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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: Hope Johnson, (703) 305-5410

Syngenta Crop Protection, LLC

Petition #4F8323

EPA has received a pesticide petition (4F8323) from Syngenta Crop Protection, 

LLC, 410 Swing Road, Greensboro, NC 27409 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

1. by establishing a tolerance for residues of

Mefenoxam: methyl N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-DL-alaninate in 

or on the raw agricultural commodity Rapeseed Crop Subgroup 20A at 0.05 parts per 

million (ppm). 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 metabolism of mefenoxam is adequately understood for 

the purpose of the proposed tolerance.]

2. Analytical method. [Canola: The analytical method used was Novartis Crop 

Protection Method 456-98, “Confirmatory Analytical Method for the Enantioselective 

Determination of Residues of Parent Metalaxyl (CGA-48988) or Mefenoxam (CGA329351) in Crop Substrates by Chiral High Performance Liquid Chromatography with 

Mass Spectrometric Detection”, March 1999, MRID 44976201.

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

tolerances have been submitted. The requested tolerances are adequately supported by

previously submitted studies. In support of the requested tolerances, Syngenta has 

conducted the necessary trials in accordance with the requirements of the EPA Residue 

Chemistry Guidelines 860.1500 to determine the magnitude of residue of mefenoxam in 

or on requested commodities.]

B. Toxicological Profile
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1. Acute toxicity. [The toxicological endpoints for mefenoxam are discussed in 

B.4. of the Federal Register Notice of July 25, 1997, (62 FR 40084) (FRL-5726-4). The 

acute toxicity profile can be summarized as follows:

Rat acute oral study with LD50 value of 490 milligrams/kilograms (mg/kg).

Rat acute dermal study with LD50 >2,000 mg/kg.

Rat inhalation study with a LC50 >2.29 milligram/liter (mg/L) air.

Primary eye irritation study in rabbit shows mefenoxam as severely irritating. 

Primary dermal irritation study in rabbit shows mefenoxam as slightly irritating. 

Skin sensitization studies in guinea pigs (maximization and Buehler Test) show 

mefenoxam is not a sensitizer.]

2. Genotoxicty. [The toxicological endpoints for mefenoxam are discussed in 

B.4. of the Federal Register Notice of July 25, 1997, (62 FR 40084). The genotoxicity

profile can be summarized as follows:

In vitro gene mutation test: Ames test-negative.

In vitro chromosomal aberration test: Chinese hamster ovary (CH0)-negative.

In vitro gene mutation tests: Ames tests (3 independent studies)- negative;

gene mutation in mouse lymphoma cells-negative; reverse mutation in 

saccharomyces cerevisiae-negative.

In vitro chromosomal aberration tests: Chinese hamster bone marrow 

cytogenetic test-negative. DNA repair study in rat hepatocytes-negative.]

3. Reproductive and developmental toxicity. [The toxicological endpoints for 

mefenoxam are discussed in B.4. of the Federal Register Notice of July 25, 1997, (62

FR 40084). The reproductive and developmental toxicity profile can be summarized as 

follows:

Teratology study in rats with a maternal no observed adverse effect level 

(NOAEL) of 10 mg/kg based on reduced body weight (bwt) gain. The 

fetuses remained entirely unaffected at the highest dose tested (HDT), 250 

mg/kg.

Teratology study in rabbits with a maternal NOAEL of 150 mg/kg based on 

bwt loss. The developmental NOAEL was greater than or equal to the 

HDT, 300 mg/kg.

Three-generation reproduction study in rats with a NOAEL of 1,250 ppm, which

was the HDT. The treatment had no effect on reproduction or fertility.

Dominant lethal study in mouse-negative. ]

4. Subchronic toxicity. [The toxicological endpoints for mefenoxam are 

discussed in B.4. of the Federal Register Notice of July 25, 1997, (62 FR 40084). The 

subchronic toxicity profile can be summarized as follows:

A 28-day cumulative toxicity study in rats with a NOAEL of 50 mg/kg based 

on liver changes.

A 90-day subchronic dietary toxicity study in rats with a NOAEL of 250 ppm

based on liver changes.

A 90-day subchronic dietary toxicity study in dogs with a NOAEL of 250 

ppm based on changes in blood biochemistry and hematology indicative 

of functional liver changes.
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A 21-day dermal toxicity study in rats with a NOAEL equal to or higher than

the limit dose of 1,000 mg/kg. No local or systemic signs of toxicity were 

found.

A 6-month dietary toxicity study in dogs with a NOAEL of 250 ppm based on 

changes in blood biochemistry indicative of hepatocellular damage.]

