Page 1 of 60 UNITED STA

TES ENVIRONMENTA L 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 - M etolachlor

on Bushberry , Caneberry , Carrot , Cucumber; L eafy Brassica Greens, Melon , Okra , Bulb and Green Onion , Sesame Seed , Sorghum , and Turnip Greens PC Code: 108800 DP Barcode: 3 68726 Decision No.: 418569 Registration No. : 100 - 816, 100 - 818 Petition No.: 6E7607 Regulatory Action: Section 3 Risk Assessment Type: Sin gle Chemical Case No.: 0001 T XR No.: NA CAS No.: 87392 - 12 - 9 MRID No.: NA 40 CFR: 180.368 

### FROM: Becky

Daiss, Biologist Susan Hummel, Chemist Iv an 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 a ssessment of proposed new uses of S - metolachlor on the following crops; bushberry , caneberry , carrot, cucumber , l eafy B rassica greens , m elon , bulb and green onion, s esame s eed , s orghum , turnip greens . Supporting documents are listed below. Res idue Chemis try

Assessment S. Hummel (D 369005, 6/ 15 /10 ) Dietary Exposure and Risk Assessment, B.Daiss (D 370429 , 6/ 30 /10 ) O ccupational and Residential Exposure and Risk Ivan (D 370432 , 6/29 /10 ) Drinking Water Assessment (D368735, C. Koper, 4/22/10). 

### TABLE OF CONTENTSPage 2 of 60 

### pg.

1.0 EXECUTIVE SUMMARY ................................ ................................ ................................ .. 4 2.0 IN GREDIENT PROFILE ................................ ................................ ................................ .... 7 2.1 Registered Products ................................ ................................ ................................ ............. 7 2.2 Proposed New Uses ................................ ................................ ................................ ............. 8 2.3 Structure, Nomenclature an d 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 ................................ ................................ ....................... 1 2 3.2.2 Reproductive Toxicity ................................ ................................ ........................... 1 4 3.2.3 Pre - and/or Postnatal Toxicity ................................ ................................ ................. 1 5 3.2.4 Immunotoxicity ................................ ................................ ................................ ..... 15 3.2.5 Neurotoxicity ................................ ................................ ................................ ......... 15 3.2.6 FQPA Factor ................................ ................................ ................................ .......... 1 6 3. 3 Toxicity

Endpoint Selection ................................ ................................ .............................. 1 6 3.3.1 Acute Reference Dose

– General Population ................................ ........................ 16 3.3.2 Chronic Reference Dose

– All Populations ................................ .......................... 17 3.3.3 In cidental 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 Carcino genic Potential ................................ ................................ 19 3.4 Margins of Exposure ................................ ................................ ................................ .......... 19 3.5 Recommen dation for Aggregate Exposure ................................ ................................ ........ 19 3.6 Summary

of Endpoints Selected for Risk Assessment ................................ ...................... 20 3.7 Endocrine Disruption ................................ ................................ ................................ ......... 21 4.0 DIETARY AND DRI NKIN G WATER EXPOSURE ASSESSMENT ............................ 21 4.1 Prop osed and Registered Food Uses ................................ ................................ .................. 21 4. 2 Residue Chemistry Profile ................................ ................................ ................................ . 2 2 4. 2 .1 Metabolism in Primary Crops and Livestock ................................ ......................... 22 4.2.2 M etabolism in Rotational Crops ................................ ................................ ............ 23 4.2.3 Residue Analy

tical Method ................................ ................................ .................... 23 4. 2 . 4 Resi dues in Crops ................................ ................................ ................................ .. 24 4.2.5 Residues in L ivestock ................................ ................................ ............................ 2 5 4.2. 6 Residues in Processed Commodities ................................ ................................ ..... 25 4.2. 7 Residues in Rotational Crops ................................ ................................ ................. 25 4. 3 Drinking Water Profile ................................ ................................ ................................ ...... 2 6 4.2.1 Environmental Fate and Transport ................................ ................................ ......... 2 6 4.2.2 Estimated Drinking Water Concentrations ................................ ............................ 2 6Page 3 of 60



### 4. 4 Dietary

and Drinking Water Exposure and Risk ................................ ................................ 2 6 5.0 AGGREGATE EXPOSURE AND RI SK ASSESSMENT ................................ ............... 28 6.0 O CCUPATI ONAL EXPOSURE AND RI SK ................................ ................................ ... 29 6.1 Exposure Scenarios ................................ ................................ ................................ ............ 29 6.1. 1 Handler Exposure Scenarios ................................ ................................ .................. 29 6.1.2 Post Application Exposure Scenarios ................................ ................................ .... 29 6.2 Occ upational 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 Handle r Exposure and Risk Estimates ................................ ................................ ... 31 6.3.2 Post - Applicatio n Exposure and Risk Estimates ................................ ..................... 32 7.0 CUMULATIVE RI SK ................................ ................................ ................................ ....... 30 8.0 DATA NEEDS ................................ ................................ ................................ ................... 33 8.1 T oxicity

