S-Metolachlor Human Health Risk Assessment DP No. D411153

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

Date: August 15, 2013

SUBJECT: S-Metolachlor, PP#2F8115. Human Health Risk Assessment for the petition for 

higher tolerances on Corn, field, forage; Corn, sweet, forage; and Corn, stover

PC Code: 108800 DP Barcode: D411153

Decision No.: 471357 Registration No.: 100-818

Petition No.: 2F8115 Regulatory Action: Petition, no amended use

Risk Assessment Type: NA Case No.: 0001

TXR 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

Ivan 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 Division, 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 Syngenta 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 Smetolachlor 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 herbicide 

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 currently registered use pattern for 

Dual II Magnum (EPA Reg. No 100-818). Residues of S-metolachlor in some samples of forage 

and stover exceeded the current tolerances.
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TABLE OF CONTENTS

1.0 Executive Summary........................................................................................................... 4

2.0 HED Recommendations.................................................................................................... 8

2.1 Data 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 Database ................................................... 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 Classification 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 Animal 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......................................................................................................... 24
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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 Summaries................................................................................................... 47

Appendix B. Metabolism Summary ......................................................................................... 60

Appendix C. Physical/Chemical Properties............................................................................. 62
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1.0 Executive Summary

Metolachlor (PC Code 108801) is a racemic herbicide that consists of 50% each of the Renantiomer 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 registered to Syngenta 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 

registered 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 

professional 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 registration is requested. The use pattern 

used was the currently 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 stover 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 assessment was required. However, an updated residential exposure assessment was 

conducted, and is included herein, since the Residential SOPs have changed since the last 

residential assessment was conducted in 2002.

Toxicology

The existing toxicological database is primarily comprised of studies conducted with 

metolachlor. However, bridging studies indicate that the metolachlor toxicology database can be 

used to assess toxicity for S-metolachlor. The toxicology database for S-metolachlor, when 

combined with the metolachlor database, is complete for risk assessment purposes, with the 

exception of a required 28 day inhalation study. The neurotoxicity 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 III), inhalation 

(Toxicity Category IV), and dermal (Toxicity Category III) 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 

systemic toxicity was observed when metolachlor was administered dermally. No neurotoxicity

studies with metolachlor or S-metolachlor are available. However, there was no evidence of 

neurotoxic effects in adult animals in available subchronic and chronic toxicity studies. Prenatal 
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developmental studies in the rat and rabbit with both metolachlor and S-metolachlor revealed no 

evidence of a qualitative or quantitative susceptibility in fetal animals. A two-generation 

reproduction study with metolachlor in rats showed no evidence of parental or reproductive 

toxicity. The FQPA safety factor was reduced to 1X because there are no residual uncertainties 

with regard to pre- and/or postnatal toxicity. 

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, metolachlor caused an increase 

in benign liver tumors in rats but this increase was seen only at the highest dose tested and was 

statistically significant compared to controls only in females. There was no evidence of 

mutagenic or cytogenetic 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 effects 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 endpoints 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 highest dose tested for 21 days. A short-term inhalation 

exposure POD (50 mg/kg/day) was selected from 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 (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).

Residue Chemistry

The qualitative nature of metolachlor residues in plants is adequately 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 (metolachlor 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 nitrogenphosphorus detector (GC/NPD) method (Method I) for determining residues in/on plant 

commodities and a gas chromatography with mass selective detector (GC/MSD) method 
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(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 

hydrolysis. 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.

Syngenta has proposed a high pressure liquid chromatography with mass spectroscopy/mass 

spectroscopy (HPLC/MS/MS) enantiomer-specific method for the enforcement of the proposed 

tolerances, Method 1848-01. The method uses a chiral 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.

Adequate field trial data have been submitted with the current petition to support the requested 

tolerances. Geographic representation was adequate. An adequate analytical method was used 

for the analysis. 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 population 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 exposures 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 the most highly exposed subgroups 

being all infants (<1 year old) at 1.5% of the acute PAD (aPAD) and 11.6% of the chronic PAD 

(cPAD). 

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. 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 assessment. 

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 

SCIGROW for ground water. Current NAWQA monitoring data was also used to determine 
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EDWCs. Based on monitoring and modeling data, total EDWCs for peak and average surface 

water respectively are 219 ppb and 119 ppb. Recommended groundwater EDWCs (peak and 

average) are 126 ppb.

