UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: May 7. 2015 

SUBJECT: S-Metolachlor - Risk Assessment for Establishment of Tolerances for New Uses 

on Let1uce, Low Growing Berry Subgroup I 3-07G, except Cranberry; Vegetable, 

Cucurbit, Group 9; Sunflower subgroup 208; Vegetable, Fruiting, Group 8-1 O; 

except Tabasco Pepper. 

FROM: 

PC Code: I 08800 

Decision No.: 488023 

Petition No.: 4E8248 

Risk Assessment Type: Risk Assessment 

TXR No.: NA 

MRID No.: NA 

Jessica Kidwell, Toxicologist!R_jk As 

Thurston Morton, Ch+!. t /j . Ivan Nieves, ORE _ ,"-

·-~ 

RABIV/HED (7509P) '" 

Health Effects Division (7509P) 

DP Barcodc: 0425168 

Registration No.: I 00-816 

Regulatory Action: Sec1ion 3 Registration 

Case No.: 0001 

CAS No.: 87392-12-9 

40 CFR: § 180.368 

~ 

THROUGH: E

RA

lissa 

BIV

Rea

/HED 

ves 

(7509P) 

PhD., Branch Chi ~ ~:.--- 1 

TO: Andy Ertman, RM 05 

Minor Use & Emergency Response Branch 

Registration Division (7505P) 
S-Metolachlor Human Health Risk Assessment DP No. D425 I 68 

Table of Contents 

I Executive Sum1nary .............. ....... ............................................................................................ 4 

2 I-lED Recommendations .......................................................................................................... 8 

2.1 Data Deficiencies ............................................................................................................. 8 

2.2 Tolerance Considerations .................... .................... ......................................................... 8 

2.2.1 Enforcement Analytical Method ..................................................... .......................... 8 

2.2.2 Recommended Tolerances ........................................................................................ 8 

2.2.3 Revisions to Petitioned-For Tolerances .................................................................... 9 

2.2.4 International Harmonization ..................................................................................... 9 

2.3 Label Recommendations ................................................................................................ 10 

2.3.1 Recommendations from Residue Reviews ............................................................. 10 

2.3.2 Recommendations from Occupational Assessment.. ........................ ....... ............... 10 

2.3.3 Reconm1endations from Residential Assessment .. ....... ...... .............. .................... .. 10 

3 Introduction ....... ............. ................................................................................. ...................... 10 

3.1 Che1nical Identity ........................................................................................................... 10 

3.2 Physical/Chemical Characteristics ................................................................................. 11 

3.3 Pesticide Use Pattern ...................................................................................................... 11 

3.4 Anticipated Exposure Pathways ..................................................................................... 14 

3 .5 Consideration of Environmental Justice ........................................................................ 14 

4 Hazard Characterization and Dose-Response Assessment. ..................................... .............. 15 

4.1 Toxicology Studies Available for Analysis ................................................................... 15 

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME) ................................... 16 

4.2.1 Dern1al Absorption .................................................................................................. 17 

4.3 'foxicological Effects ..................................................................................................... 17 

4.4 Safety Factor for Infants and Children (FQPA Safety Factor) ....................................... 18 

4.4.1 Completeness of the Toxicology Database ............................................................. 18 

4.4.2 Evidence of Neurotoxicity ...................................................................................... 18 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ......... 18 

4.4.4 Residual Uncertainty in the Exposure Database ..................................................... 19 

4.5 Toxicity Endpoint and Point of Departure Selections .................................................... 19 

4.5.1 Dose-Response Assessment ......... ........................................................................... 19 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment.. ...... 20 

4.5.3 Cancer Classification and Risk Assessment Recommendation ...... ........................ 20 

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment ............................................................................................................................ 21 

5 Dietary Exposure and Risk Assessment ................................................................................ 23 

5.1 Metabolite/Degradate Residue Profile .......................... ....... ........................... ............. .. 23 

5.1.1 Summary of Plant and Animal Metabolism Studies ............................................... 23 

Page 2of70 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 3 of 70

5.1.2 Summary of Environmental Degradation ............................................................... 23

5.1.3 Comparison of Metabolic Pathways....................................................................... 23

5.1.4 Residues of Concern Summary and Rationale........................................................ 24

5.2 Food Residue Profile...................................................................................................... 24

5.3 Water Residue Profile .................................................................................................... 25

5.4 Dietary Risk Assessment................................................................................................ 26

5.4.1 Description of Residue Data Used in Dietary Assessment..................................... 26

5.4.2 Percent Crop Treated Used in Dietary Assessment ................................................ 26

5.4.3 Acute Dietary Risk Assessment.............................................................................. 26

5.4.4 Chronic Dietary Risk Assessment .......................................................................... 27

5.4.5 Cancer Dietary Risk Assessment............................................................................ 27

5.4.6 Summary Table....................................................................................................... 27

6 Residential (Non-Occupational) Exposure/Risk Characterization ........................................ 27

6.1 Residential Handler Exposure/Risk Estimates............................................................... 27

6.2 Residential Post-application Exposure/Risk Estimates.................................................. 29

6.3 Residential Risk Estimates for Use in Aggregate Assessment ...................................... 31

6.4 Residential Bystander Post-application Inhalation Exposure ........................................ 32

6.5 Spray Drift...................................................................................................................... 32

7 Aggregate Exposure/Risk Characterization........................................................................... 33

7.1 Acute Aggregate Risk .................................................................................................... 33

7.2 Short-Term Aggregate Risk ........................................................................................... 33

7.3 Intermediate-Term Aggregate Risk................................................................................ 34

7.4 Chronic Aggregate Risk................................................................................................. 34

7.5 Cancer Aggregate Risk................................................................................................... 34

8 Cumulative Exposure/Risk Characterization......................................................................... 34

9 Occupational Exposure/Risk Characterization...................................................................... 35

9.1 Short- and Intermediate-Term Handler Risk.................................................................. 35

9.2 Short- and Intermediate-Term Post-Application Risk ................................................... 36

9.2.1 Dermal Post-application Risk ................................................................................. 37

9.2.2 Inhalation Post-application Risk............................................................................. 37

10 References.......................................................................................................................... 38

Appendix A. Toxicology Profile and Executive Summaries....................................................... 39

Appendix B. Field Trial Summaries............................................................................................ 64

Appendix C. Physical/Chemical Properties................................................................................. 69

Appendix D. Review of Human Research................................................................................... 70
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 4 of 70

1 Executive Summary

Metolachlor (PC Code 108801) is a racemic herbicide that consists of 50% each of the Renantiomer and the S-enantiomer which is the herbicidally active isomer. S-Metolachlor (an 

isomer enriched form of metolachlor, comprised of 88% S-isomer and 12% R-isomer) is a 

selective, chloroacetanilide herbicide that is applied to a variety of crops as a preplant, preplant 

incorporated, preemergence, or postemergence application, primarily for the control of grass 

weeds. S-Metolachlor is registered to Syngenta Crop Protection, Inc. for use on a wide variety 

of food and feed crops including: corn, cotton, grasses grown for seed, legume vegetables, 

peanuts, potatoes, safflower, sorghum, sunflower, and tomatoes. In addition, S-metolachlor is 

registered for use on residential lawns, commercial turf (including golf courses, sports fields, 

recreation areas, and sod farms), ornamentals and horticultural nurseries. S-metolachlor 

formulations include emulsifiable and flowable concentrates, granular, and ready-to-use 

products. Application methods for agricultural uses include ground, aerial, irrigation and 

chemigation. Applications of S-metolachlor to residential lawns or turf are limited to 

professional applicators using backpack, hose-end, or handgun sprayers.

Interregional Research Project No. 4 (IR-4) submitted petition #4E8248 requesting new uses of 

S-Metolachlor on lettuce, Low growing berry subgroup 13-07G except cranberry, along with the 

following crop group expansions: Vegetable, cucurbit group 9, Sunflower subgroup 20B, and 

Vegetable, Fruiting, group 8-10, except tabasco pepper.

The existing toxicological database is primarily comprised of studies conducted with 

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

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

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

exception of a required 28-day inhalation study for metolachlor. Although the neurotoxicity 

battery (870.6200 a and b) is required in accordance with the revised 40 CFR Part 158 

Toxicology Data Requirements, the data requirement for the neurotoxicity studies has been 

waived at the present time by the Hazard and Science Policy Council (HASPOC) in their 

meeting of February 14, 2013.

In subchronic (metolachlor and S-metolachlor) and chronic (metolachlor) toxicity studies in dogs 

and rats decreased body weight and body weight gain were the most commonly observed effects. 

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

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

evidence of neurotoxic effects in adult animals in available subchronic and chronic toxicity 

studies. There was no evidence of immunotoxicity in mice. Prenatal developmental studies in the 

rat and rabbit with both metolachlor and S-metolachlor revealed no evidence of a qualitative or 

quantitative susceptibility in fetal animals. A two-generation reproduction study 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 a mutagenic or cytogenetic effect in vivo or in vitro in studies with 

either metolachlor or S-metolachlor. Metolachlor has been evaluated for carcinogenic effects in 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 5 of 70

the mouse and the rat. Metolachlor was classified as a Group C carcinogen with risk quantitated 

using a non-linear (Margin of Exposure (MOE)) approach. 

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

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

eye irritation, and is non-irritating to the skin, but is a dermal sensitizer.

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

exposure scenarios. An acute reference dose (aRfD=3.0 mg/kg/day) for assessment of food and 

drinking water exposures was selected from a developmental toxicity study in rats (NOAEL = 

300 mg/kg/day). A chronic RfD (cRfD=0.097 mg/kg/day) was selected from a chronic toxicity 

study in dogs (NOAEL = 9.7 mg/kg/day). A short-term incidental oral POD (NOAEL = 50 

mg/kg/day) was selected from a developmental toxicity study in rats. A point of departure (POD) 

for dermal exposure was not selected because no dermal or systemic toxicity was seen in rabbits 

following repeated dermal application at the highest dose tested for 21 days. The short-and 

intermediate-term inhalation exposure POD (50 mg/kg/day) was selected from a developmental 

toxicity study in rats. An uncertainty factor of 100X was applied to endpoints selected for the 

oral exposure route (10x for interspecies extrapolation, 10x for intraspecies variation) and an 

uncertainty factor of 1000X was applied to endpoints selected for the inhalation exposure route 

due to a missing route-specific study (10x for interspecies extrapolation, 10x for intraspecies 

variation, 10x for database uncertainty factor).

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

Residues of concern in plants, livestock, and rotational crops include metolachlor and its

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

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

residues of concern for S-metolachlor in drinking water include the parent, CGA-354743 

(metolachlor ethanesulfonic acid (ESA)) and CGA-51202 (metolachlor oxanilic acid (OA)).

Adequate methodology is available for enforcing the established and recommended tolerances. 

PAM Vol. II, Pesticide Regulation Section 180.368, lists a gas chromatography with nitrogenphosphorus detector (GC/NPD) method (Method I) for determining residues in/on plant 

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

(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.

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

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

the analysis. The data were properly supported by storage stability data.

An adequate confined rotational crop study is available, although additional information 

pertaining to the study remains outstanding. 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 6 of 70

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

exceeds 100% of the population adjusted dose (PAD). Since metolachlor is classified as a Group 

C carcinogen, no separate dietary assessment was performed for cancer, since the chronic dietary 

exposure is considered protective for cancer effects. Conservative acute and chronic dietary 

exposure analyses was performed for the general U.S. population and various population 

subgroups. Tolerance-level residues and 100 percent crop treated assumptions were used. DEEM 

default processing factors were used to modify the tolerance values. The acute analysis 

incorporated the 1 in 10 year peak groundwater estimate from application of S-metolachlor on 

cotton while the chronic analysis incorporated the 10 year average surface drinking water 

estimate from application of S-metolachlor to lettuce. The acute dietary exposure estimates are 

below HED’s level of concern. The 95th percentile acute dietary exposure estimates for the 

general U.S. population and the highest exposed population subgroup, all infants < 1 year old, 

are 2.1% and 6.1%, respectively, of the acute population adjusted dose (aPAD). The chronic 

dietary exposure estimate for the general U.S. population and the highest exposed population 

subgroup, children 1-2 years old, is 6.8% and 3.1% of the chronic population adjusted dose 

(cPAD), respectively.

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. Following the recent recommendation of the Residues of Concern Knowledgebase 

Subcommittee (D424250), parent metolachlor, CGA-51202 (metolachlor-OA), CGA-40172, and 

CGA-50720 will be assessed together in the drinking water assessment using a total toxic 

residues (TTR; USEPA 2009a) approach where half-lives were recalculated (PestDF; USEPA, 

2009b) to collectively account for the parent and the combined residues of concern. These values 

will be utilized in surface and ground water modeling to generate aquatic exposure estimates. 

The EDWC used in the acute assessment is 1.060 ppm. The EDWC used in the chronic 

assessment is 0.0437 ppm.

There are no proposed residential uses at this time; however, there are existing residential uses 

that have been reassessed in this document to reflect updates to HED’s 2012 Residential SOPs1

along with policy changes for body weight assumptions. The revision of residential exposures 

will impact the human health aggregate risk assessment for S-metolachlor.

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. Even though Pennant MAGNUMTM is not intended for 

homeowner purchase or use (i.e., used by professional/commercial applicators), a handler and 

post-application exposure assessment was still quantified since it is not considered a Restricted 

Use Pesticide (RUP).

All residential handler exposure quantification resulted in MOEs above the Agency’s LOC of 

1,000. Therefore, no risk estimates of concern were identified. 

 

1 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 7 of 70

Post-application potential risk was identified for children 1<2 years old with hand-to-mouth oral 

exposure playing on treated turf. The risk estimate was calculated to be 0.038 mg/kg/day 

resulting in an MOE of 1,300, which is considered not of concern as it does not exceed the 

Agency’s level of concern (LOC=100). 

No turf transferable data were available for this chemical. Since the estimated residential turf 

post-application exposure using default turf transferable residue (TTR) values for S-metolachlor 

is minimal in comparison to the level of concern (i.e., the calculated MOE is greater than 10 

times higher than the level of concern, MOE = 1,300 compared to the LOC of 100), EPA is 

waiving the 40CFR TTR data requirement. In this instance, it is unlikely that chemical-specific 

TTR data would be needed to further refine exposure assessments or would add appreciably to 

our general understanding of the availability of turf transferable pesticide residues.

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

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

Since the dietary exposure assessment already includes the highest acute and chronic exposures 

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

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

food and drinking water are below EPA’s level of concern. The food and drinking water 

exposure estimates for the most highly exposed subgroup are 6.1% of the aPAD for all infants (<

1 year old) and 6.8% of the cPAD for children 1-2 years old.

There are no residential user exposures associated with the current petition. However, there is 

potential for residential aggregate exposure to S-metolachlor from use of registered products 

which are applied to residential lawns or turf. Potential short-term residential aggregate risk 

scenarios anticipated include adult inhalation handler exposure to turf via backpack sprayer and 

post-application incidental oral exposure of children playing on treated lawns. The Short-term 

aggregate MOEs were 10,400 for adults and 1100 for children and, therefore, are not of concern.

A second potential short-term risk results from inhalation exposure from spray drift. Although a 

very high end exposure assessment was conducted, based on exposure to flaggers from aerial 

application, this exposure was less than the potential incidental oral exposure, so the inhalation 

exposure will not be aggregated with other exposures. No intermediate-term risk scenarios are 

anticipated for the existing and proposed uses of S-metolachlor.

The occupational handler exposure and risk estimates indicate that the short- and intermediateterm inhalation Margin of Exposures (MOEs) are not of concern to HED (i.e., MOE > 1000) at 

the baseline level of personal protection (i.e., no gloves and no respirator). Based on the 

proposed use sites, it is anticipated that there may be occupational post-application exposure 

from activities such as scouting or weeding; however, there is no dermal POD for S-metolachlor, 

therefore a quantitative assessment was not conducted. However, there is a 24-hour Restricted 

Entry Interval (REI) on the registered label for Dual Magnum® (EPA Reg. No. 100-816), which 

is considered adequate under 40 CFR 156.208 (c) (2) (iii) to protect agricultural workers from 

post-application exposures to S-metolachlor. Based on the Agency's current practices, a 

quantitative non-cancer occupational post-application inhalation exposure assessment was not 

performed at this time. If new policies or procedures are put into place, the Agency may revisit 

the need for a quantitative occupational post-application inhalation exposure assessment.
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 8 of 70

2 HED Recommendations

HED has examined the database for S-metolachlor. Pending submission of analytical standards

and a revised Section F, there are no residue chemistry issues that would preclude setting of the 

recommended tolerances for S-metolachlor, as indicated in Section 2.2.2. A subchronic 

inhalation study in rats for metolachlor is a data gap. In the absence of this study, a 10X database 

uncertainty factor is applied to the inhalation risk assessment as outlined in Section 4.1. 

2.1 Data Deficiencies

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

requested by the repository staff. A subchronic inhalation toxicity study in rats for metolachlor is 

a datagap. For this action, in the absence of this study, a 10X database uncertainty factor is 

applied to the inhalation risk assessment.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate methodology is available for enforcing the established and recommended tolerances. 

PAM Vol. II, Pesticide Regulation Section 180.368, lists a gas chromatography with nitrogenphosphorus detector (GC/NPD) method (Method I) for determining residues in/on plant 

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

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

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

hydrolysis. Adequate data are also available on the recovery of metolachlor through FDA’s 

Multiresidue Method Testing Protocols which indicate that metolachlor is completely recovered 

through Method 302.

2.2.2 Recommended Tolerances

Tolerances are currently established under 40 CFR §180.368 for residues of S-metolachlor, 

including its metabolites and degradates, in or on the commodity(s), as defined. Compliance with 

the tolerance levels specified in the following table below is to be determined by measuring only 

the sum of free and bound S-metolachlor, S-2-chloro-N-(2-ethyl-6-methylphenyl)-N-(2-

methoxy-1-methylethyl)acetamide, its R-enantiomer, and its metabolites, determined as the 

derivatives, 2-(2-ethyl-6-methylphenyl)amino-1-propanol and 4-(2-ethyl-6-methylphenyl)-2-

hydroxy-5-methyl-3-morpholinone, calculated as the stoichiometric equivalent of S-metolachlor, 

in or on the commodity.

The text of the current tolerance expression is in accordance with our current guidance (S. 

Knizner, 5/10/2009)

Recommended tolerances for S-metolachlor are summarized in Table 2.2.2 below, along with 

HED’s recommendations on tolerance level, and commodity names.
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 9 of 70

Table 2.2.2. Tolerance Summary for S-Metolachlor.

