Document ID: EPA-HQ-OPP-2009-0713-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2011-01-26T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION

MEMORANDUM

DATE:	July 28, 2010

SUBJECT:	Mefenoxam. Human Health Risk Assessment for Proposed Uses on
Snap Beans and the Caneberry Subgroup, Expanded Uses on the Bulb and
Green Onion Subgroups and the Bushberry Subgroup, and Amended Use on
Spinach.

  

PC Code: 113502	DP Barcode: D369043

Decision No.: 416985	Registration Nos.: 100-801, 100-804, 100-1202 

Petition No.: 9E7591	Regulatory Actions: Section 3/Amended Section 3
Registration

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

TXR No.: NA	CAS No.: 70630-17-0

MRID No.: NA	40 CFR: §180.546 (Mefenoxam)

		              									

FROM:	Meheret Negussie, Chemist, Risk Assessor

		Nancy Dodd, Chemist

		Nancy Tsaur, Chemist, ORE assessor

		Whang Phang, Toxicologist

		Risk Assessment Branch III

		Health Effects Division (HED) (7509P)	  SEQ CHAPTER \h \r 1 

		

THROUGH:	Paula Deschamp, Branch Chief

		Risk Assessment Branch III

		Health Effects Division (7509P)

		

TO:		Barbara Madden/Laura Nollen, RM #5

		Registration Division (RD) (7505P)  SEQ CHAPTER \h \r 1   SEQ CHAPTER
\h \r 1 

HED is charged with estimating the risk to human health from exposure to
pesticides.  RD has requested that HED evaluate hazard and exposure data
and conduct dietary, occupational, residential, and aggregate exposure
assessments, as needed, to estimate the risk to human health that will
result from the proposed use of mefenoxam on snap beans and the
caneberry subgroup, expanded uses on the bulb and green onion subgroups
and the bushberry subgroup, and amended use on spinach. 

 

Introduction

This document addresses human health risk resulting from the proposed
uses and the currently registered food uses.  This risk assessment on
mefenoxam incorporates an updated screening level usage analysis (SLUA)
for mefenoxam (dated 05/05/2009) in the chronic dietary exposure
assessment.  In addition, a new occupational exposure assessment was
conducted to evaluate the proposed uses.  In the current assessment,
newly required acute neurotoxicity, subchronic neurotoxicity, and
immunotoxicity studies are required.

 

The hazard characterization elements (i.e., endpoint selection and FQPA
safety factor), residential exposure, and drinking water exposure
assessments, remain unchanged relative to the previous risk assessment
(DP#325137, M. Ottley, 05/31/2007).  

A summary of the findings and an assessment of human risk resulting from
the proposed uses of mefenoxam are provided in this document.  Nancy
Dodd performed the residue chemistry review and the dietary exposure
assessment, Nancy Tsaur performed the occupational and residential
exposure assessment, Meheret Negussie conducted the risk assessment, and
the drinking water assessment was performed by Brian Anderson of the
Environmental Fate and Effects Division (EFED).

The Residue Chemistry Chapter for the Metalaxyl Reregistration
Eligibility Decision (RED) Document was issued on 06/16/1994.  The most
recent human-health risk assessment was completed by Myron Ottley
(DP#325137, 05/31/2007).  A human health scoping document in support of
registration review was conducted by Nancy Dodd (DP#368462, 12/07/2009).

Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc268170124"  1.0  Executive
Summary	  PAGEREF _Toc268170124 \h  5  

  HYPERLINK \l "_Toc268170125"  2.0  Ingredient Profile	  PAGEREF
_Toc268170125 \h  14  

  HYPERLINK \l "_Toc268170126"  2.1	Summary of Proposed Uses	  PAGEREF
_Toc268170126 \h  14  

  HYPERLINK \l "_Toc268170127"  2.2	Structure and Nomenclature	  PAGEREF
_Toc268170127 \h  19  

  HYPERLINK \l "_Toc268170128"  2.3	Physical and Chemical Properties	 
PAGEREF _Toc268170128 \h  20  

  HYPERLINK \l "_Toc268170129"  3.0  Hazard Characterization/Assessment	
 PAGEREF _Toc268170129 \h  20  

  HYPERLINK \l "_Toc268170130"  3.1	Hazard and Dose-Response
Characterization	  PAGEREF _Toc268170130 \h  21  

  HYPERLINK \l "_Toc268170131"  3.1	Toxicology Studies Available for
Analysis	  PAGEREF _Toc268170131 \h  21  

  HYPERLINK \l "_Toc268170132"  3.2	Adsorption, Distribution,
Metabolism, and Elimination	  PAGEREF _Toc268170132 \h  21  

