### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASIDNGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### :MEMORANDUM

DATE: November 19, 2014



### SUBJECT: Metolachlor and S-Metolachlor

. Human Health Scoping Document in Support of Registration Review.



### PC Code: 108800 (S

- Metolachlor); 

### DP Barcode: 420468 108801 (Metolachlor) 

### Decision No.: 491501 

### Registration Nos.: 100-815, 11603-43, 19 7 13

- 539, 60063

- 17 

### Petition No

. : NA 

### Regulatory Action: Registration Review 

### Case No.: 0001 

### Risk Assessment Type: NA 

### TXRNo.: NA 

### CAS No.: 87392-12-9, 51218

- 45-2 

### MRIDNo.: NA 40 

### CFR: §180.368



### FROM:

THROUGH:

TO: Jessica Kidwell, Risk Assessor

# ~'h**·** (ufl.,ve.Lf SueHummel,Chemist (}

## ~~~ Ivan Nieves, ORE _..../))

_ ·

_ _... Risk Assessment Branch 4 

## U

< 

### Health Effects Division (7509P)



### Elissa Reaves, Ph.D., Branch

# Chief~'& I/ / 2 

# 1 1 '( R1sk Assessment Branch 4

- · Health Effects Division (7509P)

Steven Snyderman, Chemical Review Manager Risk Management and Implementation Branch 3 Pesticide Re-Evaluation Division (7508P)

Attached is RED's human health risk assessment scoping document for metolachlor and S

- metolachlor to support Registration Review.

### Metolachlor/S-Metolachlor Scoping Document D420468

Page 2 of 44 Executive Summary

This document summarizes the review of the He alth Effects Division’s (HED’s) human health assessments to support the Registration Review of metolachlor and S-metolachlor. To determine the scope of work necessary to support Regist ration Review, HED has considered updates to Agency science policy and risk assessment methodol ogies and to the toxic ity, exposure, and usage databases. The most recent HED risk assessment, which included an updated dietary and residential exposure assessment, was conduc ted for S-Metolachlor, PP#2F8115 in 2013, and established higher tolerances for corn forage and stover (D411153, 8/15/2013). The most current occupational risk assessment was conducted in 2010 (D370432; I. Nieves; 6/29/10) to include Smetolachlor new uses on sesame, melon subgrou p 9A, bushberry subgroup 13-07B and lowbush blueberry, caneberry subgroup 13-07A, sweet sorghum, leafy brassica greens subgroup 5B, including turnip greens, carro t, cucumber, okra, onion bulb subgroup 3-07A, and onion green subgroup 3-07B. For metolachlor, the most recen t risk assessment was a 2003 Revised Tolerance Reassessment Eligibility Decision (RED) for metolachlor and S-metolachlor (D288263). Since the risk assessments for either metolachlor or S- metolachlor consider uses, exposure and toxicity of both chemicals, the results of the most recen t risk assessments, which are for S-metolachlor, are presented in this document and are considered reflective of metolachlor.

Metolachlor (PC Code 108801) is a racemic broad spectrum herbicide that consists of 50% each of the R- enantiomer and the S -enantiomer, which is the herbicidally active isomer. S-Metolachlor (PC Code 108800) is an isomer enriched fo rm of metolachlor, comprised of 88% S -isomer and 12% R -isomer. Physical and chemical properties are presented in A ttachment 1. Metolachlor and S-metolachlor are selective, chloroacetanilide herbic ides used primarily for grassy weed control in many agricultural food and feed crop s; residential lawns; commercial turf (including golf courses, sports fields, recreation areas, a nd sod farms); ornamental plants, trees, shrubs, and vines; hedge rows; and horticultural nurseries. Corn, sorghum, and soybean account for the majority of the uses of both metolachlor and S-metolachlor, followe d by cotton, sweet corn, peanut, potato, and other minor field and vegetable crops. In addition, metol achlor, but not S-metolachlor is registered for use on tree nuts (group 14) and dill weed. S-metolachlor but not metolachlor is registered for use on asparagus, garden beets, sugar beets, Bras sica head and stem (subgroup 5A), Brassica leafy greens (subgroup 5B), bushberry (subgroup 13- 07B), caneberry (subgroup 13-07A), carrot, cilantro (coriander), cucumber, leaf petiole s (subgroup 4B), melon (subgroup 9A), onion, bulb (subgroup 3-07A), onion, green (subgroup 3-07B) , pumpkin, sesame seed, sweet sorghum, spinach, winter squash, sunflower, turnip greens, fruiting vegetables (metol achlor is registered for use on tomato only), root vegetables except sugar beets and carrots (subgroup 1B) (metolachlor is registered for use on potato only), and tuberous and corm vegetables (s ubgroup 1C). Application rates for metolachlor and s-metolachlor range from approximately one to four pounds active ingredient (a.i.) per acre. A pplication is typically made pre-emergence, one time per season, although some early post-emergence uses are regi stered, and layby use on peanuts, with split applications preemergence and postemergence.

### Metolachlor/S-Metolachlor Scoping Document D420468

Page 3 of 44 Two sets of toxicology data are available, one for metolachlor and one for S-metolachlor. The existing toxicological database is primarily co mprised of studies conduc ted with metolachlor. The toxicology database for S-me tolachlor consists of bridging data, which include an acute toxicity battery, subchronic toxi city studies in rats and dogs, de velopmental toxicity studies in rats and rabbits, a mutagenicity battery, meta bolism studies and an i mmunotoxicity study. Based on a comparison of findings in the two databa ses by HED’s Hazard Identification Assessment Review Committee (HIARC) as well as th e Metabolism Assessment Review Committee (MARC) (Dobozy, 2001), both in 2001, it was conclude d that S-metolachlor is of comparable toxicity to the racemic mixture, metolachlor, and that studies with both chemicals can be used interchangeably for toxicology endpoint selec tion. The HIARC decisi on regarding toxicology bridging stands will not be re-evaluated in re gistration review. The toxicology database for Smetolachlor, when combined with the metolach lor database, is complete for risk assessment purposes, with the exception of a required 28- day inhalation rat study with metolachlor. Metolachlor was on the Endocrine Disruptor Sc reening Program (EDSP) List 1 and OPP has received all the Tier 1 assays for the EDSP which are current ly under review. The endpoints, Points of Departure (PoDs), and uncertainty/safety factors will be reviewed at the scheduled time of preliminary risk assessment.

S-Metolachlor and metolachlor have low acute toxicity following oral, dermal and inhalation exposures (Toxicity Categories III). Metolachlo r is not irritating to the skin or eyes. S-metolachlor causes slight eye irritation but is non- irritating to the skin. Both are dermal sensitizers. In subchronic (metolachlor and S-me tolachlor) and chronic (metolachlor) toxicity studies in dogs and rats, decr eased body weight and body weight gain were the most commonly observed effects. No systemic toxicity was observed when metolachlor was administered dermally. There is no evidence of neurotoxicity. There was no qualitative or quantitative susceptibility seen in the developmental rat or rabbit studies with metolachlor or S-metolachlor or in the rat two-generation repr oductive toxicity with metolachlo r. The FQPA safety factor was reduced to 1X because there are no residual uncerta inties with regard to pre- and/or postnatal toxicity. There was no evidence of mutagenic or cytogenetic effects in vivo or in vitro

. Metolachlor has been classified as a “Group C, Possible Human Carcinogen” based on liver tumors in rats at the highest dose tested. Quan titative human cancer risk is not required. The chronic Reference Dose (RfD) is prot ective of any potenti al cancer effect.

At this time, the most current risk assessments for S-metolachlor and metolachlor do not indicate risk estimates of concern. The dietary (food and drinking water) exposure assessment did not exceed the level of concern for the general U.S. population, infants, and children. There were no risks of concern for occupationa l (with label-required PPE), re sidential or aggregate exposure risk assessments.

Use Profile

Technicals for metolachlor are registered to Agan Chemical Manufacturing, LTD, Drexel Chemical Company, and Sipcam Agro USA, Inc. S-Metolachlor is registered by Syngenta under the trade names of Dual MAGNUM ® 

### , Pennant MAGNUM ® 

### , Bicep MAGNUM ® 

### , Boundary ®



### , and Medal ® 

### . Syngenta does not currently hold any active end-use product registrations for metolachlor.

### Metolachlor/S-Metolachlor Scoping Document D420468

Page 4 of 44 Metolachlor and S-metolachlor are formulated ma inly as an emulsifiab le concentrates. Other formulations include flowable concentrates, granular, pressurized liquid and ready-to-use formulations. Application methods for agricultural uses include pr imarily broadcast applications (includes ground and aerial), irrigation system s, and chemigation (center pivot only). A backpack sprayer, hose-end sp rayer, or handgun application may be used by professional applicators for application to resi dential lawns or turf. Residentia l applications to lawns and turf are intended for use by profe ssional applicators only.