Commodity Established/

Proposed Tolerance

(ppm)

Recommended

Tolerance

(ppm)

Comments; 

Correct Commodity Definition

Proposed tolerances under §180.368(a)(2)

Lettuce 1.5 1.5

Low growing berry subgroup 

13-07G, except cranberry

0.40 0.40

Sunflower subgroup 20B 0.50 1.0 Based on existing tolerance for sunflower 

seed of 0.50 ppm. OECD Tolerance 

Calculation procedures recommend a 

tolerance of 1.0 ppm.

Vegetable, Cucurbit group 9 0.50 0.50

Vegetable, Fruiting, group 8-

10, except tabasco pepper, 

and okra

0.40 0.10 Vegetable, Fruiting, group 8-10, except 

tabasco pepper Existing tolerance of 0.1 

ppm is appropriate.

Upon establishment of the above tolerances, the following tolerances established under 

180.368(a)(2) for S-metolachlor and its metabolites on the following commodities should be 

removed, as the proposed tolerances for the above commodities will adequately cover residues of 

S-metolachlor on these commodities.

Vegetable, fruiting, group 8, except tabasco pepper...........................0.10 ppm

Cucumber............................................................................................0.13 ppm

Melon subgroup 9A ............................................................................0.10 ppm

Pumpkin ..............................................................................................0.10 ppm 

Squash, winter.....................................................................................0.10 ppm

Sunflower, seed...................................................................................0.50 ppm

Okra.............................................................................0.10 ppm

2.2.3 Revisions to Petitioned-For Tolerances

The tolerance for Sunflower subgroup 20B is based on existing tolerance for sunflower seed of 

0.50 ppm. However, the OECD Tolerance Calculation procedures recommend a tolerance of 1.0 

ppm. The existing tolerance for Vegetable, Fruiting, group 8-10, except tabasco pepper of 0.10

ppm is appropriate. The exclusion of okra is not necessary. 

2.2.4 International Harmonization

No maximum residue limits (MRLs) for S-metolachlor have been established or proposed by 

Codex, so no International Residue Status Sheet is attached. MRLs for S-metolachlor have been 

established in Canada and MRLs for metolachlor have been established in Mexico; however, no 

MRLs have been established in either country for the requested crops. 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 10 of 70

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

No label changes are needed for the proposed uses. The rotational crop restrictions on the label 

for EPA Reg. No. 100-816 have been evaluated previously (DP#s 332846, etc., 10/21/08, D. 

McNeilly). It was concluded that the proposed restrictions are supported by the available data, 

provided that that rotational crop directions for crops with a 60-day plant back interval (PBI) be 

amended to prohibit a second application of S-metolachlor to any of these crops replanted within 

60 days of the original application. This label amendment has not been made.

2.3.2 Recommendations from Occupational Assessment

There are no label recommendations based on the proposed uses.

2.3.3 Recommendations from Residential Assessment

There are no label recommendations based on the proposed uses.

3 Introduction

3.1 Chemical Identity

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

derivatives are presented in Table 3.1

Table 3.1. Nomenclature of S-Metolachlor and its Regulated Hydrolytic Derivatives.

Parent compound

Common name S-Metolachlor

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

IUPAC name (S)-2-chloro-N-(2-ethyl-6-methyl-phenyl)-N-(2-metonym-1-methyl-ethyl)-

acetamide

CAS name 2-chloro-N-(2-ethyl-6-methylphenyl)-N-[(1S)2-methoxy-1-methylethyl]-

acetamide

CAS registry number 87392-12-9

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

Dual II Magnum® Herbicide (7.64 lb/gal EC; EPA Reg. No. 100-818)

H3C

CH3

N

O

CH3

Cl

H3C

O
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 11 of 70

Table 3.1. Nomenclature of S-Metolachlor and its Regulated Hydrolytic Derivatives.

Regulated residue

Common name None

Company experimental names CGA-37913

SYN506357 (S-enantiomer of CGA 37913)

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

CAS registry number 61520-53-4

82508-08-5 (S-enantiomer)

Regulated residue

Common name None

Company experimental names CGA-49751

SYN508500 (S-enantiomer of CGA 49751)

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

CAS registry number 61520-54-5

3.2 Physical/Chemical Characteristics

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

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

dissociate. It has a high octanol-water partition coefficient (Log(KOW) = 3.0 at 25 C), indicating a 

potential for bioaccumulation or partitioning into human milk. Environmental fate data indicate 

that parent metolachlor/S-metolachlor is moderately persistent to persistent. It is mobile to highly 

mobile in different soils and has been detected extensively in surface water and groundwater. 

Metolachlor/S-metolachlor degradation appears to be dependent on microbially mediated and 

abiotic processes. The physical-chemical properties are tabulated in Appendix C, Table C1.

3.3 Pesticide Use Pattern

The petitioner provided a text listing of proposed uses in Section B of the petition; these included 

proposed uses for Dual Magnum® (EPA Reg. No. 100-816), a 7.62 lb/gal EC formulation, and 

Dual II Magnum® (EPA Reg. No. 100-818), a 7.64 lb/gal EC formulation. 

The proposed uses are presented below in Table 3. 

H3C

NH

CH3

HO

CH3

H3C

CH3

N

O

O

OH

H3C
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 12 of 70

Table 3. Summary of Proposed Directions for Use of S-Metolachlor.1

Applic. Timing; 

Type; and Equip.

(minimum volume)

Formulation

[EPA Reg. 

No.]

Applic. 

Rate

(lb ai/A)

Max. No. 

Applic. per 

Season

Max. Seasonal 

Applic. Rate

(lb ai/A)

PHI

(days)

Use Directions and 

Limitations

Cucurbits, Group 9

Pre-plant, 

Preemergence;

Broadcast; 

Ground or aerial (2 

GPA)

7.62 lb/gal

EC

[100-816]

0.64-

1.272 1 1.27 30

Preplant is no more than 

14 days before planting. 

Preemergence 

application is to be made 

after planting.

Postemergence;

Broadcast or to Row 

Middles; 

Ground or aerial 

Postemergence 

application is to be made 

to plants with at least 1 

true leaf.

Low Growing Berry Subgroup 13-07G, except Cranberry (bearberry; bilberry; blueberry (lowbush); cloudberry; 

lingonberry; muntries; partridgeberry; strawberry (annual and perennial); cultivars, varieties, and/or hybrids of 

these.

Pre-plant, Pretransplant, 

Postemergence;

Broadcast or to row 

middles;

Ground or aerial 

7.62 lb/gal 

EC

[100-816]

0.64-

1.272 2 2.4 30

Application to be made 

before transplanting. 

Pre-plant Soil 

incorporation is not 

recommended, 

Postmergence treatments 

can be made post 

transplant. 

Leaf Lettuce

Pre-plant, 

Preemergence;

Broadcast; 

Ground or aerial 

7.62 lb/gal

[100-816] 0.64-0.95 2 1.27 25

Preemergence 

application is to be made 

after planting.

Postemergence;

Broadcast; 

Ground 

7.64 lb/gal 

EC

[100-818]

0.642 2 1.27 25

The postemergence 

application may be made 

to row middles

Lettuce, Head

Pre-plant, 

Preemergence;

Broadcast; 

Ground or aerial 

7.62 lb/gal

[100-816] 0.64-0.95 2 1.9 20

Preemergence 

application is to be made 

after planting.

Postemergence;

Broadcast; 

Ground 

7.64 lb/gal 

EC

[100-818]

0. 64-

0.952 2 1.9 20

The postemergence 

application may be made 

to row middles
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 13 of 70

Table 3. Summary of Proposed Directions for Use of S-Metolachlor.1

Applic. Timing; 

Type; and Equip.

(minimum volume)

Formulation

[EPA Reg. 

No.]

Applic. 

Rate

(lb ai/A)

Max. No. 

Applic. per 

Season

Max. Seasonal 

Applic. Rate

(lb ai/A)

PHI

(days)

Use Directions and 

Limitations

Fruiting Vegetables

Pre-plant, 

Preemergence, 

Pre-transplant, 

Postemergence;

Directed spray;

Ground (10 GPA)

7.62 lb/gal 

EC

[100-816]

0.67-1.62 1 1.6 60

Pre-plant and Pretransplant application 

should not be 

incorporated; application 

may be directed to the 

soil (or row middle). 

Crop must be more than 

4” tall.

Sunflower Group 20B

Preplant 

incorporated, 

Preemergence;

Ground broadcast, 

or aerial 

7.62 lb/gal 

EC

[100-816]

1.0-1.92 1 1.9 100

Do not allow livestock to 

graze or feed treated 

area.

1

 NS = Not specified. GPA = Gallons per acre.

2

 The lower rates are to be used on soils that are relatively coarse textured and the higher rates are to be used on 

fine-textured soils. 

3

 Muck soils defined as soils with >20% organic matter.

All proposed uses specify that lower rates should be used on relatively coarse textured soils and 

higher rates should be used on fine textured soils. If crops are grown on plastic mulch, the Dual 

Magnum pre-emergence application should be made before laying the plastic. Dual Magnum 

may also be applied as a row middle application after the laying of the plastic mulch. For all 

crops with postemergence uses, it is stated that use of an adjuvant may increase risk to the crop.

Minimum gallons/A and Plantback restrictions for the proposed uses were not included in 

Section B. 

The following crop rotation restrictions are specified on accepted labels for EPA Reg. No. 100-

816:

 a 0-day plantback interval (PBI) for any crop on the Dual Magnum label, or on a 

supplemental Dual Magnum label, provided that the rate of Dual Magnum applied to the 

previous crop was not greater than the labeled rate for the crop to be replanted;

 a 4-month PBI for alfalfa (provided no more than 1.9 lb ai/A was applied to the previous 

crop);

 a 41⁄2-month PBI for barley, oats, rye, and wheat;

 a 9-month PBI for clover (provided no more than 1.9 lb ai/A was applied to the previous 

crop);

 a 60-day PBI for the crops and/or crop groups listed in the table below, depending on the 

amount of S-metolachlor applied to the previous crop;

 tobacco, buckwheat, and rice may be planted the next spring;

 a 12-month PBI for all other food or feed crops.
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 14 of 70

Crops/crop groups allowed for rotation 60 days after application of S-metolachlor.

Crop group/subgroup/crop Amount of S-metolachlor previously applied to 

field 1

≤1.3 lb ai/A ≤1.6 lb ai/A ≤1.9 lb ai/A

Root vegetables (subgroup 1B) yes no no

Bulb vegetables (group 3), green plants yes no no

Winter squash, including pumpkins yes no no

Fruiting vegetables, except cucurbits (group 8) yes yes no

Tuberous and corm vegetables (subgroup 1C) yes yes yes

Bulb vegetables (group 3), dry bulbs yes yes yes

Leaf petiole vegetables (subgroup 4B) yes yes yes

Head and stem Brassica vegetables (subgroup 5A) yes yes yes

1

 If the rate of S-metolachlor applied to the previous crop was greater than the rate listed here, crops from the 

various groups cannot be planted until the following spring.

Conclusions. The proposed use directions are adequate to allow for evaluation of the submitted 

residue data relative to the proposed uses. 

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the 

proposed new uses and crop group expansions. Humans may be exposed to S-metolachlor in 

food and drinking water since S-metolachlor may be applied directly to growing crops and Smetolachlor may reach surface and ground water sources of drinking water. The dietary exposure 

analyses have been updated. Although no residential application scenarios exist, children may be 

exposed to S-metolachlor after professional application on residential turf. In an occupational 

setting, applicators may be exposed while handling the pesticide prior to application, as well as 

during application. There is a potential for post-application exposure for workers re-entering 

treated fields. Risk assessments have been previously prepared for the existing uses of Smetolachlor. This risk assessment considers the new uses and all of the aforementioned exposure 

pathways based on the existing uses of S-metolachlor. 

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the U.S. Department of 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 15 of 70

Agriculture’s (USDA’s) National Health and Nutrition Examination Survey/What We Eat in 

America, (NHANES/WWEIA), are used in pesticide risk assessments for all registered food uses 

of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the 

year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary 

exposure to smaller, specialized subgroups and exposure assessments are performed when 

conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on 

home use of pesticide products and associated risks for adult applicators and for toddlers, youths, 

and adults entering or playing on treated areas post-application are evaluated. Further 

considerations are currently in development as OPP has committed resources and expertise to the 

development of specialized software and models that consider exposure to bystanders and farm 

workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

The existing toxicological database is comprised primarily of studies conducted with 

metolachlor. The toxicology database for S-metolachlor consists of bridging data, which include 

an acute toxicity battery, subchronic toxicity studies in rats and dogs, developmental toxicity 

studies in rats and rabbits, a mutagenicity battery, metabolism studies and an immunotoxicity 

study. Based on a comparison of findings in the two databases by HED’s Hazard Identification 

Assessment Review Committee (HIARC) as well as the Metabolism Assessment Review 

Committee (MARC) (Dobozy, 2001), both in 2001, it was concluded that S-metolachlor is of 

comparable toxicity to the racemic mixture, metolachlor, and that studies with both chemicals 

can be used interchangeably for toxicology endpoint selection. The combined metolachlor and Smetolachlor toxicity data bases are adequate to characterize the toxicity of S-metolachlor for risk 

assessment purposes, with the exception of a required subchronic inhalation study for 

metolachlor. 

The Hazard and Science Policy Council (HASPOC) recently reviewed metolachlor and Smetolachlor (VanAlstine, Julie, 2013). The HASPOC, based on a WOE approach, concluded that 

a neurotoxicity battery is not required for metolachlor at this time. This approach considered all 

of the available hazard and exposure information including: 1) the lack of evidence for clinical 

signs of neurotoxicity or neuropathology in adult animals in subchronic and chronic studies; 2) 

clinical signs of neurotoxicity were seen only at very high doses (Limit Dose) in pregnant rats 

and is used as the endpoint of concern for assessing acute dietary risk; 3) evidence for 

neurotoxicity (functional/behavioral effects) was seen only at high doses in acute neurotoxicity 

studies with structurally-related compounds (acetochlor and propachlor) and in a subchronic 

neurotoxicity study with acetochlor; 4) the POD and endpoint for chronic dietary risk assessment 

is based on effects seen in dogs which appear to be the more sensitive species; and 5) since the 

neurotoxicity studies will be tested at very high doses to elicit effects, they will not provide 

PODs lower than those currently used for overall risk assessment (TXR No. 0056586). The 

HASPOC also concluded that a subchronic inhalation study with metolachlor is required at this 

time. A 10X data base uncertainty factor will be applied only for assessing risk for inhalation 

scenarios.
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 16 of 70

The following studies are available for metolachlor:

 Acute Toxicity Battery

 90-Day Oral Toxicity in the Rat

 90-Day Oral Toxicity in the Dog

 21-Day Dermal Toxicity in the Rabbit

 Prenatal Developmental Toxicity in the Rat

 Prenatal Developmental Toxicity in the Rabbit

 Reproduction and Fertility Effects in the Rat

 Chronic Toxicity in the Dog

 Chronic Toxicity/Carcinogenicity in the Rat

 Carcinogenicity in the Mouse

 Genetic Toxicology Battery

 Metabolism and Pharmacokinetics in the Rat

The following bridging studies are available for S-Metolachlor:

 Acute Toxicity Battery

 90-Day Oral Toxicity in the Rat

 90-Day Oral Toxicity in the Dog

 Prenatal Developmental Toxicity in the Rat

 Prenatal Developmental Toxicity in the Rabbit

 Genetic Toxicology Battery

 Metabolism and Pharmacokinetics in the Rat

 Immunotoxicity in Mice

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

Metolachlor is extensively absorbed and metabolized following oral administration in the rat. 

After oral or intravenous administration of metolachlor, between 69.6% and 93.2% of the 

administered dose was absorbed. A biphasic plasma profile showed two concentration maxima 

(Cmax); a fast rising first Cmax , which was reached at 0.25 - 1 hour post dosing, which was 

succeeded by a second Cmax at 8 and at 12 - 24 hours following administration of the low and 

high dose. Elimination is via the urine and feces. Residual radioactivity at 7 days post dose were 

found in carcass (0.9 - 2.2% of the administered dose) and red blood cells (0.95 - 1.53 μg 

equivalents/gram in blood cells for all low dose male and female rats). There was no apparent 

accumulation of residual radioactivity. 

Excretion data showed that urine and feces were both significant routes for elimination of

metolachlor derived radioactivity. In the low dose groups, the urine appeared more of a 

predominant route for excretion in female rats than in males, whereas fecal excretion was 

slightly higher in males. However, at the high oral dose, there were no apparent sex related 

differences in the pattern of urinary excretion. Examination of urinary excretion data indicated 

that at the 100 mg/kg dose, excretion was delayed vs the low oral dose, suggesting saturation of 

elimination. 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 17 of 70

The major metabolic pathway proposed from analysis of urinary as well as fecal metabolites is 

one of cleavage of the ether bond and subsequent oxidation to the carboxylic acid, as well as 

hydrolytic removal of the chlorine atom. Conjugation of metolachlor or metabolites with 

gluronic acid or sulfate does not appear to occur.

4.2.1 Dermal Absorption

There was no evidence of systemic toxicity at the limit dose in a 21-day dermal toxicity 

metolachlor study in rabbits, however, dermal irritation was observed at lower doses. A dermal 

absorption study is not needed.

4.3 Toxicological Effects

In subchronic (metolachlor and S-metolachlor) and chronic (metolachlor) toxicity studies in 

dogs, rats and mice decreased body weight and body weight gain were the most commonly 

observed effects. There was no evidence of immunotoxicity in mice with S-Metolachlor. 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. No neurotoxicity 

studies with metolachlor or S-metolachlor are available, nor are they required. 

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

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

based on liver tumors in female rats with risk quantitated using a non-linear (Margin of Exposure 

(MOE)) approach (TXR No. 0011347, 1994). 

There was no evidence of increased quantitative or qualitative fetal susceptibility in the prenatal 

developmental studies in rats and rabbits with either metolachlor or S-metolachlor. In general, 

significant developmental toxicity was not seen in rats or rabbits with either compound. In the 

metolachlor rabbit prenatal developmental toxicity study, maternal animals had persistent 

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

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

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

decreased body weight gain was observed at the limit dose in maternal animals. Developmental 

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 developmental toxicity 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 of 500 

mg/kg/day. There were no developmental effects at the highest dose tested. In the rabbit, clinical 

signs of toxicity (little/non/soft stool) were observed at the mid-dose in maternal animals tested 

with S-metolachlor. No developmental effects were observed at the highest dose tested. 

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

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

dose, there was a minor decrease in fetal body weight beginning at lactation day 4. Since a 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 18 of 70

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. 

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

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

eye irritation, and is non-irritating to the skin, but is a dermal sensitizer.