Residential Exposure

There are no new residential exposure scenarios for S-metolachlor for the current petition. 

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. 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 

estimated to be 0.0609 mg/kg/day resulting in an MOE of 820. Based on this analysis, the shortterm oral MOEs are not of concern.

Aggregate Risk

The aggregate acute and chronic risk estimates include exposure to residues of S-metolachlor in 

food and drinking water, and does not include dermal, inhalation 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 estimates 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 highly exposed subgroup, all infants (< 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 Smetolachlor. 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 children 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 analysis, short-term 

aggregate MOE of 660 for toddlers is not of concern.

Occupational 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 10x 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. Some of these studies are also subject to review by the 

Human Studies Review Board. All of the studies used have received the appropriate review.

Environmental Justice
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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 Low-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 analytical standards, there are no residue 

chemistry issues that would preclude setting of the recommended tolerances for S-metolachlor 

on corn forage and 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 submissions.

2.1 Data Deficiencies

Analytical reference standards are required to be submitted to the pesticide repository now and as 

requested by the repository staff.

A deficiency remains with regard to the confined rotational crop study. This deficiency has 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 nitrogenphosphorus detector (GC/NPD) method (Method I) for determining residues in/on plant 

commodities and a gas chromatography with mass selective detector (GC/MSD) method 

(Method II) for determining residues in livestock commodities. These methods determine 

residues of metolachlor and its metabolites as either CGA-37913 or CGA-49751 following acid 

hydrolysis. 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.

Syngenta has proposed a high pressure liquid chromatography with mass spectroscopy/mass 

spectroscopy (HPLC/MS/MS) enantiomer-specific method for the enforcement of the proposed 

tolerances, Method 1848-01. The method uses a chiral 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.

2.2.2 Recommended Tolerances

Tolerances are currently 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 only 
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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 S-metolachlor, 

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 MRLs for 

pesticide residues on livestock feed stuffs. There are no Codex MRLs 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 Introduction

3.1 Chemical Identity

The chemical structure and nomenclature of S-metolachlor and its regulated hydrolytic 

derivatives are presented in Table 3.1
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Table 3.1. Nomenclature of S-Metolachlor and 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

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

H3C

CH3

N

O

CH3

Cl

H C3

O

H C3

NH

CH3

HO

CH3

H3C

CH3

N

O

O

OH

H3C
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3.2 Physical/Chemical Characteristics

S-metolachlor is fairly soluble in water (0.48 g/L), and completely miscible with typical 

pesticide solvents. It has a moderately low vapor pressure (2.8 x 10-5 mm Hg). It does not 

dissociate. It has a high octanol-water partition coefficient (Log(KOW) = 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 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; 

Type; and Equip.

(minimum volume)

Formulation

[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 Smetolachlor may be applied directly 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. 
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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 pesticide 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 previously prepared for the existing uses of S-metolachlor. This risk 

assessment considers all of the aforementioned exposure pathways 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 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 consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups 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 analyzed and categorized by subgroups based 

on age, season of the year, 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 on 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 currently in development as OPP has committed resources 

and expertise to the development of specialized software and models that consider exposure to 

bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific 

subgroups.

4.0 Hazard Characterization and Dose-Response 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 pathways 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 the toxicity of S-metolachlor 

for risk assessment purposes. An immunotoxicity study (870.7800) was submitted since the last 

S-metolachlor risk assessment (MRID 48783301).
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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 submitted, but no subchronic 

inhalation study has been submitted. 

The Hazard and Science Policy Council (HASPOC) recently reviewed metolachlor and Smetolachlor (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 intravenous 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 second 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 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). 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 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. 

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 metolachlor or metabolites with 

gluronic acid or sulfate does not appear to occur.

4.2.1 Dermal Absorption

There was no evidence of systemic 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.
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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 systemic 

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 only 

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 statistically 

significant increases in liver adenomas and combined adenomas/carcinomas in female rats. In 

male rats, there was a statistically significant trend but no pair-wise significance for liver tumors. 