Hazard Identification/Toxicology

Two sets of toxicology data are available, one for metolachlor and one for S-metolachlor. The existing toxicological database is primarily co mprised of studies conduc ted with metolachlor. Based on the 2001 Hazard Identification Asse ssment Review Committee (HIARC) and MARC decisions that metolachlor and s-metolachlor ar e of comparable toxici ty, studies of either chemical were used interchangeably for toxicology endpoint se lection (TXR No.001469, D274326). Bridging toxicology data from S-metol achlor, including acute toxicity, subchronic toxicity studies in rats and dogs, developmental toxicity studies in rats and rabbits, mutagenicity, metabolism, and immunotoxicity studies ar e available. The toxicology database for S-metolachlor, when combined with the metolachlor database, is complete for risk assessment, with the exception of a required 28-day inhalation study in rats with metolachlor (Guideline No. 870.3465). The Hazard Science Policy Council (HAS POC) evaluated the 2007 toxicology data requirements and based on a weight of eviden ce consideration granted a waiver for the neurotoxicity battery (acute and subchronic) bu t required a 28-day repeated exposure inhalation toxicity study in rats with metolachlor to asse ss risk via the inhalation route from occupational and residential uses (TXR No. 0056586). All su bmitted studies are detailed in the attached toxicology tables (See Attachment 2).

S-Metolachlor and metolachlor have low acute toxicity following oral, dermal and inhalation exposures (Toxicity Categories III). Metolachlo r is not irritating to the skin or eyes. S-metolachlor causes slight eye irritation but is non- irritating to the skin. Both are dermal sensitizers. In subchronic (metolachlor and S-me tolachlor) and chronic (metolachlor) toxicity studies in dogs and rats, decr eased body weight and body weight gain were the most commonly observed effects. No systemic toxicity was observed when metolachlor was administered dermally. No neurotoxicity studies with metolach lor or S-metolachlor are available. However, there was no evidence of neurotoxic effects in adult animals in availabl e subchronic and chronic toxicity studies. Prenatal deve lopmental studies in the rat and rabbit with both metolachlor and S-metolachlor revealed no evidence of a qualitative or quantitative susceptibility in fetal animals. A two-generation reproduction study with metolachlor in rats show ed no evidence of parental or reproductive toxicity. The FQPA safety factor wa s reduced to 1X because there are no residual uncertainties with regard to pre- and/or postnatal toxicity.

There was no evidence of mutagenic or cytogenetic effects in vivo or in vitro . Metolachlor has been classified as a Group C, possible human carcinogen based on liver tumors in rats at the highest dose tested. A linear risk assessment is not required. The chronic RfD is protective of any potential cancer effect. EPA has concluded that metolachlor does not have a common mechanism of carcinogenicity with acet ochlor and alachlor which ar e structurally similar.

### Metolachlor/S-Metolachlor Scoping Document D420468

Page 5 of 44 Dose Response Assessment

Toxicological endpoints were sel ected for dietary/drinking water, occupational and residential exposure scenarios (See Attachment 3). An acu te reference dose (aRfD= 3.0 mg/kg/day) for assessment of food and drinking wa ter exposures was selected from a developmental toxicity study in rats with metolachlor (NOAEL = 300 mg/kg/day). A chr onic RfD (cRfD= 0.097 mg/kg/day) was selected from a chronic toxicity study in dog s with metolachlor (NOAEL = 9.7 mg/kg/day). Since the Food Quality Protection Act (FQPA) Safety Factor (SF) is not retained (i.e., 1x), the acute and chronic Population Adjusted Doses (PADs) are equivalent to the acute and chronic RfDs, respectively. A short-term inci dental oral point of departure (POD) (NOAEL = 50 mg/kg/day) was selected from a developmenta l toxicity study in rats with S-metolachlor. A POD for dermal exposure was not selected because no dermal or systemic toxicity was seen in rabbits following repeated dermal application at the highest dose tested for 21 days with metolachlor. A short-term inhalation exposur e POD (NOAEL = 50 mg/kg/day) was selected from a developmental toxicity st udy in rats with S-metolachlor. An intermediate-term inhalation exposure POD (No Observed Adverse Effect Le vel (NOAEL) = 8.8 mg/kg/day) was selected from a subchronic toxicity study in dogs with meto lachlor. For assessing ri sk via incidental oral exposure, the Level of Concern (LOC) is a ta rget Margin of Exposure (MOE) of 100 which includes the conventional 10x for interspecies extr apolation and 10x for intraspecies variation. For assessing risk via inhalation exposure, the LOC is a target MOE of 1000 which includes the conventional 100 and a 10X databa se uncertainty factor (UF DB 

### ) for the lack of a repeated exposure inhalation study.

Metolachlor is on EDSP List 1 and EPA has received all the required Tier 1 assay data. The Agency is currently reviewing all of the assay data for metolachlor and planning to make the conclusions of those reviews available in early 2015. The endpoints, PODs, and uncertainty/safety factors will be reviewed at the scheduled time of preliminary risk assessment.

Conclusions: The toxicology database for S-metolachlor, when combined with the metolachlor database, is complete for risk assessment pur poses, with the exception of a required 28-day inhalation study in rats with me tolachlor (Guideline No. 870.3465).

Residue Chemistry

The qualitative nature of the residue of meto lachlor including S-metolachlor in plants and livestock is adequately underst ood. Residues of concern in plants , livestock, and rotational cropsinclude metolachlor and its metabolites, determined as the derivatives CGA-37913 and CGA49751. The residue of concern for both metol achlor and S-metolachlor includes both the Risomer and the S-isomer of metolachlor. The Ag ency previously conclude d that the residues of concern for S-metolachlor are the same as fo r metolachlor. The residues of concern for metolachlor and S-metolachlor in drinking wa ter include the parent CGA-51202 (metolachlor oxanilic acid (OA)), CGA40172, and CGA-77102. The te xt of the current tolerance expression is in accordance with our current guidance (S. Knizner, 5/10/2009).

Adequate methodology is available for enforcin g the established and recommended tolerances. PAM Vol. II, Pesticide Regulation Section 180.36 8, lists a gas chromatography with nitrogen-

### Metolachlor/S-Metolachlor Scoping Document D420468

Page 6 of 44 phosphorus detector (GC/NPD) method (Method I) for determining residues in/on plant commodities and a gas chromatography with ma ss selective detector (GC/MSD) method (Method II) for determining residues in livesto ck commodities. These methods determine residues of metolachlor and its metabolites as either CGA-37913 or CGA-49751 following acid hydrolysis. Adequate data are also available on the recovery of metolachlor through FDA’s Multiresidue Method Testing Protocols which indicat e that metolachlor is completely recovered through Method 302.

Syngenta has proposed a high pressure liquid ch romatography with mass spectroscopy/mass spectroscopy (HPLC/MS/MS) enantiomer-specifi c method for the enforcement of the proposed tolerances, Method 1848-01. The method uses a ch iral HPLC column to separate out the Senantiomers (SYN506357 and SYN508500) of the hydrolysis products CGA-37913 and CGA49751. This method has not been determined to be adequate for enforcement purposes because it monitors only a single ion transition per analyte, and because it measures only the S-isomers of metolachlor hydrolysis products, but could be adapted for enforcement by adding a second ion transition and by measuring bot h the R- and S-isomers.

Several responses were made to the RED requirement for additional clarification of the metolachlor rotational crop study, including a new confined rotational crop study (Soderberg, 2007). The requirement for a confined rotational crop study is satisfied.

The label directions for use are not all supported by residue data. Discre pancies were noted for S-metolachlor on bulb vegetables (shorter PHI th an supported by data), cotton (higher rate), soybeans (higher rate), and tomato (higher rate).

Conclusions: No additional residue chemistry data ar e required for metolachlor/S-metolachlor for Registration Review, except for the cases where discrepancies have been found in the directions for use. In those cases , the use directions must be ch anged to match the residue data submitted or field trial data will be needed for the current directions for use. Residue chemistry data submitted since the RED will be reviewed and relevant tolerances will be reassessed. All use patterns must be examined in detail during re gistration review to ensure that the uses are properly supported by residue data.

Dietary Exposure Including Drinking Water

The most recent dietary exposure assessment was conducted for S-Metolachlor, PP#2F8115, which established higher tolerances for corn forage and stover (D411153, 8/15/2013). This assessment is considered to be reflective of me tolachlor as well since the dietary risk assessment incorporates exposure and toxicity of both S-me tolachlor and metolachlo r. The residue of concern for metolachlor and S-metolachlor in pl ants and livestock including rotational crops for both tolerances and risk assessment is meto lachlor, and its metabolites and degradates convertible to the deriva tives CGA-37913 and CGA-49751.