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

The FQPA Safety Factor (SF) is 1X. The toxicity database for S-metolachlor/metolachlor is 

sufficient for a full hazard evaluation and is considered adequate to evaluate risks to infants and 

children. Acceptable developmental toxicity studies in the rat and rabbit and an acceptable 

reproduction study in the rat are available with clearly defined LOAELs and NOAELs. Based on 

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

4.4.1 Completeness of the Toxicology Database

The toxicology database for metolachlor and S-metolachlor is complete, with the exception of a 

required subchronic inhalation study for metolachlor. 

The Hazard and Science Policy Council (HASPOC) recently reviewed metolachlor and Smetolachlor (TXR No. 0056586). HASPOC, based on a WOE approach considering all 

available hazard and exposure information concluded that the acute, subchronic, and 

developmental neurotoxicity studies are not required at this time. The HASPOC concluded that a 

subchronic inhalation study with metolachlor is required at this time. A 10X data base 

uncertainty factor (UFDB) will be applied only for assessing risk for inhalation exposure 

scenarios.

4.4.2 Evidence of Neurotoxicity

There are no acute or subchronic neurotoxicity studies available for S-metolachlor or 

metolachlor. In the developmental rat study, clinical signs of neurotoxicity, including clonic 

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

lacrimation were observed in pregnant dams but only at the limit dose of 1000 mg/kg/day. There 

was no evidence of neurotoxic effects in adult animals in available subchronic or chronic toxicity 

studies. The HASPOC, based on a WOE approach, concluded that a neurotoxicity battery is not 

required for metolachlor at this time (TXR No. 0056586). 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There was no evidence of increased quantitative or qualitative fetal susceptibility in the prenatal 

developmental studies in rats and rabbits or in the reproductive toxicity study in rats, with either 

metolachlor or S-metolachlor. In general, significant developmental toxicity was not seen in rats 

or rabbits with either compound. The only effects observed in fetal animals were in the rat 

prenatal developmental study and included slightly decreased number of implantations per dam, 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 19 of 70

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

decrease in mean fetal body weight. These effects occurred at maternally toxic doses (1000 

mg/kg/day). 

4.4.4 Residual Uncertainty in the Exposure Database

There is no residual uncertainty in the exposure database. The dietary exposure assessment is 

conservative, based on tolerance level residues and 100% crop treated. The residential exposure 

assessment is based on the Residential SOPs, which are designed to produce conservative 

exposure estimates.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

The detailed description of the toxicity studies used for selecting toxicity endpoints and points of 

departure for various exposure scenarios are presented in the appendix. The specific toxicity 

endpoints and PODs are presented in Tables 4.5.4.1 and 4.5.4.2. Toxicological endpoints were 

selected for dietary/drinking water, occupational and residential exposure scenarios. An acute 

reference dose (RfD; 3.0 mg/kg/day) for assessment of food and drinking water exposures was 

selected from a developmental toxicity study in rats with metolachlor (NOAEL = 300 

mg/kg/day). The endpoint of mortality and clinical signs identified in the developmental toxicity 

study in rats (MRID 00151941) was chosen for the acute dietary (general population) endpoint 

because it was considered adverse and results from a single exposure. An endpoint was not 

selected for Females 13–49 years old because no developmental effects were identified in the 

metolachlor/S-metolachlor database that could be attributed to a single exposure. A chronic RfD 

(0.097 mg/kg/day) was selected from a chronic toxicity study in dogs with metolachlor (NOAEL 

= 9.7 mg/kg/day). The endpoint of decreased body weight gain identified in the chronic feeding 

study in dogs was chosen for the chronic dietary (all populations) endpoint because the duration 

of the exposure in this study is appropriate for a chronic dietary endpoint, and the dog study 

provides the lowest NOAEL in the database. The database shows dogs were the more sensitive 

species and decreased body weight gain the most sensitive endpoint. 

The registered uses of S-metolachlor/metolachlor are expected to result in residential exposure 

via incidental oral exposure for toddlers. A short-term incidental oral POD (NOAEL = 50 

mg/kg/day) was selected from a developmental toxicity study with S-metolachlor in rats (MRID 

43928925). This endpoint was based on increased incidence of clinical signs and decreased body 

weight/body weight gain. This study was selected because the effects were judged to be signs of 

frank toxicity and were appropriate to use for risk assessment. The NOAEL of 20 mg/kg/day for 

the prenatal developmental toxicity study in rabbits with S-metolachlor (MRID 43928924) was 

lower than the 50 mg/kg/day from the rat developmental study, however, the endpoint was based 

on weak clinical signs of toxicity (increase in little/none/soft stool observations) at 100 

mg/kg/day. Although there was a dose-related increase in this effect, it was not considered to be 

evidence of frank toxicity and was judged not to be appropriate for risk assessment.
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 20 of 70

A point of departure (POD) for dermal exposure for both occupational and residential scenarios

was not selected because no systemic toxicity was seen in rabbits following repeated dermal 

application of metolachlor at the highest dose tested for 21 days. No inhalation studies were 

available for the short-term and intermediate-term occupational inhalation scenarios. The 

HASPOC met on February 14, 2013 to discuss the need for a subchronic inhalation study for 

metolachlor (TXR #0056586). The decision was made that this study is required. In the absence 

of a route-specific study and based on the current updated HED policies, a short- and 

intermediate-term inhalation exposure POD of 50 mg/kg/day was selected from an oral 

developmental toxicity study in rats with S-metolachlor. The endpoint of increased incidence of 

clinical signs and decreased body weight/body weight gain from the developmental toxicity 

study in rats (MRID 43928925) was identified for the short-and intermediate term inhalation 

exposure endpoints. This study was selected because the effects were judged to be signs of frank 

toxicity and the durations of exposure were appropriate. (The previous intermediate-term 

inhalation POD of 9.7 mg/kg/day from a subchronic dog study was considered overly 

conservative and the current endpoint is protective of both short- and intermediate term 

exposures.) An uncertainty factor of 100X was applied to endpoints selected for the oral 

exposure route (10x for interspecies extrapolation, 10x for intraspecies variation) and an 

uncertainty factor of 1000X was applied to endpoints selected for the inhalation exposure route 

due to a missing route-specific study (10x for interspecies extrapolation, 10x for intraspecies 

variation, 10x for database uncertainty factor for the missing study).

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

Dietary and drinking water exposure are combined in the dietary exposure assessment. 

Children’s incidental oral hand-to-mouth exposure and adult handler exposure via inhalation will 

be combined with dietary and drinking water exposure. The dermal route of exposure will not be 

combined with other routes of exposure for S-metolachlor, since there was no systemic toxicity 

seen at the limit dose in dermal toxicity studies. 

4.5.3 Cancer Classification and Risk Assessment Recommendation

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

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

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

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

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

carcinogen, based on liver tumors in rats at the highest dose tested. Quantification of risk using a 

non-linear approach (i.e., reference dose (RfD)) will adequately account for all chronic toxicity, 

including carcinogenicity, that could result from exposure to metolachlor. 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 21 of 70

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

The points of departure, uncertainty factors, and toxicity endpoints are presented in the following 

tables. No endpoint is selected for dermal exposure scenarios. No hazard was identified at the 

maximum dermal dose tested.

Table 4.5.4.1. Summary of Toxicological Endpoints for S-Metolachlor for Use in Dietary Human Health 

Risk Assessments

Exposure/Scenario Point of 

Departure

Uncertainty/FQP

A Safety Factors

RfD, PAD, 

LOC for Risk 

Assessment

Study and Toxicological Effects

Acute Dietary

(General 

Population)

NOAEL = 

300 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Acute RfD = 3.0 

mg/kg/day

aPAD = 3.0 

mg/kg/day

Developmental Toxicity Study - Rat 

Metolachlor (MRID 00151941)

LOAEL = 1000 mg/kg/day based increased 

incidence of death, clinical signs (clonic 

and/or tonic convulsions, excessive 

salivation, urine-stained abdominal fur 

and/or excessive lacrimation) and 

decreased body weight gain. 

Chronic Dietary 

(All Populations)

NOAEL = 

9.7

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Chronic RfD = 

0.097

mg/kg/day

cPAD = 

0.097mg/kg/day

One Year Chronic Toxicity – Dog;

Metolachlor (MRIDs 40980701, 41164501, 

42218601 and 42218602)

LOAEL = 33 mg/kg/day based decreased 

body weight gain in females 

Cancer (all routes) Metolachlor has been classified as a Group C carcinogen with risk quantitated using a nonlinear (Margin of Exposure) approach. 

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and used to mark the beginning 

of extrapolation to determine risk associated with lower environmentally relevant human exposures. 

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

UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of 

the human population (intraspecies). 

FQPA SF = FQPA Safety Factor. 

PAD = population adjusted dose (a = acute, c = chronic). 

RfD = reference dose. 

MOE = margin of exposure. 

LOC = level of concern. 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 22 of 70

Table 4.5.4.2. Summary of Toxicological Doses and Endpoints for S-METOLACHLOR for Use in 

Residential and Occupational Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of 

Concern for 

Risk Assessment

Study and Toxicological Effects

Incidental Oral Shortterm (1-30 days) NOAEL= 

50 mg/kg/day

UFA= 10x

UFH=10x Residential LOC 

for MOE = 100

Developmental Toxicity Study - Rat 

S-Metolachlor (MRID 43928925)

LOAEL = 500 mg/kg/day based on 

increased incidence of clinical signs, 

decreased body weight/body weight gain, 

food consumption and food efficiency seen 

in maternal animals.

Dermal Short- and 

Intermediate-Term No hazard identified. 

21-day dermal toxicity study – Rabbits

Metolachlor (MRID 41833101)

Systemic LOAEL = Not observed

Systemic NOAEL = 1000 mg/kg/day.

Inhalation Short-Term 

(1-30 days) and 

Intermediate-Term (1-

6 months)

NOAEL= 

50 mg/kg/day

UFA= 10x

UFH=10x

UFD=10x

Occupational 

LOC for MOE = 

1000

Developmental Toxicity Study - Rat 

S-Metolachlor (MRID 43928925)

LOAEL = 500 mg/kg/day based on 

increased incidence of clinical signs, 

decreased body weight/body weight gain, 

food consumption and food efficiency seen 

at the LOAEL in maternal animals.

Cancer (all routes) Metolachlor has been classified as a Group C carcinogen with risk quantitated using a nonlinear (Margin of Exposure) approach. 

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

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

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

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

data (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c 

= chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 23 of 70

5 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

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

based on adequate corn, potato, and soybean metabolism studies, ruminants, poultry, and 

rotational crops. Residues of concern in plants, livestock, and rotational crops include 

metolachlor and its metabolites, determined as the derivatives CGA-37913 and CGA-49751. 

The Agency previously concluded that the residues of concern for S-metolachlor are the same as 

for metolachlor. Metolachlor is metabolized extensively in both plants and livestock. The 

residues of concern for S-metolachlor in drinking water include the parent, CGA-354743 

(metolachlor ethanesulfonic acid (ESA)) and CGA-51202 (metolachlor oxanilic acid (OA)).

5.1.2 Summary of Environmental Degradation

Environmental fate data indicate that parent metolachlor/S-metolachlor is moderately persistent 

to persistent. It is mobile to highly mobile in different soils and has been detected extensively in 

surface water and groundwater. Metolachlor/S-metolachlor degradation appears to be dependent 

on microbial 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. 

5.1.3 Comparison of Metabolic Pathways

Metolachlor and S-metolachlor are extensively metabolized in plants, livestock animals and rats. 

Side by side metabolism was studied only with a single oral dose in rats; no comparative studies 

were conducted with a high dose or repeated doses. The metabolism of metolachlor in plants 

involves conjugation with glutathione, breakage of this bond to form the mercaptan, conjugation 

of the mercaptan with glucuronic acid, O-demethylation of the methyl ether, and conjugation of 

the resultant alcohol with a neutral sugar. A minor pathway may involve sugar conjugation of 

metolachlor directly to the corresponding oxo-compounds. Most of the metabolites of 

metolachlor and S-metolachlor have not been identified. 

Metolachlor is rapidly metabolized and almost totally eliminated in the urine and feces of 

ruminants (goats), non-ruminants (rats), and poultry. There were some minor sex differences in 

the elimination pattern in rats. Metolachlor per se was not detected in any of the excreta or 

tissues. Metolachlor and S-metolachlor were readily absorbed and extensively metabolized by 

goats via glutathione conjugation and/or oxidation reactions. Oxidized metabolites were also 

conjugated with glucuronic acid. Metolachlor and S-metolachlor were extensively metabolized 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 24 of 70

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

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

plants, metolachlor residues of concern in livestock commodities include metolachlor and its 

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

5.1.4 Residues of Concern Summary and Rationale

The metabolism of metolachlor and S-metolachlor has been reviewed by the Metabolism 

Assessment Review Committee (MARC) on August 14, 2001 (Dobozy, V, 2001). The MARC 

determined that, although both metolachlor ethanesulfonic acid (ESA) (CGA-354743) and 

metolachlor oxanilic acid (OA) (CGA-51202) appear to be less toxic than the parent metolachlor 

and S-metolachlor, both should be determined in the drinking water risk assessment since these 

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

summary of metabolites and degradates is provided below. 

Table 5.1.4 Summary of Metabolites and Degradates to be included in the Risk 

Assessment and Tolerance Expression

Matrix Residues included in Risk 

Assessment

Residues included in 

Tolerance Expression

Plants

Primary Crop

Metolachlor and metabolites 

determined as the derivatives 

CGA-37913 and CGA-49751.

Metolachlor and metabolites 

determined as the derivatives 

CGA-37913 and CGA-49751.

Rotational Crop

Metolachlor and metabolites 

determined as the derivatives 

CGA-37913 and CGA-49751.

Metolachlor and metabolites 

determined as the derivatives 

CGA-37913 and CGA-49751.

Livestock

Ruminant

Metolachlor and metabolites 

determined as the derivatives 

CGA-37913 and CGA-49751.

Metolachlor and metabolites 

determined as the derivatives 

CGA-37913 and CGA-49751.

Poultry

Metolachlor and metabolites 

determined as the derivatives 

CGA-37913 and CGA-49751.

Metolachlor and metabolites 

determined as the derivatives 

CGA-37913 and CGA-49751.

Drinking Water

parent metolachlor, 

metolachlor-OA, CGA40172, 

and CGA-50720

Not Applicable

5.2 Food Residue Profile

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

based on adequate corn, potato, and soybean metabolism studies, ruminants, poultry, and 

rotational crops. Residues of concern in plants, livestock, and rotational crops include 

metolachlor and its metabolites, determined as the derivatives CGA-37913 and CGA-49751. 

The petitioner submitted field trial data in support of the proposed uses on lettuce, low growing 

berry subgroup 13-07G, except cranberry (strawberry); vegetable, cucurbit, group 9 (cantaloupe, 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 25 of 70

summer squash and previously submitted data on cucumber); vegetable, fruiting, group 8-10; 

except tabasco pepper (updating crop group, based on previously submitted data on tomato and 

pepper); and sunflower subgroup 20B (previously submitted data on sunflower). The petitioner 

is relying on existing data on cucumber to partially support the proposed use on cucurbits, and 

existing data on sunflower to support the use on the sunflower subgroup 20B. The proposed use 

on fruiting vegetables is to update the crop group. The bell pepper, hot pepper, and tomato field 

trial data are adequate and support the use of S-metolachlor (EC) as either a single preplant 

incorporated or post-emergent foliar application prior to fruit set to fruiting vegetables at ~1.70 

lb ai/A. The data support a 60-day PHI. The residue data are adequate to support a tolerance of 

0.1 ppm S-metolachlor on fruiting vegetables, group 8-10, excluding tabasco pepper. The 

exclusion of tabasco is acceptable because these crops have different use patterns and have 

separate tolerances. The number and geographic representation of the pepper and tomato field 

trials are in accordance with those specified in OPPTS Series 860 Guidelines, Section 1500. The 

submitted data support a single postemergence foliar application of S-metolachlor to cucumber at 

up to 1.3 lb ai/A, provided that application is only made to cucumber up to the 2-leaf growth 

stage. The submitted data will support a tolerance for S-metolachlor residues in/on cucumber of 

0.13 ppm, expressed as metolachlor equivalents. Samples were stored frozen from collection to 

analysis for up to 10 months, an interval supported by available stability data. The submitted 

field trial data are tentatively adequate to support the proposed uses on low growing berry 

subgroup 13-07G, except cranberry, based on field trial data for the representative commodity, 

strawberry.

The field trial data were properly supported by analytical validation data and storage stability 

data. No processing data are needed to support the current tolerance requests.

Although the new tolerance represents a large increase in the dietary burden of S-metolachlor 

and metolachlor to beef cattle, the current tolerance for beef commodities is based on a higher 

dietary burden for S-metolachlor and metolachlor to dairy cattle. The dietary burden for 

metolachlor and S-metolachlor for dairy cattle did not change as a result of the current petition, 

and no increase is needed in the tolerances in livestock commodities.

5.3 Water Residue Profile

D420047, C. Koper, 12/16/14

Following the recent recommendation of the Residues of Concern Knowledgebase 

Subcommittee (D424250), parent metolachlor, CGA-51202 (metolachlor-OA), CGA-40172, and 

CGA-50720 will be assessed together in the drinking water assessment using a total toxic 

residues (TTR; USEPA 2009a) approach where half-lives were recalculated (PestDF; USEPA, 

2009b) to collectively account for the parent and the combined residues of concern. These 

values will be utilized in surface and ground water modeling to generate aquatic exposure 

estimates. 

The highest annual application rate for the proposed IR-4 label (3.7 lbs a.i./A; note that 

sunflower maximum annual application rate is unspecified) is less than what EFED believes is 

the highest previously registered application rates (4 lbs a.i./A to corn or cotton). Therefore, 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 26 of 70

EFED is providing new EDWCs based on the scenario/annual application rate combination that 

will produce the highest EDWCs because degradates of concern and the calculation method have 

changed. Recommended EDWCs of S-metolachlor in surface water and ground water are 

reported in Table 5.3.

Table 5.3. Recommended EDWCs for S-Metolachlor Use on Various Crops

Drinking Water 

Source Crop Scenario 1-in-10 year 

acute 

(μg/L)

1-in-10 year 

chronic

(μg/L)

30- year average 

cancer chronic 

(μg/L)

Surface Water MS Corn 1(aerial) 371 -- --

CA Lettuce 2(aerial) -- 43.70* 21.80

Ground Water NC Cotton 3 (aerial) 1060* NA --

WI Corn 3 (aerial) -- NA 978

1 EDWC calculated from the maximum rate (2 apps x 2.0 lbs a.i./A) registered on corn and cotton generated using

SWCC model (aerial application; TTR approach) with a PCA factor of 0.91. 

2 Current proposed use on lettuce (2 apps x 0.95 lbs a.i./A x 2 seasons).

3 Highest EDWCs generated using PRZM-GW model based on a 30 year simulation of 2 foliar applications of 

 2.0 lbs a.i./A for a maximum annual rate of 4.0 lbs a.i/A for corn/cotton (Metolachlor RED; D185152, 172022).

