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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

 OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION

Date: January 17, 2012

MEMORANDUM

SUBJECT: S-Metolachlor. Human Health Risk Assessment for the Section 3 Requests 

for Use on Coriander (Cilantro) and Garden Beet Leaves.

PC Code: 108800 DP Barcode: D396452

Decision No.: 451816 Registration No.: 100-816

Petition No.: 1E7898 Regulatory Action: Section 3

Risk Assessment Type: Single Chemical Case No.: 0001

TXR No.: NA CAS No.: 87392-12-9

MRID No.: NA 40 CFR: 180.368

FROM: W. Cutchin, Chemist

Alternative Risk Integration Assessment Team (ARIA)

Inert Ingredients Assessment Branch (IIAB)

Registration Division (RD; 7505P)

THROUGH: S. Hummel, Senior Scientist

Registration Action Branch 4 (RAB4)

Health Effects Division (HED; 7509P)

TO: B. Madden, Risk Manager

Minor Use and Emergency Response Branch

RD (7505P)

RD of the Office of Pesticide Programs (OPP) has requested that ARIA evaluate the 

Section 3 request for the use of the herbicide S-metolachlor to control weeds on coriander 

(cilantro) and beet, garden, leaves.

INTRODUCTION

Section 3 requests has been received from the Interregional Research Project No.4 (IR-4), 

on behalf of the Agricultural Experiment Station of IR-4 and the Agricultural Experiment 

Stations of New York, North Carolina and South Carolina (coriander (cilantro)); and 

California, Oklahoma, Texas and Tennessee (beet, garden, leaves), for use of the 

herbicide S-metolachlor formulated as Dual Magnum® (EPA Reg. No. 100-816).
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Table of Contents

1.0 EXECUTIVE SUMMARY ...............................................................................................4

2.0 DETAIL DISCUSSION.................................................................................................. 10

2.1 PROPOSED NEW USES ............................................................................................... 10

2.2 PHYSICAL/CHEMICAL PROPERTIES ................................................................. 10

3.0 HAZARD ASSESSMENT.............................................................................................. 12

3.1 HAZARD PROFILE....................................................................................................... 12

3.2 FQPA Hazard Considerations....................................................................................................... 13

3.2.1 Developmental Toxicity ........................................................................................................... 13

3.2.1.1 Rat Developmental Study – Metolochlor ........................................................................ 14

3.2.1.1 Rabbit Developmental Study - Metolochlor ................................................................... 14

3.2.1.3 Rat Developmental Study – S-Metolochlor..................................................................... 15

3.2.1.4 Rabbit Developmental Study – S-Metolochlor ............................................................... 15

3.2.2 Reproductive Toxicity ............................................................................................................ 16

3.2.3 Pre-and/or Postnatal Toxicity ................................................................................................ 17

3.2.4 Immunotoxicity....................................................................................................................... 17

3.2.5 Neurotoxicity .......................................................................................................................... 17

3.2.6 FQPA Safety Factor ............................................................................................................... 17

3.3 Toxicity Endpoint Selection........................................................................................................... 18

3.3.1 Acute Reference Dose (aRfD) - General Population ................................................................. 18

3.3.4 Dermal Exposure (Short-Term) ................................................................................................. 20

3.3.5 Inhalation Exposure (Short-Term) ............................................................................................ 20

3.3.6 Inhalation Exposure (Intermediate-Term)................................................................................ 20

3.3.7 Classification of Carcinogenic Potential .................................................................................... 21

3.4 Margins of Exposure........................................................................................................................ 21

3.5 Recommendation for Aggregate Exposure Risk Assessments ...................................................... 21

3.6 Summary of Endpoints Selected for Risk Assessment .................................................................. 21

3.7 Endocrine Disruption..................................................................................................................... 23

4.0 RESIDUE CHEMISTRY CONSIDERATIONS ...................................................... 23

4.1 Metabolism in Plants/Livestock..................................................................................................... 23

4.2 Metabolism in Rotational Crops.................................................................................................... 24

4.3 Residue Analytical Methods .......................................................................................................... 25
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4.5 Residues in Processed Commodities.............................................................................................. 27

4.6 Residues in Rotational Crops......................................................................................................... 27

4.7 Drinking Water Profile.................................................................................................................. 27

4.8 Dietary Exposure Analysis and Risk Estimates............................................................................. 28

5.0 NON-DIETARY, NON-OCCUPATIONAL EXPOSURE ..................................... 29

6.0 AGGREGATE RISK ...................................................................................................... 30

6.1 Acute Aggregate Risk .................................................................................................................... 30

6.2 Short- & Intermediate-Term Aggregate Risk ............................................................................... 30

6.3 Chronic Aggregate Risk................................................................................................................. 31

6.4 Cancer Aggregate Risk .................................................................................................................. 31

7.0 OCCUPATIONAL EXPOSURE AND RISK............................................................ 31

9.0 CONCLUSION................................................................................................................. 35

10.0 DATA NEEDS ................................................................................................................ 35

10.1 Toxicology Data Requirements.................................................................................................... 35

10.2 Residue Chemistry Data Requirements....................................................................................... 36

10.3 Occupational/Residential Requirements ..................................................................................... 36

REFERENCES......................................................................................................................... 36
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1.0 EXECUTIVE SUMMARY

General Information

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 

(PC Code 108800) is an isomer enriched formula comprised of 88% S-isomer and 12% 

R-isomer. Permanent tolerances are established at 40 CFR §180.638(a)(2) for Smetolachlor in/on a variety of crop commodities, at levels ranging from 0.02 in/on meat 

and dairy products to 20 ppm in/on peanut hay and includes Brassica, leafy greens, 

subgroup 5A at 1.8 ppm and spinach at 0.5 ppm. Compliance with the tolerance levels is 

determined by measuring only the sum of free and bound S-metolachlor, S-2-chloro-N-

(2-ethyl-6-methylphenyl)-N-(2-methoxy-1-methylethyl)acetamide, its R-enantiomer, and 

its metabolites, determined as the derivatives, 2- [(2-ethyl-6- methylphenyl)amino]-1-

propanol (CGA-37913) and 4-(2-ethyl-6-methylphenyl)-2- hydroxy-5-methyl-3-

morpholinone (CGA-49751) calculated as the stoichiometric equivalent of S-metolachlor.

S-metolachlor is a selective, chloroacetanilide herbicide used primarily for grassy weed 

control in many agricultural food and feed crops, residential lawns, commercial turf 

(including golf courses, sports fields, recreation areas, and sod farms), ornamentals and 

horticultural nurseries. S-metolachlor formulations include emulsifiable and flowable 

concentrates, granular, and ready-to-use 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. 

IR-4 has proposed the use of the herbicide S-metolachlor formulated as Dual Magnum® 

(EPA Reg. No. 100-816) on coriander (cilantro) as a broadcast, foliar application (0.64-

0.96 lbs ai/A) at 30 days before the leaf harvest and 70 days before seed and on beets 

grown for leaves as a broadcast, pre-emergence soil surface treatment at 0.63 -1.26 lbs 

ai/A after the crop has been planted but before the crop and weeds emerge. A second 

application of S-metolachlor to beets may be made as one post emergence, broadcast 

treatment at 0.63 -1.26 lbs ai/A when plants are at 1 to 2 true leaf stage. 

Toxicology

The existing toxicological database is 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 Smetolachlor, when combined with the metolachlor database, is complete for risk 

assessment purposes. However, neurotoxicity (870.6200 a and b) and immunotoxicity

studies (870.7800) are required in accordance with the revised 40 CFR Part 158 

Toxicology Data Requirements.

S-Metolachlor exhibits low acute toxicity via the oral (Toxicity Category III), inhalation 

(Toxicity Category IV), and dermal (Toxicity Category III) routes of exposure. It causes 

slight eye irritation, and is non-irritating dermally but is a dermal sensitizer. In 
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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 the available toxicity studies. 

Prenatal developmental studies in the rat and rabbit with both metolachlor and Smetolachlor 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. 

There was no evidence of mutagenic or cytogenetic effects in vivo or in vitro. 

Metolachlor has been classified as a Group C, possible human carcinogen based on liver 

tumors in rats at the highest dose tested. No cancer potency factor has been established, 

as risks established based on the chronic reference dose are protective of cancer effects.

Dose Response Assessment

Toxicological endpoints were selected for dietary/drinking water, occupational and 

residential exposure scenarios. An acute reference dose (RfD) for assessment of food and 

drinking water exposures was selected from a developmental toxicity study in rats. A 

chronic RfD was selected from a chronic toxicity study in dogs. A point of departure 

(POD) for dermal exposure was not selected because no dermal or systemic toxicity was 

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

days. An inhalation exposure POD was selected from a developmental toxicity study in 

rats. An uncertainty factor of 100X was applied to endpoints selected for exposure routes 

(10x for interspecies extrapolation, 10x for intraspecies variation). 

