Mefenoxam Human Health Risk Assessment DP No. D424727 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

MEMORANDUM 

Date: April 6, 2016 

WASHINGTON, D.C. 20460 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Mcfenoxam. Human Health Risk Assessment for Proposed Use on the Rapeseed 

Subgroup 20A. 

PC Code: 113502 

Decision No.: 497002 

DP Barcodc: D424727 

Registration No.: 100-791, 100-799 

Petition No.: 4F8323 Regulatory Action: Section 3 Registration 

Risk Assessment Type: Single Chemical/ Aggregate Case No.: NA 

TXRNo.: NA 

MRIDNo.: NA 

CAS No.: 70630- 17-0 

40 CFR: § 180.546 

FROM: Minerva Mercado, Risk Assesso~-;;)' -

Nancy oodd, chemist ~ ~a.r::-- L~ura 

Vincent 

Nolle

Chen. 

n, ORE. 

Tox1colog1st 

Asse~so~ 1 __ 

-

~ 

-

c::.------ Ri s k Assessment Branch 3 (RAB3) -

Health Effects Division (HED; 7509P) 

THROUGH: Christine Olinger, Branch Chief /// /-1C 

RAB3!HED (7509P) ~ ;' c:/ '----

TO: Hope Johnson, Product Manager 

Maryam K. Muhammad, Biologists 

Fungicide Branch 

Registration Division (7505P) 

The Registration Division has requested that HED evaluate hazard and exposure data and 

conduct dietary, occupational, residential, and aggregate exposure assessments, as needed. to 

estimate the risk to human health that will result from the proposed use of mefenoxam on the 

rapeseed subgroup 20A. 

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Mefenoxam Human Health Risk Assessment DP No. 0424727 

Table of contents 

1.0 Executive Summary .............................................................................................................................. 3 

2.0 HED Recommendations ........................................................................................................................ 4 

2.1 Data Deficiencies ........................................................................................................................... 4 

2.2 Tolerance Considerations ............................................................................................................... 5 

2. 1. 1 Enforcement Analytical Method ......................................................................................... 5 

2.2.2 Recomrnended Tolerances ................................................................................................... 5 

2.2.3 Revisions to Petitioned-For Tolerances ............................................................................... 7 

2.2.4 International Harmonization ................................................................................................ 7 

2.3 Label Recomn1endations ................................................................................................................ 8 

3.0 Introduction ........................................................................................................................................... 8 

3.1 Chemica l Identity ........................................................................................................................... 8 

3.2 Physical/Chemical Characteristics .................................................................................................. 9 

3.3 Pesticide Use Panern ....................................................................................................................... 9 

3.4 Anticipated Exposure Pathways ..................................................................................................... 10 

3.5 Consideration of Environmental Justice .......................................................................................... I 0 

4.0 Hazard Characterization and Dose-Response Assessment ..................................................................... 10 

4.1 Toxicology Studies Available for Analysis .................................................................................... 11 

4.2 Absorption. Distribution. Metabolism. and Elimination (ADME) ................................................. 11 

4.2.1 Dermal Absorption ............................................................................................................... 12 

4.3 Toxicological Effects ...................................................................................................................... 12 

4.4 Safety Factor for Infants and Children (FQPA Safety Factor) ....................................................... 13 

4.4. 1 Completeness of the Toxicology Database ........................................................................... 13 

4.4.2 Evidence of Neurotoxicity .................................................................................................... 13 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ....................... 14 

4.4.4 Residual Uncertainty in the Exposure Database ................................................................... 14 

4.5 Toxicity Endpoint and Point of Departure Selections .................................................................... 14 

4.5.1 Dose-Response Assessment ................................................................................................. 14 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment ...................... 17 

4.5.3 Cancer Classification and Risk Assessment Recommendation ............................................ 17 

5.0 Dietary Exposure and Risk Assessment ................................................................................................ 17 

5.1 Residues of Concern Summary and Rationale ............................................................................... 17 

5.2 Food Residue Profile ...................................................................................................................... 18 

5.3 Water Residue Profile ..................................................................................................................... 19 

5.4 Dietary Risk Assessrnent ................................................................................................................ 20 

5.4.1 Description of Residue Data Used in Dietary Assessment ................................................... 20 

5.4.2 Acute Dietary Risk Assessment ........................................................................................... 20 

6.0 Residential (Non-Occi.ipational) Exposure/Risk Characterization ........................................................ 21 

6.1 Residential Handler Exposure ........................................................................................................ 22 

6.2 Post-Application Exposure ............................................................................................................. 25 

6.3 Residential Risk Estimates for Use in Aggregate Assessment ....................................................... 27 

6.4 Residential Bystander Post-application Inhalation Exposure ......................................................... 28 

6.5 Spray Drift ...................................................................................................................................... 28 

7.0 Aggregate Exposure/Risk Characterization ........................................................................................... 28 

7.1 Acute Aggregate Risk ..................................................................................................................... 29 

7.2 Short-Term and Intermedi ate-Term Aggregate Risk ...................................................................... 29 

8.0 Cumulative Exposure/Risk Characterization ......................................................................................... 30 

9.0 Occupational Exposure/Risk Characterization ....................................................................................... 30 

9. 1 Occupational Handler Exposure/Risk Estimates ............................................................................ 30 

9.2 Occupational Post-Application Exposure/Risk Estimates .............................................................. 33 

I 0.0 References ........................................................................................................................................... 34 

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1.0 Executive Summary

Mefenoxam is a systemic phenylamide fungicide which inhibits protein synthesis in fungi. 

Mefenoxam is an R-isomer enriched formulation. Metalaxyl (PC 113501) is the racemic R/S

isomer formulation. The Agency compared the available chemistry and toxicity data for 

mefenoxam and metalaxyl and concluded that metalaxyl data may be used in support of 

mefenoxam regulatory actions because the two chemicals have similar toxicity. 

Syngenta Crop Protection, LLC has requested a tolerance for mefenoxam in or on the rapeseed 

subgroup 20A at 0.05 ppm resulting from seed treatment with Apron XL® LS (EPA Reg. No. 

100-799). Apron XL® LS is currently registered for seed treatment use on canola as a non-food 

use (i.e., no tolerance was established on canola). In connection with this petition, HED has reevaluated the established metalaxyl livestock tolerances (40 CFR §180.408). No Codex MRLs 

have been established for the rapeseed subgroup 20A or livestock commodities; therefore, there 

are no harmonization issues with Codex.

The Agency reassessed the toxicity databases for metalaxyl and mefenoxam in accordance with 

current policies and determined that many of the effects previously noted are no longer 

considered to be adverse. In rat and dog repeat dose (i.e., subchronic and chronic) oral toxicity 

studies, there were no indications of adverse effects up to the highest dose tested (HDT).

Adverse effects were only observed from acute exposure to rats. In the rat developmental 

toxicity study of metalaxyl, maternal toxicity consisted of dose-related increased incidence of 

convulsions that occurred shortly after dosing, as well as other clinical signs. In a range-finding 

acute neurotoxicity study of mefenoxam, females showed abnormal functional observation 

battery (FOB) findings at lower doses than males. However, there was no indication of toxicity 

up to the HDT in the mefenoxam subchronic neurotoxicity study, which confirms the lack of 

adverse effects observed in all other repeated-dose studies.

There was no indication of developmental toxicity in studies of mefenoxam or metalaxyl. There 

was no indication of immunotoxicity in a mouse immunotoxicity study of mefenoxam.

Metalaxyl and mefenoxam have been classified as "not likely to be carcinogenic in humans" 

based on the results for metalaxyl in the carcinogenicity study in mice and the combined chronic 

toxicity and carcinogenicity study in rats. In rat absorption, distribution, metabolism and 

excretion (ADME) studies, metalaxyl was well-absorbed and distributed systemically (T1⁄2 was 

12-20 hours). The highest concentrations were found in the liver and kidneys; however,

bioaccumulation was low. Excretion was sex-dependent, with females excreting more in urine 

and males more in bile/feces. The rat dermal absorption factor (DAF) is 35%.

All toxicity endpoints and points of departure (PODs) are based on convulsions that occurred 

minutes after dosing in the rat developmental toxicity study of metalaxyl. This POD is 

appropriate for acute, short-term, and intermediate-term exposure scenarios via the oral and 

inhalation routes. No hazard was identified for chronic or long-term exposure scenarios, or for 

exposure via the dermal route.

For all assessment scenarios, the default 10X Food Quality Protection Act Safety Factor (FQPA 

SF) can be reduced to 1X. The toxicity databases for metalaxyl and mefenoxam are adequate for 

FQPA SF evaluation. There was no evidence for increased offspring susceptibility in 

developmental toxicity studies in rabbits and rats, or in the reproduction and fertility effects 

study in rats. In adult rats treated with metalaxyl or mefenoxam, clinical signs and abnormal 

Functional Observation Battery (FOB) findings were noted only after a bolus gavage dose, but 
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not in repeated dose studies. A developmental neurotoxicity (DNT) study is not required for 

metalaxyl or mefenoxam because there were no indications of neurotoxicity in the repeated dose 

studies for mefenoxam or metalaxyl, which include a subchronic (adult rat) neurotoxicity study 

for mefenoxam. The total safety factor is 100x (i.e., 10x for interspecies extrapolation, 10x for 

intraspecies extrapolation, and a FQPA SF of 1x).

The nature of the residue in plants has been adequately defined based on metalaxyl metabolism 

studies, which indicate that metalaxyl is taken up, translocated, and extensively metabolized by 

plants. It may also be hydrolyzed in ruminants and poultry. For mefenoxam, the residue to be 

regulated in the tolerance expression in plant and livestock commodities is mefenoxam, 

including its metabolites and degradates. Compliance with the tolerance levels is to be 

determined by measuring only metalaxyl (methyl N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-

DL-alaninate). For risk assessment, the residues of concern in plant and livestock commodities 

are mefenoxam and metabolites containing the following moieties: 2,6-dimethylaniline, 2-

hydroxymethyl-6-methylaniline (HMMA), the Ring-OH, and benzoic acid. Adequate 

enforcement methods are available for determination of the residues of concern in crop and 

livestock commodities. Adequate storage stability data, crop and rotational crop field trials and 

processing studies are available to support this petition. 

HED conducted a somewhat refined acute dietary and drinking water exposure assessment for 

the proposed food use of mefenoxam on the rapeseed subgroup 20A and the existing uses of both 

metalaxyl and mefenoxam. Results of the acute dietary assessment indicate that the general U.S. 

population and all population subgroups have exposure and risk estimates below HED’s level of 

concern. The acute dietary exposure estimate is 39% of the acute population adjusted dose 

(aPAD) for the general U.S. population, and 95% of the aPAD for the highest exposed 

population subgroup, all infants. No chronic dietary endpoint was identified for mefenoxam or 

metalaxyl. Therefore, no chronic dietary assessment was conducted in this assessment. No 

cancer assessment was conducted since metalaxyl has been classified as "not likely to be 

carcinogenic in humans".

2.0 HED Recommendations

HED recommends for a registration and tolerance for the use of mefenoxam on the rapeseed 

subgroup 20A. No additional data are needed. No label modifications are needed. The specific 

tolerance recommendations are discussed in Section 2.2.

2.1 Data Deficiencies

None.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate enforcement methods are available for determination of the residues of concern in crop 

commodities. The enforcement methods are common moiety methods which determine residues 

of metalaxyl/mefenoxam and metabolites that are convertible to 2,6-dimethylaniline (2,6-DMA). 

These methods include: (1) Method I in PAM, Vol. II (Method AG-348), which determines 

residues in plant commodities using a gas-liquid chromatography procedure employing an alkali 

flame ionization detector (GLC/AFID); (2) Method AG-395 (submitted for inclusion in PAM, 
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Vol. II as Method III), an improved version of Method AG-348, which determines residues in 

plant commodities using GLC/nitrogen phosphorus detection (NPD); and (3) the multiresidue 

method in PAM, Vol. I, Section 302 (Protocol D). Method 456-98, a chiral liquid 

chromatography/mass spectrometric detection (LC/MS) method, is available to distinguish 

between R- and S-enantiomers, to determine whether metalaxyl or mefenoxam was applied.

An enforcement method for livestock commodities (Method II in PAM II; Method AG-349) is 

available to determine regulated residues of mefenoxam in animal tissues, milk, and eggs. 

Method AG-349 converts residues of mefenoxam and its metabolites to 2,6-DMA, which is 

analyzed by GLC/AFID in the nitrogen-specific mode. An alternative procedure is gas-liquid 

chromatography/mass spectrometry in the chemical ionization mode with selected ion 

monitoring (SIM) of the M+1 ion at m/z 268.

2.2.2 Recommended Tolerances

The currently established tolerance expression for mefenoxam is adequate, and includes both 

coverage and compliance statements for enforcement purposes.

The tolerance expression for metalaxyl has not been revised according the new 

compliance/measurement policy. The tolerance expression for metalaxyl should be revised in 40 

CFR §180.408(a) and (c) as follows:

Tolerances are established for residues of metalaxyl, including its metabolites and 

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

levels specified below is to be determined by measuring only metalaxyl (methyl N-(2,6-

dimethylphenyl)-N-(methoxyacetyl)-DL-alaninate). 

Syngenta Crop Protection, LLC has requested establishment of a tolerance for the residues of 

mefenoxam in or on the rapeseed subgroup 20A as shown in Table 2.2.2.1. The associated 

changes to the metalaxyl livestock tolerances are shown in Table 2.2.2.2.

Table 2.2.2.1. Tolerance Summary for Mefenoxam

Commodity Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments

Correct Commodity 

Definition

Rapeseed Crop Subgroup 20A 0.05 0.05 Rapeseed subgroup 20A

Table 2.2.2.2. Tolerance Summary for Metalaxyl

Commodity Established 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments

Correct Commodity 

Definition

Egg 0.05 0.05

Cattle, fat

Goat, fat

Hog, fat

0.4 0.05
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Table 2.2.2.2. Tolerance Summary for Metalaxyl

Commodity Established 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments

Correct Commodity 

Definition

Horse, fat

Poultry, fat

Sheep, fat

Cattle, kidney

Goat, kidney

Hog, kidney

Horse, kidney

Poultry, kidney

Sheep, kidney

0.4 None EPA no longer establishes 

separate tolerances on 

kidney. 

Cattle, liver

Goat, liver

Hog, liver

Horse, liver

Poultry, liver

Sheep, liver

0.4 None EPA no longer establishes 

separate tolerances on liver.

Cattle, meat

Goat, meat

Hog, meat

Horse, meat

Poultry, meat

Sheep, meat

0.05 0.05

Cattle, meat byproducts, except 

kidney and liver

Goat, meat byproducts, except 

kidney and liver

Hog, meat byproducts, except 

kidney and liver

Horse, meat byproducts, except 

kidney and liver

Sheep, meat byproducts, except 

kidney and liver

0.05 2.0 Cattle, meat byproducts

Goat, meat byproducts

Hog, meat byproducts

Horse, meat byproducts

Sheep, meat byproducts

EPA no longer establishes 

separate tolerances on liver 

and kidney. Instead, 

tolerances are established for 

meat byproducts.