There was no evidence of a mutagenic or cytogenetic 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 exhibits low acute toxicity via the oral (Toxicity Category III), inhalation 

(Toxicity Category IV), and dermal (Toxicity Category III) 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 

systemic toxicity was observed when metolachlor was administered dermally. No neurotoxicity

studies with metolachlor or S-metolachlor are available. The HASPOC, based on a WOE 

approach, concluded 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 pregnant rats and is used as the endpoint of concern for assessing acute 

dietary risk; 3) evidence for neurotoxicity (functional/behavioral effects) was seen only 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 

developmental 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, maternal animals had persistent 

anorexia and decreased body weight gain. There were no developmental effects. In the rat 

prenatal developmental toxicity study on metolachlor, death, clinical signs (clonic and/or tonic 

convulsions, excessive salivation, urine-stained abdominal fur and/or excessive salivation) and 

decreased body weight gain was observed at the limit dose in maternal animals. Developmental 
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effects at the limit dose included slightly decreased number of implantations per dam, decreased 

number of live fetuses/dam, increased number of resorptions/dam and 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 animals tested with S-metolachlor. No developmental 

effects were observed at the highest dose tested. 

In the two-generation reproduction study in rats conducted with metolachlor, there was no 

evidence of parental or reproductive toxicity at the highest dose tested (80 mg/kg/day). At this 

dose, there was a minor decrease in fetal body weight beginning at lactation day 4. Since a 

similar body weight decrease was not seen on lactation day 0, the cause of the effect on later 

lactation days 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 Factor 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 available, 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 of the Toxicology Database

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 submitted, but no subchronic 

inhalation study has been submitted. 

The Hazard and Science Policy Council (HASPOC) recently reviewed metolachlor and Smetolachlor (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 exposure scenarios.

4.4.2 Evidence of Neurotoxicity

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 available 
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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 of Sensitivity/Susceptibility in the Developing or 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 maternally toxic doses (1000 

mg/kg/day). 

4.4.4 Residual Uncertainty in the Exposure Database

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 Departure Selections

4.5.1 Dose-Response Assessment

The detailed description of the toxicity 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 

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). 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 

metolachlor/S-metolachlor 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 identified in the chronic feeding 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 

were the most sensitive species and decreased body 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 study
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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 judged 

to be signs of frank toxicity and were appropriate 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 systemic toxicity

was seen in rabbits following repeated dermal application at the highest dose tested for 21 days. 

No inhalation studies 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 appropriate 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 00032174) was identified for the intermediateterm 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 there was no systemic 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 decreased 

body weight/body weight gain in both sexes were observed. In the rat combined chronic 
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toxicity/ carcinogenicity study, decreased body weight gain and food consumption were 

observed. There was no evidence of carcinogenicity in mice; however, there were statistically 

significant increases in liver adenomas and combined adenomas/carcinomas in female rats. In 

male rats, there was a statistically significant trend but no pair-wise significance for liver tumors. 

There was no evidence of a mutagenic or cytogenetic effect in vivo or in vitro in studies with 

either metolachlor or S-metolachlor. Metolachlor has been classified as a Group C, possible 

human carcinogen, based on liver tumors in rats at the highest dose tested. No cancer potency

factor has been established, as risks established based on the chronic reference dose are 

protective of cancer effects. 

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-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)

NOAEL = 

300 

mg/kg/day

UFA= 10x

UFH=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)

NOAEL = 

9.7

mg/kg/day

UFA= 10x

UFH=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 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. UFA = extrapolation from animal to human (interspecies). UFH = 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. 
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Table 4.5.4.2. Summary of Toxicological Doses and Endpoints for S-METOLACHLOR for Use in 

Residential and Occupational Human 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) NOAEL= 

50 mg/kg/day

UFA= 10x

UFH=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 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

UFA= 10x

UFH=10x

UFD=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)

NOAEL= 

8.8 mg/kg/day

UFA= 10x

UFH=10x

UFD=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 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. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key 

data (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 Studies

The qualitative nature of metolachlor residues in plants and livestock is adequately understood, 

based on adequate corn, potato, and soybean metabolism studies, ruminants, poultry, and 
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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 previously 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 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. Major degradates identified in groundwater 

include metolachlor ESA and metolachlor OA in both groundwater and surface water. 

Depending on the soil (i.e. organic 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 

metolachlor and S-metolachlor. Available data suggest that metolachlor and S-metolachlor are 

expected to be highly 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 metabolism 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 directly to the corresponding oxo-compounds. Most of the metabolites of 

metolachlor and S-metolachlor have not been identified. 