Environmental fate data indicate that parent metolachlor/S-metola chlor is moderately persistent to persistent. It is mobile to highly mobile in di fferent soils and has been detected extensively in surface water and groundwater. Major degradates identified in groundwater include metolachlor

### Metolachlor/S-Metolachlor Scoping Document D420468

Page 7 of 44 ethanesulfonic acid (ESA) and metolachlor oxani lic acid (OA) in both gr oundwater and surface water. Environmental Fate and Effects Divi sion (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 hum an health risk assessment. These were incorporated directly into the dietary assessment.

On August 20, 2014, the Residues of Concern Knowledge-Base Subcommittee (ROCKS) cochairs informally met with the EFED and HED me tolachlor registration re view teams to discuss potential residues of concern. Four major degradates of metolachlor were identified by the EFED chemical team for the drinking water assessmen t: metolachlor oxanilic acid (metolachlor-OA; CGA-51202), metolachlor ethane sulfonic acid (metolachlor ESA; CGA-354743), CGA40172, and CGA-77102. CGA40172, and CGA- 77102 were not considered as residues of concern in previous drinking water assessments. For a ll future assessments, the ROCKS members recommended excluding the metolachlor-ESA fr om the drinking water assessment since the sulfonic acid is likel y to be significantly less toxic th an the parent compound. The ROCKS members also recommended including the degradates CGA-40172, and CGA-77102, in addition to metolachlor-OA, based on the structural similar ity to parent metolachlor. It should be noted that the concern for CGA-40172 is diminished due to the presence of the carboxylic acid moiety, however, there is insufficient informati on to exclude from the drinking water assessment. Therefore, the ROCKS recommende d the following degradates as residues of concern for drinking water: parent metola chlor, metolachlor-OA, CGA40172, and CGA-77102 (see table below and degradates table in Attachment 1).

Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression

Plants Primary Field Crop metolachlor, and its metabolites and degradates convertible to the derivatives CGA-37913 and CGA-49751 metolachlor, and its metabolites and degradates convertible to the derivatives CGA-37913 and CGA-49751

Rotational Crop metolachlor, and its metabolites and degradates convertible to the derivatives CGA-37913 and CGA-49751 metolachlor, and its metabolites and degradates convertible to the derivatives CGA-37913 and CGA-49751

Livestock Ruminant & Poultry metolachlor, and its metabolites and degradates convertible to the derivatives CGA-37913 and CGA-49751 metolachlor, and its metabolites and degradates convertible to the derivatives CGA-37913 and CGA-49751
Drinking Water Metolachlor, metolachlor-OA, CGA-40172, and CGA-77102 Not Applicable



### For acute and non-cancer chronic exposures, EPA is concerned when estimated dietary risk exceeds 100% of the population adjusted dose (PAD) . Metolachlor is classified as a Group C carcinogen; therefore, no separa te dietary assessment was perfor med for cancer (i.e., the chronic dietary exposure is considered protective for cancer effects). For acute and chronic dietary exposures, an unrefined assessment was conducte d, assuming 100% crop treated, and tolerance

### Metolachlor/S-Metolachlor Scoping Document D420468

Page 8 of 44 level residues. The acute and chronic dietary ri sk estimates are below the Agency’s level of concern for the general U.S. population and a ll population subgroups, with the most highly exposed subgroups being all infants (<1 year ol d) at 1.5% of the acute PAD (aPAD) and 11.6% of the chronic PAD (cPAD).

Conclusions: A new dietary exposure and risk assessmen t will likely be conducted if there are changes to the metolachlor/S-metolachlor toxico logical PODs or UFs or significant changes to the EDWCs based on a new drinking water assess ment. The assessment, if conducted, will use the newest version of the Dietary Exposure Evaluation Model (DEEM) and reflect updated consumption information.

Residential Exposure

The most recent risk assessment (“S-Metolach lor, PP#2F8115. Human Health Risk Assessment for the petition for higher tolerances on Corn, field, forage; Corn, sweet, forage; and Corn, stover”, S. Hummel, D 411153, 8/15/13) reassessed residential exposure to S-metolachlor based on the updated Residential Standard Operating Pr ocedures (SOPs) dated February 2012. Since the maximum use rates and uses are similar between S-metolachlor and metolachlor, and since they share the same toxicological profile, the residential exposure assessment for S-metolachlor is considered to be protective of metolachlor.

S-Metolachlor is not intended for homeowner purchase or use (i.e., used by professional/ commercial applicators). The only potential residential risk sc enario anticipated was postapplication incidental oral e xposure of children playing on tr eated lawns. Although there is possibility of dermal exposure, no risks of concer n were identified in the dermal toxicity study.

S-Metolachlor incidental oral exposure was a ssumed to include hand-to-mouth exposure, objectto-mouth, and soil ingestion oral exposure. No tu rf transferable residue data were used. The maximum application rate used wa s 2.47 lb S-metolachlor/acre.

The residential exposure (absorbed dose) to ch ildren 1-2 years old for combined hand-to-mouth, object-to-mouth, and soil ingest ion oral exposure was calcula ted to be 0.0609 mg/kg/day resulting in an MOE of 820. The MOE from the residential riskscenario for exposure to Smetolachlor were above the target MOE of 100 and, therefore, this exposure scenario was not of

concern.

Since the estimated residential tu rf post-application exposure for residential turf using default Turf Transferable Residue (TTR) values is not minimal in comparison to the level of concern (i.e., the calculated MOE [820] is not greater than 10 times th e level of concern [100 x 10 = 1,000]), future refinements of this post-applica tion exposure for metolachlor/s-metolachlor may be necessary due to increased use of the chemical or advances in EPA risk assessments. Therefore, EPA is requiring the 40CFR TTR data require ment (Guideline No. 875.2100) to facilitate any necessary exposure a ssessments refinements and to further EPA’s general understanding of the av ailability of turf transferable pesticide residues.

### Metolachlor/S-Metolachlor Scoping Document D420468

Page 9 of 44 Residential exposure is considered to be short-term in duration. Furthermore, since residents are not expected to re-enter treated areas until the spray has dried (as labeled), no inhalation exposure was assessed. Residential bystander ex posures resulting from off-site transport (e.g., spray drift or volatilization) may occur as a result of applications of S-metolachlor. The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pe sticide will be considered concurrently. The approach is outlined in the revised (2012) SOPs for Residential Risk Assessment – Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantific ation of indirect non-occupationa l exposure to drift. In terms of volatilization, the agency has developed a Vo latilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/ #!docketDetail;D=EPA-HQOPP-2014-0219 )

. During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is required for S-metolachlor/metolachlor.

Conclusions: The residential exposure risk assessment did not identify risks of concern in 2013 using the updated (2012) HED ’ s Residential SOPs 1 

### and policy changes for body weight assumptions and the most current toxicological data and PODs. However, since a TTR study and a 28-day inhalation toxicity study are required, th e residential exposure risk assessment may be updated during registration review. The need for spray drift and vol atilization risk assessment for S-metolachlor will be examined during the registration review process as well

. Aggregate Risk Assessment

In the 2013 risk assessment, aggr egate exposure assessments were performed for acute aggregate exposure (food + drinking water only), chronic aggregate exposure (food + drinking water only), and short-term exposure (residentia l incidental oral + dietary). A separate cancer aggregate risk assessment was not performed because, for S-me tolachlor, the chronic reference dose is considered protective of cancer effects.

No aggregate risks of concern were identified.

Conclusions: There were no aggregate risks of concer n identified in the 2013 assessment. During Registration Review, updated aggregate asse ssments may be conducted as required to include any significant change th at might occur for toxicological PODs, FQPA and uncertainty factors, dietary exposure estimates or EDWCs. Emerging policies related to pesticide drift and volatilization assessments may dictate further cha nges to the existing aggr egate risk assessment.

Occupational Exposure

S-Metolachlor and Metolachlor ar e registered 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. Formulations in clude emulsifiable and flowable concentrates, granular, and ready-to-use pr oducts. Application methods for agricultural uses include ground,

1 Available: http://www.epa.gov/pesticides/scien ce/residential-exposure-sop.html

### Metolachlor/S-Metolachlor Scoping Document D420468

Page 10 of 44 aerial, irrigation and chemigation. Applications to residential lawns or turf are limited to professional applicators using backpack, hos e-end, or handgun sprayers. Based on this chemical’s use pattern, uses were assessed for sh ort-/intermediate-term (i.e., 1-30 days or up to 6 months) durations for exposure via the dermal and inhalation routes during mixing, loading, applying, and post-appli cation activities.

