UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                      OFFICE OF
                                                            CHEMICAL SAFETY AND
\* MERGEFORMAT
                                                           POLLUTION PREVENTION

MEMORANDUM

Date: August 15, 2013

SUBJECT:	S-Metolachlor, PP#2F8115.  Human Health Risk Assessment for the petition for higher tolerances on Corn, field, forage; Corn, sweet, forage; and Corn, stover

PC Code:  108800
DP Barcode:  D411153
Decision No.:  471357
Registration No.:  100-818
Petition No.:  2F8115
Regulatory Action:  Petition, no amended use
Risk Assessment Type:  NA
Case No.:  0001
TXR No.:  NA
CAS No.:  87392-12-9
MRID No.:  48932501
40 CFR:  180.368 (a)(2)

FROM:	Susan V. Hummel, Senior Chemist
		Thurston G. Morton, Dietary
		Angela Howard, Ph.D., DABT, Toxicologist
            Ivan Nieves, ORE
		Risk Assessment Branch 4, Health Effects Division, 7509P

THROUGH:	Elissa Reaves, Ph.D., Chief
		Risk Assessment Branch 4, Health Effects Division, 7509P

TO:		Michael Walsh, PM#23
		Fungicides Branch, Registration Division, 7505P

S-Metolachlor (an isomer enriched form of metolachlor) is a selective, chloroacetanilide herbicide that is applied to a variety of crops as a preplant, preplant incorporated, preemergence, or postemergence application, primarily for the control of grass weeds.  S-Metolachlor is registered to Syngenta Crop Protection, Inc. for use on a wide variety of crops including: corn, cotton, grasses grown for seed, legume vegetables, peanuts, potatoes, safflower, sorghum, sunflower, and tomatoes.  This document presents the human health risk assessment for the S-metolachlor higher tolerances on corn forage and stover.  No amended Section 3 registration is requested.

Pesticide petition #2F8115 was submitted to amend the established tolerances for the herbicide S-metolachlor in or on corn, field, forage; corn, sweet, forage; and corn, stover to 20 ppm; 40 ppm; and 40 ppm, respectively. The use pattern used was the currently registered use pattern for Dual II Magnum (EPA Reg. No 100-818).  Residues of S-metolachlor in some samples of forage and stover exceeded the current tolerances.

TABLE OF CONTENTS
1.0	Executive Summary	4
2.0	HED Recommendations	8
2.1	Data Deficiencies	8
2.2	Tolerance Considerations	8
2.2.1	Enforcement Analytical Method	8
2.2.2	Recommended Tolerances	8
2.2.3	Revisions to Petitioned-For Tolerances	9
2.2.4	International Harmonization	9
2.3	Label Recommendations	9
3.0	Introduction	9
3.1	Chemical Identity	9
3.2	Physical/Chemical Characteristics	11
3.3	Pesticide Use Pattern	11
3.4	Anticipated Exposure Pathways	11
3.5	Consideration of Environmental Justice	12
4.0	Hazard Characterization and Dose-Response Assessment	12
4.1	Toxicology Studies Available for Analysis	12
4.2	Absorption, Distribution, Metabolism, & Elimination (ADME)	13
4.2.1	Dermal Absorption	13
4.3	Toxicological Effects	14
4.4	Safety Factor for Infants and Children (FQPA Safety Factor)	15
4.4.1	Completeness of the Toxicology Database	16
4.4.2	Evidence of Neurotoxicity	16
4.4.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal	17
4.4.4	Residual Uncertainty in the Exposure Database	17
4.5	Toxicity Endpoint and Point of Departure Selections	18
4.5.1	Dose-Response Assessment	18
4.5.2	Recommendation for Combining Routes of Exposures for Risk Assessment	19
4.5.3	Cancer Classification and Risk Assessment Recommendation	19
4.5.4	Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment	19
5.0	Dietary Exposure and Risk Assessment	21
5.1	Metabolite/Degradate Residue Profile	21
5.1.1	Summary of Plant and Animal Metabolism Studies	21
5.1.2	Summary of Environmental Degradation	22
5.1.3	Comparison of Metabolic Pathways	22
5.2	Food Residue Profile	23
5.3	Water Residue Profile	23
5.4	Dietary Risk Assessment	24
5.4.1	Description of Residue Data Used in Dietary Assessment	24
5.4.2	Percent Crop Treated Used in Dietary Assessment	25
5.4.3	Acute Dietary Risk Assessment	25
5.4.4	Chronic Dietary Risk Assessment	25
5.4.5	Cancer Dietary Risk Assessment	26
5.4.6	Summary Table	26
6.0	Residential (Non-Occupational) Exposure/Risk Characterization	27
6.1	Residential Handler Exposure	27
6.2	Post-Application Exposure	27
6.3	Residential Bystander Post-application Inhalation Exposure	28
6.4	Spray Drift	28
7.0	Aggregate Exposure/Risk Characterization	29
7.1	Acute Aggregate Risk	29
7.2	Short-Term Aggregate Risk	29
7.3	Intermediate-Term Aggregate Risk	30
7.4	Chronic Aggregate Risk	30
7.5	Cancer Aggregate Risk	30
8.0	Cumulative Exposure/Risk Characterization	30
9.0	Occupational Exposure/Risk Characterization	31
10.0     Human Studies	31
11.0	References	32
Appendices
A.1	Toxicology Data Requirements	33
A.2	Toxicity Profiles	34
A.3	Hazard Identification and Endpoint Selection	47
A.4	Executive Summaries	49
Appendix B.  Metabolism Summary	61
Appendix C.  Physical/Chemical Properties	63

1.0	Executive Summary

Metolachlor (PC Code 108801) is a racemic herbicide that consists of 50% each of the R-enantiomer and the S-enantiomer which is the herbicidally active isomer.  S-Metolachlor (an isomer enriched form of metolachlor, comprised of 88% S-isomer and 12% R-isomer) is a selective, chloroacetanilide herbicide that is applied to a variety of crops as a preplant, preplant incorporated, preemergence, or postemergence application, primarily for the control of grass weeds.  S-Metolachlor is registered to Syngenta Crop Protection, Inc. for use on a wide variety of food and feed crops including: corn, cotton, grasses grown for seed, legume vegetables, peanuts, potatoes, safflower, sorghum, sunflower, and tomatoes.  In addition, S-metolachlor is registered for use on residential lawns, commercial turf (including golf courses, sports fields, recreation areas, and sod farms), ornamentals and horticultural nurseries. S-metolachlor formulations include emulsifiable and flowable concentrates, granular, and ready-to-use products. Application methods for agricultural uses include ground, aerial, irrigation and chemigation. Applications of S-metolachlor to residential lawns or turf are limited to professional applicators using backpack, hose-end, or handgun sprayers.

Pesticide petition #2F8115 was submitted to amend the established tolerances for the herbicide S-metolachlor in or on corn, field, forage; corn, sweet, forage; and corn, stover to 20 ppm; 40 ppm; and 40 ppm, respectively. No amended Section 3 registration is requested.  The use pattern used was the currently registered use pattern for Dual II Magnum (EPA Reg. No 100-818).  Residues of S-metolachlor in some samples of corn forage and stover exceeded the current tolerances.  Since corn forage and stover are livestock feedstuffs, and the increase in these tolerances does not change the dietary burden sufficiently to require a change in any tolerance on a food commodity, no new dietary exposure assessment was conducted, and no occupational exposure assessment was required.  However, an updated residential exposure assessment was conducted, and is included herein, since the Residential SOPs have changed since the last residential assessment was conducted in 2002.

Toxicology
The existing toxicological database is primarily comprised of studies conducted with metolachlor. However, bridging studies indicate that the metolachlor toxicology database can be used to assess toxicity for S-metolachlor. The toxicology database for S-metolachlor, when combined with the metolachlor database, is complete for risk assessment purposes, with the exception of a required 28 day inhalation study.  The neurotoxicity battery (870.6200 a and b) is required in accordance with the revised 40 CFR Part 158 Toxicology Data Requirements.  The data requirement for neurotoxicity studies has been waived at the present time by the Hazard and Science Policy Council (HASPOC) in their meeting of February 14, 2013 (JVanAlstine, 2013).

S-Metolachlor exhibits low acute toxicity via the oral (Toxicity Category III), inhalation (Toxicity Category IV), and dermal (Toxicity Category III) routes of exposure. It causes slight eye irritation, and is non-irritating to the skin, but is a dermal sensitizer. In subchronic (metolachlor and S-metolachlor) and chronic (metolachlor) toxicity studies in dogs and rats decreased body weight and body weight gain were the most commonly observed effects. No systemic toxicity was observed when metolachlor was administered dermally. No neurotoxicity studies with metolachlor or S-metolachlor are available. However, there was no evidence of neurotoxic effects in adult animals in available subchronic and chronic toxicity studies.  Prenatal developmental studies in the rat and rabbit with both metolachlor and S-metolachlor revealed no evidence of a qualitative or quantitative susceptibility in fetal animals. A two-generation reproduction study with metolachlor in rats showed no evidence of parental or reproductive toxicity. The FQPA safety factor was reduced to 1X because there are no residual uncertainties with regard to pre- and/or postnatal toxicity.

Metolachlor has been evaluated for carcinogenic effects in the mouse and the rat. Metolachlor did not cause an increase in tumors of any kind in mice. In rats, metolachlor caused an increase in benign liver tumors in rats but this increase was seen only at the highest dose tested and was statistically significant compared to controls only in females.  There was no evidence of mutagenic or cytogenetic effects in vivo or in vitro.  Based on this evidence, EPA has concluded that metolachlor does not have a common mechanism of carcinogenicity with acetochlor and alachlor which are structurally similar. Taking into account the qualitatively weak evidence on carcinogenic effects and the fact that the increase in benign tumors in female rats occurs at a dose 1,500 times the chronic reference dose (RfD), EPA has concluded that the chronic RfD is protective of any potential cancer effect.

Dose Response Assessment
Toxicological endpoints were selected for dietary/drinking water, occupational and residential exposure scenarios. An acute reference dose (RfD; 3.0 mg/kg/day) for assessment of food and drinking water exposures was selected from a developmental toxicity study in rats (NOAEL = 300 mg/kg/day). A chronic RfD (0.097 mg/kg/day) was selected from a chronic toxicity study in dogs (NOAEL = 9.7 mg/kg/day).  A short-term incidental oral POD (NOAEL = 50 mg/kg/day) was selected from a developmental toxicity study in rats.  A point of departure (POD) for dermal exposure was not selected because no dermal or systemic toxicity was seen in rabbits following repeated dermal application at the highest dose tested for 21 days. A short-term inhalation exposure POD (50 mg/kg/day) was selected from a developmental toxicity study in rats.  An intermediate-term inhalation exposure POD (8.8 mg/kg/day) was selected from a subchronic toxicity study in dogs.  An uncertainty factor of 100X was applied to endpoints selected for the oral exposure route (10x for interspecies extrapolation, 10x for intraspecies variation) and an uncertainty factor of 1000X was applied to endpoints selected for the inhalation exposure route due to a missing route-specific study (10x for interspecies extrapolation, 10x for intraspecies variation, 10x for database).

Residue Chemistry
The qualitative nature of metolachlor residues in plants is adequately understood.
Residues of concern in plants, livestock, and rotational crops include metolachlor and its
metabolites, determined as the derivatives CGA-37913 and CGA-49751. The Agency
previously concluded that the residues of concern for S-metolachlor are the same as for
metolachlor. The residues of concern for S-metolachlor in drinking water include the parent, CGA-354743 (metolachlor ethanesulfonic acid (ESA)) and CGA-51202 (metolachlor oxanilic acid (OA)).

Adequate methodology is available for enforcing the established and recommended tolerances. PAM Vol. II, Pesticide Regulation Section 180.368, lists a gas chromatography with nitrogen-phosphorus detector (GC/NPD) method (Method I) for determining residues in/on plant commodities and a gas chromatography with mass selective detector (GC/MSD) method (Method II) for determining residues in livestock commodities. These methods determine residues of metolachlor and its metabolites as either CGA-37913 or CGA-49751 following acid hydrolysis. Adequate data are also available on the recovery of metolachlor through FDA's Multiresidue Method Testing Protocols which indicate that metolachlor is completely recovered through Method 302.

Syngenta has proposed a high pressure liquid chromatography with mass spectroscopy/mass spectroscopy (HPLC/MS/MS) enantiomer-specific method for the enforcement of the proposed tolerances, Method 1848-01. The method uses a chiral HPLC column to separate out the S-enantiomers (SYN506357 and SYN508500) of the hydrolysis products CGA-37913 and CGA-49751. This method has not been determined to be adequate for enforcement purposes because it monitors only a single ion transition per analyte.

Adequate field trial data have been submitted with the current petition to support the requested tolerances.  Geographic representation was adequate.  An adequate analytical method was used for the analysis.  The data were properly supported by storage stability data.

An adequate confined rotational crop study is available, although additional information
pertaining to the study remains outstanding.

Dietary Exposure Including Drinking Water
No changes are proposed to any S-metolachlor use pattern or food tolerances.  Therefore, there is no change to the dietary exposure, including the drinking water exposure.