*Bolded EDWCs were used in the dietary exposure analyses.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

The acute and chronic dietary exposure analyses assumed tolerance level residues.

5.4.2 Percent Crop Treated Used in Dietary Assessment

The acute and chronic dietary exposure analyses assumed 100% crop treated (CT).

5.4.3 Acute Dietary Risk Assessment

A conservative acute dietary exposure analysis was performed for the general U.S. population 

and various population subgroups. Tolerance-level residues and 100 percent crop treated 

assumptions were used. DEEM default processing factors were used to modify the tolerance 

values. The acute analysis incorporated the 1 in 10 year peak groundwater estimate from 

application of S-metolachlor on cotton. This assessment concludes that, for all supported 

commodities, the acute dietary exposure estimates are below HED’s level of concern. The 95th

percentile acute dietary exposure estimates for the general U.S. population and the highest 

exposed population subgroup, all infants < 1 year old, are 2.1% and 6.1%, respectively, of the 

acute population adjusted dose (aPAD). 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 27 of 70

5.4.4 Chronic Dietary Risk Assessment

A conservative chronic dietary exposure analysis was performed for the general U.S. population 

and various population subgroups. Tolerance-level residues and 100 percent crop treated 

assumptions were used. DEEM default processing factors were used to modify the tolerance 

values. The chronic analysis incorporated the 10 year average surface drinking water estimate 

from application of S-metolachlor to lettuce. The chronic dietary exposure estimate for the 

general U.S. population and the highest exposed population subgroup, children 1-2 years old, is 

6.8% and 3.1% of the chronic population adjusted dose (cPAD), respectively.

5.4.5 Cancer Dietary Risk Assessment

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

in rats at the highest dose tested. A linear risk assessment is not required. The chronic RfD is 

protective of any potential cancer effect. 

5.4.6 Summary Table

Table 5.4.6 Summary of Dietary Food and Drinking Water Exposure and Risk 

for S-metolachlor and Metolachlor.

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary

Dietary 

Exposure 

(mg/kg/day)

% aPAD*

Dietary 

Exposure

(mg/kg/day)

% cPAD*

General U.S. Population 0.061369 2.1 0.003008 3.1

All Infants (<1 year old) 0.184165 6.1 0.005652 5.8

Children 1-2 years old 0.096061 3.2 0.006557 6.8

Children 3-5 years old 0.077899 2.6 0.005513 5.7

Children 6-12 years old 0.059378 2.0 0.003690 3.8

Youth 13-19 years old 0.049953 1.7 0.002407 2.5

Adults 20-49 years old 0.059238 2.0 0.002687 2.8

Adults 50-99 years old 0.053503 1.8 0.002644 2.7

Females 13-49 years old 0.059990 2.0 0.002687 2.8

*The subpopulation(s) with the highest risk estimates are bolded.

6 Residential (Non-Occupational) Exposure/Risk Characterization

6.1 Residential Handler Exposure/Risk Estimates

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. Even though Pennant MAGNUMTM is not intended for 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 28 of 70

homeowner purchase or use (i.e., used by professional/commercial applicators), a handler 

exposure assessment was still quantified since it is not considered a Restricted Use Pesticide 

(RUP).

HED uses the term “handlers” to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct tasks related to applications and that 

exposures can vary depending on the specifics of each task. Residential handlers are addressed 

somewhat differently by HED as homeowners are assumed to complete all elements of an 

application without use of any protective equipment.

The quantitative exposure/risk assessment developed for residential handlers is based on the 

following scenarios: 

 Mixing/loading/applying gardens/trees with manually-pressurized handwand, hose-end 

sprayer, backpack, and sprinkler can equipment; and

 Mixing/loading/applying lawns/turf with manually-pressurized handwand, hose-end 

sprayer, backpack, and sprinkler can equipment.

Residential Handler Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the residential 

handler risk assessments. Each assumption and factor is detailed below.

Application Rate: Based on registered residential uses the maximum application rate for handlers 

is of 2.6 pts/A. With 7.62 lb S-metolachlor/gallon of product the maximum application rate can 

be calculated to be 0.000056 lb ai/sq. ft. or 2.47 lb ai/A. Additionally, the label states to use a 

minimum of 10 gallons of spray mixture per acre or 0.24 lb ai/gallon. 

Unit Exposures and Area Treated or Amount Handled: Unit exposure values and estimates for 

area treated or amount handled were taken from HED’s 2012 Residential SOPs2. 

Exposure Duration: Residential handler exposure is expected to be short-term in duration. 

Intermediate-term exposures are not likely because of the intermittent nature of applications by 

homeowners.

Residential Handler Non-Cancer Exposure and Risk Estimate Equations

The algorithms used to estimate exposure and dose for residential handlers can be found in 

Appendix A and/or the 2012 Residential SOPs3.

Summary of Residential Handler Non-Cancer Exposure and Risk Estimates

All residential handler exposure quantification resulted in MOEs above the Agency’s LOC of 

1,000. Therefore, no risk estimates of concern were identified. Results from this assessment 

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

lawns. 

 

2 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html

3 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 29 of 70

Table 6.1.1. Residential Handler Non-cancer Exposure and Risk Estimates for S-metolachlor.

Exposure

Scenario

Application 

Equipment/

Method

Maximum 

Application 

Rate1

Area 

Treated or 

Amount 

Handled 

Daily2

Inhalation 

Unit 

Exposure

(mg/lb ai)

Inhalation 

Absorbed 

Dose3

(mg/kg/day)

Inhalation 

MOE4

LOC=1,000

Mixer/Loader/Applicator

Gardens / 

Trees

Manuallypressurized 

handwand

0.000056

lb ai/ft2 1200 ft2

0.018 0.000015 3,300,000

Hose-end Sprayer/

Sprinkler can 0.0014 0.0000012 43,000,000

Backpack 0.14 0.00012 430,000

Lawns / 

Turf

Hose-end Sprayer 2.47

lb ai/acre 0.5 acres 0.022 0.00034 150,000

Manuallypressurized 

handwand 0.24

lb ai/gallon 5 gallons

0.018 0.00027 190,000

Backpack 0.14 0.0021 24,000

Sprinkler can 0.000056

lb ai/ft2 1000 ft2 0.022 0.000015 3,200,000

1. Based on registered label (EPA Reg. No. 100-950).

2. Based on HED’s 2012 Residential SOPs (http://www.epa.gov/pesticides/science/residential-exposure-sop.html).

3. Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled

(A/day; ft2/day or gallons/day) ÷ BW (80 kg).

4. Inhalation MOE = Inhalation NOAEL (50 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

6.2 Residential Post-application Exposure/Risk Estimates

There is the potential for post-application exposure for individuals exposed as a result of being in 

an environment that has been previously treated with S-metolachlor. The quantitative 

exposure/risk assessment for residential post-application exposures is based on the following 

scenarios: 

 Hand-to-mouth incidental oral exposure of children 1-2 years old playing on turf treated 

with S-metolachlor.

The lifestages selected for each post-application scenario are based on an analysis provided as an 

Appendix in the 2012 Residential SOPs4. While not the only lifestage potentially exposed for 

these post-application scenarios, the lifestage that is included in the quantitative assessment is 

health protective for the exposures and risk estimates for any other potentially exposed lifestage.

Residential Post-application Exposure Data and Assumptions

 

4 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 30 of 70

A series of assumptions and exposure factors served as the basis for completing the residential 

post-application risk assessment. Each assumption and factor is detailed in the 2012 Residential 

SOPs5.

Application Rate: The maximum application rate used was 2.4 lb S-metolachlor/acre, based on 

registered product Pennant MAGNUMTM (EPA Reg. No. 100-950).

Residential Post-application Non-Cancer Exposure and Risk Equations

The algorithms used to estimate residential post-application exposure and dose can be found in 

Appendix A and/or the 2012 Residential SOPs.

Combining Exposure and Risk Estimates

The incidental oral scenarios (i.e., hand-to-mouth, object-to-mouth, and soil ingestion) should be 

considered inter-related and it is likely that they occur interspersed amongst each other across 

time. However, combining these scenarios is considered overly-conservative because of the 

conservative nature of each individual assessment. Therefore, the post-application exposure 

scenario assessed for children 1 < 2 years was the hand-to-mouth scenario since no dermal 

endpoint was selected. No turf transferable residue data were used.

Summary of Residential Post-application Non-Cancer Exposure and Risk Estimates

The residential exposure (absorbed dose) to children 1<2 for hand-to-mouth oral exposure was 

calculated to be 0.038 mg/kg/day resulting in an MOE of 1,300. The MOE from the residential 

risk scenario for exposure to S-metolachlor does not exceed the Agency’s level of concern. 

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

drinking water, and residential lawns. A summary is provided below in Table 6.2.1

 

5 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 31 of 70

Table 6.2.1. Residential Post-application Non-cancer Exposure and Risk Estimates for S-metolachlor.

Maximum Single Application Rate: 2.47 lb ai/A

Lifestage

HRt FM

SAH

(cm2)

Exposure 

Time 

(hours/

day)

N_Replen SE Freq_H

tM

Absorbed 

Dose

(mg/kg/day)

MOE

LOC=

1000

Hand 

Residue 

(mg/cm2)

Fracti

on of 

Hand 

Surfa

ce 

Area 

Mout

hed / 

Event

Number of 

replenishmen

t 

intervals per 

hr 

(intervals/hr)

Extractio

n by 

Saliva

HtM 

events 

per 

hour

1 to <2 

years

0.00404 0.127 150 1.5 4 0.48 13.9 0.038 1,300

1 Based on registered or proposed label (Reg. No. 100-950).

2 Dose (mg/kg/day) equations provided in Appendix [A].

3 MOE = POD (50 mg/kg/day) ÷ Dose (mg/kg/day).

No turf transferable data were available for this chemical. Since the estimated residential turf 

post-application exposure for residential turf using default TTR values for S-metolachlor is 

minimal in comparison to the level of concern (i.e., the calculated MOE is greater than 10 times 

higher than the level of concern, MOE = 1,300 compared to the LOC of 100); EPA is waiving 

the 40CFR TTR data requirement. In this instance, it is unlikely that chemical-specific TTR data 

would be needed to further refine exposure assessments or would add appreciably to our general 

understanding of the availability of turf transferable pesticide residues.

6.3 Residential Risk Estimates for Use in Aggregate Assessment

Table 6.3.1 reflects the residential risk estimates that are recommended for use in the aggregate 

assessment for S-metolachlor.

 The recommended residential exposure for use in the adult aggregate assessment reflects 

inhalation exposure from applications to turf via backpack sprayer.

 The recommended residential exposure for use in the children 1<2 years old aggregate 

assessment reflects hand-to-mouth exposure from post-application exposure to lawns/turf 

applications.
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 32 of 70

Table 6.3.1. Recommendations for the Residential Exposures for the S-metolachlor Aggregate 

Assessment.

Lifestage Exposure 

Scenario

Dose (mg/kg/day)1 MOE2

Inhalation Oral Total Inhalation Oral Total

Adult Backpack 0.0021 N/A 0.0021 24,000 N/A 24,000

Child

Hand-toMouth Oral 

Ingestion

N/A 0.038 0.038 N/A 1,300 1,300

1 Dose = the highest dose for each applicable lifestage of all residential scenarios assessed. Total = dermal + inhalation + incidental oral 

(where applicable).

2 MOE = the MOEs associated with the highest residential doses. Total = 1 ÷ (1/Dermal MOE) + (1/Inhalation MOE) + (1/Incidental Oral 

MOE), where applicable.

6.4 Residential Bystander Post-application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for S-metolachlor at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV), and low vapor pressure (2.8 x 10-5 mm Hg). 

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

individuals nearby pesticide applications. The Agency sought expert advice and input on issues 

related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on 

March 2, 20101. The Agency is in the process of evaluating the SAP report and may, as 

appropriate, develop policies and procedures to identify the need for and, subsequently, the way 

to incorporate post-application inhalation exposure into the Agency's risk assessments. If new 

policies or procedures are developed, the Agency may revisit the need for a quantitative postapplication inhalation exposure assessment for S-metolachlor.

6.5 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is 

particularly the case with aerial application, but, to a lesser extent, spray drift can also be a 

potential source of exposure from the ground application methods (e.g., groundboom) employed

for S-metolachlor. The Agency has been working with the Spray Drift Task Force (a task force 

composed of various registrants which was developed as a result of a Data Call-In issued by 

EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties 

to develop the best spray drift management practices (see the Agency’s Spray Drift website for 

more information). The Agency is also taking means to qualitatively and qualitatively address 

spray drift as a potential source of exposure in risk assessments for pesticides through existing 

programs such as Ag Drift and chemical specific properties of pesticides. The potential for spray 

drift will be quantitatively evaluated for each pesticide during the Registration Review process 

which ensures that all uses for that pesticide will be considered concurrently. 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 33 of 70

7 Aggregate Exposure/Risk Characterization

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

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

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure.

7.1 Acute Aggregate Risk

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

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

dietary exposure assessment already includes the highest acute exposure from the drinking water 

modeling data, no further calculations are necessary. The acute risk estimates for all populations

resulting from aggregate exposure to S-metolachlor in food and drinking water are below EPA’s 

level of concern. The food and drinking water exposure estimate for the most highly exposed 

subgroup was 6.1% of the aPAD for all infants (< 1 year old). See Section 5.4.3 for a detailed 

discussion of the acute dietary assessment.

7.2 Short-Term Aggregate Risk

Short-term aggregate assessments include exposures that will occur from one to thirty days. For 

food and water, the exposure input is taken from the chronic dietary exposure assessment. 

There are no residential user exposures associated with the current petition. However, there is 

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

applied to residential lawns or turf. Potential short-term residential risk scenarios anticipated

include adult inhalation handler exposure to turf via backpack sprayer and post-application

incidental oral exposure of children playing on treated lawns. Refer to Section 6.2. for the 

residential exposures that are likely to be combined. Results from that assessment have been 

used to assess aggregate risk from exposure to food, drinking water, and residential lawns for 

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

A second potential short-term risk results from inhalation exposure from spray drift. Although a 

very high end exposure assessment was conducted, based on exposure to flaggers from aerial 

application, this exposure was less than the potential incidental oral exposure, so the inhalation 

exposure will not be aggregated with other exposures.
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 34 of 70

Table 7.2 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) 5

Adult 50 1000 0.0027 0.0021310,400

Children 1-2 50 100 0.007 0.03841100

1 NOAEL for incidental oral exposure. 

2 The level of concern (LOC) for MOE is 1000 for the adult inhalation scenario and 100 for the children’s scenario.

3 Residential exposure for adults = [Inhalation exposure from applications to turf via backpack sprayer]

4 Residential Exposure for children 1-2 = [Incidental Oral exposure (from hand-to-mouth oral exposure)]. 

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

7.3 Intermediate-Term Aggregate Risk

Intermediate-term aggregate assessments include exposures that will occur from thirty days to 

six months. There are no residential scenarios which are expected to be intermediate-term 

exposure. 

7.4 Chronic Aggregate Risk

Chronic or long-term aggregate assessments include exposures that will exceed six months. The 

chronic risk estimates include exposure to residues of S-metolachlor in food and drinking water, 

and do not include dermal, inhalation or incidental oral exposures. Since the dietary exposure 

assessment already includes the highest chronic exposures from the drinking water modeling 

data, no further calculations are necessary. The chronic risk estimates for all populations, 

resulting from aggregate exposure to S-metolachlor in food and drinking water are below EPA’s 

level of concern. The food and drinking water exposure estimate for the most highly exposed 

subgroup is 6.8% of the cPAD for children 1-2 years old. See Section 5.4.4 for a detailed 

discussion of the chronic dietary assessment.

7.5 Cancer Aggregate Risk

As risks are estimated based on the chronic reference dose are protective of cancer effects, no 

separate cancer risk assessment is necessary. The chronic dietary aggregate risk assessment is 

below the Agency’s level of concern.

8 Cumulative Exposure/Risk Characterization

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

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

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

of toxicity.”

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

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 35 of 70

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

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 

EPA has not assumed that S-metolachlor has a common mechanism of toxicity with other 

substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9 Occupational Exposure/Risk Characterization

9.1 Short- and Intermediate-Term Handler Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct job functions or tasks related to 

applications and exposures can vary depending on the specifics of each task. Job requirements 

(amount of chemical used in each application), the kinds of equipment used, the target being 

treated, and the level of protection used by a handler can cause exposure levels to differ in a 

manner specific to each application event. 

Based on the anticipated use patterns and current labeling, types of equipment and techniques 

that can potentially be used, occupational handler exposure is expected from the proposed uses. 

The quantitative exposure/risk assessment developed for occupational handlers is based on the 

following scenarios: 

 Mixer/Loader (aerial, chemigation and groundboom equipment);

 Applicators (aerial and groundboom equipment);

 Mixer/Loader/Applicator (mechanically-pressurized handgun); and

 Flagger (from aerial spray applications).

The occupational handler exposure and risk estimates indicate that the short- and intermediateterm inhalation Margin of Exposures (MOEs) are not of concern to HED (i.e., MOE > 1000) at 

the baseline level of personal protection (i.e., no gloves and no respirator).

The Agency matches quantitative occupational exposure assessment with appropriate 

characterization of exposure potential. While HED presents quantitative risk estimates for human 

flaggers where appropriate, agricultural aviation has changed dramatically over the past two 

decades. According the 2012 National Agricultural Aviation Association (NAAA) survey of 

their membership, the use of GPS for swath guidance in agricultural aviation has grown steadily 

from the mid 1990’s. Over the same time period, the use of human flaggers for aerial pesticide 

applications has decreased steadily from ~15% in the late 1990’s to only 1% in the most recent 

(2012) NAAA survey. The Agency will continue to monitor all available information sources to 

best assess and characterize the exposure potential for human flaggers in agricultural aerial 

applications.
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 36 of 70

HED has no data to assess exposures to pilots using open cockpits. The only data available is for 

exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the 

engineering control (enclosed cockpits) and baseline attire (long-sleeve shirt, long pants, shoes, 

and socks); per the Agency’s Worker Protection Standard stipulations for engineering controls, 

pilots are not required to wear protective gloves for the duration of the application. With this 

level of protection, there are no risk estimates of concern for applicators.

Table 9.1.1. Occupational Handler Non-Cancer Inhalation Exposure and Risk Estimates for S-metolachlor.