Poultry, meat byproducts, 

except kidney and liver

0.05 0.10 Poultry, meat byproducts.

Milk 0.02 0.01
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2.2.3 Revisions to Petitioned-For Tolerances

The correct commodity definition is rapeseed subgroup 20A as shown in Table 2.2.2.1 above. 

The correct commodity definitions for livestock commodities are shown in Table 2.2.2.2.

Although changes were not proposed in livestock commodities, the established livestock 

tolerances for metalaxyl under 40 CFR §180.408 should be revised based on a new dietary 

burden calculation and revised Agency policies. Instead of the established tolerance of 0.05 ppm 

for meat byproducts except liver and kidney, a tolerance of 2.0 ppm should be proposed for meat 

byproducts of cattle, goat, hog, horse, and sheep, and a tolerance of 0.10 ppm should be proposed 

for meat byproducts of poultry. The established tolerance of 0.4 ppm for the fat of cattle, goat, 

hog, horse, poultry, and sheep should be reduced to 0.05 ppm. The established tolerance of 0.02 

ppm for milk should be reduced to 0.01 ppm. The established tolerances for liver and kidney 

should be removed since EPA no longer establishes separate tolerances for liver and kidney. The 

established tolerances are adequate for the other livestock commodities. 

2.2.4 International Harmonization

Tolerances for plants are established in the US under 40 CFR §180.546 for residues of 

mefenoxam, including its metabolites and degradates. Compliance with the tolerance levels is to 

be determined by measuring only metalaxyl (methyl N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-

DL-alaninate). No livestock tolerances for mefenoxam have been established under 40 CFR 

§180.546.

Tolerances for plants and livestock are established in the US under 40 CFR §180.408 for 

residues of the fungicide metalaxyl [N-(2,6-dimethylphenyl)-N-(methoxyacetyl)alanine methyl 

ester] and its metabolites containing the 2,6-DMA moiety, and N-(2-hydroxymethyl-6-

methylphenyl)-N-(methoxyacetyl)alanine methyl ester, each expressed as metalaxyl equivalents. 

Tolerances to support uses of mefenoxam and metalaxyl in Canada are established for residues 

of methyl N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-DL-alaninate, including metabolites that 

can be converted to the 2,6-DMA moiety, each expressed as metalaxyl equivalents.

Codex tolerances for metalaxyl include metalaxyl-M (mefenoxam). Codex maximum residue 

limits (MRLs) for plant commodities are for residues of metalaxyl. Codex MRLs for livestock 

commodities are for the sum of metalaxyl and its metabolites containing the 2,6-DMA moiety, 

expressed as metalaxyl.

Canada has an MRL for metalaxyl on the rapeseed subgroup 20A at 0.05 ppm, the same level 

that HED is recommending for mefenoxam. Canada has MRLs for metalaxyl on livestock 

kidney and liver at lower levels than the recommended US tolerances for meat byproducts. 

No Codex MRLs have been established for the rapeseed subgroup 20A or livestock 

commodities; therefore, there are no harmonization issues with Codex. Refer to the International 

Residue Limits (IRL) table (Appendix B).
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2.3 Label Recommendations

HED has no label recommendations for the proposed use directions for EPA Reg. No. 100-799. 

HED recommends that the existing labels, EPA Reg. Nos. 100-793 and 100-796, be updated to 

reflect the active ingredient density (i.e., lb ai/gallon) of the product. HED also recommends 

additional information in order to calculate the bed widths for specified banded applications. 

3.0 Introduction

3.1 Chemical Identity

Mefenoxam is a systemic phenylamide fungicide which inhibits protein synthesis in fungi. 

Mefenoxam and metalaxyl have the same empirical formula but differ in amount of R- and Sisomers. Metalaxyl is a racemic mixture whereas mefenoxam is mainly the R-isomer. 

Table 3.1 Test Compound Nomenclature

Chemical Structure

Empirical Formula C15H21NO4

Common Name mefenoxam

Company experimental name CGA-329351

IUPAC name methyl N-(methoxyacetyl)-N-(2,6-xylyl)-D-alaninate

CAS Name methyl N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-D-alaninate

CAS Registry Number 70630-17-0 & 69516-34-3

End-use product/EP Apron XL® LS, EPA Reg. No. 100-799

3.2 Physical/Chemical Characteristics

The physical/chemical properties of the technical grade of mefenoxam are shown in Appendix B.

A detailed explanation of the physical and chemical properties of mefenoxam are provided in 

“HED Risk Assessment: Human Health Risk Assessment for Mefenoxam on the Herb Subgroup, 

Globe Artichoke, and Minor/Tropical Fruits” (C. Christensen, 06/14/2001, D274784).

3.3 Pesticide Use Pattern

Mefenoxam has been proposed as a seed treatment use on Rapeseed subgroup 20A with a single 

application rate of 0.32 fl oz Apron XL® LS/100 lb of seed (7.5 x 10-5lb ai/lb of seed; 6.0 x 10-4

lb ai/A based on 8 lb canola seed per acre). The end-use product (EUP) associated with the new 

use, Apron XL LS® (EPA Reg. No. 100-799), is a flowable concentrate (FC) seed treatment 

product that is applied as a water-based slurry through slurry or mist-type commercial seed 

treatment equipment and is currently registered for use on a variety of crops, including canola. 
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The proposed label amendment, as summarized in Table 4.1.1, proposes to add the commodities 

of Rapeseed subgroup 20A. Current labels require applicators and other handlers to wear longsleeved shirts, long pants, shoes plus socks, and chemical-resistant gloves. The label also 

includes language as required under the Federal Seed Act that “this seed has been treated with 

mefenoxam fungicide. Do not use treated seed for feed, food, or oil purposes. Store away from 

feeds and foodstuffs.”

Table 3.3. Summary of Directions for Use of Mefenoxam on Rapeseed 20A; Apron XL® LS (100-799)

Application 

Timing, Type, 

and 

Equipment

Formulation 

Application 

Rate 

(fl. oz./100 

lb seed)1

Application 

Rate 

(lb ai/lb 

seed)2

Use Directions and Limitations

Rapeseed Crop Subgroup 20A

Seed Treatment 

via slurry or 

mist-type 

commercial 

equipment

Flowable 

concentrate 

(3.0 lb ai/gal)

0.32 0.000075

Maximum usage when applying both 

metalaxyl- and mefenoxam-containing 

products to the same crop within the same 

season: Do not apply more than the 

maximum seasonal total for the active 

ingredient as stated on the label of the 

product containing the lowest seasonal 

total on that crop; Do not use treated seed 

for feed, food, or oil purposes

1 Maximum application rate specified on the proposed label.

2 Calculated Rate = (0.32 fl oz/100 lb of seed) (1 gallon/128 fl oz)(3.0 lb ai/gallon) = 7.5 x 10-5

lb ai/lb of seed

3.4 Anticipated Exposure Pathways

Humans may be exposed to mefenoxam in food and drinking water, since mefenoxam may be 

applied directly to growing crops and as seed treatment, and application may result in 

mefenoxam reaching surface and ground water sources of drinking water. There are no 

residential uses for the proposed use on canola seed; however, there are residential uses of 

mefenoxam, so exposure in residential or non-occupational settings is likely. Occupational 

exposure scenarios for the proposed uses involve treating seed and planting treated seed. 

Occupational scenarios for other uses have been assessed previously (see 10.0 References). 

Post-application exposure for workers re-entering treated fields is unlikely because sustained 

levels of contact with treated seed after it has been placed in the soil or other planting media 

would not be expected. 

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, 
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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 U.S. Department of 

Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, 

(NHANES/WWEIA 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 and ethnic group. 

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. Spray drift can also potentially result in post-application 

exposure and it is also being considered whenever appropriate. 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 other types of possible bystander

exposures and farm workers as well as lifestyle and traditional dietary patterns among specific 

subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

Metalaxyl, an acylalanine that belongs to the phenylamides-fungicide group, blocks oomycete 

fungal growth by disrupting RNA synthesis through inhibiting RNA polymerase I. There are no 

mammalian molecular data to specifically show this mode of action in the test animals.

Mefenoxam (i.e., metalaxyl-M) is the enriched R-enantiomer of metalaxyl (i.e., racemic 

mixture). The Agency affirmed that the toxicity databases for mefenoxam and metalaxyl should 

be assessed together (W.F. Sette, 10/07/1997, TXR 0012380) and updated the rationale to 

include adverse effects observed in both databases (i.e., neurobehavioral effects found in the 

metalaxyl prenatal developmental toxicity study, mefenoxam range-finding acute neurotoxicity 

study, and mefenoxam oral acute (LD50) toxicity study).

4.1 Toxicology Studies Available for Analysis

Metalaxyl

The studies available for risk assessment include an acute toxicity battery; 28-day oral toxicity 

studies in rats and mice; subchronic oral toxicity studies in rats, mice, and dogs; subchronic 

dermal toxicity studies in rabbits; chronic toxicity studies in rats and dogs; carcinogenicity 

studies in rats and mice; prenatal developmental toxicity studies in rats and rabbits; a 

reproduction and fertility effects study in rats; a battery of mutagenicity and genotoxicity studies; 

and metabolism and pharmacokinetic studies in rats.

Mefenoxam

The studies available for risk assessment include an acute toxicity battery; 28-day oral toxicity 

studies in rats; subchronic oral toxicity studies in rats and dogs; a prenatal developmental toxicity 

study in rats; a battery of mutagenicity and genotoxicity studies; a range-finding acute 

neurotoxicity study in rats; a subchronic neurotoxicity study in rats; and an immunotoxicity 

study in rats. The database is considered adequate since the mefenoxam studies that were not 

submitted are addressed by their respective metalaxyl studies (e.g., prenatal developmental 

toxicity study in rabbits, cancer studies, etc.).
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4.2 Absorption, Distribution, Metabolism, and Elimination (ADME)

Metalaxyl

The available ADME database enabled evaluation of systemic availability and the comparison of 

toxicokinetics across routes of administration; the database included single oral dose, repeat oral 

dose, single dermal dose, and intravenous dose studies. 

In the single and repeat oral dose studies, absorption was ~60% of the administered dose (AD). 

Metalaxyl was distributed systemically and found in the highest concentrations in the liver and 

intestine. Metalaxyl was marginally retained in the carcass (<1% AD); the remainder was 

excreted with sex-related differences via urine (32-47% AD in males; 66-74% AD in females) 

and feces (54-64% AD in males; 31-36% AD in females). Metabolism results indicated that ether

and ester bonds of metalaxyl are hydrolyzed to form N-(2,6-dimethylphenyl)-N-(methoxyacetyl) 

alanine and N-(2,6-dimethylphenyl)-hydroxyacetamide. Urine fractions treated with 

glucuronidase showed similar patterns to urine not treated with enzyme indicating that 

metabolites are excreted as unconjugated or glucuronide conjugate products. Fecal metabolites 

were not characterized in the study beyond comparison of chromatograms for urine and feces. 

The intravenous portion of the study indicated that metalaxyl was well-absorbed based on the 

similarity between the elimination profiles between orally and intravenously dosed animals. 

Additionally, the intravenous portion of the study indicated that metalaxyl was excreted via bile 

as evidenced by the high recovery in males (59% AD) and females (36% AD).

In a single dermal dose study, absorption of ~30% AD occurred within 8 hours post-dosing; the 

absorption half-life (T1⁄2) was 12-20 hours. Metalaxyl was distributed systemically and found in 

the highest concentrations in the liver and kidneys. Metalaxyl was retained in the carcass (11-

18% AD) and to a lesser extent in the skin (0.5-2% AD); the remainder was excreted with sexrelated differences via urine (35-47% AD in males, 53-56% AD in females) and feces (33-38% 

AD in males; 25% AD in females).

4.2.1 Dermal Absorption

In a dermal penetration study where rats were exposed to mefenoxam for up to 8 hours, the rats 

absorbed up to 35% of the applied dose. The Agency concluded that the dermal absorption factor 

(DAF) is 35% (A. Lowit, 05/17/2000, TXR 0014165).

4.3 Toxicological Effects

The Agency reassessed the toxicity databases for metalaxyl and mefenoxam in accordance with 

current policies and determined that many of the effects previously noted are no longer 

considered to be adverse (e.g., hepatocellular hypertrophy or decreased body weight gain). It 

should be noted that many of the NOAELs and LOAELs presented in the toxicology profile table 

(Appendix A) have not been updated to comply with current policy. However, the studies that 

were updated are indicated in the toxicology profile table (Table A.2.3).

Metalaxyl

In rat and dog repeat dose (i.e., subchronic and chronic) oral toxicity studies, there were no 

indications of adverse effects up to the highest dose tested (HDT) based on current Agency 

policies.
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There was no evidence of increased susceptibility in the developmental and reproduction studies 

with metalaxyl. In the rat prenatal developmental toxicity study, maternal toxicity consisted of 

dose-related increases in clinical signs of toxicity (i.e., dry or wet matter on head, eyes, nose, 

abdomen, anogenital area, and/or vaginal opening; stained and/or matted hair coat on the head, 

face, ventral thorax, abdomen, back, anogenital area, and/or forelimbs; and post-dosing 

convulsions (occurred shortly after dosing)); developmental toxicity was not observed up to the 

HDT. In the rabbit prenatal developmental toxicity study, there was no indication of maternal or 

developmental toxicity up to the HDT. In the rat reproduction and fertility effects study, there 

was no indication of parental, reproductive, or offspring toxicity up to the HDT.

Metalaxyl has low acute toxicity via the oral (Toxicity Category III) and dermal (Toxicity 

Category III) routes of exposure; is a severe eye irritant (Toxicity Category II) and a mild dermal 

irritant (Toxicity Category IV); and is not a dermal sensitizer.

Mefenoxam

In rat and dog repeat dose (i.e., subchronic) oral toxicity studies, there were no indications of 

adverse effects up to the HDT.

There was no evidence of increased susceptibility in the available rat prenatal developmental 

toxicity study for mefenoxam. There was no indication of maternal or developmental toxicity in 

the study.

The neurotoxicity database consists of both a range-finding acute neurotoxicity and subchronic 

neurotoxicity study in rats. In the range-finding acute neurotoxicity study, females demonstrated 

abnormal functional observation battery (FOB) findings at doses lower than males. In the 

subchronic neurotoxicity study, there was no indication of toxicity up to the HDT. The rangefinding acute neurotoxicity study is only considered to be supportive and indications of effects 

being sex-specific are not conclusive.

In the mouse immunotoxicity study, there was no indication of increased immunotoxic potential 

in the T-cell dependent antibody response (TDAR) assay at the limit dose.

Mefenoxam has low to moderate acute toxicity via the oral (Toxicity Category II), dermal 

(Toxicity Category III), and inhalation (Toxicity Category IV) routes of exposure; is a corrosive 

eye irritant (Toxicity Category I) and a mild dermal irritant (Toxicity Category IV); and is not a 

dermal sensitizer.