Data Requirements ................................ ................................ .............................. 33 8.2 Residu e Chemistry Data Requirements ................................ ................................ ............. 33 APPENDI CES 1.0 GUIDELINE TOXICOLOGY DATA SUMMARY ................................ .......................... 34 1.1 Guideline Data Requirements ................................ ................................ ................ 34 1.2 Toxicity

Profiles ................................ ................................ ................................ ..... 35 2.0 STUDIES REVIEWED F OR ETHI CALCONDUCT ................................ ...................... 45 3. 0 CHEMI CALNAMES AND STRUCTURES OF METABOLIT ES ................................ . 46 4.0 REFERENCES FOR TOXI CI TY STUDIES ................................ ................................ ..... 4 8
1.0 EXECUTIVE SUMMARY This assessment provides information to support the issuance of an amended Section 3 registration for the use of S - met ola chlor 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), o kra, 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 ProfilePage 4 of 60



### Registered Uses Metolachlor (PC Code 108801) is a racemic herbicide that consists of 50% each of the R enantiomer and the S

- enantiomer. The S

- enantiomer is the herbicidally active isomer. S met olachlor (PC Code 108800) is an isomer enriched formula comprised of 88% S - isomer and 12% R - isomer. S - metolachlor is registered by Sy ngenta. Permanent tolerances are established at 40 CFR §180.638(a)(2) for S - metolachlor in/on a variety of crop commoditi es, 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, commerc ial 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 method s 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 (PHI s) 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 postemergenc e 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; PHI s of 64 days for carrot, 30 days for cucumber and leafy Brassica greens, 60 days for mel ons, 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 ap plication 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 to xicity

for S - metolachlor. The toxicology database for S - metolachlor, when combined with the metolachlor database, is complete for risk assessment purposes.Page 5 of 60



### S - M etolachlor exhibits low acute toxicity via the oral (Toxicity

Category III), inhalation (Toxi city 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 cy togenetic 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 Requ irements. 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 d evelopmental 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 ap plication 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 post application residential h and - to - mouth exposures are not of concern. Use of Human StudiesPage 6 of 60



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

exposed to a pesticide or other chemical. The se studies, listed in Appendix 2 .0, h ave 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 L ow - In come Populatio ns," 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 r evised 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 - metol achlor on Bushberry

subgroup 13 - 07B, Caneb erry , s ubgroup 13 - 07A, Carrot, Cu cumber, Leafy brassica greens, s ubgroup 5 - B, Melon s ubgroup 9A, Okra, Onion, Bulb, subgroup 3 - 07A, Onion, green, s ubgroup 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 on ly

the sum of free and bound S - metolachlor, S - 2 - chloro -N - (2 - ethyl - 6 - methylphenyl) -N - (2 - methoxy- 1 - methylethyl)acetamide, its R enantiomer, and its metabolites, determined as the derivatives, 2 - (2 - ethyl - 6 - methylphenyl)amino 1 - propanol and 4 - (2 - ethyl - 6 - methylphenyl) - 2 - hydroxy- 5 - methyl - 3 - morpholinone, calculated as the stoichiometric equivalent of S - metolachlor:

Bushberry

subgroup 13 - 07B ................................ ....... 0.15 ppm Caneberry , s ubgroup 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, b ulb, s ubgroup 3 - 07A ................................ ..... 0.10 ppm Onion, green, s ubgroup 3 - 07B ................................ ...... 2.0 ppm Sorghum, sweet, stalk ................................ ................... 4.0 ppm Sesame, seed ................................ ............................... 0.13 ppm Turnip greens ................................ ................................ 1.8 ppmPage 7 of 60



### Upon establishment of the above tolerances, IR - 4 requests the rem oval 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 OPPI N data base. In addition there are currently 76 Section 24 Special L ocal 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 Herbic ide 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 He rbicide 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. 83.7Page 8 of 60



### 2. 2 Proposed New Use s 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, a nd 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 inter vals (PHI s) 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; PHI s of 64 days for carrot, 30 days for cucumber and leafy

Brassica greens, 60 days for melons, and 90 days for sweet sorghum are p roposed. 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 PHIwas 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 se same 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); ho wever, 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.Page 9 of 60

TABLE 2. No me nclature 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) Regu lated 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 - mo rpholine 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: Phy sical and Chemical Characteristics (DP Num: 225258) pH 7.8 at 25°C (1% aqueous dispersion) Density 1.117 g/cm3 at 20°C Water solubility (25°C) 0.48 g/L Solvent solubility (mg/L at 25°C) Miscible with methanol, acetone, toluene, n - octanol, n hexane, ethyl acetate, dichloromethanePage 10 of 60