The most current occupational risk assessment was done in 2010 (D370432; I. Nieves; 6/29/10) to include S-metolachlor new uses on sesame , melon subgroup 9A, bushberry subgroup 13-07B and lowbush blueberry, caneberry subgroup 13- 07A, sweet sorghum, leafy brassica greens subgroup 5B, including turnip greens, carrot, cucumber, okra, onion bulb subgroup 3-07A, and onion green subgroup 3-07B. Since the maximum us e rates and uses are similar between Smetolachlor and metolachlor, and since they share the same toxi cological profile, the occupational exposure assessment for S-metolach lor is considered to be protective of metolachlor. The 2010 assessment did not indicate risk estimates of concern to handlers with label-required personal protectiv e equipment (PPE) which include d long-sleeved shirt and long pants, shoes plus socks, and chemical-resistant gloves.

Since there are no dermal endpoints of concer n, post-application derm al exposure was not examined for occupational uses

. Furthermore, EPA is waiving the 40CFR Dislodgeable Foliar Residue (DFR) data requirement as chemical-speci fic DFR data would not be needed to further refine exposure assessments nor would it add appreciably to our overall understa nding of the availability of dislodgeable foliar pesticide residues for metolachlor/s-metolachlor. Based on the Agency's current practices, a quant itative post-application inhalation exposure assessment was not performed for S- metolachlor at this time. However, volatilization of pesticides may be a potential source of post-app lication inhalation exposure to individuals nearby to pesticide applications. A st udy published in the Journal of E nvironmental Quality, Volume 38, September-October 2009, pages, 1785-1795, “Soil Moisture and Metola chlor Volatilization Observations over Three Years” demonstrated that metolachlor’s volatilization potential significantly increases with increasing surface so il water content. Furthermore, the Agency sought expert advice and input on is sues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rode nticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SA P/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and ma y, as appropriate, developing policies and procedures, to identifying the need for and, subs equently, the way to inco rporate post-application inhalation exposure into the Agency 's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative post-application inhalation exposure assessment for S- metolachlor.

The restricted entry interval (REI) is based on the acute toxicity of S- metolachlor technical material which is classified as Category III a nd IV. Acute toxicity Category III and IV chemicals require a 12 hour REI. Therefore the curre nt 24-hour labeled REI is adequate.

Conclusions: The occupational exposure database is ad equate to support the registration review process for S-metolachlor. Previous occupa tional handler and post- application exposure

### Metolachlor/S-Metolachlor Scoping Document D420468

Page 11 of 44 assessments did not identify risks of concern. Registration review may include updated handler and post-application risk estimat es based on current policies.

Public Health and Pesticide Epidemiology Data

For this evaluation, both the O PP Incident Data System (IDS) from 2006 to 2014 and the Centers for Disease Control and Prevention/National In stitute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event No tification System for Occupational Risk-Pesticides (SENSOR) databases from 1998 to 2010 were consulted for pestic ide incident data on the active ingredient metolachlor (pc codes: 108801, 108800) (D420801). The purpose of the database search is to identify potential patterns in the frequency and severity of the health effects attributed to metolachlor exposure. Metolachlor is included in the Agricultural Health Study (AHS), and, therefore, a brief summary of th ese results are included herein.

Conclusion: There does not appear to be a concern at this time that would warrant further investigation, since there is a lo w frequency of reported incidents involving metolachlor reported to IDS from 2006-2014 and SENSOR -Pesticides from 1998-2010. Re search studies within the AHS cohort observed an association between me tolachlor and lung cancer in two separate evaluations. The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the risk assessment.

Tolerance Assessment and International Harmonization

U.S. permanent tolerances are established under 40 CFR §180.368 for the registered uses of metolachlor and S-metolachlor in/on a number of commodities. The tolerance expression is in accord with our current guidance. CODEX has no MRLs for metolachlor or S-metolachlor. The tolerance expression is compatible with the Canadian expression. The United States has a higher tolerance for okra (0.5 ppm vs 0.1 ppm) than Pesticide Management Regulatory Agency (PMRA), as well as for beet, ga rden, leaves (1.8 ppm vs 0.8 ppm), and beet, garden, root (0.5 ppm vs 0.3 ppm), Brassica leafy greens (1.8 ppm vs 0.9 ppm), peppers, non-bell (0.5 ppm vs 0.1 ppm). These should be examined during regist ration review to determine if numerical harmonization is possible.

Conclusion: No changes to tolerances are anticipat ed at the current time. The tolerance expression is in accord with our current guid ance. CODEX has no MRLs for metolachlor or Smetolachlor. The tolerance e xpression is compatible with the Canadian expression. The tolerances should be examined during regist ration review to dete rmine if numerical harmonization is possible.

Environmental Justice

Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human health risk assessment, in accordance w ith U.S. Executive Order 12898, "Federal Actions to Address Environmental Just ice in Minority Populations an d Low-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 c onsumer subgroups according to well-established

### Metolachlor/S-Metolachlor Scoping Document D420468

Page 12 of 44 procedures. In line with O PP policy, HED estimates risks to population subgroups from pesticide exposures that are ba sed on patterns of that subgrou p’s food and water consumption, and activities in and around th e home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the United States Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey (NHANES), What We Eat in America (NHANES/WWEIA) and are us ed in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age and ethnic group. 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 on home use of pesticide products and associated risks for adu lt applicators and for ch ildren, youths, and adults entering or playing on treated ar eas following application are eval uated. Further considerations are currently in development as OPP has committ ed resources and expertise to the development of specialized software and models that consid er exposure to bystanders and farm workers as well as lifestyle and traditional di etary patterns among specific subgroups.

Cumulative

Unlike other pesticides for which EPA has fo llowed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to metolachlor/S-metolachlor and any other s ubstances. Metolachlor/S- Metolachlor does not appear to produce a toxic metabolite produced by other substances. Therefore, EPA has not assumed that metolachlor/S-metolachlor has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate th e cumulative effects of such chemicals, see the policy statements released by EPA’s OPP con cerning common mechanism determinations and procedures for cumulating effects from subs tances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/

.

Human Studies

Past metolachlor/S-metolachlor risk assessments rely in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure. These data, which include studies from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Re-entry Task Force (ARTF) database; and other registrant-submitted exposure monitoring studies , are subject to ethics review pursuant to 40 CFR 26, have received that revi ew, and are compliant with app licable ethics requirements. For certain studies that review may have included review by th e 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 and http://www.epa.gov/pesticides/scien ce/post-app-exposure-data.html.

Data Deficiencies and Risk Assessme nt Updates for Registration Review

 Residue Chemistry: There are no residue chemistry datadeficiencies for metolachlor/Smetolachlor, except where use patterns do not match the submitted residue data. In those

### Metolachlor/S-Metolachlor Scoping Document D420468

Page 13 of 44 cases, the use pattern can be changed or additional field trial data can be submitted. Residue chemistry data submitted since the RED will be reviewed and relevant tolerances will be reassessed. Analytical reference standards are required to be submitted to the pesticide repository now and as re quested by the repos itory staff.

 Toxicology: A 28-day inhalation toxicity study (Guideline No. 870.3465) for metolachlor is a data gap. A new endpoint selection ma y be needed for registration review. A 10X database uncertainty factor will be applied on ly for assessing risk for inhalation scenarios until receipt and evaluation of the data gap.

 ORE: A Turf Transferable Residue (TTR) st udy (Guideline No. 875.2100) is required for the residential exposure risk assessment.

 A new dietary exposure and risk assessment will likely be conducted if there are changes to the metolachlor/S-metolachlor toxicological points of departure (PODs) or Uncertainty Factors (UFs) or significant changes to the Estimated Drinking Water Concentrations (EDWCs). The assessment, if conducted, will use the newest version of DEEM and reflect updated consumption information.

 Updated occupational/resident ial exposure and risk assessments may be conducted if there are any significant changes to meto lachlor/S-metolachlor PODs, Food Quality Protection Act safety factor or other uncerta inty factors, standard operating procedures, or exposure data or assumptions. The need for spray drift an d volatilization risk assessment for S-metolachlor will be examined during the registration review process as well

.

### Metolachlor/S-Metolachlor Scoping Document D420468

Page 14 of 44 References

Table 1. Memoranda Releva nt to Registration Review.

Author Barcode Date Title
Collantes, M. D296725 4/10/2006 S- Metolachlor: Occupational Exposure Assessment. EPA Memorandum.

Dapson, S and Rinde, E. TXR No. 0011347 11/16/1994 Carcinogenicity Peer Review of Metolachlor (4 th 

### )

Dobozy, V. D274326 8/28/2001 Metolachlor and s-Metolachlor. Results of the Health Effects Division (HED) Metabolism Assessment Review Committee (MARC) Meeting Held on 14-August-2001. PC codes: 108801 and 108800. EPA Memorandum.
Dobozy, V. TXR No. 0014691 9/28/2001 Metolachlor and S-Metolachlor: Report of the Hazard Identification Assessment Review Committee (HIARC)

EPA -- 2/2012 Residential SOPs. Available athttp://www.epa.gov/pesticides/science/residentialexposure-sop.html
Evans, E. and Recore, S D420801 9/16/2014 Metolachlor: Tier 1 Review of Human Incidents

Hummel, S. D407466. 8/1/2013 S-Metol achlor. Petition for the Amendment ofPermanent Tolerances for Residues of SMetolachlor on Corn, field, forage; Corn, sweet, forage; and Corn, stover. Summary of Analytical Chemistry and Residue Data. EPA Memorandum. PP#2F8115.