 

Acute Dietary aPAD = 3.0 mg/kg/day

(General Population)

Chronic Dietary cPAD = 0.97mg/kg/day

(All Populations)

Cancer (all routes) Group C carcinogen

Incidental Oral Short-term NOAEL=50 mg/kg/day

(1-30 days)

Inhalation Short-Term NOAEL=50 mg/kg/day

(1-30 days)

Inhalation Short-Term NOAEL=8.8 mg/kg/day

(1-30 days)

Residue Chemistry

The qualitative nature of metolachlor residues in plants is 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 
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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 nitrogen-phosphorus detector (GC/NPD) method (Method I) for 

determining residues in/on plant commodities and a gas chromatography with mass 

selective detector (GC/MSD) method (Method II) for determining residues in livestock 

commodities. These methods determine residues of metolachlor and its metabolites as 

either CGA-37913 or CGA-49751 following acid 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. 

IR-4 and Syngenta have 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 S-enantiomers (SYN506357 and SYN508500) of the 

hydrolysis products CGA-37913 and CGA-49751. This method has been determined to 

be adequate for enforcement purposes.

Coriander (cilantro) fresh, dried and seed samples were analyzed using “Working Method 

for PR 09595: Analysis of s-Metolachlor in Cilantro as Metabolites s-CGA-37913 (SYN506357) and s-CGA-49751 (SYN-508500),” a modification of Syngenta Method No. 

1848-01. Samples of the raw agricultural commodities, leaves and stems, and seed were 

refluxed in acid and partitioned into dichloromethane (DCM). An aliquot was purified 

with column chromatography and concentrated into aqueous acetonitrile. The lower limit 

of method validation (LLMV) for residues of SYN 506357 and SYN 508500 was 0.05 

ppm in all matrices. Based on the LLMV, the calculated limits of detection (LOD) 

ranged from 0.0132-0.0175 ppm for SYN 506357 and SYN 508500 in coriander 

(cilantro) fresh, dried and seed samples. The calculated limits of quantitation (LOQ) 

ranged from 0.0359-0.0526 ppm for SYN 506357 and SYN 508500 in coriander 

(cilantro) fresh, dried and seed samples, respectively. The method is adequate for data 

collection.

Previously submitted storage stability data indicates that the residues of metolachlor are 

stable on a variety of commodities for up to 2 yrs. Coriander (cilantro) fresh leaves and 

stems, dried leaves and stems and seed samples were stored frozen for a maximum of 708 

days, 702 days, and 416 days, respectively. The results of the storage stability study with 

coriander (cilantro) samples and previously submitted storage stability data are adequate 

to show that residues of S-metolachlor were stable for the duration of this study.

There are no coriander (cilantro) or garden beet leaf livestock feed items of regulatory

interest; therefore, a discussion of S-metolachlor residues on livestock food items is not 

germane to this petition.

The submitted coriander (cilantro) study is adequate in number and geographic location 

of the residue field trials. At all sites, two plots received a single broadcast application of 
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S-metolachlor at the approximate rate of 0.64 lb ai/A or 0.96 lb ai/A. Coriander (cilantro) 

fresh leaf and stem samples were harvested approximately 30 (27-34) days pre-harvest 

interval (PHI), after the application and placed into frozen storage shortly after harvest. 

At one site, additional treated plots received a single broadcast application of Smetolachlor at the approximate rate of 0.64 lb ai/A or 0.96 lb ai/A, where coriander 

(cilantro) seed were collected. At another site, additional treated plots received a single 

broadcast application of S-metolachlor at the approximate rate of 0.64 lb ai/A or 0.96 lb 

ai/A, and coriander (cilantro) leaves and stems were collected at 27 days and dried in an 

oven. No spray adjuvant was used at the trials. No residue decline studies were 

submitted.

The analytical results show that after a single foliar broadcast application of Smetolachlor at the approximate rate of 0.64 lb ai/A and 0.96 lb ai/A with a 27 to 34-days 

PHI, the maximum total S-metolachlor residues as parent equivalents were approximately

3.7 ppm and 4.1 ppm in coriander (cilantro) fresh leaves and stems, respectively. The 

maximum total S-metolachlor residues as parent equivalents were increased from 

approximately <0.131 ppm (fresh samples) to 0.834 ppm (dried samples) in the 0.64 lb 

ai/A treated plot. The maximum total S-metolachlor residues as parent equivalents were 

increased from approximately 0.170 ppm (fresh samples) to 2.031 ppm (dried samples) in 

the 0.96 lb ai/A treated plot. The maximum total S-metolachlor residues as parent 

equivalents were <0.131 ppm in coriander (cilantro) seed at both application rates. Based 

on the results of these trials, the appropriate tolerance for residues of S-metolachlor in/on 

coriander (cilantro) leaves is 8.0 ppm. However, the Agency uses the preferred name 

coriander not cilantro for this raw agricultural commodity and, in addition, does not 

differentiate between dry and fresh leaves for coriander (cilantro). Therefore, a revised 

Section F should be submitted to indicate a request for coriander, leaves at 8.0 ppm and 

the cilantro dried and fresh leaves should be removed. The study data indicates that the 

requested tolerance on coriander, seed at 0.13 ppm is adequate. 

No new data have been submitted in support of the requested tolerance on beet, garden, 

leaves. The request is based on the currently established tolerance for residues of Smetolachlor on Brassica leafy vegetables (Sub-group 5B), of 1.8 ppm. The Chemistry

Science Advisory Council (ChemSAC) has considered the issue and determined that 

since the use pattern for beet greens is the same as that for leafy Brassica (sub group 5B), 

and beet greens are similar to the commodities in the leafy Brassica subgroup 5B, it is 

appropriate to translate this tolerance of 1.8 ppm to beet greens. Based on the 

CHEMSAC determination and that the proposed use pattern for beet, garden, leaves is 

the same as leafy Brassica greens, subgroup 5B, ARIA recommends for the proposed 

tolerance of 1.8 ppm on beet, garden, leaves.

There is no crop associated with this petition which requires residue data for processed 

fractions. 

The rotational crop restrictions listed on the label are appropriate for these proposed uses.

Drinking Water
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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. Since there are existing uses of Smetolachlor with higher application rates than the proposed Section 3 uses, those EDWCs 

will not increase. 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 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.

Dietary Exposure

For acute and non-cancer chronic exposures, ARIA is concerned when estimated dietary

risk exceeds 100% of the population adjusted dose (PAD). S-metolachlor is classified as 

a Group C carcinogen, so no separate dietary assessment was performed for cancer. 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).

Non-Dietary, Non-Occupational Exposure

There are no residential user exposures for the proposed new use of S-metolachlor for 

this Section 3 assessment. However, there is potential for residential exposure to Smetolachlor 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. S-metolachlor incidental oral exposure is assumed to include hand-to-mouth 

exposure, object-to-mouth exposure and exposure through incidental ingestion of soil. 

The residential exposure to toddlers for this scenario was calculated to be 0.046 

mg/kg/day resulting in an MOE of 1100. Based on this analysis, the short-term oral 

MOEs are not of concern.

Aggregate Risk

The aggregate acute and chronic risk estimates include exposure to residues of Smetolachlor in food and drinking water, and does not include dermal, inhalation or 
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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 

ARIA’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.

There are no residential user exposures for the proposed new use of S-metolachlor for 

this Section 3 assessment. No intermediate-term risk scenarios are anticipated for the 

existing and proposed uses of S-metolachlor. However, there is potential for short-term 

residential exposure to S-metolachlor from use of other registered products which are 

applied to residential lawns or turf by professional applicators via post-application 

exposure to children playing on treated lawns including hand-to-mouth exposure, objectto-mouth exposure and exposure through incidental ingestion of soil. Results from that 

assessment have been used to assess aggregate risk from exposure to food, drinking 

water, and residential lawns. Based on this analysis, short-term aggregate MOE of 860 

for toddlers is not of concern.

As estimated risks are calculated based on the chronic reference dose are protective of 

cancer effects, no separate cancer risk assessment is necessary. 

Occupational Exposure

The occupational exposure scenario of mixing, loading, and applying S-metolachlor as an 

herbicide on crops has been assessed. The proposed uses may result in short-

/intermediate-term (i.e., 1-30 days or up to 6 months) dermal and inhalation exposures 

during mixing, loading, applying, and postapplication activities. Long-term exposures 

(i.e., 6 months of continuous exposure) are not expected to occur based on the proposed 

use pattern. Dermal toxicological endpoints of concern were not identified (i.e., no 

systemic toxicity was seen following dermal exposure at the limit dose) therefore, no 

dermal exposures were calculated. Short- and intermediate-term exposures from 

inhalation exposure routes were assessed for all exposure scenarios. Occupational and 

residential exposure and risk estimates were conducted using maximum application rates 

and surrogate exposure data. Based on the Agency's current practices, a quantitative 

postapplication inhalation exposure was also not assessed. 

Data from Occupational Pesticide Handler Unit Exposure Surrogate Reference Table, 

which summarizes data from the Pesticide Handlers Exposure Database (PHED) was 

used to assess handler and post-application exposures in the absence of chemical-specific 

data. At the baseline level, all inhalation MOEs are above the target MOE of 100, thus, 

risks are not of concern. The handler exposure estimates in this assessment are based on 

a central tendency estimate of unit exposure and an upper-percentile assumption for the 

application rate, and thus assumed to represent high-end exposures. The uncertainties 

associated with this assessment stem from the use of surrogate exposure data (e.g., 

differences in use scenario and data confidence), and assumptions regarding the amount 
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of chemical handled. The estimated exposures are believed to be reasonable high-end 

estimates based on observations from field studies and professional judgment. 

