### Mefenoxam Human Health Risk Assessment DP No

. D424727



### UNITED STATES ENVIRONMENTAL PROTECTION A GENCY

MEMORAN D UM

D a t e: Apri l 6, 2016 

### WASHINGTON, D.C

. 20460

OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION



### SUBJECT : Mcfe n oxa m

. Human Health Risk Assessment for Proposed Use on the Rapeseed Subgroup 20A.



### PC Code : 113502



### Decisio n No .: 497002 

### D P Ba r codc: D424727



### R eg is t ra ti o n No.: 100-791

, 100- 799



### Pe titi o n No .: 4F8323 

### R eg ul atory A c t i o n : Section 3 Re g i stration



### Ris k Assessment Ty p e: Single C hemical/ Aggregate 

### Case No.: NA



### TXRNo. : NA



### MRIDN o .: NA 

### CAS No

. : 70630- 1 7

- 0



### 40 CF R: § 180.546



### F RO M: Minerva Mercado

, Risk

# Assesso**~-;;)'** - Nancy oodd, chem i st

# ~**~a.r::-- L~ura**  Nolle n , ORE.

## Asse~so~ __

## ~ Vincent Chen. Tox1colog1st 1

- - 

# c::.-----

- Ri s k Assessment Branch 3 (RAB3)

- He a lth Effects Division ( H ED; 7509P)



### T HR OUGH: Ch ri sti ne Olinger

, Branch Chief /// / 

# -1C

RAB3 ! HED (7509P)

# ~ ;' 

# c:/ '---

-
TO: Hop e Johnson

, Product Manager Maryam 

### K. Muhammad, Biologists Fu n g icid e Branch Registration Di vision (7505 P )

The Registration Di vision has requested that HED eva luat e ha za rd and exposu re data and

co ndu ct dietary

, occupational

, residential

, and aggregate exposure assessments , as needed. t o

es timate the risk to human health that w ill result from the proposed use of mefenoxam on the rapeseed s ub gro up 20A.

Pa ge 1 

### of 

## tff

### Mefenoxam Human Health Risk Assessment DP No. 04 24727

Table of co nt e nt s 1.0 Executive Summary

.............................................................................................................................. 3 2.0 HED Recommendation s

........................................................................................................................ 4 2.1 Data Deficiencie s

........................................................................................................................... 4 2

. 2 Tolerance Considerations

............................................................................................................... 5 2. 1

. 1 Enforcement Analytical Method

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

................................................................................................... 5 2 .2.3 Revi s ion s to Petitioned

- For Tolerances

.................. ...... .................................................... ... 7 2.2.4 Int e rnational Harmonization

..... . . . ........................ . ........... . ................................................... 7 2.3 Label Re comn1endations

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

.................................................................................................................... . ...................... 8 3.1 Chemica l I dentity

................... ..... ....... .................. ....... ....... ....... ...... ................ ... ...... ..... ..... .......... . . 8 3.2 Ph ysical / Chemical Characteristics

.................................................................................................. 9 3.3 Pe s ticide Use Pan ern

.......................................... ... .......................................................................... 9 3.4 Anticipated Exposure P a th ways

.......... ... .................................................. ..... ....... . . . ....................... 10 3.5 Consideration of Environmental Ju stice

.................................................................................... .... .. I 0 4.0 Hazard Characterization and Do se -Re spons e Assessment

......... ..... .......................... ..... ........ ..... ........... 10 4.1 Toxicology Studies Available for Analysis

...... ... ......... . . ... ............................................................. 11 4.2 Absorption. Distribution. Metabolism. and Elim ination (ADME)

................................................. 11 4.2.1 Dermal Absorption

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

............................................................................................. ....... ...... . ........... 1 2 4.4 Safety Factor for Infant s an d Children (F QPA Safety Factor)

....................................................... 13 4.4. 1 Completene ss 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 R esidua l Uncertainty in the Ex posure Database

.... . ........... ..... ......... ..... ...... ... ............ . .......... 14 4.5 Toxicity E ndpoint and Point of Departure Selections

.................................................................... 1 4 4.5.1 Do se -Respon se Assessment

