Interregional Research Project Number 4 (IR-4)

Petition #4E8248

EPA has received a pesticide petition (4E8248) from Interregional Research 

Project No. 4 (IR-4), 500 College Road East, Suite 201 W, Princeton, NJ 08540

requesting, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act 

(FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a tolerance for 

residues of S-metolachlor in or on the raw agricultural commodity lettuce at 1.5 parts per 

million (ppm), cucurbit vegetable crop group 9 at 0.50 ppm, vegetable, fruiting, group 8-

10, except tabasco pepper, low growing berry subgroup 13-07G excluding cranberry at 

0.40 ppm, and sunflower subgroup 20B at 0.50 ppm and the concurrent deletion of the 

existing tolerance for okra. EPA has determined that the petition contains data or

information regarding the elements set forth in section 408 (d)(2) of FDDCA; however, 

EPA has not fully evaluated the sufficiency of the submitted data at this time or whether 

the data supports granting of the petition. Additional data may be needed before EPA 

rules on the petition.

A. Residue Chemistry

1. Plant metabolism. The qualitative nature of S-metolachlor residues in plants is 

adequately understood for the purpose of the proposed tolerances, based upon acceptable 

corn, potato and soybean metabolism studies. The metabolism of S-metolachlor involves 

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

of the mercaptan with glucuronic acid, hydrolysis of the methyl ether, and conjugation of 

the resultant alcohol with a neutral sugar. EPA has determined that, for S-metolachlor, 

residues of concern in plants include parent and metabolites, determined as the 

derivatives CGA-37913 and CGA-49751.

2. Analytical method. Syngenta has developed and validated analytical 

methodology for enforcement purposes. A gas chromatography-nitrogen phosphorus 

detection (GC/NPD) method has been submitted to the Agency for determining residues 

in/on crop commodities and is published in PAM Vol. II, Method I. A gas 

chromatography-mass selective detection (GC/MSD) method has been submitted to the 

Agency for determining residues in livestock commodities and is published in PAM Vol. 

II, Method II. These methods determine residues of S-metolachlor and its metabolites as 

either CGA-37913 or CGA-49751 following acid hydrolysis. An extensive database of 

method validation data using these methods on various crop commodities is available.

3. Magnitude of residues. Complete residue data to support the requested 

tolerances are submitted or referenced with this petition. The residue studies were 

conducted per EPA Test Guidelines 860.1000 and 860.1500.

B. Toxicological Profile

1. Acute toxicity. The database for acute toxicity of S-metolachlor is considered to 

be complete. S-metolachlor is moderately acutely toxic (toxicity category III) by the oral 
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and dermal routes of exposure and relatively non-toxic (toxicity category IV) by the 

inhalation route of exposure. It causes slight eye irritation (toxicity category III) and is 

non-irritating dermally (toxicity category IV). The active ingredient was found to be 

positive in a dermal sensitization test but this effect is mitigated in end-use product 

formulations.

2. Genotoxicty. Gene mutation (Guideline 870.5100), micronucleus (Guideline 

870.5395) and unscheduled DNA synthesis (Guideline 870.5550) studies conducted with 

S-metolachlor have been reviewed and approved by EPA. There is no evidence of a 

mutagenic or cytogenetic effect in vivo or in vitro with S-metolachlor.

3. Reproductive and developmental toxicity. Prenatal developmental studies in the 

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

susceptibility in fetal animals. No significant developmental toxicity was observed in 

most studies even at the highest dose tested. In a two-generation reproduction study, 

there was no evidence of parental or reproductive toxicity at the highest dose tested (80 

mg/kg/day). The results indicate that S-metolachlor is not embryotoxic or teratogenic in 

either species at maternally toxic doses.

4. Subchronic toxicity. In a 90-day dietary study in rats with S-metolachlor, no 

effects were observed in males or females at 209 and 236 mg/kg/day, respectively. In 

another 90-day dietary study in rats, decreased body weight, reduced food consumption 

and food efficiency in both sexes and increased kidney weight gain in males was 

observed at 150 mg/kg/day; the NOAEL was 15 mg/kg/day. A 90-day dog study with Smetolachlor has been accepted by EPA; no effects were observed in males and females at 

62 mg/kg/day and 74 mg/kg/day, respectively, which were the highest doses tested.

