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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 

 OFFICE OF CHEMICAL SAFETY AND

 POLLUTION PREVENTION

MEMORANDUM

June 30, 2010

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

on Bushberry, Caneberry, Carrot, Cucumber; Leafy Brassica Greens, Melon, 

Okra, Bulb and Green Onion, Sesame Seed, Sorghum, and Turnip Greens

PC Code: 108800 DP Barcode: 368726

Decision No.: 418569 Registration No.: 100-816, 100-818

Petition No.: 6E7607 Regulatory Action: Section 3

Risk Assessment Type: Single Chemical Case No.: 0001

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

MRID No.: NA 40 CFR: 180.368

FROM: Becky Daiss, Biologist 

Susan Hummel, Chemist

Ivan Nieves, Chemist

Risk Assessment Branch 4

Health Effects Division (7509P)

THROUGH: Susan V. Hummel, Branch Senior Scientist

Risk Assessment Branch 4, HED (7509P)

Health Effects Division (7509P)

TO: Sydney Jackson, Risk Manager Reviewer

RIMUER Branch

Registration Division (7505P)

This document provides the Health Effects Division’s (HED’s) risk assessment of proposed new 

uses of S-metolachlor on the following crops; bushberry, caneberry, carrot, cucumber, leafy

Brassica greens, melon, bulb and green onion, sesame seed, sorghum, turnip greens. Supporting 

documents are listed below.

Residue Chemistry Assessment S. Hummel (D369005, 6/15/10)

Dietary Exposure and Risk Assessment, B.Daiss (D370429, 6/30/10)

Occupational and Residential Exposure and Risk Ivan (D370432, 6/29/10)

Drinking Water Assessment (D368735, C. Koper, 4/22/10).TABLE OF CONTENTS
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 pg.

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

2.0 INGREDIENT PROFILE ....................................................................................................7

2.1 Registered Products .............................................................................................................7

2.2 Proposed New Uses .............................................................................................................8

2.3 Structure, Nomenclature and Physical/Chemical Properties ...............................................9

3.0 HAZARD ASSESSMENT ...............................................................................................10

3.1 Hazard Profile ....................................................................................................................10

3.2 FQPA Hazard Considerations ...........................................................................................11

3.2.1 Developmental Toxicity .......................................................................................12

3.2.2 Reproductive Toxicity ...........................................................................................14

3.2.3 Pre-and/or Postnatal Toxicity.................................................................................15

3.2.4 Immunotoxicity .....................................................................................................15

3.2.5 Neurotoxicity .........................................................................................................15

3.2.6 FQPA Factor..........................................................................................................16

3.3 Toxicity Endpoint Selection ..............................................................................................16

3.3.1 Acute Reference Dose – General Population ........................................................16

3.3.2 Chronic Reference Dose – All Populations ..........................................................17

3.3.3 Incidental Oral Exposure .......................................................................................17

3.3.4 Dermal Exposure ...................................................................................................17

3.3.5 Inhalation Exposure Short-Term............................................................................18

3.3.6 Inhalation Exposure Intermediate-Term ................................................................18

3.3.7 Classification of Carcinogenic Potential................................................................19

3.4 Margins of Exposure..........................................................................................................19

3.5 Recommendation for Aggregate Exposure ........................................................................19

3.6 Summary of Endpoints Selected for Risk Assessment ......................................................20

3.7 Endocrine Disruption.........................................................................................................21

4.0 DIETARY AND DRINKING WATER EXPOSURE ASSESSMENT ............................21

4.1 Proposed and Registered Food Uses..................................................................................21

4.2 Residue Chemistry Profile .................................................................................................22

4.2.1 Metabolism in Primary Crops and Livestock.........................................................22

4.2.2 Metabolism in Rotational Crops............................................................................23

4.2.3 Residue Analytical Method....................................................................................23

4.2.4 Residues in Crops ..................................................................................................24

4.2.5 Residues in Livestock ............................................................................................25

4.2.6 Residues in Processed Commodities .....................................................................25

4.2.7 Residues in Rotational Crops.................................................................................25

4.3 Drinking Water Profile ......................................................................................................26

4.2.1 Environmental Fate and Transport.........................................................................26

4.2.2 Estimated Drinking Water Concentrations............................................................26
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4.4 Dietary and Drinking Water Exposure and Risk................................................................26

5.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT ...............................................28

6.0 OCCUPATIONAL EXPOSURE AND RISK ...................................................................29

6.1 Exposure Scenarios............................................................................................................29

6.1.1 Handler Exposure Scenarios..................................................................................29

6.1.2 Post Application Exposure Scenarios....................................................................29

6.2 Occupational Exposure Data and Assumptions.................................................................30

6.2.1 Exposure Data........................................................................................................30

6.2.2 Exposure Assumptions ..........................................................................................30

6.3 Occupational Exposure and Risk Estimates .....................................................................31

6.3.1 Handler Exposure and Risk Estimates...................................................................31

6.3.2 Post-Application Exposure and Risk Estimates.....................................................32

7.0 CUMULATIVE RISK .......................................................................................................30

8.0 DATA NEEDS...................................................................................................................33

8.1 Toxicity Data Requirements ..............................................................................................33

8.2 Residue Chemistry Data Requirements .............................................................................33

APPENDICES

1.0 GUIDELINE TOXICOLOGY DATA SUMMARY..........................................................34

1.1 Guideline Data Requirements................................................................................34

1.2 Toxicity Profiles.....................................................................................................35

2.0 STUDIES REVIEWED FOR ETHICAL CONDUCT ......................................................45

3.0 CHEMICAL NAMES AND STRUCTURES OF METABOLITES.................................46

4.0 REFERENCES FOR TOXICITY STUDIES.....................................................................48

1.0 EXECUTIVE SUMMARY

This assessment provides information to support the issuance of an amended Section 3 

registration for the use of S-metolachlor on the bulb onion subgroup (3-07A), bushberry

subgroup (13-07B), the caneberry subgroup (13-07A), carrot, cucumber, the green onion 

subgroup (3-07B), the leafy Brassica greens subgroup (5B, including turnip greens), the melon 

subgroup (9A), okra, sesame, and sweet sorghum.. The risk assessment process considers the 

human health effects of pesticides and incorporates a reassessment of tolerances (pesticide 

residue limits in food) to ensure that they meet the safety standard established by the Food 

Quality Protection Act (FQPA) of 1996. 

Use Profile
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Registered Uses

Metolachlor (PC Code 108801) is a racemic herbicide that consists of 50% each of the Renantiomer and the S-enantiomer. The S-enantiomer is the herbicidally active isomer. Smetolachlor (PC Code 108800) is an isomer enriched formula comprised of 88% S-isomer and 

12% R-isomer. S-metolachlor is registered by Syngenta. Permanent tolerances are established at 

40 CFR §180.638(a)(2) for S-metolachlor in/on a variety of crop commodities, at levels ranging 

from 0.02 in/on meat and dairy products to 20 ppm in/on peanut hay. S-metolachlor is a 

selective, chloroacetanilide herbicide used primarily for grassy weed control in many agricultural 

food and feed crops, residential lawns, commercial turf (including golf courses, sports fields, 

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

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

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

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

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

Proposed New Use

The Interregional Research Project No. 4 (IR-4) is requesting amended registration of two 

products, a 7.62 lb/gal emulsifiable concentrate (EC) formulation of S-metolachlor, Dual 

Magnum® Herbicide (EPA Reg. No. 100-816) and a 7.64 lb/gal EC formulation, Dual II 

Magnum® (EPA Reg. No. 100-818), to add uses on the bulb onion subgroup (3-07A), bushberry

subgroup (13-07B), the caneberry subgroup (13-07A), carrot, cucumber, the green onion 

subgroup (3-07B), the leafy Brassica greens subgroup (5B, including turnip greens), the melon 

subgroup (9A), okra, sesame, and sweet sorghum. The products are proposed for postemergence 

application to the bushberry subgroup, the caneberry subgroup, okra, the bulb onion subgroup, 

and the green onion subgroup at maximum application rates ranging 1.3-3.8 lb ai/A; preharvest 

intervals (PHIs) of 21 days for the green onion subgroup, 28 days for the bushberry and caneberry

subgroup, and 60 days for okra and the bulb onion subgroup are proposed. Preemergence, pretransplant, and/or postemergence applications are proposed for carrot, cucumber, leafy Brassica 

greens, the melon subgroup, and sweet sorghum at maximum application rates ranging 1.2-1.9 lb 

ai/A; PHIs of 64 days for carrot, 30 days for cucumber and leafy Brassica greens, 60 days for 

melons, and 90 days for sweet sorghum are proposed. In addition, the 7.62 lb/gal EC formulation

is proposed for preemergence application to sesame at up to 1.9 lb ai/A with a proposed PHI of 

100 days. The proposed new uses do not include homeowner use or application to residential 

areas. 

Hazard Identification

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

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

eye irritation, and is non-irritating dermally but is a dermal sensitizer. In subchronic 

(metolachlor and S-metolachlor) and chronic (metolachlor) toxicity studies in dogs and rats 

decreased body weight and body weight gain were the most commonly observed effects. No 

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

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

neurotoxic effects in the available toxicity studies. Prenatal developmental studies in the rat and 

rabbit with both metolachlor and 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 mutagenic or cytogenetic effects in vivo or in vitro. 

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

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

calculated based on the chronic reference dose are protective of cancer effects.

Neurotoxicity (870.6200 a and b) and immunotoxicity studies (870.7800) are required in 

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

Dose Response Assessment

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

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

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

RfD was selected from a chronic toxicity study in dogs. A point of departure (POD) for dermal 

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

repeated dermal application at the highest dose tested for 21 days. An inhalation exposure POD 

was selected from a developmental toxicity study in rats. An uncertainty factor of 100X was 

applied to endpoints selected for exposure routes (10x for interspecies extrapolation, 10x for 

intraspecies variation). 

Exposure/Risk Assessment and Risk Characterization

Risk assessments were conducted for dietary (food and water), occupational handler and 

residential post-application exposure pathways based on existing uses and the proposed new uses 

of S-metolachlor. Conservative acute and chronic dietary and drinking water risk assessments 

for S-metolachlor conclude that dietary and drinking water exposure estimates are below HED’s 

level of concern for the general population and all population subgroups. Occupational exposure 

and risk estimates indicate that worker handler exposures are not of concern at the maximum 

proposed application rate for the proposed new use. Aggregate risks from dietary and postapplication residential hand-to-mouth exposures are not of concern.

Use of Human Studies
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This risk assessment relies in part on data from studies in which adult human subjects 

were intentionally exposed to a pesticide or other chemical. These studies, listed in Appendix 

2.0, have been determined to require a review of their ethical conduct. Some of these studies are 

also subject to review by the Human Studies Review Board. All of the studies used have 

received the appropriate review.

Environmental Justice

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

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

Actions to Address Environmental Justice in Minority Populations and Low-Income 

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

Tolerance Recommendation

HED has examined the residue chemistry database for S-metolachlor. Pending 

submission of a revised Section B (see requirements under Directions for Use) and revised 

Section F (see requirements under Proposed Tolerances), there are no residue chemistry issues 

that would preclude granting a conditional registration for the requested uses of S-metolachlor on 

Bushberry subgroup 13-07B, Caneberry, subgroup 13-07A, Carrot, Cucumber, Leafy brassica 

greens, subgroup 5-B, Melon subgroup 9A, Okra, Onion, Bulb, subgroup 3-07A, Onion, green, 

subgroup 3-07B, Sesame, seed, Sorghum, sweet, and Turnip greens, or establishment of 

tolerances for residues of S-metolachlor and its R-enantiomer, including its metabolites and 

degradates, in or on the commodities in the table below. Compliance with the tolerance levels 

specified 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 Renantiomer, and its metabolites, determined as the derivatives, 2-(2-ethyl-6-methylphenyl)amino1-propanol and 4-(2-ethyl-6-methylphenyl)-2-hydroxy-5-methyl-3-morpholinone, calculated as 

the stoichiometric equivalent of S-metolachlor:

Bushberry subgroup 13-07B .......................................0.15 ppm

Caneberry, subgroup 13-07A......................................0.10 ppm

Carrot ..........................................................................0.40 ppm

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

Leafy brassica greens, Subgroup 5-B............................1.8 ppm

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

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

Onion, bulb, subgroup 3-07A .....................................0.10 ppm

Onion, green, subgroup 3-07B......................................2.0 ppm

Sorghum, sweet, stalk ...................................................4.0 ppm

Sesame, seed ...............................................................0.13 ppm

Turnip greens................................................................1.8 ppm
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Upon establishment of the above tolerances, IR-4 requests the removal of tolerances 

established under 180.368(a)(2) for S-metolachlor and its metabolites in/on bulb onion (0.1 ppm) 

and green onion (2.0 ppm) as the proposed tolerances for the onion subgroups 3-07A and 3-07B 

will cover bulb and green onion, respectively.

2.0 INGREDIENT PROFILE

2.1 Registered Products

There are currently 33 active Section 3 S-metolachlor registrations according to the 

OPPIN data base. In addition there are currently 76 Section 24 Special Local Needs (SLN) 

registrations and 7 Section 18 Emergency Exemptions for S-metolachlor. 

Table 1. Active Section 3 Registrations for S-Metolachlor

Reg # Name Company Name %ai

100-815 S-Metolachlor Technical

Syngenta Crop Protection, Inc.

96

100-816 Dual Magnum Herbicide 83.7

100-817 Bicep Ii Magnum Herbicide 26.1

100-818 Dual Ii Magnum Herbicide 82.4

100-827 Bicep Lite Ii Magnum Herbicide 35.8

100-829 Dual Ii Magnum Si Herbicide 71

100-886 Bicep Magnum 26.1

100-910 Dual Iig Magnum Granular Herbicide 16

100-950 Pennant Magnum Herbicide 83.7

100-958 Boundary Herbicide 68.1

100-964 Medal Herbicide 83.7

100-965 Medal Ii Herbicide 82.4

100-1148 Camix Selective Herbicide 36.8

100-1148 Camix Selective Herbicide 3.68

100-1152 Lumax Selective Herbicide 29.4

100-1185 Sequence Herbicide 29

100-1201 Lexar Herbicide 19

100-RENG New Concept Herbicide 29.4

100-1213 Bicep Lite Ii Magnum Manufacturing Use Product 35.8

100-1214 Bicep Ii Magnum Manufacturing Use Product 26.1

100-1215 Dual Ii Magnum Manufacturing Use Product 82.4

100-1268 Prefix Herbicide 46.4

100-1282 A15189 Herbicide 20.5

100-1356 Syn-Ai7227 29.4

352-623 Dupont Cinch Atz Lite Herbicide

E. I. Du Pont De Nemours And Co., 

Inc. 

35.8

352-624 Dupont Cinch Atz Herbicide 26.1

352-625 Dupont Cinch Herbicide 82.4

1381-194 Charger Max

Winfield Solutions, Llc

82.4

1381-199 Charger Max Atz 26.1

1381-207 Charger Basic 83.7

1381-208 Charger Max Atz Lite 35.8

53883-149 Metolachlor T&O Herbicide Control Solutions, Inc. 83.7
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2.2 Proposed New Uses

IR-4 is requesting amended registration of two products, a 7.62 lb/gal emulsifiable 

concentrate (EC) formulation of S-metolachlor, Dual Magnum® Herbicide (EPA Reg. No. 100-

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

on the bulb onion subgroup (3-07A), bushberry subgroup (13-07B), the caneberry subgroup (13-

07A), carrot, cucumber, the green onion subgroup (3-07B), the leafy Brassica greens subgroup 

(5B, including turnip greens), the melon subgroup (9A), okra, sesame, and sweet sorghum. The 

products are proposed for postemergence application to the bushberry subgroup, the caneberry

subgroup, okra, the bulb onion subgroup, and the green onion subgroup at maximum application 

rates ranging 1.3-3.8 lb ai/A; preharvest intervals (PHIs) of 21 days for the green onion subgroup, 

28 days for the bushberry and caneberry subgroup, and 60 days for okra and the bulb onion 

subgroup are proposed. Preemergence, pre-transplant, and/or postemergence applications are 

proposed for carrot, cucumber, leafy Brassica greens, the melon subgroup, and sweet sorghum at 

maximum application rates ranging 1.2-1.9 lb ai/A; PHIs of 64 days for carrot, 30 days for 

cucumber and leafy Brassica greens, 60 days for melons, and 90 days for sweet sorghum are 

proposed. In addition, the 7.62 lb/gal EC formulation is proposed for preemergence application 

to sesame at up to 1.9 lb ai/A with a proposed PHI of 100 days. 