For acute and non-cancer chronic exposures, EPA is concerned when estimated dietary risk exceeds 100% of the population adjusted dose (PAD).  S-metolachlor is classified as a Group C carcinogen, no separate dietary assessment was performed for cancer, since the chronic dietary exposure is considered protective for cancer effects.  For acute and chronic dietary exposures an unrefined assessment was conducted, assuming 100% crop treated, and tolerance level residues.  The acute and chronic dietary risk estimates are below the Agency's level of concern for the general U.S. population and all population subgroups with the most highly exposed subgroups being all infants (<1 year old) at 1.5% of the acute PAD (aPAD) and 11.6% of the chronic PAD (cPAD).

Environmental fate data indicate that parent metolachlor/S-metolachlor is moderately persistent to persistent.  It is mobile to highly mobile in different soils and has been detected extensively in surface water and groundwater.  Major degradates identified in groundwater include metolachlor ethanesulfonic acid (ESA) and metolachlor oxanilic acid (OA) in both groundwater and surface water.  Environmental Fate and Effects Division (EFED) calculated conservative, Tier I Estimated Drinking Water Concentrations (EDWCs) of metolachlor and S-metolachlor in ground water and surface water for use in the last human health risk assessment.

EDWCs for metolachlor and S-metolachlor were calculated for both the parent compound, metolachlor ESA and metolachlor OA degradates (see metabolites table, Appendix 1).  EDWCs were calculated using drinking water models PRZM/EXAMS and FIRST for surface water and SCIGROW for ground water.  Current NAWQA monitoring data was also used to determine EDWCs.  Based on monitoring and modeling data, total EDWCs for peak and average surface water respectively are 219 ppb and 119 ppb.  Recommended groundwater EDWCs (peak and average) are 126 ppb.

Residential Exposure
There are no new residential exposure scenarios for S-metolachlor for the current petition.  However, there is potential for residential exposure to S-metolachlor from use of other registered products which are applied to residential lawns or turf by professional applicators.  Therefore, the only potential short-term residential risk scenario anticipated is post-application exposure of children playing on treated lawns.  The residential exposure to toddlers for this scenario was estimated to be 0.0609 mg/kg/day resulting in an MOE of 820.  Based on this analysis, the short-term oral MOEs are not of concern.

Aggregate Risk
The aggregate acute and chronic risk estimates include exposure to residues of S-metolachlor in food and drinking water, and does not include dermal, inhalation or incidental oral exposure.  Since the dietary exposure assessment already includes the highest acute and chronic exposures from the drinking water modeling data, no further calculations are necessary.  The acute and chronic risk estimates for all populations, resulting from aggregate exposure to S-metolachlor in food and drinking water is below EPA's level of concern.  The food and drinking water exposure estimates for the most highly exposed subgroup, all infants (< 1 year old), is 1.5% of the aPAD and 11.6% of the cPAD.

No intermediate-term risk scenarios are anticipated for the existing and proposed uses of S-metolachlor.  However, there is potential for short-term residential exposure to S-metolachlor from use of other registered products which are applied to residential lawns or turf by professional applicators via post-application incidental oral exposure to children playing on treated lawns.  Results from that assessment have been used to assess aggregate risk from exposure to food, drinking water, and residential lawns.  Based on this analysis, short-term aggregate MOE of 660 for toddlers is not of concern.

Occupational Exposure
There are no new uses proposed in the current petition, so no occupational exposure assessment is required.  However, HASPOC has determined that a 28-day inhalation study must be conducted.  In the absence of this study, an additional 10x database uncertainty factor will be applied to any inhalation risk assessment.  The occupational exposure and risk have been previously assessed.   There are no risks of concern with the PPE required on the label.

Use of Human Studies
This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These studies have been determined to require a review of their ethical conduct.  Some of these studies are also subject to review by the Human Studies Review Board.  All of the studies used have received the appropriate review.

Environmental Justice
Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).

2.0	HED Recommendations

No change in the current registration for S-metolachlor is requested.  HED has examined the database for S-metolachlor.  Pending submission of analytical standards, there are no residue chemistry issues that would preclude setting of the recommended tolerances for S-metolachlor on corn forage and stover, as indicated in Section 2.2.2.  However, questions remain on the rotational crop study, and a 28-day inhalation study is needed for future submissions.

2.1	Data Deficiencies

Analytical reference standards are required to be submitted to the pesticide repository now and as requested by the repository staff.

A deficiency remains with regard to the confined rotational crop study.  This deficiency has been outstanding since 1994, and was reiterated in the metolachlor/S-metolachlor TRED.

2.2	Tolerance Considerations

2.2.1	Enforcement Analytical Method
Adequate methodology is available for enforcing the established and recommended tolerances. PAM Vol. II, Pesticide Regulation Section 180.368, lists a gas chromatography with nitrogen-phosphorus detector (GC/NPD) method (Method I) for determining residues in/on plant commodities and a gas chromatography with mass selective detector (GC/MSD) method (Method II) for determining residues in livestock commodities. These methods determine residues of metolachlor and its metabolites as either CGA-37913 or CGA-49751 following acid hydrolysis. Adequate data are also available on the recovery of metolachlor through FDA's Multiresidue Method Testing Protocols which indicate that metolachlor is completely recovered through Method 302.

Syngenta has proposed a high pressure liquid chromatography with mass spectroscopy/mass spectroscopy (HPLC/MS/MS) enantiomer-specific method for the enforcement of the proposed tolerances, Method 1848-01. The method uses a chiral HPLC column to separate out the S-enantiomers (SYN506357 and SYN508500) of the hydrolysis products CGA-37913 and CGA-49751. This method has not been determined to be adequate for enforcement purposes because it monitors only a single ion transition per analyte.

2.2.2	Recommended Tolerances

Tolerances are currently established under 40 CFR §180.368 for residues of S-metolachlor, including its metabolites and degradates, in or on the commodity(s), as defined. Compliance with the tolerance levels specified in the following table below is to be determined by measuring only the sum of free and bound S-metolachlor, S-2-chloro-N-(2-ethyl-6-methylphenyl)-N-(2-methoxy-1-methylethyl)acetamide, its R-enantiomer, and its metabolites, determined as the derivatives, 2-(2-ethyl-6-methylphenyl)amino-1-propanol and 4-(2-ethyl-6-methylphenyl)-2-hydroxy-5-methyl-3-morpholinone, calculated as the stoichiometric equivalent of S-metolachlor, in or on the commodity.
The text of the current tolerance expression is in accordance with our current guidance (S. Knizner, 5/10/2009)

Recommended tolerances for S-metolachlor are summarized in Table 2.2.2. below, along with HED's recommendations on tolerance level, and commodity names.

Table 2.2.2. 	Tolerance Summary for Metolachlor.
Commodity
                                 Established/
                              Proposed Tolerance
                                     (ppm)
                                  Recommended
                                   Tolerance
                                     (ppm)
Comments;
Correct Commodity Definition
Proposed tolerances under §180.368(a)(2)
Corn, field, forage
                                      20
                                      40

Corn, sweet, forage
                                      40
                                      40

Corn, stover
                                      40
                                      40
Corn, field, stover
Corn, sweet, stover
Corn, pop, stover

2.2.3	Revisions to Petitioned-For Tolerances

The tolerance for Corn, field, forage was recommended at 40 ppm, to be consistent with the tolerance for corn, sweet, forage, since both forages would be harvested at the same time.  The tolerance for corn, stover, is changed to Corn, field, stover; Corn, sweet, stover; and Corn, pop, stover; as those are the correct commodity names.

2.2.4	International Harmonization

There are no issues with international harmonization.  Canada does not establish MRLs for pesticide residues on livestock feed stuffs.  There are no Codex MRLs established for residues of S-metolachlor.

2.3	Label Recommendations

No label changes are needed, since no change to any S-metolachlor use pattern is proposed with the current petition.

3.0	Introduction

3.1	Chemical Identity

The chemical structure and nomenclature of S-metolachlor and its regulated hydrolytic derivatives are presented in Table 3.1
Table 3.1.	Nomenclature of S-Metolachlor and its Regulated Hydrolytic Derivatives.
Parent compound

Common name
S-Metolachlor
Company experimental name
CGA-77102 (R-Metolachlor is CGA-77101)
IUPAC name
(S)-2-chloro-N-(2-ethyl-6-methyl-phenyl)-N-(2-metonym-1-methyl-ethyl)-acetamide
CAS name
2-chloro-N-(2-ethyl-6-methylphenyl)-N-[(1S)2-methoxy-1-methylethyl]-acetamide
CAS registry number
87392-12-9
End-use product (EP)
Dual Magnum(R) Herbicide (7.62 lb/gal EC; EPA Reg. No. 100-816) and
Dual II Magnum(R) Herbicide (7.64 lb/gal EC; EPA Reg. No. 100-818)
Regulated residue

Common name
None
Company experimental names
CGA-37913
SYN506357 (S-enantiomer of CGA 37913)
Chemical name
2-[(2-ethyl-6-methylphenyl) amino]-1-propanol
CAS registry number
61520-53-4
82508-08-5 (S-enantiomer)
Regulated residue

Common name
None
Company experimental names
CGA-49751
SYN508500 (S-enantiomer of CGA 49751)
Chemical name
4-(2-ethyl-6-methylphenyl)-2-hydroxy-5-methyl-3-morpholinone
CAS registry number
61520-54-5

3.2	Physical/Chemical Characteristics

S-metolachlor is fairly soluble in water (0.48 g/L), and completely miscible with typical pesticide solvents.  It has a moderately low vapor pressure (2.8 x 10[-5] mm Hg).  It does not dissociate.  It has a high octanol-water partition coefficient (Log(KOW) = 3.0 at 25 C), indicating a potential for bioaccumulation or partitioning into human milk.  Environmental fate data indicate that parent metolachlor/S-metolachlor is moderately persistent to persistent.  It is mobile to highly mobile in different soils and has been detected extensively in surface water and groundwater.  Metolachlor/S-metolachlor degradation appears to be dependent on microbially mediated and abiotic processes.  The physical-chemical properties are tabulated in Appendix C, Table C1.

3.3	Pesticide Use Pattern

THE CURRENT USE PATTERN for S-metolachlor on corn is shown below in Table 3.3.  No change to the current use pattern is proposed or recommended.
TABLE 3. 3.	Summary of Current Directions for Use of S-Metolachlor.[1]
Applic. Timing; Type; and Equip.
(minimum volume)
                                  Formulation
                                [EPA Reg. No.]
                                 Applic. Rate
                                   (lb ai/A)
                          Max. No. Applic. per Season
                          Max. Seasonal Applic. Rate
                                   (lb ai/A)
                                      PHI
                                    (days)
                                     Corn
Fall Application for Spring Control/ Early Preplant
Broadcast
                                7.62 lb/gal EC
                                   [100-818]
                                  1.6  -  1.9
                                      NS
                                      3.7
                                      NS
Preplant Incorporated or Preemergence Broadcast

                                   0.95-1.9
                                      NS
                                      3.7
                                      NS
Postemergence or Layby Broadcast

                                   Up to 1.9
                                      NS
                                      3.7
                                      NS
Use higher rates on fine or >2,5-3% organic matter soils. Split application may be used. Ground application minimum 5 GPA; aerial application minimum 2 GPA.  Do not use Dual II Magnum on peat or muck soils.  Do not graze or feed forage from treated areas for 30 days following application.  Do not harvest sweet corn ears for 60 days following application.

3.4	Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed increase in tolerances on corn forages and stovers.  No new uses are proposed in this petition.  Humans may be exposed to S-metolachlor in food and drinking water, since S-metolachlor may be applied directly to growing crops and S-metolachlor may reach surface and ground water sources of drinking water.  Dietary exposure has not changed, since no changes are recommended for tolerances in human foods.  Although no residential application scenarios exist, children may be exposed to S-metolachlor after professional application on residential turf.  The last residential risk assessment was conducted in 2002, so residential exposure is reassessed in this risk assessment.

In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application.  There is a potential for post-application exposure for workers re-entering treated fields.

RISK ASSESSMENTS HAVE BEEN PREVIOUSLY PREPARED FOR THE EXISTING USES OF S-METOLACHLOR.  THIS RISK ASSESSMENT CONSIDERS ALL OF THE AFOREMENTIONED EXPOSURE PATHWAYS BASED ON THE EXISTING USES OF S-METOLACHLOR.

3.5	Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.  As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post-application are evaluated.  Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0	Hazard Characterization and Dose-Response Assessment

4.1	Toxicology Studies Available for Analysis

The existing toxicological database is comprised primarily of studies conducted with metolachlor.  Metabolism studies were inadequate for comparing the metabolic pathways of metolachlor and S-metolachlor.  However, based on a comparison of the findings in toxicity studies with both chemicals, S-metolachlor is considered to be of comparable toxicity to metolachlor and data can be bridged between the two compounds.  The combined metolachlor and S-metolachlor toxicity data bases are adequate to characterize the toxicity of S-metolachlor for risk assessment purposes.  An immunotoxicity study (870.7800) was submitted since the last S-metolachlor risk assessment (MRID 48783301).