The Agency determined that acute neurotoxicity studies for metalaxyl and mefenoxam are not 

necessary for the following reasons (U. Habiba, 08/20/2015, TXR0057208): (1) convulsions 

observed shortly after dosing in the metalaxyl rat prenatal developmental toxicity study may 

indicate neurotoxicity; and (2) a guideline ACN is unlikely to yield an acute POD that is lower 

than the current endpoint derived from the rat prenatal developmental toxicity study. 

Additionally, the Agency recommends that the metalaxyl subchronic neurotoxicity study not be 

required for the following reasons: (1) there were no indications of neurotoxicity in repeat dose 

dietary studies; and (2) there were no indications of neurotoxicity in the mefenoxam subchronic 

neurotoxicity study. 

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

For all assessment scenarios, the default 10x FQPA Safety Factor can be reduced to 1x for the 

following reasons: (1) the database is adequate to evaluate neurotoxicity and developmental 
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susceptibility; (2) neurotoxicity has been characterized; (3) there is no evidence of 

developmental susceptibility; and (4) there are no residual concerns in the exposure database.

4.4.1 Completeness of the Toxicology Database

The toxicity databases for metalaxyl and mefenoxam are adequate for FQPA SF evaluation and 

the quantification of risk for dietary, residential, and occupational exposure scenarios. The 

acceptable studies available to characterize neurotoxicity and developmental susceptibility for 

metalaxyl include rat and rabbit prenatal developmental toxicity studies and a rat reproduction 

and fertility effects study; and for mefenoxam include a rat prenatal developmental toxicity and a 

rat subchronic neurotoxicity study.

4.4.2 Evidence of Neurotoxicity

Metalaxyl

Acute and subchronic neurotoxicity studies were not performed with metalaxyl and are waived 

for the reasons noted in Section 4.4.1. However, clinical signs indicative of neurobehavioral 

effects (i.e., convulsions within minutes post-dosing) were seen in the rat prenatal developmental 

toxicity study.

Mefenoxam

An acute (range-finding) and a subchronic neurotoxicity study are available for mefenoxam. In 

the range-finding acute neurotoxicity study, females exhibited abnormal functional observation 

battery (FOB) findings at doses lower than in males; the guideline study requirement was waived 

for the reasons noted in Section 4.4.1. In the subchronic neurotoxicity study, there were no 

indications of neurotoxicity up to the HDT.

A developmental neurotoxicity (DNT) study is not required for metalaxyl or mefenoxam because 

the neurobehavioral effects were observed in studies with defined NOAELs/LOAELs and 

current endpoints are protective for fetuses and the young. 

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

In metalaxyl and mefenoxam treated animals, there was no evidence of increased susceptibility 

following pre-/post-natal exposure in the prenatal developmental toxicity studies or the 

reproduction and fertility effects study.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database. The dietary exposure assessments 

(food and water), which employed tolerance-level resides and high-end estimated drinking water 

concentrations (EDWCs), are conservative assessments. They do not underestimate the potential 

dietary exposures. Exposures are unlikely to be underestimated because the calculated residential 

risks represent conservative estimates of exposure because maximum application rates are used 

to define residue levels.

4.5 Toxicity Endpoint and Point of Departure Selections

As mentioned in Section 4.3, the Agency affirmed that metalaxyl data may be used to support 

mefenoxam regulatory actions because of the chemicals’ similar toxicity (TXR0012380, 07 
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October 1997). The Agency reassessed the toxicity databases for metalaxyl and mefenoxam in 

accordance with current policies and determined that many of the effects previously noted are no 

longer considered to be adverse (e.g., hepatocellular hypertrophy or decreased body weight 

gain). It should be noted that many of the NOAELs and LOAELs presented in the toxicology 

profile table (Appendix A) have not been updated to comply with current policy. However, the 

studies that were updated are indicated in the toxicology profile table (Table A.2.3).

4.5.1 Dose-Response Assessment

Acute Dietary Endpoint for the General Population and for Females 13-49 Years of Age: In a 

metalaxyl prenatal developmental toxicity study in rats (MRID 00144423), neurobehavioral 

clinical signs (i.e., convulsions that occurred minutes after dosing) was observed at the mid-dose 

(LOAEL=250 mg/kg/day; NOAEL=50 mg/kg/day). The route and the single-dose nature of the 

adverse effects are appropriate for acute dietary risk assessment. The total safety factor is 100x 

(i.e., 10x for interspecies extrapolation, 10x for intraspecies extrapolation, and a FQPA SF of 

1x). The aPAD for all populations is 0.5 mg/kg/day.

Chronic Dietary Endpoint for the General Population: No endpoint was identified for the 

following reasons: (1) there were no adverse effects in any of the long-term studies up to ~150 

mg/kg/day; and (2) adverse effects consisted of neurobehavioral clinical signs and were only 

observed when test animals were gavage dosed at or greater than 250 mg/kg/day.

Incidental Oral Exposure (Short-Term and Intermediate-Term): In a metalaxyl prenatal 

developmental toxicity study in rats (MRID 00144423), neurobehavioral clinical signs (i.e., 

convulsions that occurred minutes after dosing) was observed at the mid-dose (LOAEL=250 

mg/kg/day; NOAEL=50 mg/kg/day). The route and the duration are appropriate for short and 

intermediate-term exposure scenarios. The total safety factor is 100x (i.e., 10x for interspecies 

extrapolation, 10x for intraspecies extrapolation, and a FQPA SF of 1x).

Dermal Exposure (Short-Term and Intermediate-Term): No endpoint was identified because 

there was no systemic toxicity (or hazard) up to the limit dose (i.e., 1000 mg/kg/day) in the rabbit 

dermal toxicity study and no concern for susceptibility.

Inhalation Exposure (Short-Term and Intermediate-Term): In a metalaxyl prenatal 

developmental toxicity study in rats (MRID 00144423), neurobehavioral clinical signs (i.e., 

convulsions that occurred minutes after dosing) was observed at the mid-dose (LOAEL= 250 

mg/kg/day; NOAEL=50 mg/kg/day). Toxicity via the inhalation and oral routes are assumed to 

be equivalent. The durations are appropriate for short and intermediate-term exposure scenarios. 

The total safety factor is 100x (i.e., 10x for interspecies extrapolation, 10x for intraspecies 

extrapolation, and a FQPA SF of 1x).
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Table 4.5.1 Summary of Toxicological Doses and Endpoints for Mefenoxam and Metalaxyl for Use in Dietary and NonOccupational Human Health Risk Assessments

Exposure / Scenario Point of 

Departure

Uncertainty/F

QPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary 

General Population 

(including Infants and 

Children)

Females 

(13-49 years of age)

NOAEL= 50 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

aRfD = 0.5 

mg/kg/day

aPAD = 0.5 

mg/kg/day

Metalaxyl Prenatal Developmental Toxicity 

– Rat

LOAEL = 250 mg/kg/day

Based on dose-related increases in clinical 

signs of toxicity (e.g., post-dosing 

convulsions).

Chronic Dietary 

(All Populations)

No endpoint was identified. No systemic toxicity was observed in the reproduction and fertility 

effects study or in any of the chronic toxicity studies. Toxicity was only evident in gavage-dosed 

animals.

Incidental Oral 

Short-Term (1-30 days);

Intermediate-Term

(1-6 months)

NOAEL= 50 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Residential LOC 

for MOE = 100

Metalaxyl Prenatal Developmental Toxicity 

– Rat

LOAEL = 250 mg/kg/day

Based on dose-related increases in clinical 

signs of toxicity (e.g., post-dosing 

convulsions).

Dermal 

Short-Term (1-30 days);

Intermediate-Term

(1-6 months)

No endpoint was identified. No systemic toxicity was observed at the limit dose (1000 mg/kg/day) in 

rabbits treated with metalaxyl during a 21-day dermal toxicity study.

For converting oral to dermal doses for risk assessment, the Dermal Absorption Factor (DAF) = 35%

Inhalation 

Short-Term (1-30 days);

Intermediate-Term

(1-6 months)

NOAEL= 50 

mg/kg/day

Note: Toxicity via 

the inhalation and 

oral routes are 

assumed to 

equivalent.

UFA= 10x

UFH=10x

FQPA SF= 1x

Residential LOC 

for MOE = 100

Metalaxyl Prenatal Developmental Toxicity 

– Rat

LOAEL = 250 mg/kg/day

Based on dose-related increases in clinical 

signs of toxicity (e.g., post-dosing 

convulsions).

Cancer (oral, dermal, 

inhalation)

Classification: “Not Likely to be Carcinogenic to Humans” based on adequately conducted 

carcinogenicity studies in rats and mice treated with metalaxyl.

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.
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Table 4.3.2 Summary of Toxicological Doses and Endpoints for Mefenoxam and Metalaxyl for Use in 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);

Intermediate Term

(1-6 months)

NOAEL =

50 mg/kg/day

UFA = 10x

UFH = 10x

Occupational 

LOC for MOE = 

100

Metalaxyl Prenatal Developmental Toxicity 

– Rat

LOAEL = 250 mg/kg/day

Based on dose-related increases in clinical 

signs of toxicity (e.g., post-dosing 

convulsions).

Dermal

Short-Term (1-30 days);

Intermediate-Term

(1-6 months)

No endpoint was identified. No systemic toxicity was observed at the limit dose (1000 mg/kg/day) in 

rabbits treated with metalaxyl during a 21-day dermal toxicity study.

For converting oral to dermal doses for risk assessment, the Dermal Absorption Factor (DAF) = 35% 

Inhalation

Short-Term (1-30 days); 

Intermediate-Term

(1-6 months)

NOAEL= 50 

mg/kg/day

UFA=10x

UFH=10x

Occupational 

LOC for MOE = 

100

Metalaxyl Prenatal Developmental Toxicity 

– Rat

LOAEL = 250 mg/kg/day

Based on dose-related increases in clinical 

signs of toxicity (e.g., post-dosing 

convulsions).

Cancer (oral, dermal, 

inhalation)

Classification: “Not Likely to be Carcinogenic to Humans” based on adequately conducted 

carcinogenicity studies in rats and mice treated with metalaxyl.

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). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

For short- and intermediate term exposure, the incidental oral and inhalation toxicity endpoints 

were the same. Exposures to residues from food and drinking water, and residential pesticide 

uses should be aggregated.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Metalaxyl is classified as "not likely to be carcinogenic in humans" based on carcinogenicity 

studies in mice and rats. The concern for mutagenic potential is low based on the battery of 

metalaxyl in vivo and in vitro assays.
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Although cancer studies are not available for mefenoxam; the chemical has all been classified as 

"not likely to be carcinogenic in humans" based on the classification of metalaxyl. The concern 

for mutagenic potential is low based on the battery of metalaxyl and mefenoxam in vivo and in 

vitro assays.

5.0 Dietary Exposure and Risk Assessment 

HED conducted a somewhat refined acute dietary and drinking water exposure assessment for 

the proposed food use of mefenoxam on the rapeseed subgroup 20A and the existing uses of both 

metalaxyl and mefenoxam. No chronic dietary endpoint was identified for mefenoxam or 

metalaxyl. Therefore, no chronic dietary assessment was conducted in this assessment. No 

cancer assessment was conducted since metalaxyl has been classified as "not likely to be 

carcinogenic in humans".

5.1 Residues of Concern Summary and Rationale

HED has determined that the residue to be regulated in the tolerance expression in plant and 

livestock commodities is mefenoxam, including its metabolites and degradates. Compliance 

with the tolerance levels is to be determined by measuring only metalaxyl (methyl N-(2,6-

dimethylphenyl)-N-(methoxyacetyl)-DL-alaninate). For risk assessment, the residues of concern 

in plant and livestock commodities are mefenoxam, its metabolites containing the 2,6-DMA 

moiety, its metabolites containing the HMMA moiety, its metabolites containing the Ring-OH 

moiety, and its metabolites containing the benzoic acid moiety (HED RARC Report, W. Britton, 

02/14/2007). Refer to Appendix B for names and structures of metabolites.

Table 5.1. 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 and 

Rotational 

Crops

metalaxyl/mefenoxam, metabolites containing the 

2,6-DMA (2,6-dimethylalanine) moiety,

metabolites containing the HMMA (2-

hydroxymethyl-6-methylaniline) moiety, and 

metabolites containing the Ring-OH (ring 

hydroxylated dimethylaniline) moiety

metalaxyl/mefenoxam

Livestock Ruminant and 

Poultry

metalaxyl/mefenoxam, metabolites containing the 

2,6-DMA (2,6-dimethylalanine) moiety, 

metabolites containing the HMMA (2-

hydroxymethyl-6-methylaniline) moiety, and 

metabolites containing the Ring-OH (ring 

hydroxylated dimethylaniline) moiety

metalaxyl/mefenoxam

Drinking Water

metalaxyl/mefenoxam, N-(2, 6-dimethylphenyl)-N-

(methylacetyl-L-alanine) (CGA-62826), and N-(3-

hydroxy-2, 6-dimethylphenyl)-N-(methoxyacetyl)-

L-alanine (CGA 119857)

Not Applicable
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5.2 Food Residue Profile

Adequate crop and rotational crop field trials, processing studies, storage stability studies, and

ruminant and poultry feeding studies are available. Syngenta is relying on previously submitted 

studies for this tolerance petition. No additional data have been submitted with this petition. 

Crop Field Trials: Canola is the representative crop for the rapeseed subgroup 20A. The 

available field trial data for metalaxyl and mefenoxam on canola are adequate to indicate that 

residues of mefenoxam in the rapeseed subgroup 20A resulting from the proposed use will not 

exceed 0.05 ppm. 

Processing Studies: An adequate canola processing study is available for metalaxyl. The 

processing study indicated that no significant concentration of metalaxyl occurred on processing 

to canola meal or refined oil. Based on the canola processing study, no tolerances are required 

for mefenoxam on the processed commodities of the rapeseed subgroup 20A (canola meal, 

canola refined oil, flax meal, and sesame oil). 

Storage Stability: Adequate storage stability data are available to support the storage durations 

and storage conditions of samples in the field trial and processing studies.

Meat, Milk, Poultry, and Eggs: Adequate ruminant and poultry feeding studies are available. 

Considering both metalaxyl and mefenoxam feedstuffs, residues are expected to occur in 

ruminant liver and kidney. Instead of the established tolerance of 0.05 ppm for meat byproducts 

except liver and kidney, a tolerance of 2.0 ppm should be proposed for meat byproducts of cattle, 

goat, hog, horse, and sheep, and a tolerance of 0.10 ppm should be proposed for meat byproducts 

of poultry. The established tolerance of 0.4 ppm for the fat of cattle, goat, hog, horse, poultry, 

and sheep should be reduced to 0.05 ppm. The established tolerance of 0.02 ppm for milk should 

be reduced to 0.01 ppm. The established tolerances for liver and kidney should be removed 

since EPA no longer establishes separate tolerances for liver and kidney. The established 

tolerances are adequate for the other livestock commodities.