Exposure Scenario Crop or 

Target

Inhalation Unit 

Exposure 

(μg/lb ai)1

Maximum

Application 

Rate2

Area Treated or 

Amount Handled 

Daily3

Short-& Intermediateterm 

Dose 

(mg/kg/day)4

MOE5

LOC=1,000

Mixer/Loader

Aerial

Field crop, 

high acreage Baseline: 0.219 1.9 lb ai/A

1200 A 0.0062 8,000

Chemigation 350 A 0.0018 27,000

Groundboom 200 A 0.0010 48,000

Applicator

Aerial Field crop, 

high acreage

Engineering 

Controls: 0.0049 1.9 lb ai/A

1200 A 0.00014 360,000

Groundboom Baseline: 0.34 200 A 0.0016 31,000

Flagger

Aerial Equipment Field crop, 

high acreage Baseline: 0.35 1.9 lb ai/A 350 A 0.0029 17,000

Mixer/Loader/Applicator

Mechanicallypressurized Handgun

Field crop, 

typical Baseline: 3.9 0.32 lb 

ai/gallon 1,000 gallons 0.016 3,200

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2013); Level of mitigation: Baseline, 

PF5 Respirator, Eng. Controls.

2 Based on supplemental label to registered product (Reg. No. 100-816).

3 Exposure Science Advisory Council Policy #9.1.

4 Short-&Intermediate-term Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate 

(lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW (80 kg).

5 Short-& Intermediate-term Inhalation MOE = Inhalation NOAEL (50 mg/kg/day) ÷ Short-term Inhalation Dose (mg/kg/day).

9.2 Short- and Intermediate-Term Post-Application Risk

HED uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred to as reentry exposure). Such exposures may occur when workers enter previously treated areas to 

perform job functions, including activities related to crop production, such as scouting for pests 

or harvesting. Post-application exposure levels vary over time and depend on such things as the 

type of activity, the nature of the crop or target that was treated, the type of pesticide application, 

and the chemical’s degradation properties. In addition, the timing of pesticide applications, 

relative to harvest activities, can greatly reduce the potential for post-application exposure.
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 37 of 70

9.2.1 Dermal Post-application Risk

Based on the proposed use sites, it is anticipated that there may be occupational post-application 

exposure from activities related to crop production, such as scouting for pests or harvesting; 

however, there is no dermal POD for S-metolachlor, therefore, a quantitative assessment was not 

conducted. However, there’s a 24-hour Restricted Entry Interval (REI) on the registered label 

for Dual Magnum® (EPA Reg. No. 100-816). S-metolachlor is classified as Toxicity Category 

III for acute oral and dermal and as category IV for inhalation toxicity. It is classified as 

category III for eye irritation potential and IV for skin irritation potential. It is a skin sensitizer. 

Under 40 CFR 156.208 (c) (2) (iii), ai’s classified as Acute III or IV for acute dermal, eye 

irritation and primary skin irritation are assigned a 12-hour REI. Therefore the REI specified in 

the label is considered adequate to protect agricultural workers from post-application exposures 

to S-metolachlor. 

9.2.2 Inhalation Post-application Risk

There are multiple potential sources of post-application inhalation exposure to individuals 

performing post-application activities in previously treated fields. These potential sources 

include volatilization of pesticides and re-suspension of dusts and/or particulates that contain 

pesticides. The agency sought expert advice and input on issues related to volatilization of 

pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel 

(SAP) in December 2009, and received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The agency has 

evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent 

Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQOPP-2014-0219). During Registration Review, the agency will utilize this analysis to determine 

if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is 

required for S-metolachlor.

In addition, the Agency is continuing to evaluate the available post-application inhalation 

exposure data generated by the Agricultural Re-entry Task Force. Given these two efforts, the 

Agency will continue to identify the need for and, subsequently, the way to incorporate 

occupational post-application inhalation exposure into the agency's risk assessments.

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

higher exposure than post-application exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of most occupational post-application 

inhalation exposure scenarios.
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 38 of 70

10 References

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

Metolachlor (4th). 

Hummel, S. 10/27/14. D420046. S-Metolachlor. Petition for the Establishment of Permanent 

Tolerances for New Uses on Lettuce, Low Growing Berry Subgroup 13-07G, except Cranberry; 

Vegetable, Cucurbit, Group 9; Vegetable, Fruiting, Group 8-10; except Tabasco Pepper and Okra 

and Sunflower subgroup 20B. Summary of Analytical Chemistry and Residue Data.

Hummel, S/ 12/3/14. D424250. Metolachlor and S-Metolachlor. Recommended Environmental 

Degradates to Include in Drinking Water Assessment.

Koper, C. 12/16/14. D420047. Tier II Drinking Water Assessment for the Proposed SMetolachlor Use on Lettuce (Head and Leaf), Low-Growing Berry Subgroup 13-07G (excluding 

Cranberry), Cucurbit Vegetable Group 9, Sunflower Subgroup 20B and Fruiting Vegetable 

Group 8-10.

Morton, T. 5/7/15. D425169. S-Metolachlor - Acute and Chronic Aggregate Dietary (Food and 

Drinking Water) Exposure and Risk Assessment for Establishment of Tolerances for New Uses 

on Lettuce, Low Growing Berry Subgroup 13-07G, except Cranberry; Vegetable, Cucurbit, 

Group 9; Sunflower subgroup 20B; Vegetable, Fruiting, Group 8-10; except Tabasco Pepper.

Nieves, I. 3/4/2015. D420046. S-Metolachlor: Occupational and Residential Exposure 

Assessment for Proposed Uses on Lettuce, Cucurbit Group 9, Low Growing Berry Subgroup 13-

07G (except cranberry), Sunflower Subgroup 20B, and Crop Group conversion for Fruiting 

Vegetable Group 8-10.

VanAlstine, J. 3/20/13. TXR No. 0056586. Metolachlor: Summary of Hazard and Science Policy 

Council (HASPOC) Meeting of February 14, 2013. Recommendations on the Need for a 

Neurotoxicity Battery, a Developmental Neurotoxicity Study, and a Subchronic Inhalation 

Study.
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 39 of 70

Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food use for Metolachlor are listed in the Table below. Use of the new 

guideline numbers does not imply that the new (1998) guideline protocols were used. Bridging studies for SMetolachlor include an Acute Toxicity Battery, subchronic toxicity studies in rats and dogs, developmental toxicity 

studies in rats and rabbits, mutagenicity battery, metabolism studies and an immunotoxicity study.

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

870.1200 Acute Dermal Toxicity

870.1300 Acute Inhalation Toxicity

870.2400 Primary Eye Irritation

870.2500 Primary Dermal Irritation

870.2600 Dermal Sensitization

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

870.3150 Oral Subchronic (nonrodent)

870.3200 21-Day Dermal

870.3250 90-Day Dermal

870.3465 90-Day Inhalation

yes

yes

yes

no

yes

yes

yes

yes

-

noa

870.3700a Developmental Toxicity (rodent)

870.3700b Developmental Toxicity (nonrodent)

870.3800 Reproduction

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)

870.4100b Chronic Toxicity (nonrodent)

870.4200a Oncogenicity (rat)

870.4200b Oncogenicity (mouse)

870.4300 Chronic/Oncogenicity

yes

yes

yes

yes

yes

yesb

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial

870.5300 Mutagenicity—Gene Mutation - mammalian

870.5xxx Mutagenicity—Structural Chromosomal 

Aberrations

870.5xxx Mutagenicity—Other Genotoxic Effects

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)

870.6100b 90-Day Neurotoxicity (hen)

870.6200a Acute Neurotoxicity Screening Battery (rat)

870.6200b 90-Day Neurotoxicity Screening Battery (rat)

870.6300 Develop. Neurotoxicity

no

no

yesc

yesc

conditionalc

-

-

-

-

-

870.7485 General Metabolism

870.7600 Dermal Penetration

870.7800 Immunotoxicity

yes

yes

yes

yes

yes

yes

Special Studies for Ocular Effects

Acute Oral (rat)

Subchronic Oral (rat)

Six-month Oral (dog)

no

a Required by HASPOC (TXR No. 0056586)

b Satisfied with combined chronic toxicity/carcinogenicity study

cWaived by HASPOC (TXR No. 0056586)
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 40 of 70

A.2 Toxicity Profiles

Table A.2.1a Acute Toxicity Profile - Metolachlor 

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

870.1100 Acute oral - Rat 00015523 LD50 = 2780 mg/kg III

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

870.1300 Acute inhalation -Rat 00015535 LC50 = > 1.75 mg/L III

870.2400 Acute eye irritation - Rabbit 00015528 Non-irritating IV

870.2500 Acute dermal irritation - Rabbit 00015530 Non-irritating IV

870.2600 Skin sensitization – guinea pig 00015631 positive

Table A.2.1b Acute Toxicity Profile – S-Metolachlor 

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

870.1100 Acute oral - Rat 43928915 LD50 = 3267 mg/kg

(♂); 2577 mg/kg/day

(♀); 2672 mg/kg/day

(combined)

III

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

870.1300 Acute inhalation -Rat 43928917 LC50 = > 2.91 mg/L IV

870.2400 Acute eye irritation - Rabbit 43928918 Slight to moderate 

conjunctival irritation 

that cleared in 48 

hours

III

870.2500 Acute dermal irritation - Rabbit 43928919 non-irritating IV

870.2600 Skin sensitization – guinea pig 43928920 positive

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Metolachlor

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3100 90-Day oral 

toxicity (rat)

44775401 (1999)

0, 30, 300, 3000 ppm 

(M/F: 0, 2.00/2.32, 

20.2/23.4, 210/259 

mg/kg/day)

NOAEL for males = 3000 ppm

LOAEL for males not established

NOAEL for females = 300 ppm

LOAEL for females = 3000 ppm based on 

decreased body weight/body weight gain 

Acceptable/Guideline

870.3150 6-Month oral 

toxicity (dog)

00032174 (1980), 

43244001

0, 100, 300, 1000 ppm 

(M/F: 0, 2.92/2.97, 

9.71/8.77, 29.61/29.42)

NOAEL = 300 ppm

LOAEL = 1000 ppm based on decreased body 

weight gain 

Acceptable/Guideline

870.3200 21-Day dermal 

toxicity rabbits

41833101 (1987)

0, 10, 100 or 1000 

mg/kg/day

Systemic NOAEL = 1000 mg/kg/day.

Systemic LOAEL was not established

Dermal irritation NOAEL was not established 

Dermal irritation LOAEL = 10 mg/kg/day 

based on very slight erythema, dry skin and 

fissuring (one animal)

Acceptable/Guideline

870.3700a Prenatal 

developmental 

toxicity in rodents 

00151941 (1985)

0, 30, 100, 300 or 1000 

mg/kg/day

Maternal toxicity NOAEL = 300 mg/kg/day.

Maternal toxicity LOAEL = 1000 mg/kg/day 

based on an increased incidence of death, 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 41 of 70

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Metolachlor

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

(rat) clinical signs of toxicity (clonic and/or toxic 

convulsions, excessive salivation, urine-stained 

abdominal fur and/or excessive lacrimation) 

and decreased body weight gain. 

Developmental toxicity NOAEL = 300 

mg/kg/day Developmental toxicity LOAEL = 

1000 mg/kg/day based on slightly decreased 

number of implantations per dam, decreased 

number of live fetuses/dam, increased number 

of resorptions/dam and significant decrease in 

mean fetal body weight

Acceptable/Guideline

870.3700b Prenatal 

developmental in 

(New Zealand 

White) rabbits

00041283 (1980) 

0, 36, 120 or 360 

mg/kg/day

Maternal toxicity NOAEL = 120 mg/kg/day.

Maternal toxicity LOAEL = 360 mg/kg/day 

based on an increased incidence of clinical 

observations (persistent anorexia) and 

decreased body weight gain

Developmental toxicity NOAEL = 360 

mg/kg/day 

Developmental toxicity LOAEL was not 

established.

Acceptable/Guideline

870.3800 Reproduction and 

fertility effects

(CD albino) rats

00080897 (1981)

0, 30, 300 or 1000 ppm

F0 males: 0, 2.4, 23.5, and 

75.8 mg/kg/day; F0

females: 0, 2.5, 26.0, and 

85.7 mg/kg/day; F1 males: 

0, 2.3, 23.7, and 76.6 

mg/kg/day; F1 females: 0, 

2.6, 25.7, and 84.5 

mg/kg/day metolachlor 

(95.4% ai) (dietary) 

Parental/Systemic NOAEL = 1000 ppm (F0

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

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

dose tested.

LOAEL = Not established

Reproductive NOAEL = 1000 ppm (F0

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

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

dose tested.

LOAEL = Not established

Offspring NOAEL = 300 ppm (F0

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

males/females: 23.7/25.7 mg/kg/day

LOAEL = 1000 ppm (F0 males/females: 

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

76.6/84.5 mg/kg/day based on decreased body 

weight in F1 and F2 litters. 

Acceptable/Guideline

870.4100b Chronic toxicity 

dogs

40980701, 41164501, 

42218601 and 42218602. 

(1989) 

0, 100, 300 or 1000 ppm 

(males: 0, 3.5, 9.7 and 

32.7 mg/kg/day, 

respectively; females: 0, 

3.6, 9.7 and 33.0 

mg/kg/day, respectively) 

for one year. 

NOAEL = 300 ppm (9.7 mg/kg/day) for 

females

LOAEL = 1000 ppm for females (33.0 

mg/kg/day) based on decreased body weight 

gain

NOAEL = 1000 ppm (32.7 mg/kg/day).

LOAEL for males was not established; 

Acceptable/Guideline
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 42 of 70

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Metolachlor

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.4200 Chronic toxicity/

Carcinogenicity

rat

00129377 (1983)

0, 30, 300 or 3000 ppm 

(0, 1.5, 15 or 150 

mg/kg/day based on 1 

ppm in food equals 0.05 

mg/kg/day)

NOAEL = 300 ppm (15 mg/kg/day) for females

LOAEL = 3000 ppm (150 mg/kg/day) for 

females based on slightly decreased body 

weight gain and food consumption.

The LOAEL was not established for males. The 

NOAEL was 3000 ppm (150 mg/kg/day).

Administration of doses up to 3000 ppm was 

associated with statistically significant 

increases in liver adenomas and combined 

adenoma/carcinoma in female rats. In male rats, 

there was a statistically significant trend but not 

pair-wise significance for liver tumors.

Acceptable/Guideline

870.4300 Carcinogenicity

mice

00117597 (1982)

0, 300, 1000 or 3000 ppm 

(0, 45, 150 or 450 

mg/kg/day)

NOAEL = 100 ppm (150 mg/kg/day)

LOAEL = 3000 ppm (450 mg/kg/day) based on 

possible treatment-related deaths in females 

and decreased body weight/body weight gain in 

males and females

no evidence of carcinogenicity

Acceptable/Guideline

870.5100 Gene Mutation 

bacterial reverse 

mutation

00015397 (1976)

10, 100, 1000 and 10,000 

ug/plate

Negative up to cytotoxic doses (1000 ug/plate)

Acceptable/Guideline

870.5300 Gene Mutation

mouse lymphoma

00158929 (1984)

9.5-190 nL/mL without 

activation; 10.5-280 

nL/mL with activation

No effect on the incidence of mutations in the 

presence or absence of metabolic activation

Acceptable/Guideline

870.5395 Cytogenetics 

micronucleus 

assay in Chinese 

hamsters

00158925 (1984)

0, 1250, 2500 or 5000 

mg/kg

No effect of treatment on incidence of 

micronuclei induction

Acceptable/Guideline

870.5450 Cytogenetics 

dominant lethal 

assay in mice

00015630 (1978)

100 or 300 mg/kg

No effect on embryonic death, pre- and postimplantation or fertility rates in mated females

Acceptable/Guideline

870.5550 Other Effects 

DNA 

Damage/Repair in 

rat hepatocytes

00142828 (1984)

0.125, 0.625, 3.125 or 

15.625 nL/mL

Negative

Acceptable/Guideline

870.5550 Other Effects 

DNA 

Damage/Repair in 

human fibroblasts

00142827

0.125, 0.625, 3.125 or 

15.625 nL/mL

Negative

Acceptable/Guideline

870.5550 Other Effects 

Unscheduled 

DNA synthesis in 

rat hepatocytes

43244003 (1994)

1250, 2500 or 4000 mg/kg 

to males; 500, 1000 or 

1500 mg/kg to females

Negative for induction of UDS; however, 

significant increases in percentage of cells in Sphase were observed in females dosed at 500 

mg/kg (but not at 1000 or 1500 mg/kg) and 

sacrificed at 15 hours

Acceptable/Guideline

870.7485 Metabolism and 

pharmacokinetics

rodents

MRID 00015425 (1974)

52, 28 or 33 mg/kg to 

male rats

Urinary metabolites of CGA 24705 (N-(2-

methoxy-1-methylethyl)-2-ethyl-6-methylchloroacetanilide) were identified following 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 43 of 70

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Metolachlor

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

oral administration of 52 mg/kg, 28 mg/kg, and 

33 mg/kg to male rats. Two metabolites, each 

comprising approximately 5% of chloroform 

extractable urinary radioactivity, were 

identified from oral administration of CGA 

24705. 

The major metabolic pathway proposed from 

analysis of urinary as well as fecal metabolites 

is one of cleavage of the ether bond and 

subsequent oxidation to the carboxylic acid, as 

well as hydrolytic removal of the chlorine 

atom. Conjugation of CGA 24705 or 

metabolites with glucuronic acid or sulfate does 

not appear to occur.

Current guideline recommendations as to dose 

levels and use of both sexes in metabolism 

studies were not followed. Thus, whether the 

metabolic pattern is altered with dose or 

repeated exposure cannot be evaluated from 

these data.

Unacceptable/Non-guideline

870.7485 Metabolism and 

pharmacokinetics

40114401 (1987)

Single low (1.5 mg/kg), 

single high (300 mg/kg) 

and repeated low (1.5 

mg/kg/day for 15 days)

Single low (1.5 mg/kg), single high (300 

mg/kg) and repeated low (1.5 mg/kg/day for 15 

days) oral doses of metolachlor were readily 

absorbed and eliminated by male and female 

rats. Urinary and fecal elimination of 

radioactivity associated with orally 

administered [14C] metolachlor was essentially 

complete within 48 to 72 hours after dosing. 

Relatively low levels of radioactivity were 

present in the tissues of all animals at 7 days 

postdosing. 

Unacceptable/Non-guideline

870.7485 Metabolism and 

pharmacokinetics

43164201 (1992)

low oral dose (1.5 mg/kg 

x 14 days), and a single 

high dose (300 mg/kg)

Comparison of oral and intravenous data 

showed that of the administered dose, between 

69.6% and 93.2% was absorbed. Distribution 

data showed that the only significant sites of 

residual radioactivity at 7 days post-dose were 

residual carcass (0.9 - 2.2% of the administered 

dose) and red blood cells (0.95- 1.53 μg 

equivalents/gram in blood cells for all low dose 

male and female rats). Dosing regimen did not 

result in any apparent accumulation of residual 

radioactivity. 