Use of Human Studies

This risk assessment relies in part on data from studies in which adult human subjects 

were 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

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 LowIncome Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).

Conclusion

Pending resolution of the toxicology and residue chemistry concerns outlined in Section 

10 below, ARIA has no concerns regarding human health exposure and risk from the 

proposed Section 3 use of S-metolachlor on coriander and garden beet leaves.

2.0 DETAIL DISCUSSION

2.1 Proposed New Uses

S-metolachlor is to be applied to coriander (cilantro) formulated as Dual MAGNUM 

(EPA Reg. No.: 100-816) as a broadcast, foliar application (0.64-0.96 lbs ai/A) at 30 days 

before the leaf harvest and 70 days before seed. Use the lower end of S-metolachlor rate 

range for soils that are relatively coarse textured and the higher rates on fine textured 

soils. Apply S-metolachlor to beets grown for leaves as a broadcast, pre-emergence soil 

surface treatment at 0.63 -1.26 lbs ai/A after the crop has been planted but before the crop 

and weeds emerge. A second application of S-metolachlor to beets may be made as one 

post emergence, broadcast treatment at 0.63 -1.26 lbs ai/A when plants are at 1 to 2 true 

leaf stage. Use the lower end of S-metolachlor rate range for soils that are relatively

coarse textured and the higher rates on fine textured soils.

2.2 Physical/Chemical Properties 

Table 2.2.a Nomenclature of S-Metolachlor and its Regulated Hydrolytic Derivatives.
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Table 2.2.a Nomenclature of S-Metolachlor and its Regulated Hydrolytic Derivatives.

Compound

S-metolachlor

Common name S-metolachlor

Company experimental name CGA-77102

IUPAC name 2-Chloro-N-(2-ethyl-6-methylphenyl)-N-{S(2-methoxy-1-methylethyl)}acetamide

CAS name Chloro-N-(2-ethyl-6-methylphenyl)-N-(2-methoxy-1-methylethyl)acetamide

CAS # 87392-12-9

End-use product/(EP) Dual Magnum® Herbicide (7.62 lb/gal EC; EPA Reg. No. 100-816) 

Regulated residue - CGA-37913

Common name None

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

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

CAS registry number 61520-53-4

82508-08-5 (S-enantiomer)

Regulated residue - CGA-49751

Common name None

Company experimental names CGA-49751

SYN508500 (S-enantiomer of CGA 49751)

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

CAS registry number 61520-54-5

Table 2.2.b Physicochemical Properties of the Technical Grade Test Compound

Parameter Value Reference

Melting point/boiling point N/A Registration Division: 

Physical and 

Chemical 

Characteristics

(DP Num: 225258)

pH 7.8 at 25°C (1% aqueous dispersion)

Density 1.117 g/cm3at 20°C

Water solubility (25°C) 0.48 g/L
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Table 2.2.b Physicochemical Properties of the Technical Grade Test Compound

Parameter Value Reference

Solvent solubility (mg/L at 25°C) Miscible with methanol, acetone, toluene, noctanol, n-hexane, ethyl acetate, dichloromethane

Vapor pressure at 25°C 2.8 x 10-5 mm Hg

Dissociation constant (pKa) No dissociation constant in pH range 2-12

Octanol/water partition coefficient 

Log(KOW)

3.0 at 25°C

UV/visible absorption spectrum λmax Neutral: 534 L/mol•cm @ 266.4 nm

443 L/mol•cm @ 274.4 nm

Acidic: 534 L/mol•cm @ 266.4 nm

444 L/mol•cm @ 274.4 nm

Basic: 531 L/mol•cm @ 266.4 nm

411 L/mol•cm @ 274.4 nm

3.0 HAZARD ASSESSMENT

3.1 Hazard Profile

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 

metolachlor toxicology database is complete. The combined metolachlor and Smetolachlor toxicity data bases are adequate to characterize the toxicity of S-metolachlor 

for risk assessment purposes. 

In subchronic oral studies on metolachlor, the only evidence of toxicity was decreased 

body weight/body weight gain in rats and dogs in both sexes. There was no evidence of 

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 Smetolachlor. Metolachlor has been classified as a Group C carcinogen with risk 

quantitated using a non-linear (Margin of Exposure (MOE)) approach. 
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There was no evidence of increased quantitative or qualitative fetal susceptibility in the 

prenatal developmental studies in rats and rabbits with either metolachlor or Smetolachlor. 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 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/none/soft stool) were observed at the mid-dose in maternal animals tested with Smetolachlor. 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.

Both compounds are extensively absorbed and metabolized following oral administration. 

Elimination is via the urine and feces. Tissue residues were highest in red blood cells. 

Neurotoxicity battery (870.6200 a and b) and immunotoxicity studies (870.7800) are 

required in accordance with the revised 40 CFR Part 158 Toxicology Data Requirements. 

3.2 FQPA Hazard Considerations

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. Based on the results of the available toxicity

studies, there is no evidence for neurotoxicity or immunotoxicity. However, in 

accordance with the revised 40 CFR Part 158 Toxicology Data Requirements, 

neurotoxicity battery (870.6200) and immunotoxicity (870.7800) studies are required.

3.2.1 Developmental Toxicity 
Page 14 of 38

3.2.1.1 Rat Developmental Study – Metolochlor

In a prenatal developmental toxicity study (MRID 00151941), metolachlor (96.4% ai) in 

0.5% (w/v) aqueous hydroxymethylcellulose was administered by gavage (10 mL/kg) to 

25 presumed pregnant BR rats from gestation days (GD) 6 through 15, inclusive, at dose 

levels of 0, 30, 100, 300 or 1000 mg/kg/day. The animals were sacrificed on GD 20 and 

the fetuses examined for evidence of developmental effects.

There were four treatment-related deaths in animals treated at 1000 mg/kg/day. Clinical 

signs of toxicity, including clonic and/or toxic convulsions, excessive salivation, urinestained abdominal fur and/or excessive lacrimation, were observed in animals treated at 

1000 mg/kg/day. There was also an increase in excessive salivation in the 300 

mg/kg/day group. However, as this effect was most likely due to gastric irritation and 

there was no other evidence of treatment-related toxicity, the finding is not considered 

toxicologically significant. Body weight gain was significantly decreased in the 1000 

mg/kg/day group during GD 6-16, GD 6-20and GD 0-20. Food consumption was not 

affected. In the 1000 mg/kg/day group, there were a slightly decreased number of 

implantations per dam, decreased live fetuses/dam and increased number of 

resorptions/dam. There was also a statistically significant decrease in mean fetal body 

weight.

The maternal toxicity LOAEL was 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. The NOAEL was 300 mg/kg/day. The developmental toxicity LOAEL was 

conservatively established at 1000 mg/kg/day based on slightly decreased number of 

implantations per dam, decreased number of live fetuses/dam, increased number of 

resorptions/dam and significant decrease in mean fetal body weight. The NOAEL was 

300 mg/kg/day.

3.2.1.1 Rabbit Developmental Study - Metolochlor

In a prenatal developmental toxicity study (MR1D 00041283), metolachlor (95.4% ai) in 

0.75% aqueous hydroxy methylcellulose was administered by gavage to 16 pregnant New 

Zealand White rabbits/group from gestation days (GD) 6 through 18, inclusive, at dose 

levels of 0, 36, 120 or 360 mg/kg/day. The animals were sacrificed on GD 30 and the 

fetuses examined for evidence of developmental effects.

One doe at 36 mg/kg/day and another at 360 mg/kg/day died on GDs 24 and 29, 

respectively. The cause of death in both animals was attributed to persistent anorexia. 

Two rabbits aborted, one at 120 mg/kg/day (GD 25) and another at 360 mg/kg/day (GD 

17). The high-dose animal had persistent anorexia. One rabbit in each group delivered 

prior to GD 30; the control, low- and high-dose animals on GD 29 and the mid-dose 

animal on GD 30. There was a treatment-related increase in the incidence of persistent 

anorexia in the does treated at 360 mg/kg/day, which was defined as less than one-half of 

the daily food allotment consumed. However, food consumption data were not provided 
Page 15 of 38

to support this finding. There was a treatment-related decrease in body weight gain in the 

360 mg/kg/day group for GD 6-18 and GD 6-30. There was no treatment-related 

increase in gross pathological findings in maternal animals at necropsy. No treatmentrelated increase in external, visceral or skeletal developmental effects were observed. 

The maternal toxicity LOAEL was 360 mg/kg/day based on an increased incidence of 

clinical observations (persistent anorexia) and decreased body weight gain. The NOAEL 

was 120 mg/kg/day. The developmental toxicity LOAEL was not established. The 

NOAEL was 360 mg/kg/day.