Metolachlor is rapidly metabolized and almost totally 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 

in poultry via O-demethylation and subsequent glucuronic acid conjugation or oxidation to 

dihydroxy or carboxylic acid metabolites that may also be conjugated with glucuronic acid. As 

in plants, metolachlor residues of concern in livestock commodities include 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 MARC 
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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 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 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 soybean 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 livestock 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 properly supported 

by analytical validation data and storage stability data. No processing data are needed to support 

the current 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 metolachlor to dairy cattle. The dietary burden for 
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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 Smetolachlor were calculated for both the parent compound and the metolachlor ethanesulfonic 

acid (ESA) and metolachlor oxanilic acid (OA) degradates. 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. Based 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 

exposure) 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

Acute 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 assessment is still current. 
S-Metolachlor Human Health Risk Assessment DP No. D411153

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The acute and chronic dietary exposure assessments were conducted using the Dietary Exposure 

Evaluation Model software with the Food Commodity Intake Database (DEEM-FCIDTM, 

Version 1.3), which incorporates consumption data from USDA’s Continuing Surveys of Food 

Intakes by Individuals (CSFII), 1994-1996 and 1998. The dietary risk assessment incorporates 

both exposure and toxicity of S-metolachlor and metolachlor. For acute and chronic 

assessments, the risk is expressed as a percentage of a maximum acceptable dose (i.e., the dose 

which HED has concluded will result in no unreasonable adverse health effects). This dose is 

referred to as the population adjusted dose (PAD). The PAD is equivalent to the Reference Dose 

(RfD) divided by the special FQPA Safety Factor. HED is concerned when estimated dietary 

risk exceeds 100% of the PAD. 

The acute and chronic dietary exposure/risk analyses for all supported S-metolachlor/metolachlor 

food uses were conducted using conservative, unrefined exposure assessments. The unrefined 

analyses 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 both metolachlor and S-metolachlor on the same commodity, the 

higher value of the two is used in the analyses. Acute and chronic dietary S-metolachlor 

exposure and risk estimates resulting from food intake were determined for the general U.S. 

population and various population subgroups. 

Based on analyses 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 

significantly below HED’s level of concern for all supported commodities (The 95th 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 exposed population subgroup, all infants < 1 year 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 tolerances on food 

commodities.

5.4.3 Acute Dietary Risk Assessment

Based on analyses of estimated dietary risks for the general U.S. population and various 

population subgroups, the acute dietary exposure estimates for S-metolachlor are significantly

below HED’s level of concern for all supported commodities (The 95th 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
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Based on analyses of estimated dietary risks for the general U.S. population and various 

population subgroups, the chronic dietary exposure estimates for S-metolachlor are significantly

below HED’s level of concern for all supported commodities. The chronic dietary exposure 

estimate for the highest exposed population subgroup, all infants < 1 year 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 effects. 

5.4.6 Summary Table

Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure and Risk for SMetolachlor and Metolachlor

Population Subgroup

Acute Dietary

(95 Percentile) Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day)

% aPAD*

Dietary 

Exposure

(mg/kg/day)

% cPAD*

Dietary 

Exposure

(mg/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 adequately 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)
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6.1 Residential Handler Exposure

Pennant MAGNUMTM (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 MAGNUMTM is not intended for homeowner 

purchase 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-tomouth exposure 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-tomouth, 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-tomouth, and soil ingestion oral exposure was calculated to be 0.0609 mg/kg/day resulting in an 

MOE of 820. 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 

analysis, 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

HRt FM

SAH

(cm2)

Exposure 

Time 

(hours/

day)

N_Replen SE Freq_Ht

M

Absorbed 

Dose

(mg/kg/day)

MOE 

Hand (rounded) 

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
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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 pressure (2.8 x 10-5 mm Hg. 

However, volatilization of pesticides may be a source of post-application inhalation exposure to 

individuals nearby 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/scipoly/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 postapplication 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 always 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 method 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 appropriately apply the data and the AgDRIFT computer model to 

its risk assessments for pesticides applied by 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 significant 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 previously 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
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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 level of concern. The food and drinking water exposure estimates for the most 

highly exposed subgroup, all infants (< 1 year 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 days. 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 by 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 postapplication 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 likely 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 analysis. 