5. Chronic toxicity. Chronic studies in both the rat and dog with S-metolachlor 

revealed no significant chronic toxicity. In the rat, a decrease in body weight was 

observed at the highest dose tested. In the dog, the only adverse effect was decreased 

body weight gain in females at 33 mg/kg/day; the NOAEL was 10 mg/kg/day.

6. Animal metabolism. Animal metabolism studies have shown that S-metolachlor 

is extensively absorbed, rapidly metabolized and almost totally eliminated following oral 

administration in rats, goats and poultry. S-metolachlor was primarily absorbed from the 

gastrointestinal tract and ultimately eliminated in the excreta of the species tested. 

Metabolism in animals proceeds through common Phase 1 intermediates and glutathione 

conjugation.

7. Metabolite toxicology. The metabolism of S-metolachlor has been well 

characterized in standard FIFRA metabolism studies. S-metolachlor does not readily

undergo dealkylation to form an aniline or quinone imine as has been reported for other 

members of the chloroacetanilide class of chemicals. Therefore, as EPA has agreed, it is 

not appropriate to include S-metolachlor with the group of chloroacetanilides that readily 

undergo dealkylation, producing a common toxic metabolite (quinone imine). EPA has 

reviewed toxicology data submitted by Syngenta demonstrating that the S-metolachlor 

metabolites ethane sulfonic acid (CGA 354743) and oxanilic acid (CGA 51202) are not 
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absorbed by mammalian systems and/or have a significantly lower level of mammalian 

toxicity when compared to parent.

8. Endocrine disruption. S-metolachlor does not belong to a class of chemicals 

known or suspected of having adverse effects on the endocrine system. There is no 

evidence that S-metolachlor has any effect on endocrine function in developmental or 

reproduction studies. Furthermore, histological investigation of endocrine organs in the 

chronic dog, rat and mouse studies did not indicate that the endocrine system is targeted 

by S-metolachlor, even at maximally tolerated doses administered for a lifetime. There is 

no evidence that S-metolachlor bioaccumulates in the environment.

C. Aggregate Exposure

1. Dietary exposure. Acute (Tier I) and chronic (Tier II) dietary exposure 

evaluations were made for S-metolachlor using the Dietary Exposure Evaluation Model 

software with the Food Commodity Intake Database (DEEM-FCIDTM, version 3.15). 

DEEM-FCID software incorporates food consumption data from the National Health and 

Nutrition Examination Survey “What We Eat in America” (NHANES/WWEIA) dietary

survey conducted in 2003-2008. These aggregate human health assessments include all 

current and pending uses as well as proposed new IR-4 uses on head lettuce, leaf lettuce, 

low-growing berries (Subgroup 13-07G), cucurbits (Crop Group 9), and revised crop 

groupings for fruiting vegetables (Group 8-10, except tabasco peppers), and sunflowers 

(Subgroup 20B). The acute exposure assessments were based on established or proposed 

tolerances for S-metolachlor. The chronic exposure assessments were based on average 

field trial residues, established tolerances, or market basket survey data (potato and 

tomato). The percent of crop treated (%CT) was assumed to be 100% for all 

commodities. Secondary residues in animal commodities were estimated based on 

“maximum reasonably balanced dietary burdens” and transfer information from 

metabolism and feeding studies.

i. Food. Acute Risk. The acute dietary risk assessments were performed for all 

population subgroups with an acute reference dose of 3.0 mg/kg-bw/day based on an 

acute no observed adverse effect level (NOAEL) of 300 mg/kg/day prenatal 

developmental toxicity study in rats and an uncertainly factor of 100X. The 100X safety

factor includes intra- and interspecies variations. No additional FQPA safety factor was 

applied. The acute assessments were run using DEEM-FCIDTM software using 

established tolerances for S-metolachlor and 100% crop treated values. For the purpose 

of the aggregate risk assessments, the exposure values were expressed in terms of margin 

of exposure (MOE), which was calculated by dividing the NOAEL by the exposure for 

each population subgroup. In addition, exposures were expressed as a percent of the 

acute reference dose (% aRfD). Acute food exposure to the U.S. population resulted in a 

MOE of 60,235 or 0.2% of the aRfD (Benchmark MOE =100; aRfD = 3.0 mg/kgbw/day). Acute food exposure to the most sensitive subpopulation (children 1 to 2 years 

old) resulted in a MOE of 26,373 or 0.4% of the aRfD (Benchmark MOE =100; 3.0 

mg/kg-bw/day). 