3.2.1.3 Rat Developmental Study – S-Metolochlor

In a developmental (teratology) study (MRID# 43928925), rats (Strain: Tif: RAI f (SPF)) 

received either 0, 5, 50, 500, or 1000 mg/kg/day S-metolachlor (95.6% ai) suspension in 

0.5% (w/w) aqueous solution of sodium carboxymethylcellulose by oral gavage from 

gestation days 6 through 15.

No treatment related mortality was noted. There was a dose related increase in clinical 

signs seen as all 500 and 1000 mg/kg/day animals and 9/24 of the 50mg/kg/day animals 

exhibited as pushing head through bedding for about one hour. This was noted 

throughout the dosing period and may be an indication of neurotoxicity. The 500 and 

1000 mg/kg/day dose groups had lower overall body weights at gestation days 15 and 21 

and gained less weight than the control during the dosing period (gestation days 6-16) 

and for the calculated periods of gestation days 6-21 and 0-21, also for corrected body 

weight gains from gestation days 6-21. Also the 500 and 1000 mg/kg/day dose groups 

had reduced food consumption during the dosing period (gestation days 6-16, statistically

significantly different), reduced food consumption following the dosing period and for 

the overall periods (gestation days 6-21 and 0-2 1). This is also reflected in reduced food 

efficiency for the same periods (6-16, 6-21, 6-21, and 0-21). 

The maternal toxicity NOEL was 50 mg/kg/day with a LOEL of 500 mg/kg/day based on 

increased clinical signs of toxicity, decreased body weights and body weight gains and 

reduced food consumption and reduced food efficiency. No significant treatment related 

developmental toxicity was noted at the dose levels tests. The developmental toxicity

was equal to or greater than 1000 mg/kg/day, a LOEL was not reached. 

3.2.1.4 Rabbit Developmental Study – S-Metolochlor

In a developmental (teratology) study (MRID# 43928924), female New Zealand White. 

S.P.F. Rabbits received either 0, 20, 100, or 500 mg/kg/day S-metolachlor (89.6% ai

(93.7% S isomer)) suspension in 3% corn starch by oral gavage from gestation days 7 

through 19. 

No treatment related mortality was noted. There was a dose related increase in the 500 

mg/kg/day dose group had lower overall body weights at gestation days 19, 29 and 

corrected body weights at day 29 gained less weight than the control during the dosing 
Page 16 of 38

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 little/none/soft stool observations at the 

100 and 500 mg/kg/day dose levels, 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.

3.2.2 Reproductive Toxicity 

In a two-generation reproduction study (MRID 00080897), metolachlor (95.4% ai) was 

administered in the diet to two consecutive generations of 15 male/30 female CD albino 

rats at dose levels of 0, 30, 300 or 1000 ppm (F0 males: 0,2.4,23.5 and 75.8 mg/kg/day; 

F0 females: 0, 2.5, 26.0 and 85.7 mg/kg/day; F1males: 0, 2.3, 23.7 and 76.6 mg/kg/day; 

F1 females: 0, 2.6, 25.7 and 84.5 mg/kg/day).

There were no deaths in the F0 generation. Two females of the F1 generation died during 

the premating period, one in the 300 ppm group at 32 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 time points; however, there was no effect on body weight/body weight 

gain. Therefore, this finding was not considered toxicologically significant. There were 

no treatment-related effects on organ weights or gross/microscopic necropsy

examinations in either generation.

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

parameters for either generation. Offspring body weight was significantly decreased in 

the F1 litter on lactation days 14 and 21(91-96% of control value) and in the F, 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 
Page 17 of 38

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

offspring LOAEL was 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).

3.2.3 Pre-and/or Postnatal Toxicity

The database is considered adequate for selection of study endpoints and determination of 

a dose/response to characterize the potential prenatal or postnatal toxicity of metolachlor 

or S-metolachlor to infants and children. No increase in susceptibility was seen in 

developmental toxicity studies in rat and rabbit or reproductive toxicity studies in the rat. 

Toxicity to offspring was observed at dose levels the same or greater than those causing 

maternal or parental toxicity. Based on the results of developmental and reproductive 

toxicity studies, there is not a concern for increased qualitative and/or quantitative 

susceptibility following in utero exposure to metolachlor or S-metolachlor. 

3.2.4 Immunotoxicity

There are no indications in the available studies that organs associated with immune 

function, such as the thymus and spleen, are affected by metolachlor or S-metolachlor. 

There are no effects seen on the developing immune system in the existing studies. An 

immunotoxicity study is required, however, under 40 CFR Part 158 as a part of the new 

data requirements for registration of a pesticide (food and non-food uses).

3.2.5 Neurotoxicity

There is no evidence in the toxicology database that metolachlor or S-metolachlor is 

neurotoxic. In the rat developmental toxicity study with S-metolachlor (MRID 

43928925), 6/24 animals in the 1000 mg/kg/day group and 3/24 in the 500 mg/kg/day

group were described as exhibiting discomfort (pushing head through bedding for one 

hour after each dose); the sign was first observed after the initial treatment. No control 

animals were affected. In the rat prenatal developmental toxicity study with metolachlor, 

clinical signs of clonic and/or tonic convulsions and excessive salivation, possible 

neurotoxic signs, were observed at 1000 mg/kg/day. However, the signs were prior to 

death in some of the treated animals and could be agonal effects. Acute and subchronic 

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

158 Toxicology Data Requirements.

3.2.6 FQPA Safety Factor

There is low concern (and no residual uncertainty) for pre- and/or postnatal toxicity

resulting from exposure to S-metolachlor. Data available on metolachlor and Smetolachlor provided no indication of increased susceptibility (quantitative or qualitative) 

to rats or rabbits exposed in utero. The metolachlor rat reproduction study showed no 

evidence of reproductive toxicity. The dietary exposure from food and water and 
Page 18 of 38

residential exposure are not understated. Therefore, the special FQPA safety factor is 

reduced to 1x for risk assessment for this chemical. A developmental neurotoxicity study

is not required since there was no evidence of neurotoxicity or neuropathology from the 

available studies and there is no concern or residual uncertainty for pre/post-natal 

toxicity. Based on the results of the available toxicity studies, there is no evidence for 

immunotoxicity.

 

Since there are adequate developmental studies in rats and rabbits and an adequate multigeneration study in rats, and no residual uncertainties in toxicity or exposure databases

that indicate the need for a factor, the FQPA factor has been reduced to 1X. 

3.3 Toxicity Endpoint Selection

3.3.1 Acute Reference Dose (aRfD) - General Population

Selected Study: Developmental Toxicity in Rats - Metolachlor (MRID 00151941). 

In a prenatal developmental toxicity study with metolachlor on rats, the maternal toxicity

LOAEL was 1000 mg/kg/day based on an increased incidence of death, clinical signs of 

toxicity (clonic and/or toxic convulsions, excessive salivation, urine- stained abdominal 

fur and/or excessive lacrimation) and decreased body weight gain. The NOAEL was 300 

mg/kg/day. The developmental toxicity LOAEL was conservatively established at 1000 

mg/kg/day based on slightly decreased number of implantations per dam, decreased 

number of live fetuses/dam, increased number of resorptions/dam and significant 

decrease in mean fetal body weight. The NOAEL was 300 mg/kg/day.

Dose and Endpoint for Establishing an aRfD: 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. 

Uncertainty Factor (UF): 100 – 10x for interspecies extrapolation and 10x for intraspecies 

variation.

Comments about Study/Endpoint: Since clinical signs are observed after a single oral 

dose of metolachlor, the duration and route of administration are appropriate for the risk 

assessment. Developmental effects observed are not attributable to a single exposure and 

therefore, a separate acute endpoint has not been identified for females 13-50. Although 

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. 
Page 19 of 38

3.3.2 Chronic Reference Dose (RfD) – General Population

Selected Study: Chronic Feeding Study in Dogs (MRID 43744201). 

In a one year metolachlor oral feeding study in dogs, the NOAEL was 9.7 mg/kg/day and 

the LOAEL was 33 mg/kg/day based on stomach lesions in 75% of the males and by

slight sinusoidal histiocytosis in the liver of 50% of the males. 

Dose and Endpoint for Establishing an aRfD: 9.7 mg/kg/day based on a NOAEL of 9.7 

mg/kg/day and a LOAEL of 33 mg/kg/day based on decreased body weight gain in 

females.

Uncertainty Factor (UF): 100 – 10x for interspecies extrapolation and 10x for intraspecies 

variation.

3.3.3 Incidental Oral Exposure (Short-Term)

Selected Study: Developmental Toxicity Study in Rats (MRID 43928925). 

In a developmental study conducted with S-metolachlor in rats the maternal toxicity

NOAEL was 50 mg/kg/day with a LOAEL of 500 mg/kg/day based on increased clinical 

signs of toxicity, decreased body weights and body weight gains and reduced food 

consumption and reduced food efficiency. No significant treatment related 

developmental toxicity was noted at the dose levels tests. The developmental toxicity

NOAEL was equal to or greater than 1000 mg/kg/day; a LOAEL was not reached.

Dose and Endpoint: 50 mg/kg/day based on an offspring NOAEL of 50 mg/kg/day and a 

LOAEL of 500 mg/kg/day based on increased incidence of clinical signs, decreased body

weight/body weight gain, food consumption and food efficiency seen in maternal 

animals.