Based on this analysis, 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

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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 0.061 680

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 -combined hand-to-mouth, object-tomouth, 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 days 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. 

Only 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 Smetolachlor in food and drinking water is below EPA’s level of concern. The food and drinking 

water exposure estimates for the most highly 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 protective of cancer effects, no 

separate cancer risk assessment is necessary. The chronic aggregate risk assessment is below the 

Agency’s level of concern.

7.0 Cumulative Exposure/Risk Characterization

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, 

or revoke a tolerance, the Agency consider “available information” concerning the cumulative 

effects of a particular pesticide's residues and “other substances that have a common mechanism 

of toxicity.”

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to S-metolachlor and any other substances and S-metolachlor does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 
S-Metolachlor Human Health Risk Assessment DP No. D411153

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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 chemicals 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 by use of a respirator or engineering 

controls. The metolachlor label requires the use of a closed loading system, which adequately 

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, respectively. 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 other 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 by 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

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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 Tolerances for Residues of S-Metolachlor on Corn, field, forage; Corn, sweet, forage; 

and Corn, stover. Summary of Analytical 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-Metolachlor Residue Chemistry Chapter for the Tolerance 

Reassessment Eligibility Decision (TRED) and Registration for Use on Asparagus, Carrots, 

Cotton, Horseradish, Green Onions, Peppers, 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, Christopher M. 2010. “Drinking Water Assessment for S-Metolachlor and its Degradates 

Ethanesulfonic Acid (ESA) and Oxanilic Acid (OA) for Various Crop Uses.” D368735, EPA 

EFED Memorandum dated April 22, 2010. 

VanAlstine, Julie, 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 dated March 20, 2013,
S-Metolachlor Human Health Risk Assessment DP No. D411153

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Appendix 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 new (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

yesa

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 Neurotoxicity (hen)...............................

870.6100b 90-Day Neurotoxicity (hen)...........................................

870.6200a Acute Neurotoxicity Screening Battery (rat) .................

870.6200b 90-Day Neurotoxicity Screening Battery (rat)...............

870.6300 Develop. Neurotoxicity .................................................

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

Acute Oral (rat)...........................................................

Subchronic Oral (rat) ..................................................

Six-month Oral (dog)..................................................

no

a

Satisfied with combined chronic toxicity/carcinogenicity study

*Waived at HASPOC February 14, 2013 (JVanAlstine, 2013)
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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 LD50 = 2780 mg/kg III

870.1200 Acute dermal - Rabbit 00015526 LD50 = > 10 g/kg III

870.1300 Acute inhalation -Rat 00015535 LC50 = > 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 LD50 = 3267 mg/kg

(♂); 2577 mg/kg/day

(♀); 2672 mg/kg/day

(combined)

III

870.1200 Acute dermal - Rabbit 43928916 LD50 = > 2000 mg/kg III

870.1300 Acute inhalation -Rat 43928917 LC50 = > 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

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/Guideline
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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

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 in 

rodents

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 

excessive 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

870.3700b Prenatal 

developmental in 

(New Zealand 

White) rabbits

00041283 (1980) 

acceptable/guideline

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

F0 males: 0, 2.4, 23.5, and 

75.8 mg/kg/day; F0females: 

0, 2.5, 26.0, and 85.7 

mg/kg/day; F1 males: 0, 2.3, 

23.7, and 76.6 mg/kg/day; F1

females: 0, 2.6, 25.7, and 

84.5 mg/kg/day metolachlor 

(95.4% ai) (dietary) 

Parental/Systemic NOAEL = 1000 ppm (F0

males/females: 75.8/85.7 mg/kg/day; F1

males/females: 76.6/84.5 mg/kg/day) highest dose 

tested.

LOAEL = Not established

Reproductive NOAEL = 1000 ppm (F0

males/females: 75.8/85.7 mg/kg/day; F1

males/females: 76.6/84.5 mg/kg/day) highest dose 

tested.

LOAEL = Not established

Offspring NOAEL = 300 ppm (F0 males/females: 

23.5/26.0 mg/kg/day; F1 males/females: 23.7/25.7 

mg/kg/day

LOAEL = 1000 ppm (F0 males/females: 75.8/85.7 

mg/kg/day; F1 males/females: 76.6/84.5 mg/kg/day 

based on decreased body weight in F1 and F2litters. 