.................... ... .......................................................................... 14 4.5

. 2 Recommendation for Combining Routes of Exposures for Ri sk Assessment

...................... 17 4.5.3 Cancer C l assification and Ri sk As sess ment Recommendation

.................................. ...... .... 1 7 5.0 Dietar y Exposure and Risk Assessment

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

..................... ...... . ................................................... 17 5.2 Food Re s idue Profile

. ..................................................................................................................... 18 5

. 3 Water Residue Pr ofile

..................................................................................................................... 19 5.4 Dietary Ri s k Assessrnent

........ . .......................... . . . ......... ... ........... . .................................................. 20 5.4.1 De scr iption of Residue Data Use d in Dietary Assessment

................................................... 20 5.4.2 Acute Diet ary Risk Assessment

........................................................................................... 20 6.0 Resid e ntial (Non-Occi.ipa tion al) Exposure/Risk Charac t erizat i on

........................................................ 21 6.1 R eside ntial Handler Exposure

........................................................................................................ 22 6.2 P ost -Application Exposure

............................... .... .......................................................................... 25 6

. 3 Residential Risk Es timate s fo r Use in Aggregate As sess ment

.... .................. ....... ... .......... . . ... ........ 27 6.4 Re sidentia l By s tander Post-application Inh alation Expos ur e

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

...................................................................................................................................... 28 7.0 Aggregate Exposure/ Ri s k Characteri za tion

........................................................................................... 28 7.1 Acute Aggregate Ri sk

........ ..... ..... ......... ....... .................. .... ............ ............. ............ ........................ 29 7.2 Short-Term and Intermedi a te-Term Aggregate Ri sk

........... .. .......... ..... ....... ..... .......... .. .................. 29 8.0 Cumulat i ve Exposure/Risk Characte ri za tion

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

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

............................................................................ 30 9.2 Occupationa l Po s t-Application Exposure/ Ri s k Estimates

...................................... . ............ ... ........ 33 I 0.0 Ref erences

........................................................................................................................................... 34



### P

age 2 of 

## qg-

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 3 of 48 1.0 Executive Summar y Mefenoxam is a systemic phenylamide fungicide which inhibits protein synthesis in fungi. Mefenoxam is an R

- isomer en riched formulation. M etalaxyl (PC 113501) is the racemic R/S isomer formulation. The Agency compared the available chemistry and toxici ty 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 t he 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 re

evaluated the established metalaxyl livestock tolerances (40 CFR §180.408). No Codex MRLs have been established for the rapeseed subgroup 20A o r livestock commodities ; therefore, there are no harmonization iss ues 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, matern al 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 indi cation 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 sy stemically (T 1⁄2 

### 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. T he 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

- te rm 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 10 X Food Quality Protection Act Safety Factor ( FQPA SF) can be reduced to 1 X . 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 reproduct ion and fertility effects study in rats. In adult rats treated with metalaxyl or mefenoxam, clinical signs and abnormal F unctional O bservation B attery (FOB) findings were noted only after a bolus gavage dose, but

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 4 of 48 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 m efenoxam . 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 in dicate that metalaxyl is taken up, translocated, and extensively metabolized by plants. It may also be hydrolyzed in ruminants and poultry. For mefenoxam, t he residue to be regulated in the tolerance expression in plant and livestock commodities is mefen oxam, 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). F or risk assessment, the residues of concern in plant and livestock commodities are mefenoxam and metabolites containing the following moiet ies : 2,6

- dimethylaniline, 2

- hydroxymethyl

- 6

- methylaniline (HMMA), the Ring

- OH, and benzoic acid

. Adequate enforcement methods are available for determination of the residue s 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 expos ure 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 e xposure 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 like ly to be carcinogenic i n humans "

.
2.0 HED Recommendations

HED recommend s for a registration and tolerance for the use of mefenoxam on the rapeseed subgroup 20A

. No a dditional 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

- dime thylaniline ( 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,

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 5 of 48 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 (Pr otocol 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 co mmodities (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 n itrogen

- specific mode. An alternative procedure is gas

- liquid chromatography/mass spectro metry 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 e xpression 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 m etalaxyl 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 specifie d 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 subgro up 20A as shown in Table 2.2.2.1 . The associated changes to the metalaxyl livestock toler ances 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 Comm odity 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

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 6 of 48 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
H orse, 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

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 7 of 48 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 toler ance 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 establis hed 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 re moved 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 metabo lites 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 met hyl 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 li mits (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 t he rapeseed subgroup 20A or livestock commodities; therefore, there are no harmonization issues with Codex. Refer to the International Residue Limits (IRL) table (Appendix B).