5. Chronic toxicity. [The toxicological endpoints for mefenoxam are discussed 

in B.4. of the Federal Register Notice of July 25, 1997, (62 FR 40084). The chronic 

toxicity profile can be summarized as follows:

A 24-month combined chronic toxicity/carcinogenicity study conducted in 

rats with a NOAEL of 250 ppm based on liver changes. No evidence of 

oncogenicity was seen.

A 24-month oncogenicity study conducted in mice with a NOAEL of 250 ppm 

based on liver changes. No evidence of oncogenicity was seen.]

6. Animal metabolism. [The rat and goat rapidly metabolize and excrete via 

the same metabolic pathways as plants. Urinary metabolites are polar, primarily

gucuronide and other conjugates. The parent compound is not retained in animal 

tissues nor secreted in milk.]

7. Metabolite toxicology. [Metabolites are considered to be of equal or less 

toxicity than the parent material]

8. Endocrine disruption. [Mefenoxam does not belong to a class of chemicals 

known or suspected of having adverse effects on the endocrine system. Furthermore, 

supporting developmental toxicity studies in rats and rabbits, and a reproduction 

study in rats gave no indication of any effects on endocrine function related to 

development and reproduction. Subchronic and chronic treatment did not induce any 

morphological changes in endocrine organs and tissues.]

C. Aggregate Exposure

1. Dietary exposure. [Tier II chronic and short-term aggregate exposure

evaluations were made for mefenoxam using the using the Dietary Exposure 

Evaluation Model (DEEM-FCIDTM Version 3.16) from Exponent, which utilizes 

consumption data from the USDA NHANES “What We Eat in America” survey, 2003-

2008. Established tolerances for mefenoxam and/or metalaxyl were used for all 

existing uses, as well as proposed tolerances for the Oilseed Crop Group 20. Percent of 

crop treated values were conservatively estimated based upon economic, pest, and 

competitive pressures. Drinking water estimates were selected using the higher of the 

estimated drinking water concentrations (EDWCs) for surface and ground water.]

i. Food. [Acute Exposure. Acute dietary exposure assessments were not 

performed since the EPA was has not established an acute endpoint of concern for 

mefenoxam.

Chronic Exposure. The mefenoxam chronic dietary (food only) risk assessment was 
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performed for all population subgroups with a chronic reference dose (cRfD) of 0.074 

mg/kg-bw/day based on a six-month feeding study in dogs with a no observed adverse 

effect level (NOAEL) of 7.4 mg/kg-bw/day and an uncertainty factor of 100X. The 

100X safety factor includes intra- and inter-species variations. No additional FQPA 

safety factor was applied. For the purpose of aggregate risk assessment, 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,

exposure was expressed as a percent of the reference dose (%RfD). Chronic (food only) 

exposure to the U.S. population resulted in a MOE of 654 (15.3% of the cRfD of 0.074 

mg/kg-bw/day). The most exposed sub-population was children (1-2 years old) with a 

MOE of 267 (37.5% of the cRfD). Since the benchmark MOE for these assessments 

was 100 and since EPA generally has no concern for exposures above the benchmark 

or below 100% of the reference dose, Syngenta believes that there is a reasonable 

certainty that no harm will result from dietary (food only) exposure to residues arising 

from the current and proposed tolerances and label amendments for mefenoxam.

Cancer. Based on the classification of metalaxyl, mefenoxam is also considered “not 

likely to be a human carcinogen”. Therefore, no cancer risk assessment was performed 

for mefenoxam.]

ii. Drinking water. [The Estimated Drinking Water Concentrations (EDWCs) of 

mefenoxam were determined using Tier l SCI-GROW (version 2.3), which estimates 

pesticide concentrations in ground water and Tier II PRZM/EXAMS (PE version 5.0) 

which estimates pesticide concentrations in surface water. The application and use 

parameters for the proposed use on oilseeds, crop group 20 were modeled along with 

the currently registered uses to identify the highest EDWCs. The currently registered 

use on citrus based on a treatment rate of 3.0 lbs ai/A, with 2 applications at an interval 

of 60 days was determined to be the crop driver. For ground water, the SCI-GROW 

model provided a chronic EDWC of 1.72 ppb for mefenoxam. For surface water, 

employing the FL citrus standard PRZM scenario, the PRZM/EXAMS output provided 

a chronic EDWC of 22.9 ppb for mefenoxam. This surface water EDWC has not been 

adjusted for Percent Cropped Area. Since the surface water EDWC exceeds the ground 

water EDWC, the surface water chronic exposure value will be used for risk 

assessment purposes and considered protective for any ground water concentration 

concerns.