For caneberry subgroup 13-07A, okra, and sesame, the use directions provided in Section 

B of the petition differed slightly from those provided on the proposed amended label for EPA 

Reg. No. 100-816. For these crops, the proposed amended label specified a maximum seasonal 

rate and a maximum number of applications; no maximum seasonal rate or maximum number of 

applications were specified for these crops in Section B. In addition, no PHI was specified in 

Section B for application to okra and sesame; the proposed amended label specified a PHI for 

both these crops. In all cases, the proposed amended label for EPA Reg. No. 100-816 was 

considered to reflect the actual proposed uses. 

The proposed amended label for EPA Reg. No. 100-816 with uses on bulb vegetables, 

bushberries, caneberries, carrot, cucumber, leafy Brassica greens, melon, okra, and sesame did 

not include any information about application equipment, minimum application volume, or 

rotational crop restrictions. HED has assumed that the general application instructions and 

rotational crop restrictions on the parent label for EPA Reg. No. 100-816 are intended to be 

applied to the proposed uses. 

Plantback restrictions for the proposed uses in Section B refer to the master label. A 

master label was provided in Section A of the petition for Dual Magnum Herbicide (EPA Reg. 

No. 100-816); however, no master label for Dual II Magnum Herbicide (EPA Reg. No. 100-818) 

was provided. 

2.3 PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION

The nomenclature and physicochemical properties of S-metolachlor are provided in 

Tables 2 and 3.
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TABLE 2. Nomenclature of S-Metolachlor and its Regulated Hydrolytic Derivatives.

Compound

S-metolachlor

Common name S-metolachlor

Company experimental name CGA-77102

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

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

CAS # 87392-12-9

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

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

Regulated residue

Common name None

Company experimental names CGA-37913

SYN506357 (S-enantiomer of CGA 37913)

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

CAS registry number 61520-53-4

82508-08-5 (S-enantiomer)

Regulated residue

Common name None

Company experimental names CGA-49751

SYN508500 (S-enantiomer of CGA 49751)

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

CAS registry number 61520-54-5

TABLE 3. Physicochemical Properties of the Technical Grade Test Compound

Parameter Value Reference

Melting point/range N/A Registration Division: 

Physical and Chemical 

Characteristics

(DP Num: 225258)

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

Density 1.117 g/cm3at 20°C

Water solubility (25°C) 0.48 g/L

Solvent solubility (mg/L at 25°C) Miscible with methanol, acetone, toluene, n-octanol, nhexane, ethyl acetate, dichloromethane
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TABLE 3. Physicochemical Properties of the Technical Grade Test Compound

Parameter Value Reference

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

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

Octanol/water partition coefficient Log(KOW) 3.0 at 25°C

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

443 L/mol•cm @ 274.4 nm

Acidic: 534 L/mol•cm @ 266.4 nm

444 L/mol•cm @ 274.4 nm

Basic: 531 L/mol•cm @ 266.4 nm

411 L/mol•cm @ 274.4 nm

3.0 HAZARD ASSESSMENT

3.1 Hazard Profile

The existing toxicological database is comprised primarily of studies conducted with 

metolachlor. Metabolism studies were inadequate for comparing the metabolic pathways of 

metolachlor and s-metolachlor. However, based on a comparison of the findings in toxicity

studies with both chemicals, S-metolachlor is considered to be of comparable toxicity to 

metolachlor and data can be bridged between the two compounds. The metolachlor toxicology

database is complete. The combined metolachlor and S-metolachlor toxicity data bases are 

adequate to characterize the toxicity of S-metolachlor for risk assessment purposes. 

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

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

toxicity at the limit dose in a 21 day dermal toxicity metolachlor study in rabbits, however 

dermal irritation was observed at lower doses. In the chronic dog study on metolachlor, the only

adverse effect was decreased body weight gain in females. 

In the mouse carcinogenicity study, possible treatment-related deaths in females and 

decreased body weight/body weight gain in both sexes were observed. In the rat combined 

chronic toxicity/ carcinogenicity study, decreased body weight gain and food consumption were 

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

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

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

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

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

with risk quantitated using a non-linear (Margin of Exposure) approach. 

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

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

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

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

effects at the limit dose included slightly decreased number of implantations per dam, decreased 

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

mean fetal body weight. In the S-metolachlor rat study, maternal toxicity, including increased 

clinical signs (pushing head through bedding), and decreased body weight/weight gain, food 

consumption and food efficiency, was observed at the mid-dose. There were no developmental 

effects at the highest dose tested. In the rabbit, clinical signs of toxicity (little/none/soft stool) 

were observed at the mid-dose in maternal animals tested with S-metolachlor. No developmental 

effects were observed at the highest dose tested.

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

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

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

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

lactation days is most likely due to exposure of the pups to metolachlor in the diet and/or milk 

and therefore is not evidence of an increased quantitative susceptibility in post-natal animals.

Both compounds are extensively absorbed and metabolized following oral administration. 

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

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

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

3.2 FQPA Hazard Considerations

The toxicity database for S-metolachlor/metolachlor is sufficient for a full hazard 

evaluation and is considered adequate to evaluate risks to infants and children. Acceptable 

developmental toxicity studies in the rat and rabbit and an acceptable reproduction study in the 

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

neurotoxicity or immunotoxicity. However, in accordance with the revised 40 CFR Part 158 

Toxicology Data Requirements, neurotoxicity battery (870.6200) and immunotoxicity (870.7800) 

studies are required.

3.2.1 Developmental Toxicity 

3.2.1.1 Rat Developmental Study - Metolochlor

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.
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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.

3.2.1.2 Rabbit Developmental Study - Metolochlor

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

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

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

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

evidence of developmental effects.

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

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

rabbits aborted, one at 120 mg/kg/day (GD 25) and another at 360 mg/kg/day (GD 17). The highdose animal had persistent anorexia. One rabbit in each group delivered prior to GD 30; the 

control, low- and high-dose animals on GD 29 and the mid-dose animal on GD 30. There was a 

treatment-related increase in the incidence of persistent anorexia in the does treated at 360 

mg/kg/day, which was defined as less than one-half of the daily food allotment consumed. 

However, food consumption data were not provided to support this finding. There was a 

treatment-related decrease in body weight gain in the 360 mg/kg/day group for GD 6-18 and GD 

6-30. There was no treatment-related increase in gross pathological findings in maternal animals 

at necropsy. No treatment-related increase in external, visceral or skeletal developmental effects 

were observed. 

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

clinical observations (persistent anorexia) and decreased body weight gain. The NOAEL was 120 

mg/kg/day. The developmental toxicity LOAEL was not established. The NOAEL was 360 
Page 13 of 60

mg/kg/day.

3.2.1.3 Rat Developmental Study – S-Metolochlor

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

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

dosing period and may be an indication of neurotoxicity. The 500 and 1000 mg/kg/day dose 

groups had lower overall body weights at gestation days 15 and 21 and gained less weight than 

the control during the dosing period (gestation days 6-16) and for the calculated periods of 

gestation days 6-21 and 0-21, also for corrected body weight gains from gestation days 6-21. 

Also the 500 and 1000 mg/kg/day dose groups had reduced food consumption during the dosing 

period (gestation days 6-16, statistically significantly different), reduced food consumption 

following the dosing period and for the overall periods (gestation days 6-21 and 0-2 1). This is 

also reflected in reduced food efficiency for the same periods (6-16, 6-21, 6-21, and 0-21). 

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

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

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

toxicity was noted at the dose levels tests. The developmental toxicity was equal to or greater 

than 1000 mg/kg/day, a LOEL was not reached. 

3.2.1.4 Rabbit Developmental Study – S-Metolochlor

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

S.P.F. Rabbits received either 0, 20, 100, or 500 mg/kg/day S-metolachlor (89.6% a.i. (93.7% S 

isomer)) suspension in 3% corn starch by oral gavage from gestation days 7 through 19. 

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

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

body weights at day 29 gained less weight than the control during the dosing period (gestation 

days 7-19) with a rebound weight gain following the dosing period (gestation days 19-29), an 

indicator of toxicity. This group also had lower overall weight gain for the calculated periods of 

gestation days 7-29, 0-29 and corrected body weight gains for 0-29. This was supported by

reduced little/none/soft stool observations at the 100 and 500 mg/kg/day dose levels, food 

consumption during the dosing period (gestation days 7-19) and for the overall periods (gestation 

days 7-28 and 0-28) with a rebound in food consumption following dosing (gestation days 19-28) 

at the 500 mg/kg/day dose level. This is also reflected in reduced food efficiency for the same 

periods (719, 7-28, and 0-28) and increased food efficiency following dosing (19-28) at the 500 
Page 14 of 60

mg/kg/day dose level. The maternal toxicity NOEL was 20 mg/kg/day with a LOEL of 100 

mg/kg/day based on clinical signs of toxicity.

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

The developmental toxicity was equal to or greater than 500 mg/kg/day, a LOEL was not 

reached.

3.2.2 Reproductive Toxicity 

In a two-generation reproduction study (MRID 00080897), metolachlor (95.4% 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 time points; however, there was no effect

on body weight/body weight gain. Therefore, this finding was not considered toxicologically

significant. There were no treatment-related effects on organ weights or gross/microscopic 

necropsy examinations in either generation.

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

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

lactation days 14 and 21(91-96% of control value) and in the F, litter on lactation days 4, 7, 14 

and 21 (92 - 95% of control value). Although the magnitude of the decrease is small, the finding 

is regarded as toxicologically significant.

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

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

toxicity LOAEL was not established. The NOAEL was 1000 ppm (F0 males/females: 75.8/85.7 

mg/kg/day; F1males/females: 76.6/84.5 mg/kg/day). The offspring LOAEL was conservatively

established at 1000 ppm (F0 males/females: 75.8/85.7 mg/kg/day; F1males/females: 76.6/84.5 

mg/kg/day) based on decreased body weight in F1 and F2 litters. The NOAEL is 300 ppm (F0 

males/females: 23.5/ 26.0 mg/kg/day; F1males/females: 23.7/25.7 mg/kg/day).

3.2.3 Pre-and/or Postnatal Toxicity

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

a dose/response to characterize the potential prenatal or postnatal toxicity of metolachlor or S-
Page 15 of 60

metolachlor to infants and children. No increase in susceptibility was seen in developmental 

toxicity studies in rat and rabbit or reproductive toxicity studies in the rat. Toxicity to offspring 

was observed at dose levels the same or greater than those causing maternal or parental toxicity. 

Based on the results of developmental and reproductive toxicity studies, there is not a concern for 

increased qualitative and/or quantitative susceptibility following in utero exposure to metolachlor 

or S-metolachlor. 

3.2.4 Immunotoxicity

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

function, such as the thymus and spleen, are affected metolachlor or S-metolachlor. There are no 

effects seen on the developing immune system in the existing studies. An immunotoxicity study

is required, however, under 40 CFR Part 158 as a part of the new data requirements for 

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

3.2.5 Neurotoxicity

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

neurotoxic. In the rat developmental toxicity study with s-metolachlor (MRID 43928925), 6/24 

animals in the 1000 mg/kg/day group and 3/24 in the 500 mg/kg/day group were described as 

exhibiting discomfort (pushing head through bedding for one hour after each dose); the sign was 

first observed after the initial treatment. No control animals were affected. In the rat prenatal 

developmental toxicity study with metolachlor, clinical signs of clonic and/or tonic convulsions 

and excessive salivation, possible neurotoxic signs, were observed at 1000 mg/kg/day. However, 

the signs were prior to death in some of the treated animals and could be agonal effects. Acute 

and subchronic neurotoxicity studies (870.6200) are required in accordance with the revised 40 

CFR Part 158 Toxicology Data Requirements. 

3.2.6 FQPA Safety Factor

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

resulting from exposure to S-metolachlor. Data available on metolachlor and S-metolachlor 

provided no indication of increased susceptibility (quantitative or qualitative) to rats or rabbits 

exposed in utero. The metolachlor rat reproduction study showed no evidence of reproductive 

toxicity. Therefore, the special FQPA safety factor is reduced to 1x for risk assessment for this 

chemical. A developmental neurotoxicity study is not required since there was no evidence of 

neurotoxicity or neuropathology from the available studies and there is no concern or residual 

uncertainty for pre/post-natal toxicity. Based on the results of the available toxicity studies, there 

is no evidence for immunotoxicity.

 

Since there are adequate developmental studies in rats and rabbits and an adequate multigeneration study in rats, and no residual uncertainties that indicate the need for a factor, the 
Page 16 of 60

FQPA factor has been reduced to 1X. 

3.3 Toxicity Endpoint Selection

3.3.1 Acute Reference Dose (aRfD) - General Population

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

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

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

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

excessive lacrimation) and decreased body weight gain. The NOAEL was 300 mg/kg/day. The 

developmental toxicity LOAEL was conservatively established at 1000 mg/kg/day based on 

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

increased number of resorptions/dam and significant decrease in mean fetal body weight. The 

NOAEL was 300 mg/kg/day.

Dose and Endpoint for Establishing an aRfD: 300 mg/kg/day based on a NOAEL of 

1000 mg/kg/day and an LOAEL of 1000 mg/kg/day based on an increased incidence of death, 

clinical signs of toxicity (clonic and/or tonic convulsions, excessive salivation, urine-stained 

abdominal fur and/or excessive lacrimation) and decreased body weight gain. 

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

variation.

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

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

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

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

increased incidence of death is one of the effects seen, it was seen at a dose (1000 mg/kg/day) 

approximately three times higher than the dose (300 mg/kg/day) selected for risk assessment; 

therefore, the Agency is confident that adequate safety is provided to protect the public from 

dietary exposure to residues of metolachlor. 

3.3.2 Chronic Reference Dose (RfD) – General Population

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

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

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

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

 (UF) 100
Page 17 of 60

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

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

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

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

variation.

3.3.3 Incidental Oral Exposure (Short-Term)

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

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

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

toxicity, decreased body weights and body weight gains and reduced food consumption and 

reduced food efficiency. No significant treatment related developmental toxicity was noted at the 

dose levels tests. The developmental toxicity NOAEL was equal to or greater than 1000 

mg/kg/day; a LOAEL was not reached.

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

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

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

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

variation.

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

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

50 mg/kg/day from the rat developmental study. However, the endpoint was based on weak 

clinical signs of toxicity (increase in little/none/soft stool observations) at 100 mg/kg/day. 

Although there was a dose-related increase in this effect, it is not evidence of frank toxicity and 

was judged not be appropriate for risk assessment. Therefore, the rabbit study with S-metolachlor 

was not selected for this exposure scenario.

3.3.4 Dermal Exposure (Short-Term)

No hazard was identified for quantification of risk following dermal exposure. In a 21-

day dermal toxicity study (MRID 41833101), no systemic toxicity was seen following repeated 

dermal application of metolachlor (96.4% ai) to the intact skin of five New Zealand 

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

 (UF) 100
Page 18 of 60

rabbits/sex/group at doses of 0, 10, 100 or 1000 mg/kg/day for 21 days. 

3.3.5 Inhalation Exposure (Short-Term)

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

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

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

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

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

variation.

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

factor should be applied.

3.3.6 Inhalation Exposure (Intermediate-Term)

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

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

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

groups; 6/sex/group for low- and mid-dose groups) at dose levels of 0, 100, 300 or 1000 ppm 

(males: 0, 2.92, 9.71 and 29.61 mg/kg/day, respectively; females: 0, 2.97, 8.77 and 29.42 

mg/kg/day, respectively) for six months. There were no deaths or clinical signs of toxicity. Mean 

body weight gain was decreased during weeks 0-13 and 0-26 in the 1000 ppm group males (55-

63% decrease) and females (44-50% decrease), although the changes were not statistically

significant. Mean overall food consumption was not affected in the 1000 ppm group males but 

was slightly decreased (9%) in the 1000 ppm females. There was a significant decrease in the 

activated partial thromboplastin time (APTT) in the 300 and 1000 ppm group males and 300 ppm 

group females but the findings were not considered toxicologically significant because the 

decrease was slight and not dose-related. Alkaline phosphatase was 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). Dose and Endpoint for Risk Assessment: NOAEL of 8.8 mg/kg/day based 

on decreased body weight gain at 29.4 mg/kg/day

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

29.4 mg/kg/day

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

factor should be applied.
Page 19 of 60

3.3.7 Classification of Carcinogenic Potential

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

Group C carcinogen with risk quantitated using a non-linear approach. The NOAEL of 15 

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

nodules/hepatocellular carcinomas seen at the highest dose tested of 150 mg/kg/day. The

Agency notes that the tumor NOAEL of 15 mg/kg/day is comparable to the NOAEL of 9.7

mg/kg/day selected for establishing the chronic reference dose for metolachlor (TXR 014691, 

9/28/01). The recommendation for a non-linear approach should be followed since no new data 

were submitted for a re-evaluation by the CARC.