Uncertainty Factor (UF): 100 – 10x for interspecies extrapolation and 10x for intraspecies 

variation.

Comments about Study/Endpoint: The NOAEL (20 mg/kg/day) for the prenatal 

developmental toxicity study in rabbits with S-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 

Acute RfD (General Population) = (NOAEL) 300 mg/kg = 3.0 mg/kg

 (UF) 100

Chronic RfD (General Population) = (NOAEL) 9.7 mg/kg = 0.097 mg/kg

 (UF) 100
Page 20 of 38

100 mg/kg/day. Although there was a dose-related increase in this effect, it is not 

evidence of frank toxicity and was judged not be appropriate for risk assessment. 

Therefore, the rabbit study with S-metolachlor was not selected for this exposure 

scenario.

3.3.4 Dermal Exposure (Short-Term)

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. 

3.3.5 Inhalation Exposure (Short-Term)

Selected Study: Developmental Toxicity Study in Rats (MRID 43928925). 

Dose and Endpoint: 50 mg/kg/day based on an offspring NOAEL of 50 mg/kg/day and a 

LOAEL of 500 mg/kg/day based on is based on increased incidence of clinical signs, 

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

maternal animals.

Uncertainty Factor (UF): 100 – 10x for interspecies extrapolation and 10x for intraspecies 

variation.

Comments about Study/Endpoint: Since an oral study was selected, a 100% absorption 

factor should be applied.

3.3.6 Inhalation Exposure (Intermediate-Term)

Selected Study: Subchronic (6 month) Toxicity Study in the Dog (MRID 00032174)

In a subchronic oral toxicity study (MRID5 00032174 and 43244001), metolachlor 

(96.8% ai) was administered in the diet to Beagle dogs (8/sex/group for control and high 

dose groups; 6/sex/group for low- and mid-dose groups) at dose levels of 0, 100, 300 or 

1000 ppm (males: 0, 2.92, 9.71 and 29.61 mg/kg/day, respectively; females: 0, 2.97, 8.77 

and 29.42 mg/kg/day, respectively) for six months. There were no deaths or clinical 

signs of toxicity. Mean body weight gain was decreased during weeks 0-13 and 0-26 in 

the 1000 ppm group males (55-63% decrease) and females (44-50% decrease), although 

the changes were not statistically significant. Mean overall food consumption was not 

affected in the 1000 ppm group males but was slightly decreased (9%) in the 1000 ppm 

females. There was a significant decrease in the activated partial thromboplastin time 

(APTT) in the 300 and 1000 ppm group males and 300 ppm group females but the 

findings were not considered toxicologically significant because the decrease was slight 

and not dose-related. Alkaline phosphatase was significantly increased in the 300 ppm 

and 1000 ppm group males and females at week 26; however, the effect was not 

considered toxicologically significant due to the small magnitude of the increase and the 
Page 21 of 38

lack of accompanying necropsy findings. The LOAEL was 1000 ppm (males/females: 

29.61/29.42 mg/kg/day) based on decreased body weight gain. The NOAEL was 300 

ppm (males/females: 9.71/8.77 mg/kg/day). Dose and Endpoint for Risk Assessment: 

NOAEL of 8.8 mg/kg/day based on decreased body weight gain at 29.4 mg/kg/day

Dose and Endpoint: NOAEL of 8.8 mg/kg/day based on decreased body weight gain at 

29.4 mg/kg/day

Comments about Study/Endpoint: Since an oral study was selected, a 100% absorption 

factor should be applied.

3.3.7 Classification of Carcinogenic Potential

HED’s Cancer Assessment Review Committee (CARC) classified metolachlor as a 

Group C carcinogen with risk quantitated using a non-linear approach. The NOAEL of 

15 mg/kg/day from the rat combined chronic toxicity/carcinogenicity study is based on 

neoplastic nodules/hepatocellular carcinomas seen at the highest dose tested of 150 

mg/kg/day. The Agency notes that the tumor NOAEL of 15 mg/kg/day is comparable to 

the NOAEL of 9.7 mg/kg/day selected for establishing the chronic reference dose for 

metolachlor (TXR 014691, 9/28/01). The recommendation for a non-linear approach 

should be followed since no new data were submitted for a re-evaluation by the CARC.

3.4 Margins of Exposure

Table 3.4 Target Levels of Concern/Margin of Exposure S-Metolachlor

Route/Duration Short-Term

(1-30 Days)

Intermediate-Term

(1 - 6 Months)

Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal NA NA N/A

Inhalation 100 100 N/A

Residential (Non-Dietary) Exposure

Oral 100 N/A N/A

Dermal NA N/A N/A

Inhalation N/A N/A N/A

3.5 Recommendation for Aggregate Exposure Risk Assessments

When there are potential residential exposures to the pesticide, aggregate risk assessment 

must consider exposures from three major sources: oral, dermal and inhalation exposures. 

There are potential residential incidental oral exposures to S-metolachlor via postapplication hand-to-mouth exposure of children playing on treated lawns. In addition, 

dietary and incidental oral endpoints for S-metolachlor are based on common 

toxicological effects. Therefore, exposures from food and non-food oral routes should be 

aggregated for this assessment. 

3.6 Summary of Endpoints Selected for Risk Assessment
Page 22 of 38

Table 3.6.a. 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 

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 = 

0.97mg/kg/day

Chronic Toxicity – Dog;

LOAEL = 33 mg/kg/day based decreased 

body weight gain in females 

Cancer (all routes) Metolachlor has been classified as a Group C carcinogen with risk quantitated using a 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. 

Table 3.6.b. 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 

LOAEL = 500 mg/kg/day based on 

increased incidence of clinical signs, 

decreased body weight/body weight gain, 

food consumption and food efficiency seen 

at the LOAEL in maternal animals.

Inhalation Short-Term

(1-30 days)

NOAEL= 

50 mg/kg/day

UFA= 10x

UFH=10x

Occupational 

LOC for MOE = 

100

Developmental Toxicity Study - Rat 

LOAEL = 500 mg/kg/day based on 

increased incidence of clinical signs, 

decreased body weight/body weight gain, 

food consumption and food efficiency seen 

at the LOAEL in maternal animals.

Inhalation Short-Term

(1-30 days)

NOAEL= 

8.8 mg/kg/day

UFA= 10x

UFH=10x

Occupational 

LOC for MOE = 

100

Subchronic Toxicity Study - Dog 

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. 
Page 23 of 38

3.7 Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential 

adverse outcomes from exposure to chemicals. Collectively, these studies include acute, 

subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, 

developmental, reproductive, and general or systemic toxicity. These studies include 

endpoints which may be susceptible to endocrine influence, including effects on 

endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, 

fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological 

hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, 

developmental and reproductive effects in different taxonomic groups. As part of its 

most recent registration decision, EPA reviewed these data and selected the most 

sensitive endpoints for relevant risk assessment scenarios from the existing hazard 

database. However, as required by FFDCA section 408(p), S-metolachlor, as an enriched 

isomer of metolachlor, is subject to the endocrine screening part of the Endocrine 

Disruptor Screening Program (EDSP). 

EPA has developed the EDSP to determine whether certain substances (including 

pesticide active and other ingredients) may have an effect in humans or wildlife similar to 

an effect produced by a “naturally occurring estrogen, or other such endocrine effects as 

the Administrator may designate.” The EDSP employs a two-tiered approach to making 

the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays 

to identify the potential of a chemical substance to interact with the estrogen, androgen, 

or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening 

and are found to have the potential to interact with E, A, or T hormonal systems will 

proceed to the next stage of the EDSP where EPA will determine which, if any, of the 

Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to 

identify any adverse endocrine-related effects caused by the substance, and establish a 

dose-response relationship between the dose and the E, A, or T effect. 

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between 

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group 

of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. 

Metolachlor was included on that list and has been issued an order to conduct the Tier 1 

testing. Once all required Tier 1 and Tier 2 data have been received and reviewed, the 

endpoints and safety factors used for risk assessment purposes will be examined and a 

new risk assessment performed for S-metolachlor if necessary. For further information 

on the status of the EDSP, the policies and procedures, the list of 67 chemicals, future 

lists, the test guidelines and the Tier 1 screening battery, please visit our website: 

http://www.epa.gov/endo/.

4.0 RESIDUE CHEMISTRY CONSIDERATIONS

4.1 Metabolism in Plants/Livestock

The qualitative nature of metolachlor residues in plants is adequately understood based 

upon the adequate corn, potato, and soybean metabolism studies. The metabolism of 
Page 24 of 38

metolachlor 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 oxocompounds. Residues of concern in plants include metolachlor and its metabolites, 

determined as the derivatives CGA-37913 and CGA-49751. The Agency previously

concluded that the residues of concern for S-metolachlor are the same as for metolachlor.

Adequate studies are available depicting the metabolism of metolachlor in ruminants and 

poultry. Metolachlor is rapidly metabolized and almost totally eliminated in the urine 

and feces of ruminants (goats), non-ruminants (rats), and poultry. Metolachlor per se was 

not detected in any of the excreta or tissues. As in plants, metolachlor residues of 

concern in livestock commodities include metolachlor and its metabolites, determined as 

the derivatives CGA-37913 and CGA-49751. The residues of concern for S-metolachlor 

in livestock are the same as those for metolachlor. 