Hummel, S. D411153 8/15/2013 S-Metolachlor. Human Health Risk Assessment for the petition for higher tolerances on Corn, field, forage; Corn, sweet, forage; and Corn, stover. PP#2F8115
Kinard, S. D288263 2/12/2003 Metolachlor: Revised HED Science Assessment for the Tolerance Reassessment Eligibility Decision, Including the Pending Petitions on Asparagus, Carrot, Horseradish, All Peppers, Rhubarb, Sugar Beet, Sunflower, Swiss Chard, Tomato, Spinach, and Grasses Grown for Seed. PP#s: 7F04897, 9E06055, 7E04916, 2E06374, 4E04420, 8E05029,
Kinard, S. DP Barcode D292881; Rereg. Case 0001.D25548 8/15/2003 Revised Metolachlor and S-Metolachlor Residue Chemistry Chapter for the Tolerance Reassessment Eligibility Decision (TRED) and Registration for Use on Asparagus, Carrots, Cotton, Horseradish,

### Metolachlor/S-Metolachlor Scoping Document D420468

Page 15 of 44 Table 1. Memoranda Releva nt to Registration Review.

Author Barcode Date Title

4, D258813, D258816, D258825, D258958, D259117, D280858, D288570. Green Onions, Peppers, Rhubarb, Sugar Beet, Sunflower, and Swiss Chard. EPA Memorandum. PP#s: 7F04897, 9E06055, 7E04916, 2E06374, 4E04420, 8E05029, and 8E05030

Koper, C. D368735 4/22/2010 Drinking Water Assessment for S-Metolachlor and its Degradates Ethanesulfonic Acid (ESA) and Oxanilic Acid (OA) for Various Crop Uses.” EPA EFED Memorandum.

Nieves, I D370432 6/29/2010 S-Metolach lor: Occupational and Residential Exposure/Risk Assessment of Proposed Section 3 uses on sesame, melon subgroup 9A, bushberry subgroup 13-07B and lowbush blueberry, caneberry subgroup 13-07A, sweet sorghum, leafy brassica greens subgroup 5B, including turnip greens, carrot, cucumber, okra, onion bulb subgroup 3-07A, and onion green subgroup 3-07B
Soderberg, D D341704 11/27/2007 Metolachlor: A Confined Rotational Crop Study with [Phenyl-14C]-Metolachlor Using Radish, Lettuce and Wheat. Final Report.
Van Alstine, Julie N/A 3/20/2013 Metolachlor: Summary of Hazard and Science Policy Council (HASPOC) Meeting of February 14, 2013: Recommendations on the Need for a Neurotoxicity Battery, a Developmental Neurotoxicity Study, and a Subchronic Inhalation Study.” EPA Memorandum.



### Attachments

Attachment 1. Chemical Identity of Meto lachlor and S-Metolachlor and Degradates Attachment 2. Toxicity Profile Tables Attachment 3. Metolachlor/S-Metolachlor Endpoints and Doses for Risk Assessment Attachment 4. Metolachlor and S-Metolach lor International Residue Limits Table

### Metolachlor/S-Metolachlor Scoping Document D420468

Page 16 of 44 Attachment 1. Chemical Identity of Met olachlor/S-Metolachlor

Chemical Identity and Physicochemical Properties Table

The chemical structure and nomenclature of S-metolachlor and its regulated hydrolytic derivatives are presented in Table A1.1a. The chemical structure and nomenclature of metolachlor and its regulated hydrolytic derivatives are presented in Table A1.1b.

Table A1.1a Nomenclature of S-Metolachlor a nd its Regulated Hydrolytic Derivatives.

Parent compound

Common name S-Metolachlor

Company experimental name CGA-77102 (R-Metolachlor is CGA-77101)

IUPAC name (S)-2-chloro-N-(2-ethyl-6-methyl-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

Company experimental names CGA-37913
SYN506357 (S-enantiomer of CGA 37913)

Chemical name 2-[(2-ethyl-6-methylphenyl) amino]-1-propanol C H

3

CH 3 N O CH 3

Cl C H 3

O

C H

3 NH CH 3
O H

CH 3

### Metolachlor/S-Metolachlor Scoping Document D420468

Page 17 of 44 Table A1.1a Nomenclature of S-Metolachlor a nd its Regulated Hydrolytic Derivatives.

CAS registry number 61520-53-4
82508-08-5 (S-enantiomer)

Regulated residue

Common name None

Company experimental names CGA-49751
SYN508500 (S-enantiomer of CGA 49751)

Chemical name 4-(2-ethyl-6-methylphenyl)-2-hydroxy-5-methyl-3-morpholinone

CAS registry number 61520-54-5



### TABLE A1.1b Metolachlor Te st Compound Nomenclature.
Compound

Common name Metolachlor Company experimental name Not applicable
IUPAC name 2-chloro- N -(6-ethyl- o -tolyl)- N -[(1 RS )-2-methoxy-1-methylethyl]acetamide

or ( aRS ,1 RS )-2-chloro-6 ′ -ethyl- N -(2-methoxy-1-methylethyl)acet- o -toluidide CAS name 2-chloro-N-(2-ethyl-6-methylpheny l)-N-(2-methoxy-1-methylethyl)acetamide CAS registry number 51218-45-2 End-use product (EP) Stalwa rt® Herbicide (EPA Reg. No. 60063-34; 8 lb/gal EC) Compound

Common name CGA-49751 C H

3 CH 3 N O

O OH

C H

3

C

H

3 N O

Cl CH 3
O C H

3

CH 3

C H

3 CH 3 N O

O OH

C H

3

### Metolachlor/S-Metolachlor Scoping Document D420468

Page 18 of 44 TABLE A1.1b Metolachlor Te st Compound Nomenclature.
Chemical name 4-(2-eth yl-6-methylphenyl)-2-hydroxy-5-methyl-3-morpholine CAS registry number 61520-54-5 Compound

Common name CGA-37913 Chemical name 2-[(2-ethyl-6-m ethylphenyl)amino]-1-propanol CAS registry number 61520-53-4 C H 3 NH CH 3
O H