The toxicology database for metolachlor and S-metolachlor is complete with the exception of a required subchronic inhalation study.  Exposure to S-metolachlor is expected via the oral, dermal, and inhalation routes.  A route-specific dermal study was submitted, but no subchronic inhalation study has been submitted.

The Hazard and Science Policy Council (HASPOC) recently reviewed metolachlor and S-metolachlor (VanAlstine, Julie, 2013).  HASPOC, based on a WOE approach considering all available hazard and exposure information concludes that the acute, subchronic, and developmental neurotoxicity studies are not required at this time.  The HASPOC concluded that a subchronic inhalation study with metolachlor is required at this time.  A 10X data base uncertainty factor will be applied only for assessing risk for inhalation scenarios.

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

Metolachlor is extensively absorbed and metabolized following oral administration in the rat.  After oral or intravenous administration of metolachlor, between 69.6% and 93.2% of the administered dose was absorbed. A biphasic plasma profile with two concentration maxima (Cmax); a fast rising first Cmax was reached at 0.25 - 1 hour post dosing which was succeeded by a second Cmax at 8 and at 12 - 24 hours following administration of the low and high dose.   Elimination is via the urine and feces.  Residual radioactivity at 7 days post dose were residual carcass (0.9 - 2.2% of the administered dose) and red blood cells (0.95 - 1.53 ug equivalents/ gram in blood cells for all low dose male and female rats).  There was no apparent accumulation of residual radioactivity.

Excretion data showed that urine and feces were both significant routes for elimination of metolachlor derived radioactivity. In the low dose groups, the urine appeared more of a predominant route for excretion in female rats than in males, whereas fecal excretion was slightly higher in males. However, at the high oral dose, there were no apparent sex related differences in the pattern of urinary excretion. Examination of urinary excretion data as presented in graphical format indicated that at the 300 mg/kg dose, excretion was delayed vs the low oral dose, suggesting saturation of elimination.

The major metabolic pathway proposed from analysis of urinary as well as fecal metabolites is one of cleavage of the ether bond and subsequent oxidation to the carboxylic acid, as well as hydrolytic removal of the chlorine atom. Conjugation of metolachlor or metabolites with gluronic acid or sulfate does not appear to occur.

4.2.1	Dermal Absorption

There was no evidence of systemic toxicity at the limit dose in a 21 day dermal toxicity metolachlor study in rabbits, however dermal irritation was observed at lower doses.  A dermal absorption study is not needed.

4.3	Toxicological Effects

In subchronic oral studies on metolachlor, the only evidence of toxicity was decreased body weight/body weight gain in rats and dogs in both sexes.  There was no evidence of systemic toxicity at the limit dose in a 21 day dermal toxicity metolachlor study in rabbits, however dermal irritation was observed at lower doses.  In the chronic dog study on metolachlor, the only adverse effect was decreased body weight gain in females.

In the mouse carcinogenicity study, possible treatment-related deaths in females and decreased body weight/body weight gain in both sexes were observed.  In the rat combined chronic toxicity/ carcinogenicity study, decreased body weight gain and food consumption were observed.  There was no evidence of carcinogenicity in mice; however, there were statistically significant increases in liver adenomas and combined adenomas/carcinomas in female rats.  In male rats, there was a statistically significant trend but no pair-wise significance for liver tumors.  There was no evidence of a mutagenic or cytogenetic effect in vivo or in vitro in studies with either metolachlor or S-metolachlor.  Metolachlor has been classified as a Group C carcinogen with risk quantitated using a non-linear (Margin of Exposure (MOE)) approach.

S-Metolachlor exhibits low acute toxicity via the oral (Toxicity Category III), inhalation (Toxicity Category IV), and dermal (Toxicity Category III) routes of exposure. It causes slight eye irritation, and is non-irritating to the skin, but is a dermal sensitizer. In subchronic (metolachlor and S-metolachlor) and chronic (metolachlor) toxicity studies in dogs and rats decreased body weight and body weight gain were the most commonly observed effects. No systemic toxicity was observed when metolachlor was administered dermally. No neurotoxicity studies with metolachlor or S-metolachlor are available. The HASPOC, based on a WOE approach, concluded that a neurotoxicity battery is not required for metolachlor at this time.  This approach considered all of the available hazard and exposure information including:  1) the lack of evidence for clinical signs of neurotoxicity or neuropathology in adult animals in subchronic and chronic studies; 2) clinical signs of neurotoxicity were seen only at very high doses (Limit Dose) in pregnant rats and is used as the endpoint of concern for assessing acute dietary risk; 3) evidence for neurotoxicity (functional/behavioral effects) was seen only at high doses in acute neurotoxicity studies with structurally-related compounds (acetochlor and propachlor) and in a subchronic neurotoxicity study with acetochlor; 4) the POD and endpoint for chronic dietary risk assessment is based on effects seen in dogs which appear to be the most sensitive species; and 5) since the neurotoxicity studies will be tested at very high doses to elicit effects, they will not provide PODs lower than those currently used for overall risk assessment (JVanAlstine, 2013).
 There was no evidence of increased quantitative or qualitative fetal susceptibility in the prenatal developmental studies in rats and rabbits with either metolachlor or S-metolachlor.  In general, significant developmental toxicity was not seen in rats or rabbits with either compound.  In the metolachlor rabbit prenatal developmental toxicity study, maternal animals had persistent anorexia and decreased body weight gain.  There were no developmental effects.  In the rat prenatal developmental toxicity study on metolachlor, death, clinical signs (clonic and/or tonic convulsions, excessive salivation, urine-stained abdominal fur and/or excessive salivation) and decreased body weight gain was observed at the limit dose in maternal animals.  Developmental effects at the limit dose included slightly decreased number of implantations per dam, decreased number of live fetuses/dam, increased number of resorptions/dam and significant decrease in mean fetal body weight.  In the S-metolachlor rat study, maternal toxicity, including increased clinical signs (pushing head through bedding), and decreased body weight/weight gain, food consumption and food efficiency, was observed at the mid-dose.  There were no developmental effects at the highest dose tested.  In the rabbit, clinical signs of toxicity (little/non/soft stool) were observed at the mid-dose in maternal animals tested with S-metolachlor.  No developmental effects were observed at the highest dose tested.

In the two-generation reproduction study in rats conducted with metolachlor, there was no evidence of parental or reproductive toxicity at the highest dose tested (80 mg/kg/day).  At this dose, there was a minor decrease in fetal body weight beginning at lactation day 4.  Since a similar body weight decrease was not seen on lactation day 0, the cause of the effect on later lactation days is most likely due to exposure of the pups to metolachlor in the diet and/or milk and therefore is not evidence of an increased quantitative susceptibility in post-natal animals.

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

The chemical risk assessment team has recommended that the FQPA Safety Factor (SF) be reduced to 1X.  The toxicity database for S-metolachlor/metolachlor is sufficient for a full hazard evaluation and is considered adequate to evaluate risks to infants and children.  Acceptable developmental toxicity studies in the rat and rabbit and an acceptable reproduction study in the rat are available, along with an acceptable Immunotoxicity study.  Based on the results of the available toxicity studies, there is no evidence for neurotoxicity or immunotoxicity.

4.4.1	Completeness of the Toxicology Database

The toxicology database for metolachlor and S-metolachlor is complete with the exception of a required subchronic inhalation study.  Exposure to S-metolachlor is expected via the oral, dermal, and inhalation routes.  A route-specific dermal study was submitted, but no subchronic inhalation study has been submitted.

The Hazard and Science Policy Council (HASPOC) recently reviewed metolachlor and S-metolachlor (VanAlstine, Julie, 2013).  HASPOC, based on a WOE approach considering all available hazard and exposure information concludes that the acute, subchronic, and developmental neurotoxicity studies are not required at this time.  The HASPOC concluded that a subchronic inhalation study with metolachlor is required at this time.  A 10X data base uncertainty factor will be applied only for assessing risk for inhalation exposure scenarios.

4.4.2	Evidence of Neurotoxicity

There are no acute or subchronic neurotoxicity studies available for S-metolachlor or metolachlor.  Treatment-related effects of clonic and/or tonic convulsions, excessive salivation, urine-stained abdominal fur and/or excessive Lacrimation were observed in pregnant dams at 1000 mg/kg/day.  There was no evidence of neurotoxic effects in adult animals in available subchronic or chronic toxicity studies.  The HASPOC, based on a WOE approach, concluded that a neurotoxicity battery is not required for metolachlor at this time (JVanAlstine, 2013).

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

There was no evidence of increased quantitative or qualitative fetal susceptibility in the prenatal developmental studies in rats and rabbits or in the reproductive toxicity study in rats, with either metolachlor or S-metolachlor.  In general, significant developmental toxicity was not seen in rats or rabbits with either compound.  The only effects observed in fetal animals were in the rat prenatal developmental study and included slightly decreased number of implantations per dam, decreased number of live fetuses/dam, increased number of resorptions/dam and significant decrease in mean fetal body weight.  These effects occurred at maternally toxic doses (1000 mg/kg/day).

4.4.4	Residual Uncertainty in the Exposure Database

There is no residual uncertainty in the exposure database.  The dietary exposure assessment is conservative, based on tolerance level residues and 100% crop treated.  The residential exposure assessment is based on the Residential SOPs, which are designed to produce conservative exposure estimates.

4.5	Toxicity Endpoint and Point of Departure Selections

4.5.1	Dose-Response Assessment

The detailed description of the toxicity studies used for selecting toxicity endpoints and points of departure for various exposure scenarios are presented in the appendix.  The specific toxicity endpoints and PODs are presented in Tables <IP_ADDRESS> and <IP_ADDRESS>.  Toxicological endpoints were selected for dietary/drinking water, occupational and residential exposure scenarios.  An acute reference dose (RfD; 3.0 mg/kg/day) for assessment of food and drinking water exposures was selected from a developmental toxicity study in rats (NOAEL = 300 mg/kg/day). The endpoint of mortality and clinical signs identified in the developmental toxicity study in rats (MRID 00151941) was chosen for the acute dietary (general population) endpoint because it was considered adverse and results from a single exposure.  An endpoint was not selected for Females 13  -  49 years old because no developmental effects were identified in the metolachlor/S-metolachlor database that could be attributed to a single exposure.  A chronic RfD (0.097 mg/kg/day) was selected from a chronic toxicity study in dogs (NOAEL = 9.7 mg/kg/day).  The endpoint of decreased body weight gain identified in the chronic feeding study in dogs was chosen for the chronic dietary (all populations) endpoint because the duration of the exposure in this study is appropriate for a chronic dietary endpoint, and the database shows dogs were the most sensitive species and decreased body weight gain the most sensitive endpoint.  Use of this endpoint is therefore, protective for all adverse effects in other species that occur in higher doses and/or for shorter durations of exposure.
The registered uses of S-metolachlor/metolachlor are expected to result in residential exposure via inhalation for residential handlers and incidental oral exposure for toddlers.  A short-term incidental oral POD (NOAEL = 50 mg/kg/day) was selected from a developmental toxicity study in rats.  The endpoint of increased incidence of clinical signs and decreased body weight/body weight gain from the developmental toxicity study in rats (MRID 43928925) was identified for the short-term incidental oral endpoint.  This study was selected because the effects were judged to be signs of frank toxicity and were appropriate to use for risk assessment.  The NOAEL for the prenatal developmental toxicity study in rabbits with S-metolachlor (MRID 43928924) was lower than the 50 mg/kg/day from the rat developmental study, however, the endpoint was based on weak clinical signs of toxicity (increase in little/none/soft stool observations) at 100 mg/kg/day.  Although there was a dose-related increase in this effect, it was not considered to be evidence of frank toxicity and was judged not to be appropriate for risk assessment.
A point of departure (POD) for dermal exposure was not selected because no systemic toxicity was seen in rabbits following repeated dermal application at the highest dose tested for 21 days. No inhalation studies were available for the short-term and intermediate-term inhalation scenarios.  The HASPOC met on February 14, 2013 to discuss the need for a subchronic inhalation study for metolachlor (TXR #0056586).  The decision was made that this study is required. In the absence of a route-specific study, a short-term inhalation exposure POD (50 mg/kg/day) was selected from an oral developmental toxicity study in rats.  The endpoint of increased incidence of clinical signs and decreased body weight/body weight gain from the developmental toxicity study in rats (MRID 43928925) was identified for the short-term inhalation exposure endpoint.  This study was selected because the effects were judged to be signs of frank toxicity and the duration of exposure was appropriate for this endpoint.   An intermediate-term inhalation exposure POD (8.8 mg/kg/day) was selected from a subchronic toxicity study in dogs.  The endpoint of decreased body weight gain was selected from the subchronic oral toxicity study in dogs (MRID 00032174) was identified for the intermediate-term inhalation exposure endpoint.  This study was selected because the duration of the exposure in this study is appropriate for the intermediate-term endpoint, and the database shows dogs were the most sensitive species and decreased body weight gain the most sensitive endpoint.  An uncertainty factor of 100X was applied to endpoints selected for the oral exposure route (10x for interspecies extrapolation, 10x for intraspecies variation) and an uncertainty factor of 1000X was applied to endpoints selected for the inhalation exposure route due to a missing route-specific study (10x for interspecies extrapolation, 10x for intraspecies variation, 10x for database).

