmental Toxicity** Page 14 of 38 **3.2.1.1 Rat Developmental Study**  **– Metolochlor**  In a prenatal developmental toxicity study (MRID 00151941), metolachlor (96.4% ai ) in 0.5% (w/v) aqueous h ydrox ym eth yl cellulose was administ ered b y gavage (10 mL/kg) to 25 presumed pregnant BR rats from gestation days (GD) 6 through 15, inclusive, at dose levels of 0, 30, 100, 300 or 1000 mg/kg/day . The animals were sacrificed on GD 20 and the fetuses examined for evidence of developmental ef fects. There were four treatment - related deaths in animals treated at 1000 mg/kg/day . Clinical signs of toxicity , including clonic and/or toxic convulsions, excessive salivation, urine stained abdominal fur and/or excessive lacrimation, were observed in animals treated at 1000 mg/kg/day . There was also an increase in excessive salivation in the 300 mg/kg/day

group. However, as this effect was most likely due to gastric irritation and there was no other evidence of treatment - related toxicity, the finding is not considered toxicologically

significant. Body weight gain was significantl y decreased in the 1000 mg/kg/day

group during GD 6 - 16, GD 6 - 20and GD 0 - 20. Food consumption was not affected. In the 1000 mg/kg/day group, there were a slightl y decreased number of implantations per dam, decreased live fetuses/dam and increased number of resorptions/dam. There was also a statisticall y significant decrease in mean fetal body weight. The maternal toxicity

L OAELwas 1000 mg/kg/day based on an increased incid ence of death, clinical signs of toxicity (clonic and/or toxic convulsions, excessive salivation, urine - stained abdominal fur and/or excessive lacrimation) and decreased body weight gain. The NOAE L was 300 mg/kg/day . The developmental toxicity L OAEL was conservativel y established at 1000 mg/kg/day based on slightly

decreased number of implantations per dam, decreased number of live fetuses/dam, increased number of resorptions/dam and significant decrease in mean fetal body weight. The NOAEL was 300 mg/kg/day .

**3.2.1.1 Rabbit**  **Developmental Study -**  **Metolochlor** In a prenatal developmental toxicity study (MR1D 00041283), metolachlor (95.4% ai ) in 0.75% aqueous h ydrox y methylcellulose was administered by gavage to 16 pregnant New Zealand White rabbits/group f rom gestation day s (GD) 6 through 18, inclusive, at dose levels of 0, 36, 120 or 360 mg/kg/day . The animals were sacrificed on GD 30 and the fetuses examined for evidence of developmental effects. One doe at 36 mg/kg/day and another at 360 mg/kg/day died on GDs 24 and 29, respectivel y. The cause of death in both animals was attributed to persistent anorexia. Two rabbits aborted, one at 120 mg/kg/day (GD 25) and another at 360 mg/kg/day (GD 17). The high - dose animal had persistent anorexia. One rabbit in each group delivered prior to GD 30; the control, low - and high - dose animals on GD 29 and the mid - dose animal on GD 30. There was a treatment - related increase in the incidence of persistent anorexia in the does treated at 360 mg/kg/day , which was defin ed as less than one - half of the daily food allotment consumed. However, food consumption data were not providedPage 15 of 38

to support this finding. There was a treatment - related decrease in body weight gain in the 360 mg/kg/day

group for GD 6 - 18 and GD 6 - 30. There was no treatment - related increase in gross pathological findings in maternal animals at necrops y. No treatment related increase in external, visceral or skeletal developmental effects were observed. The maternal toxicity

L OAELwas 360 mg/kg/day based o n an increased incidence of clinical observations (persistent anorexia) and decreased body weight gain. The NOAEL was 120 mg/kg/day . The developmental toxicity L OAEL was not established. The NOAEL was 360 mg/kg/day .

**3.2.1.3 Rat Developmental Study**  **– S**  **- Metolochlor**  In a developmental (teratology) study (MRID# 43928925), rats (Strain: Tif: RAIf (SPF)) received either 0, 5, 50, 500, or 1000 mg/kg/day S - metolachlor (95.6% ai ) suspension in 0.5% (w/w) aqueous solution of sodium carboxy methylcellulose by

oral gavage from gestation day s 6 through 15. No treatment related mortality was noted. There was a dose related increase in clinical signs seen as all 500 and 1000 mg/kg/day animals and 9/24 of the 50mg/kg/day animals exhibited as pushing head through bedding for about one hour. This was noted throughout the dosing period and may be an indication of neurotoxicity . The 500 and 1000 mg/kg/day

dose groups had lower overall body weights at gestation day s 15 and 21 and gained less weight than the control durin g the dosing period (gestation day s 6 - 16) and for the calculated periods of gestation day s 6 - 21 and 0 - 21, also for corrected body weight gains from gestation day s 6 - 21. Also the 500 and 1000 mg/kg/day dose groups had reduced food consumption during the do sing period (gestation day s 6 - 16, statistically significantl y different), reduced food consumption following the dosing period and for the overall periods (gestation day s 6 - 21 and 0 - 2 1). This is also reflected in reduced food efficiency for the same peri ods (6 - 16, 6 - 21, 6 - 21, and 0 - 21). The maternal toxicity

NOELwas 50 mg/kg/day with a LOEL of 500 mg/kg/day based on increased clinical signs of toxicity, decreased body weights and body

weight gains and reduced food consumption and reduced food efficienc y. No significant treatment related developmental toxicity

was noted at the dose levels tests. The developmental toxicity was equal to or greater than 1000 mg/kg/day , a LOELwas not reached.

**3.2.1.4 Rabbit Developmental Study**  **– S**  **- Metolochlor**  In a deve lopmental (teratology) study (MRID# 43928924), female New Zealand White. S.P.F. Rabbits received either 0, 20, 100, or 500 mg/kg/day S - metolachlor (89.6% ai (93.7% S isomer)) suspension in 3% corn starch by oral gavage from gestation days 7 through 19. N o treatment related mortality was noted. There was a dose related increase in the 500 mg/kg/day

dose group had lower overall body weights at gestation day s 19, 29 and corrected body weights at day 29 gained less weight than the control during the dosingPage 16 of 38

p eriod (gestation day s 7 - 19) with a rebound weight gain following the dosing period (gestation day s 19 - 29), an indicator of toxicity . This group also had lower overall weight gain for the calculated periods of gestation day s 7 - 29, 0 - 29 and corrected body w eight gains for 0 - 29. This was supported by reduced little/none/soft stool observations at the 100 and 500 mg/kg/day

dose levels, food consumption during the dosing period (gestation day s 7 - 19) and for the overall periods (gestation day s 7 - 28 and 0 - 28) wi th a rebound in food consumption following dosing (gestation day s 19 - 28) at the 500 mg/kg/day

dose level. This is also reflected in reduced food efficiency for the same periods (719, 7 - 28, and 0 - 28) and increased food efficiency following dosing (19 - 28) at the 500 mg/kg/day

dose level. The maternal toxicity NOEL was 20 mg/kg/day with a LOEL of 100 mg/kg/day