  HYPERLINK \l "_Toc268170133"  3.3	Toxicological Effects	  PAGEREF
_Toc268170133 \h  21  

  HYPERLINK \l "_Toc268170134"  3.4	Safety Factor for Infants and
Children (FQPA Safety Factor)	  PAGEREF _Toc268170134 \h  22  

  HYPERLINK \l "_Toc268170135"  3.4.1	Completeness of the Toxicology
Database	  PAGEREF _Toc268170135 \h  23  

  HYPERLINK \l "_Toc268170136"  3.4.2	Evidence of Neurotoxicity	 
PAGEREF _Toc268170136 \h  23  

  HYPERLINK \l "_Toc268170137"  3.4.3	Evidence of
Sensitivity/Susceptibility in the Developing or Young Animal	  PAGEREF
_Toc268170137 \h  23  

  HYPERLINK \l "_Toc268170138"  3.4.4	Residual Uncertainty in the
Exposure Database	  PAGEREF _Toc268170138 \h  23  

  HYPERLINK \l "_Toc268170139"  3.5	Dose Response Assessment	  PAGEREF
_Toc268170139 \h  24  

  HYPERLINK \l "_Toc268170140"  3.6	Toxicity Endpoints and Points of
Departure Selections	  PAGEREF _Toc268170140 \h  24  

  HYPERLINK \l "_Toc268170141"  3.7	Recommendation for Combining Routes
of Exposure for Risk Assessment	  PAGEREF _Toc268170141 \h  25  

  HYPERLINK \l "_Toc268170142"  3.8	Endocrine Disruption	  PAGEREF
_Toc268170142 \h  26  

  HYPERLINK \l "_Toc268170143"  4.0  Public Health and Pesticide
Epidemiology Data	  PAGEREF _Toc268170143 \h  26  

  HYPERLINK \l "_Toc268170144"  5.0  Dietary Exposure/Risk
Characterization	  PAGEREF _Toc268170144 \h  26  

  HYPERLINK \l "_Toc268170145"  5.1	Summary of Proposed Uses	  PAGEREF
_Toc268170145 \h  26  

  HYPERLINK \l "_Toc268170146"  5.2	Dietary Exposure/Risk Pathway	 
PAGEREF _Toc268170146 \h  27  

  HYPERLINK \l "_Toc268170147"  5.2.1	Metabolism in Primary Crops	 
PAGEREF _Toc268170147 \h  27  

  HYPERLINK \l "_Toc268170148"  5.2.2	Metabolism in Livestock	  PAGEREF
_Toc268170148 \h  27  

  HYPERLINK \l "_Toc268170149"  5.2.3	Analytical Methodology	  PAGEREF
_Toc268170149 \h  28  

  HYPERLINK \l "_Toc268170150"  5.2.4	Pesticide Metabolites and
Degradates of Concern	  PAGEREF _Toc268170150 \h  29  

  HYPERLINK \l "_Toc268170151"  5.2.5	Drinking Water Profile	  PAGEREF
_Toc268170151 \h  31  

  HYPERLINK \l "_Toc268170152"  5.2.6	Food Residue Profile	  PAGEREF
_Toc268170152 \h  31  

  HYPERLINK \l "_Toc268170153"  5.2.7	International Residue Limits	 
PAGEREF _Toc268170153 \h  35  

  HYPERLINK \l "_Toc268170154"  5.3	Dietary Exposure and Risk	  PAGEREF
_Toc268170154 \h  36  

  HYPERLINK \l "_Toc268170155"  5.3.1	Acute Dietary	  PAGEREF
_Toc268170155 \h  36  

  HYPERLINK \l "_Toc268170156"  5.3.2	Chronic Dietary	  PAGEREF
_Toc268170156 \h  36  

  HYPERLINK \l "_Toc268170157"  5.3.3	Cancer Dietary	  PAGEREF
_Toc268170157 \h  38  

  HYPERLINK \l "_Toc268170158"  5.3.4	Anticipated Residues and Percent
Crop Treated (PCT) Information	  PAGEREF _Toc268170158 \h  38  

  HYPERLINK \l "_Toc268170159"  6.0  Residential Exposure	  PAGEREF
_Toc268170159 \h  39  

  HYPERLINK \l "_Toc268170160"  6.1	Residential Handler Exposure	 
PAGEREF _Toc268170160 \h  40  

  HYPERLINK \l "_Toc268170161"  6.2	Residential Postapplication Exposure
  PAGEREF _Toc268170161 \h  41  