4.5.2	Recommendation for Combining Routes of Exposures for Risk Assessment

Dietary and drinking water exposure are combined in the dietary exposure assessment.   Children's incidental oral hand-to-mouth exposure will be combined with dietary and drinking water exposure.  The dermal route of exposure will not be combined with other routes of exposure for S-metolachlor, since there was no systemic toxicity seen at the limit dose in dermal toxicity studies.  Although there is potential for residential inhalation exposure, a high end estimate was made, and this high end estimate will not be combined with dietary, water, and incidental oral exposure.

4.5.3	Cancer Classification and Risk Assessment Recommendation

In the mouse carcinogenicity study, possible treatment-related deaths in females and decreased body weight/body weight gain in both sexes were observed.  In the rat combined chronic toxicity/ carcinogenicity study, decreased body weight gain and food consumption were observed.  There was no evidence of carcinogenicity in mice; however, there were statistically significant increases in liver adenomas and combined adenomas/carcinomas in female rats.  In male rats, there was a statistically significant trend but no pair-wise significance for liver tumors.  There was no evidence of a mutagenic or cytogenetic effect in vivo or in vitro in studies with either metolachlor or S-metolachlor.  Metolachlor has been classified as a Group C, possible human carcinogen, based on liver tumors in rats at the highest dose tested. No cancer potency factor has been established, as risks established based on the chronic reference dose are protective of cancer effects.

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

The points of departure, uncertainty factors, and toxicity endpoints are presented in the following tables.  No endpoint is selected for dermal exposure scenarios.  No hazard was identified at the maximum dermal dose tested.

Table <IP_ADDRESS>. Summary of Toxicological Endpoints for S-metolachlor for Use in Dietary Human Health Risk Assessments
Exposure/Scenario
                              Point of Departure
                        Uncertainty/FQPA Safety Factors
                       RfD, PAD, LOC for Risk Assessment
                        Study and Toxicological Effects

Acute Dietary
(General Population)
NOAEL = 300 mg/kg/day
UFA= 10x
UFH=10x
FQPA SF= 1x
Acute RfD = 3.0 mg/kg/day
aPAD = 3.0 mg/kg/day
Developmental Toxicity Study - Rat
Metolachlor (MRID 00151941)
LOAEL = 1000 mg/kg/day based increased incidence of death, clinical signs (clonic and/or tonic convulsions, excessive salivation, urine-stained abdominal fur and/or excessive lacrimation) and decreased body weight gain.
Chronic Dietary
(All Populations)
NOAEL = 9.7
mg/kg/day
UFA= 10x
UFH=10x
FQPA SF= 1x
Chronic RfD = 0.097
mg/kg/day
cPAD = 0.097mg/kg/day
One Year Chronic Toxicity  -  Dog;
Metolachlor (MRIDs 40980701, 41164501, 42218601 and 42218602)
LOAEL = 33 mg/kg/day based decreased body weight gain in females
Cancer (all routes)
Metolachlor has been classified as a Group C carcinogen with risk quantitated using a 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 determine risk associated with lower environmentally relevant human exposures.
NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.
UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).
FQPA SF = FQPA Safety Factor.
PAD = population adjusted dose (a = acute, c = chronic).
RfD = reference dose.
MOE = margin of exposure.
LOC = level of concern.

Table <IP_ADDRESS>.  Summary of Toxicological Doses and Endpoints for S-METOLACHLOR for Use in Residential and Occupational Human Health Risk Assessments
Exposure/
Scenario
Point of Departure
Uncertainty Factors
Level of Concern for Risk Assessment
Study and Toxicological Effects
Incidental Oral Short-term (1-30 days)

NOAEL=
50 mg/kg/day
UFA= 10x
UFH=10x

Residential LOC for MOE = 100
Developmental Toxicity Study - Rat
S-Metolachlor (MRID 43928925)
LOAEL = 500 mg/kg/day based on increased incidence of clinical signs, decreased body weight/body weight gain, food consumption and food efficiency seen at the LOAEL  in maternal animals.
Dermal Short- and Intermediate-Term
No hazard identified
21-day dermal toxicity study  -  Rabbits
Metolachlor (MRID 41833101)
LOAEL = Not observed
Inhalation Short-Term (1-30 days)
NOAEL=
50 mg/kg/day
UFA= 10x
UFH=10x
UFD=10x
Occupational LOC for MOE = 1000
Developmental Toxicity Study - Rat
S-Metolachlor (MRID 43928925)
LOAEL = 500 mg/kg/day based on increased incidence of clinical signs, decreased body weight/body weight gain, food consumption and food efficiency seen at the LOAEL  in maternal animals.
Inhalation Intermediate-Term
 (1-6 months)
NOAEL=
8.8 mg/kg/day
UFA= 10x
UFH=10x
UFD=10x
Occupational LOC for MOE = 1000
Subchronic Toxicity Study - Dog
Metolachlor (MRIDs 00032174 and 43244001)
LOAEL = 29.4 mg/kg/day based on decreased body weight gain
Cancer (all routes)
Metolachlor has been classified as a Group C carcinogen with risk quantitated using a 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 determine risk associated with lower environmentally relevant human exposures.  NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use of a short-term study for long-term risk assessment.  UFDB = to account for the absence of key data (i.e., lack of a critical study).  FQPA SF = FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c = chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level of concern.  N/A = not applicable.

5.0	Dietary Exposure and Risk Assessment

5.1	Metabolite/Degradate Residue Profile

5.1.1	Summary of Plant and Animal Metabolism Studies

The qualitative nature of metolachlor residues in plants and livestock is adequately understood, based on adequate corn, potato, and soybean metabolism studies, ruminants, poultry, and rotational crops.  Residues of concern in plants, livestock, and rotational crops include metolachlor and its metabolites, determined as the derivatives CGA-37913 and CGA-49751.  The Agency previously concluded that the residues of concern for S-metolachlor are the same as for metolachlor. Metolachlor is metabolized extensively in both plants and livestock.   The residues of concern for S-metolachlor in drinking water include the parent, CGA-354743 (metolachlor ethanesulfonic acid (ESA)) and CGA-51202 (metolachlor oxanilic acid (OA)).

5.1.2	Summary of Environmental Degradation

Environmental fate data indicate that parent metolachlor/S-metolachlor is moderately persistent to persistent.  It is mobile to highly mobile in different soils and has been detected extensively in surface water and groundwater.  Metolachlor/S-metolachlor degradation appears to be dependent on microbially mediated and abiotic processes.  Major degradates identified in groundwater include metolachlor ESA and metolachlor OA in both groundwater and surface water.  Depending on the soil (i.e. organic matter content), metolachlor/S-metolachlor has the potential to range from a moderately mobile to a highly mobile material.  The Environmental Fate and Effects Division (EFED) concluded there is no difference in soil sorption affinity between metolachlor and S-metolachlor.  Available data suggest that metolachlor and S-metolachlor are expected to be highly mobile to mobile in soil and water environments.

5.1.3	Comparison of Metabolic Pathways

Metolachlor and S-metolachlor are extensively metabolized in plants, livestock animals and rats.  Side by side metabolism was studied only with a single oral dose in rats; no comparative studies were conducted with a high dose or repeated doses.  The metabolism of metolachlor in plants involves conjugation with glutathione, breakage of this bond to form the mercaptan, conjugation of the mercaptan with glucuronic acid, O-demethylation of the methyl ether, and conjugation of the resultant alcohol with a neutral sugar.  A minor pathway may involve sugar conjugation of metolachlor directly to the corresponding oxo-compounds.   Most of the metabolites of metolachlor and S-metolachlor have not been identified.

Metolachlor is rapidly metabolized and almost totally eliminated in the urine and feces of ruminants (goats), non-ruminants (rats), and poultry.  There were some minor sex differences in the elimination pattern in rats.  Metolachlor per se was not detected in any of the excreta or tissues.  Metolachlor and S-metolachlor were readily absorbed and extensively metabolized by goats via glutathione conjugation and/or oxidation reactions.  Oxidized metabolites were also conjugated with glucuronic acid.  Metolachlor and S-metolachlor were extensively metabolized in poultry via O-demethylation and subsequent glucuronic acid conjugation or oxidation to dihydroxy or carboxylic acid metabolites that may also be conjugated with glucuronic acid.   As in plants, metolachlor residues of concern in livestock commodities include metolachlor and its metabolites, determined as the derivatives CGA-37913 and CGA-49751.

5.1.4	Residues of Concern Summary and Rationale

The metabolism of metolachlor and S-metolachlor has been reviewed by the Metabolism Assessment Review Committee (MARC) on August 14, 2001 (Dobozy, V, 2001).   The MARC determined that, although both metolachlor ethanesulfonic acid (ESA) (CGA-354743), and metolachlor oxanilic acid (OA) (CGA-51202) appear to be less toxic than the parent metolachlor and S-metolachlor, both should be determined in the drinking water risk assessment since these metabolites were found in greater abundance than the parent in water monitoring studies.  The summary of metabolites and degradates is provided below.

Table 5.1.4  Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression
Matrix
Residues included in Risk Assessment
Residues included in Tolerance Expression
Plants
Primary Crop
Metolachlor and metabolites determined as the derivatives CGA-37913 and CGA-49751.
Metolachlor and metabolites determined as the derivatives CGA-37913 and CGA-49751.

Rotational Crop
Metolachlor and metabolites determined as the derivatives CGA-37913 and CGA-49751.
Metolachlor and metabolites determined as the derivatives CGA-37913 and CGA-49751.
Livestock
Ruminant
Metolachlor and metabolites determined as the derivatives CGA-37913 and CGA-49751.
Metolachlor and metabolites determined as the derivatives CGA-37913 and CGA-49751.

Poultry
Metolachlor and metabolites determined as the derivatives CGA-37913 and CGA-49751.
Metolachlor and metabolites determined as the derivatives CGA-37913 and CGA-49751.
Drinking Water
Metolachlor, metolachlor ethanesulfonic acid (ESA), and metolachlor oxanilic acid (OA)
Not Applicable

5.2	Food Residue Profile

The qualitative nature of metolachlor residues in plants and livestock is adequately understood, based on adequate corn, potato, and soybean metabolism studies, ruminants, poultry, and rotational crops.  Residues of concern in plants, livestock, and rotational crops include metolachlor and its metabolites, determined as the derivatives CGA-37913 and CGA-49751.

The current petition is a request for increase in tolerance for the livestock feed stuffs, corn forage and stover (from field-, sweet- and pop-corn), based on residue data showing tolerance exceeding residues resulting from the current use pattern.  Adequate field trial data have been submitted to support the tolerance increase.  The decline study included in the field trial data showed no decline in residues with increasing PHI.  The field trial data were properly supported by analytical validation data and storage stability data.  No processing data are needed to support the current tolerance request.

Although the new tolerance represents a large increase in the dietary burden of S-metolachlor and metolachlor to beef cattle, the current tolerance for beef commodities is based on a higher dietary burden for S-metolachlor and metolachlor to dairy cattle.  The dietary burden for metolachlor and S-metolachlor for dairy cattle did not change as a result of the current petition, and no increase is needed in the tolerances in livestock commodities.

5.3	Water Residue Profile
D368735, C. Koper, 4/22/10
D396451, R Duncan, 1/3/2012

EFED calculated conservative, Tier I Estimated Drinking Water Concentrations (EDWCs) of metolachlor and S-metolachlor in ground water and surface water for use in an earlier human health risk assessment.  Since there is no change in the existing uses of S-metolachlor as a result of the current petition, those EDWCs will not increase.  EDWCs for metolachlor and S-metolachlor were calculated for both the parent compound and the metolachlor ethanesulfonic acid (ESA) and metolachlor oxanilic acid (OA) degradates.  Although it was determined by HED's Metabolism Assessment Review Committee (MARC) that the metolachlor ESA and metolachlor OA metabolites appear to be less toxic than parent metolachlor, they are included in the risk assessment since they were found in greater abundance than the parent in water monitoring studies.

EDWCs were calculated using drinking water models PRZM/EXAMS and FIRST for surface water and SCIGROW for ground water.  Current NAWQA monitoring data was also used to determine EDWCs.  Based on a review of the current monitoring data, concentrations of parent S-metolachlor and its degradates were less than values reported from the previous monitoring data (US EPA, 2002).  Based on monitoring and modeling data, total EDWCs for peak (acute exposure) and average (chronic, non-cancer scenario)  surface water respectively are 219 ppb (78 ppb parent + 48 ppb metolachlor ESA+ 94 ppb metolachlor OA) and 119 ppb (18 ppb parent + 34 ppb metolachlor ESA+ 34 ppb metolachlor OA).  Recommended groundwater EDWCs (peak and average) are 126 ppb (33 ppb parent + 64 ppb metolachlor ESA+ 30 ppb metolachlor OA).

