S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **1** of **62** UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 **OFFICE OF CHEMICA** **L SA FETY**  **AND POLLUTION PREVENTION**  **MEMORANDUM Date**  **: August**  **15 , 2013**  **SUBJECT:** S - Metolachlor, PP# 2 F 8115 . Human Health Risk Assessment for the petition for

higher tolerances on C orn, field, forage; C orn, sweet, forage; and C orn, stover **PC Code:** 108800 **DP Barcode:** D4 11153 **Decision No.:** 471357 **Registration No. :**  100 - 818 **Petition No.:** 2 F 8115 **Regulatory Action:**  Petition, no amended use **Risk Assessment Type:** NA **Case No.:** 0001 **T XR No.:**  NA **CAS No.:** 87392 - 12 - 9 **MRID No.:** 48932501 **40 CFR:** 180.368 (a)(2) **FROM: Susan V. Hummel, Senior Chemist** 

Thurston G. Morton , Dietary Angela Howard, Ph.D., DABT, Toxicologist Iv an Nieves, ORE Risk Assessment Branch 4, Health Effects Division, 7509P **THROUGH: Elissa Reaves, Ph.D., Chief** 

Risk Assessment Branch 4, Health Effects Division, 7509P **TO: Michael Walsh, PM#23** 

Fungicides Branch, Registration Div ision, 7505P S - Metolachlor (an isomer enriched form of metolachlor) is a selective, chloroacetanilide herbicide that is applied to a variety of crops as a preplant, preplant incorporated, preemergence, or postemergence application, primarily for the control of grass weeds. S - Metolachlor is registered to S yn genta Crop Protection, Inc. for use on a wide variety of crops including: corn, cotton, grasses grown for seed, legume vegetables, peanuts, potatoes, safflower, sorghum, sunflower, and tomatoes. This document presents the human health risk assessment for the S metolachlor higher tolerances on corn forage and stover. No amended Section 3 registration is requested. Pesticide petition #2F8115 was submitted to amend the established tolerances for the herb icide S - metolachlor in or on corn, field, forage; corn, sweet, forage; and corn, stover to 20 ppm; 40 ppm; and 40 ppm, respectively . The use pattern used was the currentl y registered use pattern for Dual II Magnum (EPA Reg. No 100 - 818). Residues of S - meto lachlor in some samples of forage and stover exceeded the current tolerances.S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **2** of **62 TABLE OF CONTENTS**  **1.0 Executive Summary**  ................................ ................................ ................................ ........... 4 **2.0 HED Recommendations**  ................................ ................................ ................................ .... 8 **2.1 Da**  **ta Deficiencies** ................................ ................................ ................................ ............ 8 **2.2 Tolerance Considerations**  ................................ ................................ .............................. 8 **2.2.1 Enforcement Analytical Method**  ................................ ................................ ............... 8 **2.2.2 Recommended Tolerances**  ................................ ................................ ......................... 8 **2.2.3 Revisions to Petitioned**  **- For Tolerances**  ................................ ................................ .... 9 **2.2.4 International Harmonization**  ................................ ................................ ..................... 9 **2.3 Label Recommendations**  ................................ ................................ ................................ 9 **3.0 Introduction**  ................................ ................................ ................................ ........................ 9 **3.1 Chemical Identity**  ................................ ................................ ................................ ........... 9 **3.2 Physical/Chemical Characteristics**  ................................ ................................ ............. 11 **3.3 Pesticide Use Pattern**  ................................ ................................ ................................ .... 11 **3.4 Anticipated Exposure Pathways**  ................................ ................................ ................. 11 **3.5 Consideration of Environmental Justice**  ................................ ................................ .... 12 **4.0 Hazard Characterization and Dose**  **- Response Assessment**  ................................ .......... 12 **4.1 Toxicology Studies Available for Analysis**  ................................ ................................ . 12 **4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)**  ............................. 13 **4.2.1 Dermal Absorption**  ................................ ................................ ................................ ... 13 **4.3 Toxicological Effects**  ................................ ................................ ................................ .... 14 **4.4 Safety Factor for Infants and Children (FQPA Safety Factor)**  ............................... 15 **4.4.1 Completeness of the Toxicology Database**  ................................ .............................. 15 **4.4.2 Evidence of Neurotoxicity**  ................................ ................................ ........................ 15 **4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal**  ........ 16 **4.4.4 Residual Uncertainty in the Exposure D**  **atabase** ................................ ................... 16 **4.5 Toxicity Endpoint and Point of Departure Selections**  ................................ .............. 16 **4.5.1 Dose**  **- Response Assessment**  ................................ ................................ ...................... 16 **4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment**  ..... 17 **4.5.3 Cancer Classif** 

**ication and Risk Assessment Recommendation** ............................ 17 **4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk**  **Assessment** ................................ ................................ ................................ ............................... 18 **5.0 Dietary Exposure and Risk Assessment**  ................................ ................................ ......... 19 **5.1 Metabolite/Degradate Residue Profile**  ................................ ................................ ....... 19 **5.1.1 Summary of Plant and Anima**  **l Metabolism Studies** ................................ ............. 19 **5.1.2 Summary of Environmental Degradation**  ................................ .............................. 20 **5.1.3 Comparison of Metabolic Pathways**  ................................ ................................ ....... 20 **5.2 Food Residue Profile**  ................................ ................................ ................................ .... 21 **5.3 Water Residue Profile**  ................................ ................................ ................................ .. 22 **5.4 Dietary Risk Assessment**  ................................ ................................ .............................. 22 **5.4.1 Description of Residue Data Used in Dietary Assessment**  ................................ .... 22 **5.4.2 Percent Crop Treated Used in Dietary Assessment**  ................................ .............. 23 **5.4.3 Acute Dietary Risk Assessment**  ................................ ................................ ............... 23 **5.4.4 Chronic Dietary Risk Assessment**  ................................ ................................ ........... 23 **5.4.5 Cancer Dietary Risk Assessment**  ................................ ................................ ............. 24 **5.4.6 Summary Table**  ................................ ................................ ................................ ......... 24S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **3** of **62 6.0**  **Residential (Non -**  **Occupational) Exposure/Risk Characterization** ............................. 24 **6.1 Residential Handler Exposure**  ................................ ................................ .................... 25 **6.2 Post**  **- Application Exposure**  ................................ ................................ .......................... 25 **6.3 Residential Bystander Post**  **- application Inhalation Exposure**  ................................ . 25 **6.4 Spray Drift**  ................................ ................................ ................................ .................... 26 **7.0 Aggregate Exposure/Risk Characterization**  ................................ ................................ .. 26 **7.1 Acute Aggregate Risk**  ................................ ................................ ................................ ... 27 **7.2 Short** **- Term Aggregate Risk**  ................................ ................................ ........................ 27 **7.3 Intermediate**  **- Term Aggregate Risk**  ................................ ................................ ........... 28 **7.4 Chronic Aggregate Risk**  ................................ ................................ .............................. 28 **7.5 Cancer Aggregate Risk**  ................................ ................................ ................................ 28 **8.0 Cumulative Exposure/Risk Characterization**  ................................ ............................... 28 **9.0 Occupational Exposure/Risk Characterization**  ................................ ............................ 29 **10.0 Human Studies**  ................................ ................................ ................................ ................. 29 **11.0 References**  ................................ ................................ ................................ ......................... 30 **Appendices A.1**  **Toxicology Data Requirements** ................................ ................................ ................... 31 **A.2 Toxicity Profiles**  ................................ ................................ ................................ ............ 32 **A.3 Hazard Identification and Endpoint Selection**  ................................ .......................... 45 **A.4 Executive Summar** **ies** ................................ ................................ ................................ ... 47 **Appendix B. Metabolism Summary** ................................ ................................ ......................... 60 **Appendix C. Physical/Chemical Properties** ................................ ................................ ............. 62S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **4** of **62 1.0**  **Executive Summary**  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 (an isomer enriched form of metolachlor , comprised of 88% S - isomer and 12% R - isomer) is a selective, chloroacetanilide herbicide that is applied to a variety of crops as a preplant, preplant incorporated, preemergence, or postemergence application, primarily for the control of grass weeds. S - Metolachlor is regist ered to S yn genta Crop Protection, Inc. for use on a wide variety of food and feed crops including: corn, cotton, grasses grown for seed, legume vegetables, peanuts, potatoes, safflower, sorghum, sunflower, and tomatoes. In addition, S - metolachlor is regis tered for use on 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 products. Application methods for agricultural uses include ground, aerial, irrigation and chemigation. Applications of S - metolachlor to residential lawns or turf are limited to p rofessional applicators using backpack, hose - end, or handgun sprayers. Pesticide petition #2F8115 was submitted to amend the established tolerances for the herbicide S - metolachlor in or on corn, field, forage; corn, sweet, forage; and corn, stover to 20 ppm; 40 ppm; and 40 ppm, respectively . No amended Section 3 regis tration is requested. The use pattern used was the currentl y registered use pattern for Dual II Magnum (EPA Reg. No 100 - 818). Residues of S - metolachlor in some samples of corn forage and stover exceeded the current tolerances. Since corn forage and stov er are livestock feedstuffs, and the increase in these tolerances does not change the dietary burden sufficiently

to require a change in any tolerance on a food commodity , no new dietary exposure assessment was conducted, and no occupational exposure asses sment was required. However, an updated residential exposure assessment was conducted, and is included herein, sinc e the Residential SOPs have changed since the last residential assessment was conducted in 2002. **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 wi th the metolachlor database, is complete for risk assessment purposes , with the exception of a required 28 day inhalation study . The n eurotoxicity battery (870.6200 a and b) is required in accordance with the revised 40 CFR Part 158 Toxicology Data Requirements . The data requirement for neurotoxicity studies has been waived at the present time by the Hazard and Science Policy

Council (HASPOC) in their meeting of February 14, 2013 (JVanAlstine, 2013). 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 to the skin, but is a dermal sensitizer. In 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 sy stemic toxicity

was observed when metolachlor was administered dermally . No neurotoxicity studies with me tolachlor or S - metolachlor are available. However, there was no evidence of neurotoxic effects in adult animals in available subchronic and chronic toxicity studies . PrenatalS - Metolachlor Human Health Risk Assessment DP No. D411153

Page **5** of **62** developmental studies in the rat and rabbit with both metolachlor and S - metolach lor revealed no evidence of a qualitative or quantitative susceptibility in fetal animals. A two - generation reproduction study with metolachlor in rats showed no evidence of parental or reproductive toxicity . The FQPA safety factor was reduced to 1X becaus e there are no residual uncertainties with regard to pre - and/or postnatal toxicity . Metolachlor has been evaluated for carcinogenic effects in the mouse and the rat. Metolachlor did not cause an increase in tumors of any kind in mice. In rats, metolach lor caused an increase in benign liver tumors in rats but this increase was seen onl y at the highest dose tested and was statistically

significant compared to controls onl y in females. There was no evidence of mutagenic or cy

togenetic effects in vivo or in vitro . Based on this evidence, EPA has concluded that metolachlor does not have a common mechanism of carcinogenicity with acetochlor and alachlor which are structurally similar. Taking into account the qualitatively weak evidence on carcinogenic effect s and the fact that the increase in benign tumors in female rats occurs at a dose 1,500 times the chronic reference dose (RfD), EPA has concluded that the chronic RfD is protective of any potential cancer effect. **Dose Response Assessment** Toxicological end

points were selected for dietary /drinking water, occupational and residential exposure scenarios. An acute reference dose (RfD ; 3.0 mg/kg/day) for assessment of food and drinking water exposures was selected from a developmental toxicity study in rats (NOAEL = 300 mg/kg/day) . A chronic RfD (0.097 mg/kg/day) was selected from a chronic toxicity study in dogs (NOAEL = 9.7 mg/kg/day) . A short - term incidental oral POD (NOAEL= 50 mg/kg/day) was selected from a developmental toxicity study in rats. A point of departure (POD) for dermal exposure was not selected because no dermal or systemic toxicity was seen in rabbits following repeated dermal application at the high est dose tested for 21 day s. A short - term inhalation exposure POD (50 mg/kg/day) was selected f rom a developmental toxicity study in rats. An intermediate - term inhalation exposure POD (8.8 mg/kg/day) was selected from a subchronic toxicity study in dogs. An uncertainty factor of 100X was applied to endpoints selected for the oral exposure route (1 0x for interspecies extrapolation, 10x for intraspecies variation) and an uncertainty factor of 1000X was applied to endpoints selected for the inhalation exposure route due to a missing route - specific study (10x for interspecies extrapolation, 10x for intraspecies variation, 10x for database) . **Residue Chemistry** The qualitative nature of metolachlor residues in plants is adequatel y understood. 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 the parent, CGA - 354743 (metolac hlor ethanesulfonic acid (ESA)) and CGA - 51202 (metolachlor oxanilic acid (OA)). Adequate methodology

is available for enforcing the established and recommended tolerances. PAM Vol. II, Pesticide Regulation Section 180.368, lists a gas chromatography 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) methodS - Metolachlor Human Health Risk Assessment DP No. D411153

Page **6** of **62** (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 indicate that metolachlo r is completely recovered through Method 302. Sy ngenta has proposed a high pressure liquid chromatography with mass spectroscop y/mass spectroscop y (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 hydroly sis products CGA - 37913 and CGA 49751. This method has not been determined to be adequate for enforcement purposes because it monitors only

a single i on transition per anal yt e. Adequate field trial data have been submitted with the current petition to support the requested tolerances. Geographic representation was adequate. An adequate analy tical method was used for the analy sis. The data were properly supported by

storage stability

data. An adequate confined rotational crop study is available, although additional information pertaining to the study remains outstanding. **Dietary Exposure Including Drinking Water**  No changes are proposed to any S - metolachlor use pattern or food tolerances. Therefore, there is no change to the dietary

exposure , including the drinking water exposure. For acute and non - cancer chronic exposures, EPA is concerned when estimated dietary risk exceeds 100% of the pop ulation adjusted dose (PAD). S - metolachlor is classified as a Group C carcinogen, no separate dietary assessment was performed for cancer, since the chronic dietary exposure is considered protective for cancer effects. For acute and chronic dietary expos ures an unrefined assessment was conducted, assuming 100% crop treated, and tolerance level residues. The 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 th e most highly exposed subgroups being all infants (<1 ye ar old) at 1.5% of the acute PAD (aPAD) and 11.6% of the chronic PAD (cPAD). Environmental 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. Major degradates identified in groundwater include metolachlor ethanesulfonic 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 ground water and surface water for use in the last human health risk asse ssment. EDWCs for metolachlor and S - metolachlor were calculated 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 determineS - Metolachlor Human Health Risk Assessment DP No. D411153

Page **7** of **62** EDWCs. Based on monitoring and modeling data, total EDWCs for peak and average surface water respectivel y are 219 ppb and 119 ppb. Recommended groundwat er EDWCs (peak and average) are 126 ppb. **Residential Exposure** There are no new residential exposure scenario s for S - metolachlor for the current petition . However, there is potential for residential exposure to S - metolachlor from use of other registered p roducts which are applied to residential lawns or turf by professional applicators. Therefore, the only potential short - term residential risk scenario anticipated is post - application exposure of children playing on treated lawns. The residential exposure to toddlers for this scenario was estim ated to be 0.0 609 mg/kg/day resulting in an MOE of 820 . 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 residue s of S - metolachlor in food and drinking water, and does not include dermal, inhalation or incidental oral exposure. Since the dietary

exposure assessment already includes the highest acute and chronic exposures 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 EPA’s l evel of concern. The food and drinking water exposure estimates for the most highl y exposed subgroup, a ll i nfants (< 1 year old) , is 1.5% of the aPAD and 11.6% of the cPAD. No intermediate - term risk scenarios are anticipated for the existing and proposed uses of S metol achlor. 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 by professional applicators via post - application incidental oral exposure to chil dren playing on treated lawns. Results from that assessment have been used to assess aggregate risk from exposure to food, drinking water, and residential lawns. Based on this analy sis, short - term aggregate MOE of 660 for toddlers is not of concern. **Occ upational Exposure**  There are no new uses proposed in the current petition, so no occupational exposure assessment is required. However, HASPOC has determined that a 28 - day inhalation study

must be conducted. In the absence of this study , an additional 10 x database uncertainty factor will be applied to any inhalation risk assessment . The occupational exposure and risk have been previously

assessed. There are no risks of concern with the PPE required on the label. **Use of Human Studies** This risk assessment relies in part on data from studies in which adult human subjects were intentionally