Confined Accumulation in Rotational Crops: The nature of the residue in confined rotational 

crops is adequately understood for mefenoxam, based on confined rotational crop studies 

conducted with metalaxyl on lettuce, sugar beet, and wheat. Metabolism of metalaxyl in rotated 

crops generally proceeds by the same pathways as seen in primary crops with the formation of 

four classes of metabolites: (1) those containing the 2,6-DMA moiety; (2) those containing the 

HMMA moiety; (3) those containing a Ring-OH moiety; and (4) those containing a benzoic acid 

moiety.

Field Accumulation in Rotational Crops: Adequate field rotational crop data are available for 

metalaxyl. No rotational crop restrictions have been included or requested for mefenoxam seed 

treatments on the Apron XL® LS label (EPA Reg. No. 100-799).

5.3 Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by the 

Environmental Fate and Effects Division (EFED) in an e-mail from He Zhong dated 9/23/15 and

incorporated directly into this dietary assessment. Water residues were incorporated in the 

DEEM-FCID into the food categories “water, direct, all sources” and “water, indirect, all 

sources.” 
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The drinking water exposure assessment was conducted for metalaxyl and mefenoxam using 

updated models, the Surface Water Concentration Calculator (SWCC) and the Pesticide Root 

Zone Model – Ground Water (PRZM-GW). The recommended EDWCs are total toxic residues 

for parent and two degradates (CGA-62826 and CGA-119857) based on the highest usage rate of 

12 lb ai/A. 

Based on the revised SWCC estimates and after 0.91 default percent crop treated (PCA) 

adjustment, the highest EDWCs from surface water source are not expected to exceed 741 μg/L 

(ppb) for the 1 in 10 year daily peak concentration (FL Citrus Scenario), 224 μg/L for the 1 in 10 

year annual concentration, and 173 μg/L for the 30 year annual average concentration (CA Citrus 

Scenario). EDWCs from the ground source were revised by the Tier I PRZM-GW model, which 

estimates that the highest acute value is 3,700 μg/L for the NC cotton scenario.

As shown in Table 5.3, the value of 3,700 μg/L (3.7 ppm) was the acute point estimate from the 

Tier I PRZM-GW model using the NC cotton scenario; however, a residue distribution file based 

on the NC cotton scenario was used for drinking water in the acute dietary assessment.

Table 5.3. Summary of Estimated Surface Water and Groundwater Concentrations for 

Metalaxyl/Mefenoxam.

Scenario Surface Water Conc., ppb a Groundwater Conc., ppb b

Acute 741 3,700

Chronic (non-cancer) 224 3,200 

Chronic (cancer) 173 3,200 

a SWCC model with 0.91 PCA using the Fl citrus scenario for acute and the CA citrus scenario for chronic.

b Tier 1 PRZM-GW model using the NC cotton scenario for acute and the WI corn scenario for chronic.

The model and its description are available at the EPA internet site: 

http://www.epa.gov/oppefed1/models/water/ . 

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

HED conducted a somewhat refined acute dietary (food and drinking water) exposure assessment 

for the proposed food use of mefenoxam on the rapeseed subgroup 20A and the existing uses of 

both metalaxyl and mefenoxam. Residues were assumed to be present at tolerance levels in plant 

commodities, with additional factors applied to certain plant commodities to include all residues 

of concern for risk assessment (N. Dodd, D429030, 11/2/2015). Data from metabolism studies 

on goats and hens were used to estimate levels of metalaxyl/mefenoxam residues of concern in 

livestock commodities. DEEM default and empirical processing factors were used as available. 

It was assumed that 100% of the crops were treated (100% CT). A residue distribution file was 

used for drinking water, with data obtained from the Tier I PRZM-GW using the NC cotton 

scenario. 
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5.4.2 Acute Dietary Risk Assessment

The results of the acute dietary exposure analysis are reported in Table 5.4.2 below. The results 

indicate that the general U.S. population and all other population subgroups have exposure and 

risk estimates below HED’s level of concern. The DEEM acute dietary exposure estimate is 

39% of the aPAD for the general U.S. population, and 95% of the aPAD for the highest exposed 

population subgroup, all infants.

Table 5.4.2. Summary of Dietary (Food and Drinking Water) Exposure and Risk for 

Mefenoxam/Metalaxyl1

Population Subgroup

Acute Dietary (95th Percentile)

Dietary Exposure (mg/kg/day) % aPAD2

General U.S. Population 0.194017 39

All Infants (< 1 year old) 0.474356 95

Children 1-2 years old 0.320884 64

Children 3-5 years old 0.285663 57

Children 6-12 years old 0.198925 40

Youth 13-19 years old 0.155781 31

Adults 20-49 years old 0.182309 36

Adults 50+ years old 0.165636 33

Females 13-49 years old 0.184804 37

1 The population subgroup with the highest estimated acute dietary (food + drinking water) exposure and risk is 

indicated by bold text.

2

aPAD (acute population adjusted dose) = 0.50 mg/kg/day. 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no proposed residential uses of mefenoxam at this time; however, there are existing 

residential uses that have been reassessed in this document to reflect updates to HED’s 2012 

Residential SOPs , along with policy changes for body weight assumptions. The revision of 

residential exposures will impact the human health aggregate risk assessment for mefenoxam.

Because mefenoxam and metalaxyl are considered toxicologically similar, HED reviewed the 

representative EUPs with registered residential uses of mefenoxam and metalaxyl. These 

representative uses were previously identified in the scoping document in support of registration 

review for metalaxyl and mefenoxam, following a full review of all existing residential EUPs for 

mefenoxam and metalaxyl (N. Dodd, 12/7/2009, D368462). Since that time, no additional 

residential EUPs have been approved for mefenoxam or metalaxyl. A quantitative evaluation of 

the highest maximum application rates for all representative EUPs with potential residential 

exposures are for mefenoxam, rather than metalaxyl. Therefore, the residential handler and postapplication exposure and risk estimates are presented for mefenoxam only but are considered 

protective of the representative residential EUPs for metalaxyl. 

Five EUPs currently registered for mefenoxam were identified with representative use scenarios 

in residential areas in the scoping document; one additional mefenoxam EUP has been canceled 
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since publication of the scoping document. The registered EUPs are: (1) Subdue MAXX® EC, 

an emulsifiable concentrate (EC) liquid formulation containing 46.6% mefenoxam (EPA Reg. 

No. 100-793); (2) Subdue® GR, a granular (G) formulation containing 1.0% mefenoxam (EPA 

Reg. No. 100-794); (3) Subdue® WSP, a wettable powder packaged in a water-soluble packet 

(WSP) formulation containing 45.0% mefenoxam (EPA Reg. No. 100-795); (4) Subdue 

MAXX®, an EC formulation containing 22.0% mefenoxam (EPA Reg. No. 100-796); and (5) 

Mefenoxam 2EC®, an EC formulation containing 25.1% mefenoxam (EPA Reg. No. 400-486). 

mefenoxam may be applied to ornamental gardens, including nonbearing citrus trees, and 

residential turf using handheld equipment by residential handlers.

6.1 Residential Handler Exposure

HED uses the term “handlers” to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct tasks related to applications and that 

exposures can vary depending on the specifics of each task. Residential handlers are addressed 

somewhat differently by HED, as homeowners are assumed to complete all elements of an 

application without use of any protective equipment.

Residential handlers are expected to be exposed to mefenoxam following EC, WSP, and G 

formulation applications to residential turf and ornamentals, including nonbearing citrus trees.

The maximum application rate for each exposure scenario is presented as the worst-case scenario 

in Table 5.1.1. All inhalation risk estimates are greater than the LOC of 100; and therefore are 

not of concern (MOEs range from 79,000 to 200,000,000). Residential handler exposure is 

expected to be short-term in duration. Intermediate-term exposures are not likely because of the 

intermittent nature of applications by homeowners. The algorithms used to estimate exposure 

and dose for residential handlers may be found in the latest occupational and residential exposure 

assessment memorandum (L. Nollen, 12/3/2015, D430081). Dermal handler risk assessments 

were not conducted because an adverse systemic dermal hazard was not identified for 

mefenoxam.
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Table 6.1.1. Residential Handler Non-cancer Exposure and Risk Estimates for Mefenoxam.

Exposure Scenario Formulation

Inhalation Unit 

Exposure (mg/lb 

ai)

Maximum 

Application Rate1

Area Treated or 

Amount Handled 

Daily2

Inhalation

Dose 

(mg/kg/day)3 MOE4

Liquid Concentrate5

Manually-Pressurized 

Handwand – Gardens/Trees

Liquid 

Concentrate 0.018 0.00018 lb ai/ft2 1200 ft2 0.000049 1,000,000

Hose-end SprayerGardens/TreesLiquid 

Concentrate 0.0014 0.00018 lb ai/ft2 1200 ft2 0.0000038 13,000,000

Hose-end SprayerLawns/TurfLiquid 

Concentrate 0.022 3.1 lb ai/A 0.50 A 0.00043 120,000

Manually-Pressurized 

Handwand – Lawns/Turf

Liquid 

Concentrate 0.018 0.072 lb ai/gal 5.0 gal 0.000081 620,000

Backpack- Gardens/Trees Liquid 

Concentrate 0.14 0.00018 lb ai/ft2 1200 ft2 0.00038 130,000

Sprinkler CanGardens/TreesLiquid 

Concentrate 0.0014 0.00018 lb ai/ft2 1200 ft2 0.0000038 13,000,000

Sprinkler Can- Lawns/Turf Liquid 

Concentrate 0.022 0.000072 lb ai/ft2 1,000 ft2 0.000020 2,500,000

Backpack- Lawns/Turf Liquid 

Concentrate 0.14 0.072 lb ai/gal 5.0 gal 0.00063 79,000

Wettable Powders in Water-soluble Packaging6

Manually-Pressurized 

Handwand – Gardens/Trees WSP 0.018 0.000048 lb ai/ft2 1200 ft2 0.000013 3,900,000

Hose-end SprayerGardens/Trees WSP 0.034 0.000048 lb ai/ft2 1200 ft2 0.000024 2,000,000

Hose-end SprayerLawns/Turf WSP 0.034 0.69 lb ai/A 0.5 A 0.00015 340,000

Manually-Pressurized 

Handwand – Lawns/Turf WSP 0.018 0.016 lb ai/gal 5.0 gal 0.000018 2,800,000

Backpack- Lawns/Turf WSP 0.016 0.016 lb ai/gal 5.0 gal 0.000018 2,800,000

Sprinkler CanGardens/Trees WSP 0.034 0.000048 lb ai/ft2 1,200 ft2 0.000024 2,000,000
Mefenoxam Human Health Risk Assessment DP No. D424727

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Table 6.1.1. Residential Handler Non-cancer Exposure and Risk Estimates for Mefenoxam.

Exposure Scenario Formulation

Inhalation Unit 

Exposure (mg/lb 

ai)

Maximum 

Application Rate1

Area Treated or 

Amount Handled 

Daily2

Inhalation

Dose 

(mg/kg/day)3 MOE4

Sprinkler Can- Lawns/Turf WSP 0.034 0.000016 lb ai/ft2 1,000 ft2 0.0000067 7,500,000

Backpack- Gardens/Trees WSP 0.018 0.000048 lb ai/ft2 1,200 ft2 0.000013 3,900,000

Granular

Push-type rotary spreaderGardens/Trees G 0.0026 0.000078 lb ai/ft2 1,200 ft2 0.000003 16,000,000

Push-type rotary spreaderLawns/Turf G 0.0026 0.68 lb ai/A 0.5 A 0.000011 4,500,000

Belly grinder- Lawns/Turf G 0.039 0.000016 lb ai/ft2 1,200 ft2 0.0000091 5,500,000

Spoon- Gardens/Trees G 0.087 0.000078 lb ai/ft2 1,200 ft2 0.00010 490,000

Spoon- Lawns/Turf G 0.087 0.000016 lb ai/ft2 100 ft2 0.0000017 29,000,000

Cup- Gardens/Trees G 0.013 0.000078 lb ai/ft2 1,200 ft2 0.000015 3,300,000

Cup- Lawns/Turf G 0.013 0.000016 lb ai/ft2 100 ft2 0.00000025 200,000,000

Hand DispersalGardens/Trees

G

0.38 0.000078 lb ai/ft2 1,200 ft2 0.00045 110,000

Hand Dispersal- Lawns/Turf G 0.38 0.000016 lb ai/ft2 100 ft2 0.0000074 6,700,000

Shaker Can- Gardens/Trees G 0.013 0.000078 lb ai/ft2 1,200 ft2 0.000015 3,300,000

Shaker Can- Lawns/Turf G 0.013 0.000016 lb ai/ft2 100 ft2 0.00000025 200,000,000

1 Based on registered labels: EPA Reg. No. 100-796 for Liquid; EPA Reg. No. 100-795 for WSP; EPA Reg. No. 100-794 for Granular; 

2 Based on HED’s 2012 Residential SOPs (http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/standard-operating-procedures-residential-pesticide).

3 Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A/day or gallons/day) ÷ BW (80 kg).

4 Inhalation MOE = Inhalation NOAEL (50 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

5 Liquid Concentrate = Emulsifiable Concentrate EUPs. 

6 Wettable Powders in Water-soluble Packaging = WSP
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6.2 Residential Post-Application Exposure

There is the potential for post-application exposure for individuals exposed as a result of being in 

an environment that has been previously treated with liquid and granular formulations of 

mefenoxam. The quantitative exposure and risk assessment for residential post-application 

exposures is based on short-term incidental oral risk estimates for children 1<2 years old. The 

short-term incidental oral assessment is protective of any potential intermediate-term postapplication scenarios, including exposure from soil ingestion. A series of assumptions and 

exposure factors served as the basis for completing the residential post-application risk 

assessment. Each assumption and factor is detailed in the 2012 Residential SOPs1

The maximum application rate for each exposure scenario is presented as the worst-case 

scenario, and summaries of the short-term post-application incidental oral risk estimates for 

children 1<2 years old are included in Table 5.2.1. All incidental oral risk estimates are greater 

than the LOC of 100; and therefore are not of concern (MOEs range from 180 to 2,200,000). 

Dermal post-application risk assessments were not conducted because an adverse systemic 

dermal hazard was not identified for mefenoxam.

Table 6.2.1. Residential Post-application Non-cancer Exposure and Risk Estimates for Mefenoxam.

Lifestage

Exposure Scenario

Formulation Application 

Rate1

Dose 

(mg/kg/day)2 MOEs3

Use Site Exposure Route 

Short-Term

Child Lawns/

Turf

Hand to Mouth Liquid

3.1 lb ai/A

0.048 1,000

Object to Mouth Liquid 0.0015 34,000

Soil Ingestion Liquid 0.00011 470,000

Hand to Mouth Granular

0.68 lb ai/A

0.0010 49,000

Object to Mouth Granular 0.000060 790,000

Soil Ingestion Granular 0.000020 2,200,000

Granular 

Ingestion Granular 0.26 180

1 Based on registered labels, EPA Reg. No. 100-796 for Liquid; EPA Reg. No. 100-794 for Granular.

2 Dose (mg/kg/day) algorithms provided in 2012 Residential SOPs (http://www2.epa.gov/pesticide-science-andassessing-pesticide-risks/standard-operating-procedures-residential-pesticide).