3.4 Margins of Exposure

A summary of target Levels of Concern for risk assessment is provided in Table 4.

Table 4. Target Levels of Concern/Margin of Exposure S-Metolachlor

Route/Duration Short-Term

(1-30 Days)

Intermediate-Term

(1 - 6 Months)

Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal NA NA N/A

Inhalation 100 100 N/A

Residential (Non-Dietary) Exposure

Oral 100 N/A N/A

Dermal NA N/A N/A

Inhalation N/A N/A N/A

3.5 Recommendation for Aggregate Exposure Risk Assessments

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

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

are potential residential incidental oral exposures to S-metolachlor via post-application hand-tomouth exposure of children playing on treated lawns. In addition, dietary and incidental oral 

endpoints for S-metolachlor are based on common toxicological effects. Therefore, exposures

from food and non-food oral routes should be aggregated for this assessment. 

3.6 Summary of Endpoints Selected for Risk Assessment

A summary of the endpoints selected by HED is provided below and in Tables 5 and 6.

Table 5. 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
Page 20 of 60

Table 5. Summary of Toxicological Endpoints for S-metolachlor for Use in Dietary Human Health Risk 

Assessments

Exposure/Scenario Point of 

Departure

Uncertainty/FQP

A Safety Factors

RfD, PAD, 

LOC for Risk 

Assessment

Study and Toxicological Effects

Acute Dietary

(General 

Population)

NOAEL = 

300 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Acute RfD = 3.0 

mg/kg/day

aPAD = 3.0 

mg/kg/day

Developmental Toxicity Study - Rat 

LOAEL = 1000 mg/kg/day based increased 

incidence of death, clinical signs (clonic 

and/or tonic convulsions, excessive 

salivation, urine-stained abdominal fur 

and/or excessive lacrimation) and 

decreased body weight gain. 

Chronic Dietary 

(All Populations)

NOAEL = 

9.7

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Chronic RfD = 

0.097

mg/kg/day

cPAD = 

0.97mg/kg/day

Chronic Toxicity – Dog;

LOAEL = 33 mg/kg/day based decreased 

body weight gain in females 

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

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

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

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

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

human population (intraspecies). 

FQPA SF = FQPA Safety Factor. 

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

RfD = reference dose. 

MOE = margin of exposure. 

LOC = level of concern. 

Table 6. Summary of Toxicological Doses and Endpoints for S-METOLACHLOR for Use in Residential 

and Occupational Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of 

Concern for 

Risk Assessment

Study and Toxicological Effects

Incidental Oral Shortterm (1-30 days) NOAEL= 

50 mg/kg/day

UFA= 10x

UFH=10x Residential LOC 

for MOE = 100

Developmental Toxicity Study - Rat 

LOAEL = 500 mg/kg/day based on 

increased incidence of clinical signs, 

decreased body weight/body weight gain, 

food consumption and food efficiency seen 

at the LOAEL in maternal animals.

Inhalation Short-Term

(1-30 days)

NOAEL= 

50 mg/kg/day

UFA= 10x

UFH=10x

Occupational 

LOC for MOE = 

100

Developmental Toxicity Study - Rat 

LOAEL = 500 mg/kg/day based on 

increased incidence of clinical signs, 

decreased body weight/body weight gain, 

food consumption and food efficiency seen 

at the LOAEL in maternal animals.

Inhalation Short-Term

(1-30 days)

NOAEL= 

8.8 mg/kg/day

UFA= 10x

UFH=10x

Occupational 

LOC for MOE = 

100

Subchronic Toxicity Study - Dog 

LOAEL = 29.4 mg/kg/day based on 

decreased body weight gain

Cancer (all routes) Metolachlor has been classified as a Group C carcinogen with risk quantitated using a nonlinear (Margin of Exposure) approach. 
Page 21 of 60

3.7 Endocrine Disruption

EPA is required under the FFDCA, as amended by FQPA, to develop a screening 

program to determine whether certain substances (including all pesticide active and other 

ingredients) “may have an effect in humans that is similar to an effect produced by a naturally

occurring estrogen, or other such endocrine effects as the Administrator may designate.” 

Following recommendations of its Endocrine Disruptor and Testing Advisory Committee 

(EDSTAC), EPA determined that there was a scientific basis for including, as part of the 

program, the androgen and thyroid hormone systems, in addition to the estrogen hormone 

system. EPA also adopted EDSTAC’s recommendation that the Program include evaluations of 

potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that 

effects in wildlife may help determine whether a substance may have an effect in humans, 

FFDCA authority to require the wildlife evaluations. As the science develops and resources 

allow, screening of additional hormone systems may be added to the Endocrine Disruptor 

Screening Program (EDSP). 

4.0 DIETARY AND DRINKING WATER EXPOSURE ASSESSMENT 

4.1 Proposed and Registered Food Uses

IR-4 proposes use of the herbicide S-metolachlor for the following uses; postemergence 

application to the bushberry subgroup, the caneberry subgroup, okra, the bulb onion subgroup, 

and the green onion subgroup at maximum application rates ranging 1.3-3.8 lb ai/A, 

preemergence, pre-transplant, and/or postemergence applications for carrot, cucumber, leafy

Brassica greens, the melon subgroup, and sweet sorghum at maximum application rates ranging 

1.2-1.9 lb ai/A. and preemergence application to sesame at up to 1.9 lb ai/A. Maximum 

application rates for existing and proposed uses are provided in Table 7. Maximum rates are 

based on a review of active and proposed labels. 

Table 7. Maximum Application Rates for S-Metolachlor Existing and Proposed Uses

Application Site Max % AI Max Single AppRate Max Seasonal App Rate Reg No.

Existing Use – Potato

83.7

2.5 lb/ai A 3.5 lb/ai A

100-816 Existing Use – Corn 2 lb/ai A 4 lb/ai A

Proposed New Use – Caneberry 

Subgroup 13-07A 3.8 lb/ai A 3.8 lb/ai A

4.2 Residue Chemistry Profile

4.2.1 Metabolism in Primary Crops and Livestock

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

upon the adequate corn, potato, and soybean metabolism studies. The metabolism of metolachlor 

involves conjugation with glutathione, breakage of this bond to form the mercaptan, conjugation 
Page 22 of 60

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. Residues of concern in plants include 

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

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

for metolachlor.

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

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

of ruminants (goats), non-ruminants (rats), and poultry. Metolachlor per se was not detected in 

any of the excreta or tissues. As in plants, metolachlor residues of concern in livestock 

commodities include metolachlor and its metabolites, determined as the derivatives CGA-37913 

and CGA-49751. The residues of concern for S-metolachlor in livestock are the same as those 

for metolachlor. 

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

(OA)).

Table 8. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance 

Expression

Matrix Residues included in Risk Assessment Residues included in Tolerance 

Expression

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

CGA-37913, CGA-49751

Rotational Crop Parent, CGA-37913 & metabolites convertible 

to CGA-49751

Parent & metabolites convertible to

CGA-37913, CGA-49751

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

CGA-37913, CGA-49751

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

CGA-37913, CGA-49751

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

(ESA)) and CGA-51202 (metolachlor oxanilic 

acid (OA))

Not Applicable

4.2.2 Metabolism in Rotational Crops 

The data requirements for confined accumulation in rotational crops are not fulfilled. The 

available confined rotational crop study with [14C]metolachlor is inadequate but potentially

upgradable. Additional data are required characterizing the 14C-residues in plants, along with 

information on the percentage of the 14C-residues measured by the current enforcement method; 

sample storage conditions and intervals and supporting storage stability data were also required. 

A confined rotational crop study using S-metolachlor has also been submitted and found 

to be scientifically adequate. Although 14C-residue in the representative rotational crops were 

adequately identified and characterized, the [14C]-S-metolachlor was applied at only 1.45 lb ai/A, 
Page 23 of 60

which is ~0.4x the maximum seasonal use rate for corn. Based on the available data, HED 

concluded that the metabolism of [14C]S-metolachlor in rotational crops is similar to the 

metabolism observed in the primary crops. Metabolism in rotational crops primarily involves 

two pathways: (i) conjugation of the parent molecule with glutathione by substitution of the 

chlorine, followed by the degradation of the glutathione moiety to form a variety of sulfur 

containing metabolites; and (ii) direct oxidation of parent or secondary metabolites, primarily on 

the chloroacetyl side chain. Complete degradation of secondary metabolites either in the soil 

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

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

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

CGA-37913 and CGA-49751. 

4.2.3 Residue Analytical Methods

4.2.3.1 Enforcement Methods

Adequate methodology is available for enforcing the established and recommended 

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

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

determining residues in livestock commodities. These methods determine residues of 

metolachlor and its metabolites as either CGA-37913 or CGA-49751 following acid hydrolysis. 

IR-4 and Syngenta have proposed an LC/MS/MS enantiomer-specific method for the 

enforcement of the proposed tolerances, Method 1848-01. This method has been previously

reviewed by HED (DP# 296904, 4/17/06, R. Loranger). HED concludes that the method is not 

appropriate for enforcement purposes because it does not determine residues of the R-isomers 

which are included in the tolerance expression. The S:R ratio in the active ingredient is 88:12; 

therefore, there is potential for residues of the R-isomers of metolachlor and its metabolites in 

crop commodities. The method could be adapted for enforcement by adding detection of the Risomers of metolachlor, its metabolites, and its conversion products.

4.2.3.2 Data Collection Methods

The methods used for data collection in the submitted field trial and processing studies 

were adequately validated and residues were reported in terms of parent metolachlor equivalents.

Samples of crop commodities from the submitted field trial and processing studies were 

analyzed for residues of metolachlor and its metabolites convertible to the derivatives CGA49751 and CGA-37913 using GC/MS, GC/NPD, or LC/MS/MS methods. All methods involved 

acid hydrolysis in 6 N HCl at reflux for 16 hours to convert residues of metolachlor and its 

metabolites to either CGA-49751 or CGA-37913.

4.2.3.3 Multiresidue Methods
Page 24 of 60

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

Testing Protocols. The FDA PESTDATA database indicates that metolachlor is completely

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

4.2.4 Residues in Crops

Field trial data were submitted in support of tolerances for the proposed uses on 

bushberry, caneberry, carrot, cucumber, leafy Brassica greens, melon, sesame, and sweet 

sorghum. The petitioner is relying on existing data to support the proposed uses on bulb and 

green onion, and okra. 

The submitted field trial data are not adequate to support the proposed broadcast uses on 

the bushberry subgroup because only one field trial reflecting broadcast application was 

conducted and because results of the blueberry field trials indicate that there is a significant 

difference in residues found in blueberries treated with broadcast application and blueberries 

treated with ground directed banded applications. 

The submitted field trial data are adequate to support the proposed uses on the caneberry

subgroup, carrot, cucumber, leafy Brassica greens, cantaloupe, and sesame. The number and 

locations of field trials are in accordance with OPPTS Guideline 860.1500 for all crops except 

sorghum. The submitted field trial data on sorghum are not adequate to satisfy data requirements 

because geographic representation is inadequate. However, no additional data will be required at 

this time because adequate data on grain sorghum are available and the existing tolerance on 

sweet sorghum stover of 4.0 ppm is adequate to cover residues in/on sweet sorghum 

commodities. Total metolachlor residues, in metolachlor equivalents, in/on all treated samples of 

caneberry were below the combined LLMVs (<0.10 ppm). Cantaloupe (the representative crop 

of the melon subgroup 9A) were below the combined LLMVs (<0.13 ppm). Total metolachlor 

residues in/on carrots were <0.13-<0.38 ppm (LLMV 0.13 ppm). Total metolachlor residues 

were below the combined LLMVs (<0.13 ppm) in/on all treated samples of cucumber, sesame 

and sweet sorghum samples. Total metolachlor residues for mustard greens (the representative 

crop of the Brassica leafy greens subgroup 5B) were <0.13-0.562 ppm (LLMV 0.13 ppm). No 

field trial data were submitted to support the requested use on okra. Previously submitted residue 

data for fruiting vegetables in which combined residues were below the LOQ (<0.08 ppm) are 

considered adequate to support the proposed use on okra. No field trial data were submitted to 

support the requested uses on onion subgroups 3-07A and 3-07B. The available data for bulb 

onion are adequate to support use on the bulb onion subgroup 3-07A and the available data for 

green onion are adequate to support use on the green onion subgroup 3-07B. Combined Smetolachlor residues were <0.10 ppm in/on bulb onion (LOQ 0.08). Combined residues from 

green onion field trials ranged were 1.8 ppm (LOQ 0.08). 

4.2.5 Residues in Livestock
Page 25 of 60

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

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

for metolachlor residues in livestock commodities.

4.2.6 Residues in Processed Commodities

Processing studies were submitted for sesame and sweet sorghum. Based on the results 

of the sweet sorghum processing study, metolachlor residues appear to concentrate in sorghum 

syrup (>1.5x processing factor). However, HED concludes that no tolerance will be required 

because the observed residues in syrup (0.147 ppm) processed from sorghum treated at 1x are 

less than the established tolerance for S-metolachlor residues in/on sorghum grain (0.3 ppm). 

Although the sesame processing study was conducted at only 1x with nonquantifiable residues in 

the RAC, it is unlikely that a study conducted at an exaggerated rate will result in quantifiable 

residues in the RAC because applications are made preemergence. The submitted data indicate 

that no tolerances will be needed for sesame processed commodities.

4.2.7 Residues in Rotational Crops

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

the existing rotational crop restrictions on the labels for the 7.62 and 7.64 lb/gal EC formulations 

(EPA Reg. Nos. 100-816 and 100-818), provided that the restrictions on the label for EPA Reg. 

No. 100-816 are amended as specified under 860.1200 Directions for Use.
Page 26 of 60

4.3 Drinking Water Profile

4.3.1 Environmental Fate and Transport

Environmental fate data indicate that parent metolachlor/s-metolachlor is moderately

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

extensively in surface water and groundwater. Metolachlor/s-metolachlor degradation appears to 

be dependent on microbially mediated and abiotic processes. Major degradates identified in 

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

water). Depending on the soil (i.e. organic matter content), metolachlor/s-metolachlor has the 

potential to range from a moderately mobile to a highly mobile material. The Environmental 

Fate and Effects Division (EFED) concluded there is no difference in soil sorption affinity

between metolachlor and S-metolachlor. Available data suggest that metolachlor and Smetolachlor are expected to be highly mobile to mobile in soil and water environments. 

4.3.2 Estimated Drinking Water Concentrations

EFED calculated conservative, Tier I Estimated Drinking Water Concentrations 

(EDWCs) of metolachlor and S-metolachlor in ground water and surface water for use in the 

human health risk assessment. EDWCs for metolachlor and S-metolachlor were calculated for 

both the parent compound and the ethanesulfonic acid (ESA) and oxanilic acid (OA) degradates. 

Although it was determined by the MARC that the ESA and OA metabolites appear to be less 

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

greater abundance than the parent in water monitoring studies. 

EDWCs were calculated using drinking water models PRZM/EXAMS and FIRST for 

surface water and SCIGROW for ground water. Current NAWQA monitoring data was also 

used to determine EDWCs. Based on a review of the current monitoring data, concentrations of 

parent S-metolachlor and its degradates were less than values reported from the previous 

monitoring data (US EPA, 2002). Based on monitoring and modeling data, total EDWCs for 

peak and average surface water respectively are 219 ppb (78 ppb parent + 48 ppb metolachlor 

ESA+ 94 ppb metolachlor OA) and 119 ppb (18 ppb parent + 34 ppb metolachlor ESA+ 34 ppb

metolachlor OA). Recommended groundwater EDWCs (peak and average) are 126 ppb (33 ppb

parent + 64 ppb metolachlor ESA+ 30 ppb metolachlor OA).

4.4 Dietary and Drinking Water Exposure and Risk Analysis

Following recommendations made in the revised Tolerance Reassessment Eligibility

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

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

40 CFR §180.368. Permanent tolerances for combined S-metolachlor residues have been 

established for crop commodities ranging from 0.10 ppm in/on a variety of crop commodities to 

20 ppm in/on peanut hay (40 CFR §180.368(a)(2)). Permanent tolerances for indirect or 

inadvertent residues of S-metolachlor have also been established for non-grass animal feeds 
Page 27 of 60

(Group 18), and the forage, hay, grain and straw of small cereal grains (barley, buckwheat, millet, 

oats, rice, rye and wheat), at levels ranging 0.10 ppm in/on grains to 1.0 ppm in/on non-grass 

animal feeds (40 CFR §180.368(d)(2)).

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

Exposure Evaluation Model software with the Food Commodity Intake Database (DEEMFCIDTM, Version 1.3), which incorporates consumption data from USDA’s Continuing Surveys 

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

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

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

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

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

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

exceeds 100% of the PAD. 