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 d atabase 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. Insubchronic 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 o f 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. Inthe 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 fo od 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. I n male rats, there was a statistically significant trend but no pair - wise significance for liver tumors. There was no evidence of a mutagenic or cy togenetic 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 qu antitated 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. Inthe metolachlor rabbit prenatal developmental toxicity study , maternal animals had persistentPage 11 of 60



### 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 observ ed 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 d evelopmental 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 te sted. Inthe 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 beginnin g 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. Neurotoxici ty

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 th e available toxicity studies, there is no evidence for neurotoxicity

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

Data Requirements, n eurotoxicity b attery (870.6200) and i mmunotoxicity (870.7800) studies are required. 3.2.1 Developmental Toxicity 3.2.1.1 Rat Developmental Study - Metolochlor Ina prenatal developmental toxicity study (MRID 00151941), metolachlor (96.4% a.i.) in 0.5% (w/v) aqueous hydroxy methylcellulose wa s 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 develop mental effects.Page 12 of 60



### 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 treatment related toxicity , the f

inding 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 decrea sed 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

L OAEL was 1000 mg/kg/day based on an increased in cidence 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 L OAEL w as 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 Ina 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 G Ds 24 and 29, respectively . The cause of death in both animals was attributed to persistent anorexia. Two rabbits aborted, one at 120 mg/kg/day (GD 25) and another at 360 mg/kg/day (GD 17). The high dose animal had persistent anorexia. One rabbit in each group delivered prior to GD 30; the control, low - and high - dose animals on GD 29 and the mid - dose animal on GD 30. There was a treatment - related increase in the incidence of persistent anorexia in the does treated at 360 mg/kg/day , which was defined as less than one - half of the daily food allotment consumed. However, food consumption data were not provided 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

L OAEL 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 L OAEL was not established. The NOAEL was 360Page 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 carboxy methylcellulose 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 (gest ation 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 L OEL 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 R abbit Developmental Study
– S - Metolochlor Ina developmental (teratolo gy) 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 relat ed 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 d ays 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 - 2 9. 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 500Page 14 of 60



### mg/kg/day

d ose level. The maternal toxicity NOEL was 20 mg/kg/day with a L OEL 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 Ina two - generation reproduction study (MRID 00080897), metolachlor (95.4% a.i.) was administered in the diet to two consecutiv e 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 g estation 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

L OAEL was not established. The NOAEL was 1000 ppm (F0 males/females: 75.8/85.7 mg/kg/day ; F1males/females: 7 6.6/84.5 mg/kg/day ). The reproductive toxicity L OAEL 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/femal es: 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 infant s 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 p arental toxicity . Based on the results of developmental and reproductive toxicity studies, the re 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 thy

mus 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. Inthe 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 saliv ation, 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 n eurotoxicity 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 - metol achlor 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 multi generation study

in rats, and no residual uncert ainties that indicate the need for a factor, thePage 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 0015194 1). Ina 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

L OAEL 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 L OAEL 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 f or 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 meto lachlor.

3.3.2 Chronic Reference Dose (RfD)
– General Population Selected Study : Chronic Feeding Study in Dogs (MRID 43744201). Ina one year metolachlor oral feeding study in dogs, the NOAEL was 9.7 mg/kg/day and the L OAEL was 33 mg/kg/day b ased on stomach lesions in 75% of the males and by slight Acute RfD (General Population) = (NOAEL) 300 mg/kg = 3.0 mg/kg (UF) 100Page 17 of 60



### sinusoidal histiocy

tosis 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 decrea sed 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). Ina developmental study

conducted with S - metolachlor in rats the maternal toxicity NOAEL was 50 mg/kg/day with a L OAEL of 500 mg/kg/day based on increased clinical signs of toxicity , decreased body

weights and body

weight gains and reduced food consumpti on 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 L OAEL 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 Po pulation) = (NOAEL) 9.7 mg/kg = 0.097 mg/kg (UF) 100Page 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 i ncreased 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 ab out 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 ) Ina 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 phosph atase 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. T he 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 Carci nogenic 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 f or 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 - M etolachlor Route/Duration Short - Term (1 - 30 Days) Interm ediate - Term (1 - 6 Months) Long - Term (> 6 Months) Occupational (Worker) Exposure Dermal NA NA N/A Inhalation 100 10 0 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. T here are potential residential incidental oral exposures to S - metolachlor via post - application hand - to mouth exposure of children playing on treated lawns . In addit ion , dietary and incidental oral endpoints for S - metolachlor are based on common toxicological effects. Therefore, exposure s from food and non - food oral routes should be aggregated for this assess ment . 3.6 Summary of Endpoints Selected for Risk Asses sment A summary

of the endpoints selected by HED is provided below and in Tables 5 and 6 . Table 5 . Sum ma ry of Toxicological Endpoints for S - me tolachlor for Use in Dietary Hum an Health Risk Assessments Exposure/Scenario Point of