Chronic Risk. The chronic assessments were run using DEEM-FCIDTM software using 
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average field trial residue values, USDA-PDP residues, SMBS data, and 100% crop 

treated values. The chronic dietary risk assessments were performed for all population 

subgroups with a chronic reference dose of 0.1 mg/kg-bw/day based on a one-year 

feeding study in dogs with a NOAEL of 9.7 mg/kg/day and an uncertainly factor of 

100X. The 100-fold safety factor includes intra- and interspecies variations. No 

additional FQPA safety factor was applied. For the purpose of the aggregate risk 

assessments, the exposure values were expressed in terms of margin of exposure (MOE), 

which was calculated by dividing the NOAEL by the exposure for each population 

subgroup. In addition, exposures were expressed as a percent of the reference dose (% 

cRfD). Chronic food exposure to the U.S. population resulted in a MOE of 13,860 or 

0.7% of the cRfD (Benchmark MOE = 100; cRfD = 0.1 mg/kg-bw/day). Chronic food 

exposure to the most exposed sub-population (children, 1-2 years old) resulted in a MOE 

of 5,829 or 1.7% of the cRfD (Benchmark MOE = 100; cRfD = 0.1 mg/kg-bw/day). 

Cancer. S-metolachlor has been classified as a Group C, possible human carcinogen 

based on the occurrence of liver tumors in rats. The NOAEL that was established based 

on tumors in rats (15 mg/kg/day) is comparable to the NOAEL of 9.7 mg/kg/day selected 

for the chronic reference dose. Therefore the chronic dietary end point is protective for 

cancer dietary exposure.

ii. Drinking water. [The estimated drinking water concentrations (EDWCs) for 

surface water and groundwater were taken from the First Index Reservoir Screening Tool 

(FIRST), Pesticide Root Zone Model/Exposure Analysis Modeling System 

(PRZM/EXAMS) and Screening Concentration in Ground Water (SCI-GROW) models; 

as well as monitoring data from two National Water Quality Assessment (NAWQA) 

programs. The maximum concentration of parent metolachlor / S-metolachlor detected in 

a nationwide NAWQA surface water monitoring program (that did not analyze for the 

degradates) was used as the peak surface water EDWC for the acute assessment; the onein-ten-year maximum annual average PRZM/EXAMS concentration was used as the 

chronic surface water EDWC. For the metolachlor ethanesulfonic acid (ESA) and 

metolachlor oxanilic acid (OA) metabolites, the one-in-ten-year maximum FIRST 

concentrations were used as peak surface water EDWCs for the acute assessment; one-inten-year annual averages were used as the chronic surface water EDWCs. Groundwater 

EDWCs for parent metolachlor / S-metolachlor and the ESA metabolite were taken from 

the nationwide and Iowa / Illinois NAWQA groundwater monitoring programs; 

maximum (upper bound) detections were used for both acute and chronic groundwater 

EDWCs, since time weighted means were not available. For the OA metabolite, the SCIGROW concentration was used.

For surface water, the EDWCs of parent metolachlor / S-metolachlor and its degradates 

were estimated to be 218.78 ppb (parent: 77.60 ppb, ESA: 47.61 ppb, and OA: 93.57 

ppb) for acute exposure and 118.81 ppb (parent: 18.15 ppb, ESA: 34.04 ppb, and OA: 

66.62 ppb) for chronic exposure. For ground water the EDWCs of parent metolachlor / 

S-metolachlor and its degradates were estimated to be 126.2 ppb (parent: 32.8 ppb, ESA: 

63.7 ppb, and OA: 29.7 ppb) for both acute and chronic exposure.
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Acute Exposure from Drinking Water. The acute EDWC of 218.78 ppb for surface water 

was used in the DEEM-FCIDTM software as “water, direct and indirect, all sources” to 

model the acute drinking water exposures. The acute drinking water exposure 

contributions at the 95%-ile of exposures were determined by taking the difference 

between the aggregate (food + drinking water) exposures and the food exposures for each 

population subgroup. Acute drinking water exposure to the U.S. population resulted in 

an MOE of 29,101 or 0.3% of the aRfD (Benchmark MOE = 100; aRfD = 3.0 mg/kgbw/day). Acute drinking water exposure to the most exposed sub-population (infants, <1 

year old) resulted in an MOE of 9,465 or 1.1% of the aRfD (Benchmark MOE = 100; 

aRfD = 3.0 mg/kg-bw/day).