Excretion data showed that urine and feces 

were both significant routes for elimination of 

metolachlor derived radioactivity 

Metabolism of metolachlor in this study was 

complex, with up to 32 metabolites identified in 

urine and/or feces.

Acceptable/Guideline
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 44 of 70

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – S-Metolachlor

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

870.3100 90-Day oral 

toxicity rodents

43928923 (1995)

0, 30, 300, 3000 or 10000 

ppm (0, 1.5, 15, 150 or 

500 mg/kg/day)

NOAEL = 300 ppm

LOAEL = 3000 ppm based on lower body 

weights/body weight gains, reduced food 

consumption and food efficiency and increased 

kidney weights in males

Acceptable/Guideline

870.3100 90-Day oral 

toxicity rodents

44775402 (1999)

0, 30, 300, 3000 ppm 

(M/F: 0, 1.90/2.13, 

20.4/23.9 and 208.0/236.0 

mg/kg/day0

NOAEL = 3000 ppm (equivalent to 208 

mg/kg/day in males and 236 mg/kg/day in 

females

LOAEL cannot be defined

Unacceptable/Guideline

870.3150 90-Day oral 

toxicity 

nonrodents

43928922 (1995)

0, 300, 500, 1000 or 2000 

ppm (M/F: 0, 9/10, 

15.1/17.2, 31.1/31.5 or 

62/74 mg/kg/day)

NOAEL = 2000 ppm (M/F: 62/74 mg/kg/day)

LOAEL = not established 

Acceptable/Non-guideline

870.3700a Prenatal 

developmental in 

(Tif:RAI f (SPF)) 

rats

43928925 (1995)

0, 5, 50, 500, or 1000 

mg/kg/day S-metolachlor 

(95.6% ai) in 0.5% (w/w) 

aqueous solution of 

sodium 

carboxymethylcellulose 

(gavage) GD 6-15

Maternal NOAEL = 50 mg/kg/day

LOAEL = 500 mg/kg/day based on increased 

clinical signs of toxicity, decreased body 

weights and body weight gains and reduced 

food consumption and reduced food efficiency.

Developmental NOAEL = 1000 mg/kg/day, 

highest dose tested.

LOAEL = Not established

Acceptable/Guideline

870.3700b Prenatal 

developmental in 

(New Zealand 

White) rabbits

43928924 (1995)

0, 20, 100, or 500 

mg/kg/day S-metolachlor 

(89.6% ai (93.7% S 

isomer)) suspension in 3% 

corn starch (gavage) GD 

7-19

Maternal NOAEL = 20 mg/kg/day

LOAEL = 100 mg/kg/day based on clinical 

signs of toxicity.

Developmental NOAEL = 500 mg/kg/day, 

highest dose tested.

LOAEL = Not established

Acceptable/Guideline
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 45 of 70

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – S-Metolachlor

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

870.5100 Gene Mutation

Salmonella & 

Escherichia/Mam

malian Microsome 

Mutagenicity Test

43928927 (1995)

78.13-1250.0 ug/plate

In independently performed microbial 

mutagenicity assays, Salmonella typhimurium

TA1535, TA1537, TA98, TA100 and TA102 

and Escherichia coli WP2 uvrA were initially 

exposed to 312.5-5000.0 μg/plate CGA-77102 

technical (95.6%) in the presence and absence 

of S9 activation. For the confirmatory trial, 

doses of 78.13-1250.0 μg/plate ±S9 were 

evaluated with S. typhimurium strains TA1535, 

TA1537, TA100 and TA102; concentrations of 

312.5-5000.0 μg/plate ±S9 were examined with 

S. typhimurium TA 98 and E.coli WP2 uvrA. 

In general, doses 1250.0 μg/plate ±S9 were 

cytotoxic for S. typhimurium TA1535, TA1537, 

TA100 and TA102 and 5000.0 μg/plate ±S9 

was slightly cytotoxic for S. typhimurium TA98 

and E. coli WP2 uvrA. There was, however, no 

indication that CGA-77102 technical induced 

of a mutagenic effect in any tester strain either 

in the presence or the absence of S9 activation. 

Acceptable/Guideline

870.5395 Cytogenetics 

Micronucleus test

43928926 (1995)

500, 1000 or 2000 mg/kg

Groups of five male and five female 

Tif:MAGf(SPF) mice received single oral 

gavage administrations of 500, 1000 or 2000 

mg/kg CGA 77102 technical (95.6%). 

Toxic signs, similar to those seen in the 

preliminary range-finding studies (i.e., ataxia, 

tremors and/or hunched posture) were recorded 

for high-dose males and females throughout the 

48-hour postexposure. No bone marrow 

cytotoxicity was seen at any dose or sacrifice 

time. The positive control induced the expected 

high yield of MPEs in males and females. 

There was, however, no evidence that CGA 

77102 technical induced a clastogenic or 

aneugenic effect in either sex at any dose or 

sacrifice time. 

Acceptable/Guideline

870.5550 Other Effects 

Unscheduled 

DNA synthesis

43928928 (1995)

500, 1500, 3200 

(females), 5000 (males) 

mg/kg

CGA 77102 Technical was negative for 

genotoxicity but positive for cellular 

proliferation when tested up to overtly toxic 

and cytotoxic doses in this in vivo/in vitro rat 

hepatocyte RDS/UDS assay.

Acceptable/Guideline
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 46 of 70

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile – S-Metolachlor

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

870.7485 Metabolism and 

pharmacokinetics

44491401 (1996)

single dose of 0.5 (group 

B1) or 100 mg/kg (group 

D1) radiolabeled CGA77102; 100 mg/kg/day 

non-radiolabeled CGA 

77102 for 14 days 

followed by 0.5 mg/kg 

radiolabeled CGA-77102 

(Group V1); single dose 

of 0.5 or 100 mg/kg 

radiolabeled CGA-77102 

for bile-cannulation study

In all three dose groups (B1, D1, and V1), the 

seven day combined levels of radioactivity in 

urine were 31.1 - 36.5% for males and 40.8 -

45.5% for females; the fecal levels were 60.2 -

62.5% for males and 48.9 - 55.0% for females. 

Only 0.1% or less was eliminated in the expired 

air. The total recovery ranged from 96.5 ± 

2.3% to 99.3 ± 0.9%. 

Irrespective of the dose and sex, there seems to 

be a biphasic plasma profile with two 

concentration maxima (Cmax); a fast rising first 

Cmax was reached at 0.25 - 1 hour post dosing 

which was succeeded by a second Cmax at 8 and 

at 12 - 24 hours following administration of the 

low and high dose, respectively. 

Acceptable/Guideline

870.7485 Metabolism and 

pharmacokinetics

44491402 (1996)

single dose of 0.5 (group 

B1) or 100 mg/kg (group 

D1) radiolabeled CGA77102; 100 mg/kg/day 

non-radiolabeled CGA 

77102 for 14 days 

followed by 0.5 mg/kg 

radiolabeled CGA-77102 

(Group V1); single dose 

of 0.5 or 100 mg/kg 

radiolabeled CGA-77102 

for bile-cannulation study 

(from MRID 44491401)

single oral low dose (0.5 

mg/kg, Group B2) of 

[Phenyl-U14C] CGA24705 (R/S-Metolachlor, 

racemate)

The 72 hour mean recovery of radioactivity in 

urine, feces, and carcass following 

administration of 0.5 mg/kg of [Phenyl-U14C] 

CGA-24705 was 43.1%, 47.0%, and 7.4% in 

males and 54.0%, 39.4%, and 4.1% in females, 

respectively. In contrast, both sexes excreted 

more of the label in the feces (M:F 

59.7%:53.4%) than in the urine (M:F 

29.4%:39.8%) during the same period 

following administration of the same dose of 

[Phenyl-U14C] CGA-77102 (the S-enantiomer) 

(MRID 44491401). 

The urinary and fecal metabolite profiles, with

31 and 15 metabolite fractions, respectively, 

were qualitatively similar among all groups; 

however, there were large quantitative 

differences, based on the dosing formulation, 

on one hand, and the sex of the animal, on the 

other. 

The results clearly show that the metabolite 

profile in excreta and bile fluid is very complex 

and that Metolachlor (racemate or Senantiomer) is extensively metabolized. 

Unacceptable/Guideline

870.7800 Immunotoxicity in 

mice

48783301 (2012)

0, 1500, 3000 or 5000 

ppm (0, 304.3, 639.5, or 

1108.5 mg/kg/day

NOAEL = 5000 ppm (1108.5 mg/kg/day)

LOAEL = Not Established

Acceptable/Guideline
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 47 of 70

A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD) - Females age 13-49

An endpoint was not selected for Females 13-49 years old since no developmental effects that 

could be attributed to a single exposure were identified in the metolachlor/S-metolachlor 

database.

A.3.2 Acute Reference Dose (aRfD) - General Population

Study Selected: Developmental Toxicity in Rats - Metolachlor 

MRID No.: 00151941

Dose and Endpoint for Risk Assessment: POD= 300 mg/kg/day (NOAEL). LOAEL = 1000 

mg/kg/day based on an increased incidence of death, clinical signs of toxicity (clonic and/or 

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

lacrimation) and decreased body weight gain. 

Comments about Study/Endpoint/Uncertainty Factors: Since clinical signs are observed 

after a single oral dose of metolachlor, the duration and route of administration are appropriate 

for the risk assessment. Developmental effects observed are not attributable to a single exposure 

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

increased incidence of death is one of the effects seen, it was seen at a dose (1000 mg/kg/day) 

approximately three times higher than the dose (300 mg/kg/day) selected for risk assessment; 

therefore, the Agency is confident that adequate safety is provided to protect the public from 

dietary exposure to residues of metolachlor. The total UF is 100 (10X for interspecies 

uncertainty factor, 10X for intraspecies variability, 1X FQPA SF).

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

 (UF) 100

A.3.3 Chronic Reference Dose (cRfD) 

Study Selected: Chronic Feeding Study in Dogs (Metolachlor)

MRID No.: 40980701, 41164501, 42218601 and 42218602

Dose and Endpoint for Risk Assessment: POD= 9.7 mg/kg/day (NOAEL). LOAEL = 33 

mg/kg/day based on decreased body weight gain in females.

Comments about Study/Endpoint/Uncertainty Factors: This study was selected because the 

database shows dogs were the more sensitive species and decreased body weight gain the most 

sensitive endpoint. The duration of 1 year and route of exposure through the feed is also 

appropriate. The total UF is 100 (10X for interspecies uncertainty factor and 10X for 

intraspecies variability).

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

 (UF) 100
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 48 of 70

A.3.4 Incidental Oral Exposure (Short-Term)

Study Selected: Developmental Toxicity Study in Rats (S-Metolachlor)

MRID No.: 43928925

Dose and Endpoint for Risk Assessment: POD = 50 mg/kg/day (maternal NOAEL). LOAEL is

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

weight gain, food consumption and food efficiency seen in maternal animals.

Comments about Study/Endpoint/Uncertainty Factors: A short-term incidental oral POD 

was selected from a developmental toxicity study with S-metolachlor in rats. This endpoint was 

based on increased incidence of clinical signs and decreased body weight/body weight gain. This 

study was selected because the effects were judged to be signs of frank toxicity and were 

appropriate to use for risk assessment. The NOAEL (20 mg/kg/day) from the prenatal 

developmental toxicity study in rabbits with S-metolachlor (MRID 43928924) was lower than 

the 50 mg/kg/day from the rat developmental study. However, the endpoint was based on weak 

clinical signs of toxicity (increase in little/none/soft stool observations) at 100 mg/kg/day. 

Although there was a dose-related increase in this effect, it is not evidence of frank toxicity and 

was judged not be appropriate for risk assessment. Therefore, the rabbit study with Smetolachlor was not selected for this exposure scenario. The total UF is 100 (10X for 

interspecies uncertainty factor and 10X for intraspecies variability).

A.3.5 Dermal Exposure (Short -Term) 

No hazard was identified for quantification of risk following dermal exposure. In a 21-day 

dermal toxicity study (MRID 41833101), no systemic toxicity was seen following repeated 

dermal application of metolachlor (96.4% ai) to the intact skin of five New Zealand 

rabbits/sex/group at doses of 0, 10, 100 or 1000 mg/kg/day for 21 days. 

A.3.6 Inhalation Exposure (Short- and Intermediate Term) 

Study Selected: Developmental Toxicity Study in Rats (S-Metolachlor)

MRID No.: 43928925 

Dose and Endpoint for Risk Assessment: POD=50 mg/kg/day (NOAEL). LOAEL of 500 

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

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

Comments about Study/Endpoint/Uncertainty Factors: No inhalation study is available for 

the short- and intermediate-term occupational inhalation scenarios. In the absence of a routespecific study, a short- and intermediate-term inhalation exposure POD was selected from an oral 

developmental toxicity study in rats with S-metolachlor. The endpoint selected was increased 

incidence of clinical signs and decreased body weight/body weight gain. This study was selected 

because the effects were judged to be signs of frank toxicity and the duration of exposure is 

appropriate.

Since an oral study was selected, a 100% absorption factor should be applied. The total UF is 

1000 (10X for interspecies uncertainty factor, 10X for intraspecies variability, and 10X database 

UF for missing study).
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 49 of 70

A.4 Executive Summaries

A.4.1 Subchronic Toxicity

870.3100 90-Day Oral Toxicity – Rat

In a 90-day subchronic oral toxicity limit study (MRID 44931710), groups of 10 male and 10 

female Crl: CD BR rats were given CGA-354743 (Lot/Batch # KI-5408/6, 98% a.i.) 

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

concentrations were equivalent to 0, 25.1, 86.2, 427.0 or 1545.0 mg/kg/day for males and 0, 

28.4, 98.3, 519.0 and 1685.0 mg/kg/day for females. An additional 10 male and 10 female rats 

were given CGA-77102 (s-Metolachlor)(Lot/Batch # P.501001, 98.5% a.i.) administered in the 

diet at 5000 ppm (equivalent to 429 mg/kg/day for males and 563 mg/kg/day for females). The 

study was designed to assess the subchronic oral toxicity of CGA-354743 technical and to 

compare its toxic effects with those of its parent compound, CGA-77102 technical. 

No deaths or clinical signs of toxicity occurred during this study. In addition, no statistically 

significant changes in body weight, body weight gain, food consumption, food efficiency, 

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

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

toxicological and biological importance.

Dietary exposure to CGA-77102 produced a statistically significant decreased body weight gain 

(-20%, p  0.01) in males during week 1 only. Females exposed to CGA-77102 showed 

decreased body weight gain (-19%) by week 13, but these changes were not statistically 

significant. The food efficiency of rats fed CGA-77102 was decreased relative to their respective 

control animals. Male and female rats had increased absolute and relative liver weights. These 

results are consistent with a mild liver hypertrophy in females. 

Based on the data presented in this study, the NOAEL is 20,000 ppm (1543 mg/kg/day and 

1685 mg/kg/day for females) for CGA-354743. A LOAEL could not be established. 

At 5000 ppm (429 mg/kg/day in males and 563 mg/kg/day in females) CGA-77102 , there 

evidence of decreased body weight gain and food efficiency, increased absolute and relative 

liver weights and an increased incidence of hepatic centrilobular hypertrophy, although the 

effects were mild.

This subchronic oral toxicity study in rats is classified as Acceptable/Guideline [OPPTS 

870.3100 (§82-1a)] and satisfies the guideline requirements.

870.3100 90-Day Oral Toxicity – Rat

In a subchronic oral feeding study, (MRID 44929509), CGA-51202 technical (100% a.i.; batch 

No. JD 7069/3) was fed to groups of 10 male and 10 female albino rats at dose levels of 0, 300, 

1000, or 15,000 ppm for 3 months. The average achieved doses for the corresponding groups 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 50 of 70

were 0, 18.7, 62.1, and 1000 mg/kg bodyweight for males, and 0, 20.6, 67.3, and 1020 mg/kg for 

females. 

All animals survived to study termination and no treatment-related clinical signs were observed. 

There were no treatment-related effects on body weight, food consumption, ophthalmoscopic 

parameters, or urinalysis. Platelet counts were decreased 16% (p<0.01) in high-dose males. 

Total protein in high-dose males (5% decrease, p<0.01) and females (4% decrease, N.S.) was 

slightly decreased due to decreased globulin in males and decreased albumin and globulin 

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

treatment-related organ weight effects or macroscopic or microscopic lesions. Under the 

conditions of this study, the NOAEL is 15,000 ppm in the diet (1000 mg/kg for males, 1020 

mg/kg for females, limit dose) based on no biologically significant effects. A LOAEL was 

not identified.

This subchronic toxicity study in rats (82-1) is classified as Acceptable/Guideline. It satisfies 

the guideline requirement for a subchronic dietary toxicity study in rodents.

870.3150 90-Day Oral Toxicity – Dog

In a 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 signifcantly 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 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). 

870.3150 90-Day Oral Toxicity – Dog

In a 90-day subchronic oral toxicity study (MRID 44931709), CGA-354743 technical 

(metabolite of metolachlor) (Batch Nos. KI-5408/4 and KI-5408/5, 99% a.i.) was administered to 

4 purebred beagle dogs/sex/dose by capsule at dose levels of 0, 50, 200, 500, and 1000 

mg/kg/day for 13 weeks. An additional group of 4 males and 4 females received parent 

compound (CGA-77102 technical, Batch No. P.501001, 98.5% a.i.) at 200 mg/kg/day for 13 

weeks. 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 51 of 70

There were no significant treatment related effects on mortality, body weight, food consumption, 

food conversion ratios, ophthalmological findings, hematology and urinalysis parameters, or 

gross and histopathological findings. Vomiting did occur at a higher incidence in females treated 

with 1000 mg/kg/day of CGA-354743. Clinical signs in animals treated with CGA-77102 

included vomiting, salivation and hematuria. Mean alkaline phosphatase activity was slightly 

increased in males receiving 1000 mg/kg/day CGA-354743 at weeks 7 and 13 to levels which 

were less than double the pretest mean for this group. This finding correlated with slightly 

increased absolute liver weights, but there were no corresponding histopathological findings, or 

toxicologically significant increases in other biochemistry parameters. In females, mean ALP 

activities remained within the reference range for untreated animals and mean GGT activity 

exceeded the reference range only at week 13 and only for the 500 mg/kg/day CGA-354743 

group. Absolute liver weights and liver weights relative to body weights were increased in 

females receiving 500 and 1000 mg/kg/day. In the absence of corresponding histopathological 

findings or biologically significant increases in biochemistry parameters consistent with adverse 

hepatic effects, this finding is not considered toxicologically significant.

Mean ALP and GGT activities were significantly increased in both sexes at weeks 7 and 13 

given CGA-77102. In addition, ALT activity of males was increased at weeks 7 and 13. 