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 subj ect to review b y the Human Studies Review Board. All of the studies used have received the appropriate review. **Environmental Justice**S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **8** of **62** Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk asse ssment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations," http://www.eh.doe.gov/oepa /guidance/justice/eo12898.pdf ). **2.0 HED**  **Recommendations** No change in the current registration for S - metolachlor is requested. HED has examined the database for S - metolachlor. Pending submission of anal ytical standards, there are no residue chemistry issues that would preclude setting of the recommended tolerances for S - metolachlor on corn forage an d stover, as indicated in Section 2. 2.2 . However, questions remain on the rotational crop study, and a 28 - day inhalation study

is needed for future submiss ions. **2.1 Data Deficiencies**  Analy tical reference standards are required to be submitted to the pesticide repository now and as requested b y the repository staff. A deficiency

remains with regard to the confined rotational crop study . This deficiency ha s been outstanding since 1994, and was reiterated in the metolachlor/S - metolachlor TRED. **2.2 Tolerance Considerations**  **2.2.1 Enforcement Analytical Method**  Adequate methodology

is available for enforcing the established and recommended tolerances. PAM Vol. II, Pesticide Regulation Section 180.368, lists a gas chromatography 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 (Metho d 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 indicate that metolachlor is completely recovered through Method 302. Sy ngenta has proposed a high pressure liquid chromatography with mass spectroscop y/mass spectroscop y (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 hydroly sis products CGA - 37913 and CGA 49751. This method has not been determined to be adequate for enforcement purposes because it monitors only

a single ion transition per anal yt e. **2.2. 2**  **Recommended Tolerances** Tolerances are currentl y established under 40 CFR §180.368 for residues of S - metolachlor, including its metabolites and degradates, in or on the commodity(s), as defined. Compliance with the tolerance levels specified in the following table below is to be determined by measuring onl yS - Metolachlor Human Health Risk Assessment DP No. D411153

Page **9** of **62** the sum of free and bound S - metolachlor, S - 2 - chloro -N - (2 - ethyl - 6 - methylphenyl) -N - (2 - methoxy- 1 - methylethyl)acetamide, its R - enantiomer, and its metabolites, determined as the derivatives, 2 - (2 - ethyl - 6 - methylphenyl )amino - 1 - propanol and 4 - (2 - ethyl - 6 - methylphenyl ) - 2 - hydrox y- 5 - methyl - 3 - morpholinone, calculated as the stoichiometric equivalent of S - metol achlor, in or on the commodity . The text of the current tolerance expression is in accordance with our current guidance (S. Knizner, 5/10/2009) Recommended tolerances for S - metolachlor are summarized in Table 2.2.2. below, along with HED’s recommendations on tolerance level, and commodity names. **Table 2.2.2. Tolerance Summary for Metolachlor.**  Commodity Established/ Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments;

Correct Commodity Definition **Proposed tolerances under §180.368(a)(2)** Corn, field, forage 20 40 Corn, sweet, forage 40 40 Corn, stover 40 40 Corn, field, stover Corn, sweet, stover Corn, pop, stover **2.2. 3**  **Revisions to Petitioned -**  **For Tolerances** The tolerance for Corn, field, forage was recommended at 40 ppm, to be consistent with the tolerance for corn, sweet, forage, since both forages would be harvested at the same time. The tolerance for corn, stover, is changed to Corn, field, stover; Corn, sweet, stover; and Corn, pop, stover; as those are the correct commodity names. **2.2. 4**  **International Harmonization** There are no issues with international harmonization. Canada does not establish MRL s for pesticide residues on livestock feed stuffs. There are no Codex MRL s established for residues of S - metolachlor. **2.3 Label Recommendations**  No label changes are needed, since no change to any S - metolachlor use pattern is proposed with the current petition. **3.0 In**  **troduction 3.1**  **Chemical Identity** The chemical structure and nomenclature of S - metolachlor and its regulate d hydrol ytic derivatives are presented in Table 3. 1S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **10** of **62 Table**  **3. 1.**  **Nom enclature of S**  **- Metolachlor and its Regulated Hydrolytic Derivatives.**  Parent compound

Common name S - Metolachlor Com pany experimental name CGA - 77102 (R- Metolachlor is CGA - 77101) IUPAC name (S) - 2 - chloro -N - (2 - ethyl - 6 - me thyl -phenyl) -N - (2 - metonym - 1 - methyl - ethyl) - acetamide CAS name 2 - chloro -N - (2 - ethyl - 6 - methylphenyl) -N - [(1S)2 - methoxy - 1 - methylethyl] - acetamide CAS registry number 87392 - 12 - 9 End - use product (EP) Dual Magnum® Herbicide (7.62 lb/gal EC; EPA Reg. No. 100 - 816) and Dual II Magnum® Herbicide (7.64 lb/gal EC; EPA Reg. No. 100 - 818) Regulated residue

Common name None Com pany experimental names CGA - 37913 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

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 rpholinone CAS registry number 61520 - 54 - 5 C H3

C H 3 N O C H

3 Cl C H3

O

C H3 N H C H 3 O H C H 3

C H3 C H 3 N O O O H C H3S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **11** of **62 3.2**  **Physical/Chemical Characteristics** S - metolachlor is fairl y soluble in water (0.48 g/L), and completel y miscible with ty pical pesticide solvents. It has a moderatel y low vapor pressure ( 2.8 x 10 - 5 mm Hg) . It does not dissociate. Ithas a high octanol - water partition coefficient ( Lo g(KOW) = 3.0 at 25 C) , indicating a potential for bioaccumulation or partitioning into human milk . Environmental 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 degradation appears to be dependent on microbially mediated and abiotic processes. The phys ical - chemical properties are tabulated in Appendix C, Table C1. **3.3 Pesticide Use Pattern**  The current use pattern for S - metolachlor on corn is shown below in Table 3.3. No change to the current use pattern is proposed or recommended. **Table 3. 3. Summary of Current Directions for Use of S**  **- Metolachlor.**  **1** Applic. Timing; Ty pe; and Equip. (minimum volume) Form ulation [EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per Season Max. Seasonal

Applic. Rate (lb ai/A) PHI

(days) Corn Fall Application for Spring Control/ Early Preplant Broadcast 7.62 lb/gal EC [100 - 818] 1.6

– 1.9 NS 3.7 NS Preplant Incorporated or Preemergence Broadcast 0.95 - 1.9 NS 3.7 NS Postemergence or Layby Broadcast Up to 1.9 NS 3.7 NS Use higher rates on fine or >2,5 - 3% organic matter soils. Split application may be used. Ground application minimum 5 GPA; aerial application minimum 2 GPA. Do not use Dual II Magnum on peat or muck soils. Do not graze or feed forage from treated areas for 30 days following application. Do not harvest sweet corn ears for 60 days following application. **3.4 Anticipated Exposure Pathways**  The Registration Division has requested an assessment of human health risk to support the proposed increase in tolerances on corn forages and stovers. No new uses are proposed in this petition. Humans may

be exposed to S - metolachlor in food and drinking water, since S metolachlor may

be applied directl y to growing crops and S - metolachlor may reach surface and ground water sources of drinking water. Dietary exposure has not changed, since no changes are recommended for tolerances in human foods. Although no residential application scenarios exist, children may

be exposed to S - metolachlor after professional application on residential turf.S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **12** of **62** The last residential risk assessment was conducted in 2002, so residential exposure is reassessed in this risk assessment. In an occupational setting, applicators may be exposed while handling the pesti cide prior to application, as well as during application. There is a potential for post - application exposure for workers re - entering treated fields. Risk assessments have been previousl y prepared for the existing uses of S - metolachlor. This risk asses sment considers all of the aforementioned exposure pathway s based on the existing uses of S - metolachlor. **3.5 Consideration of 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 - Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf . As a part of every

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well - established procedures. In line with OPP policy, HED estimates risks to population subgro ups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized by subgroups based on age, season of the ye ar, ethnic group, and region of the country . Additionally , OPP is able to assess dietary

exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non - dietary exposures based o n home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post - application are evaluated. Further considerations are currentl y in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to by standers and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. **4.0 Hazard Characterization and Dose**  **- Respon**  **se Assessment 4.1**  **Toxicology Studies Available for Analysis** The 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 toxicity 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 combined metolachlor and S - metolachlor toxicity data bases are adequate to characterize th e toxicity of S - metolachlor for risk assessment purposes. An i mmunotoxicity study (870.7800) w as submitted since the last S - metolachlor risk assessment (MRID 48783301 ).S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **13** of **62** The toxicology

database for metolachlor and S - metolachlor is complete with the exception of a required subchronic inhalation study . Exposure to S - metolachlor is expected via the oral, dermal, and inhalation routes. A route - specific dermal study was submi tted, but no subchronic inhalation study

has been submitted. The Hazard and Science Policy Council ( HASPOC ) recentl y reviewed metolachlor and S metolachlor (VanAlstine, Julie, 2013) . HASPOC , based on a WOE approach considering all available hazard and exposure information concludes that the acute, subchronic, and developmental neurotoxicity studies are not required at this time. The HASPOC concluded that a subchronic inhalation study with metolachlor is required at this time. A 10X data base uncertainty

factor will be applied only for assessing risk for inhalation scenarios. **4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)**  Metolachlor is extensively absorbed and metabolized following oral administration in the rat . After oral or intrav enous administration of metolachlor, between 69.6% and 93.2% of the administered dose was absorbed. A biphasic plasma profile with two concentration maxima (Cmax); a fast rising first Cmax was reached at 0.25 - 1 hour post dosing which was succeeded by a s econd Cmax at 8 and at 12 - 24 hours following administration of the low and high dose. Elimination is via the urine and feces. Residual radioactivity at 7 day s post dose were residual carcass (0.9 - 2.2% of the administered dose) and red blood cells (0 .95 - 1.53 μg equivalents/ gram in blood cells for all low dose male and female rats). There was no apparent accumulation of residual radioactivity . Excretion data showed that urine and feces were both significant routes for elimination of metolachlor derived radioactivity . In the low dose groups, the urine appeared more of a predominant route for excretion in female rats than in males, whereas fecal e xcretion was slightly higher in males. However, at the high oral dose, there were no apparent sex related differences in the pattern of urinary excretion. Examination of urinary excretion data as presented in graphical format indicated that at the 300 mg/kg dose, excretion was delayed vs the low oral dose, suggesting saturation of elimination. The major metabolic pathway proposed from analy sis of urinary as well as fecal metabolites is one of cleavage of the ether bond and subsequent oxidation to the carb oxylic acid, as well as hydrol ytic removal of the chlorine atom. Conjugation of metolachlor or metabolites with gluronic acid or sulfate does not appear to occur. **4.2.1 Dermal Absorption**  There was no evidence of sy stemic toxicity at the limit dose in a 21 day dermal toxicity metolachlor study

in rabbits, however dermal irritation was observed at lower doses. A dermal absorption study is not needed .S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **14** of **62 4.3**  **Toxicological Effects** 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 s ys temic toxicity at the limit dose in a 21 day dermal toxicity

metolachlor study in rabbits, however dermal irritation 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 , decreased body weight gain and food consumption were observed. There was no evidence of carcinogenicity in mice; however, there were statisticall y 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. S - Metolachlor e xhibits 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 to the skin, but is a dermal sensitizer. In su bchronic (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 sy stemic toxicity

was observed when metolachlor was administered der mally . No neurotoxicity studies with metolachlor or S - metolachlor are available. The HASPOC, based on a WOE approach, conclude d that a neurotoxicity battery is not required for metolachlor at this time. This approach considered all of the available hazard and exposure information including: 1) the lack of evidence for clinical signs of neurotoxicity or neuropathology in adult animals in subchronic and chronic studies; 2) clinical signs of neurotoxicity were seen only

at very high doses (Limit Dose) in pre gnant rats and is used as the endpoint of concern for assessing acute dietary risk; 3) evidence for neurotoxicity (functional/behavioral effects) was seen onl y at high doses in acute neurotoxicity studies with structurally- related compounds (acetochlor and propachlor) and in a subchronic neurotoxicity study with acetochlor; 4) the POD and endpoint for chronic dietary

risk assessment is based on effects seen in dogs which appear to be the most sensitive species; and 5) since the neurotoxicity studies will be tested at very high doses to elicit effects, they

will not provide PODs lower than those currently used for overall risk assessment ( JVanAlstine, 2013) . There was no evidence of increased quantitative or qualitative fetal susceptibility in the prenatal d evelopmental studies in rats and rabbits with either metolachlor 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 , mater

nal animals had persist ent 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 decreased body weight gain was observed at the limit dose in maternal animals. DevelopmentalS - Metolachlor Human Health Risk Assessment DP No. D411153

Page **15** of **62** effects at the limit dose included slightl y 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. 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/non/soft stool) were observed at the mid - dose in maternal animal s 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 decrease in fetal body weight beginning at l actation 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. **4.4 Safety F**  **actor for Infants and Children (FQPA Safety Factor)** The chemical risk assessment team has recommended that the FQPA Safety Factor (SF) be reduced to 1X. The toxicity database for S - metolachlor/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 av ailable , along with an acceptable Immunotoxicity study . Based on the results of the available toxicity

studies, there is no evidence for neurotoxicity or immunotoxicity . **4.4 .1**  **Completeness o**  **f the**  **Toxicology Database** The toxicology

database for metolach lor and S - metolachlor is complete with the exception of a required subchronic inhalation study . Exposure to S - metolachlor is expected via the oral, dermal, and inhalation routes. A route - specific dermal study was submitted, but no subchronic inhalation s tudy

has been submitted. The Hazard and Science Policy Council ( HASPOC ) recentl y reviewed metolachlor and S metolachlor (VanAlstine, Julie, 2013). HASPOC , based on a WOE approach considering all available hazard and exposure information concludes that the acute, subchronic, and developmental neurotoxicity studies are not required at this time. The HASPOC concluded that a subchronic inhalation study with metolachlor is required at this time. A 10X data base uncertainty factor will be applied only for a ssessing risk for inhalation exposure scenarios. **4.4.2 Evidence of N**  **eurotoxicity** There are no acute or subchronic neurotoxicity studies available for S - metolachlor or metolachlor. Treatment - related effects of clonic and/or tonic convulsions, excessive salivation, urine - stained abdominal fur and/or excessive Lacrimation were observed in pregnant dams at 1000 mg/kg/day . There was no evidence of neurotoxic effects in adult animals in availableS - Metolachlor Human Health Risk Assessment DP No. D411153

Page **16** of **62** subchronic or chronic toxicity studies. The HASPOC, based on a WOE approach, concluded that a neurotoxicity

battery is not required for metolachlor at this time ( JVanAlstine, 2013) . **4.4.3 Evidence**  **o f Sensitivity/Su**  **sceptibility in the Developing o r Young Animal**  There was no evidence of increased quantitative or qualitative fetal susceptibility in the prenatal developmental studies in rats and rabbits or in the reproductive toxicity study in rats, with either metolachlor or S - metolachlor. In general, significant developmental toxicity was not seen in rats or rabbits with either compound. The only effects observed in fetal animals were in the rat prenatal developmental study and included 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. These effects occurred at maternall y tox ic doses (1000 mg/kg/day). **4.4.4 Residual**  **Uncertainty in the Exposure Datab ase**  There is no residual uncertainty in the exposure database. The dietary exposure assessment is conservative, based on tolerance level residues and 100% crop treated. The residential exposure assessment is based on the Residential SOPs, which are designed to produce conservative exposure estimates. **4.5 Toxicity Endpoint and Point of**  **D eparture Selections**  **4.5.1 Dose**  **- Response Assessment**  The detailed description of the toxic ity studies used for selecting toxicity endpoints and points of departure for various exposure scenarios are presented in the appendix. The specific toxicity endpoints and PODs are presented in Tables 4.5.4.1 and 4.5.4.2. Toxicological endpoints were sel ected for dietary

/drinking water, occupational and residential exposure scenarios. An acute reference dose (RfD; 3.0 mg/kg/day) for assessment of food and drinking water exposures was selected from a developmental toxicity study in rats (NOAEL = 300 mg/kg/day). The endpoint of mortality and clinical signs identified in the developmental toxicity study in rats (MRID 00151941) was chosen for the acute dietary (general population) endpoint because it was considered adverse and results from a single exposure. An endpoint was not selected for Females 13

– 49 years old because no developmental effects were identified in the metolac hlor/S - met olachlor database that could be attributed to a single exposure. A chronic RfD (0.097 mg/kg/day) was selected from a chronic toxicity study in dogs (NOAEL= 9.7 mg/kg/day). The endpoint of decreased body weight gain identi fied in the chronic fe eding study in dogs was chosen for the chronic dietary (all populations) endpoint because the duration of the exposure in this study

is appropriate for a chronic dietary endpoint, and the database shows dogs w ere the most sensitive species and decreased bo dy weight gain the most sensitive endpoint. Use of this endpoint is therefore, protective for all adverse effects in other species that occur in higher doses and/or for shorter durations of exposure. The registered uses of S - metolachlor/metolachlor are expected to result in residential exposure via inhalation for residential handlers and incidental oral exposure for toddlers. A short - term incidental oral POD (NOAEL= 50 mg/kg/day) was selected from a developmental toxicity studyS - Metolachlor Human Health Risk Assessment DP No. D411153