Departure Uncertainty/F QP

A Safety Factors RfD, PAD,

LOC for Risk Assessment Study and Toxicological EffectsPage 20 of 60

Table 5 . Sum ma ry of Toxicological Endpoints for S - me tolachlor for Use in Dietary Hum an Health Risk Assessments Exposure/Scenario Point of

Departure Uncertainty/F QP

A Safety Factors RfD, PAD,

LOC for Risk Assessment Study and Toxicological Effects
Acute Dietary (General Population) NOAEL =

300 mg/kg/day UF A= 10x

UF H =10x FQPA SF= 1x Acute RfD = 3.0

mg/kg/day aPAD = 3.0 mg/kg/day Developmental Toxicity Study - Rat

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 Population s) NOAEL =

9.7 mg/kg/day UF A= 10x

UF H =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 Gr oup C carcinogen with risk quantitated using a non linear (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 d etermine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LO C = level of con cern. Table 6 . Sum ma ry of Toxicological Doses and Endpoints for S - ME TOLACHLOR for Use in Residential and Occupational Hum an Health Risk Assessm ents Exposure/ Scenario Point of

Departure Uncertainty

Factors Level of

Concern for Risk Assessment Study an d Toxicological Effects Incidental Oral Short term (1 - 30 days) NOAEL=

50 mg/kg/day UF A= 10x

UF H =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 UF A= 10x

UF H =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 UF A= 10x

UF H =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 non linear (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 w as a scientific basis for including, as part of the program, the androgen and thy roid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC’s recommendation that the Program include evaluations of potential effects in wildli fe. 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 al low, 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 - metolach lor 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 propo sed uses are provided in Table 7 . Maximum rates are based on a review of active and proposed labels. Table 7 . Maxim um Application Rates for S - Metolachlor Existing and Proposed Uses Application Site Max % AI Max Single AppRate Max Se asonal 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 Pr imary Crops and Livestock The qualitative nature of metolachlor residues in plants is adequately understood based upon the adequate corn, potato, and soy bean metabolism studies. The metabolism of metolachlor involves conjugation with glutathione, breakage of this bond to form the mercaptan, conjugationPage 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. Th e 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, CGA 354743 (metolachlor ethanesulfonic acid (ESA)) and CGA - 51202 (metolachlor oxanilic acid (OA)) . Table 8 . Sum ma ry of Metabolites and Degradates to be included in the Risk Assessm ent and Tolerance Expression Matrix Residues included in Risk Assessm ent Residues included in Tolerance Expression Plants Primary Crop Parent & metaboli tes convertible to CGA 37913, CGA - 49751 Parent & 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 CGA 37913, CGA - 49751 Parent & metabolites convertible to CGA - 37913, CGA - 49751 Poultry Parent & metabolites convertible to CGA 37913, CGA - 49751 Parent & metabolites convertible to CGA - 37913, CGA - 49751 Drinking Water Parent & metabolites convertible to CGA 354743 ( 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 [ 14 

### C]metolachlor is inadequate but potentially upgradable. Additional data are required characterizing the 14 

### C - residues in plants, along with information on the percentage of the 14 

### C - residues mea sured 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

adequ ate. Although 14 

### C - residue in the representative rotational crops were adequately

identified and characterized, the [ 14 

### C] - 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, H ED concluded that the metabolism of [ 14 

### C]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 toleran ces. 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 o f metolachlor and its metabolites as either CGA - 37913 or CGA - 49751 following acid hydrolysis. IR - 4 and Sy

ngenta have proposed an LC/MS/MS enantiomer - specific method for the enforcement of the proposed tolerances, Method 1848 - 01. This method has been pre viously reviewed by

HED (DP# 296904, 4/17/06, R. L oranger). 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 i n 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 R isomers of metolachlor, its meta bolites, 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 equivalent s. Samples of crop commodities from the submitted field trial and processing studies were analy zed for residues of metolachlor and its metabolites convertible to the derivatives CGA 49751 and CGA - 37913 using GC/MS, GC/NPD, or L C/MS/MS methods. All method s 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 MethodsPage 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 (3 rd 

### 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 differen ce 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, cucumb er, 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 combi ned LLMVs (<0.13 ppm). Total metolachlor residues in/on carrots were <0.13 - <0.38 ppm (LLM V 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 met olachlor residues for mustard greens (the representative crop of the Brassica leafy greens subgroup 5B) were <0.13 - 0.562 ppm (LLM V 0.13 ppm). No field trial data were submitted to support the requested use on okra. Previously submitted residue data for f ruiting 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 d ata 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 S metolachlor residues were <0.10 ppm in/on bulb onio n ( LOQ 0.08 ). Combined residues from green onion field trials ranged were 1.8 ppm (LOQ 0.08 ). 4.2. 5 Residues in LivestockPage 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 c hanges 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 processi ng study , metolachlor residues appear to concentrate in sorghum sy rup (>1.5x processing factor). However, HED concludes that no tolerance will be required because the observed residues in sy rup (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. 1 00 - 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 groundwat er 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 Envi ronmental Fate and Effects Division (EFED) concluded there is no difference in soil sorption affinity between metolachlor and S - metolachlor. Available data suggest that metolachlor and S metolachlor are expected to be highly mobile to mobile in soil and water environments. 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 assess ment . 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 SCI GR OW 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 d ata (US EPA, 2002). Based on monitoring and modeling data, total EDWCs for peak and average surface water respectively are 219 pp b ( 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 EDW Cs (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 comb ined 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 feedsPage 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 (DEEM FCIDTM, Version 1.3), which incorporates consumption data from USDA’s Continuing Surveys of Food Intakes by