CH 3Metolachlor/S-Metolachlor Scoping Document D420468Page19of44Table 2. Metolachlor/S-Metolachlor and Its Environmental DegradatesCode Name/SynonymChemical NameChemical StructureStudy TypeMRIDMaximum Formation(% Applied)ParentMetolachlor(CGA-24705)CAS Name:(R)2-Chloro-N-(2-ethyl-6-methylphenyl)-N-(2-methoxy-1-methylethyl) acetamideCAS Number:051218-45-2Molecular Weight:283.80g/molChemical Formula:C15H22NO2ClSMILES:CCC1=CC=CC(=C1N(C(C)COC)C(=O)CCl)CParent structure shown for referenceS-Metolachlor(CGA-77102)CAS Name:(S)-2-Chloro-N-(2-ethyl-6-methylphenyl)-N-(2-methoxy-1-methylethyl) acetamideCAS Number:087392-12-9Molecular Weight:283.80g/molChemical Formula:C15H22NO2ClSMILES:CCC1=CC=CC(=C1N([C@@H](C)COC)C(=O)CCl)CParent structure shown for referenceMetolachlor/S-Metolachlor Scoping Document D420468Page20of44Code Name/SynonymChemical NameChemical StructureStudy TypeMRIDMaximum Formation(% Applied)Transformation ProductsMetolachlorOxanilic Acid/Metolachlor-OA(CGA-51202)CAS Name:[(2-ethyl-6-methylphenyl) (2-methoxy-1-methylethyl) amino]oxo-acetic acidMolecular Weight:389.06g/molAqueous Photolysis 404302023.54Aerobic Soil Metabolism 4549960611.3 (day 48)Aerobic Soil Metabolism 4392893610.3 (day 21, met)10.9 (day 21, S-met)Aerobic Soil Metabolism31309801A-B28.09 (day 90)Anaerobic SoilMetabolism31309801A-B23.33 (day 29)Terrestrial FieldDissipation458480013.0% of applied S-metolachlor at 93 daysin 0-15 cm soil depth.Metolachlorethane sulfonicacid/MetolachlorESA(CGA-354743)CAS Name:Not assignedI found2-((2-ethyl-6-methylphenyl)(2-methoxy-1-methylethyl)amino)-2-oxoethanesulfonic acidhttp://sitem.herts.ac.uk/aeru/iupac/1031.htmMolecular Weight:329 g/molAerobic Soil Metabolism 4549960611.6 ( day 33)Aerobic Soil Metabolism 4392893610.7 (day 60, met)12.4 (day 60, S-met)Terrestrial FieldDissipation458480012.8% of applied Smetolachlor at 93 daysin 0-15 cm soil depthCGA-41507 CAS Name:Not assignedAerobic AquaticMetabolism411857013.34 (day 29)Metolachlor/S-Metolachlor Scoping Document D420468Page21of44Code Name/SynonymChemical NameChemical StructureStudy TypeMRIDMaximum Formation(% Applied)Molecular Weight:157 g/molAnaerobic AquaticMetabolism411857014.85 (12 months)CGA-40172 CAS Name:Not assigned (not reported)Molecular Weight:346.03g/molAerobic AquaticMetabolism411857011.13Anaerobic AquaticMetabolism411857015.64 (12 months)Aerobic Soil Metabolism 4549960611.6 (day 19)11.3 (day 48)CGA-41638 CAS Name:Not assigned (not reported)Molecular Weight:346.03g/molAqueous Photolysis 404302023.63Aerobic Soil Metabolism31309801A-B2.06 (day 90)Anaerobic SoilMetabolism31309801A-B8.30 (day 60)CGA-50720 CAS Name:Not assigned (not reported)Molecular Weight:346.03g/molAerobic AquaticMetabolism411857011.17Aqueous Photolysis 404302023.20Aerobic Soil Metabolism31309801A-B14.85 (day 272)Metolachlor/S-Metolachlor Scoping Document D420468Page22of44Code Name/SynonymChemical NameChemical StructureStudy TypeMRIDMaximum Formation(% Applied)Anaerobic SoilMetabolism31309801A-B7.34 (day 60)CGA-37913Anaerobic AquaticMetabolism411857014.28 (6 months)CGA-37735Aerobic Soil Metabolism31309801A-B1.27 (day 30)Anaerobic SoilMetabolism31309801A-B1.25 (day 29)CGA-13656Aerobic Soil Metabolism31309801A-B1.02 (day 1)Anaerobic SoilMetabolism31309801A-B1.46 (day 29)Metolachlor/S-Metolachlor Scoping Document D420468Page23of44Code Name/SynonymChemical NameChemical StructureStudy TypeMRIDMaximum Formation(% Applied)CGA-46129Aqueous Photolysis 404302023.42CGA-46127Aerobic AquaticMetabolism411857011.54Anaerobic AquaticMetabolism411857014.69 (12 months)Note: Bold values denote major (> 10%) degradates.

### Metolachlor/S-Metolachlor Scoping Document D420468

Page 24 of 44 Physical/Chemical Characteristics


### S-Metolachlor is fairly soluble in water (0.48 g/L), and completely miscible with typical pesticide solvents. It has a modera tely low vapor pressure (2.8 x 10 -5 

### mm Hg). It does not dissociate. It has a high octanol-w ater partition coefficient (Log(K OW 

### ) = 3.0 at 25 C), indicating a potential for bioaccumulation or partitioning into human milk. Environmental fate data indicate that parent metolachlor/S-metolachlor is moderately 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 physical-chemical prope rties for S-metolachlor and metolachlor are tabulated in Table A1.2a and A1.2b, respectively.

Table A1.2. Physicochemical Pr operties 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/cm 3 at 20 oC

Water solubility (25°C) 0.48 g/L

Solvent solubility (mg/L at 25°C) Completely 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 (pK a ) No dissociation constant in pH range 2-12

Octanol/water partition coefficient Log(K OW ) 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

### Metolachlor/S-Metolachlor Scoping Document D420468

Page 25 of 44 TABLE 2. Physicochemical Propertie s of Technical Grade Metolachlor

Parameter Value Reference 1
Physical state (color) Liquid (pale yellow to light brown) TRED Product Chemistry Chapter (D274330) Boiling point 100 O C at 0.001 mm mercury. RED pH 7-9 @ 25 O C (1% aqueous dispersion) TRED Product Chemistry Chapter (D274330) Density 1.117 g/mL at 20 O C TRED Product Chemistry Chapter (D274330) Water solubility 0.48 g/L @ 25 O C TRED Product Chemistry Chapter (D274330) Solvent solubility Miscible in xylene, toluene, ethylene dichloride, and cyclohexanone. RED

Vapor pressure 2.8 x 10 -5 mm Hg @ 25 O C TRED Product Chemistry Chapter (D274330) Octanol/water partition coefficient, Log(K OW ) 3.05 @ 25 O C TRED Product Chemistry Chapter (D274330)

### Metolachlor/S-Metolachlor Scoping Document D420468

Page 26 of 44 Attachment 2. Toxicity Profile Tables
A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile - Metolachlor

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral - Rat 00015523 LD 50 = 2780 mg/kg III

870.1200 Acute dermal - Rabbit 00015526 LD 50 = > 10 g/kg III

870.1300 Acute inhalation -Rat 00015535 LC 50 = > 1.75 mg/L III

870.2400 Acute eye irritation - Rabbit 00015528 Non-irritating IV

870.2500 Acute 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 Acute oral - Rat 43928915 LD 50 = 3267 mg/kg
( ♂ ); 2577 mg/kg/day
( ♀ ); 2672 mg/kg/day
(combined) III

870.1200 Acute dermal - Rabbit 43928916 LD 50 = > 2000 mg/kg III

870.1300 Acute inhalation -Rat 43928917 LC 50 = > 2.91 mg/L IV

870.2400 Acute eye irritation - Rabbit 43928918 Slight to moderate conjunctival irritation that cleared in 48 hours III

870.2500 Acute dermal irritation - Rabbit 43928919 non-irritating IV

870.2600 Skin sensitization – guinea pig 43928920 positive

### Metolachlor/S-Metolachlor Scoping Document D420468

Page 27 of 44 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 (rat) 44775401 (1999)

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 (dog) 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/Guideline

870.3200 21-Day dermal toxicity rabbits 41833101 (1987)

0, 10, 100 or 1000 mg/kg/day Systemic NOAEL = 1000 mg/kg/day.
Systemic 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 toxicity in rodents (rat) 00151941 (1985)

0, 30, 100, 300 or 1000 mg/kg/day Maternal toxicity NOAEL = 300 mg/kg/day.
Maternal 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/or ex cessive lacrimation) and decreased body weight gain.
Developmental toxicity NOAEL = 300 mg/kg/day Developmental toxicity LOAEL = 1000 mg/kg/day based on slightly decreased number of implantations per dam, decreased number of live fetuses/dam, increased number of resorptions/dam and significant decrease in mean fetal body weight
Acceptable/Guideline

### Metolachlor/S-Metolachlor Scoping Document D420468

Page 28 of 44 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Metolachlor

Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.3700b Prenatal developmental in (New Zealand White) rabbits 00041283 (1980)

0, 36, 120 or 360 mg/kg/day Maternal toxicity NOAEL = 120 mg/kg/day.
Maternal toxicity LOAEL = 360 mg/kg/day based on an increased incidence of clinical observations (persistent anorexia) and decreased body weight gain
Developmental toxicity NOAEL = 360 mg/kg/day
Developmental 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 = 300 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 (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. 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 gain
NOAEL = 1000 ppm (32.7 mg/kg/day).

LOAEL for males was not established;
Acceptable/Guideline

### Metolachlor/S-Metolachlor Scoping Document D420468

Page 29 of 44 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Metolachlor

Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.4200 Chronic toxicity/
Carcinogenicity

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 ad enomas and combined adenoma/carcinoma in female rats. In male rats, there was a statistically 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 incide nce of mutations in the presence or absence of metabolic activation
Acceptable/Guideline

870.5395 Cytogenetics

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 Cytogenetics dominant lethal assay in mice 00015630 (1978)
100 or 300 mg/kg No effect on embryonic death, pre- and postimplantation or fertility rates in mated females
Acceptable/Guideline

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Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

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 Damage/Repair in human fibroblasts 00142827

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

870.5550 Other Effects

Unscheduled DNA synthesis 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 Sphase 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 Urinary metabolites of CGA 24705 (N-(2-methoxy-1-methylethyl)-2-ethyl-6-methylchloroacetanilide) were identified following oral administration of 52 mg/kg, 28 mg/kg, and 33 mg/kg to male rats. Two metabolites, each comprising approximately 5% of chloroform extractable urinary radioactivity, were identified from oral administration of CGA 24705.
The major metabolic pathway proposed from analysis of urinary as well as fecal metabolites is one of cleavage 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 glucuronic acid or sulfate does not appear to occur.
Current guidelin e recommendations as to dose levels and use of both sexes in metabolism studies were not followed. Thus, whether the metabolic pattern is altered with dose or repeated exposure cannot be evaluated from these data.
Unacceptable/Non-guideline

870.7485 Metabolism and pharmacokinetics 40114401 (1987) 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 readily

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Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

Single low (1.5 mg/kg), 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.
Relatively low levels of radioactivity were present in the tissues of all animals at 7 days postdosing.
Unacceptable/Non-guideline

870.7485 Metabolism and pharmacokinetics 43164201 (1992)
low oral dose (1.5 mg/kg x 14 days), and a single high dose (300 mg/kg) Comparison of oral and intravenous data showed that of the admi nistered 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 rout es for elimination of metolachlor derived radioactivity
Metabolism of metolachlor in this study was complex, with up to 32 metabolites identified in urine and/or feces.
Acceptable/Guideline

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Page 32 of 44 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – S-Metolachlor

Guideline No. Study Type MRID No. (year)/ Classification /Doses

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 ef ficiency 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/Non-guideline

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 NOAEL = 50 mg/kg/day
LOAEL = 500 mg/kg/day based on increased clinical signs of toxi city, 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/Guideline

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 NOAEL = 20 mg/kg/day
LOAEL = 100 mg/kg/day based on clinical signs of toxicity.
Developmental NOAEL = 500 mg/kg/day, highest dose tested.