Page **17** of **62** in rats. The endpoint of increased incidence of clinical signs and decreased body weight/body weight gain from the developmental toxicity study in rats (MRID 43928925) was identified for the short - term incidental oral endpoint. This study was selected because the effects were jud ged to be signs of frank toxicity and were app ropriate to use for risk assessment. The NOAEL for the prenatal developmental toxicity study in rabbits with S - metolachlor (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 100 mg/kg/day . Although there was a dose - related increase in this effect, it was not considered to be evidence of frank toxicity and was judged not to be appropriate for risk assessment. A point of departure (POD) for dermal exposure was not selected because no sy stemic toxicity was seen in rabbits following repeated dermal application at the highest dose tested for 21 days. No inhalation stu dies were available for the short - term and intermediate - term inhalation scenarios. The HASPOC met on February 14, 2013 to discuss the need for a subchronic inhalation study

for metolachlor (TXR #0056586). The decision was made that this study is required . In the absence of a route - specific study , a short - term inhalation exposure POD (50 mg/kg/day) was selected from an oral developmental toxicity study in rats. The endpoint of increased incidence of clinical signs and decreased body weight/body

weight gain from the developmental toxicity

study in rats (MRID 43928925) was identified for the short - term inhalation exposure endpoint. This study was selected because the effects were judged to be signs of frank toxicity

and the duration of exposure was appropri ate for this endpoint. An intermediate - term inhalation exposure POD (8.8 mg/kg/day) was selected from a subchronic toxicity study in dogs. The endpoint of decreased body weight gain was selected from the subchronic oral toxicity

study in dogs (MRID 0003 2174) was identified for the intermediate term inhalation exposure endpoint. This study was selected because the duration of the exposure in this study

is appropriate for the intermediate - term endpoint, and the database shows dogs were the most sensitive species and decreased body weight gain the most sensitive endpoint. An uncertainty factor of 100X was applied to endpoints selected for the oral exposure route (10x for interspecies extrapolation, 10x for intraspecies variation) and an uncertainty factor of 1000X was applied to endpoints selected for the inhalation exposure route due to a missing route - specific study (10x for interspecies extrapolation, 10x for intraspecies variation, 10x for database). **4.5.2 Recommendation for Combining Routes of**  **Exposures for Risk Assessment** Dietary and drinking water exposure are combined in the dietary exposure assessment. Children’s incidental oral hand - to - mouth exposure will be combined with dietary and drinking water exposure. The dermal route of exposure will not be combined with other routes of exposure for S - metolachlor , since th ere was no s ys temic toxicity seen at the limit dose in dermal toxicity studies. Although there is potential for residential inhalation exposure, a high end estimate was made, and this high end estimate will not be combined with dietary , water, and incidental oral exposure. **4.5.3 Cancer Classification and Risk Assessment Recommendation**  In the mouse carcinogenicity study , possible treatment - related deaths in females and decreas ed body weight/body

weight gain in both sexes were observed. In the rat combined chronicS - Metolachlor Human Health Risk Assessment DP No. D411153

Page **18** of **62** toxicity / carcinogenicity study , decreased body weight gain and food consumption were observed. There was no evidence of carcinogenicity in mice; however, there were statisticall y 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 to genetic effect in vivo or in vitro in studies with either metolachlor or S - metolachlor. Metolachlor h as 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 es tablished, as risks established based on the chronic reference dose are protective of cancer effects. **4. 5**  **. 4**  **Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment**  The points of departure, uncertainty factors, and toxicity endpoints are presented in the following tables. No endpoint is selected for dermal exposure scenarios. No hazard was identified at the maximum dermal dose tested. **Table 4.5.4.1**  **. Summary of Toxicological Endpoints for S -**  **me tolachlor 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 Effects**

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

Metolachlor (MRID 00151941) 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. 0 97mg/kg/day One Year Chronic Toxicity

– Dog;

Metolachlor (MRIDs 40980701, 41164501, 42218601 and 42218602) 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) approach. 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. NOAEL = 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.S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **19** of **62 Table 4.5.4.2**  **. Summ ary of Toxicological Doses and Endpoints for S**  **- ME**  **TOLACHLOR 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

S - Metolachlor (MRID 43928925) LOAEL = 500 mg/kg/day based on increased incidence of clinical signs, decreased body weight/body weight gain, food consumption and f

ood efficiency seen at the LOAEL in maternal animals. Dermal Short - and Intermediate - Term No hazard identified 21 - day dermal toxicity study

– Rabbits Metolachlor (MRID 41833101) LOAEL = Not observed

Inhalation Short - Term (1 - 30 days) NOAEL=

50 mg/kg/day UF A= 10x

UF H=10x UF D =10x Occupational

LOC for MOE = 100 0 Developmental Toxicity Study - Rat

S - Metolachlor (MRID 43928925) 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 Intermediate - Term (1 - 6 mo nths ) NOAEL=

8.8 mg/kg/day UF A= 10x

UF H=10x UF D =10x Occupational

LOC for MOE = 100 0 Subchronic Toxicity Study - Dog

Metolachlor (MRIDs 00032174 and 43244001) LOAEL = 29.4 mg/kg/day 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. 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. NOAEL = no ob served 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). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short - term study for long - term

risk assessment. UF DB = to account for the absence of key dat a (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. **5.0 Dietary Exposure and Risk Assessment**  **5.1 Metabolite/Degradate Residue Profile**  **5.1.1 Summary of Plant and Animal Metabolism St**  **udies** The qualitative nature of metolachlor residues in plants and livestock is adequately understood , based on adequate corn, potato, and soy bean metabolism studies, ruminants, poultry , andS - Metolachlor Human Health Risk Assessment DP No. D411153

Page **20** of **62** rotational crops . 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

previousl y concluded that the residues of concern for S - metolachlor are the same as for metolachlor. Metolachlor is metabolized extensively in both plants and livestock. 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)) . **5.1.2 Summary of Environmental**  **Degradation** Environmental 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 degradation 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 moderately mobile to a highly

mobile material. The Environmental Fate and Effects Division (EFED) concluded there is no difference in soil sorption affinity between metolachlo r 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. **5.1.3 Comparison of Metabolic Pathways**  Metolachlor and S - metolachlor are extensively metabolized in plants, livestock animals and rats. Side by side metabolism was studied only with a single oral dose in rats; no comparative studies were conducted with a high dose or repeated doses. The metab olism of metolachlor in plants involves conjugation with glutathione, breakage of this bond to form the mercaptan, conjugation of the mercaptan with glucuronic acid, O - demethylation of the methyl ether, and conjugation of the resultant alcohol with a neutral sugar. A minor pathway may involve sugar conjugation of metolachlor directl y to the corresponding oxo - compounds. Most of the metabolites of metolachlor and S - metolachlor have not been identified. Metolachlor is rapidl y m etabolized and almost total ly eliminated in the urine and feces of ruminants (goats), non - ruminants (rats), and poultry . There were some minor sex differences in the elimination pattern in rats. Metolachlor per se was not detected in any of the excreta or tissues. Metolachlor and S - metolachlor were readily absorbed and extensively metabolized by goats via glutathione conjugation and/or oxidation reactions. Oxidized metabolites were also conjugated with glucuronic acid. Metolachlor and S - metolachlor were extensively metabolized i n poultry via O - demethylation and subsequent glucuronic acid conjugation or oxidation to dihydrox y or carbox yl ic acid metabolites that may also be conjugated with glucuronic acid. As in plants, metolachlor residues of concern in livestock commodities inc lude metolachlor and its metabolites, determined as the derivatives CGA - 37913 and CGA - 49751. **5.1.4 Residues of Concern Summary and Rationale**  The metabolism of metolachlor and S - metolachlor has been reviewed by the Metabolism Assessment Review Committee (MARC) on August 14, 2001 (Dobozy , V, 2001) . The MARCS - Metolachlor Human Health Risk Assessment DP No. D411153

Page **21** of **62** determined that , although both metolachlor ethanesulfonic acid (ESA) (CGA - 354743) , and metolachlor oxanilic acid (OA) ( CGA - 51202 ) appear to be less toxic than the parent metolachlor and S - metolachlor, both should be determined in the drinking water risk assessment since these metabolites were found in greater abundance than the parent in water monitoring studies. The summary of metabolites and degradates is provided below. **Table 5.1.4 Summary of M**  **etabolites and Degradates to be included in th e Risk**  **Assessment and Tolerance Expression**  Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants Primary Crop Metolachlor and metabolites determined as the derivatives CGA - 37913 and CGA - 49751. Metolachlor and metabolites determined as the derivatives CGA - 37913 and CGA - 49751. Rotational Crop Metolachlor and metabolites determined as the derivatives CGA - 37913 and CGA - 49751. Metolachlor and metabolites determined as the derivatives CGA - 37913 and CGA - 49751. Livestock Ruminant Metolachlor and metabolites determined as the derivatives CGA - 37913 and CGA - 49751. Metolachlor and metabolites determined as the derivatives CGA - 37913 and CGA - 49751. Poultry Metolachlor and metabolites determined as the derivatives CGA - 37913 and CGA - 49751. Metolachlor and metabolites determined as the derivatives CGA - 37913 and CGA - 49751. Drinking Water Metolachlor, metolachlor ethanesulfonic acid (ESA), and metolachlor oxanilic acid (OA) Not Applicable

**5 .2**  **Food Residue**  **Profile** The qualitative nature of metolachlor residues in plants and livestock is adequately understood, based on adequate corn, potato, and soy bean metabolism studies, ruminants, poultry , and rotational crops . Residues of concern in plants, livestock, and rotational crops include metolachlor and its metabolites, determined as the derivatives CGA - 37913 and CGA - 49751. The current petition is a request for increase in tolerance for the livesto ck feed stuffs, corn forage and stover (from field - , sweet - and pop - corn), based on residue data showing tolerance exceeding residues resulting from the current use pattern . Adequate field trial data have been submitted to support the tolerance increase . The decline study included in the field trial data showed no decline in residues with increasing PHI. The field trial data were properl y supported by anal ytical validation data and storage stability data. No processing data are needed to support the cur rent tolerance request. Although the new tolerance represents a large increase in the dietary burden of S - metolachlor and metolachlor to beef cattle, the current tolerance for beef commodities is based on a higher dietary burden for S - metolachlor and meto lachlor to dairy cattle. The dietary

burden forS - Metolachlor Human Health Risk Assessment DP No. D411153

Page **22** of **62** metolachlor and S - metolachlor for dairy cattle did not change as a result of the current petition , and no increase is needed in the tolerances in livestock commodities . **5.3 Water Residue Profile**  D368735, C. Koper, 4/22/10 D396451, R Duncan , 1/3/2012 EFED calculated conservative, Tier I Estimated Drinking Water Concentrations (EDWCs) of metolachlor and S - metolachlor in ground water and surface water for use in an earlier human health risk assessment. Since there is no change in the existing uses of S - metolachlor as a result of the current petition, 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) degradate s. Although it was determined by HED’s Metabolism Assessment Review Committee (MARC) that the metolachlor ESA and metolachlor 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 using 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. Base d on a review of the current monitoring data, concentrations of parent S - metolachlor and its degradates were less than values reported from the previous monitoring data (US EPA, 2002). Based on monitoring and modeling data, total EDWCs for peak (acute exp osure) and average (chronic, non - cancer scenario) surface water respectively are 219 ppb ( 78 ppb parent + 48 ppb metolachlor ESA+ 94 ppb metolachlor 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) . **Table 5. 3**  **Summary of Estimated Surface Water and Groundwater Concentrations**

**for S**  **- Metolachlor**  Scenario Surface Water Conc., ppb a Groundwater Conc., ppb b Ac ute 219 126 Chronic (non - cancer) 119 126 Chronic (cancer) 119 126 a From the Tier I PRZM - EXAMS and FIRST . b From the SCI - GROW model. Source of EDWCs: D368735, C. Koper, 4/22/10 **5.4 Dietary Risk Assessment**  D396451, R. Duncan , 1/3/2012 **5.4.1 Description of Residue Data Used in Dietary Assessment**  No changes in tolerances for any food commodity are proposed or recommended as a result of the current petition. Thus, there is no change to the dietary exposure, and the last dietary exposure assess ment is still current.S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **23** of **62** 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 USD A’s Continuing Survey s of Food Intakes b y 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 as a percent age 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 b y 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 conservative, unrefine d 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 b oth 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 an d 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 level of conc ern 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 highest expo sed population subgroup, all infants < 1 ye ar old, is 0.012 mg/kg/day or 11.6 % of the cPAD . **5.4.2 Percent Crop Treated Used in Dietary Assessment**  The conservative assumption of 100% crop treated was used for all commodities with existing tolerances on food commodities. The current petition does not change any t olerances on food commodities. **5.4.3 Acute Dietary Risk Assessment**  Based on anal ys es of estimated dietary risks for the general U.S. population and various population subgroups, the acute die tary exposure estimates for S - metolachlor are significantly below HED’s level 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. **5.4.4 Chronic Dietary Risk Assessment** S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **24** of **62** Based on anal ys es of estimated dietary risks for the general U.S. population and various population subgroups, the chronic dietary exposure estimates for S - metolachlor are significantly be low HED’s level of concern for all supported commodities . The chronic dietary exposure estimate for the highest exposed population subgroup, all infants < 1 ye ar old, is 0.012 mg/kg/day

or 11.6 % of the cPAD . **5.4.5 Cancer Dietary Risk Assessment**  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 ef fects. **5.4.6 Summary Table**  **Table 5.4.6. Summary of Dietary**  **(Food and Drinking Water) Exposure**  **and Risk for S**  **** **Metolachlor and Metolachlor Population Subgroup**  **Acute Dietary (**  **95 Percentile)**  **Chronic Dietary Cancer**  **Dietary Exposure**  **(m g/kg/day)**  **% aPAD*** **Dietary Exposure**  **(m g/kg/day)**  **% cPAD*** **Dietary Exposure**  **(m g/kg/day)**  **Risk** General U.S. Population 0.014688 <1.0 0.004550 4.5 All Infants (< 1 year old) 0.046244 **1.5** 0.011574 **11.6**

N/A N/A Children 1 - 2 years old 0.025061 <1.0 0.008666 8.7 Children 3 - 5 years old 0.022362 <1.0 0.007852 7.9 Children 6 - 12 years old 0.015532 <1.0 0.005372 5.4 Youth 13 - 19 years old 0.011553 <1.0 0.003698 3.7 Adults 20 - 49 years old 0.012690 <1.0 0.003994 4.0 Adults 50+ years old 0.011471 <1.0 0.004017 4.0 Females 13 - 49 years old 0.012602 <1.0 0.003929 3.9 * The aPAD is 3.0 mg/kg/day . The cPAD is 0.1 mg/kg/day . Cancer risk is adequatel y covered by chronic dietary

exposure assessment. **Residential (Non -**  **Occupational) Exposure/Risk Characterization** There are no residential exposures for the current petition proposing increases in tolerances on livestock feed stuffs. However, there is potential for residential exposure to S - metolachlor from use of other registered products which are applied to residential lawns or turf by professional applicators. Residential post - application exposure to children 1 - 2 is reassessed in this document based on the Residential SOPs dated February 2012. (EPA, 2012)S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **25** of **62 6.1**  **Residential Handler Exposure** 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 purcha se or use (i.e., used by professional/commercial applicators), there is no potential for Residential Handler Exposure. **6.2 Post**  **- Application Exposure**  The only potential short - term residential risk scenario anticipated is post - application hand - to mouth exp osure of children playing on treated lawns. Although there is possibility of dermal exposure, no risks of concern were identified in the dermal toxicity study . S - metolachlor incidental oral exposure is assumed to include hand - to - mouth exposure , object - to mouth, and soil ingestion oral exposure . Residential post application exposure to S - metolachlor for this scenario is being reassessed in this document using the updated Residential SOPs . No turf transferable residue data were used. Exposure is due to a single application, at the maximum label rate of 2.47 lb a.i./acre for S - metolachlor and 4.0 lb a.i. acre/ for metolachlor. The residential exposure (absorbed dose) to children 1 - 2 for combined hand - to - mouth, object - to mouth, and soil ingestion oral exposure was calculated to be 0.0609 mg/kg/day resulting in an MOE of 82 0. 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. Based on this anal ys is, short - term oral MOEs are not of concern. **Table 6.2: Short**  **- Term Residential Post** **- application Exposure and Risk Estimates for S**  **- Metolachlor:**  **Children Turf Hand**  **to Mouth Exposure (LOC = 100)**

Formulation Lifestage HR t F M SAH (cm2 ) Exposure

Time (hours/ day) N_Replen SE Freq_Ht M Absorbed

Dose (mg/kg/day) MOE

(rounded) Hand Residue (mg/cm2 ) Fraction of

Hand Surface Area Mouthed / Event Number of replenishment intervals per hr (intervals/hr) Extraction

by Saliva HtM

events per hour Liquid 1 to <2

years 0.00654 0.127 150 1.5 4 0.48 13.9 0.0609 820 **6.3 Residential Bystander**  **Post -**  **application Inhalation Exposure** S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **26** of **62** Based on the Agency's current practices, a quantitative post - application inhalation exposure assessment was not performed for S - metolachlor at this time primarily because of the low acute inhalation toxicity (Toxicity Category III and IV) and low vapor pre ssure ( 2.8 x 10 - 5 mm Hg . However, volatilization of pesticides may be a source of post - application inhalation exposure to individuals nearb y pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory

Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipol y/ sap/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may , as appropriate, develop policies and procedures to identify the need for and, subsequently , the way to incorporate post application inhalation exposure into the Agency's risk assessments. If new policies or procedures are developed, the Agency may revisit the need for a quantitative post - application inhalation exposure assessment for (chemical). **6. 4**  **Spray Drift** Spray drift is alway s a potential source of exposure to residents nearby to spraying operations. This is particularly

the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application metho d employed for S - metolachlor . The Agency

has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency ’s Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by

the Spray

Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy

on how to appropriatel y apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied b y air, orchard airblast and ground hydraulic methods. After the policy

is in place, the Agency

may impose further refinements in spray drift management practices to reduce off - target drift with specific products with si gnificant risks associated with drift. Although a quantitative residential post - application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment has been previousl y performed for S - metolachlor exposure to flaggers on sod farms . This exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post - application inhalation exposure scenarios . Flaggers for applications on sod farms, where the S - metolachlor application rate is 2.5 lb ai/A, could be exposed short term to 0.0051 mg/kg/day , which would result in an MOE of 9800, which is below the Agency ’s level of concern. (M. Collantes, D296725 , April 10, 2006 ). **6.0 Aggregate Exposure/Risk Characterization** S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **27** of **62** In accordance with the FQPA, HED must consider and aggregate (add) 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 estimates 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 existing Section 3 uses, which do not change as a result of the current petition, acute, short - 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 residential 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 pathways were assessed in the aggregate risk assessment. **7.1 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 - metolachlor in food and drinking water is below EPA’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. **7.2 Short** **- Term Aggregate Risk**  Short - term aggregate assessments include exposures that will occur from one to thirty day s. For food and water, the exposure input is taken from the chronic dietary exposure assessment. There are no residential user exposures associated with the current petition to raise S - metolachlor on livestock feeds . However, there is potential for residential exposure to S - metolachlor from use of registered products which are applied to residential lawns or turf b y professional applicators. No intermediate - term risk scenarios are anticipated for the existing and proposed uses of S - metolachlor. 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 combined hand - to - mouth exposure, object - to - mouth exposure and exposure through incidental ingestion of soil. Refer to Section 6.2 . for the residential exposures that are likel y to be combined. Results from that assessment have been used to assess aggregate risk from exposure to food, drinking water, and residential lawns for this anal ys is. Based on this analy sis, short - term aggregate MOEs are not of concern. **Table 7**  **.2 Short -**  **Term Aggregate Risk Calculations for S -**  **metolachlor**S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **28** of **62 Population**  **NOAEL 1** 

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

**(food/water and residential)**  **4** Children 1 - 2 50 100 0.012 0.0 61 680 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)] **7.3 Intermediate**  **- Term Aggregate Risk**  Intermediate - term aggregate assessments include exposures that will occur from thirty day s to six months. There are no residential scenarios which are expected to be intermediate - term exposure. **7.4 Chronic Aggregate Risk**  Chronic or long - term aggregate assessments include exposures that will exceed six months. O nly food and water exposure are included in the chronic aggregate assessment , and does not dermal, inhalation or incidental oral exposure. Refer to section 5.4.4 for a detailed discussion of the chronic dietary

assessment. 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, resulting from aggregate exposure to S metolachlor in food and drinking water is below EPA’s level of concern. The food and drinking water exposure estimates for the most highl y exposed subgroup, all infants (< 1 year old) , is 11.6% of the cPAD. **7.5 Cancer Aggregate Risk**  As risks are estimated based on the chronic reference dose are prot ective 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 Cumulative Exposure/Risk Characterization**  Section 408(b)(2)(D)(v) of FFDCA requires that, when cons idering whether to establish, modify , or revoke a tolerance, the Agency consider “available information” concerning the cumulative effects of a particular pesticide's residues and “other substances that have a common mechanism of toxicity .” Unlike other p esticides 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 tox ic metabolite produced b y other substances. For the purposes of this tolerance action, therefore,S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **29** of **62** EPA has not assumed that S - metolachlor has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which ch emicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by

EPA’s Office of Pesticide Programs 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/. **8.0 Occupational Exposure/Risk Characterization**  No new uses are proposed with the current petition. Thus, there are no new occupational exposure scenarios to assess. Occupational exposure and risk from the use of S - metolachlor was last assessed in connection with PP# 3E6787, a petition for new uses of S - metolachlor on a number of commodities (M. Collantes, D296725, 4/2/2006). Estimated short - term and intermediate - term inhalation risk to mixer/loaders with no PPE, from the use of S - metolachlor on corn resulted in MOEs of 1100 and 230, respectively . With the additional 10X database uncertainty factor, the level of concern is now and MOE of 1000. The intermediate - term inhalation risk is now of concern. The risk can be mitigated b y use of a respirator or engineering controls . The metolachlor label requires the use of a closed loading s ys tem , which adequatel y mitigates this risk . Estimated short - term and intermediate - term inhalation risk to aerial applicators using engineering controls resulted in MOEs of 19,000 and 4000, respectivel y. These MOEs are not of concern. Estimated short - term and intermediate - term inhalation risk to flaggers resulted in MOEs of 13,000 and 2600. These MOEs are not of concern. **10.0 Human Studies**  This risk assessment relies in part on data from studies in which adult human subjects were intentionally

exposed to a pesticide or o ther chemical. These data, which include studies from PHED 1.1; the AHETF database; the Outdoor Residential Exposure Task Force (ORETF) database; the ARTF database ; and HED’s 2012 Residential SOPs, are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review b y the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at http://www.epa.gov/pesticides/science/handler - exposure - data.html , http://www.epa.gov/pesticides/science/residential - exposure - sop.html , and http://www.epa.gov/pesticides/science/post - app - exposure - data.html .S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **30** of **62 11**  **.0 References**  Collantes, Margarita. 2006. “ S - Metolachlor: Occupational Exposure Assessment.” D296725 , EPA Memorandum dated April 10, 2006 . Dobozy , Virginia, 2001. “ Metolachlor and s - Metolachlor. Results of the Health Effects Division (HED) Metabolism Assessment Review Committee (MARC) Meeting Held on 14 - August - 2001. Chemical#s 108801 and 108800. Barcode D274326 . EPA Memorandum dated 8/28/2001. Duncan, R., CDPR, 2012. “ S - Metolachlor **-** Acute and Chronic Dietary and Drinking Water Exposure and Risk Assessment for Proposed Section 3 Use on Cilantro and Garden Beet, Leaves.” D396451 . EPA Memorandum prepared by California EPA Department of Pesticide Regulation , dated January 3, 2012. EPA, 2012. “ Residential SOPs ” , dated February 2012, Available at http://www.epa.gov/pesticides/science/residential - exposure - sop.html Hummel, Susan V., 2013. “ S - Metolachlor, PP#2F8115. Petition for the Amendment of Permanent Tol erances for Residues of S - Metolachlor on Corn, field, forage; Corn, sweet, forage; and Corn, stover. Summary of Analy tical Chemistry

and Residue Data. ” D407466. EPA Memorandum dated August 1, 2013. Kinard, Sherie. 2003. “ PP#s: 7F04897, 9E06055, 7E04916, 2E06374, 4E04420, 8E05029, and 8E05030. Revised Metolachlor and S - M etolachlor Residue Chemistry Chapter for the Tolerance Reassessment Eligibility

Decision (TRED) and Registration for Use on Asparagus, Carrots, Cotton, Horseradish, Green Onions, P eppers, Rhubarb, Sugar Beet, Sunflower, and Swiss Chard; DP Barcode D292881; Rereg. Case 0001. ” D255484, D258813, D258816, D258825, D258958, D259117, D280858, D288570 . EPA Memorandum dated August 15, 2003 Koper, C hristopher M . 2010. “ Drinking Water Ass essment for S - Metolachlor and its Degradates Ethanesulfonic Acid (ESA) and Oxanilic Acid (OA) for Various Crop Uses .” D 368735, EPA EFED Memorandum dated April 22, 2010 . VanAlstine, Julie, 2013. “ Metolachlor: Summary of Hazard and Science Policy Council (HASPOC) Meeting of Fe bruary 14, 2013: Recommendations on the Need for a Neurotoxicity Battery , a Developmental Neurotoxicity Study, and a Subchronic Inhalation Study. ” EPA Memorandum dated March 20, 2013,S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **31** of **62 A** **ppendix A**  **. Toxicology Profile and Executive Summaries**  **A.1 Toxicology Data Requirements**  The requirements (40 CFR 158.340) for food use for Metolachlor are in Table 1. Use of the new guideline numbers does not imply that the ne w (1998) guideline protocols were used. **Study Technical**  **Required Satisfied**  870.1100 Acute Oral Toxicity ................................ ....................... 870.1200 Acute Dermal Toxicity ................................ .................. 870.1300 Acute Inhalation Toxicity ................................ .............. 870.2400 Primary Eye Irritation ................................ .................... 870.2500 Primary Dermal Irritation ................................ .............. 870.2600 Dermal Sensitization ................................ ...................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 Oral Subchronic (rodent) ................................ ............... 870.3150 Oral Subchronic (nonrodent) ................................ ......... 870.3200 21 - Day

Dermal ................................ .............................. 870.3250 90 - Day

Dermal ................................ .............................. 870.3465 90 - Day

Inhalation ................................ .......................... yes yes yes no yes yes

yes yes

- no 870.3700a Developmental Toxicity (rodent) ................................ ... 870.3700b Developmental Toxicity (nonrodent) ............................. 870.3800 Reproduction ................................ ................................ . yes yes yes yes

yes yes 870.4100a Chronic Toxicity (rodent) ................................ .............. 870.4100b Chronic Toxicity (nonrodent) ................................ ........ 870.4200a Oncogenicity (rat) ................................ .......................... 870.4200b Oncogenicity (mouse) ................................ .................... 870.4300 Chronic/Oncogenicity ................................ .................... yes yes yes yes yes yes a

yes yes yes yes 870.5100 Mutagenicity

—Gene Mutation - bacterial ..................... 870.5300 Mutagenicity

—Gene Mutation - mammalian ................ 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations ... 870.5xxx Mutagenicity

—Other Genotoxic Effects ....................... yes yes yes yes yes

yes yes yes 870.6100a Acute Delayed Neurotox icity (hen) ............................... 870.6100b 90 - Day

Neurotoxicity (hen) ................................ ........... 870.6200a Acute Neurotox icity Screening Battery (rat) ................. 870.6200b 90 - Day

Neuro toxicity Screening Battery (rat) ............... 870.6300 Develop. Neuro toxicity ................................ ................. no no no * no * no -

-

-

-

- 870.7485 General Metabolism ................................ ...................... 870.7600 Dermal Penetration ................................ ........................ 870.7800 Immunotoxicity ................................ ............................. yes yes yes yes

yes yes Special Studies for Ocular Effects

Ac ute Oral (rat) ................................ ........................... Subchronic Oral (rat) ................................ .................. Six - mo nth Oral (dog) ................................ .................. no

a Satisfied with combined chronic toxicity/carcinogenicity study * Waived at HASPOC February 14, 2013 (JVanAlstine, 2013)S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **32** of **62 A.2**  **Toxicity Profile s**  **Table A.2.1 Acute Toxicity Profile**  **- Metolachlor**  **Guideline No. Study Type**  **MRID(s) Results**  **Toxicity Category** 870.1100 Ac ute oral - Rat 00015523 LD 50 = 2780 mg/kg III 870.1200 Ac ute dermal - Rabbit 00015526 LD 50 = > 10 g/kg III 870.1300 Ac ute inhalation - Rat 00015535 LC 50 = > 1.75 mg/L III 870.2400 Ac ute eye irritation - Rabbit 00015528 Non - irritating IV 870.2500 Ac ute dermal irritation - Rabbit 00015530 Non - irritating IV 870.2600 Skin sensitization

– guinea pig 00015631 positive **Table A.2.1 Acute Toxicity Profile**  **– S**  **- Metolachlor**  **Guideline No. Study Type**  **MRID(s) Results**  **Toxicity Category** 870.1100 Ac ute oral - Rat 43928915 LD 50 = 3267 mg/kg ( ♂); 2577 mg/kg/day ( ♀); 2672 mg/kg/day (combined) III

870.1200 Ac ute dermal - Rabbit 43928916 LD 50 = > 2000 mg/kg III 870.1300 Ac ute inhalation - Rat 43928917 LC 50 = > 2.91 mg/L IV 870.2400 Ac ute eye irritation - Rabbit 43928918 Slight to moderate conjunctival irritation that cleared in 48 hours III

870.2500 Ac ute dermal irritation - Rabbit 43928919 non - irritating IV 870.2600 Skin sensitization

– guinea pig 43928920 positive

**Table A.2.2 Subchronic, Chronic and Other Toxicity Profile**  **- Metolachlor**  **Guideline No.**  **Study Type MRID No. (year)/**  **Classification /Doses Results**  870.3100 90 - Day oral toxicity

rodents 44775401 (1999)

Acceptable/guideline 0, 30, 300, 3000 ppm (M/F: 0, 2.00/2.32, 20.2/23.4, 210/259 mg/kg/day) NOAEL for males = 3000 ppm LOAEL for males not established NOAEL for females = 300 ppm LOAEL for females = 3000 ppm based on decreased body weight/body weight gain Acceptable/Guideline 870.3150 180 - Day oral

toxicity in nonrodents 00032174 (1980), 43244001

0, 100, 300, 1000 ppm (M/F: 0, 2.92/2.97, 9.71/8.77, 29.61/29.42) NOAEL = 300 ppm LOAEL = 1000 ppm based on decreased body weight gain Unacceptable/GuidelineS - Metolachlor Human Health Risk Assessment DP No. D411153

Page **33** of **62 Table A.2.2**  **Subchronic, Chronic and Other Toxicity Profile -**  **Metolachlor Guideline**  **No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** 870.3200 21 - Day dermal

toxicity rabbits 41833101 (1987)

0, 10, 100 or 1000 mg/kg/day sy stemic NOAEL = 1000 mg/kg/day. sy stemic LOAEL was not established dermal irritation NOAEL was not established dermal irritation LOAEL = 10 mg/kg/day based on very slight erythema, dry skin and fissuring (one animal) Acceptable/Guideline 870.3700a Prenatal

developmental in rodents 00151941 (1985)

0, 30, 100, 300 or 1000 mg/kg/day M aternal toxicity NOAEL = 300 mg/kg/day. M aternal toxicity LOAEL = 1000 mg/kg/day based on an increased incidence of death, clinical signs of toxicity (clonic and/or toxic convulsions, excessive salivation, urine - stained abdominal fur and/o r excessive lacrimation) and decreased body weight gain. D evelopmental toxicity NOAEL = 300 mg/kg/day D evelopmental toxicity LOAEL = 1000 mg/kg/day based on slightly decreased number of implantations per dam, decreased number of live fetuses/dam, increas ed number of resorptions/dam and significant decrease in mean fetal body weight Acceptable/Guideline 870.3700b Prenatal

developmental in (New Zealand White) rabbits 00041283 (1980)

acceptable/guideline 0, 36, 120 or 360 mg/kg/day M aternal toxicity NOAEL = 120 mg/kg/day. M aternal toxicity LOAEL = 360 mg/kg/day based on an increased incidence of clinical observations (persistent anorexia) and decreased body weight gain D evelopmental toxicity NOAEL = 360 mg/kg/day D evelopmental toxicity LOAEL was not established. Acceptable/Guideline 870.3800 Reproduction and

fertility effects (CD albino) rats 00080897 (1981)

0, 30, 300 or 1000 ppm F 0 males: 0, 2.4, 23.5, and 75.8 mg/kg/day; F 0 females: 0, 2.5, 26.0, and 85.7 mg/kg/day; F 1 males: 0, 2.3, 23.7, and 76.6 mg/kg/day; F 1 females: 0, 2.6, 25.7, and 84.5 mg/kg/day metolachlor (95.4% ai) (dietary) Parental/Systemic NOAEL = 1000 ppm (F 0 males/females: 75.8/85.7 mg/kg/day; F 1 males/females: 76.6/84.5 mg/kg/day) highest dose tested. LOAEL = Not established Reproductive NOAEL = 1000 ppm (F 0 males/females: 75.8/85.7 mg/kg/day; F 1 males/females: 76.6/84.5 mg/kg/day) highest dose tested. LOAEL = Not established Offspring NOAEL = 30 0 ppm (F 0 males/females: 23.5/26.0 mg/kg/day; F 1 males/females: 23.7/25.7 mg/kg/day LOAEL = 1000 ppm (F 0 males/females: 75.8/85.7 mg/kg/day; F 1 males/females: 76.6/84.5 mg/kg/day based on decreased body weight in F 1 and F 2 litters. Acceptable/Guideline 870.4100b Chronic toxicity

dogs 40980701, 41164501,

42218601 and 42218602. (1989) 0, 100, 300 or 1000 ppm NOAEL = 300 ppm (9.7 mg/kg/day) for females LOAEL = 1000 ppm for females (33.0 mg/kg/day) based on decreased body weight gainS - Metolachlor Human Health Risk Assessment DP No. D411153