The acute and chronic dietary exposure/risk analyses for all supported Smetolachlor/metolachlor food uses were conducted using conservative, Tier 1 exposure 

assessments. The Tier I analyses assume tolerance level residues for all registered uses, 100% 

crop treated for all commodities with existing tolerances, and default processing factors. In cases 

where separate tolerance listings occur for both metolachlor and S-metolachlor on the same 

commodity, the higher value of the two is used in the analyses. Acute and chronic dietary Smetolachlor exposure and risk estimates resulting from food intake were determined for the 

general U.S. population and various population subgroups. 

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

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

significantly below HED’s level of concern for all supported commodities (Tables 9 and 10). 

The 95th percentile acute dietary exposure estimate for the highest exposed population subgroup, 

infants < 1 year old, is 0.05 mg/kg/day or 2% of the aPAD. The chronic dietary exposure 

estimate for the highest exposed population subgroup, infants < 1 year old, is 0.012 mg/kg/day or 

12% of the cPAD. 

Table 9: Summary of Acute Dietary Exposure and Risk for S-metolachlor and Metolachlor

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

Exposure (mg/kg/day) %aPAD

General U.S. Population

3.0

0.0146 <1

All Infants (< 1 year old) 0.0460 2

Children 1-2 years old 0.0248 <1

Children 3-5 years old 0.0222 <1

Children 6-12 years old 0.0154 <1

Youth 13-19 years old 0.0115 <1

Adults 20-49 years old 0.0127 <1

Adults 50+ years old 0.0114 <1

Females 13-49 years old 0.0126 <1
Page 28 of 60

Table 10: Summary of Chronic Dietary Exposure and Risk for S-metolachlor and Metolachlor

Population Subgroup cPAD (mg/kg/day) Chronic

Exposure (mg/kg/day) %cPAD

General U.S. Population

0.1

0.0045 5

All Infants (< 1 year old) 0.0114 11

Children 1-2 years old 0.0085 9

Children 3-5 years old 0.0077 8

Children 6-12 years old 0.0053 5

Youth 13-19 years old 0.0036 4

Adults 20-49 years old 0.0039 4

Adults 50+ years old 0.0040 4

Females 13-49 years old 0.0039 4

5.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT 

In accordance with the FQPA, when there are potential residential exposures to a 

pesticide, aggregate risk assessment must consider exposures from three major routes: oral, 

dermal, and inhalation. There are three sources for these types of exposures: food, drinking 

water, and residential uses. 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. 

There are no residential exposures for the proposed new uses of S-metolachlor analyzed 

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

by professional applicators. Pennant MAGNUMTM (EPA Reg. No. 100-950) is labeled for use 

on commercial (sod farm) and residential warm-season turf grasses and other non-crop land 

including golf courses, sports fields, and ornamental gardens. Since Pennant MAGNUMTM is 

not intended for homeowner purchase or use (i.e., used by professional/commercial applicators), 

the only potential short-term residential risk scenario anticipated is post-application hand-tomouth exposure of children playing on treated lawns. S-metolachlor incidental oral exposure is 

assumed to include hand-to-mouth exposure, object-to-mouth exposure and exposure through 

incidental ingestion of soil. Residential post application exposure to S-metolachlor for this 

scenario has been assessed in a separate document (“Metolachlor/S-metolachlor Residential Risk 

Assessment”, R. Griffin, D274331, 2/20/02). Results from that assessment have been used to 

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

Section 3 analysis. Based on this analysis, short-term aggregate MOEs are not of concern (Table 

11).

Table 7. Short-Term Aggregate Risk Calculations for S-metolachlor

Population NOAEL 1

mg/kg/day LOC 2

Average

Food & Water

Exposure mg/kg/day

Residential 

Exposure 3

mg/kg/day

Aggregate MOE

(food/water and

residential) 4

Toddlers 50 100 0.012 0.046 860

1 NOAEL for incidental oral exposure. 
Page 29 of 60

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

3 Residential Exposure = [Incidental Oral exposure from all possible sources -combined hand-to-mouth, object-tomouth, and soil ingestion oral exposure]. No residential oral exposure is expected for adults

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

6.0 OCCUPATIONAL EXPOSURE AND RISK

6.1 Exposure Scenarios

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

Reg. No. 100-818)) EC formulations as an herbicide on crops. The proposed uses may result in 

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

during mixing, loading, applying, and postapplication activities. Long-term exposures (i.e., 6 

months of continuous exposure) are not expected to occur based on the proposed use pattern. 

Dermal toxicological endpoints of concern were not identified (i.e., no systemic toxicity was seen

following dermal exposure at the limit dose) therefore, no dermal exposures were calculated. 

Short- and intermediate-term exposures from inhalation exposure routes were assessed for all 

exposure scenarios. Occupational and residential exposure and risk estimates were conducted 

using maximum application rates and surrogate exposure data from the Pesticide Handlers 

Exposure Database and the Residential Exposure Assessment SOPs. 

6.1.1 Handler Exposure Scenarios

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

Based on the use pattern, two occupational exposure scenarios were identified for S-metolachlor.

1) mixing/loading liquid formulation for groundboom application;

2) applying spray with groundboom equipment. 

6.1.2 Post-Application Exposure Scenarios

Since there are no dermal endpoints of concern, post-application dermal exposure was not 

examined for occupational uses. Based on the Agency's current practices, a quantitative 

postapplication inhalation exposure was also not assessed. However, volatilization of pesticides 

may be a potential source of postapplication inhalation exposure to individuals nearby to 

pesticide applications. A study published in the Journal of Environmental Quality, Volume 38, 

September-October 2009, pages, 1785-1795, “Soil Moisture and Metolachlor Volatilization 

Observations over Three Years” demonstrated that metolachlor can see its volatilization 

properties significantly increase with increasing surface soil water content. Furthermore, OPP

recently sought and received expert advice on pesticide volatilization from the Agency’s 

Scientific Advisory Panel (SAP). The Agency is in the process of evaluating the SAP’s final

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

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

be incorporated into the Agency's risk assessments. Consequently, the Agency may revisit the 
Page 30 of 60

need for a quantitative postapplication inhalation exposure assessment for S-metolachlor as 

appropriate based on new policies that may result from this effort.

6.2 Occupational Exposure Data and Assumptions

6.2.1 Exposure Data

6.2.1.1 Application Parameters

The maximum application rate for each crop that was listed on the proposed label and 

Section B of the tolerance petition provided by the Registration Division was used for all 

exposure assessments. This ranges from 1.21 to 3.80 lb ai/A.

6.2.1.2 Occupational Exposure Data

Data from the Pesticide Handlers Exposure Database(PHED) Version 1.1 was used to 

assess handler and post-application exposures in the absence of chemical-specific data. PHED 

was designed by a task force of representatives from the U.S. EPA, Health Canada, the California 

Department of Pesticide Regulation, and member companies of the American Crop Protection 

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

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

subset and statistically summarize the selected data. 

6.2.2 Exposure Assumptions

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

from exposure to S-metolachlor for the proposed new uses on ....

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

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

observed in females

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

intermediate-term noncancer risk assessment based on an oral study where the effects 

were observed in males and females

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

• Maximum application rates as determined by proposed label requirements review were 

used for all types and methods of application.

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

Policy Number 9.1. For groundboom applications, a default area of 80 acres was used.
Page 31 of 60

6.3 Occupational Exposure and Risk Estimates

6.3.1 Handler Exposure

Assumptions and calculations of the risks for handlers are presented in Table 8. At the 

baseline level, all inhalation MOEs are above the target MOE of 100, thus, risks are not of 

concern. The handler exposure estimates in this assessment are based on a central tendency

estimate of unit exposure and an upper-percentile assumption for the application rate, and thus 

assumed to represent high-end exposures. The uncertainties associated with this assessment stem 

from the use of surrogate exposure data (e.g., differences in use scenario and data confidence), 

and assumptions regarding the amount of chemical handled. The estimated exposures are 

believed to be reasonable high-end estimates based on observations from field studies and 

professional judgment. In order to refine this occupational risk assessment, data on actual use 

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

Table 8. S-metolachlor Short-term and Intermediate-term Inhalation Risks

Exposure 

Scenario Crop 

Applic 

Ratea 

(lbs ai/A)

Area 

Treated b

(A/day)

Unit 

Exposures 

(μg/lb ai) c

Short-termd

(No respirator)

Intermediate-terme

(No respirator)

Dose 

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

Mixing/Loading Emulsifiable Concentrates (Liquids)

Groundboom

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

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

Bushberry and 

Lowbush 

Blueberry

1.27 80 1.2 0.002 25,000 0.002 5,100

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

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

Leafy Brassica 

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

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

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

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

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

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

Applying Liquid Sprays

Groundboom

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

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

Bushberry and 

Lowbush 

Blueberry

1.27 80 0.74 0.001 40,000 0.001 8,200

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

Sweet Sorghum 1.67 80 0.74 0.002 30,000 0.001 6,200
Page 32 of 60

Table 8. S-metolachlor Short-term and Intermediate-term Inhalation Risks

Exposure 

Scenario Crop 

Applic 

Ratea 

(lbs ai/A)

Area 

Treated b

(A/day)

Unit 

Exposures 

(μg/lb ai) c

Short-termd

(No respirator)

Intermediate-terme

(No respirator)

Dose 

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

Leafy Brassica 

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

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

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

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

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

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

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

Herbicide.

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

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

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

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

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

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

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

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

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

6.3.2 Post Application Exposure

Since there are no dermal endpoints of concern, post-application dermal exposure was not 

examined for occupational uses.

7.0. CUMULATIVE EXPOSURE

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

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

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

mechanism of toxicity.”

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

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

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

not made a common mechanism of toxicity finding as to S-metolachlor and any other substances 

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

which have tolerances in the U. S. For the purposes of this tolerance reassessment action, 

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

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

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

policy statements released by EPA’s OPP concerning common mechanism determinations and 

procedures for cumulating effects from substances found to have a common mechanism on 
Page 33 of 60

EPA’s website at http://www.epa.gov/fedrgstr/EPA_PEST/2002/January/Day_16/.

8.0 DATA NEEDS

8.1 Toxicology Data Requirements 

- Acute Neurotoxicity (GLN 870. 6200a)

- Subchronic Neurotoxicity (GLN 870.6200b) 

- Immunotoxicity (GLN 870.7800) 

8.2 Residue Chemistry Data Requirements

- Additional data are required to support the confined rotational crop study submitted under 

MRID 41470601; Data requirements include data characterizing the 14C-residues in 

plants, along with information on the percentage of the 14C-residues measured by the 

current enforcement method and sample storage conditions and intervals and supporting 

storage stability data. These data requirements were included in the Metolachlor TRED 

(DP# 292881, 8/15/03). (GLN 860.1850)

- If the petitioner wishes to support use on lowbush blueberry, two additional field trials 

representing broadcast application would be required. Alternatively, the petitioner may

wish to submit data and propose a tolerance for the low growing berry, except strawberry, 

subgroup, 13-07H. Four additional field trials, conducted on lowbush blueberry or 

cranberry, would be required. (GLN 860.1500)
Page 34 of 60

APPENDICES

1.0 TOXICOLOGY DATA SUMMARY

1.1 Guideline Data Requirements

Table 1. Guideline Data Requirements

Test 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

-

yes

870.3700a Developmental Toxicity (rodent)...................................

870.3700b Developmental Toxicity (nonrodent).............................

870.3800 Reproduction .................................................................

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)..............................................

870.4100b Chronic Toxicity (nonrodent)........................................

870.4200a Oncogenicity (rat)..........................................................

870.4200b Oncogenicity (mouse)....................................................

870.4300 Chronic/Oncogenicity....................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial .....................

870.5300 Mutagenicity—Gene Mutation - mammalian ................

870.5375 Mutagenicity—Structural Chromosomal Aberrations ...

870.5900 Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotox. (hen) .....................................

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

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

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

870.6300 Develop. Neuro .............................................................

no

no

yes

yes

no

-

-

no

no

-

870.7485 General Metabolism ......................................................

870.7600 Dermal Penetration........................................................

870.7800 Dermal Penetration........................................................

yes

-

Yes

yes

-

no
Page 35 of 60

1.2 Toxicity Profiles

Table 1. Acute Toxicity Profile of S-metolachlor (PC Code 108800)

Guideline 

No. Study Type MRIDs # Results Toxicity Category

870.1100 Acute Oral- Rats 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- Rats 43928917 LC50 = > 2.91 mg/L IV

870.2400 Primary Eye Irritation- Rabbits 43928918 slight to moderate conjunctival 

irritation that cleared in 48 hours

III

870.2500 Primary Skin Irritation- Rabbits 43928919 non-irritating IV

870.2600 Dermal Sensitization- Guinea 

pigs

43928920 Positive

Table 1. Toxicity Profile for S-Metolachlor (PC Code 108800)

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

Classification /Doses

Results

870.3100

90-Day oral toxicity rodents

43928923 (1995)

acceptable/guideline

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

870.3100

90-Day oral toxicity rodents

44775402 (1999)

unacceptable/guideline

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

870.3150

90-Day oral toxicity in 

nonrodents

43928922 (1995)

acceptable/nonguideline

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

870.3700a

Prenatal developmental in 

rodents

43928925 (1995)

acceptable/guideline

0, 5, 50, 500 or 1000 

mg/kg/day

Maternal NOAEL = 50 mg/kg/day

LOAEL = 500 mg/kg/day based on increased clinical signs of toxicity, 

decreased body weights/body weight gains, food consumption and food 

efficiency.

Developmental NOAEL = 1000 mg/kg/day

LOAEL = not established

870.3700b

Prenatal developmental in 

nonrodents

43928924 (1995)

acceptable/guideline

0, 20, 100 or 500 

mg/kg/day

Maternal NOAEL = 20 mg/kg/day

LOAEL = 100 mg/kg/day based on clinical signs of toxicity 

Developmental NOAEL = 500 mg/kg/day

LOAEL = not established
Page 36 of 60

Gene Mutation

870.5100

Salmonella & 

Escherichia/Mammalian 

Microsome Mutagenicity Test

43928927 (1995)

acceptable/guideline

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 g/plate CGA-77102 

technical (95.6%) in the presence and absence of S9 activation. For the 

confirmatory trial, doses of 78.13-1250.0 g/plate ±S9 were evaluated with S. 

typhimurium strains TA1535, TA1537, TA100 and TA102; concentrations of 

312.5-5000.0 g/plate ±S9 were examined with S. typhimurium TA 98 and 

E.coli WP2 uvrA. 

In general, doses 1250.0 g/plate ±S9 were cytotoxic for S. typhimurium

TA1535, TA1537, TA100 and TA102 and 5000.0 g/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. 

Other Effects 

870.5550

Unscheduled DNA synthesis

43928928 (1995)

acceptable/guideline

500, 1500, 3200 (females), 

5000 (males) mg/kg

Groups consisting of three to four rats per sex received single oral gavage 

administrations of CGA-77102 Technical (95.6%) at doses of 500, 1500 or 

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

harvested at 15 and 38 hours were evaluated for viability and replicative DNA 

synthesis (RDS). For the UDS determination, additional groups (3/sex/dose) 

were exposed to 500 or 1500 mg/kg and the recovered hepatocytes were 

scored at 2 or 15 hours postexposure. 

Two of four females in the 3200-mg/kg group and 2 of 4 males in the 5000-

mg/kg group died prior to the scheduled sacrifice at 38 hours. Severe 

cytotoxicity was seen in the hepatocytes recovered from 1 of 2 surviving 

males and both female survivors in the high-dose groups. Lower levels were 

neither toxic to the animals nor cytotoxic to the target cells. A clear doserelated increase in the percentage of cells in S-phase (RDS) was obtained from 

hepatocytes harvested 38 hours posttreatment of the male rats. The response 

ranged from a 5.3-fold increase at 1500 mg/kg to a 16.1-fold increase at the 

high dose (5000 mg/kg). In females, a marked increase in RDS was initially 

seen at 1500 mg/kg but the response declined over time with a 24.4-fold 

increase at 15 hours and a 12.2-fold increase at 38 hours. There was, 

however, no evidence that the CGA 77102 Technical at doses of 500 or 1500 

mg/kg induced a genotoxic response at 2 or 15 hours posttreatment. We 

conclude, therefore, that the data indicate that CGA 77102 Technical was 

negative for genotoxicity but positive for cellular proliferation when tested up 

to overtly toxic and cytotoxic doses in this in vivo/in vitro rat hepatocyte 

RDS/UDS assay.
Page 37 of 60

870.7485

Metabolism and 

pharmacokinetics

44491401 (1996)

acceptable/guideline

single dose of 0.5 (group 

B1) or 100 mg/kg (group 

D1) radio labeled CGA77102; 100 mg/kg/day nonradio labeled CGA 77102 

for 14 days followed by 0.5 

mg/kg radio labeled CGA77102 (Group V1); single 

dose of 0.5 or 100 mg/kg 

radio labeled CGA-77102 

for bile-cannulation study

In all three dose groups (B1, D1, and V1), the seven day combined levels of 

radioactivity in urine were 31.1 - 36.5% for males and 40.8 - 45.5% for 

females; the fecal levels were 60.2 - 62.5% for males and 48.9 - 55.0% for 

females. Only 0.1% or less was eliminated in the expired air. The total 

recovery ranged from 96.5 ± 2.3% to 99.3 ± 0.9%. The route or extent of 

excretion was slightly influenced by the sex of the animal but not by 

pretreatment with non-radio labeled CGA-77102 or by the dose level. The 

degree of absorption, based on adding the cumulative urinary excretion to the 

total residues in tissues, was 35 - 39% in males and 43 - 49% in females of 

both dose groups. However, based on the bile duct cannulation study, most of 

CGA-77102 was absorbed from the gastrointestinal tract since 85% of the 

dose was recovered in urine, bile fluid, and tissues during the 48 hours study 

period. Therefore, the biliary excretion and enterohepatic circulation play a 

significant role in the elimination process of CGA-77102. 