Absolute and relative liver weights were significantly increased in males and females. There 

were small increases in the incidences and severity of bile duct hyperplasia, perilobular fatty 

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

parent compound group. 

The results appear to indicate that CGA-354743 may have effects (vomiting, slight increases in 

ALT and liver weight) similar to those of its parent compound, CGA-77102; however, at the 

limit dose, 1000 mg/kg/day, the effects observed were so slight and of questionable toxicological 

significance in CGA-35743-treated dogs that a definitive comparison of the two compounds 

cannot be made. 

Based on the data presented in this study, the LOAEL was not determined, and the 

NOAEL was greater than or equal to 1000 mg/kg/day. 

This subchronic oral toxicity study in dogs is classified as Acceptable/Guideline and satisfies 

the guideline requirements for a subchronic oral study [OPPTS: 870.3150 (§82-1b)] in dogs 

since the limit dose was tested.

870.3200 21/28-Day Dermal Toxicity – Rat

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. 

The Systemic LOAEL = not observed. The Systemic NOAEL = 1000 mg/kg/day.
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 52 of 70

870.3465 90-Day Inhalation – Rat

Data gap.

A.4.2 Prenatal Developmental Toxicity

There was no evidence of maternal or developmental toxicity in the rat prenatal developmental 

study with CGA 354743 or CGA 51202 at the limit dose of 1000 mg/kg/day.

870.3700a Prenatal Developmental Toxicity Study – Rat

In a prenatal developmental toxicity study (MRID 00151941), metolachlor (96.4% a.i.) 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, urine-stained 

abdominal fur and/or excessive lacrimation, were observed in animals treated at 1000 mg/kg/day. 

There was also an increase in excessive salivation in the 300 mg/kg/day group. However, as this 

effect was most likely due to gastric irritation and there was no other evidence of treatmentrelated 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, urinestained 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.

870.3700a Prenatal Developmental Toxicity Study – Rat

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% a.i.) 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 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 53 of 70

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. 

870.3700a Prenatal Developmental Toxicity Study – Rat

In a developmental toxicity study (MRID 44931711), 28 presumed pregnant Wistar B: 

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

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

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

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

fetuses examined externally. Approximately one-half of each litter was processed for visceral 

examination and the remaining one-half was processed for skeletal examination.

All animals survived to terminal sacrifice. No clinical signs of toxicity were observed in any 

animal. Maternal body weights, body weight gains, and food consumption were similar between 

the treated and control groups throughout the study. Maternal necropsy was unremarkable.

Therefore, the maternal toxicity NOAEL is 1000 mg/kg/day and the maternal toxicity 

LOAEL was not identified.

No differences were observed between the treated and control groups for number of corpora 

lutea, number of implantation sites, live fetuses/dam, pre- and post-implantation losses, fetal 

body weights, or fetal sex ratios.

No treatment-related external, visceral, or skeletal malformations/variations were observed in 

any fetus from any group.

The high dose is equivalent to the limit dose for developmental toxicity studies.

Therefore, the developmental toxicity NOAEL is 1000 mg/kg/day and the developmental 

toxicity LOAEL was not identified.

This study is classified as Acceptable/Guideline and satisfies the requirements for a 

developmental toxicity study [870.3700 (§83-3a)] in rats.
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 54 of 70

870.3700a Prenatal Developmental Toxicity Study - Rat

In a developmental toxicity study (MRID 44929510), 24 presumed pregnant Tif: RAI f (SPF) 

(hybrids of RII/1  RII/2) rats per group were administered CGA 51202 Technical (100%; Batch 

No. JD 7069/3) by gavage in 0.5% aqueous sodium carboxymethylcellulose solution at doses of 

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

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

subjected to gross necropsy, and all fetuses examined externally. Approximately one-half of 

each litter was processed for visceral examination and the remaining one-half was processed for 

skeletal examination.

One low-dose animal was sacrificed moribund on GD 20 with a urogenital infection. All other 

animals survived to terminal sacrifice. No clinical signs of toxicity were observed in any animal. 

Maternal body weights and body weight gains were similar between the treated and control 

groups throughout the study. Food consumption was not affected by treatment. Maternal 

necropsy was unremarkable.

Therefore, the maternal toxicity NOAEL is 1000 mg/kg/day and the maternal toxicity 

LOAEL was not identified.

No differences were observed between the treated and control groups for number of corpora 

lutea, number of implantation sites, live fetuses/dam, pre- and post-implantation losses, fetal 

body weights, or fetal sex ratios.

No treatment-related external, visceral, or skeletal malformations/variations were observed in 

any fetus from any group.

The high dose is equivalent to the limit dose for developmental toxicity studies.

Therefore, the developmental toxicity NOAEL is 1000 mg/kg/day and the developmental 

toxicity LOAEL was not identified.

This study is classified as Acceptable/Guideline and satisfies the requirements for a developmental toxicity study [870.3700 (§83-3a)] in rats.

870.3700b Prenatal Developmental Toxicity Study – Rabbit

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

Zealand White, S.P.F. Rabbits (Strain: Har:PF/CF(NZW)BR) from H.A.R.E., Rabbits for 

Research, Hewitt, N.J. Received either 0, 20, 100, or 500 mg/kg/day CGA-77102 Technical (Lot 

No. FL-830813 with a purity of 89.6% (93.7% S isomer) suspension in 3% corn starch 

containing 0.5% Tween 80 by oral gavage from gestation days 7 through 19. 

No treatment related mortality was noted. There was a dose related increase in little/none/soft 

stool observations at the 100 and 500 mg/kg/day dose levels. The 500 mg/kg/day dose group 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 55 of 70

had lower overall body weights at gestation days 19, 29 and corrected body weights at day 29 

gained less weight than the control during the dosing period (gestation days 7-19) with a rebound 

weight gain following the dosing period (gestation days 19-29), an indicator of toxicity. This 

group also had lower overall weight gain for the calculated periods of gestation days 7-29, 0-29 

and corrected body weight gains for 0-29. This was supported by reduced food consumption 

during the dosing period (gestation days 7-19) and for the overall periods (gestation days 7-28 

and 0-28) with a rebound in food consumption following dosing (gestation days 19-28) at the 

500 mg/kg/day dose level. This is also reflected in reduced food efficiency for the same periods 

(719, 7-28, and 0-28) and increased food efficiency following dosing (19-28) at the 500 

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

mg/kg/day based on clinical signs of toxicity.

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

developmental toxicity was equal to or greater than 500 mg/kg/day, a LOEL was not 

reached.

This study is classified as Acceptable-Guideline and satisfies the guideline requirements 

[870.3700 (§83-3b)] for a teratology study in rabbits.

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects - Rat

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

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

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

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

and 84.5 mg/kg/day).

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

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

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

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

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

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

decreased in females of the 1000 ppm group at several timepoints; however, there was no effect 

on body weight/body weight gain. Therefore, this finding was not considered toxicologically 

significant. There were no treatment-related effects on organ weights or gross/microscopic 

necropsy examinations in either generation.

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

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

days 14 and 21 (91- 96% of control value) and in the F2 litter on lactation days 4, 7, 14 and 21 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 56 of 70

(92 - 95% of control value). Although the magnitude of the decrease is small, the finding is 

regarded as toxicologically significant.

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

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

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

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

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

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

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

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

The study is classified as Acceptable/guideline and satisfies the guideline requirements for a 

multi-generation reproduction study in rats (83-4; OPPTS 870.3800).

A.4.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity – Rat

See Carcinogenicity section below.

870.4100b Chronic Toxicity - Dog

In a chronic toxicity study (MRIDs 40980701, 41164501, 42218601 and 42218602), 

metolachlor (97% a.i.) was administered in the diet to Beagle dogs (6/sex/group for control and 

high dose groups; 4/sex/group for low- and mid-dose groups) at dose levels of 0, 100, 300 or 

1000 ppm (males: 0, 3.5, 9.7 and 32.7 mg/kg/day, respectively; females: 0, 3.6, 9.7 and 33.0 

mg/kg/day, respectively) for one year. Two dogs of each sex in the control and high-dose group 

designated as recovery animals were treated for 52 weeks and were then allowed a 4-week 

recovery period. An additional 4 dogs/sex/group were treated at the same dose levels and 

sacrificed at 13 weeks. 

There were no treatment-related deaths or clinical signs of toxicity. Mean body weight gain was 

decreased in the 1000 ppm group females, considering both all animals (5-17% decrease) and 

only those treated for 52 weeks (5-17% decrease). Alkaline phosphatase was significantly 

increased in the 1000 ppm females at weeks 12, 26 and 40; however, the increase was not 

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

accompanying necropsy findings. 

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

gain. The NOAEL was 300 ppm (9.7 mg/kg/day). The LOAEL for males was not 

established. The NOAEL for males was 1000 ppm (32.7 mg/kg/day).

The study is classified as Acceptable/guideline and satisfies the guideline requirements for a 

chronic toxicity study in dogs (83-1; OPPTS 870.4100). 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 57 of 70

A.4.5 Carcinogenicity

870.4200a Carcinogenicity Study - rat

In a chronic toxicity/carcinogenicity study (MRID 00129377), metolachlor (95.3%), was 

administered in the diet to 60 CD-Crl:CD albino rats/sex/group at dose levels of 0, 30, 300 or 

3000 ppm (0, 1.5, 15 or 150 mg/kg/day) for two years. An additional 10 rats/sex/group were 

administered either 0 ppm or 3000 ppm in the diet for 12 months; 5 rats/sex/group were 

sacrificed after treatment and the remaining 5/sex/group were allowed to recover for four weeks 

and then sacrificed. Comparable mortality were observed in the treated and control animals. 

There were no treatment-related clinical signs of toxicity. Mean body weight gain was slightly 

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

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

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

increases were also observed in the 3000 ppm males after four-week recovery period. However, 

the toxicological significance of the finding is questionable as there were no accompanying 

clinical pathology or histologic changes. 

For chronic toxicity, in males, the NOAEL was 3000 ppm (150 mg/kg/day), a LOAEL was 

not established. For females, the NOAEL was 300 ppm (15 mg/kg/day) and the LOAEL 

was 3000 ppm (150 mg/kg/day) based on slightly decreased body weight gain and food 

consumption. 

The study is classified as acceptable/guideline and satisfies the guideline requirements for a 

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

870.4200b Carcinogenicity (feeding) - Mouse

In a carcinogenicity study (MRID 00117597 6), metolachlor (reported to be 95% a.i.) was 

administered in the diet to 68 CD-1 mice/sex/group at doses of 0, 300, 1000 or 3000 ppm (0, 45, 

150 or 450 mg/kg/day, based on 1ppm equals 0.150 mg/kg/day). Eight mice/sex/group were 

sacrificed at 12 and 18 months. High dose females had a significant increased mortality rate due 

to a number of deaths during the first few weeks of treatment (control: 24/52; high dose females: 

34/52 at termination). Although the deaths were possibly attributable to a viral infection, the 

contribution of the test material can not be dismissed. Body weight was statistically significantly 

decreased (91-95% of control value) throughout the study in the 3000 ppm males and during the 

latter half of the study in the 3000 ppm females (93-95%). Body weight gain was consistently 

decreased in the 3000 ppm males (48-48%) and females (59-86%). Food consumption was 

comparable between treated and control group until week 90 of treatment, at which time the 

3000 ppm males consumed 10% less than controls. The decrease was statistically significant at 

weeks 98, 102 and 104. There was no significant effect on female food consumption. There was 

 

6 According to the Second Peer Review of Metolachlor (April 17, 1991), a mouse 

carcinogenicity study (MRIDs 00042725, 00084003) conducted by Industrial Biotest (validated by 

EPA)at doses of 0, 30, 1000 and 3000 ppm also showed no evidence of carcinogenic effects.
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 58 of 70

no evidence of treatment-related effect on hematology or clinical chemistry parameters. Organ 

weight was not affected except for a dose-related decrease in absolute and relative weight of the 

seminal vesicles of males which was statistically significant at the high dose. However, there 

was no effect on testes weight and no accompanying histological changes in the seminal vesicles; 

therefore, the toxicological significance of the finding is questionable. There were no treatmentrelated microscopic changes. There were no treatment-related increases in tumor incidence in 

the study. 

The NOAEL was 1000 ppm (150 mg/kg/day) and the LOAEL was 3000 ppm (450 

mg/kg/day) based on possible treatment-related deaths in females and decreased body 

weight/body weight gain in males and females.

The study is classified as acceptable/guideline and satisfies the guideline requirements for a 

carcinogenicity toxicity study in mice (83-5; OPPTS 870.4200).

A.4.6 Mutagenicity

There was no evidence of mutagenicity in vitro or in vivo with either CGA 354743 or CGA 

51202.

Mutagenicity Studies with CGA 354743

Gene Mutation

870.5100

Salmonella/Escheri

chia

bacterial reverse 

mutation assay

44931712 (1996)

acceptable/guideline

312.5, 625.0, 1250.0, 

2500.0 and 5000.0 

μg/plate in the 

presence and absence 

of mammalian 

metabolic activation 

(S9-mix)

Strains TA98, TA100, TA102, TA1535 and 

TA1537 of S. typhimurium and strain WP2(uvrA) 

of E. coli were exposed to CGA-354743 tech. in 

DMSO at concentrations of 312.5- 5000.0 μg/plate 

in the presence and absence of mammalian 

metabolic activation (S9-mix). There was no 

evidence of induced mutant colonies over 

background.

Gene Mutation

870.5300

mammalian cell 

gene mutation 

assay at the HPRT 

locus, Chinese 

hamster V79 cells

44991102 (1999)

acceptable/guideline

concentrations of 

185.19, 555.56, 

1666.67, 5000.00 

μg/mL in the 

presence and absence 

of mammalian 

metabolic activation 

(S9-mix).

Chinese hamster V79 cells in culture were exposed 

to CGA-354743 tech. in bidistilled water at 

concentrations of 185.19 - 5000.00 μg/mL in the 

presence and absence of mammalian metabolic 

activation (S9-mix). There was suggestive 

(statistical) evidence of a possible induction of 

mutant colonies over background; however, the 

results are unlikely to be biologically significant 

because the absolute numbers of mutant colonies 

were low and within the testing laboratory’s 

historical solvent control ranges.

Cytogenetics 

870.5395 

44931713 (1998)

acceptable/guideline

Five mice/sex/dose were treated once each via oral 

gavage with CGA-354743 tech. at doses of 1250 -
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 59 of 70

Micronucleus assay 

in mouse bone 

marrow cells

1250, 2500 and 5000 

mg/kg body weight

5000 mg/kg body weight. There was no significant 

increase in the frequency of micronucleated 

polychromatic erythrocytes in bone marrow after 

any dose or treatment time.

Other Effects 

870.5503, 

Unscheduled DNA 

Synthesis

44931714 (1998)

acceptable/guideline

concentrations of 

9.77, 39.06, 156.25, 

625.00, 2500.00, 

5000.00 μg/mL

Primary rat hepatocyte cultures were exposed to 

CGA-354743 tech in bidistilled water at 

concentrations of 9.77 - 5000.00 μg/mL for 16 to 

18 hours in an initial assay and to concentrations of 

78.13 - 2500 μg/mL for 16 to 18 hours in a 

confirmatory assay. There was no evidence that 

unscheduled DNA synthesis, as determined by 

radioactive tracer procedures (nuclear silver grain 

counts), was induced.

Mutagenicity Studies with CGA 51202

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

Gene Mutation

870.5100 

Salmonella/Escheri

chia

bacterial reverse 

mutation assay

44929512 (1992)

acceptable/guideline

312.5, 625, 1250, 

2500, 5000 ug/plate

Strains TA98, TA100, TA1535 and TA1537 of S. 

typhimurium and strain WP2(uvrA) of E. coli 

were exposed to CGA-51202 technical in DMSO 

at concentrations of 312.5 - 5000.0 μg/plate in the 

presence and absence of mammalian metabolic 

activation. 

There was no evidence of induced mutant colonies 

over background.

Cytogenetics

870.5395, 

Micronucleus assay 

in mouse bone 

marrow cells

MRID 44929511 

(1992)

600, 1200 or 2400 

mg/kg

acceptable/guideline

Five mice/sex/dose were treated once via oral 

gavage with CGA-51202 technical at doses of 600-

2400 mg/kg body weight. There was no 

biologically significant increase in the frequency 

of micronucleated polychromatic erythrocytes in 

bone marrow after any dose or treatment time used 

in the study.

Gene Mutation

870.5300

MRID 45001201 

(1999)

CGA 51202 tech. was tested up to cytotoxic 

concentrations. Statistically significant increases 

in mean mutant frequency were seen in the initial 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 60 of 70

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

mammalian cell 

gene mutation 

assay at the HPRT 

locus, Chinese 

hamster V79 cells

500, 1000, 2000 or 

4000 ug/mL in initial 

assay; 375, 750, 1500 

or 3000 ug/mL in 

confirmatory assay, 

in the presence and 

absence of 

mammalian 

metabolic activation 

(S9-mix).

assay with S9-mix at 500 μg/mL (6.66 x 106) and 

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

control value of 4.02 x 106and without S9-mix at 

500 μg/mL (15.35 x 106) compared to the solvent 

control value of 12.90 x 106. The increases were 

small and the actual mean mutant frequencies were 

within the range of historical solvent control 

values. No positive dose-response was seen and 

no statistically significant increases in mean 

mutant frequencies were seen in the confirmatory 

assay. The solvent and positive controls induced 

the appropriate response. There was no evidence 

of a biologically significant induction of mutant 

colonies over background.

A.4.8 Metabolism

870.7485 Metabolism - Rat

In a metabolism study (MRID 44931715), groups of three male and three female rats were each 

given [phenyl-U14C] CGA 77102 (batch no. ILS-143.1; purity 98.9%) and non-radiolabeled 

CGA 77102 (batch no. AMS 757-101; purity 99.8%) to provide a total single oral dose of 0.5 or 

100 mg/kg. Urinary and fecal excretion were monitored over 72 hours and major metabolites 

identified and quantified. The study focused on evaluating the presence of the metabolites CGA 

354743, CGA 368208, and CGA 357704 in the excreta of rats.

There were no deaths or overt signs of toxicity attributed to the test material. Actual administered doses were 3-8% greater than nominal. Overall recovery of administered radioactivity was 

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

was approximately 38-49% of the administered dose. Most (86.5-91.7%) of the radioactivity 

recovered at 72 hours post was associated with the urine and feces. The available data suggested 

that urinary excretion was slightly greater in female rats than male rats (42% for low- and highdose females as compared to 30% and 32% of low- and high-dose males, respectively), and fecal 

elimination was expectedly less (approximately 13-15%) for females than for males. However, 

the small sample size (three rats per sex) precludes a definitive assessment of gender-specific 

differences in excretory pattern. Time-course data for absorption and excretion were not 

provided. Based upon the residual radioactivity in the carcasses, accumulation in the tissues was 

less than 10% of the administered dose at 72 hours after administration.
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 61 of 70

Both urinary and fecal metabolites were identified and quantified. For both routes of elimination, three major metabolites were identified but none represented more than 0.25% of the 

administered dose. Characterization of these metabolites and comparison to known reference 

standards revealed them to be CGA 357704, CGA 354743, and CGA 368208. In the feces, CGA 

357704 and CGA 354743 represented a notably greater percent of the administered dose than in 

the urine. The amounts of CGA 368208 were similar in the feces and urine. Biliary excretion 

experiments were not performed and, therefore, no assessment can be made regarding biliary or 

gut microflora as the source of these biotransformation products in the feces.