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 gain
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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 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 incidence 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

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 

Negative
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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 

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 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-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. These were the 

products CGA 37735 (2-ethyl-6-methylhydroxyacetanilide), in which N-dealkylation of R1

(the N-(2-methoxy-1-methylethyl side chain) and 

side chain dechlorination and oxidation of R2(the Nchloroacetyl side chain) have occurred, and CGA 

46129 (N-(1-carboxy-ethyl)-2-ethyl-6-methyl 

hydroxyacetanilide) in which the ether bond of R1

has been split and oxidized to the corresponding 

carboxylic acid, while R2is similar to R2found 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 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 

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 

followed. 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 readily 
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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 [14C]

metolachlor was essentially complete within 48 to 72 

hours after dosing. Low- and high-dose females 

eliminated 14C 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 14C 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 females and repeateddose rats of both sexes; these animals excreted 

approximately 58 to 64 percent of the 14C 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 14C 

(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 postdosing. 

Tissues of low- and repeated-dose rats contained 

approximately 1.6 to 2.5 percent of the 14C 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 

[

14C] metolachlor 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 heart, lung, kidney, liver and spleen. 

Brain, bone and muscle contained the smallest 

amounts of radioactivity (0.004 to 0.015 ppm, lowand repeated-dose rats; 1.7 to 3.5 ppm, high-dose 

rats). Tissue 14C 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 14C 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 14C was retained by all animals and that 
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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 [14C] 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),14C-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, U17, 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 similarly complex metabolite profile was 
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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, F14, 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 NOAEL = 50 mg/kg/day

LOAEL = 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/ Guideline
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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 

uvrA 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 uvrA. 

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 control 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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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 

synthesis

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 CGA77102 Technical (95.6%) at doses of 500, 1500 or 

5000 mg/kg (males) or 500, 1500 or 3200 mg/kg 

(females). Hepatocytes harvested at 15 and 38 hours 

were evaluated for viability and replicative DNA 

synthesis (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 Sphase (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 

hours 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 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
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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 nonradiolabeled CGA 77102 for 

14 days followed by 0.5 

mg/kg radiolabeled CGA77102 (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%. The route 

or extent of excretion was slightly influenced by the 

sex of the animal but not by pretreatment with nonradiolabeled CGA-77102 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, most 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 the elimination process of 

CGA-77102. 

Irrespective of the dose and sex, there seems to be 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 

second Cmax 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 Cmax were nearly identical (~ 0.03 

μg/mL); in the high dose group (D1), the first and 

second Cmax 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 concentration curve (AUC0-

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 

AUC0-48hr (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 Cmax levels.

Acceptable/Guideline
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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 from 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. 
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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 nonradiolabeled CGA 77102 for 

14 days followed by 0.5 

mg/kg radiolabeled CGA77102 (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-U14C] 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-U14C] 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-U14C] CGA-77102 (the Senantiomer) (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 racemicMetolachlor (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 case of CGA-77102 than 

CGA-24705. On the other hand, there were sexrelated 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 stereochemical 

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 metabolite 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. 
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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 the 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 higher 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 23, 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/Guideline
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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 years 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

Dose 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 appropriate for the risk assessment. Developmental effects observed are not 

attributable to a single exposure and therefore, a separate acute endpoint has not been identified 

for females 13-50. Although 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 residues 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 NOAEL of 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
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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 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/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 systemic 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 days. 

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 based on an offspring NOAEL of 50 

mg/kg/day and a LOAEL of 500 mg/kg/day based on is based on increased incidence of clinical 

signs, decreased body weight/body weight gain, food consumption and food efficiency seen in 

maternal animals.

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.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] 
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Dose and Endpoint for Risk Assessment: NOAEL of 8.8 mg/kg/day based on decreased body

weight gain at 29.4 mg/kg/day

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 (Lot/Batch # KI-5408/6, 98% a.i.) 

administered in the diet at concentrations of 0, 360, 1200, 6000, or 20,000 ppm. These 

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, urinalysis, or histopathology was reported for animals fed CGA354743. Limited and sporadic statistically significant changes in hematology, clinical chemistry, 

water intake and organ weight data were not dose-dependent, and were of questionable 