based on clinical signs of toxicity . No significant treatment related developmental toxicity was noted at the dose levels tests. The developmental t oxicity was equal to or greater than 500 mg/kg/day , a LOELwas not reached. **3.2.2 Reproductive Toxicity**  In a two - generation reproduction study (MRID 00080897), metolachlor (95.4% ai ) was administered in the diet to two consecutive generations of 15 male/30 female CD albino rats at dose levels of 0, 30, 300 or 1000 ppm (F0 males: 0,2.4,23.5 and 75.8 mg/kg/day ; F0 females: 0, 2.5, 26.0 and 85.7 mg/kg/day ; F1males: 0, 2.3, 23.7 and 76.6 mg/kg/day ; F1 females: 0, 2.6, 25.7 and 84.5 mg/kg/day). There were no deaths in the F0 generation. Two females of the F1 generation died during the premating period, one in the 300 ppm group at 32 day s and the other in the 1000 ppm group at 52 day s. One female in the 300 ppm group was found dead on gestation day 19 and a control group female was sacrificed in a moribund condition on lactation day 1. Based on necropsy

examinations, none of the deaths was treatment - related. There were no treatment - related clinical signs of toxicity in either generation. Body weight, body w eight gain and food consumption were unaffected in the F0 generation. In the F1 generation, food consumption was significantl y decreased in females of the 1000 ppm group at several time points; however, there was no effect on body weight/body

weight gain. Therefore, this finding was not considered toxicologically significant. There were no treatment - related effects on organ weights or gross/microscopic necropsy examinations in either generation. There was no evidence of a treatment - related effect on any of the reproductive parameters for either generation. Offspring body weight was significantl y decreased in the F1 litter on lactation day s 14 and 21(91 - 96% of control value) and in the F, litter on lactation day s 4, 7, 14 and 21 (92 - 95% of control valu e). Although the magnitude of the decrease is small, the finding is regarded as toxicologicall y significant. The parental toxicity

L OAELwas not established. The NOAEL was 1000 ppm (F0 males/females: 75.8/85.7 mg/kg/day ; F1males/females: 76.6/84.5 mg/kg/day). The reproductive toxicity

L OAELwas not established. The NOAEL was 1000 ppm (F0Page 17 of 38

males/females: 75.8/85.7 mg/kg/day ; F1males/females: 76.6/84.5 mg/kg/day). The offspring LOAEL was conservativel y established at 1000 ppm (F0 males/females: 75.8/85.7 mg/kg/day ; F1males/females: 76.6/84.5 mg/kg/day) based on decreased body weight in F1 and F2 litters. The NOAEL is 300 ppm (F0 males/females: 23.5/ 26.0 mg/kg/day ; F1males/females: 23.7/25.7 mg/kg/day). **3.2.3 Pre**  **- and/or Postnatal Toxicity**  The database is considered adequate for selection of study endpoints and determination of a dose/response to characterize the potential prenatal or postnatal toxicity of metolachlor or S - metolachlor to infants and children. No increase in susceptibility was seen in de velopmental toxicity

studies in rat and rabbit or reproductive toxicity studies in the rat. Toxicity to offspring was observed at dose levels the same or greater than those causing maternal or parental toxicity . Based on the results of developmental and reproductive toxicity studies, there is not a concern for increased qualitative and/or quantitative susceptibility

following in utero exposure to metolachlor or S - metolachlor . **3.2.4 Immunotoxicity**  There are no indications in the available studies that o rgans associated with immune function, such as the th ymus and spleen, are affected by metolachlor or S - metolachlor . There are no effects seen on the developing immune sy stem in the existing studies. An immunotoxicity

study is required , however, under 40 CFR Part 158 as a part of the new data requirements for registration of a pesticide (food and non - food uses). **3.2.5 Neurotoxicity**  There is no evidence in the toxicology database that metolachlor or S - metolachlor is neurotoxic. Inthe rat developmental t oxicity study wi th S - metolachlor (MRID 43928925), 6/24 animals in the 1000 mg/kg/day group and 3/24 in the 500 mg/kg/day group were described as exhibiting discomfort (pushing head through bedding for one hour after each dose); the sign was first observed after the initial treatment. No control animals were affected. Inthe rat prenatal developmental toxicity study with metolachlor, clinical signs of clonic and/or tonic convulsions and excessive salivation, possible neurotoxic signs, were observed at 1000 mg/kg/day . However, the signs were prior to death in some of the treated animals and could be agonal effects. Acute and subchronic n eurotoxicity

studies (870.6200) are required in accordance with the revised 40 CFR Part 158 Toxicology

Data Requirements. **3.2.6 FQ**  **PA Safety Factor** There is low concern (and no residual uncertainty) for pre - and/or postnatal toxicity resulting from exposure to S - metolachlor. Data available on metolachlor and S metolachlor provided no indication of increased susceptibility (quantitative or qualitative) to rats or rabbits exposed in utero. The metolachlor rat reproduction study showed no evidence of reproductive toxicity . The dietary exposure from food and water andPage 18 of 38

residential exposure are not understated. Therefore , the special FQPA safety factor is reduced to 1x for risk assessment for this chemical. A developmental neurotoxicity study is not required since there was no evidence of neurotoxicity or neuropathology

from the available studies and there is no concern or re sidual uncertainty for pre/post - natal toxicity . Based on the results of the available toxicity studies, there is no evidence for immunotoxicity . Since there are adequate developmental studies in rats and rabbits and an adequate multi generation study i n rats, and no residual uncertainties in toxicity or exposure databases that indicate the need for a factor, the FQPA factor has been reduced to 1X. **3.3 Toxicity Endpoint Selection**  **3.3.1 Acute Reference Dose (aRfD)**  **- General Population**  Selected Study : Developmental Toxicity in Rats - Metolachlor (MRID 00151941). In a prenatal developmental toxicity study with metolachlor on rats, the maternal toxicity LOAEL was 1000 mg/kg/day based on an increased incidence of death, clinical signs of toxicity (clon ic and/or toxic convulsions, excessive salivation, urine - stained abdominal fur and/or excessive lacrimation) and decreased body weight gain. The NOAEL was 300 mg/kg/day . The developmental toxicity L OAEL was conservativel y established at 1000 mg/kg/day

b ased on slightly

decreased number of implantations per dam, decreased number of live fetuses/dam, increased number of resorptions/dam and significant decrease in mean fetal body weight. The NOAEL was 300 mg/kg/day . Dose and Endpoint for Establishing an aR fD : 300 mg/kg/day based on a NOAEL of 1000 mg/kg/day

and an LOAEL of 1000 mg/kg/day based on an increased incidence of death, clinical signs of toxicity (clonic and/or tonic convulsions, excessive salivation, urine - stained abdominal fur and/or excessive l acrimation) and decreased body weight gain. Uncertainty Factor (UF ): 100

– 10x for interspecies extrapolation and 10x for intraspecies variation. Comments about Study

/Endpoint : Since clinical signs are observed after a single oral dose of metolachlor, the duration and route of administration are appropriate for the risk assessment. Developmental effects observed are not attributable to a single exposure and therefore, a separate acute endpoint has not been identified for females 13 - 50. Although incre ased incidence of death is one of the effects seen, it was seen at a dose (1000 mg/kg/day) approximately three times higher than the dose (300 mg/kg/day) selected for risk assessment; therefore, the Agency is confident that adequate safety is provided to p rotect the public from dietary exposure to residues of metolachlor.Page 19 of 38 **3.3.2 C**  **hronic Reference Dose (RfD) –**  **General Population** Selected Study : Chronic Feeding Study in Dogs (MRID 43744201). In a one ye ar metolachlor oral feeding study in dogs, the NOAEL was 9.7 mg/kg/day and the L OAEL was 33 mg/kg/day based on stomach lesions in 75% of the males and by slight sinusoidal histiocy

tosis in the liver of 50% of the males. Dose and Endpoint for Establishing an aRfD : 9.7 mg/kg/day based on a NOAEL of 9 .7 mg/kg/day

and a LOAEL of 33 mg/kg/day based on decreased body weight gain in females. Uncertainty Factor (UF ): 100

– 10x for interspecies extrapolation and 10x for intraspecies variation.