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 8 of 48 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 t o calculate the bed widths for specified banded applications.

3.0 In troduction

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 dif fer in amount of R

- and S

isomers. Metalaxyl is a racemic mixture whereas mefenoxam is mainly the R

- isomer.

Table 3.1 Test Compound Nomenclature

Chemical Structure

Empirical Formula C 15 

### H 21 

### NO 4


### 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 appl ication rate of 0.32 fl oz Apron XL ® 

### LS /100 lb of seed (7.5 x 10

- 5 

### lb 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 concentra te (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.

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 9 of 48 The proposed label amendmen t, 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 long

sleeved shirts, long pants, shoes plus socks, and chemical

- resistant gloves. The label also includes language as re quired 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

, t here 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. O ccupational scenarios for other uses have been assessed previously ( see 10.0 References )

. P ost

- a pplication 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

Po tential 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 accord ing 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,

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 10 of 48 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 area s 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 Dos e - 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 m efenoxam oral acute (LD 50 

### ) 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.).

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 11 of 48 4.2 Absorption, Distr ibution, 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, si ngle 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. Metal axyl 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 indicatin g 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 w as 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 sex

related differences via urine (35

- 47% AD in males, 53

- 56% AD in females) and feces (33

- 38% A D in m ales; 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 studie s 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) bas ed on current Agency policies.

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 12 of 48 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 clinic al 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 convul sions (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 fer tility 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 irrit ant (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 w as 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 acu te 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 range

finding 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 in creased 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 fo r 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 o f 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 1 0x FQPA Safety Factor can be reduced to 1x for the following reasons: (1) the database is adequate to evaluate neurotoxicity and developmental

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 13 of 48 susceptibility; (2) neurotoxicity has been characterized; (3) there is no evidence of developmental susceptibilit y; 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 neu rotoxicity 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 incr eased 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. Expo sures 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 me ntioned 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

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 14 of 48 October 1997). The Agency reassessed the toxicity databases for metalaxyl and mef enoxam 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 LOAE Ls 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 intraspeci es 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 stud ies 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 met alaxyl 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 a re 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 e ndpoint 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 metala xyl 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 an d 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 ).

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 15 of 48 Table 4.5.1 Summary of Toxicological Doses and Endpoints for Mefenoxam and Metalaxyl for Use in Dietary and Non

Occupational 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 UF A = 10x

UF H =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 ob served 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 UF A = 10x

UF H =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); Intermediat e

- 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. UF A = 10x

UF H =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 extrap olation 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. UF A = extrapolation from animal to human (intersp ecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short

- term study for long

- term risk assessment. UF DB = 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.

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 16 of 48 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 UF A =10x

UF H =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 extrap olation 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. UF A = extrapolation from animal to human (intersp ecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short

- term study for long

- term risk assessment. UF DB = 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

Me talaxyl 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.

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 17 of 48 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

v itro 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 mef

enoxam. 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 like ly to be carcino genic 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, 0 2/14/ 20 07 ). 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 dimethyl aniline) 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

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 18 of 48 5 .2 Food Residue Profile Adequate crop and rotational crop field trial s , 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 c anola 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 s upport 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, res idues 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, a nd 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 s hould 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. Confine d 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 metalax yl 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; an d (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 Ap ron 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.”

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 19 of 48 The drinking water exposure assessment was conducted for metalaxyl and me fenoxam 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 th e 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 co ncentration (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 th at 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 base d 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 mefenoxa m. 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, D4290 30

, 11/2/ 20 15 )

. 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 w ere 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.