Page **34** of **62 Table A.2.2**  **Subchronic, Chronic and Other Toxicity Profile -**  **Metolachlor Guideline**  **No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** (males: 0, 3.5, 9.7 and 32.7 mg/kg/day, respectively; females: 0, 3.6, 9.7 and 33.0 mg/kg/day, respectively) for one year. LOAEL for males was not established; NOAEL = 1000 ppm (32.7 mg/kg/day). Acceptable/Guideline

870.4200 Chronic

toxicity/Carcinogeni city rat 00129377 (1983)

0, 30, 300 or 3000 ppm (0, 1.5, 15 or 150 mg/kg/day based on 1 ppm in food equals 0.05 mg/kg/day) NOAEL = 300 ppm (15 mg/kg/day) for females LOAEL = 3000 ppm (150 mg/kg/day) for females based on slightly decreased body weight gain and food consumption. The LOAEL was not established for males. The NOAEL was 3000 ppm (150 mg/kg/day). Administration of doses up to 3000 ppm was associated with statistically significant increases in liver adenomas and combined adenoma/carcinoma in female rats . In male rats, there was a stati sti cally significant trend but not pair - wise significance for liver tumors. Acceptable/Guideline 870.4300 Carcinogenicity

mice 00117597 (1982)

0, 300, 1000 or 3000 ppm (0, 45, 150 or 450 mg/kg/day) NOAEL = 100 ppm (150 mg/kg/day) LOAEL = 3000 ppm (450 mg/kg/day) based on possible treatment - related deaths in females and decreased body weight/body weight gain in males and females no evidence of carcinogenicity Acceptable/Guideline 870.5100 Gene Mutation

bacterial reverse mutation 00015397 (1976)

10, 100, 1000 and 10,000 ug/plate negative up to cytotoxic doses (1000 ug/plate) Acceptable/Guideline 870.5300 Gene Mutation

mouse lymphoma 00158929 (1984)

9.5 - 190 nL/mL without activation; 10.5 - 280 nL/mL with activation no effect on the incidence of mutations in the presence or absence of metabolic activation Acceptable/Guideline 870.5395 Cy

togenetics micronucleus assay in Chinese hamsters 00158925 (1984)

0, 1250, 2500 or 5000 mg/kg no effect of treatment on incidence of micronuclei induction Acceptable/Guideline 870.5450 Cy

togenetics dominant lethal assay in mice 00015630 (1978)

100 or 300 mg/kg no effect on embryonic death, pre - and post implantation or fertility rates in mated females Acceptable/Guideline 870.5550 Other Effects

DNA Damage/Repair in rat hepatocytes 00142828 (1984)

0.125, 0.625, 3.125 or 15.625 nL/mL Negative Acceptable/Guideline 870.5550 Other Effects

DNA 00142827

0.125, 0.625, 3.125 or 15.625 NegativeS - Metolachlor Human Health Risk Assessment DP No. D411153

Page **35** of **62 Table A.2.2**  **Subchronic, Chronic and Other Toxicity Profile -**  **Metolachlor Guideline**  **No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** Damage/Repair in human fibroblasts nL/mL Acceptable/Guideline 870.5550 Other Effects

Unscheduled DNA sy nthesis in rat hepatocytes 43244003 (1994)

1250, 2500 or 4000 mg/kg to males; 500, 1000 or 1500 mg/kg to females negative for induction of UDS; however, significant increases in percentage of cells in S - phase were observed in females dosed at 500 mg/kg (but not at 1000 or 1500 mg/kg) and sacrificed at 15 hours Acceptable/Guideline 870.7485 Metabolism and

pharmacokinetics rodents MRID 00015425 (1974)

52, 28 or 33 mg/kg to male rats Conclusions : Urinary metabolites of CGA 24705 (N - (2 - methoxy- 1 - methylethyl) - 2 - ethyl - 6 - methyl chloroacetanilide) were identified following oral administration of 52 mg/kg, 28 mg/kg, and 33 mg/kg to male rats. Two metab olites, each comprising approximately 5% of chloroform extractable urinary radioactivity, were identified from oral administration of CGA 24705. These were the products CGA 37735 (2 - ethyl - 6 - methyl hydroxyacetanilide), in which N - dealkylation of R 1 (the N - ( 2 - methoxy- 1 - methylethyl side chain) and side chain dechlorination and oxidation of R2 (the N chloroacetyl side chain) have occurred, and CGA 46129 (N - (1 - carboxy- ethyl) - 2 - ethyl - 6 - methyl hydroxyacetanilide) in which the ether bond of R 1 has been split and oxidized to the corresponding carboxylic acid, while R2 is similar to R2 found in CGA 37735. In study #7/74, these 2 metabolites each represented approximately 5% of organic extractable urinary radioactivity, while in study #12/74, the percentage found as CGA 46129 was between 20 - 25% of urinary radioactivity, and CGA 37735 represented between 3 - 5% of organic extractable radioactivity. The major metabolic pathway proposed from analysis of urinary as well as fecal metabolites is one of cl eavage of the ether bond and subsequent oxidation to the carboxylic acid, as well as hydrolytic removal of the chlorine atom. Conjugation of CGA 24705 or metabolites with gluronic acid or sulfate does not appear to occur. Aqueous extractable urinary radioactivity contained 58% of the total urinary radioactivity and was composed of 5 different radioactive fractions, which were not identified. Current guideline recommendations as to dose levels and use of both sexes in metabolism studies were not follo wed. Thus, whether the metabolic pattern is altered with dose or repeated exposure cannot be evaluated from these data. Unacceptable/Nonguideline 870.7485 Metabolism and

pharmacokinetics 40114401 (1987)

Single low (1.5 mg/kg), Conclusions : Single low (1.5 mg/kg), single high (300 mg/kg) and repeated low (1.5 mg/kg/day for 15 days) oral doses of metolachlor were readilyS - Metolachlor Human Health Risk Assessment DP No. D411153

Page **36** of **62 Table A.2.2**  **Subchronic, Chronic and Other Toxicity Profile -**  **Metolachlor Guideline**  **No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** single high (300 mg/kg) and repeated low (1.5 mg/kg/day for 15 days) absorbed and eliminated by male and female rats. Urinary and fecal elimination of radioactivity associated with orally administered [ 14 C] metolachlor was essentially complete within 48 to 72 hours after dosing. Low - and high - dose females eliminated 14 C more rapidly (p<0.003, half - lives of elimination, 16.6 and 15.6 hours , respectively) than low - and high - dose males and repeated - dose animals of both sexes (half

- lives, 18.2 and 20.0 hours). Elimination by all animals followed first - order kinetics. Approximately one - half to two - thirds (48 to 64 percent) of the 14 C administered was recovered from the urine within 7 days; similar amounts were present in the feces. Low - dose males eliminated slightly more of the radioactive dose in the feces (55 percent) than the urine (48 percent). The opposite trend was seen in the low - dose fem ales and repeated dose rats of both sexes; these animals excreted approximately 58 to 64 percent of the 14 C dose in the urine and 42.5 to 46.5 percent in the feces within 7 days after dosing. High - dose animals excreted similar amounts (58 to 60 percent) of the radioactive dose in the urine and feces. Total recoveries of 14 C (urine, feces, and tissues) tended to be high and were between 105 and 122.5 percent. Relatively low levels of radioactivity were present in the tissues of all animals at 7 days postdos ing. Tissues of low - and repeated - dose rats contained approximately 1.6 to 2.5 percent of the 14 C dose; tissues of high - dose rats accounted for 3.2 (females) and 4.2 (males) percent. For all groups, most of the tissue radioactivity (1.1 to 3.0 percent of the dose) was associated with red blood cells (RBCs); RBCs also contained the highest concentrations of radiolabeled compound (0.6 to 0.9 ppm, low - and repeated - dose rats; 232 and 247 ppm, high - dose females and males, respectively), indicating that [ 14 C] me tolachlor and/or its metabolites bind extensively to these cells. The next highest concentrations of radiolabel (0.03 to 0.13 ppm, lowand repeated - dose rats; 7.3 to 37 ppm, high - dose animals) were present in metabolically active tissues, including the he art, lung, kidney, liver and spleen. Brain, bone and muscle contained the smallest amounts of radioactivity (0.004 to 0.015 ppm, low and repeated - dose rats; 1.7 to 3.5 ppm, high - dose rats). Tissue 14 C residues in high - dose males were approximately 250 to 500 times greater than those of low - dose males, indicating that the ratio of tissue concentrations (high dose:low dose) was much larger than the corresponding dose ratio of 200:1 (300 mg/kg: 1.5 mg/kg). In contrast, tissue 14 C levels of females were, in general, proportionate to dose. Tissues of low - and repeated - dose rats contained similar amounts of radioactivity. These data indicate that some 14 C was retained by all animals and thatS - Metolachlor Human Health Risk Assessment DP No. D411153

Page **37** of **62 Table A.2.2**  **Subchronic, Chronic and Other Toxicity Profile -**  **Metolachlor Guideline**  **No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** the greatest potential for accumulation of radioactivity was in male rats given a single high oral dose of [ 14 C] metolachlor. Unacceptable/Nonguideline 870.7485 Metabolism and

pharmacokinetics 43164201 (1992)

acceptable/guideline low oral dose (1.5 mg/kg x 14 days), and a single high dose (300 mg/kg) In a rat metabolism study (MRID # 431642 - 01), 14 C - Metolachlor was administered orally in PEG - 200 [HWI 6117 - 208] or corn oil [ABR- 94001] to groups (5 sex/dose) of male and female Sprague - Dawley rats at a low oral dose (1.5 mg/kg), repeated low oral dose (1.5 mg/kg x 14 days), and a single high dose (300 mg/kg). Control animals (1/sex) received blank formulation. Comparison of oral and intravenous data showed that of the administered dose, between 69.6% and 93.2% was absorbed. Distribution data showed that the only significant sites of residual radioactivity at 7 days post - dose were residual carcass (0.9 - 2.2% of the administered dose) and red blood cells (0.95 - 1.53 μg equivalents/gram in blood cells for all low dose male and female rats). Dosing regimen did not result in any apparent accumulation of residual radioactivity. Excretion data showed that urine and feces were both significant routes for elimination of metolachlor derived radioactivity. In the low dose groups, the urine appeared more of a predominant route for excretion in female rats than in males, whereas fecal excretion was slightly higher in males. However, at the high oral dose, there were no apparent sex - related differences in the pattern of urinary excretion. Examination of urinary excretion data as presented in graphical format indicated that at the 300 mg/kg dose, excretion was delayed vs the low oral dose, suggesting saturation of elimination. Metabolism of metolachlor in this study was complex, with up to 32 metabolites identified in urine and/or feces. The “major” urinary metabolite found in all dose groups was the metabolite designated CGA - 46129. This metabolite was present as 5.6 - 13.1% of the total radioactive residue (TRR) in rat urine across all dose groups, and was highest in the intravenously dosed group. In the orally dosed rats, the percentage of this metabolite decreased from approximately 13% of TRR to between 5.6 - 9.2% of TRR. Other metabolites identified in urine which constituted near or at 5% of TRR were U10 (CGA - 37735), U13, U 17, U1, “polar 1”, and “polar 2.” The radioactivity constituting the ‘polar 1’ and ‘polar 2’ regions was further broken down to at least 12 components by TLC, but the identity of the metabolites in these regions was not demonstrated. In feces, a similarl y complex metabolite profile wasS - Metolachlor Human Health Risk Assessment DP No. D411153

Page **38** of **62 Table A.2.2**  **Subchronic, Chronic and Other Toxicity Profile -**  **Metolachlor Guideline**  **No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** obtained. The “major” metabolite observed in feces, F9, was identical to U7, or CGA - 46129. Except for intravenously dosed rats, where the percentage of this metabolite in feces was equivalent in male and female rats (11.6 and 13.2% of TRR, respectively), the percentage of F9 in feces of orally dosed rats was always higher in males than in females. Other fecal metabolites identified at or near 5% of TRR in feces included F2 (CGA - 41638), F3 (CGA - 133275), F7, F8 and F8’, F16, F 14, and F17. Based on these data, a scheme for metabolism of metolachlor was proposed. Acceptable/Guideline **Table A.2.2 Subchronic, Chronic and Other Toxicity Profile**  **– S**  **- Metolachlor**  **Guideline No.**  **Study Type MRID No. (year)/**  **Classification /Doses Results**  870.3100 90 - Day oral toxicity

rodents 43928923 (1995)

0, 30, 300, 3000 or 10000 ppm (0, 1.5, 15, 150 or 500 mg/kg/day) NOAEL = 300 ppm LOAEL = 3000 ppm based on lower body weights/body weight gains, reduced food consumption and food efficiency and increased kidney weights in males Acceptable/Guideline 870.3100 90 - Day oral toxicity

rodents 44775402 (1999)

0, 30, 300, 3000 ppm (M/F: 0, 1.90/2.13, 20.4/23.9 and 208.0/236.0 mg/kg/day0 NOAEL = 3000 ppm (equivalent to 208 mg/kg/day in males and 236 mg/kg/day in females LOAEL cannot be defined Unacceptable/Guideline 870.3150 90 - Day oral toxicity

nonrodents 43928922 (1995)

0, 300, 500, 1000 or 2000 ppm (M/F: 0, 9/10, 15.1/17.2, 31.1/31.5 or 62/74 mg/kg/day) NOAEL = 2000 ppm (M/F: 62/74 mg/kg/day) LOAEL = not established Acceptable/Nonguideline 870.3700a Prenatal

developmental in (Tif:RAI f (SPF)) rats 43928925 (1995)

0, 5, 50, 500, or 1000 mg/kg/day S - metolachlor (95.6% ai) in 0.5% (w/w) aqueous solution of sodium carboxymethylcellulose (gavage) GD 6 - 15 Maternal NO AEL = 50 mg/kg/day LO AEL = 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. Developmental NOAEL = 1000 mg/kg/day, highest dose tested. LOAEL = Not established Acceptable/ GuidelineS - Metolachlor Human Health Risk Assessment DP No. D411153

Page **39** of **62 Table A.2.2**  **Subchronic, Chronic and Other Toxicity Profile –**  **S -**  **Metolachlor Guideline**  **No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** 870.3700b Prenatal

developmental in (New Zealand White) rabbits 43928924 (1995)

0, 20, 100, or 500 mg/kg/day S - metolachlor (89.6% ai (93.7% S isomer)) suspension in 3% corn starch (gavage) GD 7 - 19 Maternal NOEL = 20 mg/kg/day LOEL = 100 mg/kg/day based on clinical signs of toxicity. Developmental NOAEL = 500 mg/kg/day, highest dose tested. LOAEL = Not established Acceptable/ Guideline 870.5100 Gene Mutation

Salmonella & Escherichia/Mamma lian Microsome Mutagenicity Test 43928927 (1995)

78.13 - 1250.0 ug/plate In independently performed microbial mutagenicity assays, Salmonella typhimurium TA1535, TA1537, TA98, TA100 and TA102 and Escherichia coli WP2 uvr A were initially exposed to 312.5 - 5000.0 μg/plate CGA - 77102 technical (95.6%) in the presence and absence of S9 activation. For the confirmatory trial, doses of 78.13 - 1250.0 μg/plate ±S9 were evaluated with S. typhimurium strains TA1535, TA1537, TA100 and TA102 ; concentrations of 312.5 - 5000.0 μg/plate ±S9 were examined with S. typhimurium TA 98 and E.coli WP2 uvr A. In general, doses  1250.0 μg/plate ±S9 were cy totoxic for S. typhimurium TA1 535, TA1537, TA100 and TA102 and 5000.0 μg/plate ±S9 was slightly cytotoxic for S. typhimurium TA98 and E. coli WP2 uvrA. There was, however, no indication that CGA - 77102 technical induced of a mutagenic effect in any tester strain either in the presen ce or the absence of S9 activation. Acceptable/Guideline 870.5395 Cy

togenetics Micronucleus test 43928926 (1995)

500, 1000 or 2000 mg/kg Groups of five male and five female Tif:MAGf(SPF) mice received single oral gavage administrations of 500, 1000 or 2000 mg/kg CGA 77102 technical (95.6%). Toxic signs, similar to those seen in the preliminary range - finding studies (i.e., ataxia, tremors and/or hunched posture) were recorded for high - dose males and females throughout the 48 - hour postexposure. No bone marrow cytotoxicity was seen at any dose or sacrifice time. The positive control induced the expected high yield of MPEs in males and femal es. There was, however, no evidence that CGA 77102 technical induced a clastogenic or aneugenic effect in either sex at any dose or sacrifice time. Acceptable/GuidelineS - Metolachlor Human Health Risk Assessment DP No. D411153