Irrespective of the dose and sex, there seems to be a biphasic plasma profile 

with two concentration maxima (Cmax); a fast rising first Cmax was reached at 

0.25 - 1 hour post dosing which was succeeded by a second Cmax at 8 and at 

12 - 24 hours following administration of the low and high dose, respectively. 

In the low dose group (B1), the first and second Cmax were nearly identical (~ 

0.03 g/ml); in the high dose group (D1), the first and second Cmax were, 

respectively, 4.6 and >3.9 g/ml in males and 2.2 and 4.5 g/ml in females. 

The time to half maximum plasma concentration (tcmax/2) in males/females was 

31/24 hours at the low dose and 44/32 hours at the high dose. Bioavailability, 

or the area under the plasma concentration curve (AUC0-48hr), was nearly 

identical (~ 0.8 mg/kg.hr) among males and females of the low dose group. 

Also, both sexes in the high dose group had similar plasma AUC0-48hr (M/F: 

143/125 mg/kg.hr) which increased almost proportionately with the 200-fold 

increase in the dose level. The residues in RBC increased steadily with time 

reaching peak levels (at 24 - 48 hours post-dosing) of 0.5-0.6 and 90 ppm (or 

g/g) CGA-77102 equivalents for the low (B1) and high (D1) dose groups, 

respectively. The peak levels in RBC remained high and were nearly 20 fold 

higher than the respective plasma Cmax levels.

The kinetics of tissue distribution and depletion in both sexes were also 

followed for up to 144 hours following a single low or high oral dose (Groups 

F1 - F4). Peak residue levels were reached within 12 - 24 hours and ranged 

from 0.007 ppm (female muscle) to 0.123 ppm (male kidneys) at the low dose, 

and from 1.29 ppm (male brain) to 16.82 ppm (male liver) at the high dose, 

with the highest levels being among some of the well-perfused tissues (e.g., 

liver, kidneys, spleen, and lungs). The extent of residue depletion was 

variable among the tissue types but was minimally affected by the dose or the 

sex of the animal. The radiolabel was most persistent in some of the wellperfused organs (e.g., the heart, lungs, and spleen) in addition to the brain and 

bone where, after 144 hours, the levels were decreased to only 45 - 94% of 

their maximal concentrations. In Groups F1 - F4, peak residue concentration 

in the whole blood (0.2 and 42 - 47 g/ml in the low and high dose groups, 

respectively) was reached at 24 hours and was maintained throughout the 

study. Overall, the high/low dose peak tissue levels (including blood) ranged 

from 132 to 282 which approximates the 200-fold increase in dosage.

CGA-77102 has a high affinity for and a long half-life in blood (especially 

RBC) which might contribute to the retarded depletion of tissue residues.

200-fold increase in dosage.

CGA-77102 has a high affinity for and a long half-life in blood (especially 

RBC) which might contribute to the retarded depletion of tissue residues. 
Page 38 of 60

870.7485

Metabolism and 

pharmacokinetics

44491402 (1996)

unacceptable/guideline

single dose of 0.5 (group 

B1) or 100 mg/kg (group 

D1) radio labeled CGA77102; 100 mg/kg/day nonradio labeled CGA 77102 

for 14 days followed by 0.5 

mg/kg radio labeled CGA77102 (Group V1); single 

dose of 0.5 or 100 mg/kg 

radio labeled 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] CGA77102 (the S-enantiomer) (MRID 44491401). 

The urinary and fecal metabolite profiles, with 31 and 15 metabolite fractions, 

respectively, were qualitatively similar among all groups; however, there were 

large quantitative differences, based on the dosing formulation, on one hand, 

and the sex of the animal, on the other. Based on a percentage of the dose, 

several of the major urinary metabolite fractions (e.g., U1, U2, U3, U18, U24, 

and U30) were more abundant in the case of the racemic-Metolachlor (CGA24705) than the S-metolachlor (CGA-77102); in contrast, several fecal 

metabolite fractions (e.g., F9, F10, F12, and F13) were present at higher levels 

in the case of CGA-77102 than CGA-24705. On the other hand, there were 

sex-related differences regardless of the dosing formulation where, for 

instance, females had greater urinary concentrations than males of several 

metabolite fractions, including U3, U4, U8, U9, U18, U20, and U30; the 

males, however, excreted more of fractions U1 and U24 than the females. 

Also, several fecal fractions including F1, F3, F5, F6, F7, F8, and F13 were 

influenced by the sex regardless of the dose level (e.g. B1 vs. D1) or the 

stereochemical make-up of Metolachlor (B1 vs. B2). Other metabolite 

fractions were dependent on both the sex and the chemical formulation as, for 

instance, in the case of metabolite U2 which, relative to the opposite sex 

within the same group, was more abundant in the urine of the females of 

Group B2 (CGA-24705) and in the urine of the males of Group B1 (CGA77102).

The bile fluid accounted for 79.8% of the administered low or high dose of 

CGA-77102 (Groups G1 and G2) where the 2D-TLC showed 14 biliary 

metabolite fractions (G1-G14) in the high dose Group and only six 

metabolites in the low dose Group. The two metabolite fractions G7 and G8 

accounted, respectively, for 33.3% and 9.6% of the administered low dose and 

31.3% and 14.6% of the administered high dose. Other major biliary 

metabolites were G3, G9, and G10 which accounted for about 5%, 5-7%, and 

3-5%, respectively, of either dose group. 

The results clearly show that the metabolite profile in excreta and bile fluid is 

very complex and that Metolachlor (racemate or S-enantiomer) is extensively 

metabolized. This was also shown earlier by another rat metabolism study on 

the absorption, distribution, excretion, and metabolite identification of 

racemic CGA-24705 (MRID 43164201, reviewed by T. McMahon, HED doc. 

no. 010990 dated May 23, 1994). 
Page 39 of 60

No actual metabolites or pathways were identified in the current study and 

there were no data to support or refute the previous findings of four major 

degradation pathways with more than 30 metabolites. However, knowing the 

enantiomeric stereospecific reactions/metabolites is not likely to help in 

making comparative risk assessments between R/ S-metolachlor (CGA-24705) 

and S-metolachlor (CGA-77102) since the contribution of each metabolite to 

the overall toxicity of Metolachlor is not well understood. Furthermore, other 

bridging animal studies with CGA-77102 should highlight possible toxicity 

differences from the well-studied CGA-24705 due to variations in the 

metabolite profiles. 

The Registrant is requested to comment on or provide information on a 

number of issues including: 1) The stereoisomeric purity of CGA-24705 and 

CGA-77102. 2) The adequacy of the storage conditions and the validity of the 

metabolite profile results in light of the storage-related results variability. 3) 

Explain why, relative to the other dosing formulation, some metabolite 

fractions (e.g., F10, F12, and F13) were up to 7-fold higher in the case of the 

S-enantiomer (CGA-77102) while some urinary metabolite fractions (e.g., U1, 

U2, and U3) were up to 4-fold higher in the case of CGA-24705. 4) Provide 

rational for dose selection. 5) The Registrant might also have to comment on 

the possible formation and the level of methylethylaniline from either dosing 

formulation and the possible contribution of this metabolite to the 

carcinogenicity of Metolachlor. This issue was raised earlier by T. McMahon 

(HED document no. 010990 dated May 23, 1994) and might need to be 

followed up by HED’s risk assessors who are in charge of S-metolachlor. 

Table 2. Toxicity Profile for Metolachlor (PC Code 108801)

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

Classification /Doses

Results

870.3100

90-Day oral toxicity rodents

44775401 (1999)

Acceptable/guideline

0, 30, 300, 3000 ppm (M/F: 

0, 2.00/2.32, 20.2/23.4, 

210/259 mg/kg/day)

NOAEL for males = 3000 ppm

LOAEL for males not established

NOAEL for females = 300 ppm

LOAEL for females = 3000 ppm based on decreased body weight/body 

weight gain

870.3150

180-Day oral toxicity in 

nonrodents

00032174 (1980), 43244001

acceptable/guideline

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

870.3200

21/28-Day dermal toxicity

41833101 (1987)

acceptable/guideline

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) 
Page 40 of 60

Table 2. Toxicity Profile for Metolachlor (PC Code 108801)

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

Classification /Doses

Results

870.3700a

Prenatal developmental in 

rodents

00151941 (1985)

acceptable/guideline 

0, 30, 100, 300 or 1000 

mg/kg/day

maternal toxicity NOAEL = 300 mg/kg/day.

maternal toxicity LOAEL = 1000 mg/kg/day based on an increased 

incidence of death, clinical signs of toxicity (clonic and/or toxic 

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

excessive lacrimation) and decreased body weight gain. 

developmental toxicity NOAEL = 300 mg/kg/day developmental toxicity 

LOAEL = 1000 mg/kg/day based on slightly decreased number of 

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

number of resorptions/dam and significant decrease in mean fetal body 

weight

870.3700b

Prenatal developmental in 

nonrodents

00041283 (1980) 

acceptable/guideline

0, 36, 120 or 360 mg/kg/day

maternal toxicity NOAEL = 120 mg/kg/day.

maternal toxicity LOAEL = 360 mg/kg/day based on an increased incidence 

of clinical observations (persistent anorexia) and decreased body weight gain

developmental toxicity NOAEL = 360 mg/kg/day developmental toxicity 

LOAEL was not established. 

870.3800

Reproduction and fertility 

effects

00080897 (1981) 

acceptable/guideline

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).

Parental toxicity NOAEL = 1000 ppm (F0 males/females: 75.8/85.7 

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

Parental toxicity LOAEL was not established

Reproduction toxicity NOAEL = 1000 ppm (F0 males/females: 75.8/85.7 

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

Reproduction toxicity LOAEL was not established

Offspring NOAEL = 300 ppm (F0 males/females: 23.5/ 26.0 mg/kg/day; 

F1males/females: 23.7/25.7 mg/kg/day). Offspring LOAEL = 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. 

870.4100b

Chronic toxicity dogs

40980701, 41164501, 

42218601 and 42218602. 

(1989) 

acceptable/guideline 

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

LOAEL for males was not established; NOAEL = 1000 ppm (32.7 

mg/kg/day). 

870.4300

Chronic toxicity/

carcinogenicity rodents

00129377 (1983)

acceptable/guideline

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.
Page 41 of 60

Table 2. Toxicity Profile for Metolachlor (PC Code 108801)

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

Classification /Doses

Results

870.4300

Carcinogenicity mice

00117597 (1982)

acceptable/guideline

0, 300, 1000 or 3000 ppm (0, 

45, 150 or 450 mg/kg/day 

based on 1 ppm in food 

equals 0.150 mg/kg/day)

NOAEL = 1000 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

Gene Mutation

870.5100 - bacterial reverse 

mutation

00015397 (1976)

acceptable/guideline

10, 100, 1000 and 10,000 

ug/plate

negative up to cytotoxic doses (1000 ug/plate)

Gene Mutation

870.5300 - mouse lymphoma

00158929 (1984)

acceptable/guideline

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

Cytogenetics 

870.5395 - micronucleus assay 

in Chinese hamsters

00158925 (1984)

acceptable/guideline

0, 1250, 2500 or 5000 mg/kg

no effect of treatment on incidence of micronuclei induction

Cytogenetics 870.5450 -

dominant lethal assay in mice

00015630 (1978)

acceptable/guideline

100 or 300 mg/kg

no effect on embryonic death, pre- and post-implantation or fertility rates in

mated females

Other Effects 

870.5550 - DNA 

Damage/Repair in rat 

hepatocytes

00142828 (1984)

acceptable/guideline

0.25, 1.25, 6.25, or 31.25 

nl/ml

negative

Other Effects 

870.5550 - DNA 

Damage/Repair in human 

fibroblasts

00142827

acceptable/guideline

0.125, 0.625, 3.125 or 

15.625 nl/ml

negative

Other Effects 

870.5550 - Unscheduled DNA 

synthesis in rat hepatocytes

43244003 (1994)

acceptable/guideline

1250, 2500 or 4000 mg/kg to 

males; 500, 1000 or 1500 

mg/kg to females

negative for induction of UDS; however, significant increases in percentage 

of cells in S-phase were observed in females dosed at 500 mg/kg (but not at 

1000 or 1500 mg/kg) and sacrificed at 15 hours
Page 42 of 60

Table 2. Toxicity Profile for Metolachlor (PC Code 108801)

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

Classification /Doses

Results

870.7485

Metabolism and 

pharmacokinetics

MRID 00015425 (1974)

unacceptable

52, 28 or 33 mg/kg to male 

rats

Conclusions: Urinary metabolites of CGA 24705 (N-(2-methoxy-1-

methylethyl)-2-ethyl-6-methyl-chloroacetanilide) were identified following 

oral administration of 52 mg/kg, 28 mg/kg, and 33 mg/kg to male rats. Two 

metabolites, each comprising approximately 5% of chloroform extractable 

urinary radioactivity, were identified from oral administration of CGA 

24705. These were the products CGA 37735 (2-ethyl-6-methylhydroxyacetanilide), in which N-dealkylation of R1

(the N-(2-methoxy-1-

methylethyl side chain) and side chain dechlorination and oxidation of R2

(the N-chloroacetyl side chain) have occurred, and CGA 46129 (N-(1-

carboxy-ethyl)-2-ethyl-6-methyl hydroxyacetanilide) in which the ether 

bond of R1 has been split and oxidized to the corresponding carboxylic acid, 

while R2is similar to R2found in CGA 37735. In study #7/74, these 2 

metabolites each represented approximately 5% of organic extractable 

urinary radioactivity, while in study #12/74, the percentage found as CGA 

46129 was between 20-25% of urinary radioactivity, and CGA 37735 

represented between 3-5% of organic extractable radioactivity.

The major metabolic pathway proposed from analysis of urinary as well as 

fecal metabolites is one of cleavage of the ether bond and subsequent 

oxidation to the carboxylic acid, as well as hydrolytic removal of the 

chlorine atom. Conjugation of CGA 24705 or metabolites with gluronic acid 

or sulfate does not appear to occur.

Aqueous extractable urinary radioactivity contained 58% of the total urinary 

radioactivity and was composed of 5 different radioactive fractions, which 

were not identified.

Current guideline recommendations as to dose levels and use of both sexes 

in metabolism studies were not followed. Thus, whether the metabolic 

pattern is altered with dose or repeated exposure cannot be evaluated from 

these data.
Page 43 of 60

Table 2. Toxicity Profile for Metolachlor (PC Code 108801)

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

Classification /Doses

Results

870.7485

Metabolism and 

pharmacokinetics

40114401 (1987)

unacceptable

Single low (1.5 mg/kg), 

single high (300 mg/kg) and 

repeated low (1.5 mg/kg/day 

for 15 days)

Conclusions: Single low (1.5 mg/kg), single high (300 mg/kg) and repeated 

low (1.5 mg/kg/day for 15 days) oral doses of metolachlor were readily 

absorbed and eliminated by male and female rats. Urinary and fecal 

elimination of radioactivity associated with orally administered [

14C] 

metolachlor was essentially complete within 48 to 72 hours after dosing. 

Low- and high-dose females eliminated 14C more rapidly (p<0.003, halflives of elimination, 16.6 and 15.6 hours, respectively) than low- and highdose males and repeated-dose animals of both sexes (half-lives, 18.2 and 

20.0 hours). Elimination by all animals followed first-order kinetics. 