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 only. Females exposed to CGA-77102 showed 

decreased body weight gain (-19%) by week 13, but these 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 hypertrophy 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
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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 bodyweight 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 urinalysis. 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 decreased due to decreased globulin in males and decreased albumin and globulin 

fractions in females. These effects were not considered biologically significant. There were no 

treatment-related organ weight effects or macroscopic or microscopic lesions. Under 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 classified as Acceptable/Guideline. It satisfies 

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 purebred 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 technical, 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 urinalysis 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 phosphatase activity was slightly 

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 only 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 

findings or biologically significant increases in biochemistry parameters consistent with adverse 

hepatic effects, this finding is not considered toxicologically significant.
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Mean ALP and GGT activities were significantly increased in both sexes at weeks 7 and 13 

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 hyperplasia, perilobular fatty 

change in the livers of both sexes, and cystic hyperplasia of the gallbladder occurred only 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 compounds 

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:WIST rats per group were administered CGA 354743 Technical (98%; Batch No. KI5408/6) by gavage in 0.5% aqueous sodium carboxymethylcellulose in 0.1% aqueous 

polysorbate 80 at doses of 0, 250, 500, or 1000 mg/kg/day on gestation days (GD) 6-15, 

inclusive. Controls were treated with 0.5% sodium carboxymethylcellulose in 0.1% aqueous 

polysorbate 80 (vehicle). On GD 21, dams were sacrificed, subjected to gross necropsy, and all 

fetuses examined externally. 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 necropsy was unremarkable.
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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.

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: RAI f (SPF) 

(hybrids 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 carboxymethylcellulose solution at doses of 

0, 10, 100, or 1000 mg/kg/day on gestation days (GD) 6-15, inclusive. Controls were treated 

with 0.5% sodium carboxymethylcellulose (vehicle). On GD 21, dams were sacrificed, 

subjected to gross necropsy, and all fetuses examined 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 other 

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 

necropsy 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.
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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.

870.3700b Prenatal Developmental Toxicity Study – Rabbit

In a developmental (teratology) study (MRID# 43928924), sexually mature virgin female New 

Zealand White, 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 days 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 days 7-19) with a rebound weight gain following the dosing period (gestation 

days 19-29), an indicator of toxicity. This group also had lower overall weight gain for the 

calculated periods of gestation days 7-29, 0-29 and corrected body weight gains for 0-29. This 

was supported by reduced food consumption during the dosing period (gestation days 7-19) and 

for the overall periods (gestation days 7-28 and 0-28) with a rebound in food consumption 

following dosing (gestation days 19-28) at the 500 mg/kg/day dose level. This is also reflected 

in reduced food efficiency for the same periods (719, 7-28, and 0-28) and increased food 

efficiency following dosing (19-28) at the 500 mg/kg/day dose level. The maternal toxicity 

NOEL was 20 mg/kg/day with a LOEL of 100 mg/kg/day based on clinical signs of toxicity.

No significant treatment related developmental toxicity was noted at the dose levels tests. The 

developmental 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 (§83-3b)] 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 (F0 males: 0, 2.4, 23.5 and 75.8 mg/kg/day; F0 females: 0, 

2.5, 26.0 and 85.7 mg/kg/day; F1males: 0, 2.3, 23.7 and 76.6 mg/kg/day; F1 females: 0, 2.6, 25.7 

and 84.5 mg/kg/day).
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There were no deaths in the F0 generation. Two females of the F1 generation died during the premating period, one in the 300 ppm group at 32 days and the other in the 1000 ppm group at 52 

days. One female in the 300 ppm group was found dead on gestation day 19 and a control group 

female was sacrificed in a moribund condition on lactation day 1. Based on necropsy 

examinations, none of the deaths was treatment-related. There were no treatment-related clinical 

signs of toxicity in either generation. Body weight, body weight gain and food consumption were 

unaffected in the F0 generation. In the F1 generation, food consumption was significantly 

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 

necropsy examinations in either generation.

There was no evidence of a treatment-related effect on any of the reproductive parameters for 

either generation. Offspring body weight was significantly decreased in the F1 litter on lactation 

days 14 and 21 (91- 96% of control value) and in the F2 litter on lactation days 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 (F0

males/females: 75.8/85.7 mg/kg/day; F1males/females: 76.6/84.5 mg/kg/day).