Page **40** of **62 Table A.2.2**  **Subchronic, Chronic and Other Toxicity Profile –**  **S -**  **Metolachlor Guideline**  **No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** 870.5550 Other Effects

Unscheduled DNA sy nthesis 43928928 (1995)

500, 1500, 3200 (females), 5000 (males) mg/kg Groups consisting of three to four rats per sex received single oral gavage administrations of CGA 77102 Technical (95.6%) at doses of 500, 1500 or 5000 mg/kg (males) or 500, 1500 or 3200 mg/kg (females). Hepatocytes harvest ed at 15 and 38 hours were evaluated for viability and replicative DNA sy nthesis (RDS). For the UDS determination, additional groups (3/sex/dose) were exposed to 500 or 1500 mg/kg and the recovered hepatocytes were scored at 2 or 15 hours postexposure. Two of four females in the 3200 - mg/kg group and 2 of 4 males in the 5000 - mg/kg group died prior to the scheduled sacrifice at 38 hours. Severe cytotoxicity was seen in the hepatocytes recovered from 1 of 2 surviving males and both female survivors in the high - dose groups. Lower levels were neither toxic to the animals nor cytotoxic to the target cells. A clear dose - related increase in the percentage of cells in S phase (RDS) was obtained from hepatocytes harvested 38 hours posttreatment of the male rats. The response ranged from a 5.3 - fold increase at 1500 mg/kg to a 16.1 - fold increase at the high dose (5000 mg/kg). In females, a marked increase in RDS was initially seen at 1500 mg/kg but the response declined over time with a 24.4 - fold increase at 15 h ours and a 12.2 - fold increase at 38 hours. There was, however, no evidence that the CGA 77102 Technical at doses of 500 or 1500 mg/kg induced a genotoxic response at 2 or 15 hours posttreatment. We conclude, therefore, that the data indicate that CGA 771 02 Technical was negative for genotoxicity but positive for cellular proliferation when tested up to overtly toxic and cytotoxic doses in this in vivo /in vitro rat hepatocyte RDS/UDS assay. Acceptable/GuidelineS - Metolachlor Human Health Risk Assessment DP No. D411153

Page **41** of **62 Table A.2.2**  **Subchronic, Chronic and Other Toxicity Profile –**  **S -**  **Metolachlor Guideline**  **No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** 870.7485 Metabolism and

pharmacokinetics 44491401 (1996)

single dose of 0.5 (group B1) or 100 mg/kg (group D1) radiolabeled CGA - 77102; 100 mg/kg/day non radiolabeled CGA 77102 for 14 days followed by 0.5 mg/kg radiolabeled CGA 77102 (Group V1); single dose of 0.5 or 100 mg/kg radiolabeled CGA - 771 02 for bile - cannulation study In all three dose groups (B1, D1, and V1), the seven day combined levels of radioactivity in urine were 31.1 - 36.5% for males and 40.8 - 45.5% for females; the fecal levels were 60.2 - 62.5% for males and 48.9

- 55.0% for females. Only 0.1% or less was eliminated in the expired air. The total recovery ranged from 96.5 ± 2.3% to 99.3 ± 0.9%. The route or extent of excretion was slightly influenced by the sex of the animal but not by pretreatment with non radiolabeled CGA - 771 02 or by the dose level. The degree of absorption, based on adding the cumulative urinary excretion to the total residues in tissues, was 35 - 39% in males and 43 - 49% in females of both dose groups. However, based on the bile duct cannulation study, mos t of CGA - 77102 was absorbed from the gastrointestinal tract since 85% of the dose was recovered in urine, bile fluid, and tissues during the 48 hours study period. Therefore, the biliary excretion and enterohepatic circulation play a significant role in t he elimination process of CGA - 77102. Irrespective of the dose and sex, there seems to be a biphasic plasma profile with two concentration maxima (C max); a fast rising first C max was reached at 0.25 - 1 hour post dosing which was succeeded by a second C max at 8 and at 12 - 24 hours following administration of the low and high dose, respectively. In the low dose group (B1), the first and second C max were nearly identical (~ 0.03 μg/mL); in the high dose group (D1), the first and second C max were, respectively, 4.6 and >3.9 μg/mL in males and 2.2 and 4.5 μg/mL in females. The time to half maximum plasma concentration (tcmax/2 ) in males/females was 31/24 hours at the low dose and 44/32 hours at the high dose. Bioavailability, or the area under the plasma c oncentration curve (AUC 0 - 48hr), was nearly identical (~ 0.8 mg/kg.hr) among males and females of the low dose group. Also, both sexes in the high dose group had similar plasma AUC 0 - 48hr (M/F: 143/125 mg/kg.hr) which increased almost proportionately with the 200 - fold increase in the dose level. The residues in RBC increased steadily with time reaching peak levels (at 24 - 48 hours post - dosing) of 0.5 - 0.6 and 90 ppm (or μg/g) CGA - 77102 equivalents for the low (B1) and high (D1) dose groups, respectively. The peak levels in RBC remained high and were nearly 20 fold higher than the respective plasma C max levels. Acceptable/GuidelineS - Metolachlor Human Health Risk Assessment DP No. D411153

Page **42** of **62 Table A.2.2**  **Subchronic, Chronic and Other Toxicity Profile –**  **S -**  **Metolachlor Guideline**  **No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** The kinetics of tissue distribution and depletion in both sexes were also followed for up to 144 hours following a single low or high oral dose (Groups F1

- F4). Peak residue levels were reached within 12 - 24 hours and ranged from 0.007 ppm (female muscle) to 0.123 ppm (male kidneys) at the low dose, and from 1.29 ppm (male brain) to 16.82 ppm (male liver) at the high dose, with the highest levels being among some of the well - perfused tissues (e.g., liver, kidneys, spleen, and lungs). The extent of residue depletion was variable among the tissue types but was minimally affected by the dose or the sex of the animal. The radiolabel was most persistent in some of the well - perfused organs (e.g., the heart, lungs, and spleen) in addition to the brain and bone where, after 144 hours, the levels were decreased to only 45 - 94% of their maximal concentrations. In Groups F1 - F4 , peak residue concentration in the whole blood (0.2 and 42 - 47 μg/mL in the low and high dose groups, respectively) was reached at 24 hours and was maintained throughout the study. Overall, the high/low dose peak tissue levels (including blood) ranged f rom 132 to 282 which approximates the 200 - fold increase in dosage. CGA - 77102 has a high affinity for and a long halflife in blood (especially RBC) which might contribute to the retarded depletion of tissue residues.S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **43** of **62 Table A.2.2**  **Subchronic, Chronic and Other Toxicity Profile –**  **S -**  **Metolachlor Guideline**  **No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** 870.7485 Metabolism and

pharmacokinetics 44491402 (1996)

single dose of 0.5 (group B1) or 100 mg/kg (group D1) radiolabeled CGA - 77102; 100 mg/kg/day non radiolabeled CGA 77102 for 14 days followed by 0.5 mg/kg radiolabeled CGA 77102 (Group V1); single dose of 0.5 or 100 mg/kg rad iolabeled CGA - 77102 for bile - cannulation study (from MRID 44491401) single oral low dose (0.5 mg/kg, Group B2) of [Phenyl - U 14 C] CGA - 24705 (R/S - Metolachlor, racemate) The 72 hour mean recovery of radioactivity in urine, feces, and carcass following administration of 0.5 mg/kg of [Phenyl - U 14 C] CGA - 24705 was 43.1%, 47.0%, and 7.4% in males and 54.0%, 39.4%, and 4.1% in females, respectively. In contrast, both sexes excreted more of the label in the feces (M:F 59.7%:53.4%) than in the urine (M:F 29.4% :39.8%) during the same period following administration of the same dose of [Phenyl - U 14 C] CGA - 77102 (the S enantiomer) (MRID 44491401). The urinary and fecal metabolite profiles, with 31 and 15 metabolite fractions, respectively, were qualitatively similar among all groups; however, there were large quantitative differences, based on the dosing formulation, on one hand, and the sex of the animal, on the other. Based on a percentage of the dose, several of the major urinary metabolite fractions (e.g. , U1, U2, U3, U18, U24, and U30) were more abundant in the case of the racemic Metolachlor (CGA - 24705) than the S - Metolachlor (CGA - 77102); in contrast, several fecal metabolite fractions (e.g., F9, F10, F12, and F13) were present at higher levels in the ca se of CGA - 77102 than CGA - 24705. On the other hand, there were sex related differences regardless of the dosing formulation where, for instance, females had greater urinary concentrations than males of several metabolite fractions, including U3, U4, U8, U9 , U18, U20, and U30; the males, however, excreted more of fractions U1 and U24 than the females. Also, several fecal fractions including F1, F3, F5, F6, F7, F8, and F13 were influenced by the sex regardless of the dose level (e.g. B1 vs. D1) or the stereo chemical make - up of Metolachlor (B1 vs. B2). Other metabolite fractions were dependent on both the sex and the chemical formulation as, for instance, in the case of metabolite U2 which, relative to the opposite sex within the same group, was more abundant in the urine of the females of Group B2 (CGA - 24705) and in the urine of the males of Group B1 (CGA - 77102). The bile fluid accounted for 79.8% of the administered low or high dose of CGA - 77102 (Groups G1 and G2) where the 2D - TLC showed 14 biliary metaboli te fractions (G1 - G14) in the high dose Group and only six metabolites in the low dose Group. The two metabolite fractions G7 and G8 accounted, respectively, for 33.3% and 9.6% of the administered low dose and 31.3% and 14.6% of the administered high dose. Other major biliary metabolites were G3, G9, and G10 which accounted for about 5%, 5 - 7%, and 3 - 5%, respectively, of either dose group.S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **44** of **62 Table A.2.2**  **Subchronic, Chronic and Other Toxicity Profile –**  **S -**  **Metolachlor Guideline**  **No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** The results clearly show that the metabolite profile in excreta and bile fluid is very complex and that Metolachlor (racemate or S - enantiomer) is extensively metabolized. This was also shown earlier by another rat metabolism study on the absorption, distribution, excretion, and metabolite identification of racemic CGA - 24705 (MRID 43164201, reviewed by T. McMahon, HED doc. no. 010990 dated May 23, 1994). No actual metabolites or pathways were identified in the current study and there were no data to support or refute the previous findings of four major degradation pathways with more than 30 metabolites. However, knowing the enantiomeric stereospecific reactions/metabolites is not likely to help in making comparative risk assessments between R/S - Metolachlor (CGA - 24705) and S - Metolachlor (CGA - 77102) since the contribution of each metabolite to the overall toxicity of Metolachlor is not well understood. Furthermore, other bridging animal studies with CGA - 77102 should highlight possible toxicity differences from the well - studied CGA - 24705 due to variations in the metabolite profiles. The Registrant is requested to comment on or provide information on a number of issues including: 1) The stereoisomeric purity of CGA - 24705 and CGA - 77102. 2) The adequacy of th e storage conditions and the validity of the metabolite profile results in light of the storage - related results variability. 3) Explain why, relative to the other dosing formulation, some metabolite fractions (e.g., F10, F12, and F13) were up to 7 - fold hi gher in the case of the S - enantiomer (CGA - 77102) while some urinary metabolite fractions (e.g., U1, U2, and U3) were up to 4 - fold higher in the case of CGA - 24705. 4) Provide rational for dose selection. 5) The Registrant might also have to comment on the possible formation and the level of methylethylaniline from either dosing formulation and the possible contribution of this metabolite to the carcinogenicity of Metolachlor. This issue was raised earlier by T. McMahon (HED document no. 010990 dated May 2 3, 1994) and might need to be followed up by HED’s risk assessors who are in charge of S - Metolachlor. Unacceptable/Guideline 870.7800 Immunotoxicity in

mice 48783301 (2012)

0, 1500, 3000 or 5000 ppm (0, 304.3, 639.5, or 1108.5 mg/kg/day NOAEL = 5000 ppm (1108.5 mg/kg/day) LOAEL = Not Established Acceptable/GuidelineS - Metolachlor Human Health Risk Assessment DP No. D411153

Page **45** of **62 A.3**  **Hazard Identification and Endpoint Selection A.3.1**  **Acute Reference Dose (aRfD) -**  **Females age 13**  **- 49**  An endpoint was not selected for Females 13 - 49 ye ars old since no developmental effects that could be attributed to a single exposure were identified in the metolachlor/s - motolachlor database. **A.3.2 Acute Reference Dose (aRfD)**  **- General Population**  **Study Selected:** Developmental Toxicity in Rats - Metolachlor **MRID No.:** 00151941 **Do se and Endpoint for Risk Assessment:**  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 lacrimation) and decreased body weight gain. **Comments about Study/Endpoint/Uncertainty Factors:** Since clinical signs are observed after a single oral dose of metolachlor, the duration and route of administration are app ropriate 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 increased 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 protect the public from dietary exposure to residu es of metolachlor. The total UF is 100 (10X for interspecies uncertainty factor and 10X for intraspecies variability . **Acute RfD (General Population) = (NOAEL) 300 mg/kg**  **= 3.0 mg/kg (UF) 100**  **A.3.3 Chronic**  **Reference Dose (cRfD )**  **` Study Selected:**  Chronic Feeding Study in Dogs **MRID No.:** 43744201 **Dose and Endpoint for Risk Assessment:** 9.7 mg/kg/day based on a NOAELof 9.7 mg/kg/day and a LOAEL of 33 mg/kg/day based on decreased body weight gain in females. **Comments about Study/Endpoint/Uncertainty Factors:** This study was selected because the database shows dogs were the most sensitive species and decreased body weight gain the most sensitive endpoint. The duration of 1 year and route of exposure through the feed is also appropriate. The total UF is 100 (10X for interspecies uncertainty factor and 10X for intraspecies variability).

**Chronic RfD (General Population) = (NOAEL) 9.7 mg/kg**  **= 0.097 mg/kg (UF) 100** S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **46** of **62 A.3.4**  **Incidental Oral Exposure (Short -**  **and Intermediate -**  **Term) Study Selected:**  Developmental Toxicity Study in Rats **MRID No.:** 43928925 **Dose and Endpoint for Risk Assessment:** 50 mg/kg/day based on a maternal NOAEL of 50 mg/kg/day

and a LOAEL of 500 mg/kg/day ba sed on increased incidence of clinical signs, decreased body weight/body weight gain, food consumption and food efficiency seen in maternal animals. **Comments about Study/Endpoint/Uncertainty Factors:** The NOAEL (20 mg/kg/day) for the prenatal developmental toxicity study in rabbits with S