Approximately one-half to two-thirds (48 to 64 percent) of the 14C 

administered was recovered from the urine within 7 days; similar amounts 

were present in the feces. Low-dose males eliminated slightly more of the 

radioactive dose in the feces (55 percent) than the urine (48 percent). The 

opposite trend was seen in the low-dose females and repeated-dose rats of 

both sexes; these animals excreted approximately 58 to 64 percent of the 14C 

dose in the urine and 42.5 to 46.5 percent in the feces within 7 days after 

dosing. High-dose animals excreted similar amounts (58 to 60 percent) of 

the radioactive dose in the urine and feces. Total recoveries of 14C (urine, 

feces, and tissues) tended to be high and were between 105 and 122.5 

percent.

Relatively low levels of radioactivity were present in the tissues of all 

animals at 7 days postdosing. Tissues of low- and repeated-dose rats 

contained approximately 1.6 to 2.5 percent of the 14C dose; tissues of highdose rats accounted for 3.2 (females) and 4.2 (males) percent. For all groups, 

most of the tissue radioactivity (1.1 to 3.0 percent of the dose) was 

associated with red blood cells (RBCs); RBCs also contained the highest 

concentrations of radio labeled compound (0.6 to 0.9 ppm, low- and 

repeated-dose rats; 232 and 247 ppm, high-dose females and males, 

respectively), indicating that [14C] metolachlor and/or its metabolites bind 

extensively to these cells. The next highest concentrations of radiolabel 

(0.03 to 0.13 ppm, low- and repeated-dose rats; 7.3 to 37 ppm, high-dose 

animals) were present in metabolically active tissues, including the heart, 

lung, kidney, liver and spleen. Brain, bone and muscle contained the 

smallest amounts of radioactivity (0.004 to 0.015 ppm, low- and repeateddose rats; 1.7 to 3.5 ppm, high-dose rats). Tissue 14C residues in high-dose 

males were approximately 250 to 500 times greater than those of low-dose 

males, indicating that the ratio of tissue concentrations (high dose:low dose) 

was much larger than the corresponding dose ratio of 200:1 (300 mg/kg: 1.5 

mg/kg). In contrast, tissue 14C levels of females were, in general, 

proportionate to dose. Tissues of low- and repeated-dose rats contained 

similar amounts of radioactivity. These data indicate that some 14C was 

retained by all animals and that the greatest potential for accumulation of 

radioactivity was in male rats given a single high oral dose of [14C] 

metolachlor.
Page 44 of 60

Table 2. Toxicity Profile for Metolachlor (PC Code 108801)

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

Classification /Doses

Results

870.7485

Metabolism and 

pharmacokinetics

43164201 (1992)

acceptable/guideline

low oral dose (1.5 mg/kg x 

14 days), and a single high 

dose (300 mg/kg)

In a rat metabolism study (MRID # 431642-01),14C-Metolachlor was 

administered orally in PEG-200 [HWI 6117-208] or corn oil [ABR-94001] 

to groups (5 sex/dose) of male and female Sprague-Dawley rats at a low oral 

dose (1.5 mg/kg), repeated low oral dose (1.5 mg/kg x 14 days), and a single 

high dose (300 mg/kg). Control animals (1/sex) received blank formulation. 

 

Comparison of oral and intravenous data showed that of the administered 

dose, between 69.6% and 93.2% was absorbed. Distribution data showed 

that the only significant sites of residual radioactivity at 7 days post-dose 

were residual carcass (0.9 - 2.2% of the administered dose) and red blood 

cells (0.95- 1.53 g equivalents/gram in blood cells for all low dose male 

and female rats). Dosing regimen did not result in any apparent 

accumulation of residual radioactivity. 

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

elimination of metolachlor derived radioactivity. In the low dose groups, the 

urine appeared more of a predominant route for excretion in female rats than 

in males, whereas fecal excretion was slightly higher in males. However, at 

the high oral dose, there were no apparent sex-related differences in the 

pattern of urinary excretion. Examination of urinary excretion data as 

presented in graphical format indicated that at the 300 mg/kg dose, excretion 

was delayed vs the low oral dose, suggesting saturation of elimination. 

Metabolism of metolachlor in this study was complex, with up to 32 

metabolites identified in urine and/or feces. The “major” urinary metabolite 

found in all dose groups was the metabolite designated CGA-46129. This 

metabolite was present as 5.6-13.1% of the total radioactive residue (TRR) 

in rat urine across all dose groups, and was highest in the intravenously 

dosed group. In the orally dosed rats, the percentage of this metabolite 

decreased from approximately 13% of TRR to between 5.6-9.2% of TRR. 

Other metabolites identified in urine which constituted near or at 5% of TRR 

were U10 (CGA-37735), U13, U17, U1, “polar 1”, and “polar 2.” The 

radioactivity constituting the ‘polar 1’ and ‘polar 2’ regions was further 

broken down to at least 12 components by TLC, but the identity of the 

metabolites in these regions was not demonstrated. 

In feces, a similarly complex metabolite profile was obtained. The “major” 

metabolite observed in feces, F9, was identical to U7, or CGA-46129. 

Except for intravenously dosed rats, where the percentage of this metabolite 

in feces was equivalent in male and female rats (11.6 and 13.2% of TRR, 

respectively), the percentage of F9 in feces of orally dosed rats was always 

higher in males than in females. Other fecal metabolites identified at or near 

5% of TRR in feces included F2 (CGA-41638), F3 (CGA-133275), F7, F8 

and F8’, F16, F14, and F17. 

Based on these data, a scheme for metabolism of metolachlor was proposed.
Page 45 of 60

2.0 STUDIES REVIEWED FOR ETHICAL CONDUCT

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Task 

Force members Health Canada, U.S. Environmental Protection Agency, and the National 

Agricultural Chemicals Association, released February, 1995.
Page 46 of 60

3.0 CHEMICAL STRUCTURES
Page 47 of 60
Page 48 of 60

4.0 REFERENCES FOR TOXICITY STUDIES

S-metolachlor

82-1 Subchronic Oral Toxicity: 90-Day Study

MRID Citation Reference

43928922 Chang, J. (1995) 90-Day Dietary Toxicity in Dogs: CGA-77102 Technical: Final Report: 

Lab Project Number: F-00193. Unpublished study prepared by Ciba Crop Protection. 

438 p. 

43928923 Chang, J. (1995) 13-Week Oral Toxicity in Rats: CGA-77102 Technical: Lab Project 

Number: F-00191. Unpublished study prepared by Ciba Crop Protection. 400 p. 

44775402 Fankhauser, H. (1999) CGA-77102: 3-Month Oral Toxicity Study in Rats (Administration 

in Food): Final Report: Lab Project Number: 971144: 1161-98: RHA98009. Unpublished 

study prepared by Novartis Crop Protection AG. 475 p. 

44929509 Schneider, M. (1992) 3-Month Oral Toxicity Study in Rats (Administration in Food): 

CGA-51202: Final Report: Lab Project Number: 91134: 528-92. Unpublished study

prepared by Ciba-Geigy Limited. 298 p. 

44931709 Altmann, B. (1999) 3-Month Subchronic, Comparative Oral Toxicity Study in Beagle 

Dogs: CGA-354743: Final Report: Lab Project Number: 971089: 794-97. Unpublished 

study prepared by Novartis Crop Protection AG. 524 p. 

44931710 Bachmann, P. (1999) 3-Month Oral Toxicity Study in Rats (Administration in Food): 

CGA-354743: Final Report: Lab Project Number: 971142: 1187-98. Unpublished study

prepared by Novartis Crop Protection AG. 575 p. 

83-3 Teratogenicity -- 2 Species

MRID Citation Reference

43928924 Gilles, P.; Giknis, M. (1995) A Teratology Study of CGA-77102 Technical in New 

Zealand White Rabbits: Final Report: Lab Project Number: F-00192. Unpublished study

prepared by Ciba Crop Protection. 271 p. 

43928925 Khalil, S. (1995) CGA-77102 Technical: Rat Oral Teratogenicity: (Final Report): Lab 

Project Number: 941058. Unpublished study prepared by Ciba-Geigy Ltd. 421 p. 

44929510 Marty, J. (1992) CGA-51202 Technical: Rat Oral Teratogenicity: Final Report: Lab 

Project Number: 911351: 527-92. Unpublished study prepared by Ciba-Geigy Limited. 

285 p. 

44931711 Doubovetzky, M. (1999) CGA-354743 Technical: Rat Oral Teratogenicity: CGA-354743: 

Final Report: Lab Project Number: 981009: 1188-98. Unpublished study prepared by

Novartis Crop Protection AG. 464 p. 

84-2 Interaction with Gonadal DNA

MRID Citation Reference
Page 49 of 60

43928926 Hertner, T. (1995) CGA-77102 Technical: Micronucleus Test, Mouse (OECD Conform): 

Lab Project Number: 941061. Unpublished study prepared by Ciba-Geigy Ltd. 45 p. 

43928927 Hertner, T. (1995) CGA-77102 Technical: Salmonella and Escerichia/MammalianMicrosome Mutagenicity Test: Lab Project Number: 941060. Unpublished study

prepared by Ciba-Geigy Ltd. 77 p. 

43928928 Hertner, T. (1995) CGA-77102 Technical: In vivo/in vitro Unscheduled DNA Synthesis in 

Rat Hepatocytes: Lab Project Number: 941062: 94-50: 300202. Unpublished study

prepared by Ciba-Geigy Ltd. 141 p. 

44929511 Hertner, T. (1992) Micronucleus Test, Mouse: CGA-51202: Final Report: Lab Project 

Number: 911343: 410-91. Unpublished study prepared by Ciba-Geigy Limited. 51 p. 

44929512 Hertner, T. (1992) Salmonella and Escherichia/Liver-Microsome Test: CGA-51202: 

Final Report: Lab Project Number: 911342: 411-91. Unpublished study prepared by

Ciba-Geigy Limited. 74 p. 

44931712 Ogorek, B. (1996) Salmonella and Escherichia/Mammalian -Microsome Mutagenicity

Test: CGA-354743: Final Report: Lab Project Number: 951133: 813-95. Unpublished 

study prepared by Ciba-Geigy Ltd. 76 p. 

44931713 Deparade, E. (1998) Micronucleus Test, Mouse: CGA-354743: Final Report: Lab Project

Number: 981016: 1190-98. Unpublished study prepared by Novartis Crop Protection 

AG. 42 p. 

44931714 Ogorek, B. (1998) Autoradiographic DNA Repair Test on Rat Hepatocytes (OECD 

Conform) In Vitro: CGA-354743: Final Report: Lab Project Number: 981017: 1189-98. 

Unpublished study prepared by Novartis Crop Protection AG. 87 p. 

44991102 Ogorek, B. (1999) Gene Mutation Test with Chinese Hamster Cells V79: CGA-354743 

Tech. (Metabolite of CGA-24705): Final Report: Lab Project Number: 981018: 1193-98. 

Unpublished study prepared by Novartis Crop Protection, Inc. 54 p. {OPPTS 870.5300} 

45001201 Ogorek, B. (1999) Gene Mutation Test with Chinese Hamster Cells V79: CGA-51202 

Tech. (Metabolite of CGA-24705): Final Report: Lab Project Number: 981112: 1192-98. 

Unpublished study prepared by Novartis Crop Protection Ag. 48 p. {OPPTS 870.5300} 

85-1 General metabolism

MRID Citation Reference

44491401 Muller, T. (1996) Absorption, Distribution, and Excretion of (Phenyl-U-(carbon 14)) CGA77102 in the Rat: Lab Project Number: PR 15/96: 491-96: 15-96. Unpublished study

prepared by Novartis Crop Protection Ag. 105 p. 

44491402 Muller, T. (1996) Comparison of Metabolite Pattern in Rat Excreta After Administration 

of (Phenyl-U-(carbon 14)) CGA-77102 and (Phenyl-U-(carbon 14)) CGA-24705: Lab 

Project Number: PR 18/96: 490-96: 30AM02. Unpublished study prepared by Novartis 

Crop Protection Ag. 64 p. 

44931715 Mewes, K. (1998) Determination of the Soil Metabolites CGA-354743, CGA-368208, 

and CGA-357704 in Excreta of Administered (Phenyl-U-(carbon-14)) CGA-77102: Final 
Page 50 of 60

Report: Lab Project Number: 030AM07: 796-97. Unpublished study prepared by

Novartis Crop Protection AG. 86 p. 

44931716 Hassler, S. (1999) Disposition of (Phenyl-U-(carbon-14)) CGA-376944, A Sulfonic Acid 

Soil Metabolite, In Bile-Duct Cannulated Rats After Oral Administration: Final Report: 

Lab Project Number: 030AM08: 1066-99. Unpublished study prepared by Novartis Crop 

Protection AG. 42 p. {OPPTS 870.7485} 

44931717 Muller, T. (1997) Disposition of (Phenyl-U-(carbon-14)) CGA-376944, A Sulfonic Acid 

Soil Metabolite of CGA-77102 in the Rat: Final Report: Lab Project Number: 030AM06: 

795-97. Unpublished study prepared by Novartis Crop Protection AG. 37 p. {OPPTS 

870.7485} 

Metolachlor

82-1 Subchronic Oral Toxicity: 90-Day Study

MRID Citation Reference

15417 Pelfrene, A.F. (1978) CGA 24 705: 3 Month Oral Toxicity in Dogs: IFREB-R 805226. 

(Unpublished study received Jul 7, 1978 under 100-583; prepared by Institut Francais 

de Recherches et Essais Biologiques, submitted by Ciba-Geigy Corp., Greensboro, 

N.C.; CDL:097168-C) 

15633 Pelfrene, A.F. (1978) CGA 24 705: 3 Month Oral Toxicity in Rats: IFREB-R 807247. 

(Unpublished study received Oct 20, 1978 under 7F1913; prepared by Institut Francais 

de Recherches et Essais Biologiques, submitted by Ciba-Geigy Corp., Greensboro, 

N.C.; CDL:097459-B) 

15674 Fouillet, X. (1974) Toxicity de 3 Mois chez le Rat par Voie Orale du Produit CGA 24 705. 

Three-Month Dietary Feeding Study in Rats: CGA 24 705: IC-DREB-R 741009|. 

(Unpublished study includ- ing translation, received Mar 26, 1975 under 5F1606; 

prepared by Oncins Research and Breeding Center, submitted by Ciba-Geigy Corp., 

Greensboro, N.C.; CDL:094377-D) 

16630 Ciba-Geigy Corporation (1979) Reports of Investigations Made with Respect to the 

Subchronic Feeding of Metolachlor Technical in the Dog. Summary of studies 099116-B 

and 099116-C. (Unpub- lished study received Dec 11, 1979 under 100-597; 

CDL:099116-A) 

16631 Goldenthal, E.I.; Jessup, D.C.; Mehring, J.S. (1979) Range-Finding Study with 

Metolachlor Technical in Beagle Dogs: IRDC No. 382- 053. (Unpublished study received 

Dec 11, 1979 under 100-597; prepared by International Research and Development 

Corp., sub- mitted by Ciba-Geigy Corp., Greensboro, N.C.; CDL:099116-B) 

16632 Jessup, D.C.; Estes, F.L.; Jefferson, N.D.; et al. (1979) 6-Month Chronic Oral Toxicity

Study in Beagle Dogs: IRDC No. 382-054. (Unpublished study including Addendum and 

AG-A No. 5358, re- ceived Dec 11, 1979 under 100-597, prepared by International 

Research and Development Corp., submitted by Ciba-Geigy Corp., Greensboro, N.C.; 

CDL:099116-C) 
Page 51 of 60

17690 Coquet, B.; Galland, L.; Guyot, D.; et al. (1974) Essai de Toxicite de 3 Mois chez le 

Chien par Voie Orale du Produit CGA 24 705. ?Three-Month Oral Toxicity Test of CGA 

24 705 in Dog: IC-DREB-R 740119|. (Unpublished study including translation, received 

Sep 26, 1974 under 5G1553; prepared by Oncins Research and Breeding Center, 

submitted by Ciba-Geigy Corp., Greensboro, N.C.; CDL: 112842-A) 

18700 Pelfrene, A.F. (1978) CGA 24 705: 3 Month Oral Toxicity in Rats: IFREB-R 805227. 

(Unpublished study received Jul 7, 1978 under 100-583; prepared by Institut Francais 

de Recherches et Essais Biologiques, submitted by Ciba-Geigy Corp., Greensboro, 

N.C.; CDL:097168-B) 

32174 Jessup, D.C.; Arceo, R.J.; Estes, F.L.; et al. (1980) 6-Month Chronic Oral Toxicity Study

in Beagle Dogs: IRDC No. 382-054. (Unpublished study received Jun 5, 1980 under 

100-587; prepared by International Research and Development Corp., submitted by

Ciba-Geigy Corp., Greensboro, N.C.; CDL:242672-A) 

40652 Kahn, A.C., III; Jessup, D.C.; Shoemaker, R.; et al. (1980) ?Tox- icity of Metolachor in 

Beagle Dogs|. (Unpublished study re- ceived Jan 21, 1980 under 100-597; prepared in 

cooperation with International Research and Development Corp., submitted by CibaGeigy Corp., Greensboro, N.C.; CDL:099203-A) 

52477 Coquet, B.; Galland, L.; Guyot, D.; et al. (1974) Three-Month Oral Toxicity Test of CGA 

24 705 in Dog. A Translation of: Essai de Toxicite de 3 Mois chez le Chien par Voie 

Orale du Produit CGA 24705: IC-DREB-R 740119. (Unpublished study including french 

text, received Sep 26, 1974 under 5G1553; prepared by Centre de Recherche et 

d'Elevage des Oncins, submitted by Ciba-Geigy Corp., Greensboro, N.C.; CDL:094223-

A) 

92446 Kennedy, G.L. (1975) Letter sent to George L. Rolofson dated Nov 21, 1975 ?Results of 

28-day mouse pilot study with CGA-24705|. (Unpublished study received Feb 16, 1978 

under 100-583; prepared by Industrial Bio-Test Laboratories, Inc., submitted by CibaGeigy Corp., Greensboro, N.C.; CDL:232855-B) 

130775 International Research and Development Corp. (1979) ?Toxicity: CGA- 24705 in Dogs|. 

(Unpublished study received Jan 17, 1980 under 8F2098; submitted by Ciba-Geigy

Corp., Greensboro, NC; CDL: 071923-A) 

43244001 Breckenridge, C. (1994) Metolachlor Technical: A Supplement to the 6-Month Chronic 

Oral Toxicity Study in Beagle Dogs: (MRID # 00032174). Unpublished study prepared by

Ciba-Geigy Corp. Plant Protection Division. 5 p. 