3 MOE = POD (50 mg/kg/day) ÷ Dose (mg/kg/day)

Turf Transferable Residue (TTR): 

In accordance with 40 CFR 158, TTR data are required for all occupational (e.g., sod farms, golf 

courses, parks, and recreational areas) or residential turf uses that could result in post-application 

exposure to turf. In the absence of chemical-specific TTR data, EPA uses default values. The 

 

1 Available: http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/standard-operating-proceduresresidential-pesticide
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2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment includes an 

analysis of all TTR data, available at the time, which resulted in the selection of revised liquid 

and granular default values for the fraction of the application rate available for transfer after a 

turf application (FAR). These values are based on an analysis of 59 TTR studies performed with 

the Modified California Roller Method (36 studies using liquids, 11 studies using wettable 

powders/water dispersible granules, and 12 studies using granules). The liquid results (N=131) 

indicate a range of FAR values from 0.0005% to 6.1% and the granular results (N=37) indicate a 

range of 0.00064% to 0.69%. In both the liquid and granular data, a large range of transferability 

is observed and this variability can potentially be attributable to many factors such as active 

ingredient; formulation; field conditions in the studies; weather conditions (e.g., humidity); or 

many other difficult to quantify factors. Although witnessed across multiple chemicals, this 

range in FAR values is not expected when considering TTR data for a single chemical. HED 

selected 1% and 0.2% as high-end default values for liquid and granular products, respectively. 

Because TTR data are not available for mefenoxam, EPA is using the default values of 1% and 

0.2% as high-end default values for liquid and granular products, respectively. Although there 

may be a small degree of uncertainty in the use of the default TTR value for mefenoxam (i.e., 

there is a small chance that the FAR value may exceed the applicable default value), it is likely 

that the health-protective aspects of EPA’s residential post-application turf assessment 

methodology will more than compensate for this potential uncertainty (i.e., the methodology is 

likely to overestimate exposure by a factor greater than the factor than the highest measured FAR 

values exceed the defaults). For example, when assessing residential post-application turf 

exposure, EPA assumes the following: exposures occur to zero-day (i.e., day of application) 

residues every day of the assessed exposure duration (i.e., EPA assumes that no dissipation or 

degradation occurs, it doesn’t rain, the grass is not mowed, etc); individuals perform the same 

post-application activities performed in the turf transfer coefficient study day after day (e.g., 

tumbling, playing on turf with toys, etc.); and individuals engage in these post-application 

activities for a high-end amount of time every day that is represented by data reflecting time 

children spend outdoors and not specifically engaged in activities on turf, when in actuality 

children do not spend all of their outdoor time on turf and high-end levels of activity will not

occur every day. 

Given the conservatisms discussed above and the potential compounding nature of these 

conservatisms, EPA is able to rely upon the calculated exposure estimates with confidence that 

exposure is not being underestimated. 

Since the estimated residential turf post-application exposure for residential turf using default 

TTR values for mefenoxam is minimal in comparison to the level of concern (i.e., the calculated 

MOE is greater than 10 times higher than the level of concern, MOE = 1,000 compared to the 

LOC of 100); EPA is waiving the 40CFR TTR data requirement. In this instance, it is unlikely 

that chemical-specific TTR data would be needed to further refine exposure assessments or 

would add appreciably to our general understanding of the availability of turf transferable 

pesticide residues. 
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Dislodgeable Foliar Residue (DFR): 

In accordance with 40 CFR 158, DFR data are required for all occupational (e.g., crop, nursery, 

greenhouse use sites) or residential (e.g., ornamental and vegetable gardens, pick your own 

farms, retail tree farms) uses that could result in post-application exposure to foliage. Chemicalspecific DFR studies have been submitted for the use of mefenoxam on peppers and on non-food 

greenhouse ornamentals, but have not been employed in this or previous risk assessments 

because HED has determined that there is no hazard via the dermal route of exposure to 

mefenoxam.

6.3 Residential Risk Estimates for Use in Aggregate Assessment

Ingestion of granules is considered an episodic event and not a routine behavior. Because HED 

does not believe that this would occur on a regular basis, our concern for human health is related 

to acute poisoning rather than short-term residue exposure. Therefore, an acute dietary dose is 

used to estimate exposure and risk resulting from episodic ingestion of granules. For these same 

reasons, the episodic ingestion scenario is not recommended for inclusion in the aggregate 

assessment. 

Table 5.3.1 reflects the residential risk estimates that are recommended for use in the aggregate 

assessment for mefenoxam. The recommended residential exposure for use in the adult 

aggregate assessment reflects inhalation exposure from liquid concentrate applications to lawns 

or turf via a backpack sprayer. The recommended residential exposure for use in the children 

1<2 years old aggregate assessment reflects hand-to-mouth exposure following liquid 

concentrate applications to turf.

Table 5.3.1. Recommendations for the Residential Exposures for Mefenoxam Aggregate Assessment.

Lifestage Exposure Scenario

Dose (mg/kg/day)1 MOE2

Dermal Inhalation Oral Total Dermal Inhalation Oral Total

Adult

Backpack 

ApplicationsLawns/Turf Liquid 

Concentrate

NA 0.00063 NA 0.00063 N/A 79,000 NA 79,000

Child 1<2 

year old

(ShortTerm)

Hand-to-mouth 

Exposure- Liquid 

Application to 

Lawns/Turf

NA NA 0.048 0.048 NA NA 1,000 1,000

1 Dose = the highest dose for each applicable lifestage of all residential scenarios assessed. (Table 5.1.1 presents the Residential 

Handler Exposure and Risk Estimates; Table 5.2.1 presents the Residential Post-application Exposure and Risk Estimates.)

2 MOE = the MOEs associated with the highest residential doses. 
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6.4 Residential Bystander Post-application Inhalation Exposure

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.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2009-0687-

0037). The Agency has evaluated the SAP report and has developed a Volatilization Screening 

Tool and a subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). During Registration 

Review, the Agency will utilize this analysis to determine if data (i.e., flux studies, route-specific 

inhalation toxicological studies) or further analysis is required for mefenoxam.

6.5 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is 

particularly the case with aerial application, but, to a lesser extent, spray drift can also be a 

potential source of exposure from the ground application methods (e.g., groundboom and 

airblast) employed for mefenoxam. The agency has been working with the Spray Drift Task 

Force (a task force composed of various registrants which was developed as a result of a Data 

Call-In issued by EPA), 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). The agency has also developed a policy on how to 

appropriately consider spray drift as a potential source of exposure in risk assessments for 

pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during 

the Registration Review process which ensures that all uses for that pesticide will be considered 

concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures For 

Residential Risk Assessment (SOPs) - Residential Exposure Assessment Standard Operating 

Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification 

of indirect non-occupational exposure to drift

7.0 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.

For mefenoxam, only acute and short-term aggregate risks were calculated. Chronic aggregate 

risk was not calculated because no chronic dietary or residential intermediate- or long-term 

hazards were identified for mefenoxam.

7.1 Acute Aggregate Risk

The acute aggregate risk assessment considers exposure estimates from dietary consumption of 

mefenoxam (food and drinking water). The acute aggregate food and drinking water assessment 

results are presented in Section 5.4 above. The most highly exposed subgroup is children <1 

years old at 95% of the aPAD, which is below the level of concern.
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7.2 Short-Term and Intermediate-Term Aggregate Risk

The short- and intermediate-term risk assessments considers only exposure estimates from 

incidental oral and inhalation exposures to mefenoxam (Table 7.2.1). Since no hazard was 

identified for non-acute dietary or dermal exposure scenarios, these scenarios are not included in 

the assessment. The exposure scenarios used represent the most conservative scenarios for 

mefenoxam residential uses, and are further discussed in section 5.3 above. 

Table 7.2.1 Short-Term and Intermediate Term Aggregate Risk Calculations

Population

Short- or Intermediate-Term Scenario

NOAEL 

mg/kg/day LOC1

Max 

Allowable 

Exposure2

mg/kg/day

Average

Food and 

Water 

Exposure 

mg/kg/day

Residential 

Exposure 

mg/kg/day3

Total 

Exposure 

mg/kg/day4

Aggregate 

MOE (food, 

water, and 

residential)5

Adult 50 100 0.5 NA6 0.00063 0.00063 79,000

Children 1<2 

years old 50 100 0.5 NA6 0.048 0.048 1,000

1 LOC includes the standard inter- and intra-species uncertainty factors (UFA and UFH, respectively) totaling 100.

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Residential Exposure = [Oral exposure + Inhalation Exposure]. For mefenoxam, dermal exposure was not assessed 

because no hazard was identified via the dermal route. See Table 5.3.1.

4 Total Exposure = [Food & Water Exposure + Residential Exposure. For mefenoxam, food & water exposure was 

not assessed because no hazard was identified for non-acute dietary scenarios. See Section 5.4.

5 Aggregate MOE = [NOAEL / (Total Exposure)]

6 NA = not applicable because no hazard was identified for non-acute dietary scenarios.

8.0 Cumulative Exposure/Risk Characterization

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 mefenoxam and any other substances and mefenoxam 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 mefenoxam 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/.

9.0 Occupational Exposure/Risk Characterization

Mefenoxam has been proposed for use as a seed treatment on the commodities in Rapeseed 

subgroup 20A. This use results in potential exposure and risk to workers.
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9.1 Occupational Handler Exposure/Risk Estimates

HED uses the term handlers to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct job functions or tasks related to 

applications and exposures can vary depending on the specifics of each task. Job requirements 

(amount of chemical used in each application), the kinds of equipment used, the target being 

treated, and the level of protection used by a handler can cause exposure levels to differ in a 

manner specific to each application event. 

Chemical-specific handler exposure data were not submitted in support of this registration. 

Estimates of exposure to primary and secondary pesticide seed treatment handlers are based 

upon ExpoSAC Policies 14, 15, and 15.1, and a memorandum from the Biological and Economic 

Analysis Division (BEAD), “Acres Planted Per Day and Seeding Rates of Crops Grown in the 

United States” (J. Becker, March 2011). Based on the anticipated use patterns and current 

labeling, types of equipment and techniques that can potentially be used, short- and intermediateoccupational handler exposure is expected from the proposed use. The quantitative exposure and 

risk assessment developed for occupational handlers is based on the primary and secondary 

handler scenarios.

Primary and Secondary Handler Scenarios:

Treating Seed (Primary Handler):

Potential occupational exposure scenarios from the use of mefenoxam as a commercial seed 

treatment include: Mixing, loading, and applying liquid formulations to seed; bagging treated 

seed; sewing bags with treated seeds; and multiple of these activities. Typically, for large-scale 

commercial seed treatments, workers perform only those specific individual tasks listed above; 

however, it is assumed that workers also may perform multiple activities throughout the day. As 

a result, a “multiple activities” scenario (i.e. where one worker performs all seed treatment tasks 

such as loading/applying, sewing, bagging, cleaning, calibration, repair, forklift driver, etc.) was 

also assessed.

Planting Treated Seed (Secondary Handler):

Potential occupational exposure scenarios from the use of mefenoxam as a commercial seed 

treatment include planting treated seed (secondary handler). Planting treated seed consists of the 

farmer purchasing bags of treated seed, placing the seed in the hopper and applying seed to 

fields, considered a secondary handler exposure scenario.

Occupational Handler Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the occupational 

handler risk assessments. Each assumption and factor is detailed below on an individual basis.

Application Rate: 

Refer to the proposed use pattern table for Rapeseed subgroup 20A, in Table 4.1.1., for 

application rate information.

Exposure Duration: 

Occupational seed treatment handlers may experience short- and intermediate-term exposures to 

mefenoxam while performing seed treatment activities. In addition, occupational secondary 

handlers may experience short- and intermediate-term exposure while planting mefenoxamtreated seeds. A short- and intermediate-term dermal exposure assessment was not performed 
Mefenoxam Human Health Risk Assessment DP No. D424727

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because no endpoint attributable to dermal exposure was identified. Additionally, since the 

inhalation endpoint was selected for short- and intermediate-term exposure durations, short-term 

exposure and risk estimates are considered to be protective of intermediate-term exposure. 

Unit Exposures: 

It is the policy of HED to use the best available data to assess handler exposure. Chemicalspecific data for assessing exposure during commercial seed treatment and seed planting 

activities were not submitted to the Agency in support of this Section 3 application. Unit 

exposures are from ExpoSAC Policy 14: SOPs for Seed Treatment (May 1, 2003) and are based 

on data for open mixing/loading/application systems.

Amount Handled: 

HED is currently in the process of revising ExpoSAC Policy 15: Amount of Seed Treated or 

Planted per Day (March 2, 2004) in efforts to update the daily amount of seed treated in 

commercial seed treatment facilities. With the increasing demand for hybridized treated seeds, 

there have been modifications not only in the seed treatment equipment, but in the market shares 

of new and currently registered pesticide products. HED understands that due to the high cost of 

producing hybrid seeds, direct seeding is done in a precise manner which requires lower volumes 

of seed per acre. However, this does not provide a direct correlation to the amount of seed which 

is treated in the commercial seed treatment facilities. 

The amount of mefenoxam handled depends on the application rate (lb ai/lb seed) and the 

pounds of seed treated in a day (or the pounds of seed that can be planted in a day), all of which 

vary depending upon the seed type. Values for the amount of seed treated and planted per day, as 

well as the maximum seeds per acre were obtained from HED ExpoSAC Policy 15 and 15.1, and 

the BEAD memo: “Acres Planted Per Day and Seeding Rates of Crops Grown in the United 

States.” 

For both short- and intermediate-term exposure durations, 125,000 lb of canola seed are assumed 

to be treated per day at a commercial facility (ExpoSAC Policy 15.1, surveyed from AHETF 

2012). The amount of seed planted (ASP) per day is assumed to be 658 lbs of seed, and is 

calculated with the maximum seeds per acre, the number of acres treated in a day, and the 

minimum number of seeds per pound [(740,520 seeds/acre * 80 acres/day)/90,000 min 

seeds/lb)].

Mitigation/Personal Protective Equipment: 

Estimates of inhalation exposure were calculated for various levels of clothing or PPE. Results 

are presented for “baseline,” defined as a single layer of clothing consisting of a long sleeved 

shirt, long pants, shoes plus socks, no protective gloves, and no respirator. The proposed 

mefenoxam EUP label directs mixers, loaders, applicators and other handlers to wear a longsleeved shirt and long pants; chemical-resistant gloves made of any waterproof material; shoes 

plus socks; and protective eyewear.

Occupational Handler Non-Cancer Exposure and Risk Estimate Equations

The algorithms used to estimate non-cancer exposure and dose for occupational handlers can be 

found in Appendix A.

Combining Exposures/Risk Estimates:

The dermal route of exposure does not need to be combined with the assessed inhalation route of 
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exposure because there is no identified dermal hazard.