- metolachlor (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 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. The total UF is 100 (10X for interspecies uncertainty factor and 10X for intraspecies variability) . **A.3.5 Dermal Exposure (Short**  **- Term**  **)** No hazard was identified for quantification of risk following dermal exposure. In a 21 - day dermal toxicity

study (MRID 41833101), no s ys temic toxicity was seen following repeated dermal application of metolachlor (96.4% ai) to the intact skin of five New Zealand rabbits/sex/group at doses of 0, 10, 100 or 1000 mg/kg/day for 21 day s. **A.3.6 Inhalation Exposure (Short**  **- Term)**  **Study Selected:** Developmental Toxicity Study in Rats **MRID No.:** 43928925 **Dose and Endpoint for Risk Assessment:** 50 mg/kg/day base d 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. **Comments about Study/End point/Uncertainty Factors:**  Since an oral study was selected, a 100% absorption factor should be applied. The total UF is 100 (10X for interspecies uncertainty factor and 10X for intraspecies variability . **A.3.7 Inhalation Exposure (Intermediate**  **- Term)**  **Study Selected:** Subchronic (6 month) Toxicity Study in the Dog **MRID No.:** 00032174 **Executive Summary :**  See Appendix A, Guideline [§ 870.xxix]S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **47** of **62 Dose and Endpoint for Risk Assessment:**  NOAELof 8.8 mg/kg/day based on decreased body weight gain at 29.4 mg/kg/day **Comments about Study/Endpoint/Uncertainty Factors:** Since an oral study was selected, a 100% absorption factor should be applied. The total UF is 100 (10X for interspecies uncertainty factor and 10X for intraspecies variability . **A.4 Executive**  **Summaries A.4.1**  **Subchronic Toxicity 870.3100**  **90 -**  **Day Oral Toxicity –**  **Rat** In a 90 - day

subchronic oral toxicity

limit study

(MRID 44931710), groups of 10 male and 10 female Crl: CD BR rats were given CGA - 354743 (L ot/Batch # KI - 5408/6, 98% a.i.) administered in the diet at concentrations of 0, 360, 1200, 6000, or 20,000 ppm. Thes e concentrations were equivalent to 0, 25.1, 86.2, 427.0 or 1545.0 mg/kg/day for males and 0, 28.4, 98.3, 519.0 and 1685.0 mg/kg/day for females. An additional 10 male and 10 female rats were given CGA - 77102 (s - Metolachlor)(Lot/Batch # P.501001, 98.5% a.i .) administered in the diet at 5000 ppm (equivalent to 429 mg/kg/day for males and 563 mg/kg/day for females). The study was designed to assess the subchronic oral toxicity of CGA - 354743 technical and to compare its toxic effects with those of its parent compound, CGA - 77102 technical. No deaths or clinical signs of toxicity occurred during this study . In addition, no statistically significant changes in body weight, body weight gain, food consumption, food efficiency, ophthalmologic examination, urinaly sis, or histopathology was reported for animals fed CGA 354743. Limited and sporadic statistically significant changes in hematology , clinical chemistry , water intake and organ weight data were not dose - dependent, and were of question able toxicological and biological importance. Dietary exposure to CGA - 77102 produced a statistically significant decreased body weight gain ( - 20%, p  0.01) in males during week 1 onl y. Females exposed to CGA - 77102 showed decreased body weight gain ( - 19%) b y week 13, but th ese changes were not statistically significant. The food efficiency of rats fed CGA - 77102 was decreased relative to their respective control animals. Male and female rats had increased absolute and relative liver weights. These results are consistent with a mild liver hy pertrophy in females. **Based on the data presented in this study, the NOAEL is**  **20,000 ppm (1543 mg/kg/day and 1685 mg/kg/day for females) for CGA**  **- 354743. A LOAEL could not be established.**  **At 5000 ppm (429 mg/kg/day in males and 563 mg/ kg/day in females) CGA**  **- 77102 , there**  **evidence of decreased body weight gain and food efficiency, increased absolute and relative liver weights and an increased incidence of hepatic centrilobular hypertrophy, although the**  **effects were mild** . This subchronic oral toxicity study in rats is classified as **Acceptable/Guideline [OPPTS 870.3100 (§82**  **- 1a)]**  and satisfies the guideline requirements. **870.3100 90**  **- Day Oral Toxicity**  **– Rat** S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **48** of **62** In a subchronic oral feeding study, (MRID 44929509), CGA - 51202 technical (100% a.i.; batch No. JD 7069/3) was fed to groups of 10 male and 10 female albino rats at dose levels of 0, 300, 1000, or 15,000 ppm for 3 months. The average achieved doses for the corresponding groups were 0, 18.7, 62.1, and 1000 mg/kg bodywei ght for males, and 0, 20.6, 67.3, and 1020 mg/kg for females. All animals survived to study termination and no treatment - related clinical signs were observed. There were no treatment - related effects on body weight, food consumption, ophthalmoscopic parameters, or urinal ys is. Platelet counts were decreased 16% (p<0.01) in high - dose males. Total protein in high - dose males (5% decrease, p<0.01) and females (4% decrease, N.S.) was slightly decr eased due to decreased globulin in males and decreased albumin and globulin fractions in females. These effects were not considered biologicall y significant. There were no treatment - related organ weight effects or macroscopic or microscopic lesions. **Unde r the**  **conditions of this study, the NOAEL is 15,000 ppm in the diet (1000 mg/kg for males, 1020 mg/kg for females, limit dose) based on no biologically significant effects. A LOAEL was**  **not identified.** This subchronic toxicity

study in rats (82 - 1) is clas sified as **Acceptable/Guideline.** Itsatisfies the guideline requirement for a subchronic dietary toxicity study in rodents. **870.3150 90**  **- Day Oral Toxicity**  **– Dog**  In a 90 - day

subchronic oral toxicity

study (MRID 44931709), CGA - 354743 technical (Batch Nos. KI - 5408/4 and KI - 5408/5, 99% a.i.) was administered to 4 pure bred beagle dogs/sex/dose by capsule at dose levels of 0, 50, 200, 500, and 1000 mg/kg/day for 13 weeks. An additional group of 4 males and 4 females received parent compound (CGA - 77102 techni cal, Batch No. P.501001, 98.5% a.i.) at 200 mg/kg/day for 13 weeks. There were no significant treatment related effects on mortality , body weight, food consumption, food conversion ratios, ophthalmological findings, hematology and urinal ysis parameters, or gross and histopathological findings. Vomiting did occur at a higher incidence in females treated with 1000 mg/kg/day

of CGA - 354743. Clinical signs in animals treated with CGA - 77102 included vomiting, salivation and hematuria. Mean alkaline phosphatas e activity was slightl y increased in males receiving 1000 mg/kg/day CGA - 354743 at weeks 7 and 13 to levels which were less than double the pretest mean for this group. This finding correlated with slightly increased absolute liver weights, but there were no corresponding histopathological findings, or toxicologically

significant increases in other biochemistry parameters. In females, mean ALP activities remained within the reference range for untreated animals and mean GGT activity exceeded the reference range onl y at week 13 and only for the 500 mg/kg/day

CGA - 354743 group. Absolute liver weights and liver weights relative to body weights were increased in females receiving 500 and 1000 mg/kg/day . In the absence of corresponding histopathological finding s or biologicall y s ignificant increases in biochemistry parameters consistent with adverse hepatic effects, this finding is not considered toxicologically significant.S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **49** of **62** Mean ALP and GGT activities were significantl y i ncreased in both sexes at weeks 7 and 1 3 given CGA - 77102. In addition, ALT activity of males was increased at weeks 7 and 13. Absolute and relative liver weights were significantly increased in males and females. There were small increases in the incidences and severity of bile duct hyperpla sia, perilobular fatty change in the livers of both sexes, and cy stic hy perplasia of the gallbladder occurred onl y in the parent compound group. The results appear to indicate that CGA - 354743 may have effects (vomiting, slight increases in ALT and liver weight) similar to those of its parent compound, CGA - 77102; however, at the limit dose, 1000 mg/kg/day , the effects observed were so slight and of questionable toxicological significance in CGA - 35743 - treated dogs that a definitive comparison of the two co mpounds cannot be made. **Based on the data presented in this study, the LOAEL was not determined, and the NOAEL was greater than or equal to 1000 mg/kg/day.**  This subchronic oral toxicity study in dogs is classified as **Acceptable/Guideline** and satisfies the guideline requirements for a subchronic oral study [OPPTS: 870.3150 (§82 - 1b)] in dogs since the limit dose was tested. **870.3200 21/28**  **- Day Dermal Toxicity**  **– Rat**  **870.3465 90**  **- Day Inhalation**  **– Rat**  **A.4.2 Prenatal Developmental Toxicity**  There was no evidence of maternal or developmental toxicity in the rat prenatal developmental study with CGA 354743 or CGA 51202 at the limit dose of 1000 mg/kg/day . **870.3700a Prenatal Developmental Toxicity Study –**  **Rat** In a developmental toxicity study (MRID 44931711), 28 presumed pregnant Wistar B: Hanlbm:WI ST rats per group were administered CGA 354743 Technical (98%; Batch No. KI 5408/6) by

gavage in 0.5% aqueous sodium carboxy methylcellulose in 0.1% aqueous poly sorbate 80 at doses of 0, 250, 500, or 1000 mg/kg/day on gestation day s (GD) 6 - 15, inclusive. Controls were treated with 0.5% sodium carbox ym ethyl cellulose in 0.1% aqueous poly sorbate 80 (vehicle). On GD 21, dams were sacrificed, subjected to gross necrops y, and all fetuses examined external ly . Approximately one - half of each litter was processed for visceral examination and the remaining one - half was processed for skeletal examination. All animals survived to terminal sacrifice. No clinical signs of toxicity were observed in any animal. Maternal body weights, body weight gains, and food consumption were similar between the treated and control groups throughout the study. Maternal necrops y was unremarkable.S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **50** of **62 Therefore, the maternal toxicity NOAEL is**   **1000 mg/kg/day and the maternal toxicity LOAEL was not identified.**  No differences were observed between the treated and control groups for number of corpora lutea, number of implantation sites, live fetuses/dam, pre - and post - implantation losses, fetal body weights, or fetal sex ratios. No tre atment - related external, visceral, or skeletal malformations/variations were observed in any fetus from any

group. The high dose is equivalent to the limit dose for developmental toxicity studies. **Therefore, the developmental toxicity NOAEL is**  **1000 mg/kg/day and the developmental**  **toxicity LOAEL was not identified.** This study

is classified as **Acceptable/Guideline** and satisfies the requirements for a developmental toxicity

study [870.3700 (§83 - 3a)] in rats. **870. 3700a**  **Prenatal Developmental Toxicity Study**  **- Rat**  In a developmental toxicity study (MRID 44929510), 24 presumed pregnant Tif: RAIf (SPF) (hy brids of RII/1  RII/2) rats per group were administered CGA 51202 Technical (100%; Batch No. JD 7069/3) by

gavage in 0.5% aqueous sodium carboxymethyl cellulose solution at doses of 0, 10, 100, or 1000 mg/kg/day on gestation day s (GD) 6 - 15, inclusive. Controls were treated with 0.5% sodium carboxy methylcellulose (vehicle). On GD 21, dams were sacrificed, subjected to gross necropsy , and all fetuses e xamined externally . Approximately one - half of each litter was processed for visceral examination and the remaining one - half was processed for skeletal examination. One low - dose animal was sacrificed moribund on GD 20 with a urogenital infection. All oth er animals survived to terminal sacrifice. No clinical signs of toxicity were observed in any

animal. Maternal body weights and body weight gains were similar between the treated and control groups throughout the study . Food consumption was not affected by treatment. Maternal necrops y was unremarkable. **Therefore, the maternal toxicity NOAEL is**  **1000 mg/kg/day and the maternal toxicity LOAEL was not identified.**  No differences were observed between the treated and control groups for number of corpora lutea, number of implantation sites, live fetuses/dam, pre - and post - implantation losses, fetal body weights, or fetal sex ratios. No treatment - related external, visceral, or skeletal malformations/variations were observed in any fetus from any

group. The high dose is equivalent to the limit dose for developmental toxicity studies.S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **51** of **62 Therefore, the developmental toxicity NOAEL is**   **1000 mg/kg/day and the developmental toxicity LOAEL was not identified.**  This study

is classified as **Acceptable/Guideline** and satisfies the requirements for a develop mental toxicity

study [870.3700 (§83 - 3a)] in rats. **870.3700b Prenatal Developmental Toxicity Study –**  **Rabbit** In a developmental (teratology) study (MRID# 43928924), sexually mature virgin female New Zealand Wh ite, S.P.F. Rabbits (Strain: Har:PF/CF(NZW)BR) from H.A.R.E., Rabbits for Research, Hewitt, N.J. Received either 0, 20, 100, or 500 mg/kg/day CGA - 77102 Technical (Lot No. FL - 830813 with a purity of 89.6% (93.7% S isomer) suspension in 3% corn starch containing 0.5% Tween 80 by oral gavage from gestation day s 7 through 19. No treatment related mortality was noted. There was a dose related increase in little/none/soft stool observations at the 100 and 500 mg/kg/day dose levels. The 500 mg/kg/day dose group had lower overall body weights at gestation days 19, 29 and corrected body weights at day 29 gained less weight than the control during the dosing period (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 weight gains for 0 - 29. This was supported b y reduced food consumption during the dosing period (gestation day s 7 - 19) and for the overall periods (gestation day s 7 - 28 and 0 - 28) with 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 (7 19, 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 dev elopmental toxicity was noted at the dose levels tests. **The developmental toxicity was equal to or greater than 500 mg/kg/day, a LOEL was not**  **reached. This study is classified as**  **Acceptable -**  **Guideline and satisfies the guideline requirements**  [870.3700 (§8 3 - 3b)] **for a teratology study in rabbits. A.4.3**  **Reproductive Toxicity 870.3800 Reproduction and Fertility Effects**  **- Rat**  In a two - generation reproduction study (MRID 00080897), metolachlor (95.4% a.i.) 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 (F 0 males: 0, 2.4, 23.5 and 75.8 mg/kg/day ; F 0 females: 0, 2.5, 26.0 and 85.7 mg/kg/day ; F 1 males: 0, 2.3, 23.7 and 76.6 mg/kg/day ; F 1 females: 0, 2.6, 25.7 and 84.5 mg/kg/day).S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **52** of **62** There were no deaths in the F 0 generation. Two females of the F 1 generation died during the pre mating 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 th e 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 necrops y examinations, none of the deaths was treatment - related. There were no treatment - related clinical sign s of toxicity

in either generation. Body weight, body

weight gain and food consumption were unaffected in the F 0 generation. In the F 1 generation, food consumption was significantl y decreased in females of the 1000 ppm group at several timepoints; 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 necrops y examinations in either generation. There w as no evidence of a treatment - related effect on any of the reproductive parameters for either generation. Offspring body weight was significantly decreased in the F 1 litter on lactation day s 14 and 21 (91 - 96% of control value) and in the F 2 litter on lact ation day s 4, 7, 14 and 21 (92 - 95% of control value). Although the magnitude of the decrease is small, the finding is regarded as toxicologically significant. **The parental toxicity LOAEL was not established. The NOAEL was 1000 ppm (F 0**  **males/females: 75. 8/85.7 mg/kg/day; F**  **1 males/females: 76.6/84.5 mg/kg/day).**  **The reproductive toxicity LOAEL was not established. The NOAEL was 1000 ppm (F 0**  **males/females: 75.8/85.7 mg/kg/day; F 1**  **males/females: 76.6/84.5 mg/kg/day). The offspring LOAEL was conservatively**  **established at 1000 ppm (F 0**  **males/females: 75.8/85.7 mg/kg/day; F**  **1 males/females: 76.6/84.5 mg/kg/day) based on decreased body**  **weight in F 1**  **and F 2**  **litters . The NOAEL is 300 ppm (F 0**  **males/females: 23.5/ 26.0 mg/kg/day; F**  **1 males/females: 23.7/25.7 mg/kg/day)**  **.** The study is classified as **Acceptable/guideline** and **satisfies** the guideline requirements for a multi - generation reproduction study in rats (83 - 4; OPPTS 870.3800). **A.4.4 Chronic Toxicity**  **870.4100a (870.4300) Chronic Toxicity –**  **Rat** See Carcinogenicity section below. **870.4100b Chronic Toxicity -**  **Dog** In a chronic toxicity

study (MRIDs 40980701, 41164501, 42218601 and 42218602), metolachlor (97% a.i.) was administered in the diet to Beagle dogs (6/sex/group for control and high dose groups; 4/sex/group for low - and mid - dose groups) at dose levels of 0, 100, 300 or 1000 ppm (males: 0, 3.5, 9.7 and 32.7 mg/kg/day , respectivel y; females: 0, 3.6, 9.7 and 33.0 mg/kg/day , respectivel y) for one ye ar. Two dogs of each sex in the control and high - dose group designated as recovery

animals were treated for 52 weeks and were then allowed a 4 - weekS - Metolachlor Human Health Risk Assessment DP No. D411153

Page **53** of **62** recovery period. An additional 4 dogs/sex/group were treated at the same dose levels and sacrificed at 13 weeks. There were no treatment - related deaths or clinical signs o f toxicity . Mean body weight gain was decreased in the 1000 ppm group females, considering both all animals (5 - 17% decrease) and only those treated for 52 weeks (5 - 17% decrease). Alkaline phosphatase was significantly increased in the 1000 ppm females at w eeks 12, 26 and 40; however, the increase was not considered toxicologically significant due to the small magnitude of the effect and the lack of accompanyi ng necrops y findings. **The LOAEL was 1000 ppm for females (33.0 mg/kg/day) based on decreased body w eight**  **gain. The NOAEL was 300 ppm (9.7 mg/kg/day). The LOAEL for males was not**  **established. The NOAEL for males was 1000 ppm (32.7 mg/kg/day).** The study is classified as **Acceptable/guideline** and **satisfies** the guideline requirements for a chronic toxicity

study in dogs (83 - 1; OPPTS 870.4100). **A.4.5 Carcinogenicity**  **870.4200a Carcinogenicity Study -**  **rat** In a chronic toxicity