The residues of concern for S-metolachlor in drinking water include the parent, CGA354743 (metolachlor ethanesulfonic acid (ESA)) and CGA-51202 (metolachlor oxanilic 

acid (OA)).

4.2 Metabolism in Rotational Crops 

Based on the available data, HED concluded that the metabolism of [14C]S-metolachlor 

in rotational crops is similar to the metabolism observed in the primary crops. 

Metabolism in rotational crops primarily involves two pathways: (i) conjugation of the 

parent molecule with glutathione by substitution of the chlorine, followed by the 

degradation of the glutathione moiety to form a variety of sulfur containing metabolites; 

and (ii) direct oxidation of parent or secondary metabolites, primarily on the chloroacetyl 

side chain. Complete degradation of secondary metabolites either in the soil and/or 

plants also resulted in the incorporation of molecule fragments into natural plant 

constituents. The residues of concern for both metolachlor and S-metolachlor in 

rotational crops are the same as for primary crops, metolachlor and its metabolites, 

determined as the derivatives CGA-37913 and CGA-49751. 

Table 4.2 Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance 

Expression

Matrix Residues included in Risk Assessment Residues included in Tolerance 

Expression

Plants Primary Crop Parent & metabolites convertible to CGA37913, CGA-49751Parent & metabolites convertible to 

CGA-37913, CGA-49751

Rotational Crop Parent, CGA-37913 & metabolites convertible 

to CGA-49751

Parent & metabolites convertible to 

CGA-37913, CGA-49751

Livestock Ruminant Parent & metabolites convertible to CGA37913, CGA-49751Parent & metabolites convertible to 

CGA-37913, CGA-49751

Poultry Parent & metabolites convertible to CGA37913, CGA-49751Parent & metabolites convertible to 

CGA-37913, CGA-49751
Page 25 of 38

Table 4.2 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

Drinking Water Parent & metabolites convertible to CGA354743 (metolachlor ethanesulfonic acid 

(ESA)) and CGA-51202 (metolachlor oxanilic 

acid (OA))

Not Applicable

4.3 Residue Analytical Methods

4.3.1 Enforcement Methods

Adequate methodology is available for enforcing the established and recommended 

tolerances. PAM Vol. II, Pesticide Regulation Section 180.368, lists a GC/NPD method 

(Method I) for determining residues in/on crop commodities and a GC/MSD method 

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

determine residues of metolachlor and its metabolites as either CGA-37913 or CGA49751 following acid hydrolysis. 

4.3.2 Multiresidue Methods

Adequate data are available on the recovery of metolachlor through Multiresidue Method 

Testing Protocols. The FDA PESTDATA database indicates that metolachlor is 

completely recovered through Method 302, PAM Vol. I (3rd ed., revised 10/97).

4.3.3 Residues in Crops

Coriander (Cilantro)

The submitted study is adequate in number and geographic location of residue field trials. 

Five field trials were conducted in EPA Regions 2 (2), 6, 9, and 10. At all sites, two plots 

received a single broadcast application of S-metolachlor at the approximate rate of 0.64 

lb ai/A or 0.96 lb ai/A. Coriander (cilantro) fresh leaf and stem samples were harvested 

approximately 30 (27-34) days pre-harvest interval (PHI), after the application and placed 

into frozen storage shortly after harvest. At one site, additional treated plots received a 

single broadcast application of S-metolachlor at the approximate rate of 0.64 lb ai/A or 

0.96 lb ai/A, where coriander (cilantro) seed were collected. At another site, additional 

treated plots received a single broadcast application of S-metolachlor at the approximate 

rate of 0.64 lb ai/A or 0.96 lb ai/A, and coriander (cilantro) leaves and stems were 

collected at 27 days and dried in an oven. No spray adjuvant was used at the trials. No 

residue decline studies were submitted.

Coriander (cilantro) fresh, dried and seed samples were analyzed for residues of Smetolachor using the “Working Method for PR 09595: Analysis of s-Metolachlor in 

Cilantro as Metabolites s-CGA-37913 (SYN-506357) and s-CGA-49751 (SYN508500),” a modification of Syngenta Method No. 1848-01, dated June 26, 2003 entitled 

“Analytical Method for the Enantioselective Determination of Residues of s-Metolachlor 
Page 26 of 38

as Metabolites SYN-506357 and SYN-508500 in Agricultural Commodities by Chiral 

High Performance Liquid Chromatograph with Mass Spectrometric Detection.” 

The residue analytical method for S-metolachlor residues in/on coriander (cilantro)

samples was validated both prior to and concurrently with field samples. Based on 

recoveries at the LLMV, the LOD (std. dev. x one-tailed t-statistic) were calculated. The 

LOQ (3 x LOD) were also calculated. The LLMV, LOD and LOQ for SYN-506357 and 

SYN-508500 in/on the three matrices are listed below:

Table 4.4.3. Summary of S-Metolachlor Analytical Method Limits

Commodity Analyte Calculated LOD

(ppm)

Calculated LOQ

(ppm)

LLMV

(ppm)

Coriander 

(cilantro) Fresh 

Samples

SYN-506357

SYN-508500

0.0145

0.0132

0.0436

0.0396

0.05

0.05

Coriander 

(cilantro) Dried 

Samples

SYN-506357

SYN-508500

0.0160

0.0175

0.0480

0.0526

0.05

0.05

Coriander 

(cilantro) Seed 

Samples

SYN-506357

SYN-508500

0.0154

0.0120

0.0463

0.0359

0.05

0.05

The data collection method was adequate for the determination of S-metolachlor residues 

in coriander (cilantro) commodities.

The analytical results show that after a single foliar broadcast application of Smetolachlor at the approximate rate of 0.64 lb ai/A and 0.96 lb ai/A with a 27 to 34-days 

PHI, the maximum total S-metolachlor residues as parent equivalents were approximately

3.7 ppm and 4.1 ppm in coriander (cilantro) fresh leaves and stems, respectively. The 

maximum total S-metolachlor residues as parent equivalents were increased from 

approximately <0.131 ppm (fresh samples) to 0.834 ppm (dried samples) in the 0.64 lb 

ai/A treated plot. The maximum total S-metolachlor residues as parent equivalents were 

increased from approximately 0.170 ppm (fresh samples) to 2.031 ppm (dried samples) in 

the 0.96 lb ai/A treated plot. The maximum total S-metolachlor residues as parent 

equivalents were <0.131 ppm in coriander (cilantro) seed at both application rates. 

Based on the results of these trials, the appropriate tolerance for residues of Smetolachlor in/on coriander (cilantro) leaves is 8.0 ppm. However, the Agency uses the 

preferred name coriander not cilantro for this raw agricultural commodity and, in 

addition, does not differentiate between dry and fresh leaves for coriander (cilantro). 

Therefore, a revised Section F should be submitted to indicate a request for coriander, 

leaves at 8.0 ppm and the cilantro dried and fresh leaves should be removed. The study

data indicates that the requested tolerance on coriander, seed at 0.13 ppm is adequate. 

Beet, Garden, Leaves

No new data have been submitted in support of the requested tolerance on beet, garden, 

leaves. The request is based on the currently established tolerance for residues of Smetolachlor on Brassica leafy vegetables (Sub-group 5B), of 1.8 ppm. The Chemistry
Page 27 of 38

Science Advisory Council (ChemSAC) has considered the issue and determined that 

since the use pattern for beet greens is the same as that for leafy Brassica (sub group 5B), 

and beet greens are similar to the commodities in the leafy Brassica subgroup 5B, it is 

appropriate to translate this tolerance of 1.8 ppm to beet greens. 

Based on the CHEMSAC determination and that the proposed use pattern for beet, 

garden, leaves is the same as leafy Brassica greens, subgroup 5B, ARIA recommends for 

the proposed tolerance of 1.8 ppm on beet, garden, leaves.

4.4 Residues in Livestock

The proposed use for S-metolachlor will have no significant impact on the dietary burden 

of metolachlor to livestock. As a result, no changes are required in the current tolerances 

for metolachlor residues in livestock commodities.

4.5 Residues in Processed Commodities

The proposed use for S-metolachlor on coriander (cilantro) and beet, garden, leaves will 

result in no processed commodities of regulatory interest. A discussion of processed 

commodities is not germane to this action

4.6 Residues in Rotational Crops

Field rotational crop data have been submitted previously which are adequate to support 

the existing rotational crop restrictions. Do not rotate to food or feed crops other than 

those listed in the Dual Magnum® label. For all crops not listed, wait at least 12 months 

following the last application of Dual Magnum® before planting.

4.7 Drinking Water Profile

4.7.1 Environmental Fate and Transport

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 Smetolachlor. Available data suggest that metolachlor and S-metolachlor are expected to 

be highly mobile to mobile in soil and water environments. 