**3.3.3 Incidental Oral Exposure (Short**  **- Term)**  Selected Study : Developmental Toxicity Study in Rats (MRID 43928925). In a developmental study conducted with S - metolachlor in rats the maternal toxicity NOAEL was 50 mg/kg/day with a LOAEL of 500 mg/kg/day based on increased clinical signs of toxicity , decreased body weights and body weight gains and reduced food consumption and reduced food efficiency . No significant treatment related developmental toxicity

was noted at the dose levels tests. The developmental toxicity NOAEL was equal to or greater than 1000 mg/kg/day; a LOAEL was not reached. Dose and Endpoint : 50 mg/kg/day based on an offspring NOAEL of 50 mg/kg/day and a LOAEL of 500 mg/kg/day based on increased incidence of clinical signs, decreased body weight/body weight gain, food consumption and food efficiency seen in maternal animals. Uncertainty Factor (UF ): 100

– 10x for interspecies extrapolation and 10x for intraspecies variation. Comments about Study

/Endpoint : The NOAEL (20 mg/kg/day) for the prenatal developmental toxicity

study in rabbits with S

- m etolachlor (MRID 43928924) was lower than the 50 mg/kg/day

from the rat developmental study . However, the endpoint was based on weak clinical signs of toxicity (increase in little/none/soft stool observations) at **Acute RfD (General Population) = (NOAEL) 300 mg/kg**  **= 3.0 mg/kg (UF) 100** 

**Chronic RfD (General Population) = (NOAEL) 9.7 mg/kg**  **= 0.097 mg/kg (UF) 100** Page 20 of 38

100 mg/kg/day . Although there was a dose - related increase in this effect, it is not evidence of frank toxicity and was judged not be appropriate for risk assessment. Therefore, the rabbit study with S - metolachlor was not selected for this exposure scenario. **3.3.4 Dermal Exposure (Short**  **- Term)**  N o hazard was identified for quantification of risk following dermal exposure. In a 21 - day dermal toxicity

study (MRID 41833101), no sy stemic toxicity was seen following repeated dermal application of metolachlor (96.4% ai) to the intact skin of five New Z ealand rabbits/sex/group at doses of 0, 10, 100 or 1000 mg/kg/day for 21 day s. **3.3.5 Inhalation Exposure (Short**  **- Term)**  Selected Study : Developmental Toxicity Study in Rats (MRID 43928925). Dose and Endpoint : 50 mg/kg/day based on an offspring NOAEL of 50 mg/kg/day and a LOAEL of 500 mg/kg/day based on is based on increased incidence of clinical signs, decreased body weight/body weight gain, food consumption and food efficiency seen in maternal animals. Uncertainty Factor (UF ): 100

– 10x for interspe cies extrapolation and 10x for intraspecies variation. Comments about Study

/Endpoint : Since an oral study was selected, a 100% absorption factor should be applied. 

### 3.3.6 **Inhalation Exposure (Intermediate -**  **Term)** Selected Study : Subchronic (6 month) Toxic ity Study in the Dog ( MRID 00032174 ) In a subchronic oral toxicity study (MRID5 00032174 and 43244001), metolachlor (96.8% ai) was administered in the diet to Beagle dogs (8/sex/group for control and high dose groups; 6/sex/group for low - and mid - dose groups) at dose levels of 0, 100, 300 or 1000 ppm (males: 0, 2.92, 9.71 and 29.61 mg/kg/day , respectivel y; females: 0, 2.97, 8.77 and 29.42 mg/kg/day , respectivel y) for six months. There were no deaths or clinical signs of toxicity . Mean body weight gain w as decreased during weeks 0 - 13 and 0 - 26 in the 1000 ppm group males (55 - 63% decrease) and females (44 - 50% decrease), although the changes were not statistically significant. Mean overall food consumption was not affected in the 1000 ppm group males but wa s slightly decreased (9%) in the 1000 ppm females. There was a significant decrease in the activated partial thromboplastin time (APTT) in the 300 and 1000 ppm group males and 300 ppm group females but the findings were not considered toxicologicall y sign ificant because the decrease was slight and not dose - related. Alkaline phosphatase was significantl y increased in the 300 ppm and 1000 ppm group males and females at week 26; however, the effect was not considered toxicologically significant due to the sm all magnitude of the increase and thePage 21 of 38

lack of accompanyi ng necrops y findings. The LOAELwas 1000 ppm (males/females: 29.61/29.42 mg/kg/day) based on decreased body weight gain. The NOAEL was 300 ppm (mal es/females: 9.71/8.77 mg/kg/day). Dose and Endpoint for Risk Assessment: NOAEL of 8.8 mg/kg/day based on decreased body weight gain at 29.4 mg/kg/day Dose and Endpoint : NOAELof 8.8 mg/kg/day based on decreased body weight gain at 29.4 mg/kg/day Comments about Study

/Endpoint : Since an oral study was se lected, a 100% absorption factor should be applied. **3.3.7 Classification of Carcinogenic Potential**  HED’s Cancer Assessment Review Committee (CARC) classified metolachlor as a Group C carcinogen with risk quantitated using a non - linear approach. The NOAE L of 15 mg/kg/day from the rat combined chronic toxicity /carcinogenicity study is based on neoplastic nodules/hepatocellular carcinomas seen at the highest dose tested of 150 mg/kg/day . The Agency

notes that the tumor NOAELof 15 mg/kg/day is comparable t o the NOAEL of 9.7 mg/kg/day selected for establishing the chronic reference dose for metolachlor (TXR 014691, 9/28/01). The recommendation for a non - linear approach should be followed since no new data were submitted for a re - evaluation b y the CARC . **3 .**  **4 Margins of Exposure**  **Table 3**  **. 4**  **Target Levels of Concern/Margin of Exposure S -**  **Me tolachlor**  **Route/Duration Short**  **- Term**  **(1 -**  **30 Days) Intermediate**  **- Ter**  **m (1**  **- 6 M**  **onths) Long**  **- Term**  **(> 6 Months) Occupational (Worker) Exposure**  Dermal NA NA N/A Inhalation 100 100 N/A **Residential (Non -**  **Dietary) Exposure** Oral 100 N/A N/A Dermal NA N/A N/A Inhalation N/A N/A N/A **3.5 Recommendation for Aggregate Exposure Risk Assessments**  When there are potential residential exposures to the pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal and inhalation exposures. There are potential residential incidental oral exposures to S - metolachlor via post application hand - to - mouth exposure of children playing on treated lawns. In addition , dietary and incidental oral endpoints for S - metolachlor are based on common toxicological effects. Therefore, exposure s from food and non - food oral routes should be aggregated for this assessment. **3.6 Summary of Endpoints Selected for Risk Asses**  **sment**Page 22 of 38

**Table 3.6.a**  **. Summary of Toxicological Endpoints for S -**  **metolachlor for Use in Dietary Hum an Health Risk**  **Assessments Exposure/Scenario**  **Point of**