Table 5.3	Summary of Estimated Surface Water and Groundwater Concentrations for S-Metolachlor
Scenario
Surface Water Conc., ppb a
Groundwater Conc., ppb b
Acute
                                      219
                                      126
Chronic (non-cancer)
                                      119
                                      126
Chronic (cancer)
                                      119
                                      126
[a] From the Tier I PRZM-EXAMS and FIRST.
[b] From the SCI-GROW model.
Source of EDWCs: D368735, C. Koper, 4/22/10

5.4	Dietary Risk Assessment
D396451, R. Duncan, 1/3/2012

5.4.1	Description of Residue Data Used in Dietary Assessment

No changes in tolerances for any food commodity are proposed or recommended as a result of the current petition.  Thus, there is no change to the dietary exposure, and the last dietary exposure assessment is still current.

The acute and chronic dietary exposure assessments were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID(TM), Version 1.3), which incorporates consumption data from USDA's Continuing Surveys of Food Intakes by Individuals (CSFII), 1994-1996 and 1998.  The dietary risk assessment incorporates both exposure and toxicity of S-metolachlor and metolachlor.  For acute and chronic assessments, the risk is expressed as a percentage of a maximum acceptable dose (i.e., the dose which HED has concluded will result in no unreasonable adverse health effects).  This dose is referred to as the population adjusted dose (PAD).  The PAD is equivalent to the Reference Dose (RfD) divided by the special FQPA Safety Factor.  HED is concerned when estimated dietary risk exceeds 100% of the PAD.

The acute and chronic dietary exposure/risk analyses for all supported S-metolachlor/metolachlor food uses were conducted using conservative, unrefined exposure assessments.  The unrefined analyses assume tolerance level residues for all registered uses, 100% crop treated for all commodities with existing tolerances, and default processing factors.  In cases where separate tolerance listings occur for both metolachlor and S-metolachlor on the same commodity, the higher value of the two is used in the analyses.  Acute and chronic dietary S-metolachlor exposure and risk estimates resulting from food intake were determined for the general U.S. population and various population subgroups.

Based on analyses of estimated dietary risks for the general U.S. population and various population subgroups, the acute and chronic dietary exposure estimates for S-metolachlor are significantly below HED's level of concern for all supported commodities (The 95[th] percentile acute dietary exposure estimate for the highest exposed population subgroup, all infants < 1 year old, is 0.05 mg/kg/day or 1.5% of the aPAD.  The chronic dietary exposure estimate for the highest exposed population subgroup, all infants < 1 year old, is 0.012 mg/kg/day or 11.6% of the cPAD.

5.4.2	Percent Crop Treated Used in Dietary Assessment

The conservative assumption of 100% crop treated was used for all commodities with existing tolerances on food commodities.  The current petition does not change any tolerances on food commodities.

5.4.3	Acute Dietary Risk Assessment

Based on analyses of estimated dietary risks for the general U.S. population and various population subgroups, the acute dietary exposure estimates for S-metolachlor are significantly below HED's level of concern for all supported commodities (The 95[th] percentile acute dietary exposure estimate for the highest exposed population subgroup, all infants < 1 year old, is 0.05 mg/kg/day or 1.5% of the aPAD.

5.4.4	Chronic Dietary Risk Assessment

Based on analyses of estimated dietary risks for the general U.S. population and various population subgroups, the chronic dietary exposure estimates for S-metolachlor are significantly below HED's level of concern for all supported commodities.  The chronic dietary exposure estimate for the highest exposed population subgroup, all infants < 1 year old, is 0.012 mg/kg/day or 11.6% of the cPAD.

5.4.5	Cancer Dietary Risk Assessment

Metolachlor has been classified as a Group C, possible human carcinogen, based on liver tumors in rats at the highest dose tested. No cancer potency factor has been established, as risks established based on the chronic reference dose are protective of cancer effects.

5.4.6	Summary Table

 Table 5.4.6.  Summary of Dietary (Food and Drinking Water) Exposure and Risk for S-Metolachlor and Metolachlor
                              Population Subgroup
                                 Acute Dietary
                                (95 Percentile)
                                Chronic Dietary
                                     Cancer

                          Dietary Exposure (mg/kg/day)
                                    % aPAD*
                                Dietary Exposure
                                  (mg/kg/day)
                                    % cPAD*
                                Dietary Exposure
                                  (mg/kg/day)
                                      Risk
 General U.S. Population
                                   0.014688
                                    <1.0
                                   0.004550
                                      4.5

 All Infants (< 1 year old)
                                   0.046244
                                      1.5
                                   0.011574
                                     11.6
                                      N/A
                                      N/A
 Children 1-2 years old
                                   0.025061
                                    <1.0
                                   0.008666
                                      8.7

 Children 3-5 years old
                                   0.022362
                                    <1.0
                                   0.007852
                                      7.9

 Children 6-12 years old
                                   0.015532
                                    <1.0
                                   0.005372
                                      5.4

 Youth 13-19 years old
                                   0.011553
                                    <1.0
                                   0.003698
                                      3.7

 Adults 20-49 years old
                                   0.012690
                                    <1.0
                                   0.003994
                                      4.0

 Adults 50+ years old
                                   0.011471
                                    <1.0
                                   0.004017
                                      4.0

 Females 13-49 years old
                                   0.012602
                                    <1.0
                                   0.003929
                                      3.9

 * The aPAD is 3.0 mg/kg/day.  The cPAD is 0.1 mg/kg/day.  Cancer risk is adequately covered by chronic dietary exposure assessment.

Residential (Non-Occupational) Exposure/Risk Characterization

There are no residential exposures for the current petition proposing increases in tolerances on livestock feed stuffs.  However, there is potential for residential exposure to S-metolachlor from use of other registered products which are applied to residential lawns or turf by professional applicators.  Residential post-application exposure to children 1-2 is reassessed in this document based on the Residential SOPs dated February 2012. (EPA, 2012)

6.1	Residential Handler Exposure

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 fields, and ornamental gardens.  Since Pennant MAGNUM[TM] is not intended for homeowner purchase or use (i.e., used by professional/commercial applicators), there is no potential for Residential Handler Exposure.

6.2	Post-Application Exposure

The only potential short-term residential risk scenario anticipated is post-application hand-to-mouth exposure of children playing on treated lawns.  Although there is possibility of dermal exposure, no risks of concern were identified in the dermal toxicity study.

S-metolachlor incidental oral exposure is assumed to include hand-to-mouth exposure, object-to-mouth, and soil ingestion oral exposure.  Residential post application exposure to S-metolachlor for this scenario is being reassessed in this document using the updated Residential SOPs.  No turf transferable residue data were used.  Exposure is due to a single application, at the maximum label rate of 2.47 lb a.i./acre for S-metolachlor and 4.0 lb a.i. acre/ for metolachlor.

The residential exposure (absorbed dose) to children 1-2 for combined hand-to-mouth, object-to-mouth, and soil ingestion oral exposure was calculated to be 0.0609 mg/kg/day resulting in an MOE of 820.  The MOE from the residential risk scenario for exposure to S-metolachlor does not exceed the Agency's level of concern.  Results from that assessment have been used to assess aggregate risk from exposure to food, drinking water, and residential lawns.  Based on this analysis, short-term oral MOEs are not of concern.

Table 6.2:  Short- Term Residential Post-application Exposure and Risk Estimates for S-Metolachlor: Children Turf Hand to Mouth Exposure (LOC = 100)
                                  Formulation
                                   Lifestage
                                      HRt
                                      FM
                                  SAH (cm[2])
                          Exposure Time (hours/ day)
                                   N_Replen
                                      SE
                                   Freq_HtM
                           Absorbed Dose
(mg/kg/day)
                                MOE (rounded)

                            Hand Residue (mg/cm[2])
                 Fraction of Hand Surface Area Mouthed / Event

            Number of replenishment intervals per hr (intervals/hr)
                             Extraction by Saliva
                              HtM events per hour

                                    Liquid
                               1 to <2 years
                                    0.00654
                                     0.127
                                      150
                                      1.5
                                       4
                                     0.48
                                     13.9
                                    0.0609
                                      820

6.3	Residential Bystander Post-application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for S-metolachlor at this time primarily because of the low acute inhalation toxicity (Toxicity Category III and IV) and low vapor pressure (2.8 x 10[-5] mm Hg. However, volatilization of pesticides may be a source of post-application inhalation exposure to individuals nearby pesticide applications.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/sap/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are developed, the Agency may revisit the need for a quantitative post-application inhalation exposure assessment for (chemical).

6.4	Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations.  This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for S-metolachlor.  The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency's Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm).  On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling.  The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods.  After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift with specific products with significant risks associated with drift.

Although a quantitative residential post-application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment has been previously performed for S-metolachlor exposure to flaggers on sod farms.  This exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post-application inhalation exposure scenarios.  Flaggers for applications on sod farms, where the S-metolachlor application rate is 2.5 lb ai/A, could be exposed short term to 0.0051 mg/kg/day, which would result in an MOE of 9800, which is below the Agency's level of concern.  (M. Collantes, D296725, April 10, 2006).

6.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures.  In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated.  When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

Based on the existing Section 3 uses, which do not change as a result of the current petition, acute, short-term, and chronic aggregate exposures are anticipated.  Aggregate exposure assessments were performed for acute aggregate dietary exposure (food + drinking water), chronic aggregate dietary exposure (food + drinking water), and residential short-term exposure to children from incidental oral exposures.  A cancer aggregate risk assessment was not performed because for S-metolachlor the chronic reference dose is considered protective of cancer effects.  All potential exposure pathways were assessed in the aggregate risk assessment.

7.1	Acute Aggregate Risk

The aggregate acute risk estimates include exposure to residues of S-metolachlor in food and drinking water, and does not include dermal, inhalation or incidental oral exposure.  Since the acute dietary exposure assessment already includes the highest acute exposure from the drinking water modeling data, no further calculations are necessary.  The acute risk estimate for all populations, resulting from aggregate exposure to S-metolachlor in food and drinking water is below EPA's level of concern.  The food and drinking water exposure estimates for the most highly exposed subgroup, all infants (< 1 year old), is 1.5% of the aPAD.

42.2 Short-Term Aggregate Risk

Short-term aggregate assessments include exposures that will occur from one to thirty days.  For food and water, the exposure input is taken from the chronic dietary exposure assessment.

There are no residential user exposures associated with the current petition to raise S-metolachlor on livestock feeds.  However, there is potential for residential exposure to S-metolachlor from use of registered products which are applied to residential lawns or turf by professional applicators.  No intermediate-term risk scenarios are anticipated for the existing and proposed uses of S-metolachlor.  The only potential short-term residential risk scenario anticipated is post-application exposure of children playing on treated lawns.  S-metolachlor incidental oral exposure is assumed to include combined hand-to-mouth exposure, object-to-mouth exposure and exposure through incidental ingestion of soil.  Refer to Section 6.2. for the residential exposures that are likely to be combined.  Results from that assessment have been used to assess aggregate risk from exposure to food, drinking water, and residential lawns for this analysis.  Based on this analysis, short-term aggregate MOEs are not of concern.

Table 7.2  Short-Term Aggregate Risk Calculations for S-metolachlor
                                  Population
                                   NOAEL [1]
                                   mg/kg/day
                                    LOC [2]
                                    Average
                               Food & Water
                              Exposure mg/kg/day
                           Residential Exposure [3]
                                   mg/kg/day
                                 Aggregate MOE
                                (food/water and
                               residential) [4]
                                 Children 1-2
                                      50
                                      100
                                     0.012
                                     0.061
                                      680
[1] NOAEL for incidental oral exposure.
[2] The level of concern (LOC) MOE is 100, based on inter- and intra-species safety factors totaling 100.
[3] Residential Exposure = [Incidental Oral exposure from all possible sources -combined hand-to-mouth, object-to-mouth, and soil ingestion oral exposure].  No residential oral exposure is expected for adults
[3] Aggregate MOE = [NOAEL / (Avg Food & Water Exposure + Residential Exposure)]

7.3	Intermediate-Term Aggregate Risk

Intermediate-term aggregate assessments include exposures that will occur from thirty days to six months.  There are no residential scenarios which are expected to be intermediate-term exposure.

7.4	Chronic Aggregate Risk

Chronic or long-term aggregate assessments include exposures that will exceed six months.  Only food and water exposure are included in the chronic aggregate assessment, and does not  dermal, inhalation or incidental oral exposure.  Refer to section 5.4.4 for a detailed discussion of the chronic dietary assessment.  Since the chronic dietary exposure assessment already includes the highest chronic exposure from the drinking water modeling data, no further calculations are necessary.  The chronic risk estimate for all populations, resulting from aggregate exposure to S-metolachlor in food and drinking water is below EPA's level of concern.  The food and drinking water exposure estimates for the most highly exposed subgroup, all infants (< 1 year old), is 11.6% of the cPAD.

7.5	Cancer Aggregate Risk

As risks are estimated based on the chronic reference dose are protective of cancer effects, no separate cancer risk assessment is necessary.  The chronic aggregate risk assessment is below the Agency's level of concern.