LOAEL = Not established
Acceptable/Guideline

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Page 33 of 44 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – S-Metolachlor

Guideline No. Study Type MRID No. (year)/ Classification /Doses

870.5100 Gene Mutation

Salmonella & Escherichia/Mam malian 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 cytotoxic for S. typhimurium TA1535, 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 presence or the absence of S9 activation.
Acceptable/Guideline

870.5395 Cytogenetics 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 contro l induced the expected high yield of MPEs in males and females. 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/Guideline

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Page 34 of 44 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – S-Metolachlor

Guideline No. Study Type MRID No. (year)/ Classification /Doses

870.5550 Other Effects Unscheduled DNA synthesis 43928928 (1995)

500, 1500, 3200 (females), 5000 (males) mg/kg CGA 77102 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/Guideline

870.7485 Metabolism and pharmacokinetics 44491401 (1996)
single dose of 0.5 (group B1) or 100 mg/kg (groupD1) radiolabeled CGA77102; 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-77102 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%.
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.
Acceptable/Guideline

870.7485 Metabolism and pharmacokinetics 44491402 (1996)
single dose of 0.5 (group B1) or 100 mg/kg (groupD1) radiolabeled CGA77102; 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-77102 for bile-cannulation study (from MRID 44491401)
single oral low dose (0.5 mg/kg, Group B2) of [Phenyl-U- 14 C] CGA24705 (R/S-Metolachlor, racemate) The 72 hour mean recove ry 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 me tabolite 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.

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Page 35 of 44 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – S-Metolachlor

Guideline No. Study Type MRID No. (year)/ Classification /Doses

The results clearly show that the metabolite profile in excreta and bile fluid is very complexand that Metolachlor (racemate or Senantiomer) is extensively metabolized.
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/Guideline

### Metolachlor/S-Metolachlor Scoping Document D420468

Page 36 of 44 Attachment 3. Metolachlor/S-Metolachlor En dpoints and Doses for Risk Assessment
The points of departure, uncertain ty factors, and toxicity endpoi nts are presented in the following tables. No endpoint is selected for dermal expos ure scenarios. No hazard was identified at the maximum dermal dose tested.

Table 4.5.4.1. Summary of Toxico logical Endpoints for S-metolachlo r/Metolachlor for Use in Dietary Human Health Risk Assessments

Exposure/Scenario Point of Departure Uncertainty/FQP A Safety Factors RfD, PAD, LOC for Risk Assessment Study and Toxicological Effects

Acute Dietary
(General Population) N OAEL = 300 mg/kg/day UF A = 10x

UF H =10x

FQPA SF= 1x Acute 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) N OAEL = 9.7
mg/kg/day UF A = 10x

UF H =10x

FQPA SF= 1x Chronic RfD = 0.097
mg/kg/day

cPAD = 0.097mg/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 nonlinear (Margin of Exposure) approach.

Point of Departure (POD) = A data point or an estimated poin t that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower en vironmentally relevant human
exposures.

NOAEL = no observed adverse effect level. LOAEL = lowest observ ed 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.

### Metolachlor/S-Metolachlor Scoping Document D420468

Page 37 of 44 Table 4.5.4.2. Summary of Toxicological Doses and Endpoints for S-METOLACHLOR for Use in Residential and Occupational Hu man Health Risk Assessments

Exposure/

Scenario Point of Departure Uncertainty Factors Level of Concern for Risk Assessment Study and Toxicological Effects

Incidental Oral Shortterm (1-30 days) N OAEL=
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 food efficiency seen at the LOAEL in maternal animals.

Dermal Short- and Intermediate-Term N o hazard identified 21-day dermal toxicity study – Rabbits
Metolachlor (MRID 41833101)

LOAEL = Not observed

Inhalation Short-Term (1-30 days) N OAEL=
50 mg/kg/day UF A = 10x

UF H =10x

UF D =10x Occupational LOC for MOE = 1000 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 months) N OAEL=
8.8 mg/kg/day UF A = 10x

UF H =10x

UF D =10x Occupational LOC for MOE = 1000 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 nonlinear (Margin of Exposure) approach.

Point of Departure (POD) = A data point or an estimated poin t that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower en vironmentally 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). 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 data (i.e., lack of a critical study). FQPA SF = FQPA Sa fety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

### Metolachlor/S-Metolachlor Scoping Document D420468

Page 38 of 44 Attachment 4. Metolachlor/S-Metolachlor International Residue Limits Table



## International Re sidue Limits

Metolachlor (108801) and S-Metolachlor (PC Code 108800; Date of Request 6/26/14) Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 

### Codex 40 CFR: 180.368

(a)General (1) Tolerances are established for the combined residu es (free and bound) of the herbicide metolachlor, 2-chloro-N- (2- ethyl-6-methylphenyl)-N-(2-methoxy-1- methylethyl)acetamide, and its metabolites,determined as the derivatives, 2- [(2-ethyl6- methylphenyl)amino]-1-propanol and 4- (2-ethyl-6-methylphenyl)-2- hydroxy-5- methyl-3-morpholinone, each expressed as the parent compound 2-chloro-N-(2-ethyl-6-methylphenyl)-N-[(1S)-2-methoxy1-methylethyl)acetamide and 2-chloro-N-(2-ethyl-6- methylphenyl)-N-[(1R)-2- methoxy-1- methylethyl)acetamide, including the metabolites 2-[(2-ethyl-6- methylphenyl)amino]-1-propanol and 4-(2-ethyl-6-methylphenyl)-2- hydroxy-5-methyl-3-morpholinone None



### Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 1 

### Codex Almond, hulls 0.30 Animal feed, nongrass, group 18 1.0

Cattle, fat 0.02 Cattle, kidney 0.20 0.2 Cattle, liver 0.05 0.05 Cattle, meat 0.02 0.02 Cattle, meat byproducts, except kidney and liver 0.04

Corn, field, forage 6.0 Corn, field, grain 0.10 0.1 corn Corn, field, stover 6.0 Corn, pop, grain 0.10 0.1 corn Corn, pop, stover 6.0 Corn, sweet, forage 6.0 Corn, sweet, kernel plus cob with husks removed 0.10 0.1 corn

Corn, sweet, stover 6.0 Cotton, gin byproducts 4.0 Cotton, undelinted seed 0.10 Dillweed 0.50 Egg 0.02 0.02 Goat, fat 0.02 Goat, kidney 0.20 Goat, liver 0.05 Goat, meat 0.02 0.02 Goat, meat byproducts, except kidney and liver 0.04

Grass, forage 10 Grass, hay 0.20 Horse, fat 0.02

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### Codex Horse, kidney 0.20 Horse, liver 0.05 Horse, meat 0.02 Horse, meat byproducts, except kidney and liver 0.04

Milk 0.02 0.02 Nut, tree, group 14 0.10 Okra 0.50 0.1 Peanut 0.20 0.2 Peanut, hay 20 Peanut, meal 0.40 Potato 0.20 0.2 Poultry, fat 0.02 Poultry, meat 0.02 0.02 Poultry, meat byproducts 0.05 0.05 liver of poultry Safflower, seed 0.10 Sheep, fat 0.02 Sheep, kidney 0.20 Sheep, liver 0.05 Sheep, meat 0.02 0.02 Sheep, meat byproducts, except kidney and liver 0.04

Sorghum, grain, forage 1.0 Sorghum, grain, grain 0.30 Sorghum, grain, stover 4.0 Soybean, forage 5.0 Soybean, hay 8.0 Soybean, seed 0.20 0.2 dry soybeans Tomato 0.10 0.1 Vegetable, foliage of legume, subgroup 7A, except soybean 15.0