Individuals (CSFII), 1994 - 1996 and 1998. The dietary risk assessment incorporates both exposure and toxicity of S - metolachlor and met olachlor. 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 adj usted 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 supporte d S metolachlor/metolachlor food uses were conducted using conservative, Tier 1 exposure assessments. The Tier Ianalyses assume tolerance level residues for all registered uses, 100% crop treated for all commodities with existing tolerances, and default processing factors. In cases where separate tolerance listings occur for both metolachlor and S - metolachlor on the same commodity , the higher value of the two is used in the analyses. Acute and chronic dietary S metolachlor exposure and risk estimates re sulting 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 expos ure estimates for S - metolachlor are significantly

below HED’s level of concern for all supported commodities (Tables 9 and 10 ). The 95 th 

### percentile acute dietary exposure estimate for the highest exposed population subgroup, infants < 1 year old, is 0.0 5 mg/kg/day or 2% of the aPAD. The chronic dietary exposure estimate for the highest exposed population subgroup, infants < 1 year old, is 0.01 2 mg/kg/day or 1 2 % of the cPAD . Table 9 : Sum ma ry of Acute Dietary Exposure and Risk for S - me tolachlor and Meto lachlor Population Subgroup aPAD (m g/kg/day) Acute (95th Percentile) Exposure (m g/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 <1Page 28 of 60

Table 10 : Sum ma ry of Chronic Dietary Exposure and Risk for S - me tolachlor and Metolachlo r Population Subgroup cPAD (m g/kg/day) Chronic Exposure (m g/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 Inaccordance 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 ty pes 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 an d duration of exposure. There are no residential exposures for the proposed new uses of S - metolachlor analy zed for this Section 3 assessment. However, there is potential for residential exposure to S metolachlor from use of other registered products wh ich are applied to residential lawns or turf by professional applicators. Pennant MAGNUM TM 

### (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 f ields, and ornamental gardens. Since Pennant MAGNUM TM 

### 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 - to mouth 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 - met olachlor 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, drinki ng 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 - me tolachlor Population NOAEL 1

mg/kg/day LOC 2 Average F ood & Water Exposure m g/kg/day Residential Exposure 3 mg/kg/day Aggregate MOE

(food/water and residential) 4 Toddlers 50 100 0. 012 0. 0 46 8 60 1 NOAEL for incidental oral exposure.Page 29 of 60 2 The level of concern (LOC) MOE is 100, based on inter - and intra - specie s safety factors totaling 100. 3 Residential Exposure = [Incidental Oral exposure from all possible sources - combined hand - to - mo uth, object - to mo uth, 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 apply ing S metolachlor (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, applyi ng, and postapplication activities. L ong - 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 see n 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 groundbo om 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 o n 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 thePage 30 of 60



### need for a quantitative postapplication inhalation exposure assessment for S - metolachlor as ap propriate 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 dat a. 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 w ere 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 whe re 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 durat ion is short - term and intermediate - term for all workers assessed. • Maximum application rates as determined by proposed label requirements review were used for all ty

pes 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 h andlers 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 - perce ntile 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 assump tions 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 act ual use patterns including rates, timing, and areas treated would better characterize S - metolachlor risks.

Table 8 . S

- me tolachlor Short - termand Interm ediate - termInhalation Risks Exposure Scenario Crop Applic Rate a (lbs ai/A) Area

Treated b (A/day) Unit

Exposures (μg/lb ai) c Short - term d

(No respirator) Interm ediate - term e

(No respirator) Dose (m g/kg/day) MOE Dose

(m g/kg/day) MOE Mixing/Loading Em ulsifiable 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 6,200Page 32 of 60 Table 8 . S

- me tolachlor Short - termand Interm ediate - termInhalation Risks Exposure Scenario Crop Applic Rate a (lbs ai/A) Area

Treated b (A/day) Unit

Exposures (μg/lb ai) c Short - term d

(No respirator) Interm ediate - term e

(No respirator) Dose (m g/kg/day) MOE Dose

(m g/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 p er 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 B aseline level risk mitigation with no respirator. When enginee ring 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 no t 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 effe cts 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 prod uce 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 p rocedures 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 Res idue Chemistry Data Requirements

- A dditional data are required t o 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 condi tions 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 blueberr y or cranberry , would be required. (GLN 860.1500)