  HYPERLINK \l "_Toc268170162"  6.3	Residential Bystander
Postapplication Inhalation Exposure	  PAGEREF _Toc268170162 \h  42  

  HYPERLINK \l "_Toc268170163"  6.4	Recreational	  PAGEREF _Toc268170163
\h  42  

  HYPERLINK \l "_Toc268170164"  6.5	Other (Spray Drift, etc.)	  PAGEREF
_Toc268170164 \h  43  

  HYPERLINK \l "_Toc268170165"  7.0  Aggregate Risk Assessments and Risk
Characterization	  PAGEREF _Toc268170165 \h  43  

  HYPERLINK \l "_Toc268170166"  7.1	Acute Aggregate Risk	  PAGEREF
_Toc268170166 \h  43  

  HYPERLINK \l "_Toc268170167"  7.2	Short-Term Aggregate Risk	  PAGEREF
_Toc268170167 \h  43  

  HYPERLINK \l "_Toc268170168"  7.3	Intermediate-Term Aggregate Risk	 
PAGEREF _Toc268170168 \h  44  

  HYPERLINK \l "_Toc268170169"  7.4	Chronic Aggregate Risk	  PAGEREF
_Toc268170169 \h  45  

  HYPERLINK \l "_Toc268170170"  7.5	Cancer Risk	  PAGEREF _Toc268170170
\h  45  

  HYPERLINK \l "_Toc268170171"  8.0  Cumulative Risk
Characterization/Assessment	  PAGEREF _Toc268170171 \h  45  

  HYPERLINK \l "_Toc268170172"  9.0  Occupational Exposure/Risk Pathway	
 PAGEREF _Toc268170172 \h  46  

  HYPERLINK \l "_Toc268170173"  9.1	Occupational Handler	  PAGEREF
_Toc268170173 \h  46  

  HYPERLINK \l "_Toc268170174"  9.2	Occupational Postapplication	 
PAGEREF _Toc268170174 \h  48  

  HYPERLINK \l "_Toc268170178"  Appendix A:	Toxicity Profile	  PAGEREF
_Toc268170178 \h  50  

  HYPERLINK \l "_Toc268170179"  Appendix B:	International Residue Limit
Status Sheet	  PAGEREF _Toc268170179 \h  54  

  HYPERLINK \l "_Toc268170180"  Appendix C:	Chemical Structures	 
PAGEREF _Toc268170180 \h  55  

  HYPERLINK \l "_Toc268170181"  Appendix D:	Rationale for Immunotoxicity
Data Requirement	  PAGEREF _Toc268170181 \h  58  

  HYPERLINK \l "_Toc268170182"  Appendix E:	Rationale for Acute and
Subchronic Toxicity Data Requirement	  PAGEREF _Toc268170182 \h  59  

 1.0	Executive Summary

The   SEQ CHAPTER \h \r 1 Interregional Research Project No. 4 (IR-4)
has submitted a request for amended registration for three Syngenta
products for agricultural uses: a 4 lb ai/gal emulsifiable concentrate
(EC) formulation, Ridomil Gold® EC (EPA Reg. No. 100-801); a 4 lb
ai/gal liquid soluble concentrate (SL) formulation, Ridomil Gold® SL
(EPA Reg. No. 100-1202); and a 5% wettable powder (WP) formulation,
Ridomil Gold®/Copper (EPA Reg. No. 100-804).  The 5% WP formulation is
a multiple active ingredient (MAI) product containing 5% mefenoxam and
60% copper hydroxide.

Mefenoxam is the enriched R-enantiomer of metalaxyl, which is a racemic
mixture of R- and S-enantiomers (also referred to as the D- and
L-enantiomers, respectively): (R)-and
(S)-2-[(2,6-dimethylphenyl)-methoxyacetylamino]-propionic acid methyl
ester.  The basic producer, Syngenta (formerly Novartis Crop Protection,
Inc. and formerly Ciba Crop Protection), has replaced metalaxyl with
mefenoxam.  Because it is the most fungicidally active component of the
mixture, it may be used at half the application rates of metalaxyl. 
Based on bridging data, EPA has concluded that the established
tolerances for metalaxyl will be adequate to support the use of
mefenoxam on the same crops provided that (i) the use rates for
mefenoxam are one-half the rate of metalaxyl; (ii) mefenoxam
applications are made in the same way as for metalaxyl; (iii) and the
labels restrict the use of both pesticides concurrently on the same crop
(DP#223261, L. Kutney, 04/24/1996).