44775401 Fankhauser, H. (1999) CGA-24705: 3-Month Oral Toxicity Study in Rats (Administration 

in Food): Final Report: Lab Project Number: 971143: 1162-98: RHA98005. Unpublished 

study prepared by Novartis Crop Protection AG. 469 p. 

44929509 Schneider, M. (1992) 3-Month Oral Toxicity Study in Rats (Administration in Food): 

CGA-51202: Final Report: Lab Project Number: 91134: 528-92. Unpublished study

prepared by Ciba-Geigy Limited. 298 p. 

44931709 Altmann, B. (1999) 3-Month Subchronic, Comparative Oral Toxicity Study in Beagle 

Dogs: CGA-354743: Final Report: Lab Project Number: 971089: 794-97. Unpublished 

study prepared by Novartis Crop Protection AG. 524 p. 

44931710 Bachmann, P. (1999) 3-Month Oral Toxicity Study in Rats (Administration in Food): 

CGA-354743: Final Report: Lab Project Number: 971142: 1187-98. Unpublished study
Page 52 of 60

prepared by Novartis Crop Protection AG. 575 p. 

82-2 21-day dermal-rabbit/rat

MRID Citation Reference

15536 Bach, K.J. (1974) Final Report: Twenty-One Day Repeated Dermal Tox- icity of CGA24705-6E in Rabbits: Contract No. 120-2255-34. (Unpublished study received on 

unknown date under 5G1553; pre- pared by Affiliated Medical Research, Inc., submitted 

by Ciba- Geigy Corp., Greensboro, N.C.; CDL:094220-Q) 

41833101 Mastrocco, F.; Huber, K.; Schiavo, D.; et al. (1987) Metolachlor Technical: 21-Day

Dermal Toxicity Study in Rabbits: Lab Project Number: 862012. Unpublished study

prepared by Ciba-Geigy Corp. 173 p. 

42563401 Breckenridge, C. (1992) Metolachlor: Supplement to 21-day Dermal Toxicity Study in 

Rabbits. Unpublished study prepared by CIBA-GEIGY Corp. 8 p. 

83-1 Chronic Toxicity

MRID Citation Reference

15418 Gordon, D.E. (1978) ?Two-Year Chronic Oral Toxicity Study--Albino Rats|: IBT No. 

8532-07926. (Unpublished study received Jul 7, 1978 under 100-583; prepared by

Industrial Bio-Test Laborato- ries, Inc., submitted by Ciba-Geigy Corp., Greensboro, 

N.C.; CDL:097168-D) 

15634 Farmer, C.; Gesme, J.; Albanese, L.; et al. (1977) Summary: Two- Year Chronic Mouse 

Feeding Study with CGA-24705 Technical (IBT 622-07925) Observations. (Unpublished 

study received Mar 9, 1978 under 100-583; prepared in cooperation with Industrial BioTest Laboratories, Inc., submitted by Ciba-Geigy Corp., Greens- boro, N.C.; 

CDL:096868-A) 

16627 Ciba-Geigy Corporation (1979) Discussion on Questions Raised by the Reviewer 

Concerning the 2-Year Chronic Rat Feeding Study with Metolachlor: IBT No. 622-07926.

(Unpublished study received Dec 14, 1979 under 8F2098; prepared in cooperation with 

International Bio-Test Laboratories, Inc. and International Research and Development 

Corp.; CDL:099119-A) 

16628 Ciba-Geigy Corporation (1979) Discussion of Questions Raised by the Reviewer 

Concerning the 2-Year Chronic Rat Feeding Study with Metolachlor: IBT No. 622-07925.

Summary of study 099090-B. (Unpublished study received Nov 19, 1979 under 8F2081; 

CDL: 099090-A) 

16629 Ciba-Geigy Corporation (1979) (Two-Year Chronic Rat Feeding Study with Metolachlor: 

Statistical Analyses: IBT No. 622-07926). (Unpublished study received Nov 19, 1979 

under 8F2081; prepared in cooperation with Industrial Bio-Test Laboratories, Inc.; CDL: 

099090-B) 

32174 Jessup, D.C.; Arceo, R.J.; Estes, F.L.; et al. (1980) 6-Month Chronic Oral Toxicity Study

in Beagle Dogs: IRDC No. 382-054. (Unpublished study received Jun 5, 1980 under 

100-587; prepared by International Research and Development Corp., submitted by

Ciba-Geigy Corp., Greensboro, N.C.; CDL:242672-A) 
Page 53 of 60

63398 Tisdel, M. (1981) Two-Year Chronic Oral Toxicity and Oncogenicity Study with 

Metolachlor Technical in Albino Rats: Raltech Study No. 80030. (Unpublished study

received Jan 28, 1981 under 100- 587; prepared by Ralston Purina Co., submitted by

Ciba-Geigy Corp., Greensboro, N.C.; CDL:244166-A) 

63399 Friess, S.L.; Drill, V.A.; Hays, H.W.; et al. (1980) Retrospective Audit of Two-Year Study

of Feeding of CGA-24705 to Albino Rats. (Unpublished study received Jan 28, 1981 

under 100-587; prepared by Drill, Friess, Hays, Loomis & Shaffer, Inc., submitted by

Ciba-Geigy Corp., Greensboro, N.C.; CDL:244167-A) 

84005 Tisdel, M.; Jackson, T.A. (1981) Two-year Chronic Oral Toxicity and Oncogenicity Study

with Metolachlor Technical in Albino Rats: Raltech Study No. 80030. One-year progress 

rept. (Un- published study received Sep 30, 1981 under 100-597; prepared by Raltech 

Scientific Services, submitted by Ciba-Geigy Corp., Greensboro, N.C.; CDL:245957-B; 

245958) 

89932 Kennedy, G.L. (1976) Letter sent to George Rolofson dated Dec 13, 1976 ?2 year 

chronic oral toxicity study in albino rats treated with CGA 24705|. (Unpublished study

received Jan 19, 1977 under 100-583; prepared by Industrial Bio-Test Laboratories, 

Inc., submitted by Ciba-Geigy Corp., Greensboro, N.C.; CDL:095768-J) 

129377 Tisdel, M.; Jackson, T.; MacWilliams, P.; et al. (1983) Two-year Chronic Oral Toxicity

and Oncogenicity Study with Metolachlor in Albino Rats: Study No. 80030. Final rept. 

(Unpublished study received May 24, 1983 under 100-587; prepared by Hazleton 

Raltech, Inc., submitted by Ciba-Geigy Corp., Greensboro, NC; CDL: 250369-A; 

250370; 250371; 250372; 250373; 250374; 250375) 

130776 Ciba-Geigy Corp. (1979) Two-year Chronic Oral Toxicity Study with CGA-24705 

Technical in Albino Rats: Study No. 8532-07926. (Com- pilation; unpublished study 

received Dec 11, 1979 under 8F2098; CDL:071924-A) 

144364 Tisdel, M. (1985) Two-Year Chronic Oral Toxicity and Oncogenicity Study with 

Metolachlor in Albino Rats: Study No. 80030: Micro- scopic Evaluation of Nasal 

Turbinates: Amendment No. 1 to Final Report. Unpublished study prepared by Hazelton 

Laboratories America, Inc. 54 p. 

153880 Ciba-Geigy Corporation. (19??) Two-year Chronic Oral Toxicity Study Albino Rats: 

[CGA-24705 Technical: IBT No. 853207926]. Unpub- lished study. 677 p. 

158924 Tisdel, M. (1985) Two-year Chronic Oral Toxicity and Oncogenicity Study with 

Metolachlor in Albino Rats: Microscopic Evaluation of Nasal Turbinates: Amendment 

No. 2 to Final Report: Study No. 80030. Unpublished study prepared by Hazleton 

Laboratories Ame- rica, Inc. 45 p. 

159221 Oscarson, E.; Tinerella, J.; Miller, L.; et al. (1979) Two-year Chronic Oral Toxicity Study

with CGA-24705 Technical in Albino Rats: Final Report: IBT No. 622-07926 (8532-

07926). Unpublished study prepared by Industrial Bio-Test Laboratories. 1934 p. 

40261701 Phelps, W. (1987) 1-Year Dog Feeding Study with Metolachlor--Pro- gress Report on 

Clotting Factors: Laboratory Study No.: MIN 862253. Unpublished study prepared by

Ciba-Geigy Corp. 22 p. 

40399401 Hazelette, J.; Barringer, M. (1987) One Year Feeding Study in Beagle Dogs with 

Technical Metolachlor: Examination of Clotting Factors: Lab Project ID MIN862253. 

Unpublished study prepared by Ciba-Geigy Corporation. 7 p. 
Page 54 of 60

40560801 Jessup, D. (1980) A Supplement to Two-year Chronic Oral Toxicity Study in Rats. 

Unpublished study prepared by Ciba-Geigy. 16 p. 

40980701 Hazelette, J. (1989) Metolachlor Technical: Chronic Toxicity Study in Dogs: Study No. 

862253. Unpublished study prepared by Ciba- Geigy Corp. 758 p. 

41164501 Hazelette, J.; Arthur, A. (1989) Supplement to 13/52 Week Oral Tox- icity Study in 

Dogs: Metolachlor Technical: MIN 862253: Report No. 88086. Unpublished study

prepared by Ciba-Geigy Corpora- tion. 23 p. 

42218601 Hazelette, J.; Arthur, A. (1989) Metolachlor Technical: 13/52-Week Oral Toxicity Study

in Dogs: Final Report Amendment No. 2: Lab Project Number: MIN/862253. 

Unpublished study prepared by Ciba-Geigy Corp. 19 p. 

42218602 Ciba-Geigy Corp. (1992) Metolachlor Technical: A Supplement to the Chronic Toxicity

Study in Dogs. Unpublished study. 16 p. 

43244001 Breckenridge, C. (1994) Metolachlor Technical: A Supplement to the 6-Month Chronic 

Oral Toxicity Study in Beagle Dogs: (MRID # 00032174). Unpublished study prepared by

Ciba-Geigy Corp. Plant Protection Division. 5 p. 

83-2 Oncogenicity

MRID Citation Reference

16627 Ciba-Geigy Corporation (1979) Discussion on Questions Raised by the Reviewer 

Concerning the 2-Year Chronic Rat Feeding Study with Metolachlor: IBT No. 622-07926.

(Unpublished study received Dec 14, 1979 under 8F2098; prepared in cooperation with 

International Bio-Test Laboratories, Inc. and International Research and Development 

Corp.; CDL:099119-A) 

16629 Ciba-Geigy Corporation (1979) (Two-Year Chronic Rat Feeding Study with Metolachlor: 

Statistical Analyses: IBT No. 622-07926). (Unpublished study received Nov 19, 1979 

under 8F2081; prepared in cooperation with Industrial Bio-Test Laboratories, Inc.; CDL: 

099090-B) 

39194 Tisdel, M.; Balk, M.W.; Jackson, T.; et al. (1980) ?Toxicity Study: Metolachlor on Mice|. 

(Unpublished study including study no. 79020, received Jul 25, 1980 under 100-587; 

prepared by Raltech Scientific Services, Inc. and American College of Laboratory

Animal Medicine, submitted by Ciba-Geigy Corp., Greensboro, N.C.; CDL:242941-A) 

42725 Marias, A.J.; Gesme, J.; Albanese, E.; et al. (1977) Report to Ci- ba-Geigy Corporation: 

Carcinogenicity Study with CGA-24705 Tech- nical in Albino Mice: IBT No. 622-07925 

(8532-07925). (Unpub- lished study including submitter summary, received Jan 18, 

1978 under 100-583; prepared by Industrial Bio-Test Laboratories, Inc., submitted by

Ciba-Geigy Corp., Greensboro, N.C.; CDL: 096719-A; 096720) 

63398 Tisdel, M. (1981) Two-Year Chronic Oral Toxicity and Oncogenicity Study with 

Metolachlor Technical in Albino Rats: Raltech Study No. 80030. (Unpublished study

received Jan 28, 1981 under 100- 587; prepared by Ralston Purina Co., submitted by

Ciba-Geigy Corp., Greensboro, N.C.; CDL:244166-A) 

84003 Marias, A.J.; Gesme, J.; Albanese, E.; et al. (1977) Revised Final Report to Ciba-Geigy

Corporation: Carcinogenicity Study with CGA-24705 Technical in Albino Mice: IBT No. 

622-07925 (8532- 07925). (Unpublished study received Jul 7, 1978 under 100-583; 
Page 55 of 60

prepared by Industrial Bio-Test Laboratories, Inc., submitted by Ciba-Geigy Corp., 

Greensboro, N.C.; CDL:097169-A; 097170) 

89931 Kennedy, G.L. (1976) Letter sent to George Rolofson dated Dec 13, 1976 ?2 year 

carcinogenicity study in albino mice treated with CGA 24705|. (Unpublished study

received Jan 19, 1977 under 100- 583; prepared by Industrial Bio-Test Laboratories, 

Inc., sub- mitted by Ciba-Geigy Corp., Greensboro, N.C.; CDL:095768-G) 

117597 Tisdel, M.; MacWilliams, P.; Dahlgren, R.; et al. (1982) Carcino- genicity Study with 

Metolachlor in Albino Mice: Study No. 79020. (Unpublished study received Nov 2, 1982 

under 100-587; prepared by Hazleton Laboratories America, Inc., submitted by CibaGeigy Corp., Greensboro, NC; CDL:248722-A; 248723; 248724; 248725) 

126006 Hansen, W.; Jacobson, K. (1966) Chronic Toxicity of Chlorinated Hydrocarbon 

Pesticides: Project No. T-003-04. (Unpublished study received 1966 under 5F0441; 

prepared by U.S. Food and Drug Administration, Bureau of Science, Div. of 

Toxicological Evalu- ation, Laboratory Investigations Branch, submitted by Califor- nia, 

Dept. of Agriculture, Sacramento, CA; CDL:092730-E) 

129377 Tisdel, M.; Jackson, T.; MacWilliams, P.; et al. (1983) Two-year Chronic Oral Toxicity

and Oncogenicity Study with Metolachlor in Albino Rats: Study No. 80030. Final rept. 

(Unpublished study received May 24, 1983 under 100-587; prepared by Hazleton 

Raltech, Inc., submitted by Ciba-Geigy Corp., Greensboro, NC; CDL: 250369-A; 

250370; 250371; 250372; 250373; 250374; 250375) 

144364 Tisdel, M. (1985) Two-Year Chronic Oral Toxicity and Oncogenicity Study with 

Metolachlor in Albino Rats: Study No. 80030: Micro- scopic Evaluation of Nasal 

Turbinates: Amendment No. 1 to Final Report. Unpublished study prepared by Hazelton 

Laboratories America, Inc. 54 p. 

158924 Tisdel, M. (1985) Two-year Chronic Oral Toxicity and Oncogenicity Study with 

Metolachlor in Albino Rats: Microscopic Evaluation of Nasal Turbinates: Amendment 

No. 2 to Final Report: Study No. 80030. Unpublished study prepared by Hazleton 

Laboratories Ame- rica, Inc. 45 p. 