### Page 34 of 60

APPENDI CES 1.0 TOXICOLOGY DATA SUMMARY 1.1 Guideline Data Requirements Table 1. Guideline Data Requirem ents 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 - me tolachlor (PC Code 108800) Guideline No. Study Type MRIDs # Results Toxicity Category 870.1 100 Acute Oral - Rats 43928915 LD 50 = 3267 mg/kg (  ); 2577 mg/kg/day (  ); 2672 mg/kg/day (combined) III 870.1200 Acute Dermal - Rabbit 43928916 LD 50 = > 2000 mg/kg III 870.1300 Acute Inhalation - Rats 43928917 LC 50 = > 2.91 mg/L IV 870.2400 Primary Eye I rritation - 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 Pro file 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) N OAEL = 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 870.37 00b 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 an d TA102 and Escherichia coli WP 2 uvr

A 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. typhimuri um 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 WP 2 uvr

A. 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 WP 2 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 activatio n. 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 (9 5.6%) 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) w ere 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 cyto toxicity was seen in the hepatocytes recovered from 1 of 2 surviving males and both female survivors in the high - dose groups. Lower levels were neither toxic to the animals nor cytotoxic to the target cells. A clear dose related increase in the percentag e 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 i n 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 gen otoxic 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 vi vo / in vitro rat hepatocyte RDS/UDS assay.

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870.7485 Metabolism and pharmacokinetics 44491401 (1996) acceptable/guideline single dose of 0.5 (group B1) or 100 mg/kg (group D1) radio labeled CGA 77102; 100 mg/kg/day non radio labeled CGA 77102 for 14 days followed by 0.5 mg/kg radio labeled CGA 77102 (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 3 5 - 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 (C max); a fast rising first C max was reached at 0.25 - 1 hour post dosing which was succeeded by a second C max at 8 and at 12 - 24 hours following administration of the low and high dose, respectively. In the low dose group (B1), the first and secon d C max were nearly identical (~ 0.03  g/ml); in the high dose group (D1), the first and second C max 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 (AUC 0 - 48hr), was nearly identical (~ 0.8 mg/kg.hr) among males and females of the low dose group. Also, both sexes in the h igh dose group had similar plasma AUC 0 - 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 C max 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 well perfused organs (e.g., the heart, lungs, and spleen) in addition to the brain and bone where, after 144 hours, the leve ls 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 (especi ally RBC) which might contribute to the retarded depletion of tissue residues.

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870.7485 Metabolism and pharmacokinetics 44491402 (1996) unacceptable/guideline single dose of 0.5 (group B1) or 100 mg/kg (group D1) radio labeled CGA 77102; 100 mg/kg/day no n radio labeled CGA 77102 for 14 days followed by 0.5 mg/kg radio labeled CGA 77102 (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 - U 14 C] CGA 24705 (R / S- metolachlo 

### r , racemate) The 72 hour mean recovery of radioactivity in urine, feces, and carcass following administration of 0.5 mg/kg of [Phenyl - U 14 C] CGA - 24705 was 43.1%, 47.0%, and 7.4% in males and 54.0%, 39.4%, and 4.1% in females, respectively. In contrast, both sexes excreted more of the label in the feces (M:F 59.7%:53.4%) than in the urine (M:F 29.4%:39.8%) during the same period following administration of the same dose of [Phenyl - U 14 C] CGA 77102 (the S- enantiomer) (MRID 4449 1401). 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 s ex 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 (CGA 24705) than the S- metolachlor (CGA - 77 102); 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, fo r 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 inclu ding F1, F3, F5, F6, F7, F8, and F13 were influenced by the sex regardless of the dose level (e.g. B1 vs. D1) or the stereochemical make - up of Metolachlor (B1 vs. B2). Other metabolite fractions were dependent on both the sex and the chemical formulation as, for instance, in the case of metabolite U2 which, relative to the opposite sex within the same group, was more abundant in the urine of the females of Group B2 (CGA - 24705) and in the urine of the males of Group B1 (CGA 77102). The bile fluid accounted for 79.8% of the administered low or high dose of CGA - 77102 (Groups G1 and G2) where the 2D - TLC showed 14 biliary metabolite fractions (G1 - G14) in the high dose Group and only six metabolites in the low dose Group. The two metabolite fractions G7 and G8 accounted, respectively, for 33.3% and 9.6% of the administered low dose and 31.3% and 14.6% of the administered high dose. Other major biliary metabolites were G3, G9, and G10 which accounted for about 5%, 5 - 7%, and 3 - 5%, respectively, of either dose gro up. 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 dat a 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 di fferences 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 ad equacy 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 co mment 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 pp m 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 decre ased 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)