Summary of Occupational Handler Non-Cancer Exposure and Risk Estimates

The results of the occupational handler exposure and risk assessment resulting from the proposed 

use of mefenoxam are presented in Table 9.1.1 and indicate that short-term inhalation risks do 

not exceed HED’s LOC (i.e. an MOE < 100 for short-term exposures) at baseline mitigation (no 

PPE). Short-term risk exposure estimates are protective of intermediate-term exposure risk 

estimates because the throughput (amount of seed treated) of short-term exposure is equal to the 

throughput of intermediate-term exposure. The inhalation MOEs range from 270,000 to 

24,000,000 for handlers (treaters and planters). Because the short- and intermediate-term 

inhalation PODs are the same, and the intermediate-term exposure inputs are less conservative 

than the short-term exposure inputs for seed treatment, short-term exposure risk estimates are 

protective of intermediate-term exposures.

Table 9.1.1. Summary of Short-/Intermediate-Term Primary and Secondary Handler Exposures 

and Risks for Mefenoxam Seed Treatment of Canola Grown for Seeda

Maximum 

Application Rateb

Inhalation Unit 

Exposurec

Seed Amount Treated 

or Planted Per Dayd

Inhalation DoseeInhalation MOEf

lb ai/lb seed mg/lb lb seed/day mg/kg/day LOC = 100

Loader/Applicator

0.000075 0.00034 125,000 0.004 1,300,000

Sewer

0.000075 0.00023 125,000 0.0027 1,900,000

Bagger

0.000075 0.00016 125,000 0.0019 2,700,000

Multiple Activities

0.000075 0.0016 125,000 0.019 270,000

Planters

0.000075 0.0034 660 0.0000021 24,000,000

a Seed treatment rate calculations are based on the following assumptions: Canola: 9,000 seeds per lb; 8.0 lb of seed 

planted per acre, 80 acres planted per day, and 740,520 seeds/acre.

b Application Rate based on proposed label for mefenoxam (EPA Reg. No. 100-799).

c Unit Exposures from HED Exposure Science Advisory Council Policy 14: Standard Operating Procedures for Seed 

Treatment (baseline inhalation = no respirator).

d HED default for lb seed treated/planted per day from HED Exposure Science Advisory Council Interim Policy 

15.1 and the BEAD memo “Acres Planted Per Day and Seeding Rates of Crops Grown in the United States” (J. 

Becker, March 2011).

e Daily Inhalation Dose (mg/kg/day) = daily inhalation unit exposure (mg/¬lb ai) × application rate (lb ai/lb seed) × 

amount planted (lb seed/day) ÷¬ body weight (80 kg adult).

f

Inhalation MOE = NOAEL (50 mg/kg/day) ÷ Inhalation Dose (mg/kg/day). Short-term level of concern = 100.
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9.2 Occupational Post-Application Exposure/Risk Estimates

HED uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred to as reentry exposure). Such exposures may occur when workers enter previously treated areas to 

perform job functions, including activities related to crop production, such as scouting for pests 

or harvesting. 

The potential for dermal and inhalation post-application exposures following the planting of 

mefenoxam-treated seeds is unlikely because sustained levels of contact with treated seed after it 

has been placed in the soil or other planting media would not be expected because no routine 

cultural practice required for the production of agricultural commodities involves such an 

activity as defined in the no/low contact criteria in the Worker Protection Standard (WPS). 

Therefore, while the requirement of a 48-hour restricted entry interval (REI) for potential contact 

with treated seed following planting applies based on the acute toxicity of technical mefenoxam, 

so does the potential exception to this requirement per WPS guidance for situations where 

contact with residue is not expected. 

A post-application inhalation exposure assessment is not required as exposure is expected to be 

negligible. However, the seed treatment handler assessments provide quantitative inhalation 

exposure assessments for primary and secondary handlers. It is expected that these exposure 

estimates would be protective of any potential low-level post-application inhalation exposure 

that could result from these types of applications.

10.0 References

Christensen C., 06/14/2001, D274784, HED Risk Assessment: Human Health Risk Assessment 

for Mefenoxam on the Herb Subgroup, Globe Artichoke, and Minor/Tropical Fruits.

N. Dodd, 12/7/2009, D368462, Metalaxyl/Mefenoxam. Human Health Assessment Scoping 

Document in Support of Registration Review.

N. Dodd, 4/13/10, D368461, Metalaxyl/Mefenoxam. Response to Public Comments regarding 

Registration Review Summary Document (EPA-HQ-OPP-2009-0002).

Dodd N., 11/2/2015, D429030, Mefenoxam Acute Aggregate Dietary (Food and Drinking 

Water) Exposure and Risk Assessment for the Section 3 Registration Action on the Rapeseed 

Subgroup 20A.

Dodd, N., 11/2/2015, D429028, Mefenoxam. Petition Proposing Establishment of a Permanent 

Tolerance and Registration for Use on the Rapeseed Subgroup 20A. Summary of Analytical 

Chemistry and Residue Data.

Engler R., 6/21/1985, TXR 0004874, Peer Review of Metalaxyl, Tox Chem No. 375AA.

Kutney L., 4/24/1996, D223261, Mefenoxam: Replacement of Metalaxyl Technical with 

Mefenoxam Technical; Review of Bridging Data, CBTS No. 16909. PRIORITY 6. TOX 375AA, 

ID #:000100-TOR PRAT CASE #: 039771

Lowit A., 5/17/2000, TXR 0014165, MEFANOXAM - 2nd Report of the Hazard Identification 

Assessment Review Committee.
Mefenoxam Human Health Risk Assessment DP No. D424727

Page 33 of 48

Negussie M., 7/28/2010, D369043, Mefenoxam. Human Health Risk Assessment for Proposed 

Uses on Snap Beans and the Caneberry Subgroup, Expanded Uses on the Bulb and Green Onion 

Subgroups and the Bushberry Subgroup, and Amended Use on Spinach.

Nollen L., 12/3/2015, D430081, Mefenoxam. Occupational and Residential Exposure 

Assessment for a Proposed Seed Treatment Use on Rapeseed Subgroup 20A and Updated 

Residential Exposure Assessment for All Existing Residential Uses (Turf and Ornamentals).

Sette W.F., 10/7/1997, TXR 0012380, MEFENOXAM: PC Code: 113502. Report of the Hazard 

Identification Assessment Review Committee.

Habiba U., 8/20/2015, TXR 0057208, Hazard and Science Policy Council (HASPOC) Meeting 

on August 20, 2015 for Metalaxyl and Mefenoxam.
Mefenoxam Human Health Risk Assessment DP No. D424727

Page 34 of 48

Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.500) for food uses are below. Use of the new guideline numbers does not imply that 

the current (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 Acute Eye Irritation.......................................................

870.2500 Acute Dermal Irritation .................................................

870.2600 Skin Sensitization ..........................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 90-Day Oral Toxicity in Rodents ..................................

870.3150 90-Day Oral Toxicity in Nonrodents.............................

870.3200 21/28-Day Dermal Toxicity ..........................................

870.3250 90-Day Dermal Toxicity................................................

870.3465 90-Day Inhalation Toxicity ...........................................

yes

yes

yes

no

yes

yes

yes

yes

--

waived1

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

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

870.3800 Reproduction and Fertility Effects ................................

yes

yes

yes

yes

yes

yes

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

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

870.4200a Carcinogenicity (rat)......................................................

870.4200b Carcinogenicity (mouse) ...............................................

870.4300 Combined Chronic Toxicity/Carcinogenicity................

yes

yes

yes

yes

yes

yes2

yes

yes2

yes

yes

870.5100 Mutagenicity—Bacterial Reverse Mutation Test ..........

870.5300 Mutagenicity—In vitro Mammalian Gene Mutation ....

870.5375 Mutagenicity—In vitro Mammalian Chromosome Aberration

870.5385 Mutagenicity—In vivo Mammalian Chromosomal Aberration

yes

yes3

yes3

yes4

yes

yes

yes

yes

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

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

870.6300 Developmental Neurotoxicity .......................................

yes

yes

no

yes5

yes

--

870.7485 Metabolism and Pharmacokinetics................................

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

870.7800 Immunotoxicity .............................................................

yes

no 

yes

yes

--

yes

1 Requirement waived (TXR0057208, 20 August 2015).

2 A chronic/carcinogenicity study (870.4300) is available for the rat, thus separate chronic (870.4100a) and carcinogenicity 

(870.4200a) studies are not necessary.

3 Either study guideline 870.5300 or 870.5375 may be used to satisfy the mutagenicity in vitro data requirement.

4 Either study guideline 870.5385 or 870.5395 may be used to satisfy the mutagenicity in vivo data requirement.

5 Requirement for a guideline study waived (TXR0057208, 20 August 2015). A dose range finding study is available.
Mefenoxam Human Health Risk Assessment DP No. D424727

Page 35 of 48

A.2 Toxicity Profiles 

Table A.2.1 Acute Toxicity Profile – Metalaxyl 

Guideline Study Type MRID(s) Results Toxicity Category

870.1100 Acute Oral Toxicity (Rat) 00063990 LD50 = 669 mg/kg III

Acute Oral Toxicity (Mouse) 00063991 LD50 = 788 mg/kg III

870.1200 Acute Dermal Toxicity (Rat) 00063994 LD50 > 3170 mg/kg III

Acute Dermal Toxicity (Rabbit) 00063993 LD50 > 6000 mg/kg III

870.1300 Acute Inhalation Toxicity (Rat) 00109156 LC50 > 3.38 mg/L Not established since the 

study is supplemental

870.2400 Acute Eye Irritation (Rabbit) 00084108 Mild irritant II

870.2500 Acute Dermal Irritation (Rabbit) 00084107 Slight irritant IV

870.2600 Skin Sensitization (Guinea Pig) 00084109 Not a dermal sensitizer NA

Table A.2.2 Acute Toxicity Profile – Mefenoxam 

Guideline Study Type MRID(s) Results Toxicity Category

870.1100 Acute Oral Toxicity (Rat) 43800383 LD50 = 1269 mg/kg II

870.1200 Acute Dermal Toxicity (Rat) 43800384 LD50 > 2000 mg/kg III

870.1300 Acute Inhalation Toxicity (Rat) 43800385 LC50 > 2.29 mg/L IV

870.2400 Acute Eye Irritation (Rabbit) 43800386 Persistent corneal opacity I

870.2500 Acute Dermal Irritation (Rabbit) 43800387 Slight irritant IV

870.2600 Skin Sensitization (Guinea Pig) 43800388 

43800389

Not a dermal sensitizer NA

Table A.2.3 Subchronic, Chronic and Other Toxicity Profile – Metalaxyl and Mefenoxam

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

/Doses

Results

870.3050

Repeated Dose 28-Day Oral 

Toxicity in Rodents – gavage

(Rat)

43800390 (1994) 

Acceptable/non-guideline

0, 10, 50, 150 or 300 mg/kg/d

Metalaxyl

NOAEL = 10 mg/kg/day 

LOAEL = 50 mg/kg/day based on extra-medullary 

hematopoiesis of the spleen (females only) and 

hepatocellular hypertrophy.

870.3050

Repeated Dose 28-Day Oral 

Toxicity in Rodents – gavage

(Rat)

43800390 (1994)

Acceptable/non-guideline

0, 10, 50, 150 or 300 mg/kg/d 

Mefenoxam

NOAEL = 50 mg/kg/day 

LOAEL = 150 mg/kg/day based on histology of the 

liver and clinical signs, including hypoactivity postdosing (only occurred during the initial dose).

870.3050

Repeated Dose 28-Day Oral 

Toxicity in Rodents – feed

(Mouse)

48104701 (2003) 

Acceptable/guideline

0, 250, 1250 or 7000 ppm

M: 0, 52, 242 or 1364 mg/kg/d

F: 0, 65, 290 or 1960 mg/kg/d

Metalaxyl

NOAEL = 1364 mg/kg/day 

LOAEL was not observed.
Mefenoxam Human Health Risk Assessment DP No. D424727

Page 36 of 48

Table A.2.3 Subchronic, Chronic and Other Toxicity Profile – Metalaxyl and Mefenoxam

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

/Doses

Results

870.3050

Repeated Dose 28-Day Oral 

Toxicity in Rodents – feed

(Rat)

43800391 (1994)

Acceptable/non-guideline 

0, 0, 500, 3000 or 6000 ppm

M: 0, 43, 257 or 534 mg/kg/d

F: 0, 47, 263 or 650 mg/kg/d

Mefenoxam

NOAEL was no observed 

LOAEL = 43 mg/kg/day based on liver weights and 

liver histology (e.g., hepatocellular hypertrophy)

870.3100

90-Day Oral Toxicity in 

Rodents – feed

(Rat)

00084110 (1977)

Core/guideline

0, 50, 250 or 1250 ppm

0, 3.4, 17 or 83 mg/kg/d

Metalaxyl

NOEL = 17 mg/kg/day 

LOEL = 83 mg/kg/day based on slightly reduced food 

consumption in males, and in females increased 

incidences of minimal hepatocellular hypertrophy.

870.3100

90-Day Oral Toxicity in 

Rodents – feed

(Rat)

48104702 (2003)

Acceptable/guideline

0, 250, 1250, 7500 or 20000 ppm

M: 0, 16, 83, 496 or 1304 mg/kg/d

F: 0, 19, 101, 595 or 1672 mg/kg/d

Metalaxyl

NOAEL = 16/101 mg/kg/day (M/F)

LOAEL = 83/595 mg/kg/day (M/F) based on 

increased incidences of nephropathy in males, and in 

females decreased body weights, body weight gains, 

and food consumption.

870.3100

90-Day Oral Toxicity in 

Rodents – feed

(Rat)

43823202 (1995) 

Acceptable/guideline

0, 25, 50, 250, 625 or 1250 ppm

M: 0, 1.7, 3.5, 17, 45 or 91 mg/kg/d

F: 0, 1.9, 3.7, 18, 49 or 95 mg/kg/d

Mefenoxam

NOAEL = 45 mg/kg/day

LOAEL = 91 mg/kg/day based on histopathological 

changes in the liver.

870.3100

90-Day Oral Toxicity in 

Rodents – feed

(Mouse)

00148087 (1985) 

Core/supplementary

0, 1250, 2500 or 5000 ppm

0, 188, NA or NA mg/kg/d

Metalaxyl

NOEL was not observed.

LOEL = 188 mg/kg/day based on elevated liver 

weight and liver-to-body weight ratio. Changes in 

glycogen content, fatty vacuolization, hypertrophy in 

hepatocytes of males given 2500 and 5000 ppm diets 

after 1 month, not present after 3 months.

870.3150

90-Day Oral Toxicity in 

Nonrodents – feed

(Dog)

00084111 (1977)

Core/supplementary

0, 50, 250 or 1250 ppm 

Metalaxyl

NOEL = 1250 ppm

LOEL was not observed.

870.3150

90-Day Oral Toxicity in 

Nonrodents – feed

(Dog) 

43800392 (1995) 

Acceptable/guideline

0, 50, 125, 250 or 1250 ppm

M: 0, 1.6, 4.1, 7.3 or 39 mg/kg/d

F: 0, 1.6, 4.3, 7.9 or 40 mg/kg/d

Mefenoxam

NOEL = 7.3 mg/kg/day

LOEL = 39 mg/kg/day based on increased alkaline 

phosphatase activity and increased absolute and 

relative liver weights.