**Departure Uncertainty/FQP** 

**A Safety Factors RfD, PAD,** 

**LOC for Risk Assessment**  **Study and Toxicological Effec ts** 

Ac ute Dietary (General Population) NOAEL =

300 mg/kg/day UF A= 10x

UF H =10x FQPA SF= 1x Ac ute RfD = 3.0

mg/kg/day aPAD = 3.0 mg/kg/day Developmental Toxicity Study - Rat

LOAEL = 1000 mg/kg/day based increased incidence of death, clinical signs (clonic and/or tonic convulsions, excessive salivation, urine - stained abdominal fur and/or excessive lacrimation) and decreased body weight gain. Chronic Dietary (All Populations) NOAEL =

9.7 mg/kg/day UF A= 10x

UF H =10x FQPA SF= 1x Chronic RfD =

0.097 mg/kg/day cPAD = 0.97mg/kg/day Chronic Toxicity

– Dog;

LOAEL = 33 mg/kg/day based decreased body weight gain in females Cancer (all routes) Metolachlor has been classified as a Group C carcinogen with risk quantitated using a non linear (Margin of Exposure) app roach. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NO AE L = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. **Table 3.6.b . Summary of Toxicological Doses and Endpoints for S**  **- ME**  **TOLAC HLOR for Use in Residential**  **and Occupational Hum an Health Risk Assessments**  **Exposure/ Scenario**  **Point of**

**Departure Uncertainty** 

**Factors Level of** 

**Concern for Risk Assessment**  **Study and Toxicological Effects** Incidental Oral Short term (1 - 30 days) NOAEL=

50 mg/kg/day UF A= 10x

UF H =10x Residential LOC

for MOE = 100 Developmental Toxicity Study - Rat

LOAEL = 500 mg/kg/day based on increased incidence of clinical signs, decreased body weight/body weight gain, food consumption and food efficiency seen at the LOAE L in maternal animals. Inhalation Short - Term (1 - 30 days) NOAEL=

50 mg/kg/day UF A= 10x

UF H =10x Occupational

LOC for MOE = 100 Developmental Toxicity Study - Rat

LOAEL = 500 mg/kg/day based on increased incidence of clinical signs, decreased body weight/body weight gain, food consumption and food efficiency seen at the LOAEL in maternal animals. Inhalation Short - Term (1 - 30 days) NOAEL=

8.8 mg/kg/day UF A= 10x

UF H =10x Occupational

LOC for MOE = 100 Subchronic Toxicity Study - Dog

LOAEL = 29.4 mg/kg/d ay based on decreased body weight gain Cancer (all routes) Metolachlor has been classified as a Group C carcinogen with risk quantitated using a non linear (Margin of Exposure) approach.Page 23 of 38 **3.7 Endocrine Disruption**  As required b y FIFRA and FFDCA, EPA re views numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively , these studies include acute, subchronic and chronic toxicity , including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and g eneral or s ys temic toxicity . These studies include endpoints which may

be susceptible to endocrine influence, including effects on endocrine target organ histopathology , organ weights, estrus cyclicity , sexual maturation, fertility , pregnancy

rates, repro ductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its most recent registration decision , EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), S - metolachlor, as an enriched isomer of metolachlor, is sub ject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced b y a “naturally occurring estrogen, or other such endocrine effects as the Administrator may

designate.” The EDSP employ s a two - tiered approach to making the statutorily

required determinations. Tier 1 consists of a battery of 11 s creening assay s to identify

the potential of a chemical substance to interact with the estrogen, androgen, or thy roid (E, A, or T) hormonal sy stems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal s ys tems will proceed to the next stage of the EDSP where EPA will determine which, if any , of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine - related effects caused by the s ubstance, and establish a dose - response relationship between the dose and the E, A, or T effect. Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call - ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Metolachlor was included on that list and has been issued an order to conduct the Tier 1 testing. Once all required Tier 1 and Tier 2 data have been received and reviewed, the endpoints and safety factors used for risk assessment purposes will be examined and a new risk assessment performed for S - metolachlor if necessary . For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery , please visit our website: http://www.epa.gov/endo/ . **4.0 RESIDUE CHEMISTRY CONSIDERATIONS**  **4.1 Metabolism in Plants/Liv**  **estock** The qualitative nature of metolachlor residues in plants is adequatel y understood based upon the adequate corn, potato, and soy bean metabolism studies. The metabolism ofPage 24 of 38

metolachlor involves conjugation with glutathione, breakage of this bond to f orm the mercaptan, conjugation of the mercaptan with glucuronic acid, O - demeth yl ation of the methyl ether, and conjugation of the resultant alcohol with a neutral sugar. A minor pathway may involve sugar conjugation of metolachlor directly to the correspo nding oxo compounds. Residues of concern in plants include metolachlor and its metabolites, determined as the derivatives CGA - 37913 and CGA - 49751. The Agency previously concluded that the residues of concern for S - metolachlor are the same as for metolach lor. Adequate studies are available depicting the metabolism of metolachlor in ruminants and poultry . Metolachlor is rapidly metabolized and almost totally eliminated in the urine and feces of ruminants (goats), non - ruminants (rats), and poultry . Metola chlor per se was not detected in any of the excreta or tissues. As in plants, metolachlor residues of concern in livestock commodities include metolachlor and its metabolites, determined as the derivatives CGA - 37913 and CGA - 49751. The residues of concern for S - metolachlor in livestock are the same as those for metolachlor. The residues of concern for S - metolachlor in drinking water include the parent, CGA 354743 (metolachlor ethanesulfonic acid (ESA)) and CGA - 51202 (metolachlor oxanilic acid (OA)) . **4.2 Metabolism in Rotational Crops**  Based on the available data, HED concluded that the metabolism of [ 14 C]S - metolachlor in rotational crops is similar to the metabolism observed in the primary crops. Metabolism in rotational crops primaril y involves two p athway s: (i) conjugation of the parent molecule with glutathione by substitution of the chlorine, followed by the degradation of the glutathione moiety to form a variety of sulfur containing metabolites; and (ii) direct oxidation of parent or secondary met abolites, primarily

on the chloroacetyl side chain. Complete degradation of secondary metabolites either in the soil and/or plants also resulted in the incorporation of molecule fragments into natural plant constituents. The residues of concern for both metolachlor and S - metolachlor in rotational crops are the same as for primary crops, metolachlor and its metabolites, determined as the derivatives CGA - 37913 and CGA - 49751. **Table 4.2**  **Summary of Metabolites and Degradates to be included in the Risk Asse ssment and Tolerance**  **Expression Matrix**  **Residues included in Risk Assessment Residues included in Tolerance**  **Expression** Plants Primary Crop Parent & metabolites convertible to CGA 37913, CGA - 49751 Parent & metabolites convertible to CGA - 37913, CGA - 49751 Rotational Crop Parent, CGA - 37913 & metabolites convertible

to CGA - 49751 Parent & metabolites convertible to CGA - 37913, CGA - 49751 Livestock Ruminant Parent & metabolites convertible to CGA 37913, CGA - 49751 Parent & metabolites convertible to CGA - 37913, CGA - 49751 Poultry Parent & metabolites convertible to CGA 37913, CGA - 49751 Parent & metabolites convertible to CGA - 37913, CGA - 49751Page 25 of 38

**Table 4.2**  **Summary of Metabolites and Degradates to be included in the Risk Asse ssment and Tolerance**  **Expression Matrix**  **Residues included in Risk Assessment Residues included in Tolerance**  **Expression** Drinking Water Parent & metabolites convertible to CGA 354743 (metolachlor ethanesulfonic acid (ESA)) and CGA - 51202 (met olachlor oxanilic acid (OA)) Not Applicable