Mefenoxam is a systemic fungicide which is absorbed through the leaves,
stems, and roots of plants.  Mefenoxam inhibits protein synthesis in
fungi.  Mefenoxam belongs to the phenylamide class of systemic
fungicides that are effective against soil-borne diseases caused by
Pythium and Phytophthora and foliar diseases caused by the Phycomycetes
(downy mildews).  Mefenoxam may enter the environment through use as
foliar, soil, or seed treatments for agricultural crops or as a
treatment in the residential environment.  

There are numerous metalaxyl/mefenoxam products registered for use on a
number of terrestrial food, feed, and nonfood crops, greenhouse nonfood
crops, and outdoor residential plants. Metalaxyl and mefenoxam
formulations include granulars, wettable powders, dusts, emulsifiable
concentrates, dry flowable concentrates, water soluble powders, water
soluble packets, and crystalline and liquid ready-to-use products. 
Application may be multiple foliar or soil incorporation, surface
spraying (broadcast or band), drenching, sprinkler or drip irrigation,
soil mix, or seed treatment.

Tolerances for mefenoxam are established under 40 CFR §180.546 and are
expressed in terms of combined residues of (R)- and
(S)-2-[2,6-dimethyl(phenyl)-methoxyacetylamine]-propionic acid methyl
ester and its metabolites containing the 2,6-dimethylaniline moiety, and
N-(2-hydroxymethyl-6-methylphenyl)-N-(methoxyacetyl)-alanine methyl
ester, each expressed as mefenoxam equivalents.  Tolerances are
established on globe artichoke, fresh and dried herbs, and a variety of
tropical fruits, and range 0.05-55 ppm.

Tolerances for metalaxyl are established under 40 CFR §180.408 and are
expressed in terms of the combined residues of the fungicide metalaxyl
[N-(2,6-dimethylphenyl)-N-(methoxyacetyl) alanine methyl ester], and its
metabolites containing the 2,6-dimethylaniline moiety, and
N-(2-hydroxymethyl-6-methylphenyl)-N-(methoxyacetyl)-alanine methyl
ester, each expressed as metalaxyl equivalents.  The established
tolerances for crop commodities ranged from 0.1-25 ppm, and established
tolerances for livestock commodities range from 0.02 ppm for milk to 0.4
ppm for fat, kidney, and liver of cattle, goat, hog, horse, poultry, and
sheep.  In addition, a tolerance with regional registration has been
established under 180.408(c) for papaya at 0.1 ppm, and tolerances for
indirect or inadvertent residues of metalaxyl are established under
180.408(d) for barley, cereal grain, oat, and wheat commodities ranging
from 0.2 ppm (grain) to 2.0 ppm (forage and straw).

Proposed Use Profile

IR-4 has submitted proposed amended use directions for three products
registered to Syngenta: 4 lb ai/gal EC and SL formulations and a 5% WP
formulation.  The 5% WP formulation is an MAI product containing 5%
mefenoxam and 60% copper hydroxide.  

For the 4 lb ai/gal EC and SL formulations, the petitioner is proposing
to: (1) expand the registered use on onions to include additional crops
that are now included in the bulb vegetable crop group 3-07; (2) reduce
the preharvest interval (PHI) for spinach from 21 to 3 days; (3) expand
the registered foliar use of the 4 lb ai/gal EC and SL formulations on
head and leaf lettuce to cover all members of the leafy vegetables
group; (4) add new uses on the caneberry subgroup 13-07A; and (5) expand
the registered use on blueberries to cover the bushberry subgroup
13-07B.  HED notes that mefenoxam is currently registered for use on
legume vegetables and raspberries; however, the proposed uses reflect
less restrictive use patterns than those currently registered.  For the
5% WP formulation, the petitioner is proposing to: (1) expand the
registered use on onions to include additional crops that are now
included in the bulb vegetable crop group 3-07 and snap beans; (2)
reduce the PHI for spinach from 21 to 3 days; (3) add new uses on snap
beans; and (4) add new uses on the caneberry subgroup.  The proposed use
directions are summarized in Table 2.1.1.