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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 obse rvations (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 (F 0 males: 0, 2.4, 23.5 and 75.8 mg/kg/day; F 0 females: 0, 2.5, 26.0 and 85.7 mg/kg/day; F 1 males: 0, 2.3, 23.7 and 76.6 mg/kg/day; F 1 females: 0, 2.6, 25.7 and 84.5 mg/kg/day). Parental toxicity NOAEL = 1000 ppm (F 0 males/females: 75.8/85.7 mg/kg/ day; F 1 males/females: 76.6/84.5 mg/kg/day). Parental toxicity LOAEL was not established Reproduction toxicity NOAEL = 1000 ppm (F 0 males/females: 75.8/85.7 mg/kg/day; F 1 males/females: 76.6/84.5 mg/kg/day). Reproduction toxicity LOAEL was not established Offspring NOAEL = 300 ppm (F 0 males/females: 23.5/ 26.0 mg/kg/day; F 1 males/females: 23.7/25.7 mg/kg/day). Offspring LOAEL = 1000 ppm (F 0 males/females: 75.8/85.7 mg/kg/day; F 1 males/females: 76.6/84.5 mg/kg/day) based on decreased body weight. 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.

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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 foo d 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 500 0 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; how ever, 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

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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 - methyl hydroxyacetanilide), in which N - dealkylation of R 1 (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 R 1 has been split and oxidized to the correspon ding carboxylic acid, while R2 is similar to R2 found 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 r adioactivity 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 altere d 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 l ow (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 [ 14 C] metolachlor was essentially complete within 48 to 72 hours after dosing. Low - and high - dose females eliminated 14 C more rapidly (p<0.003, halflives of elimination, 16.6 and 15.6 hours, respectively) than low - and high dose males and repeated - dose an imals 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 14 C administered was recovered from the urine within 7 days; similar amounts wer e 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 14 C 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 14 C (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 approximatel y 1.6 to 2.5 percent of the 14 C dose; tissues of high dose rats accounted for 3.2 (females) and 4.2 (males) percent. For all groups, most of the tissue radioactivity (1.1 to 3.0 percent of the dose) was associated with red blood cells (RBCs); RBCs also contained the highest concentrations of 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 [ 14 C] 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 cont ained the smallest amounts of radioactivity (0.004 to 0.015 ppm, low - and repeated dose rats; 1.7 to 3.5 ppm, high - dose rats). Tissue 14 C 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 14 C levels of females were, in general, proportionate to dose. Tissues of low - and repeated - dos e rats contained similar amounts of radioactivity. These data indicate that some 14 C 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 [ 14 C] metolachlor.

### Page 44 of 60

Table 2 . Toxicity Profile for Metolachlor (PC Code 108801) Guideline No./ Study Type MRID No. (year)/ Classification /Doses Results 870.74 85 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), 14 C - Metolachlor was administered orally in PEG - 200 [HWI 6117 - 208] o r 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 male s. 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 C GA - 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 w as 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 i n 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 STUD IES 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 Febr uary , 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: Fi nal Report: Lab Project Number: F - 00193. Unpublished study prepared by

Ciba Crop Protection. 438 p. 43928923 Chang, J. (1995) 13 - We ek Oral Toxicity in Rats: CGA- 77102 Technical: Lab Project Number: F - 00191. Unpublished study prepared by

Ciba Crop Protect ion. 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

Lim ited. 298 p. 44931709 Altm ann, B. (1999) 3 - Month Subchronic, Compar ative 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 Teratolo gy Study of CGA- 77102 Technical in New Zealand W hite 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): L ab

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

Lim ited. 28 5 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: Salm onella and Escerichia/Mammalian Microsome 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 Sy nthesis in

Rat Hepatocy

tes: L ab Project Number: 941062: 94 - 50: 300202. Unpublished study prepared by

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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

Lim ited. 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

Lim ited. 74 p. 44931712 Ogorek, B. (1996) Salmonella and Esch erichia/Mammalian - Microsome Mutagenicity

Test: CGA- 354743: Final Report: Lab Project Number: 951133: 813 - 95. Unpublished study prepared by

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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 Hepatocy tes (OECD Conform) In Vitro: CGA- 354743: Final Report: Lab Project Number: 981017: 1189 - 98. Unpublished study

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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. Unpublishe d study

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Novartis Crop Protection Ag. 48 p. {OPPTS 870.5300} 85 - 1 General m etabolism MRID Citation Reference 44491401 Muller, T. (1996) Absorption, Distribution, and Excretion of (Pheny l - U - (carbon 14)) CGA 77102 in the Rat: Lab Pro ject 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 (Pheny l - U - (carbon 14)) CGA - 77102 and (Pheny l - U - (car bon 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 Admini stered (Pheny l - 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 (Pheny l - U - (carbon - 14)) CGA- 376944, A Sulfonic Acid

Soi l 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 (Pheny l - 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

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### 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 Bi ologiques, 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 Reche rches 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 Voi e Orale du Produit CGA 24 705. Three - Month Dietary

Feeding Study

in Rats: CGA 24 705: IC - DREB - R 74 1009|. (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 Investig ations 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 - mi tted by