Drinking water estimates were incorporated directly into the dietary exposure 

assessment along with the food exposure using the higher of the estimated drinking 

water concentrations (EDWCs) for surface water (22.9 ppb). Chronic drinking water 

exposure to the U.S. population resulted in a MOE of 15,433 (0.6% of the cRfD of 

0.074 mg/kg-bw/day). The most exposed sub-population was infants <1 year old with 

a MOE of 5,985 (1.7% of the cRfD). Since the benchmark MOE for these assessments 

was 100 and since EPA generally has no concern for exposures above the benchmark 

or below 100% of the reference dose, Syngenta believes that there is a reasonable 

certainty that no harm will result from drinking water exposure to residues arising 

from all current and proposed uses for mefenoxam.]
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2. Non-dietary exposure. [The use of mefenoxam on residential turf may result 

in short- or intermediate-term exposures to selected subgroups. A short-term inhalation 

toxicological endpoint of 50 mg/kg-bw/day was selected based upon the no observed 

adverse effect level (NOAEL) from a dev tox study in rats, with an uncertainty factor 

of 100X, which includes intra- and inter-species variations; no additional FQPA safety 

factor was applied. An intermediate-term inhalation toxicological endpoint of 7.41 

mg/kg-bw/day was selected based upon the no observed adverse effect level (NOAEL) 

from a 6-month feeding study in the dog, with an uncertainty factor of 100X, which 

includes intra- and inter-species variations; no additional FQPA safety factor was

applied. Exposure values were expressed in terms of margin of exposure (MOE), which 

was calculated by dividing the NOAEL by the exposure for each subgroup. Residential 

exposure risk assessments were performed for use of mefenoxam formulated as Subdue 

GR, Subdue WSP, and Subdue MAXX for residential turf). Assessments were also 

performed for exposure due to off-site drift of agricultural products. Application of 

mefenoxam by residents is allowed; therefore residential handler exposure assessments 

are required. Adults 13+ years old had a short-term residential MOE of 501,974 (hoseend sprayer; liquid concentrate); children 1-6 years old had MOEs of 4,786 (hand-tomouth; liquid concentrate). Since the Benchmark MOE for this assessment was 100 

and since the EPA generally has no concern for exposures above the Benchmark MOE, 

Syngenta believes that there is a reasonable certainty that no harm will result from 

short- and intermediate-term residential exposure to residues arising from all current 

and proposed uses of mefenoxam.]

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 does not have, at this time, available data 

to determine whether mefenoxam has a common mechanism of toxicity with other 

substances or how to include this pesticide in a cumulative risk assessment. For the 

purposes of this tolerance action, the EPA has not assumed that mefenoxam has a 

common mechanism of toxicity with other substances.]

E. Safety Determination

1. U.S. population. [Using the conservative assumptions described above, and 

based on the completeness and reliability of the toxicity data, the short- and 

intermediate-term aggregate exposure calculations for all current and proposed uses of 

mefenoxam provided MOEs of 4,238 and 628, respectively, for the U.S. population. 

The chronic aggregate exposure calculation for all current and proposed uses of 

mefenoxam provided a MOE of 627 (15.9% of the cRfD 0f 0.074 mg/kg-bw/day) for 

the U.S. population. Since the aggregate MOEs exceed the Benchmark MOE of 100, 

Syngenta believes that there is a reasonable certainty that no harm will result from 

aggregate exposure to residues arising from all current and proposed uses of 
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mefenoxam, including anticipated dietary exposure from food, water, and all other 

types of non-occupational residential exposures.]

2. Infants and children. [Using the conservative assumptions described above, 

and based on the completeness and reliability of the toxicity data, the short- and 

intermediate-term aggregate exposure calculations for all current and proposed uses of 

mefenoxam provided MOEs of 1,286 and 261, respectively, for children 1-2 years old. 

The chronic aggregate exposure calculation for all current and proposed uses of 

mefenoxam provided a MOE of 260 (38.4% of the cRfD 0f 0.074 mg/kg-bw/day) for 

children 1-2 years old. Since the aggregate MOEs exceed the Benchmark MOE of 100, 

Syngenta believes that there is a reasonable certainty that no harm will result from 

aggregate exposure to residues arising from all current and proposed uses of 

mefenoxam, including anticipated dietary exposure from food, water, and all other 

types of non-occupational residential exposures.]

F. International Tolerances

[There are no Codex MRLs established for residues of mefenoxam in any 

plant or animal commodity. Codex MRLs have been established for metalaxyl, the 

racemic fungicide mixture containing the active isomer mefenoxam, in a number of 

commodities including asparagus, avocado, broccoli, Brussels sprouts, cabbage, 

cacao, carrot, cauliflower, cereal grains, citrus, cotton seed, cucumbers, grapes, hops, 

lettuce, melons, onions, peanuts, peas (succulent), peppers, pome fruits, potatoes, 

raspberries, soybeans, spices, spinach, squash, sugar beet, sunflower seed, and 

tomatoes.]