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 20 of 48 5.4. 2 Acute Dietary Risk Assessment The results of the acute dietary exposure analysis are reported i n T able 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/Metalaxyl 1

Population Subgroup Acute Dietary (95th Percentile)
Dietary Exposure (mg/kg/day) % aPAD 2
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 a PAD ( 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 thi s 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 metalaxy l 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 m etalaxyl 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 evalua tion 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 post

application exposure and risk estimates are presented for m efenoxam 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 m efenoxam EUP has been canceled

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 21 of 48 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) fo rmulation 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% mefe noxam (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 expect ed 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 like ly 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, D4 30081) . Dermal handler risk assessments were not conducted because an adverse systemic dermal hazard w as not identified for mefenoxam.

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 22 of 48 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 Rate 1 

### Area Treated or

Amount Handled Daily 2 

### Inhalation

Dose (mg/kg/day) 3 

### MOE 4


### Liquid Concentrate 5 

### Manually

- Pressurized Handwand

– Gardens/Trees Liquid Concentrate 0.018 0.00018 lb ai/ft 2 

### 1200 ft 2 

### 0.000049 1,000,000

Hose

- end Sprayer

Gardens/Trees Liquid Concentrate 0.0014 0.00018 lb ai/ft 2 

### 1200 ft 2 

### 0.0000038 13,000,000

Hose

- end Sprayer

Lawns/Turf Liquid

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/ft 2 

### 1200 ft 2 

### 0.00038 130,000
Sprinkler Can

Gardens/Trees Liquid Concentrate 0.0014 0.00018 lb ai/ft 2 

### 1200 ft 2 

### 0.0000038 13,000,000
Sprinkler Can

- Lawns/Turf Liquid Concentrate 0.022 0.000072 lb ai/ft 2 

### 1,000 ft 2 

### 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 Packaging 6 

### Manually

- Pressurized Handwand

– Gardens/Trees WSP 0.018 0.000048 lb ai/ft 2 

### 1200 ft 2 

### 0.000013 3,900,000

Hose

- end Sprayer

Gardens/Trees WSP 0.034 0.000048 lb ai/ft 2 

### 1200 ft 2 

### 0.000024 2,000,000

Hose

- end Sprayer

Lawns/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 Can

Gardens/Trees WSP 0.034 0.000048 lb ai/ft 2 

### 1,200 ft 2 

### 0.000024 2,000,000

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 23 of 48 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 Rate 1 

### Area Treated or

Amount Handled Daily 2 

### Inhalation

Dose (mg/kg/day) 3 

### MOE 4


### Sprinkler Can

- Lawns/Turf WSP 0.034 0.000016 lb ai/ft 2 

### 1,000 ft 2 

### 0.0000067 7,500,000 Backpack

- Gardens/Trees WSP 0.018 0.000048 lb ai/ft 2 

### 1,200 ft 2 

### 0.000013 3,900,000 Granular Push

- type rotary spreader

Gardens/Trees G 0.0026 0.000078 lb ai/ft 2 

### 1,200 ft 2 

### 0.000003 16,000,000

Push

- type rotary spreader

Lawns/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/ft 2 

### 1,200 ft 2 

### 0.0000091 5,500,000 Spoon

- Gardens/Trees G 0.087 0.000078 lb ai/ft 2 

### 1,200 ft 2 

### 0.00010 490,000 Spoon

- Lawns/Turf G 0.087 0.000016 lb ai/ft 2 

### 100 ft 2 

### 0.0000017 29,000,000 Cup

- Gardens/Trees G 0.013 0.000078 lb ai/ft 2 

### 1,200 ft 2 

### 0.000015 3,300,000 Cup

- Lawns/Turf G 0.013 0.000016 lb ai/ft 2 

### 100 ft 2 

### 0.00000025 200,000,000 Hand Dispersal

Gardens/Trees G 0.38 0.000078 lb ai/ft 2 

### 1,200 ft 2 

### 0.00045 110,000
Hand Dispersal

- Lawns/Turf G 0.38 0.000016 lb ai/ft 2 

### 100 ft 2 

### 0.0000074 6,700,000 Shaker Can

- Gardens/Trees G 0.013 0.000078 lb ai/ft 2 

### 1,200 ft 2 

### 0.000015 3,300,000 Shaker Can

- Lawns/Turf G 0.013 0.000016 lb ai/ft 2 

### 100 ft 2 

### 0.00000025 200,000,000

1 Based on registered label s: 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 Pow ders in Water

- soluble Packaging = WSP

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 24 of 48 6.2 Residential Post