4.7.2 Estimated Drinking Water Concentrations
Page 28 of 38

EFED calculated conservative, Tier I EDWCs of metolachlor and S-metolachlor in 

ground water and surface water for use in the last human health risk assessment. Since 

there are existing uses of S-metolachlor with higher application rates than the proposed 

Section 3 uses, 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 (see 

metabolites table, Appendix 1). Although it was determined by HED’s Metabolism 

Assessment Review Committee (MARC) that the ESA and OA metabolites appear to be 

less toxic than parent metolachlor, they are included in the risk assessment since they

were found in greater abundance than the parent in water monitoring studies. 

EDWCs were calculated 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 and average 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).

4.8 Dietary Exposure Analysis and Risk Estimates

Following recommendations made in the revised Tolerance Reassessment Eligibility

Decision (TRED) for Metolachlor and S-Metolachlor (DP# 292881, S. Kinard, 8/15/03), 

tolerances for metolachlor and S-metolachlor have been separated into different 

subsections of 40 CFR §180.368. 

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

Exposure Evaluation Model software with the Food Commodity Intake Database 

(DEEM-FCIDTM, Version 1.3), which incorporates consumption data from USDA’s 

Continuing 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 Smetolachlor/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 
Page 29 of 38

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. 

Table 4.8.a. Summary of Acute Dietary Exposure and Risk for S-metolachlor and Metolachlor

Population Subgroup aPAD (mg/kg/day) Acute (95th Percentile)

Exposure (mg/kg/day) %aPAD

General U.S. Population

3.0

0.014688 <1.0

All Infants (< 1 year old) 0.046244 1.5

Children 1-2 years old 0.025061 <1.0

Children 3-5 years old 0.022362 <1.0

Children 6-12 years old 0.015532 <1.0

Youth 13-19 years old 0.011553 <1.0

Adults 20-49 years old 0.012690 <1.0

Adults 50+ years old 0.011471 <1.0

Females 13-49 years old 0.012602 <1.0

Table 4.8.b. Summary of Chronic Dietary Exposure and Risk for S-metolachlor and Metolachlor

Population Subgroup cPAD (mg/kg/day) Chronic

Exposure (mg/kg/day) %cPAD

General U.S. Population

0.1

0.004550 4.5

All Infants (< 1 year old) 0.011574 11.6

Children 1-2 years old 0.008666 8.7

Children 3-5 years old 0.007852 7.9

Children 6-12 years old 0.005372 5.4

Youth 13-19 years old 0.003698 3.7

Adults 20-49 years old 0.003994 4.0

Adults 50+ years old 0.004017 4.0

Females 13-49 years old 0.003929 3.9

5.0 NON-DIETARY, NON-OCCUPATIONAL EXPOSURE

There are no residential exposures for the proposed new use of S-metolachlor for this 

Section 3 assessment. However, there is potential for residential exposure to Smetolachlor from use of other registered products which are applied to residential lawns 

or turf by professional applicators. 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), the only potential short-term residential risk 
Page 30 of 38

scenario anticipated is post-application hand-to-mouth exposure of children playing on 

treated lawns. S-metolachlor incidental oral exposure is assumed to include hand-tomouth exposure, object-to-mouth exposure and exposure through incidental ingestion of 

soil. Residential post application exposure to S-metolachlor for this scenario has been 

assessed in a separate document (D274331, R. Griffin, 2/20/02). The residential 

exposure to toddlers for this scenario was calculated to be 0.046 mg/kg/day resulting in 

an MOE of 1100. The MOE from the residential risk scenario for exposure to Smetolachlor does not exceed the Agency’s level of concern. Results from that assessment 

have been used to assess aggregate risk from exposure to food, drinking water, and 

residential lawns for this Section 3 analysis. Based on this analysis, short-term oral

MOEs are not of concern.

6.0 AGGREGATE RISK

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and 

risks from three major sources: food, drinking water, and residential exposures. In an 

aggregate assessment, exposures from relevant sources are added together and compared 

to quantitative 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 proposed and existing Section 3 uses, acute, short-term, intermediate-term 

and chronic aggregate exposures are anticipated. Aggregate exposure assessments were 

performed for acute aggregate dietary exposure (food + drinking water), chronic 

aggregate dietary exposure (food + drinking water), and 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. 

6.1 Acute Aggregate Risk

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

and drinking water, and does not include dermal, inhalation or incidental oral exposure. 

Since the acute dietary exposure assessment already includes the highest acute exposure 

from the drinking water modeling data, no further calculations are necessary. The acute 

risk estimate for all populations, resulting from aggregate exposure to S-metolachlor in 

food and drinking water is below ARIA’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.

6.2 Short- & Intermediate-Term Aggregate Risk

There are no residential user exposures for the proposed new use of S-metolachlor for 

this Section 3 assessment. However, there is potential for residential exposure to Smetolachlor from use of other registered products which are applied to residential lawns 
Page 31 of 38

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 post-application exposure of children playing on 

treated lawns. S-metolachlor incidental oral exposure is assumed to include hand-tomouth exposure, object-to-mouth exposure and exposure through incidental ingestion of 

soil. Results from that assessment have been used to assess aggregate risk from exposure 

to food, drinking water, and residential lawns for this Section 3 analysis. Based on this 

analysis, short-term aggregate MOEs are not of concern.

Table 6.2 Short-Term Aggregate Risk Calculations for S-metolachlor

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

Toddlers 50 100 0.012 0.046 860

1 NOAEL for incidental oral exposure. 

2 The level of concern (LOC) MOE is 100, based on inter- and intra-species safety factors totaling 100.

3 Residential Exposure = [Incidental Oral exposure from all possible sources -combined hand-to-mouth, 

object-to-mouth, and soil ingestion oral exposure]. No residential oral exposure is expected for adults

3 Aggregate MOE = [NOAEL ÷ (Avg Food & Water Exposure + Residential Exposure)]

6.3 Chronic Aggregate Risk

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

food and drinking water, and does not include dermal, inhalation or incidental oral 

exposure. Since the chronic dietary exposure assessment already includes the highest 

chronic exposure from the drinking water modeling data, no further calculations are 

necessary. The chronic risk estimate for all populations, resulting from aggregate 

exposure to S-metolachlor in food and drinking water is below ARIA’s level of concern. 

The food and drinking water exposure estimates for the most highly exposed subgroup, 

all infants (< 1 year old), is 11.6% of the cPAD.

6.4 Cancer Aggregate Risk

As risks are calculated based on the chronic reference dose are protective of cancer 

effects, no separate cancer risk assessment is necessary. The chronic aggregate risk 

assessment is below the Agency’s level of concern.

7.0 OCCUPATIONAL EXPOSURE AND RISK

7.1 Exposure Scenarios

HED assessed the occupational exposure scenario of mixing, loading, and applying Smetolachlor (Dual Magnum® Herbicide (EPA Reg. No. 100-816) and Dual II Magnum® 

(EPA Reg. No. 100-818)) EC formulations as an herbicide on crops. The proposed uses 

may result in short-/intermediate-term (i.e., 1-30 days or up to 6 months) dermal and 

inhalation exposures during mixing, loading, applying, and postapplication activities. 

Long-term exposures (i.e., 6 months of continuous exposure) are not expected to occur 
Page 32 of 38

based on the proposed use pattern. Dermal toxicological endpoints of concern were not 

identified (i.e., no systemic toxicity was seen following dermal exposure at the limit 

dose) therefore, no dermal exposures were calculated. Short- and intermediate-term 

exposures from inhalation exposure routes were assessed for all exposure scenarios. 

Occupational and residential exposure and risk estimates were conducted using maximum 

application rates and surrogate exposure data from the Pesticide Handlers Exposure 

Database and the Residential Exposure Assessment SOPs. 

7.1.1 Handler Exposure Scenarios

The term “handler” applies to individuals who mix, load, and apply the pesticide product. 

Based on the use pattern, two occupational exposure scenarios were identified for Smetolachlor. 

1) mixing/loading liquid formulation for groundboom application;

2) applying spray with groundboom equipment. 

7.1.2 Post-Application Exposure Scenarios

Since there are no dermal endpoints of concern, post-application dermal exposure was 

not examined for occupational uses. Based on the Agency's current practices, a 

quantitative postapplication inhalation exposure was also not assessed. However, 

volatilization of pesticides may be a potential source of postapplication inhalation 

exposure to individuals nearby to pesticide applications. A study published in the Journal 

of Environmental Quality, Volume 38, September-October 2009, pages, 1785-1795, “Soil 

Moisture and Metolachlor Volatilization Observations over Three Years” demonstrated 

that metolachlor can see its volatilization properties significantly increase with increasing 

surface soil water content. Furthermore, OPP recently sought and received expert advice 

on pesticide volatilization from the Agency’s Scientific Advisory Panel (SAP). The 

Agency is in the process of evaluating the SAP’s final report 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html) and may develop 

policies and procedures to identify the when and how postapplication inhalation exposure 

should be incorporated into the Agency's risk assessments. Consequently, the Agency

may revisit the need for a quantitative postapplication inhalation exposure assessment for 

S-metolachlor as appropriate based on new policies that may result from this effort.