6.0 Cumulative Exposure/Risk Characterization

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider "available information" concerning the cumulative effects of a particular pesticide's residues and "other substances that have a common mechanism of toxicity."

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to S-metolachlor and any other substances and S-metolachlor does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that S-metolachlor has a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.

7.0 Occupational Exposure/Risk Characterization

No new uses are proposed with the current petition.  Thus, there are no new occupational exposure scenarios to assess.  Occupational exposure and risk from the use of S-metolachlor was last assessed in connection with PP# 3E6787, a petition for new uses of S-metolachlor on a number of commodities (M. Collantes, D296725, 4/2/2006).  Estimated short-term and intermediate-term inhalation risk to mixer/loaders with no PPE, from the use of S-metolachlor on corn resulted in MOEs of 1100 and 230, respectively.  With the additional 10X database uncertainty factor, the level of concern is now and MOE of 1000.  The intermediate-term inhalation risk is now of concern.  The risk can be mitigated by use of a respirator or engineering controls.  The metolachlor label requires the use of a closed loading system, which adequately mitigates this risk.

Estimated short-term and intermediate-term inhalation risk to aerial applicators using engineering controls resulted in MOEs of 19,000 and 4000, respectively.  These MOEs are not of concern.  Estimated short-term and intermediate-term inhalation risk to flaggers resulted in MOEs of 13,000 and 2600.  These MOEs are not of concern.

10.0	Human Studies

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These data, which include studies from PHED 1.1; the AHETF database; the Outdoor Residential Exposure Task Force (ORETF) database; the ARTF database; and HED's 2012 Residential SOPs, are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements.  For certain studies, the ethics review may have included review by the Human Studies Review Board.  Descriptions of data sources, as well as guidance on their use, can be found at http://www.epa.gov/pesticides/science/handler-exposure-data.html, http://www.epa.gov/pesticides/science/residential-exposure-sop.html, and http://www.epa.gov/pesticides/science/post-app-exposure-data.html.

11.0	References

Collantes, Margarita.  2006.   "S-Metolachlor: Occupational Exposure Assessment."  D296725, EPA Memorandum dated April 10, 2006.

Dobozy, Virginia, 2001.  "Metolachlor and s-Metolachlor. Results of the Health Effects Division (HED) Metabolism Assessment Review Committee (MARC) Meeting Held on 14-August-2001. Chemical#s 108801 and 108800. Barcode D274326.  EPA Memorandum dated 8/28/2001.

Duncan, R., CDPR, 2012.  "S-Metolachlor - Acute and Chronic Dietary and Drinking Water Exposure and Risk Assessment for Proposed Section 3 Use on Cilantro and Garden Beet, Leaves."  D396451.  EPA Memorandum prepared by California EPA Department of Pesticide Regulation, dated January 3, 2012.

EPA, 2012.  "Residential SOPs", dated February 2012, Available at http://www.epa.gov/pesticides/science/residential-exposure-sop.html

Hummel, Susan V., 2013. "S-Metolachlor, PP#2F8115.  Petition for the Amendment of Permanent Tolerances for Residues of S-Metolachlor on Corn, field, forage; Corn, sweet, forage; and Corn, stover.  Summary of Analytical Chemistry and Residue Data."  D407466.  EPA Memorandum dated August 1, 2013.

Kinard, Sherie.  2003.  "PP#s:  7F04897, 9E06055, 7E04916, 2E06374, 4E04420, 8E05029, and 8E05030. Revised Metolachlor and S-Metolachlor Residue Chemistry Chapter for the Tolerance Reassessment Eligibility Decision (TRED) and Registration for Use on Asparagus, Carrots, Cotton, Horseradish, Green Onions, Peppers, Rhubarb, Sugar Beet, Sunflower, and Swiss Chard; DP Barcode D292881; Rereg. Case 0001."  D255484, D258813, D258816, D258825, D258958, D259117, D280858, D288570.  EPA Memorandum dated August 15, 2003

Koper, Christopher M.  2010. "Drinking Water Assessment for S-Metolachlor and its Degradates Ethanesulfonic Acid (ESA) and Oxanilic Acid (OA) for Various Crop Uses."  D368735, EPA EFED Memorandum dated April 22, 2010.

VanAlstine, Julie, 2013.  "Metolachlor: Summary of Hazard and Science Policy Council (HASPOC) Meeting of February 14, 2013: Recommendations on the Need for a Neurotoxicity Battery, a Developmental Neurotoxicity Study, and a Subchronic Inhalation Study."   EPA Memorandum dated March 20, 2013,Appendix A.  Toxicology Profile and Executive Summaries

A.1	Toxicology Data Requirements
The requirements (40 CFR 158.340) for food use for Metolachlor  are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

                                     Study
                                   Technical

                                   Required
                                   Satisfied
870.1100    Acute Oral Toxicity
870.1200    Acute Dermal Toxicity
870.1300    Acute Inhalation Toxicity
870.2400    Primary Eye Irritation
870.2500    Primary Dermal Irritation
870.2600    Dermal Sensitization
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.3100    Oral Subchronic (rodent)
870.3150    Oral Subchronic (nonrodent)
870.3200    21-Day Dermal
870.3250    90-Day Dermal
870.3465    90-Day Inhalation
                                      yes
                                      yes
                                      yes
                                      no
                                      yes
                                      yes
                                      yes
                                      yes
                                       -
                                      no
870.3700a  Developmental Toxicity (rodent)
870.3700b  Developmental Toxicity (nonrodent)
870.3800    Reproduction
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.4100a  Chronic Toxicity (rodent)
870.4100b  Chronic Toxicity (nonrodent)
870.4200a  Oncogenicity (rat)
870.4200b  Oncogenicity (mouse)
870.4300    Chronic/Oncogenicity
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                    yes[a]
                                      yes
                                      yes
                                      yes
                                      yes
870.5100    Mutagenicity -- Gene Mutation - bacterial
870.5300    Mutagenicity -- Gene Mutation - mammalian
870.5xxx    Mutagenicity -- Structural Chromosomal Aberrations
870.5xxx    Mutagenicity -- Other Genotoxic Effects
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.6100a  Acute Delayed Neurotoxicity (hen)
870.6100b  90-Day Neurotoxicity (hen)
870.6200a  Acute Neurotoxicity Screening Battery (rat)
870.6200b  90-Day Neurotoxicity Screening Battery (rat)
870.6300    Develop. Neurotoxicity
                                      no
                                      no
                                      no*
                                      no*
                                      no
                                       -
                                       -
                                       -
                                       -
                                       -
870.7485    General Metabolism
870.7600    Dermal Penetration
870.7800    Immunotoxicity
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
Special Studies for Ocular Effects
         Acute Oral (rat)
         Subchronic Oral (rat)
         Six-month Oral (dog)
                                      no

[a] Satisfied with combined chronic toxicity/carcinogenicity study
[*]Waived at HASPOC February 14, 2013 (JVanAlstine, 2013)
A.2	Toxicity Profiles

Table A.2.1	Acute Toxicity Profile - Metolachlor
Guideline No.
Study Type
MRID(s)
                                    Results
                               Toxicity Category
870.1100
Acute oral - Rat
                                   00015523
LD50 = 2780 mg/kg
                                      III
870.1200
Acute dermal - Rabbit
                                   00015526
LD50 = > 10 g/kg
                                      III
870.1300
Acute inhalation -Rat
                                   00015535
LC50 = > 1.75 mg/L
                                      III
870.2400
Acute eye irritation - Rabbit
                                   00015528
Non-irritating
                                      IV
870.2500
Acute dermal irritation - Rabbit
                                   00015530
Non-irritating
                                      IV
870.2600
Skin sensitization  -  guinea pig
                                   00015631
positive

Table A.2.1	Acute Toxicity Profile  -  S-Metolachlor
Guideline No.
Study Type
MRID(s)
                                    Results
                               Toxicity Category
870.1100
Acute oral - Rat
                                   43928915
LD50 = 3267 mg/kg
(♂); 2577 mg/kg/day
(♀); 2672 mg/kg/day
(combined)
                                      III
870.1200
Acute dermal - Rabbit
                                   43928916
LD50 = > 2000 mg/kg
                                      III
870.1300
Acute inhalation -Rat
                                   43928917
LC50 = > 2.91 mg/L
                                      IV
870.2400
Acute eye irritation - Rabbit
                                   43928918
Slight to moderate conjunctival irritation that cleared in 48 hours
                                      III
870.2500
Acute dermal irritation - Rabbit
                                   43928919
non-irritating
                                      IV
870.2600
Skin sensitization  -  guinea pig
                                   43928920
positive

Table A.2.2	Subchronic, Chronic and Other Toxicity Profile - Metolachlor
                                Guideline No.
                                  Study Type
                    MRID No. (year)/ Classification /Doses
                                    Results
870.3100

90-Day oral toxicity rodents
44775401 (1999)
Acceptable/guideline
0, 30, 300, 3000 ppm (M/F: 0, 2.00/2.32, 20.2/23.4, 210/259 mg/kg/day)
NOAEL for males = 3000 ppm
LOAEL for males not established
NOAEL for females = 300 ppm
LOAEL for females = 3000 ppm based on decreased body weight/body weight gain
Acceptable/Guideline
870.3150

180-Day oral toxicity in nonrodents

00032174 (1980), 43244001
0, 100, 300, 1000 ppm (M/F: 0, 2.92/2.97, 9.71/8.77, 29.61/29.42)

NOAEL = 300 ppm
LOAEL = 1000 ppm based on decreased body weight gain
Unacceptable/Guideline

870.3200

21-Day dermal toxicity rabbits

41833101 (1987)
0, 10, 100 or 1000 mg/kg/day

systemic  NOAEL = 1000 mg/kg/day.
systemic LOAEL was not established

dermal irritation NOAEL was not established
dermal irritation LOAEL = 10 mg/kg/day based on very slight erythema, dry skin and fissuring (one animal)
Acceptable/Guideline
870.3700a

Prenatal developmental in rodents

00151941 (1985)
0, 30, 100, 300 or 1000 mg/kg/day

Maternal toxicity NOAEL = 300 mg/kg/day.
Maternal toxicity LOAEL = 1000 mg/kg/day based on an increased incidence of death, clinical signs of toxicity (clonic and/or toxic convulsions, excessive salivation, urine-stained abdominal fur and/or excessive lacrimation) and decreased body weight gain.

Developmental toxicity NOAEL = 300 mg/kg/day Developmental toxicity LOAEL = 1000 mg/kg/day based on slightly decreased number of implantations per dam, decreased number of live fetuses/dam, increased number of resorptions/dam and significant decrease in mean fetal body weight
Acceptable/Guideline
870.3700b

Prenatal developmental in (New Zealand White) rabbits

00041283 (1980)
acceptable/guideline
0, 36, 120 or 360 mg/kg/day

Maternal toxicity NOAEL = 120 mg/kg/day.
Maternal toxicity LOAEL = 360 mg/kg/day based on an increased incidence of clinical observations (persistent anorexia) and decreased body weight gain

Developmental toxicity NOAEL = 360 mg/kg/day Developmental toxicity LOAEL was not established.
Acceptable/Guideline
870.3800

Reproduction and fertility effects
(CD albino) rats
00080897 (1981)
0, 30, 300 or 1000 ppm
F0 males: 0, 2.4, 23.5, and 75.8 mg/kg/day; F0 females: 0, 2.5, 26.0, and 85.7 mg/kg/day; F1 males: 0, 2.3, 23.7, and 76.6 mg/kg/day; F1 females: 0, 2.6, 25.7, and 84.5 mg/kg/day metolachlor (95.4% ai) (dietary)
Parental/Systemic NOAEL = 1000 ppm (F0 males/females: 75.8/85.7 mg/kg/day; F1 males/females: 76.6/84.5 mg/kg/day) highest dose tested.
LOAEL = Not established
Reproductive NOAEL = 1000 ppm (F0 males/females: 75.8/85.7 mg/kg/day; F1 males/females: 76.6/84.5 mg/kg/day) highest dose tested.
LOAEL = Not established
Offspring NOAEL = 300 ppm (F0 males/females: 23.5/26.0 mg/kg/day; F1 males/females: 23.7/25.7 mg/kg/day
LOAEL = 1000 ppm (F0 males/females: 75.8/85.7 mg/kg/day; F1 males/females: 76.6/84.5 mg/kg/day based on decreased body weight in F1 and F2 litters.
Acceptable/Guideline
870.4100b

Chronic toxicity dogs
40980701, 41164501, 42218601 and 42218602. (1989)
0, 100, 300 or 1000 ppm (males: 0, 3.5, 9.7 and 32.7 mg/kg/day, respectively; females: 0, 3.6, 9.7 and 33.0 mg/kg/day, respectively) for one year.