Chronic Exposure from Drinking Water. The predicted chronic ground water value of 

126.2 ppb was input directly into the DEEM-FCIDTM software as water, direct and 

indirect, all sources to model the chronic drinking water exposure. Chronic drinking 

water exposure to the U.S. population resulted in an MOE of 3,677 or 2.6% of the cRfD 

(Benchmark MOE = 100; cRfD = 0.1 mg/kg-bw/day). Chronic drinking water exposure 

to the most exposed subpopulation (infants, <1 year old) resulted in an MOE of 1,426 or 

6.8% of the cRfD (Benchmark MOE = 100; cRfD = 0.1 mg/kg-bw/day).

2. Non-dietary exposure. There is a potential for post-application exposure to 

adults and children resulting from professionally-applied treatments of S-metolachlor on 

residential lawns. Post-application exposure is considered to be short-term based on label 

directions limiting application to one time per season. Since toxicity was not observed in 

a dermal toxicity study, up to a dose level of 1,000 mg/kg/day, the only parameter of 

short-term residential risk that needs to be addressed is the possible oral exposure of 

toddlers and children from treated turf or soil. Using these exposure assumptions, the 

short-term residential exposures from metolachlor/S-metolachlor resulted in an aggregate 

MOE of 1,314 for children, 1-2 years. Note that there are no non-dietary contributions to 

the aggregate MOE for adults or infants (<1 year) from turf uses since none of the oral 

exposure scenarios (hand-to-mouth, object-to-mouth, soil ingestion) would be applicable 

to these subpopulations.

D. Cumulative Effects

Cumulative Exposure to Substances With a Common Mechanism of Toxicity. 

Section 408(b)(2)(D)(v) 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”. The EPA has examined the common mechanism 

potential for S-metolachlor and has concluded that S-metolachlor should not be included 

with the chloroacetanilide pesticides designated as a “Common Mechanism Group.” The 

Agency’s position is that only some chloroacetanilides, namely acetochlor, alachlor and 

butachlor should be considered as a “Common Mechanism Group” due to their ability to 

cause nasal turbinate tumors.

E. Safety Determination
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1. U.S. population. Using the conservative assumptions described above, and 

based on the completeness and reliability of the toxicity data, the acute aggregate 

exposure calculation for all current, pending, and proposed uses of S-metolachlor 

provided an MOE of 19,621 or 0.5% of the aRfD (Benchmark MOE = 100; aRfD = 3.0 

mg/kg-bw/day) for the U.S. population. The chronic aggregate exposure calculation for 

all current, pending, and proposed uses of S-metolachlor provided an MOE of 2,906 or 

3.3% of the cRfD (Benchmark MOE = 100; cRfD = 0.1 mg/kg-bw/day) for the U.S. 

population.

2. Infants and children. Using the conservative assumptions described in the 

exposure section above, and based on the completeness and reliability of the toxicity

data, the acute aggregate exposure calculation for all current, pending, and proposed uses 

of S-metolachlor provided an MOE of 7,357 or 1.4% of the aRfD (Benchmark MOE = 

100; aRfD = 3.0 mg/kg-bw/day) for infants < 1 year old (the most sensitive 

subpopulation for the acute assessment). The short-term aggregate assessment resulted in 

an MOE of 1,149 for the children (1-2 years old) population subgroup (Benchmark MOE 

= 100). The chronic aggregate exposure calculation for all current, pending, and 

proposed uses of S-metolachlor provided an MOE of 1,220 or 7.9% of the cRfD 

(Benchmark MOE = 100; cRfD = 0.1 mg/kg-bw/day) for infants <1 year old (the most 

sensitive subpopulation for the chronic assessment).

F. International Tolerances

There are currently no Maximum Residue Limits (MRLs) set for S-metolachlor 

for crops by the Codex Alimentarius Commission. International MRLs for the herbicide 

S-metolachlor have been established for various agricultural commodities in a number of 

countries including Argentina, Australia, Austria, Belarus, Belgium, Brazil, Canada, 

Czech Republic, France, Georgia, Germany, Greece, Hungary, India, Italy, Japan, Korea 

(South), Luxembourg, Malaysia, Moldova, Morocco, Netherlands, New Zealand, Russia, 

Serbia and Montenegro, Slovak Republic, Slovenia, Spain, Switzerland, Taiwan, and 

Ukraine.