**4.3 Residue Analytical Methods**  **4.3.1 Enforcement Methods**  Adequate methodology

is available for enforcing the established and recommended tolerances. PAM Vol. II, Pesticide Regulation Section 180.368, lists a GC/NPD method (Method I) for determining residues in/on crop commodities and a GC/MSD method (Method II) for determining residues in livestock commodities. These methods determine residues of metolachlor and its metabolites as either CGA - 37913 or CGA 497 51 following acid hydroly sis. **4. 3.**  **2 Multiresidue Methods**  Adequate data are available on the recovery of metolachlor through Multiresidue Method Testing Protocols. The FDA PESTDATA database indicates that metolachlor is completely

recovered through Method 302, PAM Vol. I(3 rd ed., revised 10/97). **4.3.3 Residues in Crops**  Coriander (Cilantro) The submitted study

is adequate in number and geographic location of residue field trials. Five field trials were conducted in EPA Regions 2 (2), 6, 9, and 10. At all sites, two plots received a single broadcast application of S - metolachlor at the approximate rate of 0.64 lb ai/A or 0.96 lb ai/A. Coriander (cilantro) fresh leaf and stem samples were harvested approximately

30 (27 - 34) day s pre - harvest interval (PHI ), after the application and placed into frozen storage shortly after harvest. At one site, additional treated plots received a single broadcast application of S - metolachlor at the approximate rate of 0.64 lb ai/A or 0.96 lb ai/A, where coriander (cilantro) seed were collected. At another site, additional treated plots received a single broadcast application of S - metolachlor at the approximate rate of 0.64 lb ai/A or 0.96 lb ai/A, and coriander (cilantro) leaves and stems were collected at 27 day s and dri ed in an oven. No spray adjuvant was used at the trials. No residue decline studies were submitted. Coriander (cilantro) fresh, dried and seed samples were anal yz ed for residues of S metolachor using the “Working Method for PR 09595: Analy sis of s - Metol achlor in Cilantro as Metabolites s - CGA - 37913 (SYN - 506357 ) and s - CGA - 49751 (SYN 508500) ,” a modification of Sy ngenta Method No. 1848 - 01, dated June 26, 2003 entitled “Anal ytical Method for the Enantioselective Determination of Residues of s - MetolachlorPage 26 of 38

as Metabolites SYN - 506357 and SYN - 508500 in Agricultural Commodities by Chiral High Performance Liquid Chromatograph with Mass Spectrometric Detection.” The residue anal ytical method for S - metolachlor residues in/on coriander (cilantro) samples was validat ed both prior to and concurrently with field samples. Based on recoveries at the LLMV, the L OD ( std. dev. x one - tailed t - statistic) were calculated . The LOQ ( 3 x L OD) were also calculated . The LLMV, L OD and LOQ for SYN - 506357 and SYN - 508500 in/on the three matrices are listed below: **Table 4.4.3**  **. Summary of S -**  **Me tolachlor Analytical Method Limits**  **Comm odity**  **Analyte Calculated LOD**  **(ppm) Calculated LOQ** 

**(ppm) LLM**  **V**

**(ppm)** Coriander (cilantro) Fresh Sam ples SYN - 506357

SYN - 508500 0.0145 0.0132 0.0436

0.0396 0. 05

0.05 Coriander (cilantro) Dried Sam ples SYN - 506357

SYN - 508500 0.0160 0.0175 0.0480

0.0526 0.05

0.05 Coriander (cilantro) Seed Sam ples SYN - 506357

SYN - 508500 0.0154 0.0120 0.0463

0.0359 0.05

0.05 The data collection method was adequate for the determination of S - metolachlor residues in coriander (cilantro) commodities. The anal ytical results show that after a single foliar broadcast application of S metolachlor at the approximate rate of 0.64 lb ai/A and 0.96 lb ai/A with a 27 to 34 - days PHI , the maxi mum total S - metolachlor residues as parent equivalents were approximately 3.7 ppm and 4.1 ppm in coriander (cilantro) fresh leaves and stems, respectively . The maximum total S - metolachlor residues as parent equivalents were increased from approximately

<0 .131 ppm (fresh samples) to 0.834 ppm (dried samples) in the 0.64 lb ai/A treated plot. The maximum total S - metolachlor residues as parent equivalents were increased from approximately 0.170 ppm (fresh samples) to 2.031 ppm (dried samples) in the 0.96 lb ai/A treated plot. The maximum total S - metolachlor residues as parent equivalents were <0.131 ppm in coriander (cilantro) seed at both application rates. Based on the results of these trials, the appropriate tolerance for residues of S metolachlor in/on coriander (cilantro) leaves is 8.0 ppm. However, the Agency uses the preferred name coriander not cilantro for this raw agricultural commodity and, in addition, does not differentiate between dry and fresh leaves for coriander (cilantro). Therefore, a revised Section F should be submitted to indicate a request for coriander, leaves at 8.0 ppm and the cilantro dried and fresh leaves should be removed. The study data indicates that the requested tolerance on coriander, seed at 0.13 ppm is adequate. Beet , Garden, Leaves No new data have been submitted in support of the requested tolerance on beet, garden, leaves. The request is based on the currently established tolerance for residues of S metolachlor on Brassica leafy vegetables (Sub - group 5B), of 1.8 p pm. The ChemistryPage 27 of 38

Science Advisory

Council (ChemSAC) has considered the issue and determined that since the use pattern for beet greens is the same as that for leafy Brassica (sub group 5B), and beet greens are similar to the commodities in the leafy Bras sica subgroup 5B, it is appropriate to translate this tolerance of 1.8 ppm to beet greens. Based on the CHEMSAC determination and that the proposed use pattern for beet, garden, leaves is the same as leafy Brassica greens, subgroup 5B, ARIA recommends fo r the proposed tolerance of 1.8 ppm on beet, garden, leaves. **4.4 Residues in Livestock**  The proposed use for S - metolachlor will have no significant impact on the dietary burden of metolachlor to livestock. As a result, no changes are required in the current tolerances for metolachlor residues in livestock commodities. **4. 5**  **Residues in Processed Commodities** The proposed use for S - metolachlor on coriander (cilantro) and beet, garden, leaves will result in no processed commodities of regulatory interest. A discussion of processed commodities is not germane to this action **4. 6**  **Residues in Rotational Crops** Field rotational crop data have been submitted previously which are adequate to support the existing rotational crop restrictions . Do not rotate to food or feed crops other than those listed in the Dual Magnum® label . For all crops not listed, wait at least 12 months following the last application of Dual Magnum ® before planting. **4. 7**  **Drinking Water Profile 4.7.1**  **Environmental Fate and Transport** Enviro nmental fate data in dicate that parent metolachlor/S - metolachlor is moderatel y persistent to persistent. It is mobile to highly mobile in different soils and has been detected extensively

in surface water and groundwater. Metolachlor/S - metolachlor degrad ation appears to be dependent on microbially mediated and abiotic processes. Major degradates identified in groundwater include metolachlor ESA and metolachlor OA in both groundwater and surface water. D epending on the soil (i.e. organi c matter content), metolachlor/S - metolachlor has the potential to range from a moderatel y mobile to a highl y mobile material. The Environmental Fate and Effects Division (EFED) concluded there is no difference in soil sorption affinity between metolachlor and S metolachlor . Available data suggest that metolachlor and S - metolachlor are expected to be highl y mobile to mobile in soil and water environments. **4.7.2 Estimated Drinking Water Concentrations** Page 28 of 38