This metabolism study in rats is Acceptable/Non-guideline. Although not satisfying the 

requirements for a Metabolism and Pharmacokinetics study [OPPTS 870.7485 (85-1)], the study 

was well designed and conducted, and provided supplemental data regarding the quantitation and 

identification of urinary and fecal metabolites in rats given a single oral dose of CGA 77102.

Executive Summary: In a metabolism study (MRIDs 44931716 and 44931717), groups of four 

male and female and six male Tif: RAI f (SPF) rats were given single oral doses of [Phenyl-U14C]-CGA-376944 (0.5 mg/kg nominal; Batch No. ILS-125.4 radiochemical purity >95.5%), for 

the metabolism and bile-duct cannulation studies, respectively.

There were no deaths or overt signs of toxicity that could be attributed to the test material. 

Weight loss in bile-duct cannulated rats was attributed to surgical trauma. Radioactivity 

inventory indicated an acceptable 96.46-99.01% recovery of the administered dose among the 

experimental groups. Based on urinary excretion, biliary excretion, and carcass burden, 17.35% 

of the administered radioactivity was absorbed following a single oral dose of 0.5 mg/kg of 

[Phenyl-U14C]-CGA-376944. Absorption was rapid but limited and most of the absorbed 

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

measurable radioactivity was found only in the liver of non-cannulated rats. Carcass burdens 

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

 

Fecal elimination was the major route of excretion, accounting for most of the administered oral 

dose in non-cannulated rats (94.24-96.27%). Fecal excretion was rapid with 98.8-99.2% of the 

fecal excretion occurring within 24 hours post-dosing. Urinary excretion, accounted for only 

2.1-4.4% of the dose in non-cannulated rats and 5.3% in bile-duct cannulated rats. Urinary 

excretion was rapid and nearly complete within 24 hours of dosing. Biliary excretion represented 11.5% of the administered dose at 48 hours. The majority of biliary excretion (99.2%) 

occurred within 24 hours after dosing. In bile-duct cannulated animals, an additional 76.8% of 

the administered dose was excreted in the feces. Based on these data, biliary excretion is a 

contributor to fecal elimination of the test material. This appears consistent with the occurrence 

of enterohepatic circulation via the hepatic portal system and bile-duct. Only a minor percentage 

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

the kidneys. No biologically relevant gender-related differences were detected in the oral dose 

groups.

Blood pharmacokinetic parameters could not be calculated due to low blood concentrations and 

rapid clearance of the administered dose. Blood levels of radioactivity peaked in both sexes 

within one hour post-dosing. 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 62 of 70

It is evident from the results of this study that the test material undergoes limited but rapid 

absorption and nearly complete excretion within 24 hours. The primary route of excretion is via 

the feces with biliary excretion products representing about 15.0% of the fecal excretion products. At the dose tested, [14C]-CGA-376944 exhibits little potential for accumulation in the 

tissues. There were no significant gender-related differences in absorption and disposition of the 

test material. The unchanged test material accounted for >90% of the dose in both males and 

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

of the administered radioactivity and were not characterized further.

This combined metabolism study in rats is Acceptable/Guideline and satisfies the requirements 

for a Metabolism and Pharmacokinetics study [OPPTS 870.7485 (§85-1)].

A.4.9 Immunotoxicity

870.7800 Immunotoxicity

In an immunotoxicity study (MRID 48783301), S-Metolachlor (98.6% a.i., Lot # CAB9J054) 

was administered in the diet for 28 consecutive days (Days 0-27) to female Crl:CD-1 (ICR) mice 

(10 animals/dose) at doses of 0, 1500, 3000 or 5000 ppm (0, 304.3, 639.5 or 1108.5 mg/kg/day, 

respectively). Four days prior to sacrifice, animals in all groups were immunized with a 

suspension of sheep red blood cells (SRBC) by intravenous injection (1 x 108 SRBC/animal, 0.2 

mL/animal dose volume). Animals in the positive control group received intraperitoneal 

injections of cyclophosphamide (50 mg/kg bw/day) on Days 24-27. All animals were evaluated 

for mortality, clinical signs, body weight changes, and gross pathology. On Day 28, animals 

were sacrificed and spleens were collected. Spleen cell suspensions were prepared, spleen cell 

counts were performed, and the numbers of specific IgM antibody-forming cells directed 

towards the SRBC antigen were determined to measure the humoral immune response using the 

splenic Antibody-Forming Cell (AFC) assay. 

There were no treatment-related effects on clinical observations, body weight, body weight gain, 

food consumption, and spleen or thymus weights. A higher liver weight (absolute and adjusted) 

was noted at all dosage levels of S-Metolachlor, with significant differences noted in the mid and 

high doses. 

The NOAEL for systemic toxicity in female mice is 5000 ppm (actual dose of 1108.5 mg/kg/ 

bw/day); the LOAEL was not determined, tested above the limit dose.

For immunotoxicity, there were no statistically significant treatment-related effects on antiSRBC AFC response. A high inter-individual variability was noted in all the treatment groups as 

well as in the control group. Examination of individual animal data did not show any trend or 

distribution that would demonstrate significant suppression of the anti-SRBC AFC response. 

The positive control group showed a statistically significant reduction in the anti-SRBC AFC 

response, confirming the validity of the immunotoxicity assay.

A natural killer (NK) cell activity assay was not performed. The toxicology database for Smetolachlor does not reveal any evidence of treatment-related effects on the immune system. 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 63 of 70

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

system. Under HED guidance, a NK cell activity assay is not required at this time.

Under the conditions of this study, the NOAEL for immunotoxicity in female mice is 5000 

ppm (actual dose of 1108.5 mg/kg/ bw/day). The LOAEL for immunotoxicity was not 

determined.

This immunotoxicity study is classified acceptable/guideline and satisfies the guideline 

requirement for an immunotoxicity study (OPPTS 870.7800) in the mice. 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 64 of 70

Appendix B. Field Trial Summaries

Table B.1. Summary of Residues from Cantaloupe Field Trials with S-Metolachlor.

Crop 

Matrix

Trt1 Total 

Application 

Rate

(lb ai/A)

[kg ai/ha]

PHI 

(days)

n

2 S-Metolachlor residues3

(ppm)

Min.4 Max.4 LAFT

5

HAFT

5

Media

n

5

Mean

5

SD5

Cantalou

pe

2 1.26-1.33

[1.42-1.49]

27-33 9 <0.13

0

0.391 <0.13

0

<0.322 0.130 0.165 0.06

46

3 1.26-1.34

[1.42-1.50]

8 <0.13

0

0.170 <0.13

0

0.166 0.130 0.135 0.01

27

1 TRT 2 reflected foliar broadcast application, and TRT 3 reflected application banded to row middles. 

2 n = number of field trials.

3 Combined residues of SYN-506357 and SYN-508500 in parent equivalents.

4 Values based on total number of samples.

5 Values based on per-trial averages. LAFT = lowest average field trial, HAFT = highest average field 

trial, SD = standard deviation. For computation of the LAFT, HAFT, median, mean, and standard 

deviation, values < LOQ (converted to parent equivalents) are assumed to be at the LOQ (0.130 ppm). 

Table B.2. Summary of Residues from Summer Squash Field Trials with S-Metolachlor.

Crop 

Matrix

TRT 

No.1

Total 

Application 

Rate

lb ai/A

(g ai/ha)

PHI 

(day

s)

n

2 S-Metolachlor residues3

(ppm)

Min.4 Max.4 LAFT

5

HAF

T

5

Medi

an5

Mean

5

SD5

Summer 

squash

02 0.66-0.72

(735-802)

30-

75

9 <0.13

0

<0.13

0

<0.13

0

<0.13

0

0.130 0.130 N/A

03 1.24-1.35

(1393-1513)

9 <0.13

0

<0.13

0

<0.13

0

<0.13

0

0.130 0.130 N/A

04 0.65-0.70

(724-788)

21-

50

9 <0.13

0

<0.13

0

<0.13

0

<0.13

0

0.130 0.130 N/A

05 1.28-1.36

(1436-1528)

9 <0.13

0

<0.13

0

<0.13

0

<0.13

0

0.130 0.130 N/A

1 TRTs 2 and 3 reflected preemergence application, and TRTs 4 and 5 reflected foliar application.

2 n = number of field trials.

3 Combined residues of SYN-506357 and SYN-508500 in parent equivalents. 

4 Values based on total number of samples.

5 Values based on per-trial averages. LAFT = lowest average field trial, HAFT = highest average field 

trial, SD = standard deviation. For computation of the LAFT, HAFT, median, mean, and standard 

deviation, values < LOQ (converted to parent equivalents) are assumed to be at the LOQ (0.13 ppm). 

N/A = Not applicable.
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 65 of 70

TABLE B.3. Summary of Residue Data from Crop Field Trials with S-Metolachlor.

Commodit

y

Total 

Applic. 

Rate

(lb ai/A)

[kg ai/ha]

Treatment

PHI 

(days

)

Analyte Residue Levels (ppm)1

n Min. Max. HAF

T

2

Median

(STMd

R)

Mean

(STM

R)

Std.

Dev.3

Cucumber 0.89-1.00

[1.00-1.12]

Postemergence

32-52 CGA4975122 <0.05 <0.05 0.05 0.05 0.05 --

CGA3791322 <0.05 <0.05 0.05 0.05 0.05 --

Total 22 <0.10 <0.13 0.13 0.13 0.13 --

1.22-1.31

[1.36-1.47]

Postemergence

32-52 CGA4975120 <0.05 <0.05 0.05 0.05 0.05 --

CGA3791320 <0.05 <0.05 0.05 0.05 0.05 --

Total 20 <0.13 <0.13 0.13 0.13 0.13 --

0.92-1.00

[1.03-1.12]

Preemergence

45-76 CGA4975121 <0.05 <0.05 0.05 0.05 0.05 --

CGA3791321 <0.05 <0.05 0.05 0.05 0.05 --

Total 21 <0.13 <0.13 0.13 0.13 0.13 --

1.22-1.36

[1.36-1.51]

Preemergence

45-76 CGA4975120 <0.05 <0.05 0.05 0.05 0.05 --

CGA3791320 <0.05 <0.05 0.05 0.05 0.05 --

Total 20 <0.13 <0.13 0.13 0.13 0.13 --

1

 For statistical calculations, the LLMV (0.05 ppm for each analyte) was used for values 

reported as <LLMV in Table C.3.

Total residues are expressed as parent equivalents by using the following equation.

CGA-49751 x 1.14 + CGA-37913 x 1.47 = total metolachlor equivalents. 

2

 HAFT = Highest Average Field Trial.

3

 Standard deviation is not calculated when all samples have nonquantifiable residues.
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 66 of 70

Table B.4. Summary of Residues from Head Lettuce Field Trials with S-Metolachlor.

Crop 

Matrix

TR

T 

No.1

Total 

Application 

Rate

(lb ai/A)

PHI 

(days)

n

2 S-Metolachlor Residues3

(ppm)

Min.4 Max.4 LAFT

5

HAFT

5

Media

n

5

Mean

5

SD5

Head 

Lettuce

02 1.283-1.331 18-21 7 <0.13

0

<0.183 <0.13

0

<0.182 0.134 0.141 0.01

83

03 1.988-2.059 18-21 7 <0.13

0

0.414 <0.13

0

0.412 0.276 0.272 0.09

34

04 0.988-1.030 18-21 7 <0.13

0

<0.365 <0.13

0

<0.340 0.155 0.198 0.09

40

1 TRTs 02 and 03 reflected soil or foliar broadcast at transplant + mid/late-season foliar application. TRT 

04 reflected a single mid/late season foliar application.

2 n = number of field trials.

3 Combined residues of SYN-506357 and SYN-508500 in parent equivalents.

4 Values based on total number of samples.

5 Values based on per-trial averages. LAFT = lowest average field trial, HAFT = highest average field 

trial, SD = standard deviation. For computation of the LAFT, HAFT, median, mean, and standard 

deviation, values < LOQ (converted to parent equivalents) are assumed to be at the LOQ (0.13 ppm).

Table B.5. Summary of Residues from Leaf Lettuce Field Trials with S-Metolachlor.

Crop 

Matrix

TRT 

No.1

Total 

Application 

Rate

(lb ai/A)

PHI 

(days)

n

2 S-Metolachlor residues3

(ppm)

Min.4 Max.4 LAFT

3

HAFT

3

Media

n

3

Mean

3

SD3

Leaf 

lettuce

02 0.64-0.66 27-28 6 <0.13

0

0.519 <0.13

0

0.501 0.186 0.244 0.14

6

03 & 

05

0.92-1.04 25-30 8 <0.13

0

1.415 <0.13

0

1.228 0.320 0.462 0.39

0

04 & 

06

1.28-1.33 20-30 8 <0.13

0

0.758 <0.13

0

0.754 0.163 0.255 0.21

3

07 2.01-2.03 20-21 2 0.338 1.050 0.351 1.021 0.686 0.686 0.47

3

08 1.00-1.02 20-21 2 <0.13

1

1.275 <0.14

7

1.173 0.660 0.660 0.72

6

1 TRTs 02 and 03 reflected preemergence application, TRT 04 reflected preemergence + foliar 

application, TRTs 05 and 08 reflected a single foliar application, and TRTs 06 and 07 reflected attransplant + foliar application. 

2 n = number of field trials.

3

 Combined residues of SYN-506357 and SYN-508500 in parent equivalents.

4 Values based on total number of samples.

5 Values based on per-trial averages. LAFT = lowest average field trial, HAFT = highest average field 

trial, SD = standard deviation. For computation of the LAFT, HAFT, median, mean, and standard 

deviation, values < LOQ (converted to parent equivalents) are assumed to be at the LOQ (0.13 ppm). 
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 67 of 70

Table B.6. Summary of Residues from Strawberry Field Trials with S-Metolachlor.

Crop 

Matrix

Total 

Application 

Rate

(lb ai/A)

PHI 

(day

s)

n

1 S-Metolachlor residues3

(ppm)

Min.2 Max.2 LAFT3 HAFT

3

Median

3

Mean3 SD3

Strawberr

y

1.19-1.23 24-

33

8 <0.13

0

<0.13

4

<0.130 <0.132 0.130 0.130 0.001

2.38-2.50 24-

33

8 <0.13

0

<0.25

2

<0.130 <0.244 0.133 0.152 0.041

1

n = number of field trials.

2 Values based on total number of samples.

3 Combined residues of SYN-506357 and SYN-508500 in parent equivalents. 

4 Values based on per-trial averages. LAFT = lowest average field trial, HAFT = highest 

average field trial, SD = standard deviation. For computation of the LAFT, HAFT, median, 

mean, and standard deviation, values < LOQ (converted to parent equivalents) are assumed to be 

at the LOQ (0.130 ppm). 

Table B.7. Summary of Residue Data in/on Sunflower Seed from Crop Field Trials with SMetolachlor.

Total 

Applic. Rate 

(lb ai/A)

Applic. Method a PHI 

(days)

Combined S-Metolachlor Residue Levels (ppm)

Minimu

m

Maximum HAFT Mean Std. 

Dev.

2.0 Preplant Incorp. (PPI) 122-

147

<0.08 <0.26 0.22 0.14 b0.07

2.0 Broadcast 

Preemergence

107-

147

<0.08 <0.49 0.47 0.26 b0.17

2.0 PPI or Preemergence 107-

147

<0.08 <0.49 0.47 0.20 c0.14

a A single application of S-metolachlor (7.64 lb/gal EC) was made at planting for all tests.

b N = 8. (The replicates from the trials were individually included in the statistics.)

c N = 16. (The replicates from the trials were individually included in the statistics.)
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 68 of 70

TABLE B.8. Summary of Total Residue Data for Peppers and Tomatoes from Crop Field 

Trials using S-Metolachlor (7.6 lb/gal EC) 1

Commodi

ty

Total 

Rate

(lb 

a.i./A) 

PHI 

(days)

Combined SYN508500 and SYN506357 Residue Levels (ppm)2

n Min. Max. HAFT 

3

Median 

(STMdR4)

Mean 

(STMR5)

Std. 

Dev.

Bell 

Pepper

1.65-

1.79

39-

125

60 <0.08 <0.08 <0.08 <0.08 <0.08 <0.08

Hot 

Pepper

1.63-

1.75

60-

124

32 <0.08 <0.08 <0.08 <0.08 <0.08 <0.08

Tomato 1.62-

1.75

36-

120

10

6

<0.08 <0.08 <0.08 <0.08 <0.08 <0.08

1 Three different application regimes were used; either a preplant incorporated or foliar 

applications. The data for each type of application were pooled as residues were identical. 

2 Residues are expressed as S-Metolachlor equivalents. The LOQ is 0.05 ppm for 

SYN508500, 0.03 ppm for SYN506357, and 0.08 ppm for combined residues.

3 HAFT = Highest Average Field Trial. 

4 STMdR = Supervised Trial Median Residue.
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 69 of 70

Appendix C. Physical/Chemical Properties

Table C1. Physico-Chemical Properties

Parameter Value Reference

Molecular Weight

MRID 47121701 (DP#s 

332846, etc., 10/21/08, D. 

McNeilly)

pH 7.8 at 25 oC (1% 

aqueous dispersion)

Water solubility (20°C) 0.48 g/L

Solvent solubility (20°C to 25°C)

Completely 

miscible with 

methanol, acetone, 

toluene, n-octanol, 

n-hexane, ethyl 

acetate, and 

dichloromethane

Vapor pressure (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 (25°C) 3.05 at 25 oC

Soil Half-life (or other relevant 

information from EFED Drinking 

water assessment)
S-Metolachlor Human Health Risk Assessment DP No. D425168

Page 70 of 70

Appendix D. Review of Human Research

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

intentionally exposed to a pesticide or other chemical. These data, which include studies from 

the PHED 1.1, and the AHETF database, are (1) subject to ethics review pursuant to 40 CFR 26, 

(2) have received that review, and (3) are compliant with applicable ethics requirements. For 

certain studies, the ethics review may have included review by the Human Studies Review 

Board. Descriptions of data sources, as well as guidance on their use, can be found at the 

Agency website.

[7]

 

7 http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html