NOAEL = 300 ppm (9.7 mg/kg/day) for females
LOAEL = 1000 ppm for females (33.0 mg/kg/day) based on decreased body weight gain

 LOAEL for males was not established; NOAEL = 1000 ppm (32.7 mg/kg/day).
Acceptable/Guideline
870.4200

Chronic toxicity/Carcinogenicity
rat

00129377 (1983)
0, 30, 300 or 3000 ppm (0, 1.5, 15 or 150 mg/kg/day based on 1 ppm in food equals 0.05 mg/kg/day)

NOAEL = 300 ppm (15 mg/kg/day) for females
LOAEL = 3000 ppm (150 mg/kg/day) for females based on slightly decreased body weight gain and food consumption.

The LOAEL was not established for males. The NOAEL was 3000 ppm (150 mg/kg/day).

Administration of doses up to 3000 ppm was associated with statistically significant increases in liver adenomas and combined adenoma/carcinoma in female rats. In male rats, there was a statistically significant trend but not pair-wise significance for liver tumors.
Acceptable/Guideline

870.4300

Carcinogenicity
mice

00117597 (1982)
0, 300, 1000 or 3000 ppm (0, 45, 150 or 450 mg/kg/day)

NOAEL = 100 ppm (150 mg/kg/day)
LOAEL = 3000 ppm (450 mg/kg/day) based on possible treatment-related deaths in females and decreased body weight/body weight gain in males and females

no evidence of carcinogenicity
Acceptable/Guideline
870.5100

Gene Mutation bacterial reverse mutation

00015397 (1976)
10, 100, 1000 and 10,000 ug/plate

negative up to cytotoxic doses (1000 ug/plate)
Acceptable/Guideline
870.5300

Gene Mutation
mouse lymphoma

00158929 (1984)
9.5-190 nL/mL without activation; 10.5-280 nL/mL with activation

no effect on the incidence of mutations in the presence or absence of metabolic activation
Acceptable/Guideline
870.5395

Cytogenetics
micronucleus assay in Chinese hamsters

00158925 (1984)
0, 1250, 2500 or 5000 mg/kg

no effect of treatment on incidence of micronuclei induction
Acceptable/Guideline
870.5450

Cytogenetics dominant lethal assay in mice

00015630 (1978)
100 or 300 mg/kg

no effect on embryonic death, pre- and post-implantation or fertility rates in mated females
Acceptable/Guideline
870.5550

Other Effects
DNA Damage/Repair in rat hepatocytes

00142828 (1984)
0.125, 0.625, 3.125 or 15.625 nL/mL

Negative
Acceptable/Guideline
870.5550

Other Effects
DNA Damage/Repair in human fibroblasts

00142827
0.125, 0.625, 3.125 or 15.625 nL/mL

Negative
Acceptable/Guideline
870.5550

Other Effects
Unscheduled DNA synthesis in rat hepatocytes

43244003 (1994)
1250, 2500 or 4000 mg/kg to males; 500, 1000 or 1500 mg/kg to females

negative for induction of UDS; however, significant increases in percentage of cells in S-phase were observed in females dosed at 500 mg/kg (but not at 1000 or 1500 mg/kg) and sacrificed at 15 hours
Acceptable/Guideline
870.7485

Metabolism and pharmacokinetics
rodents

MRID 00015425 (1974)
52, 28 or 33 mg/kg to male rats

Conclusions: Urinary metabolites of CGA 24705 (N-(2-methoxy-1-methylethyl)-2-ethyl-6-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 R1 (the N-(2-methoxy-1-methylethyl side chain) and side chain dechlorination and oxidation of R2 (the N-chloroacetyl side chain) have occurred, and CGA 46129 (N-(1-carboxy-ethyl)-2-ethyl-6-methyl hydroxyacetanilide) in which the ether bond of R1 has been split and oxidized to the corresponding carboxylic acid, while 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 radioactivity and was composed of 5 different radioactive fractions, which were not identified.

Current guideline recommendations as to dose levels and use of both sexes in metabolism studies were not followed. Thus, whether the metabolic pattern is altered with dose or repeated exposure cannot be evaluated from these data.
Unacceptable/Nonguideline

870.7485

Metabolism and pharmacokinetics

40114401 (1987)
Single low (1.5 mg/kg), single high (300 mg/kg) and repeated low (1.5 mg/kg/day for 15 days)
Conclusions: Single low (1.5 mg/kg), single high (300 mg/kg) and repeated low (1.5 mg/kg/day for 15 days) oral doses of metolachlor were readily absorbed and eliminated by male and female rats. Urinary and fecal elimination of radioactivity associated with orally administered [[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, half-lives of elimination, 16.6 and 15.6 hours, respectively) than low- and high-dose males and repeated-dose animals of both sexes (half-lives, 18.2 and 20.0 hours). Elimination by all animals followed first-order kinetics. Approximately one-half to two-thirds (48 to 64 percent) of the [14]C administered was recovered from the urine within 7 days; similar amounts were present in the feces. Low-dose males eliminated slightly more of the radioactive dose in the feces (55 percent) than the urine (48 percent). The opposite trend was seen in the low-dose females and repeated-dose rats of both sexes; these animals excreted approximately 58 to 64 percent of the [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 approximately 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 radiolabeled compound (0.6 to 0.9 ppm, low- and repeated-dose rats; 232 and 247 ppm, high-dose females and males, respectively), indicating that [[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 contained 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-dose 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.
Unacceptable/Nonguideline
870.7485

Metabolism and pharmacokinetics

43164201 (1992)
acceptable/guideline
low oral dose (1.5 mg/kg x 14 days), and a single high dose (300 mg/kg)

In a rat metabolism study (MRID # 431642-01),[14]C-Metolachlor was administered orally in PEG-200 [HWI 6117-208] or corn oil [ABR-94001] to groups (5 sex/dose) of male and female Sprague-Dawley rats at a low oral dose (1.5 mg/kg), repeated low oral dose (1.5 mg/kg x 14 days), and a single high dose (300 mg/kg). Control animals (1/sex) received blank formulation.

Comparison of oral and intravenous data showed that of the administered dose, between 69.6% and 93.2% was absorbed. Distribution data showed that the only significant sites of residual radioactivity at 7 days post-dose were residual carcass (0.9 - 2.2% of the administered dose) and red blood cells (0.95- 1.53 ug equivalents/gram in blood cells for all low dose male and female rats). Dosing regimen did not result in any apparent accumulation of residual radioactivity.

Excretion data showed that urine and feces were both significant routes for elimination of metolachlor derived radioactivity. In the low dose groups, the urine appeared more of a predominant route for excretion in female rats than in males, whereas fecal excretion was slightly higher in males. However, at the high oral dose, there were no apparent sex-related differences in the pattern of urinary excretion. Examination of urinary excretion data as presented in graphical format indicated that at the 300 mg/kg dose, excretion was delayed vs the low oral dose, suggesting saturation of elimination.

Metabolism of metolachlor in this study was complex, with up to 32 metabolites identified in urine and/or feces. The "major" urinary metabolite found in all dose groups was the metabolite designated CGA-46129. This metabolite was present as 5.6-13.1% of the total radioactive residue (TRR) in rat urine across all dose groups, and was highest in the intravenously dosed group. In the orally dosed rats, the percentage of this metabolite decreased from approximately 13% of TRR to between 5.6-9.2% of TRR. Other metabolites identified in urine which constituted near or at 5% of TRR were U10 (CGA-37735), U13, U17, U1, "polar 1", and "polar 2." The radioactivity constituting the `polar 1' and `polar 2' regions was further broken down to at least 12 components by TLC, but the identity of the metabolites in these regions was not demonstrated.

In feces, a similarly complex metabolite profile was obtained. The "major" metabolite observed in feces, F9, was identical to U7, or CGA-46129. Except for intravenously dosed rats, where the percentage of this metabolite in feces was equivalent in male and female rats (11.6 and 13.2% of TRR, respectively), the percentage of F9 in feces of orally dosed rats was always higher in males than in females. Other fecal metabolites identified at or near 5% of TRR in feces included F2 (CGA-41638), F3 (CGA-133275), F7, F8 and F8', F16, F14, and F17.

Based on these data, a scheme for metabolism of metolachlor was proposed.

Acceptable/Guideline

Table A.2.2	Subchronic, Chronic and Other Toxicity Profile  -  S-Metolachlor
                                Guideline No.
                                  Study Type
                    MRID No. (year)/ Classification /Doses
                                    Results
870.3100

90-Day oral toxicity rodents

43928923 (1995)
0, 30, 300, 3000 or 10000 ppm (0, 1.5, 15, 150 or 500 mg/kg/day)

NOAEL = 300 ppm
LOAEL = 3000 ppm based on lower body weights/body weight gains, reduced food consumption and food efficiency and increased kidney weights in males
Acceptable/Guideline
870.3100

90-Day oral toxicity rodents

44775402 (1999)
0, 30, 300, 3000 ppm (M/F: 0, 1.90/2.13, 20.4/23.9 and 208.0/236.0 mg/kg/day0

NOAEL = 3000 ppm (equivalent to 208 mg/kg/day in males and 236 mg/kg/day in females
LOAEL cannot be defined
Unacceptable/Guideline
870.3150

90-Day oral toxicity nonrodents

43928922 (1995)
0, 300, 500, 1000 or 2000 ppm (M/F: 0, 9/10, 15.1/17.2, 31.1/31.5 or 62/74 mg/kg/day)

NOAEL = 2000 ppm (M/F: 62/74 mg/kg/day)
LOAEL = not established
Acceptable/Nonguideline

870.3700a

Prenatal developmental in (Tif:RAI f (SPF)) rats
43928925 (1995)
0, 5, 50, 500, or 1000 mg/kg/day S-metolachlor (95.6% ai) in 0.5% (w/w) aqueous solution of sodium carboxymethylcellulose (gavage) GD 6-15
Maternal NOAEL = 50 mg/kg/day
LOAEL = 500 mg/kg/day based on increased clinical signs of toxicity, decreased body weights and body weight gains and reduced food consumption and reduced food efficiency.
Developmental NOAEL = 1000 mg/kg/day, highest dose tested.
LOAEL = Not established
Acceptable/ Guideline
870.3700b

Prenatal developmental in (New Zealand White) rabbits
43928924 (1995)
0, 20, 100, or 500 mg/kg/day S-metolachlor (89.6% ai (93.7% S isomer)) suspension in 3% corn starch (gavage) GD 7-19
Maternal NOEL = 20 mg/kg/day
LOEL = 100 mg/kg/day based on clinical signs of toxicity.
Developmental NOAEL = 500 mg/kg/day, highest dose tested.
LOAEL = Not established
Acceptable/ Guideline
870.5100

Gene Mutation
Salmonella & Escherichia/Mammalian Microsome Mutagenicity Test

43928927 (1995)
78.13-1250.0 ug/plate

In independently performed microbial mutagenicity assays, Salmonella typhimurium TA1535, TA1537, TA98, TA100 and TA102 and Escherichia coli WP2 uvrA were initially exposed to 312.5-5000.0 ug/plate CGA-77102 technical (95.6%) in the presence and absence of S9 activation.  For the confirmatory trial, doses of 78.13-1250.0 ug/plate +-S9 were evaluated with S. typhimurium strains TA1535, TA1537, TA100 and TA102; concentrations of 312.5-5000.0 ug/plate +-S9 were examined with S. typhimurium TA 98 and E.coli WP2 uvrA.

In general, doses 1250.0 ug/plate +-S9 were cytotoxic for S. typhimurium TA1535, TA1537, TA100 and TA102 and 5000.0 ug/plate +-S9 was slightly cytotoxic for S. typhimurium TA98 and E. coli WP2 uvrA. There was, however, no indication that CGA-77102 technical induced of a mutagenic effect in any tester strain either in the presence or the absence of S9 activation.
Acceptable/Guideline
870.5395

Cytogenetics Micronucleus test

43928926 (1995)
500, 1000 or 2000 mg/kg

Groups of five male and five female Tif:MAGf(SPF) mice received single oral gavage administrations of 500, 1000 or 2000 mg/kg CGA 77102 technical (95.6%).

Toxic signs, similar to those seen in the preliminary range-finding studies (i.e., ataxia, tremors and/or hunched posture) were recorded for high-dose males and females throughout the 48-hour postexposure.  No bone marrow cytotoxicity was seen at any dose or sacrifice time.  The positive control induced the expected high yield of MPEs in males and females.  There was, however, no evidence that CGA 77102 technical induced a clastogenic or aneugenic effect in either sex at any dose or sacrifice time.
Acceptable/Guideline
870.5550

Other Effects Unscheduled DNA synthesis

43928928 (1995)
500, 1500,  3200 (females), 5000 (males) mg/kg

Groups consisting of three to four rats per sex received single oral gavage administrations of CGA-77102 Technical (95.6%) at doses of 500, 1500 or 5000 mg/kg (males) or 500, 1500 or 3200 mg/kg (females).  Hepatocytes harvested at 15 and 38 hours were evaluated for viability and replicative DNA synthesis (RDS).  For the UDS determination, additional groups (3/sex/dose) were exposed to 500 or 1500 mg/kg and the recovered hepatocytes were scored at 2 or 15 hours postexposure.