EFED calculated conservative, Tier I EDWCs of metolachlor and S - metola chlor in ground water and surface water for use in the last human health risk assessment. Since there are existing uses of S - metolachlor with higher application rates than the proposed S ection 3 use s , those EDWCs will not increase. EDWCs for metolachlor and S metolachlor were calculated for both the parent compound and the metolachlor ethanesulfonic acid (ESA) and metolachlor oxanilic acid (OA) degradates (see metabolites table, Appendix 1) . Although it was determined b y HED’s Metabolism Assessment Review Committee ( MARC ) that the ESA and OA metabolites appear to be less toxic than parent metolachlor, they are included in the risk assessment since they were found in greater abundance than the parent in water monitoring studies. EDWCs were calculated us ing drinking water models PRZM/EXAMS and FIRST for surface water and SCIGROW for ground water. Current NAWQA monitoring data was also used to determine EDWCs. Based on a review of the current monitoring data, concentrations of parent S - metolachlor and it s degradates were less than values reported from the previous monitoring data (US EPA, 2002). Based on monitoring and modeling data, total EDWCs for peak and average surface water respectivel y are 219 ppb ( 78 ppb parent + 48 ppb metolachlor ESA+ 94 ppb me tolachlor OA) and 119 ppb ( 18 ppb parent + 34 ppb metolachlor ESA+ 34 ppb metolachlor OA) . Recommended groundwater EDWCs (peak and average) are 126 ppb ( 33 ppb parent + 64 ppb metolachlor ESA+ 30 ppb metolachlor OA) . **4. 8**  **Dietary Exposure Analysis and Ris k Estimates**  Following recommendations made in the revised Tolerance Reassessment Eligibility Decision (TRED) for Metolachlor and S - Metolachlor (DP# 292881, S. Kinard , 8/15/03 ), tolerances for metolachlor and S - metolachlor have been separated into different subsections of 40 CFR §180.368. The acute and chronic dietary exposure assessments were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM - FCIDTM, Version 1.3), which incorporates consumption data from USDA’s Continuing Survey s of Food Intakes by Individuals (CSFII), 1994 - 1996 and 1998. The dietary risk assessment incorporates both exposure and toxicity of S - metolachlor and metolachlor. For acute and chronic assessments, the risk is expressed a s a percentage of a maximum acceptable dose (i.e., the dose which HED has concluded will result in no unreasonable adverse health effects). This dose is referred to as the population adjusted dose (PAD). The PAD is equivalent to the Reference Dose (RfD) divided by the special FQPA Safety Factor. HED is concerned when estimated dietary risk exceeds 100% of the PAD. The acute and chronic dietary exposure/risk anal yses for all supported S metolachlor/metolachlor food uses were conducted using conservativ e, unrefined exposure assessments. The unrefined anal ys es assume tolerance level residues for all registered uses, 100% crop treated for all commodities with existing tolerances, and default processing factors. In cases where separate tolerance listings occur for bothPage 29 of 38

metolachlor and S - metolachlor on the same commodity, the higher value of the two is used in the anal ys es. Acute and chronic dietary S - metolachlor exposure and risk estimates resulting from food intake were determined for the general U.S. population and various population subgroups. Based on anal ys es of estimated dietary risks for the general U.S. population and various population subgroups, the acute and chronic dietary exposure estimates for S - metolachlor are significantl y below HED’s le vel of concern for all supported commodities ( The 95 th percentile acute dietary

exposure estimate for the highest exposed population subgroup, all infants < 1 year old, is 0.05 mg/kg/day or 1.5 % of the aPAD. The chronic dietary exposure estimate for the h ighest exposed population subgroup, all infants < 1 ye ar old, is 0.012 mg/kg/day

or 11 .6 % of the cPAD . **Table 4.8.a. Summary of Acute Dietary Exposure and Risk for S -**  **me tolachlor and Metolachlor**  **Population Subgroup aPAD (m**  **g/kg/day) Acute (95th Percentil**  **e) Exposure (mg/kg/day)**  **%aPAD** General U.S. Population 3.0 0.014688 <1.0 All Infants (< 1 year old) 0.046244 1.5 Children 1 - 2 years old 0.025061 <1.0 Children 3 - 5 years old 0.022362 <1.0 Children 6 - 12 years old 0.015532 <1.0 Youth 13 - 19 years o ld 0.011553 <1.0 Adults 20 - 49 years old 0.012690 <1.0 Adults 50+ years old 0.011471 <1.0 Females 13 - 49 years old 0.012602 <1.0 **Table 4.8.b. Summary of Chronic Dietary Exposure and Risk for S -**  **metolachlor and Metolachlor Population Subgroup**  **cPAD (m**  **g/kg/day) Chronic**  **Exposure (mg/kg/day) %cPAD**  General U.S. Population 0.1 0.004550 4.5 All Infants (< 1 year old) 0.011574 11.6 Children 1 - 2 years old 0.008666 8.7 Children 3 - 5 years old 0.007852 7.9 Children 6 - 12 years old 0.005372 5.4 Youth 13 - 19 years old 0.003698 3.7 Adults 20 - 49 years old 0.003994 4.0 Adults 50+ years old 0.004017 4.0 Females 13 - 49 years old 0.003929 3.9 **5.0 NON**  **- DIETARY, NON**  **- OCCUPATIONAL EXPOSURE**  There are no residential exposures for the proposed new use of S - metolachlor for this Section 3 assessment. However, there is potential for residential exposure to S metolachlor from use of other registered products which are applied to residential lawns or turf b y professional applicators. Pennant MAGNUM TM (EPA Reg. No. 100 - 950) is labeled for use on commercial (sod farm) and residential warm - season turf grasses and other non - crop land including golf courses, sports fields, and ornamental gardens. Since Pennant MAGNUM TM is not intended for homeowner purchase or use (i.e., used by professional/commercial applicators), the onl y potential short - term residential riskPage 30 of 38

scenario anticipated is post - application hand - to - mouth exposure of children playing on treated lawns. S - metolachlor incidental oral exposure is assumed to include hand - to mouth exposure, object - to - mouth exposure and exposure through incidental ingestion of soil. Residential post application exposure to S - metolachlor for this scenario has been assessed in a separate document (D274331, R. Griffin, 2/20/02). The residential exposure to toddlers for this scenario was calculated to be 0.046 mg/kg/day resulting in an MOE of 1100. The MOE from the residential risk scenario for exposure to S metolachlor does not exceed the Agency ’s level of concern. Results from that assessment have been used to assess aggregate risk from exposure to food, drinking water, and residential lawns for this Section 3 anal ys is. Based on this analy sis, short - term oral MOEs are not of concern. **6.0 AGGREGATE RISK**  In accordance with the F QPA, HED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estim ates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. Based on the proposed and existing Section 3 uses, acute, short - term, intermediate - term and chronic aggregate exposures are anticipated. Aggregate exposure assessments were performed for acute aggregate dietary exposure (food + drinking water), chronic aggregate dietary

exposure (food + drinking water), and resi dential short - term exposure to children from incidental oral exposures. A cancer aggregate risk assessment was not performed because for S - metolachlor the chronic reference dose is considered protective of cancer effects . All potential exposure pathway s were assessed in the aggregate risk assessment. **6.1 Acute Aggregate Risk**  The aggregate acute risk estimates include exposure to residues of S - metolachlor in food and drinking water, and does not include dermal, inhalation or incidental oral exposure. Since the acute dietary