870.3200

21/28-Day Dermal Toxicity

(Rabbit)

00072394 (1980) 

Acceptable/guideline

0, 10, 100, 1000 mg/kg/day

Metalaxyl

NOAEL = 1000 mg/kg/day

LOAEL was not observed.
Mefenoxam Human Health Risk Assessment DP No. D424727

Page 37 of 48

Table A.2.3 Subchronic, Chronic and Other Toxicity Profile – Metalaxyl and Mefenoxam

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

/Doses

Results

870.3465

90-Day Inhalation Toxicity

Waived (TXR0057208, 20 August 

2015)

Metalaxyl

Not be required at this time for the following reason: 

the MOEs are greater than the Agency’s target MOE 

for inhalation waivers (i.e., >1000).

870.3465

90-Day Inhalation Toxicity

Waived (TXR0057208, 20 August 

2015)

Mefenoxam

Not required at this time for the following reasons: (1) 

the MOEs are greater than the Agency’s target MOE 

for inhalation waivers (i.e., >1000); and (2) the 

corrosive classification (Toxicity Category I) in the 

acute eye irritation study indicates that metalaxyl-M 

may cause portal of entry effects.

870.3700a

Prenatal developmental 

Toxicity – gavage

(Rat)

00144423 (1985), 00144422 (1985)

Acceptable/guideline

Note: DER Updated

0, 50, 250 or 400 mg/kg/day

Metalaxyl

Maternal NOAEL = 50 mg/kg/day 

LOAEL = 250 mg/kg/day based on dose-related 

increases in clinical signs (dry or wet matter on head, 

eyes, nose, abdomen, anogenital area, and/or vaginal 

opening; stained and/or matted hair coat on the head, 

face, ventral thorax, abdomen, back, anogenital area, 

and/or forelimbs) and post-dosing convulsions that 

occurred shortly after dosing.

Developmental NOAEL = 400 mg/kg/day

LOAEL was not observed.

870.3700a

Prenatal developmental 

Toxicity – gavage

(Rat)

43800393 (1995), 44208401 (1994)

Acceptable/guideline

0, 10, 50 or 250 mg/kg/day

Mefenoxam

Maternal NOAEL = 50 mg/kg/day

LOAEL = 250 mg/kg/day based on decreased body 

weight gains and food consumption.

Developmental NOAEL = 250 mg/kg/day

LOAEL was not observed.

870.3700b

Prenatal developmental 

Toxicity – gavage

(Rabbit)

00144372, 00144371, 00148866 (1984); 

00154938 (1983)

Acceptable/guideline

0, 30, 150 or 300 mg/kg/day (main)

0, 30, 100, 250, 500 or 1000 mg/kg/day 

(range-finder)

Metalaxyl

Maternal NOAEL = 150 mg/kg/day

LOAEL = 300 mg/kg/day based on body weight gain.

Developmental NOAEL = 300 mg/kg/day

LOAEL = 500 mg/kg/day based on number of dams 

with viable fetuses.

870.3800

Reproduction and Fertility 

Effects – feed

(Rat)

00071600 (1980)

Acceptable/guideline

Note: DER Updated

0, 50, 250 or 1250 ppm

0, 2.5, 13 or 63 mg/kg/day

Metalaxyl

Parental/Systemic NOAEL = 63 mg/kg/day

LOAEL was not observed.

Reproductive NOAEL = 63 mg/kg/day

LOAEL was not observed.

Offspring NOAEL = 63 mg/kg/day

LOAEL was not observed.

870.4100b

Chronic toxicity – feed

(Dog)

00071598 (1981) 

Acceptable/guideline

Note: DER Updated

0, 50, 250, 1000 ppm

M: 0, 1.6, 7.8, 31 mg/kg/day

F: 0, 1.7, 7.4, 32 mg/kg/day

Metalaxyl

NOAEL = 32 mg/kg/day

LOAEL was not observed.
Mefenoxam Human Health Risk Assessment DP No. D424727

Page 38 of 48

Table A.2.3 Subchronic, Chronic and Other Toxicity Profile – Metalaxyl and Mefenoxam

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

/Doses

Results

870.4200b

Carcinogenicity – feed

(Mouse)

00103354 (1981); 00150094 (1985) 

Acceptable/guideline 

Note: DER Updated

0, 50, 250 or 1250 ppm

M: 0, 5.0, 25, 129 mg/kg/day

F: 0, 5.7, 30, 148 mg/kg/day

Metalaxyl

NOAEL = 148 mg/kg/day

LOAEL was not observed.

No evidence of carcinogenicity.

870.4300

Combined Chronic 

Toxicity/Carcinogenicity– feed

(Rat)

00098481 (1980); 00132009 (1983); 

00150185 (1985)

Acceptable/guideline

Note: DER Updated

0, 50, 250, 1250 ppm

M: 0, 1.9, 9.4, 47 mg/kg/day

F: 0, 2.2, 10, 55 mg/kg/day 

Metalaxyl

NOAEL = 55 mg/kg/day

LOAEL was not observed.

No evidence of carcinogenicity.

870.5100

Bacterial Reverse Mutation 

Test

(Salmonella typhimurium)

00084113 (1978); 00154301 (1985); 

00154302 (1981)

Core/acceptable 

25, 75, 225, 675, 2025 μg/0.1 mL 

Metalaxyl

Not mutagenic. Tested with and without S9 metabolic 

activation.

870.5100

Bacterial Reverse Mutation 

Test

(Salmonella typhimurium)

43800394 (1994)

Acceptable/guideline

21, 62, 185, 556, 1667 or 5000 μg/plate

Mefenoxam

There was no concentration related positive response 

of induced mutant colonies over background. Tested 

with and without S9 metabolic activation, up to the 

limit concentration. 

870.5100

Bacterial Reverse Mutation 

Test

(Salmonella typhimurium)

43800401 (1995)

Acceptable/guideline

313, 625, 1250 or 5000 μg/plate

Mefenoxam intermediate (CA 2331 A)

There was no concentration related positive response 

of induced mutant colonies over background. Tested 

with and without S9 metabolic activation.

Non-guideline

Reverse Mutation Test in Yeast 

Cells (Saccharomyces 

cereviseae)

00103359 (1982)

Core/acceptable 

0, 400, 2000, 4000, 8000 or 10000 

μg/mL

Metalaxyl

No mutagenic activity (mitotic recombination, mitotic 

gene conversion, or reverse mutations) was observed. 

However, marginal results with positive controls in 

the mitotic recombination assay and variation in 

positive and negative control group results limited 

sensitivity of the assays. The results or such a study 

must be confirmed by another test system sensitive to 

the same type of genetic toxicity.

870.5300 

In vitro Mammalian Gene 

Mutation Test

(Mouse lymphoma cells)

00103362 (1982); 00154309 (1985)

Core/acceptable 

-S0: 0.125, 0.25, 0.5 or 1.0 mg/mL

+S9: 0.0625, 0.125, 0.25, or 0.5 mg/mL

Metalaxyl

Treatment with or without S9 metabolic activation did 

not increase the frequency of forward mutations at the 

Tk locus of L5175Y cells.
Mefenoxam Human Health Risk Assessment DP No. D424727

Page 39 of 48

Table A.2.3 Subchronic, Chronic and Other Toxicity Profile – Metalaxyl and Mefenoxam

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

/Doses

Results

870.5375 

In vitro Mammalian 

Chromosome Aberration

(Chinese hamster ovary cells)

43800395 (1994)

Acceptable/guideline

16, 32, 63, 127, 254, 508, 1015 or 2030 

μg/mL

Mefenoxam

Negative in this test system. Cells were tested with S9 

metabolic activation for 3 hr, with recovery periods of 

15 or 39 hr. Cells were tested without S9 metabolic 

for 18 or 42 hr without recovery period. 

870.5375 

In vitro Mammalian 

Chromosome Aberration

(Chinese hamster ovary cells)

43800404 (1995) 

Acceptable/guideline

+S9: 1000 μg/mL mefenoxam and 1, 10 

or 1000 ppm CA 2332 A

-S9: 1000 μg/mL mefenoxam and 1, 10, 

100, 1000 or 2000.

Mefenoxam and its intermediate (CA 

2332 A)

Positive for inducing chromosome aberrations in the 

presence of both 1000 μg/mL mefenoxam and 2,000 

ppm CA 2331 A, in the absence of S9 metabolic 

activation.

870.5375 

In vitro Mammalian 

Chromosome Aberration

(Chinese hamster ovary cells)

43800402 (1995)

Acceptable/guideline

1.22 – 5000 μg/mL

Mefenoxam intermediate (CA 2332 A)

Positive for inducing chromosome aberrations, at 39 

μg/mL without S9 metabolic activation and at 156 

μg/mL with S9 metabolic activation.

870.5375 

In vitro Mammalian 

Chromosome Aberration

(Chinese hamster ovary cells)

43800403 (1995)

Acceptable/guideline

-S9: 0.5, 1.0, 10, 100, 500 μg/mL

Mefenoxam intermediate (CA 2332 A)

Positive for inducing chromosome at 10 μg/ml 

without S9 metabolic activation.

870.5385 

In vivo Mammalian Bone 

Marrow Chromosomal 

Aberration – gavage 

(Chinese hamster)

00103361 (1979); 00154307 (1985)

Acceptable/guideline

0, 595, 1190 or 2380 mg/kg (two 

consecutive, daily doses)

Metalaxyl

No effect on the incidence of cells with nuclear 

anomalies.

870.5450

Rodent Dominant Lethal Assay

(Mouse)

00084114 (1979); 00154310 (1985)

Core/minimum 

0, 65, 195 mg/kg 

Metalaxyl

No effect on mating, pregnancy, number of implants, 

or embryo viability.

87.5550

Unscheduled DNA Synthesis in 

Mammalian Cells in Culture 

(Rat hepatocytes)

00103363, 00154663 (1982); 00154306, 

00160037 (1985)

0 – 2000 μg/mL

Core/acceptable

Metalaxyl

Under the conditions of the experiment, metalaxyl did 

not induce unscheduled DNA synthesis.

870.6200a

Acute Neurotoxicity Screening 

Battery

Waived (TXR0057208, 20 August 

2015)

Metalaxyl

The acute neurotoxicity study is not required at this 

time for the following reasons: (1) the rat prenatal 

developmental toxicity study indicated neurotoxicity 

(i.e., convulsions) that occurred shortly after being 

gavage dosed; and (2) an acute neurotoxicity study is 

unlikely to yield an acute point of departure that is 

lower than the current endpoint derived from the rat 

prenatal developmental toxicity study.
Mefenoxam Human Health Risk Assessment DP No. D424727

Page 40 of 48

Table A.2.3 Subchronic, Chronic and Other Toxicity Profile – Metalaxyl and Mefenoxam

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

/Doses

Results

870.6200a

Acute Neurotoxicity Screening 

Battery

(Rat) 

Range Finding Study

48865901 (2012)

Unacceptable

M: 0, 250, 500, 1000 mg/kg

F: 0, 75, 150, 300 mg/kg

Note: The study is not acceptable for 

risk assessment for numerous reasons 

(e.g., small sample sizes, missing motor 

activity, and missing histology) but it is 

acceptable for setting dose levels and 

establishing the post-dose peak time of 

effect in a future acute neurotoxicity 

study.

Mefenoxam

NOAEL = 500/150 mg/kg/day (M/F)

LOAEL = 1000/300 mg/kg/day based on FOB effects 

(i.e., slight salivation, slight lacrimation, slightly 

soiled appearance of fur, slightly droopy eyelids, 

decreased respiration rate and/or dyspnea, slight to 

moderately impaired mobility, dragging of the body, 

hunched poster, low arousal, and increased urination).

870.6200a

Acute Neurotoxicity Screening 

Battery

Waived (TXR0057208, 20 August 

2015)

Mefenoxam

A full acute neurotoxicity study is not required at this 

time for the following reason: the rat range-finding 

acute neurotoxicity study suggests that 

neurobehavioral effects occur at doses greater than the 

points of departures currently being used for 

endpoints.

870.6200b

Subchronic Neurotoxicity 

Screening Battery

Waived (TXR0057208, 20 August 

2015)

Metalaxyl

The subchronic neurotoxicity study is not required at 

this time for the following reasons: (1) there were no 

indications of neurotoxicity in repeat dose dietary 

studies; and (2) there were no indications of 

neurotoxicity in the metalaxyl-M subchronic 

neurotoxicity study

870.6200b

Subchronic Neurotoxicity 

Screening Battery – feed 

(Rat)

48865902 (2005)

Acceptable/non-guideline

0, 50, 250 or 1250 ppm

M: 0, 3.8, 19 or 96 mg/kg/day

F: 0, 4.4, 21 or 109 mg/kg/day

Mefenoxam

NOAEL = 109 mg/kg/day

LOAEL was not observed.

870.7485

Metabolism and 

Pharmacokinetics

(Rat)

00071613 (1977)

Acceptable/guideline

Single gavage: 0.5 or 25 mg/kg

Metalaxyl

Over 60% of the low or high dose was excreted within 

24 hours in urine or feces. Negligible amounts were 

eliminated in expired air. Low tissue residues six days 

after treatment indicated no appreciable 

bioaccumulation. Females eliminated the majority of 

the dose (55-65%) in urine, and males eliminated most 

(60-70%) in feces. Although metabolites were not 

identified, the chromatographic pattern were similar 

for both sexes and doses.

870.7485

Metabolism and 

Pharmacokinetics

(Rat)

00071614 (1978)

Acceptable/guideline

Single gavage: 28 mg/kg

Metalaxyl

Within 48 hours 96% of the dose had been excreted in 

urine or feces. Consistent with the previous study, 

females excreted over 60% of the dose in urine and 

about 30% in feces. Approximately 20% of the 

metabolites in urine were identified. Hydrolysis of the 

ether and ester bonds was shown to be a significant 

metabolic pathway. Glucuronidase treatment of urine 

fractions indicated metabolites were either 

unconjugated or glucuronide conjugates. Fecal 

metabolites were not identified
Mefenoxam Human Health Risk Assessment DP No. D424727

Page 41 of 48

Table A.2.3 Subchronic, Chronic and Other Toxicity Profile – Metalaxyl and Mefenoxam

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

/Doses

Results

870.7485

Metabolism and 

Pharmacokinetics

(Rat – females only)

00099084 (1981)

Acceptable/non-guideline 

Single gavage: 27.9 mg/kg

Metalaxyl

Study confirmed that ester and ether bond hydrolysis 

is a primary metabolic pathway. Secondary pathways 

included oxidation of methyl groups of the phenyl 

moiety and oxidation of the phenyl moiety itself. 

Some metabolites in urine were present as glucuronic 

acid conjugates. A large portion of the metabolites 

were unidentified.