- A pplication 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 post

application scenarios, i ncluding 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 SOPs 1


### The maximum appl ication 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 Rate 1 

### Dose

(mg/kg/day) 2 

### MOEs 3 

### 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

- and

assessing

- 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

- procedures

residential

- pesticide

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 25 of 48 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 dispers ible granules, and 12 studies using granules). The liquid results (N=131) indicate a range of F AR 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 tr ansferability 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. Altho ugh 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 n ot 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 uncerta inty (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 followin g: 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

- a pplication 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 conservati sms 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 waiv ing 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 pest icide residues.

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 26 of 48 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. Chemical

specific 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 a ssessments 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. Be cause 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 e pisodic 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

assessme nt 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 th e 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 

### MOE 2



### Dermal Inhala

tion Oral Total Dermal Inhala

tion Oral Total

Adult Backpack

Applications

Lawns/Turf Liquid Concentrate NA 0.00063 NA 0.00063 N/A 79,000 NA 79,000

Child 1<2 year old (Short

Term) 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 Reside ntial Handler Exposure and Risk Estimates; Table 5.2.1 presents the Residential Post

- application Exposure and Risk Estimates.)

2 M OE = the MOEs associated with the highest residential doses.

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 27 of 48 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, 201 0 (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/#!docketD etail;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 Spra y 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 Stat e 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 drif t 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 conside red 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 o utlines 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 exposur es 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 drink ing water assessment results are presented in Section 5.4 above. The most highly exposed subgroup is children < 1 years old at 9 5 % of the aPAD, which is below the level of concern.

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 28 of 48 7.2 Short

- Term and Intermediate

- Term Aggregate Risk

The short

- and intermed iate

- term risk assessments considers only exposure estimates from incidental oral and inhalation exposures to mefenoxam (Table 7.2.1)

. Since n o hazard was identified for non

- acute dietary or dermal exposure scenarios , these scenarios are not included in
t he 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 LOC 1 Max

Allowable Exposure 2 mg/kg/day Average

Food and Water Exposure mg/kg/day Residential

Exposure mg/kg/day 3 Tota l

Exposure mg/kg/day 4 Aggregate

MOE (food, water, and residential) 5



### Adult 50 100 0.5 NA 6 

### 0.00063 0.00063 79,000

Children 1< 2
year s old 50 100 0.5 NA 6 

### 0.048 0.048 1,000

1 LOC includes the standard inter

- and intra

- species uncertainty factors (UF A and UF H , 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 Agg regate MOE = [NOAEL / ( Total Exposure)]

6 

### NA = not applicable because n o hazard w as identified for non

- acute diet ary scenario s

.


### 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 subst ances. 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 co mmon 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.

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 29 of 48 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 k inds 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 t his 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 Seed ing 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 intermediate

occupational handler exposure is exp ected 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 s econdary 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 intermediat e

- term exposures to mefenoxam while performing seed treatment activities. In addition, occupational secondary handlers may experience short

- and intermediate

- term exposure while planting mefenoxam

treated seeds. A short

- and intermediate

- term dermal exposu re assessment was not performed

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 30 of 48 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 con sidered 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. Chemical

specific data for assessing exposure during commercial seed treatment and seed planting

ac tivities 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 treat ed 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 applicat ion 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 p er 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 handl ers to wear a long

sleeved 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

- c ancer 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

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 31 of 48 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 tre ated) of short

- term exposure is equal to the throughput of intermediate

- term exposure. The inhalation MOEs range from 270

, 0 00 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 Seed a



### Maximum Application Rate b 

### Inhalation Unit

Exposure c 

### Seed Amount Treated

or Planted Per Day d 

### Inhalation Dose e 

### Inhalation MOE f



### 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 HE D 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 (m g/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.