exposure assessment already includes the highest acute exposure from the drinking water modeling data, no further calculations are necessary. The acute risk estimate for all populations, resulting from aggregate exposure to S - metol achlor in food and drinking water is below ARIA’s l evel of concern. The food and drinking water exposure estimates for the most highly exposed subgroup, all i nfants (< 1 year old) , is 1.5 % of the aPAD. **6.2 Short -**  **& Intermediate -**  **Term Aggregate Risk** There are no residential user exposures for the proposed new use of S - metolachlor for this Section 3 assessment. However, there is potential for residential exposure to S metolachlor from use of other registered products which are applied to residential lawnsPage 31 of 38

or turf b y professional applicators. No intermediate - term risk scenarios are anticipated for the existing and proposed uses of S - metolachlor. The onl y potential short - term residential risk scenario anticipated is post - application exposure of children playi ng on treated lawns. S - metolachlor incidental oral exposure is assumed to include hand - to mouth exposure, object - to - mouth exposure and exposure through incidental ingestion of soil. Results from that assessment have been used to assess aggregate risk f rom exposure to food, drinking water, and residential lawns for this Section 3 analy sis. Based on this anal ys is, short - term aggregate MOEs are not of concern. **Table 6.2**  **Short -**  **Term Aggregate Risk Calculations for S**  **- metolachlor**  **Population NOAEL**  **1**

**mg/kg/d ay**  **LOC 2**  **Average Food & Water**  **Exposure mg/kg/day Residential**  **Exposure 3**  **mg/kg/day Aggregate MOE** 

**(food/water and residential)**  **4** Toddlers 50 100 0.012 0.046 860 1 NOAEL for incidental oral exposure. 2 The level of concern (LOC) MOE is 100, based on inter - and intra - species safety factors totaling 100. 3 Residential Exposure = [Incidental Oral exposure from all possible sources - com bined hand - to - mo uth, object - to - mo uth, and soil ingestion oral exposure]. No residential oral exposure is expected for adults 3 Aggregate MOE = [NOAEL ÷ (Avg Food & Water Exposure + Residential Exposure)] **6.3 Chronic Aggregate Risk**  The aggregate chronic risk estimates include exposure to residues of S - metolachlor in food and drinking water, and does not include dermal, inhalati on or incidental oral exposure. Since the chronic dietary exposure assessment already includes the highest chronic exposure from the drinking water modeling data, no further calculations are necessary . The chronic risk estimate for all populations, resul ting from aggregate exposure to S - metolachlor in food and drinking water is below ARIA’s level of concern. The food and drinking water exposure estimates for the most highl y exposed subgroup, all i nfants (< 1 ye ar old) , is 11 .6 % of the cPAD . **6.4 Cancer A ggregate Risk**  A s risks are calculated based on the chronic reference dose are protective of cancer effects, no separate cancer risk assessment is necessary . The chronic aggregate risk assessment is below the Agency ’s level of concern. **7 .0**  **OCCUPATIONAL E XPOSURE AND RISK**  **7 .1**  **Exposure Scenarios** HED assessed the occupational exposure scenario of mixing, loading, and applying S metolachlor (Dual Magnum® Herbicide (EPA Reg. No. 100 - 816) and Dual II Magnum® (EPA Reg. No. 100 - 818)) EC formulations as an herbi cide on crops. The proposed uses may result in short - /intermediate - term (i.e., 1 - 30 day s or up to 6 months) dermal and inhalation exposures during mixing, loading, applying , and postapplication activities. Long - term exposures (i.e., 6 months of continuou s exposure) are not expected to occurPage 32 of 38

based on the proposed use pattern. Dermal toxicological endpoints of concern were not identified (i.e., no s ys temic toxicity was seen following dermal exposure at the limit dose) therefore, no dermal exposures were calculated. Short - and intermediate - term exposures from inhalation exposure routes were assessed for all exposure scenarios. Occupational and residential exposure and risk estimates were conducted using maximum application rates and surrogate exposure data from the Pesticide Handlers Exposure Database and the Residential Exposure Assessment SOPs. 

### 7 **.1.1 Handler Exposure Scenarios**  The term “handler” applies to individuals who mix, load, and apply the pesticide product. Based on the use pattern, two occupational exposure scenarios were identified for S metolachlor. 1) mixing/loading liquid formulation for groundboom application; 2) applying spray

with groundboom equipment. 

### 7 **.1.2 Post**  **- Application Exposure Scenarios**  Since there are no dermal end points of concern, post - application dermal exposure was not examined for occupational uses. Based on the Agency's current practices, a quantitative postapplication inhalation exposure was also not assessed. However, volatilization of pesticides may be a potential source of postapplication inhalation exposure to individuals nearb y to pesticide applications. A study published in the Journal of Environmental Quality , Volume 38, September - October 2009, pages, 1785 - 1795, “Soil Moisture and Metolachlor Volatil ization Observations over Three Years” demonstrated that metolachlor can see its volatilization properties significantl y increase with increasing surface soil water content. Furthermore, OPP recently sought and received expert advice o n pesticide volatili zation from the Agency ’s Scientific Advisory Panel (SAP) . The Agency is in the process of evaluating the SAP ’s final report (http://www.epa.gov/scipoly /SAP/meetings/2009/12010 9meeting.html ) and may develop policies and procedures to identify the when and how postapplication inhalation exposure should be incorporated into the Agency's risk assessments. Consequently , the Agency may revisit the need for a quantitative postapplic ation inhalation exposure assessment for S - metolachlor as appropriate based on new policies that may result from this effort . **7 .2**  **Occupational Exposure Data and Assumptions 7**  **.2.1 ..**  **Exposure Data 7**  **.2.1.1 Application Parameters**  The maximum application rate for each crop that was listed on the label ranges from 1.21 to 3.80 lb ai/A.Page 33 of 38 **7 .2.1.2**  **Occupational Exposure Data** Data from Occupational Pesticide Handler Unit Expo sure Surrogate Reference Table, which summarizes data from PHED was used to assess han dler and post - application exposures in the absence of chemical - specific data. PHED was designed b y a task force of representatives from the U.S. EPA, Health Canada, the California Department of Pesticide Regulation, and member companies of the American Crop Protection Association. It consists of a database of measured exposures for workers involved in the handling of pesticides under actual field conditions and a set of computer algorithms used to subset and statistically summarize the selected data. 