83-3 Teratogenicity -- 2 Species

MRID Citation Reference

15396 Fritz, H. (1976) Reproduction Study: CGA 24705 Tech.: Rat: Seg. II. (Unpublished study

including addendum, received Jan 19, 1977 un- der 100-583; prepared by Ciba-Geigy, 

Ltd., submitted by Ciba- Geigy Corp., Greensboro, N.C.; CDL:095768-E) 

41283 Lightkep, G.E.; Christian, M.S.; Christian, G.D.; et al. (1980) Teratogenic Potential of 

CGA-24705 in New Zealand White Rabbits: Segment II Evaluation--Project 203-001. 

(Unpublished study re- ceived Sep 15, 1980 under 100-597; prepared by Argus 

Research Laboratories, Inc., submitted by Ciba-Geigy Corp., Greensboro, N.C.; 

CDL:099630-A) 

151941 Lochry, E. (1985) Embryo/Fetal Toxicity and Teratogenic Potential Study of CGA-24705 

(...) Administered Orally Via Gavage to (...) Presumed Pregnant Rats: Final Report: 

Project No. 203-004. Unpublished study prepared by Argus Research Laboratories, Inc. 

178 p. 
Page 56 of 60

40775701 Morseth, S. (1986) Amendment I to Report: Rabbit Teratology Study: (Inert Ingredient) 

Technical. Unpublished study prepared by Ciba-Geigy Corp. 18 p. 

40775702 Morseth, S. (1986) Amendment II to Report: Rabbit Teratology Study: CGA-154281 

Technical. Unpublished study prepared by Ciba-Geigy Corp. 77 p. 

44929510 Marty, J. (1992) CGA-51202 Technical: Rat Oral Teratogenicity: Final Report: Lab 

Project Number: 911351: 527-92. Unpublished study prepared by Ciba-Geigy Limited. 

285 p. 

44931711 Doubovetzky, M. (1999) CGA-354743 Technical: Rat Oral Teratogenicity: CGA-354743: 

Final Report: Lab Project Number: 981009: 1188-98. Unpublished study prepared by

Novartis Crop Protection AG. 464 p. 

83-4 2-generation repro.-rat

MRID Citation Reference

15632 Adler, G.L.; Smith, S.H. (1978) Final Report to Ciba-Geigy Corpora- tion: ThreeGeneration Reproduction Study with CGA-24705 Techni- cal in Albino Rats: IBT No. 

8533-07928. (Unpublished study in- cluding IBT No. 623-07928, received Jan 18, 1978 

under 100-583; prepared by Industrial Bio-Test Laboratories, Inc., submitted by CibaGeigy Corp., Greensboro, N.C.; CDL:096718-A) 

80897 Smith, S.H.; O'Loughlin, C.K.; Salamon, C.M.; et al. (1981) Two- generation 

Reproduction Study in Albino Rats with Metolachlor Technical: Study No. 450-0272. 

Final rept. (Unpublished study received Sep 30, 1981 under 100-597; prepared by Whittaker Corp., submitted by Ciba-Geigy Corp., Greensboro, N.C.; CDL:245959-A; 245960; 

245961) 

89933 Kennedy, G.L. (1976) Letter sent to George Rolofson dated Dec 10, 1976 ?Threegeneration reproduction study in albino rats with CGA 24705: First generation results|. 

(Unpublished study re- ceived Jan 19, 1977 under 100-583; prepared by Industrial BioTest Laboratories, Inc., submitted by Ciba-Geigy Corp., Greens- boro, N.C.; 

CDL:095768-K) 

92453 Mennear, J.H. (1978) Letter sent to Daryl Sumner dated Feb 16, 1978: IBT No. 8533-

07928: Three-generation reproduction study with CGA-24705 technical in albino rats. 

(Unpublished study, including letter dated Jan 23, 1978 from J.H. Mennear to George L. 

Rolofson, received Feb 17, 1978 under 100-583; prepared by Industrial Bio-Test 

Laboratories, Inc., submitted by Ciba-Geigy Corp., Greensboro, N.C.; CDL:096717-B) 

45208302 Birge, W.; Black, J.; Kuehne, R. (1979) Effects of Organic Compounds on Amphibian 

Reproduction: Lab Project Number: A-074-KY. Unpublished study prepared by

University of Kentucky. 39 p. 

84-2 Interaction with Gonadal DNA

MRID Citation Reference

15397 Arni, P.; Muller, D. (1976) Salmonella/Mammalian--Microsome Muta- genicity Test. 

(Unpublished study received Jan 19, 1977 under 100-583; prepared by Ciba-Geigy, Ltd., 

submitted by Ciba-Geigy Corp., Greensboro, N.C.; CDL:095768-F) 
Page 57 of 60

15630 Fritz, H. (1976) Dominant Lethal Study on CGA 24705 Technical: Mouse: Test for 

Cytotoxic or Mutagenic Effects on Male Germinal Cells. (Unpublished study including 

addendum, received Jan 18, 1978 under 100-583; prepared by Ciba-Geigy, Ltd., 

submitted by Ciba-Geigy Corp., Greensboro, N.C.; CDL:096717-E) 

142826 Strasser, F. (1984) Nucleus Anomaly Test in Somatic Interphase Nuclei of Chinese 

Hamster: Final Report: Report No. 831498. Un- published study prepared by Ciba Geigy

Ltd -- Switz. 14 p. 

142827 Puri, E. (1984) Autoradiographic DNA Repair Test on Human Fibro- blasts: Final 

Report: Report No. 831499. Unpublished study. 30 p. 

142828 Puri, E. (1984) Autoradiographic DNA Repair Test on Rat Hepato- cytes: Final Report: 

Report No. 831497. Unpublished study. 31 p. 

158925 Strasser, F. (1986) Nucleus Anomaly Test in Somatic Interphase Nuclei of Chinese 

Hamster: CGA 24'705 Technical: Rep. No. 831498. Unpublished study prepared by

Ciba-Geigy Ltd. 15 p. 

158927 Puri, E. (1986) Autoradiographic DNA Repair Test on Human Fibro- blasts: CGA 24'705 

Techn.: Final Report: Rep. No: 831499. Un- published study prepared by Ciba-Geigy

Ltd. 15 p. 

158928 Puri, E. (1986) Autoradiographic DNA Repair Test on Rat Hepato- cytes: CGA 24'705 

Techn.: Final Report: Rep. No: 831497. Unpub- lished study prepared by Ciba-Geigy

Ltd. 16 p. 

158929 Beilstein, P. (1984) L5178Y/TK+/- Mouse Lymphoma Mutagenicity Test: CGA 24'705 

Techn.: Final Report: Rep. No: 831500. Unpublished study prepared by Ciba-Geigy Ltd. 

31 p. 

40732103 Deparade, E. (1988) Gene Mutations Test Salmonella/Mammalian-- Microsome 

Mutagenicity Test: (Inert Ingredient) Technical: Lab Study No.: 881320. Unpublished 

study prepared by Ciba-Geigy Ltd. 27 p. 

40732104 Deparade, E. (1988) Gene Mutations Test Salmonella/Mammalian-- Microsome 

Mutagenicity Test: (Inert Ingredient) Lab Study No. 881321. Unpublished study prepared 

by Ciba-Geigy Ltd. 28 p. 

42043301 Cifone, M. (1988) Evaluation of Metachlor Technical in the in vivo/ in vitro Rat 

Hepatocyte Unscheduled DNA Synthesis Assay: Final Report: Lab Project Number: 

8147: 10992-001. Unpublished study prepared by Hazleton Biotechnologies Co. 21 p. 

42563402 Breckenridge, C. (1992) Metolachlor: Supplement to in vivo/in vitro Unscheduled DNA 

Synthesis. Unpublished study prepared by CIBA-GEIGY Corp. 8 p. 

43244003 Ham, A. (1994) Metolachlor: Test for Other Genotoxic Effects in the in vivo/ in vitro 

Assay for Unscheduled DNA Synthesis in Rat Primary Hepatocytes with Two 

Timepoints: Final Report: Lab Project Number: 15881/0/494. Unpublished study

prepared by Hazleton Washington, Inc. 46 p. 

43244004 Ham, A. (1994) Metolachlor: Test for Other Genotoxic Effects in a Cell Proliferation 

Assay in Rat Liver Cells: Final Report: Lab Project Number: 483/290. Unpublished study

prepared by Hazleton Washington, Inc. 79 p. 

44929511 Hertner, T. (1992) Micronucleus Test, Mouse: CGA-51202: Final Report: Lab Project 
Page 58 of 60

Number: 911343: 410-91. Unpublished study prepared by Ciba-Geigy Limited. 51 p. 

44929512 Hertner, T. (1992) Salmonella and Escherichia/Liver-Microsome Test: CGA-51202: 

Final Report: Lab Project Number: 911342: 411-91. Unpublished study prepared by

Ciba-Geigy Limited. 74 p. 

44931712 Ogorek, B. (1996) Salmonella and Escherichia/Mammalian -Microsome Mutagenicity

Test: CGA-354743: Final Report: Lab Project Number: 951133: 813-95. Unpublished 

study prepared by Ciba-Geigy Ltd. 76 p. 

44931713 Deparade, E. (1998) Micronucleus Test, Mouse: CGA-354743: Final Report: Lab Project 

Number: 981016: 1190-98. Unpublished study prepared by Novartis Crop Protection 

AG. 42 p. 

44931714 Ogorek, B. (1998) Autoradiographic DNA Repair Test on Rat Hepatocytes (OECD 

Conform) In Vitro: CGA-354743: Final Report: Lab Project Number: 981017: 1189-98. 

Unpublished study prepared by Novartis Crop Protection AG. 87 p. 

44991102 Ogorek, B. (1999) Gene Mutation Test with Chinese Hamster Cells V79: CGA-354743 

Tech. (Metabolite of CGA-24705): Final Report: Lab Project Number: 981018: 1193-98. 

Unpublished study prepared by Novartis Crop Protection, Inc. 54 p. {OPPTS 870.5300} 

45001201 Ogorek, B. (1999) Gene Mutation Test with Chinese Hamster Cells V79: CGA-51202 

Tech. (Metabolite of CGA-24705): Final Report: Lab Project Number: 981112: 1192-98. 

Unpublished study prepared by Novartis Crop Protection Ag. 48 p. {OPPTS 870.5300} 

85-1 General metabolism

MRID Citation Reference

15394 Houseworth, L.D.; Rolla, H. (1976) Residues from Metolachlor Alone and in Tank Mix 

with Linuron, Metribuzin and Liquid Fertilizer in Soybeans: Report No. ABR-76077. 

(Unpublished study received Jan 19, 1977 under 100-583; submitted by Ciba-Geigy

Corp., Greensboro, N.C.; CDL:095767-A) 

15425 Hambock, H. (1974) Metabolism of CGA 24 705 in the Rat: Project Re- port 12/74: 

Addendum to Project Report 7/74. (Unpublished study received Mar 26, 1975 under 

5F1606; prepared by Ciba-Geigy, Ltd., submitted by Ciba-Geigy Corp., Greensboro, 

N.C.; CDL: 094378-O) 

15548 Houseworth, L.D.; Rolla, H. (1977) Residues of Metolachlor in or on Sorghum Resulting 

from Preplant Incorporated and Preemergence Applications: Report No. ABR-77086. 

(Unpublished study received Nov 14, 1977 under 8G2019; submitted by Ciba-Geigy

Corp., Greensboro, N.C.; CDL:096625-A) 

15553 Kahrs, R.A. (1979) Residues of Metolachlor in Peanuts Resulting from Preplant 

Incorporated or Preemergence Applications: Report No. ABR-79059. Summary of 

studies 098298-B, 098298-C, 098298-F, 098298-I and 098298-J. (Unpublished study

received May 18, 1979 under 100-583; submitted by Ciba-Geigy Corp., Greensboro, 

N.C.; CDL:098298-A) 

15559 Ciba-Geigy Corporation (1979) Reasonable Grounds in Support of This Petition: 

?Metolachlor|. (Unpublished study received May 18, 1979 under 100-583; CDL:098299-

A) 
Page 59 of 60

15654 Hambock, H. (1974) Distribution, Degradation and Excretion of CGA 24 705 in the Rat: 

Project Report No. 1/74. (Unpublished study received Sep 26, 1974 under 5G1553; 

prepared by Ciba-Geigy, Ltd., submitted by Ciba-Geigy Corp., Greensboro, N.C.; CDL: 

094217-J) 

15655 Hambock, H. (1974) Metabolism of CGA 24 705 in the Rat: Project Re- port No. 7/74. 

(Unpublished study received Sep 26, 1974 under 5G1553; prepared by Ciba-Geigy, 

Ltd., submitted by Ciba-Geigy Corp., Greensboro, N.C.; CDL:094217-K) 

39192 Hambock, H. (1974) Distribution, Degradation and Excretion of CGA 24 705 in the Rat: 

Project Report No. 1/74. (Unpublished study received Nov 25, 1975 under 6G1708; 

prepared by Ciba-Geigy, Ltd., submitted by Ciba-Geigy Corp., Greensboro, N.C.; CDL: 

094984-N) 

39193 Hambock, H. (1974) Metabolism of CGA 24 705 in the Rat: Project Report No. 7/74. 

(Unpublished study received Nov 25, 1975 un- der 6G1708; prepared by Ciba-Geigy, 

Ltd., submitted by Ciba- Geigy Corp., Greensboro, N.C.; CDL:094984-O) 

68003 Ciba-Geigy Corporation (1981) Reasonable Grounds in Support of This Petition: 

Metolachlor--Corn. (Unpublished study received May 14, 1981 under 100-597; 

CDL:070081-A) 

93150 Houseworth, L.D. (1978) Residues of Metolachlor in or on Sorghum Resulting from 

Alone and Tank Mix Applications with Atrazine or Terbutryn--Preplant Incorporated and 

Preemergence Applications: Report No. ABR-78031. (Unpublished study received Jul 

12, 1978 under 100-597; submitted by Ciba-Geigy Corp., Greensboro, N.C.; 

CDL:097225-A) 

158923 Muecke, W. (1981) New Faeces Metabolites of CGA 24 705 in the Rat: Project Report 

26/81. Unpublished study prepared by Ciba-Geigy Ltd. 27 p. 

40114401 Orr, G. (1987) Disposition of Metolachlor in the Rat: (General Metabolism): 

Laboratory/Study No. ABR-86111. Unpublished study prepared by Ciba-Geigy Corp. 78 

p. 

43164201 Capps, T. (1994) Characterization and Identification of Metabolites in Rats Treated with 

(carbon 14)-Metolachlor: Lab Project Number: ABR-94001: HWI 6117-208: 173-91. 

Unpublished study prepared by Ciba-Geigy Corp., Biochemistry Dept. and Hazleton 

Wisconsin, Inc. 593 p. 

43164202 Hambock, H. (1977) Metabolism of CGA-24705 in the Rat: Addendum 2 to Project 

Report 7/74: Lab Project Number: 1/77: 7/74. Unpublished study prepared by CibaGeigy Limited, Agrochemicals Div. 12 p. 

44931715 Mewes, K. (1998) Determination of the Soil Metabolites CGA-354743, CGA-368208, 

and CGA-357704 in Excreta of Administered (Phenyl-U-(carbon-14)) CGA-77102: Final 

Report: Lab Project Number: 030AM07: 796-97. Unpublished study prepared by

Novartis Crop Protection AG. 86 p. 

44931716 Hassler, S. (1999) Disposition of (Phenyl-U-(carbon-14)) CGA-376944, A Sulfonic Acid 

Soil Metabolite, In Bile-Duct Cannulated Rats After Oral Administration: Final Report: 

Lab Project Number: 030AM08: 1066-99. Unpublished study prepared by Novartis Crop 

Protection AG. 42 p. {OPPTS 870.7485} 

44931717 Muller, T. (1997) Disposition of (Phenyl-U-(carbon-14)) CGA-376944, A Sulfonic Acid 

Soil Metabolite of CGA-77102 in the Rat: Final Report: Lab Project Number: 030AM06: 
Page 60 of 60

795-97. Unpublished study prepared by Novartis Crop Protection AG. 37 p. {OPPTS 

870.7485} 

85-2 Dermal penetration

MRID Citation Reference

41833102 Murphy, T. (1987) Dermal Absorption of Metolachlor in Rats: Lab Project Number: ABR87051. Unpublished study prepared by Ciba- Geigy Corp. in coop. with WIL Research, 

Inc. 120 p. 

85-3 Dermal Penetration/Absorption

MRID Citation Reference

40732105 Murphy, T. (1987) Dermal Absorption of (Inert Ingredient) in Rats: Laboratory/Study No. 

ABR-87086. Unpublished study prepared by Ciba- Geigy Corp. 69 p.