Vegetable, legume, group 6 0.30 0.3 dry (beans, lima beans) 0.3 edible podded snap beans, peas, succulent shelled lima beans 0.2 dry soybeans

40 CFR 180.368

(2) sum of free and bound S-metolachlor, S2-chloro-N-(2-ethyl-6-methylphenyl)-N-(2-methoxy-1-methylethyl)acetamide, its Renantiomer, and its metabolites, determined as the derivatives, 2-(2-ethyl-6- methylphenyl)amino-1-propanol and 4-(2- ethyl-6-methylphenyl)-2-hydroxy-5- methyl-3-morpholinone, calculated as the stoichiometric equivalent of S-metolachlor Same as above None



### Commodity 1 

### Tolerance (ppm) /Maximum Residue Limit (mg/kg) Asparagus 0.10 0.1 Beet, garden, leaves 1.8 0.8 garden beet tops

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### Codex Beet, sugar, molasses 2.0 Beet, sugar, roots 0.5 0.3 Beet, sugar, tops 15.0 Brassica, head and stem, subgroup 5A 0.60

Brassica, leafy greens, subgroup 5B 1.8 0.9 bok choy Chinese cabbages, broccoli raab collards, kale, mustard greens; mustard spinach; rape leaves Bushberry subgroup 13-07B 0.15 Caneberry subgroup 13-07A 0.10 Carrot, roots 0.40 0.4 Cattle, fat 0.02 Cattle, kidney 0.20 0.2 Cattle, liver 0.05 0.05 Cattle, meat 0.02 0.02 Cattle, meat byproducts, except kidney and liver 0.04

Cilantro, leaves 8.0 Coriander, seed 0.13 Corn, field, forage 40 Corn, field, grain 0.10 0.1 corn Corn, field, stover 40 Corn, pop, grain 0.10 0.1 corn Corn, pop, stover 40 Corn, sweet, forage 40 Corn, sweet, kernel plus cob with husks removed 0.10 0.1 corn

Corn, sweet, stover 40 Cotton, gin byproducts 4.0 Cotton, undelinted seed 0.10 Cucumber 0.13 0.13 Egg 0.02 0.02 Grain, aspirated fractions 0.70 Goat, fat 0.02 Goat, kidney 0.20 Goat, liver 0.05 Goat, meat 0.02 0.02 Goat, meat byproducts, except kidney and liver 0.04

Grass, forage 10.0 Grass, hay 0.20 Horse, fat 0.02 Horse, kidney 0.20 Horse, liver 0.05 Horse, meat 0.02 Horse, meat byproducts, except kidney and liver 0.04

Leaf petioles, subgroup 4B 0.10

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### Codex Melon, subgroup 9A 0.10 0.1 cantaloupe, citron melons, muskmelons (other than those listed in this item), watermelons Milk 0.02 0.02 Okra 0.10 0.1 Onion, bulb, subgroup 3-07A 0.10 Onion, green, subgroup 3- 07B 2.0

Peanut 0.20 0.2 Peanut, hay 20.0 Peanut, meal 0.40 Poultry, fat 0.02 Poultry, meat 0.02 0.02 Poultry, meat byproducts 0.05 0.05 liver of poultry Pumpkin 0.10 0.1 Safflower, seed 0.10 Sesame, seed 0.13 Sheep, fat 0.02 Sheep, kidney 0.20 Sheep, liver 0.05 Sheep, meat 0.02 0.02 Sheep, meat byproducts, except kidney and liver 0.04

Sorghum, grain, forage 1.0 Sorghum, grain, grain 0.3 Sorghum, grain, stover 4.0 Sorghum, sweet, stalk 4.0 Soybean, forage 5.0 Soybean, hay 8.0 Soybean, seed 0.20 0.2 dry soybeans Spinach 0.50 Squash, winter 0.10 0.1 Sunflower, seed 0.50 Sunflower, meal 1.0 Tomato, paste 0.30 Turnip, greens 1.8 Vegetable, foliage of legume, except soybean, subgroup 7A 15.0

Vegetable, fruiting, group 8, except tabasco pepper 0.10 0.1 African eggplants, bell peppers, bush tomatoes, coconas, currant tomatoes, eggplants, garden huckleberries, goji berries, groundcherries, martynias, naranjillas, nonbell peppers, okras, pea eggplants, pepinos, roselles, scarlet eggplants, sunberries, tomatillos, tomatoes, tree tomatoes Vegetable, legume, group 6 0.30 0.3 dry (beans, lima beans) 0.3 edible podded snap beans, peas, succulent shelled lima beans 0.2 dry soybeans

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### Codex Vegetable, root, except sugar beet, subgroup 1B, except
carrot 0.30 0.3 garden beet roots 0.1 rutabaga roots

Vegetable, tuberous and corm, subgroup 1C 0.20 0.2 potatoes, sweet potato roots

MRLs With NO US Equivalent Apples 0.1 Apricots 0.1 Cherries 0.1 Meat of hogs 0.02 Nectarines 0.1 Peaches 0.1 Pears 0.1 Plums 0.1 Strawberries 0.1

Completed: M. Negussie; 07/10/14

1 Mexico adopts U.S. tolerances and/or Codex MRLs for its export purposes.



### Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 

### Codex 40 CFR 180.368 (c) Tolerances with regional registrations (1) Tolerances with regional registration as defined in 180.1(l) are established for the combined residues (free and bound) of the herbicide metolachlor [2-chloro-N-(2- ethyl-6-methylphenyl)-N-(2-methoxy-1- methylethyl)acetamide] and its metabolites, determined as the derivatives, 2-[2-ethyl-6-methylphenyl)amino]-1- propanol and 4-(2-ethyl-6-methylphenyl)-2-hydroxy-5- methyl-3-morpholinone, each expressed as the parent compound, in or on the following raw agricultural commodities: Same as above None



### Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 1 

### Codex Pepper, nonbell 0.50 0.1

### Metolachlor/S-Metolachlor Scoping Document D420468

Page 43 of 44 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 

### Codex 40 CFR 180.368 (c) Tolerances with regional registrations

(2) Compliance with the tolerance levels specified in the following table below is to be determined by measuring only 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-hydroxy-5-methyl-3-morpholinone,calculated as the stoichiometric equivalent of Smetolachlor Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 1 Codex Pepper, tabasco 0.50



### Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 

### Codex (d) Indirect or inadvertent residues.

(1) Tolerances are estab lished for the indirect or inadvertent combined residues (free and bound) of the herbicide metolachlor, 2-chloro-N-(2-ethyl-6- methylphenyl)-N-(2- methoxy-1-methylethyl)acetamide, and its metabolites, determined as the derivatives, 2-[(2- ethyl-6-methylphenyl)amino]-1-propanol and 4-(2-ethyl-6- methylphenyl)-2- hydroxy-5-methyl-3-morpholinone, each expressed as the parent compound None



### Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 1 

### Codex Animal feed, nongrass, group 18 1.0

Barley, grain 0.10 Barley, hay 0.80 Barley, straw 0.80 Buckwheat, grain 0.10 Millet, forage 0.50 Millet, grain 0.10 Millet, hay 0.80 Millet, straw 0.80 Oat, forage 0.50 Oat, grain 0.10 Oat, hay 0.80 Oat, straw 0.80 Rice, grain 0.10 Rye, forage 0.50 Rye, grain 0.10

### Metolachlor/S-Metolachlor Scoping Document D420468

Page 44 of 44 Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 

### Codex Rye, straw 0.80 Wheat, forage 0.50 Wheat, grain 0.10 Wheat, hay 0.80 Wheat, straw 0.80 40 CFR 180.368

(2) Tolerances for are established for the indirect or inadvertent residues of S-metolachlor, including its metabolites and degradates, in or on the commodities identified in the following table below. Compliance with the tolerance levels specified in the following table below is to be determined by measuring only 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-hydroxy-5-methyl-3- morpholinone, calculated as th e stoichiometric equivalent of S-metolachlor 

### Commodity 1 

### Tolerance (ppm) /Maximum Residue Limit (mg/kg) Animal feed, nongrass, group 18 1.0

Barley, grain 0.10 Barley, hay 0.50 Barley, straw 0.50 Buckwheat, grain 0.10 Millet, forage 0.50 Millet, grain 0.10 Millet, hay 0.50 Millet, straw 0.50 Oat, forage 0.50 Oat, grain 0.10 Oat, hay 0.50 Oat, straw 0.50 Rice, grain 0.10 Rye, forage 0.50 Rye, grain 0.10 Rye, straw 0.50 Wheat, forage 0.50 Wheat, grain 0.10 Wheat, hay 0.50 Wheat, straw 0.50 Completed: M. Negussie; 07/10/14

1 Mexico adopts U.S. tolerances and/or Codex MRLs for its export purposes.

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