7.2 Occupational Exposure Data and Assumptions

7.2.1..Exposure Data

7.2.1.1 Application Parameters

The maximum application rate for each crop that was listed on the label ranges from 1.21 

to 3.80 lb ai/A.
Page 33 of 38

7.2.1.2 Occupational Exposure Data

Data from Occupational Pesticide Handler Unit Exposure Surrogate Reference Table, 

which summarizes data from PHED was used to assess handler and post-application 

exposures in the absence of chemical-specific data. PHED was designed by a task force 

of representatives from the U.S. EPA, Health Canada, the California Department of 

Pesticide Regulation, and member companies of the American Crop Protection 

Association. It consists of a database of measured exposures for workers involved in the 

handling of pesticides under actual field conditions and a set of computer algorithms used 

to subset and statistically summarize the selected data. 

7.2.2 Exposure Assumptions

The following standard exposure assumptions were used in estimating risks to handlers 

from exposure to S-metolachlor:

• 60 kg, the average body weight of an adult female handler was used to complete 

the short-term inhalation risk assessment based on an oral study where the effects 

were observed in females

• 70 kg, the average body weight of an adult handler was used to complete the 

intermediate-term non-cancer risk assessment based on an oral study where the 

effects were observed in males and females

• Exposure duration is short-term and intermediate-term for all workers assessed. 

• Maximum application rates as determined by proposed label requirements review 

were used for all types and methods of application.

• The area treated for each crop was based on HED’s Exposure Science Advisory

Council Policy Number 9.1. For groundboom applications, a default area of 80 

acres was used.

7.3 Occupational Exposure and Risk Estimates

7.3.1 Handler Exposure

Assumptions and calculations of the risks for handlers are presented in Table 7.3.1. At 

the baseline level, all inhalation MOEs are above the target MOE of 100, thus, risks are 

not of concern. The handler exposure estimates in this assessment are based on a central 

tendency estimate of unit exposure and an upper-percentile assumption for the 

application rate, and thus assumed to represent high-end exposures. The uncertainties 

associated with this assessment stem from the use of surrogate exposure data (e.g., 

differences in use scenario and data confidence), and assumptions regarding the amount 

of chemical handled. The estimated exposures are believed to be reasonable high-end 

estimates based on observations from field studies and professional judgment. In order to 

refine this occupational risk assessment, data on actual use patterns including rates, 

timing, and areas treated would better characterize S-metolachlor risks. 

Table 7.3.1 S-metolachlor Short-term and Intermediate-term Inhalation Risks
Page 34 of 38

Exposure 

Scenario Crop 

Applic

Ratea 

(lbs ai/A)

Area 

Treated b

(A/day)

Unit 

Exposures 

(μg/lb ai) c

Short-termd

(No respirator)

Intermediate-terme

(No respirator)

Dose 

(mg/kg/day) MOE Dose (mg/kg/day) MOE

Mixing/Loading Emulsifiable Concentrates (Liquids)

Groundboom

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

Melon 1.21 80 1.2 0.002 26,000 0.002 5,300

Bushberry and 

Lowbush 

Blueberry

1.27 80 1.2 0.002 25,000 0.002 5,100

Caneberry 3.81 80 1.2 0.006 8,000 0.005 1,700

Sweet Sorghum 1.67 80 1.2 0.003 19,000 0.002 3,800

Leafy Brassica 

Mustard Greens 1.27 80 1.2 0.002 25,000 0.002 5,100

Carrot 1.9 80 1.2 0.003 16,000 0.003 3,400

Cucumber 1.27 80 1.2 0.002 25,000 0.002 5,100

Okra 1.9 80 1.2 0.003 16,000 0.003 3,400

Bulb Onion 1.27 80 1.2 0.002 25,000 0.002 5,100

Green Onion 1.27 80 1.2 0.002 25,000 0.002 5,100

Applying Liquid Sprays

Groundboom

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

Melon 1.21 80 0.74 0.001 42,000 0.001 8,600

Bushberry and 

Lowbush 

Blueberry

1.27 80 0.74 0.001 40,000 0.001 8,200

Caneberry 3.81 80 0.74 0.004 13,000 0.003 2,700

Sweet Sorghum 1.67 80 0.74 0.002 30,000 0.001 6,200

Leafy Brassica 

Mustard Greens 1.27 80 0.74 0.001 40,000 0.001 8,200

Carrot 1.9 80 0.74 0.002 27,000 0.002 5,500

Cucumber 1.27 80 0.74 0.001 40,000 0.001 8,200

Okra 1.9 80 0.74 0.002 27,000 0.002 5,500

Bulb Onion 1.27 80 0.74 0.001 40,000 0.001 8,200

Green Onion 1.27 80 0.74 0.001 40,000 0.001 8,200

a Application rates are the maximum application rates determined Section B of the tolerance petition for Dual 

Magnum® Herbicide.

b Amount handled per day values are HED estimates of acres or tons treated applied based on Exposure SAC SOP #9 

“Standard Values for Daily Acres Treated in Agriculture,” industry sources, and HED estimates.

c Baseline level risk mitigation with no respirator. When engineering controls are noted enclosed cockpits are 

assumed.

d Short-term inhalation MOE = NOAEL (50 mg/kg/day) / inhalation daily dose (mg/kg/day), where inhalation dose = 

daily unit exposure (μg/lb ai) x inhalation absorption factor x application rate x amount handled per day x conversion 

factor (1 mg/1,000 μg) / body weight (60 kg adult female).

e Intermediate-term inhalation MOE = NOAEL (8.8 mg/kg/day) / inhalation daily dose (mg/kg/day), where inhalation 

dose = daily unit exposure (μg/lb ai) x inhalation absorption factor x application rate x amount handled per day x 

conversion factor (1 mg/1,000 μg) / body weight (70 kg adult female)
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7.3.2 Post Application Exposure

Since there are no dermal endpoints of concern, post-application dermal exposure was 

not examined for occupational uses.

8.0 CUMULATIVE RISK

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

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

the cumulative effects of a particular pesticide's residues and “other substances that have 

a common mechanism of toxicity.”

EPA does not have, at this time, available data to determine whether S-metolachlor has a 

common mechanism of toxicity with other substances. Unlike other pesticides for which 

EPA has followed a cumulative risk approach based on a common mechanism of toxicity, 

EPA has not made a common mechanism of toxicity finding as to S-metolachlor and any 

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

produced by other substances which have tolerances in the U. S. For the purposes of this 

tolerance reassessment action, therefore, EPA has not assumed that S-metolachlor has a 

common mechanism 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 OPP concerning common mechanism determinations and procedures for 

cumulating effects from substances found to have a common mechanism on EPA’s 

website at http://www.epa.gov/pesticides/cumulative/.

9.0 CONCLUSION

Pending resolution of the data needs described in Section 10 below, ARIA has no 

concerns regarding human health exposure and risk from the proposed Section 3 uses of 

S-metolachlor on coriander and garden beet leaves:

Commodity Recommended Tolerance (ppm)

Coriander, seed 0.13

Coriander, leaves 8.0

Beet, garden, leaves 1.8

. 

10.0 DATA NEEDS

10.1 Toxicology Data Requirements 

- Acute Neurotoxicity (GLN 870. 6200a)

- Subchronic Neurotoxicity (GLN 870.6200b) 

- Immunotoxicity (GLN 870.7800) 
Page 36 of 38

10.2 Residue Chemistry Data Requirements

- Section F for coriander, leaves at 8.0 ppm with the cilantro, dried and fresh leaves 

removed.

10.3 Occupational/Residential Requirements

None

References

S-Metolachlor: HED Risk Assessment for Proposed New Use of S-Metolachlor on 

Bushberry, Caneberry, Carrot, Cucumber; Leafy Brassica Greens, Melon, Okra, Bulb 

and Green Onion, Sesame Seed, Sorghum, and Turnip Greens. PP#: 6E7607, DP Barcode:

D368726, B. Daiss, 6/30/10

Metolachlor and S-Metolachlor Residue Chemistry Chapter for the Tolerance 

Reassessment Eligibility Decision (TRED). DP Barcode: D274328, S. Kinard, 2/28/02

Section 18 Exemption for Use of Metolachlor on Spinach. ID#: 94OK001, DP Barcode: 

D196641, J. Stokes, 11/24/93

Metolachlor/S-metolachlor Residential Risk Assessment. DP Barcode: D274331, R. 

Griffin, 2/20/02

S-Metolachlor. Petition for the Use on Coriander (Cilantro) and Garden Beet Leaves. 

Summary of Analytical Chemistry and Residue Data. PP#1E7898, DP Barcode: 

D392447, W. Cutchin, 12/6/11

S-metolachlor - Acute and Chronic Dietary and Drinking Water Exposure and Risk 

Assessment for Proposed Section 3 Use on Cilantro and Garden Beet, Leaves.

PP#1E7898, DP Barcode: D396451, W. Cutchin, 1/3/12

US Environmental Protection Agency, Office of Pesticide Programs, Occupational 

Pesticide Handler Unit Exposure Surrogate Reference Table, June 21, 2011, 

http://www.epa.gov/pesticides/science/handler-exposure-table.pdf.
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Appendix 1. CHEMICAL STRUCTURES
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