### Mefenoxam Human Health Risk Assessment DP No. D424727

Page 32 of 48 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 re

entry ex posure). 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 ex posures 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 wit h 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 exp osure 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 Sub group 20A

. Dodd, N., 1 1 /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.

E ngler 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 th e 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 005 7 208, Ha zard 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 A ppendix A

. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements
The requirements (40 CFR 158.500) for food uses are below. Use of th e 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

-- waived 1 870.3700a 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 yes 2

yes yes 2
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
yes 3

yes 3

yes 4 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 yes 5

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 vitr o 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 LD 50 = 669 mg/kg III

Acute Oral Toxicity (Mouse) 00063991 LD 50 = 788 mg/kg III

870.1200 Acute Dermal Toxicity (Rat) 00063994 LD 50 > 3170 mg/kg III

Acute Dermal Toxicity (Rabbit) 00063993 LD 50 > 6000 mg/kg III

870.1300 Acute Inhalation Toxicity (Rat) 00109156 LC 50 > 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 LD 50 = 1269 mg/kg II

870.1200 Acute Dermal Toxicity (Rat) 43800384 LD 50 > 2000 mg/kg III

870.1300 Acute Inhalation Toxicity (Rat) 43800385 LC 50 > 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 post

dosing ( 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 metalax yl

- 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 Materna l 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. Developmenta l 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 Materna l NOAEL = 150 mg/kg/day LOAEL = 300 mg/kg/day based on body weight gain. Developmenta l 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 sensiti ve 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 neu rotoxicity (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 toxicit y 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 m g/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 neurotoxi city 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 c hromatographic 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. Consi stent 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. Gl ucuronidase 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 moie ty 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 metabolite s 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 an d 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 i dentified.

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,

r espectively. 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/cm 2
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

con sidered 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, 0 5/17/200, TXR 0014165).

870.7600 Dermal pe netration (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, d ichloromethane, 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 K OW (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

m etalaxyl /mefenoxam (CGA

- 48988 /CGA

329351 ) 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 foliage a 00114379, 0071610, 00071680 grape and grape leaves a 00071607, 00071606 potato tubers and foliage a 00071603, 00071604

potato foliage 00071609

III N

- (3

- hydroxy

- 2,6

- dimethylphenyl)

- N

lettuce foliage a 00114379, 0071610, 00071680 grapes and grape leaves a 00071607, 00071606

### 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 foliage a 00071603, 00071604

IV N

- (2,6

- dimethylphenyl)

- N

- (methoxyacetyl)alanine (CGA

- 62826) lettuce foliage a 00114379, 00071610 grapes and grape leaves a 00071607, 00071606 potato tubers 00071603, 00071604 potato tubers and foliage a 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 foliage a 00114379, 00071610 potato tubers and foliage a 00071603, 00071604

grapes and grape leaves a 00071607

### 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 foliage b 00071604

IX N

- (2,6

- dimethylphenyl)

- 2

- hydroxyacetamide (CGA

- 37734) lettuce foliage c 00114379, 00071610

X N

- (2,6

- dimethylphenyl)

- N

- (hydroxyacetyl)alanine methyl ester (CGA

- 67869) lettuce foliage c 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

- (methoxy acetyl) alanine methyl ester metalaxyl /mefenoxam
(CGA

- 48988 /CGA

- 329351 ) Poultry ( 42115804 ) : Whole egg

N

- [(2

- hydroxymethyl)

- 6

- methyl phenyl]

- N

- (methoxyacetyl) alanine methyl ester isomers
(CGA

- 94689) Ruminant ( 41664503 ) : Milk Liver Kidney Leg muscle Perirenal fat Urine Tenderloin

### 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

- dimethyl phenyl)

- 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

### 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

- dimethyl phenyl)

- 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

- dimethyl phenyl)

- 2

- hydroxyacetamide
(CGA

- 37734) Ruminant ( 41664503) : Tenderloin Milk Liver Urine Kidney Leg muscle Perirenal fat

N

- (2,6

- dimethyl phenyl)

- 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

### 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

- [(methoxy acetyl) (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