Ciba - Geigy

Corp., Greensboro, N.C.; CD L: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 - Mo nth 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 C orp., 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 Ciba Geigy 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 d e 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 Ciba Geigy 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 Divis ion. 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 Sc hneider, 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

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Lim ited. 298 p. 44931709 Altm ann, B. (1999) 3 - Month Subchronic, Comparat ive 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 Fo od): CGA- 354743: Final Report: Lab Project Number: 971142: 1187 - 98. Unpublished study

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Novartis Crop Protection AG. 575 p. 82 - 2 21 - day derm al - rabbit/rat MRID Citation Reference 15536 Bach, K.J. (1974) Final Report: Twenty- One Day R epeated 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) 418 33101 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

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Corp. 173 p. 42563401 Breckenridge, C. (1992) Metolachlor: Sup plem ent 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 Bio Test 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 c ooperation 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 w ith Metolachlor: IBT No. 622 - 07925. Sum ma ry

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. 6 22 - 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 Beagl e 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 Toxici ty 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 Fr iess, 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 C iba - Geigy

Corp., Greensboro, N.C.; CDL:244167 - A) 84005 Tisdel, M.; Jackson, T.A. (1981) Two - ye ar Chronic Oral Toxicity and Oncogenicity

Study with Metolachlor Technical in Albino Rats: Raltech Study No. 80030. One - ye ar 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 toxici ty

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.; Ma cW illiam s, P.; et al. (1983) Two - ye ar 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 - G eigy

Corp., Greensboro, NC; CDL: 250369 - A; 250370; 250371; 250372; 250373; 250374; 250375) 130776 Ciba - Geigy Corp. (1979) Two - ye ar Chronic Oral Toxicity Study with CGA- 24705 Technical in Albino Rats: Study No. 8532 - 07926. (Com - pilation; unpublished stud y 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 Re port. Unpublished study prepared by

Hazelton Laboratories America, Inc. 54 p. 153880 Ciba - Geigy Corporation. (19??) Two - ye ar Chronic Oral Toxicity Study Albino Rats: [CGA- 24705 Technical: IBT No. 853207926]. Unpub - lished study . 677 p. 158924 Tisdel, M . (1985) Two - ye ar 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 - ye ar 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 Laboratori es. 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

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Corporation. 7 p.

### Page 54 of 60

40560801 Jessup, D. (1980) A Supplement to Two - ye ar Chronic Oral Toxi city 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 W eek 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 - We ek Oral Toxicity Study in Dogs: Final Report Amendment No. 2: Lab Project Number: MIN/862253. Unpublished study

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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: St atistical 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 : M etolachlor 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 Anim al Medicine, submitted by Ciba - Geigy

Corp., Greensboro, N.C.; CDL:2 42941 - 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 , rec eived 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 T echnical 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 m ice treated with CGA 24705|. (Unpublished study received Jan 19 , 1977 under 100 - 583; prepared by Industrial Bio - Test Laboratories, Inc., sub - mi tted by

Ciba - Geigy

Corp., Greensboro, N.C.; CDL:095768 - G) 117597 Tisdel, M.; MacW illiam s, 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 Am erica, Inc., submitted by Ciba Geigy Corp., Greensboro, NC; CDL:248722 - A; 248723; 248724; 248725) 126006 Hansen, W .; Jacobson, K. (1966) Ch ronic 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 Branc h, submitted by Califor- nia, Dept. of Agriculture, Sacramento, CA; CDL:092730 - E) 129377 Tisdel, M.; Jackson, T.; MacW illiam s, P.; et al. (1983) Two - ye ar 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 Ora l 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 - ye ar 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. 4 5 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 W hite 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 (...) A dm inistered Orally Via Gavage to (...) Presumed Pregnant Rats: Final Report: Project No. 203 - 004. Unpublished study prepared by

Argus Research Laboratories, Inc. 178 p.

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40775701 Morseth, S. (1986) Amendment I to Report: Rabbit Teratology Study : (Inert In gredient) 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

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Lim ited. 285 p. 44931711 Doubovetzky , M. (1999) CGA- 354743 Technical: Rat Oral Teratogenicity : CGA- 354743:

Final Repo rt: 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: Th ree Generation 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 Ciba Ge igy Corp., Greensboro, N.C.; CDL:096718 - A) 80897 Sm ith, 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 W hit taker 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 ?Three generation reproduction study in albino rats with CGA 24705: First generation results|. (Unpublished study

re - ceived Jan 19, 1977 under 100 - 583; prepared by Industrial Bio Test Laboratories, Inc., submitted by Ciba - Geigy

Corp., Greens - boro, N.C.; CDL:095768 - K) 92453 Mennear, J.H. (1978) Le tter sent to Dary l Sum ner 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 N um ber: 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 Cy totoxic or Mutagenic Effects on Male G erminal Cells. (Unpublished study including addendum , received Jan 18, 1978 under 100 - 583; prepared by Ciba - Geigy , Ltd., submitted by

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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

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