870.7485

Metabolism and 

Pharmacokinetics

(Rat)

41664501 (1990)

Acceptable/guideline 

Single intravenous: 1 mg/kg

Single gavage: 1 or 200 mg/kg

Repeated gavage: 1 mg/kg/day

Metalaxyl

Metalaxyl was readily absorbed (similar i.v. and oral 

elimination profiles), extensively metabolized (<1% 

parent compound in excreta), and rapidly eliminated 

(70-80% in 24 hours). Ten metabolites were 

identified. The majority of urinary metabolites were 

conjugated (glucuronide or sulfate) whereas fecal 

metabolites were mostly unconjugated. The major 

metabolite in urine and feces was N-(2,6-

dimethylphenyl)-N-(hydroxyacetyl) alanine. Three 

major and one minor metabolic pathways were 

proposed. One pathway involved hydrolysis of the 

ether, followed by oxidation of the resulting alcohol, 

ester hydrolysis, or N-dealkylation of the ester chain. 

A second pathway involved oxidation of an aromatic 

methyl to the benzylic acid or ester hydrolysis. The 

third major pathway was ester hydrolysis, sometimes 

followed by benzylic acid formation. The minor 

pathway involved hydroxylation at the meta position 

of the phenyl ring. Two major metabolites in urine 

were not identified.

870.7485

Metabolism and 

Pharmacokinetics

(Rat )

00161402 (1984)

Acceptable/guideline

Dermally applied: 1 or 10 mg/kg

Note: This study is unacceptable for the 

approximation of the dermal absorption 

factor because conditions of the study 

did not reasonably approximate field 

conditions with respect to the use of 

THF. THF is known to be irritating to 

skin, eyes, and mucous membranes 

which could potentially enhance dermal 

absorption.

Metalaxyl

In the first 8 hr of treatment, about 30% of the dose 

was absorbed with 1% in the skin at the application 

site. Male absorption T1⁄2 for were 12 and 20 hr in 1 

and 10 mg/kg groups, respectively. Female absorption 

T1⁄2 was 13 hours in 1 and 10 mg/kg groups. Male 

excretion T1⁄2 were 36 and 49 hr in 1 and 10 mg/kg 

groups. Female excretion T1⁄2 were 42 and 44 hours 

for 1 and 10 mg/kg groups. 

1 mg/kg group results: 108% of the dose was 

recovered. In the feces, 38% and 25% was recovered 

from males and females, respectively. In the urine, 

47% and 56% was recovered from males and females. 

The carcass contained 11% and 18% in males and 

females. The dose remaining in the tissues and 

dissolved in the skin was 1-2% of the total recovery. 

10 mg/kg group results: 103% and 99% of the total 

dose was recovered from males and females, 

respectively. In the feces, 33% and 25% of was 

recovered from males and females. In the urine, 36% 

and 53% of the radioactivity was recovered from 

males and females. The carcass contained 15% and 

12% in male and female. The dose remaining in the 

tissues and dissolved in the skin was 0.5-2% of the 

total recovery. 

Among visceral tissues, liver and kidney contained the 

most radioactivity in both groups.
Mefenoxam Human Health Risk Assessment DP No. D424727

Page 42 of 48

Table A.2.3 Subchronic, Chronic and Other Toxicity Profile – Metalaxyl and Mefenoxam

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

/Doses

Results

870.7600

Dermal penetration 

(Rat – male only)

45085901 (1998)

Acceptable/non-guideline 

0.094 or 4.7 mg/cm2

Mefenoxam formulation: Ridomil 

Gold EC (A-9408B)

Percent absorbed was 25, 35 and 35 for the low dose 

and 3.0, 9.3 and 16 for the high dose. The value of 

35% absorbed should be used for converting oral to 

dermal doses for risk assessment. The study is 

considered of minimal value and use of the data 

should not be unduly extended.

Note: The dermal absorption factor (DAF) value of 

35% should be used for converting oral to dermal 

doses for risk assessment (A. Lowit, 05/17/200, TXR 

0014165).

870.7600

Dermal penetration 

(Rat and human, in vitro)

45085902 (1998)

Unacceptable 

Mefenoxam formulation: Ridomil 

Gold EC (A-9408B)

The Agency possesses sufficient information to 

conclude that this experimental in vitro procedure 

utilizing the ‘isolated epidermal membrane’ does not 

accurately determine in vivo dermal penetration of test 

chemicals. Results using this procedure have been 

shown to over or under estimate in vitro penetration in 

an inconsistent and unpredictable manner in relation 

to dose and duration of exposure. Further the data 

generated cannot be used to convert rat dermal 

penetration values to human values. This is clearly 

shown by the data generated in this study. The relation 

between percent absorbed in rat and human varies 

with dose and duration of exposure in an inconsistent 

and unpredictable manner.

870.7800

Immunotoxicity – feed 

(Mouse – female only)

48865903 (2012)

Acceptable/guideline 

0, 200, 2000 or 5000 ppm

0, 40, 406 or 1079 mg/kg/day

Mefenoxam

NOAEL = 1079 mg/kg/day

LOAEL was not observed.
Mefenoxam Human Health Risk Assessment DP No. D424727

Page 43 of 48

Appendix B. Physical/Chemical Properties

Table B.1 Physico-Chemical Properties

Parameter Value Reference

Molecular Weight 279.3 --

Boiling point/range >270oC (PAI) L. Kutney, 4/24/1996, 

D223261

pH 5-6 at 25°C (1% aqueous dispersion; 

TGAI)

Density 1.125 g/cm3 (20°C; TGAI)

Water solubility (20°C) 26 g/L (25°C; PAI)

Solvent solubility (20°C to 25°C)

Completely miscible in acetone, 

dichloromethane, ethyl acetate, 

methanol, N-octanol, and toluene; 59 

g/L in N-hexane at 25°C (TGAI).

Vapor pressure (25°C) 3.3 x 10-3 Pa (25°C; PAI)

Dissociation constant, pKa None in 1-10 pH range (PAI)

Octanol/water partition coefficient, log KOW

(25°C) 1.71 at 25°C (TGAI)

Table B.2. Chemical Names and Structures of Metalaxyl and its Metabolites in Plants

Code Structure Chemical Name

Common Name

(Company Code)

Substrate MRID

I N-(2,6-dimethylphenyl)-

N-(methoxyacetyl)alanine 

methyl ester

metalaxyl/mefenoxam

(CGA-48988/CGA329351)

lettuce foliage 00114379, 00071610

grapes and grape leaves 00071607, 00071606

potato tubers and foliage 00071603, 00071604

potato foliage 00071609

II N-(2-hydroxymethyl-6-

methylphenyl)-N-

(methoxy-acetyl)alanine 

methyl ester

(CGA-94689)

lettuce foliagea 00114379, 0071610,

00071680

grape and grape leavesa 00071607, 00071606

potato tubers and 

foliagea

00071603, 00071604

potato foliage 00071609

III N-(3-hydroxy-2,6-

dimethylphenyl)-Nlettuce foliagea 00114379, 0071610,

00071680

grapes and grape leavesa 00071607, 00071606

N

O

CH3

C O

O O

H3C

H3C

H3C CH3

N

O

CH3

C O

O O

H3C

H3C

HOCH2 CH3
Mefenoxam Human Health Risk Assessment DP No. D424727

Page 44 of 48

Table B.2. Chemical Names and Structures of Metalaxyl and its Metabolites in Plants

Code Structure Chemical Name

Common Name

(Company Code)

Substrate MRID

(methoxyacetyl)alanine 

methyl ester

(CGA-100255)

potato tubers and 

foliagea

00071603, 00071604

IV N-(2,6-dimethylphenyl)-

N-(methoxyacetyl)alanine

(CGA-62826)

lettuce foliagea 00114379, 00071610

grapes and grape leavesa 00071607, 00071606

potato tubers 00071603, 00071604

potato tubers and 

foliagea

00071609, 00071604

V N-(2-carboxy-6-

methylphenyl)-N-

(methoxyacetyl)alanine 

methyl ester

2-[(methoxyacetyl) (2-

methoxy-1-methyl-2-

oxoethyl)amino]-3-

methylbenzoic acid

(CGA-108905)

lettuce foliage 00071610

potato tubers and foliage 00071603, 00071604

potato foliage 00071609

VI N-(2-carboxy-6-

methylphenyl)-N-

(methoxyacetyl)alanine

(CGA-108906)

potato tubers 00071603

potato foliage 00071609

VII N-(2,6-dimethylphenyl)-

N-(hydroxyacetyl)alanine

(CGA-107955)

lettuce foliagea 00114379, 00071610

potato tubers and 

foliagea

00071603, 00071604

grapes and grape leavesa 00071607

N

O

CH3

C O

O O

H3C

H3C

H3C CH3

HO

N

O

CH3

C O

HO O

H3C

H3C CH3

N

O

CH3

C O

O O

H3C

H3C

HOOC CH3

N

O

CH3

C O

HO O

H3C

HOOC CH3

N

OH

C O

HO O

H3C

H3C CH3
Mefenoxam Human Health Risk Assessment DP No. D424727

Page 45 of 48

Table B.2. Chemical Names and Structures of Metalaxyl and its Metabolites in Plants

Code Structure Chemical Name

Common Name

(Company Code)

Substrate MRID

VIII N-(2,6-dimethylphenyl)-

2-methyl-3,6-

dioxomorpholine

(CGA-68125)

potato tubers and 

foliageb

00071604

IX N-(2,6-dimethylphenyl)-

2-hydroxyacetamide

(CGA-37734)

lettuce foliagec 00114379, 00071610

X N-(2,6-dimethylphenyl)-

N-(hydroxyacetyl)alanine 

methyl ester

(CGA-67869)

lettuce foliagec 00114379, 00071610

Table B.3. Chemical Names and Molecular Structures of Metalaxyl Metabolites Identified in Animal Tissues

Structure Chemical Name

Common Name

(Company code)

Substrate (MRID)

N-(2,6-dimethyl phenyl)-N-

(methoxyacetyl)alanine methyl ester

metalaxyl/mefenoxam

(CGA-48988/CGA-329351)

Poultry (42115804):

Whole egg 

N-[(2-hydroxymethyl)-6-methylphenyl]-N-

(methoxyacetyl)alanine methyl ester isomers

(CGA-94689)

Ruminant (41664503):

Milk 

Liver 

Kidney 

Leg muscle

Perirenal fat

Urine

Tenderloin

O N

O O

H3C

H3C CH3

HN

OH

O

H3C CH3

N

OH

C O

O O

H3C

H3C

H3C CH3

N

O

CH3

C O

O O

H3C

H3C

H3C CH3

N

O

CH3

C O

O O

H3C

H3C

HOCH2 CH3
Mefenoxam Human Health Risk Assessment DP No. D424727

Page 46 of 48

Table B.3. Chemical Names and Molecular Structures of Metalaxyl Metabolites Identified in Animal Tissues

Structure Chemical Name

Common Name

(Company code)

Substrate (MRID)

Poultry (42115804):

Whole egg 

N-(2,6-dimethylphenyl)-N-

(hydroxyacetyl)alanine methyl ester

(CGA-67869)

Ruminant (41664503):

Urine

Tenderloin

Milk

Liver

Kidney

Leg muscle

Perirenal fat

N-decanoic acid ester of CGA-67869 Ruminant (42115802):

Milk

Sulfuric acid conjugate of CGA-94689

(P4)

Poultry (42115804):

Thigh muscle

Whole egg

Peritoneal fat

N-[2-(hydroxymethyl)-6-methylphenyl-N-

(hydroxyacetyl)alanine

(P1/P2)

Poultry (42115804):

Thigh muscle

Whole egg

Peritoneal fat

Fatty acid conjugates of P1, P2

(Fat U3)

Poultry (42115804):

Whole egg

Peritoneal fat

N

OH

C O

O O

H3C

H3C

H3C CH3

N

O

C O

O O

H3C

H3C

H3C CH3

(CH2)

8

-CH3

O

N

O

CH3

C O

O O

H3C

H3C

HOCH2 CH3

N

OH

C O

HO O

H3C

HOCH2 CH3

N

(CH2)n-CH3

C O

HO O

H3C

HOCH2 CH3

n=14, 16
Mefenoxam Human Health Risk Assessment DP No. D424727

Page 47 of 48

Table B.3. Chemical Names and Molecular Structures of Metalaxyl Metabolites Identified in Animal Tissues

Structure Chemical Name

Common Name

(Company code)

Substrate (MRID)

N-(2,6-dimethylphenyl)-N-

(hydroxyacetyl)alanine

(CGA-107955)

Ruminant (41664503):

Milk

Liver

Urine

Tenderloin

Kidney

Leg muscle

Perirenal fat

Poultry (42115804):

Whole egg

Peritoneal fat

N-[(2-hydroxymethyl)-6-methylphenyl]-N-

(methoxyacetyl)alanine

(P0)

Poultry (42115804):

Whole egg

N-(2,6-dimethylphenyl)-2-hydroxyacetamide

(CGA-37734)

Ruminant (41664503):

Tenderloin

Milk

Liver

Urine

Kidney

Leg muscle

Perirenal fat

N-(2,6-dimethylphenyl)-N-

(methoxyacetyl)alanine

(CGA-62826)

Ruminant (41664503):

Tenderloin

Milk

Liver

Urine

Kidney

Leg muscle

Perirenal fat

N-(2,6-dimethylphenyl)alanine

(CGA-67867)

Ruminant (41664503):

Urine

N

OH

C O

HO O

H3C

H3C CH3

N

O

CH3

C O

HO O

H3C

HOCH2 CH3

HN

OH

O

H3C CH3

N

O

CH3

C O

HO O

H3C

H3C CH3

NH

C

O O

H3C

H3C CH3
Mefenoxam Human Health Risk Assessment DP No. D424727

Page 48 of 48

Table B.3. Chemical Names and Molecular Structures of Metalaxyl Metabolites Identified in Animal Tissues

Structure Chemical Name

Common Name

(Company code)

Substrate (MRID)

N-(3-hydroxy-2,6-dimethylphenyl)-N-

(methoxyacetyl)alanine methyl ester

(CGA-100255)

Ruminant (41664503):

Tenderloin

Milk

Liver

Urine

Kidney

Leg muscle

Perirenal fat

2-[(methoxyacetyl) (2-methoxy-1-methyl-2-

oxoethyl)amino]-3-methyl-benzoic acid

(CGA-108905)

Poultry (42115804):

Whole egg

[(2,6-dimethylphenyl)-amino]oxoacetic acid;

N-(oxalyl)-2,6-dimethylaniline

(CGA-68124)

Poultry* (42115804):

egg whites

liver

thigh muscle

breast muscle

skin and 

attached fat

N-(carboxycarbonyl)-N-(2,6-

dimethylphenyl)alanine methyl ester;

N-(oxalyl)-N-(2,6-dimethylphenyl)alanine 

methyl ester

(CGA-79353)

Poultry* (42115804):

egg whites

thigh muscle

breast muscle

skin and 

attached fat

N-(carboxycarbonyl)-N-(2,6-

dimethylphenyl)alanine;

N-(oxalyl)-N-(2,6-dimethylphenyl)alanine

(CGA-78532)

Poultry* (42115804):

egg whites

liver

thigh muscle

breast muscle

skin and 

attached tubby

N

O

CH3

C O

O O

H3C

H3C

H3C CH3

HO

N

O

CH3

C O

O O

H3C

H3C

HOOC CH3

HN

OH

O

H3C CH3

O

N

OH

C O

HO O

H3C

H3C CH3

O