### 7 **. 2.2**  **Exposure Assumptions** The following standard exposure assumptions were used in estimating risks to handlers from exposure to S - metolachlor :

• 60 kg, the average body weight of an adult female handler was used to complete the short - term inhalation ri sk assessment based on an oral study where the effects were observed in females • 70 kg, the average body weight of an adult handler was used to complete the intermediate - term non - cancer risk assessment based on an oral study where the effects were observ ed in males and females • Exposure duration is short - term and intermediate - term for all workers assessed. • Maximum application rates as determined b y proposed label requirements review were used for all ty

pes and methods of application. • The area treated for each crop was based on HED’s Exposure Science Advisory Council Policy

Number 9.1. For groundboom applications, a default area of 80 acres was used. **7 .3**  **Occupational Exposure and Risk Estimates** 

### 7 **.3.1 Handler Exposure**  Assumptions and calculatio ns of the risks for handlers are presented in Table 7.3.1 . At the baseline level, all inhalation MOEs are above the target MOE of 100, thus, risks are not of concern. The handler exposure estimates in this assessment are based on a central tendency estim ate of unit exposure and an upper - percentile assumption for the application rate, and thus assumed to represent high - end exposures. The uncertainties associated with this assessment stem from the use of surrogate exposure data (e.g., differences in use sc enario and data confidence), and assumptions regarding the amount of chemical handled. The estimated exposures are believed to be reasonable high - end estimates based on observations from field studies and professional judgment. In order to refine this oc cupational risk assessment, data on actual use patterns including rates, timing, and areas treated would better characterize S - metolachlor risks. **Table 7.3.1**  **S -**  **me tolachlor S**  **hort -**  **term and Inter**  **mediate -**  **term Inhalation Risks** Page 34 of 38

**Exposure Scenario**  **Crop Applic**  **Rate a**  **(lbs ai/A) Area** 

**Treated b**  **(A/day) Unit** 

**Exposures (μg/lb ai)**  **c Short**  **- term**  **d**

**(No respirator) Intermediate**  **- term**  **e**

**(No respirator) Dose**  **(m g/kg/day)**  **MOE Dose** 

**(m g/kg/day)**  **MOE** Mixing/Loading Emulsifiable Concentrates (Liquids)

Groundboom Sesame 1.9 80 1.2 0.003 16,000 0.003 3,400

Melon 1.21 80 1.2 0.002 26,000 0.002 5,300 Bushberry and Lo wb ush Blueberry 1.27 80 1.2 0.002 25,000 0.002 5,100 Caneberry 3.81 80 1.2 0.006 8,000 0.005 1,700 Sweet Sorghum 1.67 80 1.2 0.003 19,000 0.002 3,800 Leafy Brassica Mustard Greens 1.27 80 1.2 0.002 25,000 0.002 5,100 Carrot 1.9 80 1.2 0.003 16,000 0.003 3,400 Cucumber 1.27 80 1.2 0.002 25,000 0.002 5,100 Okra 1.9 80 1.2 0.003 16,000 0.003 3,400 Bulb Onion 1.27 80 1.2 0.002 25,000 0.002 5,100 Green Onion 1.27 80 1.2 0.002 25,000 0.002 5,100 Applying Liquid Sprays

Groundboom Sesame 1.9 80 0.74 0.002 27,000 0.002 5,500

Melon 1.21 80 0.74 0.001 42,000 0.001 8,600 Bushberry and Lo wb ush Blueberry 1.27 80 0.74 0.001 40,000 0.001 8,200 Caneberry 3.81 80 0.74 0.004 13,000 0.003 2,700 Sweet Sorghum 1.67 80 0.74 0.002 30,000 0.001 6,200 Leafy Brassica Mustard Greens 1.27 80 0.74 0.001 40,000 0.001 8,200 Carrot 1.9 80 0.74 0.002 27,000 0.002 5,500 Cucumber 1.27 80 0.74 0.001 40,000 0.001 8,2 00 Okra 1.9 80 0.74 0.002 27,000 0.002 5,500 Bulb Onion 1.27 80 0.74 0.001 40,000 0.001 8,200 Green Onion 1.27 80 0.74 0.001 40,000 0.001 8,200 a Application rates are the maximum application rates determined Section B of the tolerance petition for Dual Magnum® Herbicide. b Amount handled per day values are HED estimates of acres or tons treated applied based o n Exposure SAC SOP #9 “Standard Values for Daily Acres Treated in Agriculture,” industry sources, and HED estimates. c Baseline level risk mitigation with no respirator. When engineering controls are noted enclosed cockpits are assumed. d Short - term inhalation MOE = NOAEL (50 mg/kg/day) / inhalation daily dose (mg/kg/day), where inhalation dose = daily unit exposure (μg/lb ai) x inhalatio n absorption factor x application rate x amount handled per day x conversion factor (1 mg/1,000 μg) / body weight (60 kg adult female). e Intermediate - term inhalation MOE = NOAEL (8.8 mg/kg/day) / inhalation daily dose (mg/kg/day), where inhalation dose = daily unit exposure (μg/lb ai) x inhalation absorption factor x application rate x amount handled per day x conversion factor (1 mg/1,000 μg) / body weight (70 kg adult female)Page 35 of 38



### 7 **.3.2 Post Application Exposure**  Since there are no dermal endpoints of c oncern, post - application dermal exposure was not examined for occupational uses. **8.0 CUMULATIVE RISK** Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify , or revoke a tolerance, the Agency consider “available info rmation” 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 S - metolachlor has a common mechanism of t oxicity with other substances. Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity , EPA has not made a common mechanism of toxicity finding as to S - metolachlor and any other substances and, S - metolachlor does not appear to produce a toxic metabolite produced b y other substances which have tolerances in the U. S. For the purposes of this tolerance reassessment action, therefore, EPA has not assumed that S - metolachlor has a common mechanism o f toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s OPP concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/. **9.0 CONCLUSION** Pending resolution of the data needs described in Sectio n 10 below, ARIA has no concerns regarding human health exposure and risk from the proposed Section 3 uses of S - metolachlor on coriander and garden beet leaves :

Commodity Recommended Tolerance (ppm) Coriander, seed 0.13 Coriander, leaves 8.0 Beet, gard en, leaves 1.8

. **10.0 DATA NEEDS**  **10.1 Toxicology Data Requirements** 

- Acute Neurotoxicity

(GLN 870. 6200a)

- Subchronic Neurotoxicity (GLN 870.6200b)

- Immunotoxicity

(GLN 870.7800)Page 36 of 38 **10.2 Residue Chemistry Data Requirements**

- Section F f

or coriander , leaves at 8.0 ppm with the cilantro, dried and fresh l eaves removed . **10.3 Occupational/Residential Requirements** None **References** S - Metolachlor: HED Risk Assessment for Proposed New Use of S - Metolachlor on Bushberry, Caneberry, Carrot, Cuc umber; Leafy Brassica Greens, Melon, Okra, Bulb and Green Onion, Sesame Seed, Sorghum, and Turnip Greens. PP#: 6E7607 , DP Barcode: D 3 68726, B. Daiss, 6/30/10 Metolachlor and S

- Metolachlor Residue Chemistry Chapter for the Tolerance Reassessment Eligibili ty Decision (TRED). DP Barcode: D274328, S. Kinard, 2/28/02 Section 18 Exemption for Use of Metolachlor on Spinach. ID#: 94OK001, DP Barcode: D196641, J. Stokes, 11/24/93 Metolachlor/S

- metolachlor Residential Risk Assessment. DP Barcode: D274331, R. Griffin, 2/20/02 S - Metolachlor. Petition for the Use on Coriander (Cilantro) and Garden Beet Leaves. Summary of Analytical Chemistry and Residue Data. PP#1E7898, DP Barcode: D 39 2447 , W. Cutchin, 12/6/11 S - metolachlor - Acute and Chronic Dietary and Drink ing W ater Exposure and Risk Assessment for Proposed Section 3 Use on Cilantro and Garden Beet, Leaves. PP #1 E7898 , DP Barcode: D 396451 , W. Cutchin, 1 / 3 /1 2 US Environmental Protection Agenc y, Office of Pesticide Programs , Occupational Pesticide Handler Unit Exposure Surrogate Reference Table, June 21, 2011, http://www.epa.gov/pesticides/science/handler- exposure - table.pdf.Page 37 of 38

**Appendix 1. CHEMICAL STRUCTURES** Page 38 of 38