/carcinogenicity study (MRID 00129377), metolachlor (95.3%), was administered in the diet to 60 CD - Crl:CD albino rats/sex/group at dose levels of 0, 30, 300 or 3000 ppm (0, 1.5, 15 or 150 mg/kg/day) for two years. An additional 10 rats/sex/group were administered either 0 ppm or 3000 ppm in th e diet for 12 months; 5 rats/sex/group were sacrificed after treatment and the remaining 5/sex/group were allowed to recover for four weeks and then sacrificed. Comparable mortality were observed in the treated and control animals. There were no treatment - related clinical signs of toxicity . Mean body weight gain was slightl y decreased in the 3000 ppm females (6 - 17% decrease) throughout the study; the changes were not statistically

significant. Mean food consumption was slightl y decreased (4 - 9% decrease) in the 3000 ppm females; the decrease was not statistically significant. Absolute, relative and liver - to brain weight were increased (7%, 13%, and 5%, respectivel y) in the 3000 ppm males. These increases were also observed in the 3000 ppm males after four- week recovery period. However, the toxicological significance of the finding is questionable as there were no accompanyi ng clinical pathology

or histologic changes. **For chronic toxicity, in males, the NOAEL was 3000 ppm (150 mg/kg/day), a LOAEL was not established. For females, the NOAEL was 300 ppm (15 mg/kg/day) and the LOAEL**  **was 3000 ppm (150 mg/kg/day) based on slightly decreased body weight gain and food consumption.**  The study is classified as **acceptable/guideline** and **satisfies** the guidelin e requirements for a chronic toxicity

study in rats (83 - 1; OPPTS 870.4200a). **870.4200b Carcinogenicity (feeding) -**  **Mouse**S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **54** of **62** In a carcinogenicity

study (MRID 00117597 1 ), metolachlor (reported to be 95% a.i.) was administered in the diet to 68 CD - 1 mice/sex/group at doses of 0, 300, 1000 or 3000 ppm (0, 45, 150 or 450 mg/kg/day , based on 1ppm equals 0.150 mg/kg/day). Eight mice/sex/group were sacrificed at 12 and 18 months. High dose females had a significant increased mortality rate due to a number of death s during the first few weeks of treatment (control: 24/52; high dose females: 34/52 at termination). Although the deaths were possibly attributable to a viral infection, the contribution of the test material can not be dismissed. Body weight was statisti cally significantly decreased (91 - 95% of control value) throughout the study in the 3000 ppm males and during the latter half of the study in the 3000 ppm females (93 - 95%). Body weight gain was consistently decreased in the 3000 ppm males (48 - 48%) and fem ales (59 - 86%). Food consumption was comparable between treated and control group until week 90 of treatment, at which time the 3000 ppm males consumed 10% less than controls. The decrease was statistically significant at weeks 98, 102 and 104. There wa s no significant effect on female food consumption. There was no evidence of treatment - related effect on hematology or clinical chemistry

parameters. Organ weight was not affected except for a dose - related decrease in absolute and relative weight of the seminal vesicles of males which was statistically significant at the high dose. However, there was no effect on testes weight and no accompanying histological changes in the seminal vesicles; therefore, the toxicological significance of the finding is questionable. There were no treatment related microscopic changes. There were no treatment - related increases in tumor incidence in the study . **The NOAEL was 1000 ppm (150 mg/kg/day) and the LOAEL was 3000 ppm (450 mg/kg/day) based on possible**  **treatment -**  **related deaths in females and decreased body weight/body weight gain in males and females.**  The study is classified as **acceptable/guideline** and **satisfies** the guideline requirements for a carcinogenicity

toxicity study in mice (83 - 5; OPPTS 870.420 0). **A.4.6 Mutagenicity**  There was no evidence of mutagenicity in vitro or in vivo with either CGA 354743 or CGA 51202. Mutagenicity

Studies with CGA 354743 Gene Mutation 870.5100 Salmonella/Escherichia bacterial reverse mutation assay 44931712 (1996) acceptable/guideline 312.5, 625.0, 1250.0, 2500.0 and 5000.0 μg/plate in the presence and absence of mammalian metabolic activation (S9 - mix) Strains TA98, TA100, TA102, TA1535 and TA1537 of S. typhimurium and strain WP2(uvrA) of E. coli were exposed to CG A - 354743 tech. in DMSO at con centrations of 312.5 - 5000.0 μg/plate in the presence and absence of mammalian metabolic activation (S9 - mix). There was no evidence of induced mutant colonies over background. Gene Mutation 44991102 (1999) Chinese hamster V79 cells in culture were exposed to CGA -

1 According to the Second Peer Review of Metolachlor (April 17, 1991), a mouse carcinogenicity study (MRIDs 00042725, 00084003) conducted by Industrial Biotest (validated by EPA)at doses of 0, 30, 1000 and 3000 ppm also showed no evidence of carcinogenic effects.S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **55** of **62** 870.5300 mammalian cell gene mutation assay at the HPRT locus, Chinese hamster V79 cells acceptable/guideline concentrations of 185.19, 555.56, 1666.67, 5000.00 μg/mL in the presence and absence of mammalian metabolic activation (S9 - mix). 354743 tech. in bidistilled water at concentrations of 185.19

- 5000.00 μg/mL in the presence and absence of mammalian metabolic activation (S9 - mix). There was suggestive (statistical) evidence of a possible induction of mutant colonies over background; however, the results are unlikely to be biologically significant because the absolute numbers of mutant colonies were low and within the testing laboratory’s historical solvent control ranges. Cy togenetics 870.5395 Micronucleus assay in mo use bone marrow cells 44931713 (1998) acceptable/guideline 1250, 2500 and 5000 mg/kg body weight Five mice/sex/dose were treated once each via oral gavage with CGA - 354743 tech. at doses of 1250 - 5000 mg/kg body weight. There was no significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow after any dose or treatment time. Other Effects 870.5503, Unscheduled DNA Synthesis 44931714 (1998) acceptable/guideline concentrations of 9.77, 39.06, 156.25, 625.00, 2500.00, 5000.00 μg/mL Primary rat hepatocyte cultures were exposed to CGA 354743 tech in bidistilled water at concentrations of 9.77 - 5000.00 μg/mL for 16 to 18 hours in an initial assay and to concentrations of 78.13 - 2500 μg/mL for 16 to 18 hours in a confirmatory assay. There was no evidence that unscheduled DNA synthesis, as determined by radioactive tracer procedures (nuclear silver grain counts), was induced. Mutagenicity

Studies with CGA 51202 **Guideline No./ Study Type**  **MRID No. (year)/**

**Classification /Doses Results**  Gene Mutation 870.5100 Salmonella/Escherichia bacterial reverse mutation assay 44929512 (1992) acceptable/guideline 312.5, 625, 1250, 2500, 5000 ug/plate Strains TA98, TA100, TA1535 and TA1537 of S. typhimurium and strain WP2(uvrA) of E. coli were exposed to CGA - 51202 technical in DMSO at concentrations of 312.5

- 5000.0 μ g/plate in the presence and absence of mammalian metabolic activation. There was no evidence of induced mutant colonies over b ackground. Cy togenetics 870.5395, Micronucleus assay in mo use bone marrow cells MRID 44929511 (1992) 600, 1200 or 2400 mg/kg acceptable/guideline Five mice/sex/dose were treated once via oral gavage with CGA - 51202 technical at doses of 600 - 2400 mg/kg body weight. There was no biologically significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow

after any dose or treatment time used in the study. Gene Mutation 870.5300 mammalian cell gene mutation assay at the HPRT locus, Chinese hamster V79 cel ls MRID 45001201 (1999) 500, 1000, 2000 or 4000 ug/mL in initial assay; 375, 750, 1500 or 3000 ug/mL in confirmatory assay, in the presence and CGA 51202 tech. was tested up to cytotoxic concentrations. Statistically significant increases in mean mutant frequency were seen in the initial assay with S9 - mix at 500 μg/mL (6.66 x 10 6 ) and 1000 μg/mL (5.56 x 10 6 ) compared to the solvent control value of 4.02 x 10 6 and without S9 - mix at 500 μg/mL (15.35 x 10 6 ) compared to the solvent control value of 12.90S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **56** of **62 Guideline No./ Study**  **Type MRID No. (year)/** 

**Classification /Doses Results**  absence of mammalian metabolic activation (S9 - mix). x 10 6 . The increases were small and the actual mean mutant frequencies were within the range of historical solvent control values. No positive dose - response was se en and no statistically significant increases in mean mutant frequencies were seen in the confirmatory assay. The solvent and positive controls induced the appropriate response. **There was no evidence of a biologically significant induction of**  **mutant col onies over background.**  **A.4.8 Metabolism**  **870.7485 Metabolism**  **- Rat**  In a metabolism study

(MRID 44931715), groups of three male and three female rats were each given [phenyl - U 14 C] CGA 77102 (batch no. ILS - 143.1; purity 98.9%) and non - radiolabeled CGA 77102 (batch no. AMS 757 - 101; purity 99.8%) to provide a total single oral dose of 0.5 or 100 mg/kg. Urinary

and fecal excretion were monitored over 72 hours and major metabolites identified and quantified. The study focused on evaluating the presence of the metabolites CGA 354743, CGA 368208, and CGA 357704 in the excreta of rats. There were no deaths or overt signs of toxicity attributed to the test material. Actual adminis tered doses were 3 - 8% greater than nominal. Overall recovery of administered radio activity was an acceptable 93.83 - 99.18%. Urinary excretion and carcass burden data implied that absorption was approximately

38 - 49% of the adminis tered dose. Most (86.5 - 91.7%) of the radioactivity recovered at 72 hours post was associated with the urine and feces. The available data suggested that urinary

excretion was slightly

greater in female rats than male rats (42% for low - and high dose females as compared to 30% and 32% of low - and high - dose males, respectively), and fecal elimination was e xpectedly less (approximately

13 - 15%) for females than for males. However, the small sample size (three rats per sex) precludes a definitive assessment of gender- specific differences in excretory

pattern. Time - course data for absorption and excretion were not provided. Based upon the residual radioactivity in the carcasses, accumulation in the tissues was less than 10% of the administered dose at 72 hours after administration. Both urinary

and fecal metabolites were identified and quantified. For both routes of elimina tion, three major metabolites were identified but none represented more than 0.25% of the administered dose. Characterization of these metabolites and comparison to known reference standards revealed them to be CGA 357704, CGA 354743, an d CGA 368208. In the feces, CGA 357704 and CGA 354743 represented a notabl y greater percent of the administered dose than in the urine. The amounts of CGA 368208 were similar in the feces and urine. Biliary excretion experiments were not performed and, therefore, no assessment can be made regarding biliary or gut microflora as the source of these biotransformation products in the feces.S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **57** of **62** This metabolism study

in rats is **Acceptable/Non -**  **guideline** . Although not satisfying the requirements for a Metabolism and Pharmacokinetics study [OPPTS 870.7485 (85 - 1)], the study was well designed and conducted, and provided supplemental data regarding the quantitation and identification of urinary

and fecal metabolites in rats given a single oral dose of CGA 77102. Ex ecutive Summary : In a metabolism study (MRIDs 44931716 and 44931717), groups of four male and female and six male Tif: RAI f (SPF) rats were given single oral doses of [Phenyl - U 14 C] - CGA - 376944 (0.5 mg/kg nominal; Batch No. ILS - 125.4 radiochemical purity > 95.5%), for the metabolism and bile - duct cannulation studies, respectivel y. There were no deaths or overt signs of toxicity that could be attributed to the test material. Weight loss in bile - duct cannulated rats was attributed to surgical trauma. Radioactivity inventory indicated an acceptable 96.46 - 99.01% recovery of the administered dose among the experimental groups. Based on urinary excretion, biliary

excretion, and carcass burden, 17.35% of the administered radioactivity was absorbed following a sin gle oral dose of 0.5 mg/kg of [Phenyl - U 14 C] - CGA - 376944. Absorption was rapid but limited and most of the absorbed radioactivity

(92.3%) was excreted within 24 hours; primarily in the bile. At 72 hours, measurable radioactivity

was found onl y in the liver of non - cannulated rats. Carcass burdens accounted for <0.01% of the administered dose at necrops y. Fecal elimination was the major route of excretion, accounting for most of the administered oral dose in non - cannulated rats (94.24 - 96.27%). Fecal ex cretion was rapid with 98.8 - 99.2% of the fecal excretion occurring within 24 hours post - dosing. Urinary excretion, accounted for only 2.1 - 4.4% of the dose in non - cannulated rats and 5.3% in bile - duct cannulated rats. Urinary excretion was rapid and nearl y complete within 24 hours of dosing. Biliary excretion repre sented 11.5% of the administered dose at 48 hours. The majority of biliary excretion (99.2%) occurred within 24 hours after dosing. In bile - duct cannulated animals, an additional 76.8% of the administered dose was excreted in the feces. Based on these data, biliary excretion is a contributor to fecal elimination of the test material. This appears consistent with the occurrence of enterohepatic circulation via the hepatic portal sy stem and bi le - duct. Only a minor percentage of the dose (5.3%) appeared to enter the sy stemic circulation where it was rapidly excreted by the kidney s. No biologically relevant gender- related differences were detected in the oral dose groups. Blood pharmacokinetic parameters could not be calculated due to low blood concentrations and rapid clearance of the administered dose. Blood levels of radioactivity peaked in both sexes within one hour post - dosing. It is evident from the results of this study that the test material undergoes limited but rapid absorp tion and nearly

complete excretion within 24 hours. The primary route of excretion is via the feces with biliary

excretion products representing about 15.0% of the fecal excretion pro ducts. At the dose tested , [ 14 C] - CGA - 376944 exhibits little potential for accumulation in the tissues. There were no significant gender- related differences in absorption and disposition of the test material. The unchanged test material accounted for >90% of the dose in both male s and females. The unknown metabolites of urine and feces, separated b y TLC accounted for 0.2 - 2.8% of the administered radioactivity and were not characterized further.S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **58** of **62** This combined metabolism study in rats is **Acceptable/Guideline** and satisfies the requirements for a Metabolism and Pharmacokinetics study [OPPTS 870.7485 (§85 - 1)]. **A.4.9 Immunotoxicity**  **870.7800 Immunotoxicity**  In an immunotoxicity

study (MRID 48783301), S - Metolachlor (98.6% a.i., Lot # CAB9J054) was administrered in the diet for 28 consecutive day s (Day s 0 - 27) to female Crl:CD - 1 (ICR) mice (10 animals/dose) at doses of 0, 1500, 3000 or 5000 ppm (0, 304.3, 639.5 or 1108.5 mg/kg/day , respectivel y). Four day s prior to sacrifice, animals in all groups were immunized with a suspension of sheep red blood cells (SRBC) by intravenous injection (1 x 108 SRBC/animal, 0.2 mL/animal dose volume). Animals in the positive co ntrol group received intraperitoneal injections of cyclophosphamide (50 mg/kg bw/day) on Day s 24 - 27. All animals were evaluated for mortality, clinical signs, body weight changes, and gross pathology . On Day 28, animals were sacrificed and spleens were c ollected. Spleen cell suspensions were prepared, spleen cell counts were performed, and the numbers of specific IgM antibody- forming cells directed towards the SRBC antigen were determined to measure the humoral immune response using the splenic Antibody- Forming Cell (AFC) assay . There were no treatment - relaetd effects on clinical observations, body weigh, body weight gain, food consumption, and spleen or thymus weights. A higher liver weight (absolute and adjusted) was noted at all dosage levels of S - M etolachlor, with significant differences noted in the mid and high doses. The NOAEL for s ys temic toxicity in female mice is 5000 ppm (actual dose of 1108.5 mg/kg/ bw/day); the LOAEL was not determined, tested above the limit dose. For immunotoxicity, th ere were no statistically significant treatment - related effects on anti SRBC AFC response. A high inter- individual variability was noted in all the treatment groups as well as in the control group. Examination of individual animal data did not show any trend or distribution that would demonstrate significant suppression of the anti - SRBC AFC response. The positive control group showed a statistically significant reduction in the anti - SRBC AFC response, confirming the validity of the immunotoxicity

assay . A natural killer (NK) cell activity assay was not performed. The toxicology database for S metolachlor does not reveal any evidence of treatment - related effects on the immune sy stem. The overall weight of evidence suggests that this chemical does not directly target the immune sy stem. Under HED guidance, a NK cell activity assay is not required at this time. **Under the conditions of this study, the NOAEL for immunotoxicity in female mice is 5000 ppm (actual dose of 1108.5 mg/kg/ bw/day). The LOAEL for**  **immunotoxicity was not determined.**  This immunotoxicity

study is classified acceptable/guideline and satisfies the guideline requirement for an immunotoxicity study (OPPTS 870.7800) in the mice.S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **59** of **62**S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **60** of **62** 

### Appendix B . Metabolism	SummaryS - Metolachlor Human Health Risk Assessment DP No. D411153

Page **61** of **62**S - Metolachlor Human Health Risk Assessment DP No. D411153

Page **62** of **62 Appendix C.**  **Physical/Chemical Properties Table C1.**  **Physicochemical Properties of S -**  **Metolachlor.** Parameter Value Reference Melting point/range Not applicable, liquid at room temperature MRID 47121701 (DP#s 332846, etc., 10/21/08, D. McNeilly) pH 7.8 at 25 oC (1% aqueous dispersion) Density 1.117 g/cm3 at 20 oC Water solubility (25°C) 0.48 g/L Solvent solubility (mg/L at 25°C) Com pletely miscible with methanol, acetone, toluene, n - octanol, n - hexane, ethyl acetate, and dichloromethane. Vapor pressure at 25°C 2.8 x 10 - 5 mm Hg Dissociation constant (pKa) No dissociation constant in pH range 2 - 12 Octanol/water partition coefficient Log(KOW) 3.05 at 25 oC UV/visible absorption spectrum 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