Two of four females in the 3200-mg/kg group and 2 of 4 males in the 5000-mg/kg group died prior to the scheduled sacrifice at 38 hours.  Severe cytotoxicity was seen in the hepatocytes recovered from 1 of 2 surviving males and both female survivors in the high-dose groups.  Lower levels were neither toxic to the animals nor cytotoxic to the target cells.  A clear dose-related increase in the percentage of cells in S-phase (RDS) was obtained from hepatocytes harvested 38 hours posttreatment of the male rats.  The response ranged from a 5.3-fold increase at 1500 mg/kg to a 16.1-fold increase at the high dose (5000 mg/kg).  In females, a marked increase in RDS was initially seen at 1500 mg/kg but the response declined over time with a 24.4-fold increase at 15 hours and a 12.2-fold increase at 38 hours.  There was, however, no evidence that the CGA 77102 Technical at doses of 500 or 1500 mg/kg induced a genotoxic response at 2 or 15 hours posttreatment.  We conclude, therefore, that the data indicate that CGA 77102 Technical was negative for genotoxicity but positive for cellular proliferation when tested up to overtly toxic and cytotoxic doses in this in vivo/in vitro rat hepatocyte RDS/UDS assay.
Acceptable/Guideline
870.7485

Metabolism and pharmacokinetics
44491401 (1996)
single dose of 0.5 (group B1) or 100 mg/kg (group D1) radiolabeled CGA-77102; 100 mg/kg/day non-radiolabeled CGA 77102 for 14 days followed by 0.5 mg/kg radiolabeled CGA-77102 (Group V1); single dose of 0.5 or 100 mg/kg radiolabeled CGA-77102 for bile-cannulation study
In all three dose groups (B1, D1, and V1), the seven day combined levels of radioactivity in urine were 31.1 - 36.5% for males and 40.8 - 45.5% for females; the fecal levels were 60.2 - 62.5% for males and 48.9 - 55.0% for females.  Only 0.1% or less was eliminated in the expired air.  The total recovery ranged from 96.5 +- 2.3% to 99.3 +- 0.9%.  The route or extent of excretion was slightly influenced by the sex of the animal but not by pretreatment with non-radiolabeled CGA-77102 or by the dose level.  The degree of absorption, based on adding the cumulative urinary excretion to the total residues in tissues, was 35 - 39% in males and 43 - 49% in females of both dose groups. However, based on the bile duct cannulation study, most of CGA-77102 was absorbed from the gastrointestinal tract since 85% of the dose was recovered in urine, bile fluid, and tissues during the 48 hours study period.  Therefore, the biliary excretion and enterohepatic circulation play a significant role in the elimination process of CGA-77102.

Irrespective of the dose and sex, there seems to be a biphasic plasma profile with two concentration maxima (Cmax); a fast rising first Cmax was reached at 0.25 - 1 hour post dosing which was succeeded by a second Cmax at 8 and at 12 - 24 hours following administration of the low and high dose, respectively.  In the low dose group (B1), the first and second Cmax were nearly identical (~ 0.03 ug/mL); in the high dose group (D1), the first and second Cmax were, respectively, 4.6 and >3.9 ug/mL in males and 2.2 and 4.5 ug/mL in females. The time to half maximum plasma concentration (tcmax/2) in males/females was 31/24 hours at the low dose and 44/32 hours at the high dose.  Bioavailability, or the area under the plasma concentration curve (AUC0-48hr), was nearly identical (~ 0.8 mg/kg.hr) among males and females of the low dose group.  Also, both sexes in the high dose group had similar plasma AUC0-48hr (M/F: 143/125 mg/kg.hr) which increased almost  proportionately with the 200-fold increase in the dose level.  The residues in RBC increased steadily with time reaching peak levels (at 24 - 48 hours post-dosing) of 0.5-0.6 and 90 ppm (or ug/g) CGA-77102 equivalents for the low (B1) and high (D1) dose groups, respectively.  The peak levels in RBC remained high and were nearly 20 fold higher than the respective plasma Cmax levels.
Acceptable/Guideline

The kinetics of tissue distribution and depletion in both sexes were also followed for up to 144 hours following a single low or high oral dose (Groups F1 - F4).  Peak residue levels were reached within 12 - 24 hours and ranged from 0.007 ppm (female muscle) to 0.123 ppm (male kidneys) at the low dose, and from 1.29 ppm (male brain) to 16.82 ppm (male liver) at the high dose, with the highest levels being among some of the well-perfused tissues (e.g., liver, kidneys, spleen, and lungs).    The extent of residue depletion was variable among the tissue types but was minimally affected by the dose or the sex of the animal.  The radiolabel was most persistent in some of the well-perfused organs (e.g., the heart, lungs, and spleen) in addition to the brain and bone where, after 144 hours, the levels were decreased to only 45 - 94% of their maximal concentrations.   In Groups F1 - F4, peak residue concentration in the whole blood (0.2 and 42 - 47 ug/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.

870.7485

Metabolism and pharmacokinetics
44491402 (1996)
single dose of 0.5 (group B1) or 100 mg/kg (group D1) radiolabeled CGA-77102; 100 mg/kg/day non-radiolabeled CGA 77102 for 14 days followed by 0.5 mg/kg radiolabeled CGA-77102 (Group V1); single dose of 0.5 or 100 mg/kg radiolabeled CGA-77102 for bile-cannulation study (from MRID 44491401)
single oral low dose (0.5 mg/kg, Group B2) of [Phenyl-U-[14]C] CGA-24705 (R/S-Metolachlor, racemate)

The 72 hour mean recovery of radioactivity in urine, feces, and carcass following administration of 0.5 mg/kg of [Phenyl-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 44491401).

The urinary and fecal metabolite profiles, with 31 and 15 metabolite fractions, respectively, were qualitatively similar among all groups; however, there were large quantitative differences, based on the dosing formulation, on one hand, and the sex of the animal, on the other.  Based on a percentage of the dose, several of the major urinary metabolite fractions (e.g., U1, U2, U3, U18, U24, and U30) were more abundant in the case of the racemic-Metolachlor (CGA-24705) than the S-Metolachlor (CGA-77102); in contrast, several fecal metabolite fractions (e.g., F9, F10, F12, and F13) were present at higher levels in the case of CGA-77102 than CGA-24705.  On the other hand, there were sex-related differences regardless of the dosing formulation where, for instance, females had greater urinary concentrations than males of several metabolite fractions, including U3, U4, U8, U9, U18, U20, and U30; the males, however, excreted more of fractions U1 and U24 than the females.  Also, several fecal fractions including F1, F3, F5, F6, F7, F8, and F13 were influenced by the sex regardless of the dose level (e.g. B1 vs. D1) or the stereochemical make-up of Metolachlor (B1 vs. B2).  Other metabolite fractions were dependent on both the sex and the chemical formulation as, for instance, in the case of metabolite U2 which, relative to the opposite sex within the same group, was more abundant in the urine of the females of Group B2 (CGA-24705) and in the urine of the males of Group B1 (CGA-77102).

The bile fluid accounted for 79.8% of the administered low or high dose of CGA-77102 (Groups G1 and G2) where the 2D-TLC showed 14 biliary metabolite fractions (G1-G14) in the high dose Group and only six metabolites in the low dose Group.  The two metabolite fractions G7 and G8 accounted, respectively, for 33.3% and 9.6% of the administered low dose and 31.3% and 14.6% of the administered high dose.  Other major biliary metabolites were G3, G9, and G10 which accounted for about 5%, 5-7%, and 3-5%, respectively, of either dose group.

The results clearly show that the metabolite profile in excreta and bile fluid is very complex and that Metolachlor (racemate or S-enantiomer) is extensively metabolized.  This was also shown earlier by another rat metabolism study on the absorption, distribution, excretion, and metabolite identification of racemic CGA-24705 (MRID 43164201, reviewed by T. McMahon, HED doc. no. 010990 dated May 23, 1994).  No actual metabolites or pathways were identified in the current study and there were no data to support or refute the previous findings of four major degradation pathways with more than 30 metabolites.  However, knowing the enantiomeric stereospecific reactions/metabolites is not likely to help in making comparative risk assessments between R/S-Metolachlor (CGA-24705) and S-Metolachlor (CGA-77102) since the contribution of each metabolite to the overall toxicity of Metolachlor is not well understood.  Furthermore, other bridging animal studies with CGA-77102 should highlight possible toxicity differences from the well-studied CGA-24705 due to variations in the metabolite profiles.

The Registrant is requested to comment on or provide information on a number of issues including:  1) The stereoisomeric purity of CGA-24705 and CGA-77102.  2) The adequacy of the storage conditions and the validity of the metabolite profile results in light of the storage-related results variability.  3) Explain why, relative to the other dosing formulation, some metabolite fractions (e.g., F10, F12, and F13) were up to 7-fold higher in the case of the S-enantiomer (CGA-77102) while some urinary metabolite fractions (e.g., U1, U2, and U3) were up to 4-fold higher in the case of CGA-24705.  4) Provide rational for dose selection.  5) The Registrant might also have to comment on the possible formation and the level of methylethylaniline from either dosing formulation and the possible contribution of this metabolite to the carcinogenicity of Metolachlor.  This issue was raised earlier by T. McMahon (HED document no. 010990 dated May 23, 1994) and might need to be followed up by HED's risk assessors who are in charge of S-Metolachlor.
Unacceptable/Guideline
870.7800
Immunotoxicity in mice
48783301 (2012)
0, 1500, 3000 or 5000 ppm (0, 304.3, 639.5, or 1108.5 mg/kg/day

NOAEL = 5000 ppm (1108.5 mg/kg/day)
LOAEL = Not Established

Acceptable/Guideline

A.3	Hazard Identification and Endpoint Selection

A.3.1	Acute Reference Dose (aRfD) - Females age 13-49

An endpoint was not selected for Females 13-49 years old since no developmental effects that could be attributed to a single exposure were identified in the metolachlor/s-motolachlor database.

A.3.2	Acute Reference Dose (aRfD) - General Population

Study Selected: Developmental Toxicity in Rats - Metolachlor
MRID No.: 00151941
Dose and Endpoint for Risk Assessment:
300 mg/kg/day based on a NOAEL of 1000 mg/kg/day and an LOAEL of 1000 mg/kg/day based on an increased incidence of death, clinical signs of toxicity (clonic and/or tonic convulsions, excessive salivation, urine-stained abdominal fur and/or excessive lacrimation) and decreased body weight gain.
Comments about Study/Endpoint/Uncertainty Factors:
Since clinical signs are observed after a single oral dose of metolachlor, the duration and route of administration are appropriate for the risk assessment.  Developmental effects observed are not attributable to a single exposure and therefore, a separate acute endpoint has not been identified for females 13-50.  Although increased incidence of death is one of the effects seen, it was seen at a dose (1000 mg/kg/day) approximately three times higher than the dose (300 mg/kg/day) selected for risk assessment; therefore, the Agency is confident that adequate safety is provided to protect the public from dietary exposure to residues of metolachlor.   The total UF is 100 (10X for interspecies uncertainty factor and 10X for intraspecies variability.
       Acute RfD  (General Population) =  (NOAEL) 300 mg/kg =  3.0 mg/kg
                                                      (UF) 100

A.3.3	Chronic Reference Dose (cRfD) `

Study Selected: Chronic Feeding Study in Dogs
MRID No.: 43744201
Dose and Endpoint for Risk Assessment: 9.7 mg/kg/day based on a NOAEL of 9.7 mg/kg/day and a LOAEL of 33 mg/kg/day based on decreased body weight gain in females.
Comments about Study/Endpoint/Uncertainty Factors:   This study was selected because the database shows dogs were the most sensitive species and decreased body weight gain the most sensitive endpoint.  The duration of 1 year and route of exposure through the feed is also appropriate.  The total UF is 100 (10X for interspecies uncertainty factor and 10X for intraspecies variability).

     Chronic RfD  (General Population) =  (NOAEL) 9.7 mg/kg =  0.097 mg/kg
                                                      (UF) 100

A.3.4	Incidental Oral Exposure (Short- and Intermediate-Term)

Study Selected: Developmental Toxicity Study in Rats
MRID No.: 43928925
Dose and Endpoint for Risk Assessment: 50 mg/kg/day based on a maternal NOAEL of 50 mg/kg/day and a LOAEL of 500 mg/kg/day based on increased incidence of clinical signs, decreased body weight/body weight gain, food consumption and food efficiency seen in maternal animals.
Comments about Study/Endpoint/Uncertainty Factors:   The NOAEL (20 mg/kg/day) for the prenatal developmental toxicity study in rabbits with S-metolachlor (MRID 43928924) was lower than the 50 mg/kg/day from the rat developmental study.  However, the endpoint was based on weak clinical signs of toxicity (increase in little/none/soft stool observations) at 100 mg/kg/day.  Although there was a dose-related increase in this effect, it is not evidence of frank toxicity and was judged not be appropriate for risk assessment.  Therefore, the rabbit study with S-metolachlor was not selected for this exposure scenario.  The total UF is 100 (10X for interspecies uncertainty factor and 10X for intraspecies variability).

A.3.5	Dermal Exposure (Short -Term)