The reproductive toxicity LOAEL was not established. The NOAEL was 1000 ppm (F0

males/females: 75.8/85.7 mg/kg/day; F1males/females: 76.6/84.5 mg/kg/day).

The offspring LOAEL was conservatively established at 1000 ppm (F0 males/females: 

75.8/85.7 mg/kg/day; F1males/females: 76.6/84.5 mg/kg/day) based on decreased body 

weight in F1 and F2 litters . The NOAEL is 300 ppm (F0 males/females: 23.5/ 26.0 

mg/kg/day; F1males/females: 23.7/25.7 mg/kg/day).

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, respectively; females: 0, 3.6, 9.7 and 33.0 

mg/kg/day, respectively) for one year. 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-week 
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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 of 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 weeks 12, 26 and 40; however, the increase was not 

considered toxicologically significant due to the small magnitude of the effect and the lack of 

accompanying necropsy findings. 

The LOAEL was 1000 ppm for females (33.0 mg/kg/day) based on decreased body weight 

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 the 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 slightly 

decreased in the 3000 ppm females (6-17% decrease) throughout the study; the changes were not 

statistically significant. Mean food consumption was slightly decreased (4-9% decrease) in the 

3000 ppm females; the decrease was not statistically significant. Absolute, relative and liver-tobrain weight were increased (7%, 13%, and 5%, respectively) 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 accompanying 

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 guideline requirements for a 

chronic toxicity study in rats (83-1; OPPTS 870.4200a).

870.4200b Carcinogenicity (feeding) - Mouse
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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 deaths 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 statistically 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 females (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 was 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 treatmentrelated 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 870.4200).

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 CGA-354743 tech. in DMSO at concentrations 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.
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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.

Cytogenetics 870.5395 

Micronucleus assay in 

mouse 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 CGA354743 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 μg/plate in the presence and absence of mammalian 

metabolic activation. 

There was no evidence of induced mutant colonies over 

background.

Cytogenetics

870.5395, 

Micronucleus assay in 

mouse 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 cells

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 106) and 1000 μg/mL (5.56 x 106) compared to the solvent 

control value of 4.02 x 106and without S9-mix at 500 μg/mL 

(15.35 x 106) compared to the solvent control value of 12.90 
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Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

absence of mammalian 

metabolic activation (S9-

mix).

x 106. The increases were small and the actual mean mutant 

frequencies were within the range of historical solvent 

control values. No positive dose-response was seen 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 colonies 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-U14C] 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 administered doses were 3-8% greater than nominal. Overall recovery of administered radioactivity was 

an acceptable 93.83-99.18%. Urinary excretion and carcass burden data implied that absorption 

was approximately 38-49% of the administered 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 highdose females as compared to 30% and 32% of low- and high-dose males, respectively), and fecal 

elimination was expectedly 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 elimination, 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, and CGA 368208. In the feces, CGA 

357704 and CGA 354743 represented a notably 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.
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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.

Executive 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-U14C]-CGA-376944 (0.5 mg/kg nominal; Batch No. ILS-125.4 radiochemical purity >95.5%), for 

the metabolism and bile-duct cannulation studies, respectively.

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 single oral dose of 0.5 mg/kg of 

[Phenyl-U14C]-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 only in the liver of non-cannulated rats. Carcass burdens 

accounted for <0.01% of the administered dose at necropsy. 

 

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 excretion 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 nearly complete within 24 hours of dosing. Biliary excretion represented 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 system and bile-duct. Only a minor percentage 

of the dose (5.3%) appeared to enter the systemic circulation where it was rapidly excreted by

the kidneys. 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 

absorption 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 products. At the dose tested, [14C]-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 males and 

females. The unknown metabolites of urine and feces, separated by TLC accounted for 0.2-2.8% 

of the administered radioactivity and were not characterized further.
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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 days (Days 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, respectively). Four days 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 control group received 

intraperitoneal injections of cyclophosphamide (50 mg/kg bw/day) on Days 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 collected. 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-Metolachlor, with significant differences noted in the mid and 

high doses. 

The NOAEL for systemic 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, there were no statistically significant treatment-related effects on antiSRBC 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 Smetolachlor does not reveal any evidence of treatment-related effects on the immune system. 

The overall weight of evidence suggests that this chemical does not directly target the immune 

system. 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. 
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Appendix	B.		Metabolism	Summary
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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/cm3at 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 (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