Hazard Profile

The database for mefenoxam indicated that the major target organ is the
liver.  Liver effects observed in oral studies in rat, mouse, and dog
included increased liver enzymes (alanine amino-transferase, aspartate
amino-transferase, alkaline phosphatase), increased incidence of
pathological observations in the liver (hepatocyte hypertrophy,
vacuolation of hepatocytes, fatty infiltration) and increased liver
weights (both relative and absolute).  In guideline studies, the dog
appeared to be the most sensitive species.  Metalaxyl/mefenoxam had been
classified as "not likely to be carcinogenic in humans," and no cancer
risk assessment was needed. The developmental toxicity in rat and rabbit
and the multigeneration reproduction study did not show
metalaxyl/mefenoxam to be developmental or reproductive toxicant.  No
increased susceptibility in fetuses and pups which were exposed
prenatally and post natally.  However, in the studies, for which gavage
dosing was used (metalaxyl developmental toxicity studies in rat and
rabbit and a mefenoxam 28-day oral toxicity study), clinical signs
(ataxia, tremors, hypoactivity, and prostrate behavior) including
convulsion at one study were observed at relative high doses >150 mg/kg.
 These clinical signs are believed to result from metalaxyl/mefenoxam
induced bradycardia mediated through alpha-adrenoreceptors and did not
result from neurotoxicity.  The quality and completeness of the toxicity
and exposure data was evaluated; no susceptibility, neurotoxicity, or
residual uncertainty was identified, and the point of departure selected
for risk assessment was protective of all the effects reported. 
Therefore, the FQPA safety factor was reduced to 1X. 

Drinking Water Exposure

Estimated drinking water concentrations (EDWCs) for the proposed uses
did not exceed residue levels in drinking water which were determined in
a previous assessment (DP#324495, J. Hetrick, 02/22/2007). 

 

36.7 μg/L was used to assess contributions from drinking water for the
chronic dietary assessment.

Dietary Exposure

Residues of Concern: HED has determined that the residue to be regulated
(in the tolerance expression) in plant and livestock commodities is (R)-
and (S)-2-[(2,6-dimethylphenyl)-methoxyacetylamino]-propionic acid
methyl ester. To be consistent with Codex, these residues should be
expressed as methyl
N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-DL-alaninate in 40 CFR 180.546.

HED has also determined that the metalaxyl/mefenoxam residues of concern
in plant and livestock commodities for risk assessments are
metalaxyl/mefenoxam, its metabolites containing the 2,6-DMA moiety, HMMA
moiety, Ring-OH moiety, and benzoic acid moiety.  Essentially, all
residues identified in plant and livestock commodities from the
available metabolism studies are of concern for risk assessment since
none can be excluded for toxicological reasons.

Acute Dietary Exposure/Risk: There was no indication of an adverse
effect attributable to a single dose.  An acute reference dose (aRfD)
was not established. 

    

Chronic Dietary Exposure/Risk: A refined chronic aggregate dietary (food
and drinking water) exposure and risk assessment was conducted for all
existing and proposed new food uses of metalaxyl/mefenoxam.  It was
assumed that residues were present at tolerance levels in plant
commodities for both direct use tolerances for metalaxyl/mefenoxam and
indirect or inadvertent tolerances for metalaxyl.  Additional factors
were applied to certain plant commodities to address concerns regarding
the adequacy of the residue analytical method to determine
metalaxyl/mefenoxam residues of concern in plant and animal commodities.
 This concern was raised during the review of method validation data
required for reregistration which were submitted with a previous
petition.  Data from metabolism studies on goats and hens were used to
estimate conservative levels of metalaxyl/mefenoxam in livestock
commodities.  Processing data were used when available and DEEM default
processing factors were used when processing data were not available. 
Estimated average percent crop treated (PCT) data for mefenoxam and
metalaxyl was used when available.  The 1 in 10 year annual estimated
surface water concentration was used to assess contributions from
drinking water.  

Results of the chronic dietary assessment indicate that the general U.S.
population and all other population subgroups have exposure and risk
estimates below HED’s level of concern (LOC).  The chronic dietary
exposure estimates are 26% of the chronic population adjusted dose
(cPAD) for the general U.S. population and 58% of the cPAD for the
highest exposed population subgroup, children 1-2 years of age. 

Residential Exposure

No residential uses and no occupational uses at residential sites are
being requested in this petition; therefore, a residential risk
assessment was not conducted.  However, metalaxyl/mefenoxam products are
currently registered for use on residential turf and ornamentals as well
as recreational turf such as golf courses and athletic fields.  These
residential risks have been previously assessed under the requirements
of the FQPA.

Short- and intermediate-term oral endpoints were identified for use in
assessing children’s incidental ingestion of residues following
mefenoxam use on residential turf.  However, because no acute oral
endpoint was identified, an assessment of episodic granular ingestion by
children was not performed.  Chronic exposure is not expected for any
mefenoxam use pattern.

Since dermal endpoints for short- or intermediate-term were not
identified, only inhalation exposure (adult handler) and incidental oral
exposure (child postappplication) assessments have been conducted. 

Adult handler inhalation exposure was assessed for the short-term
exposure scenario for homeowners who mix/load and apply mefenoxam for
use on turf.  The scenario with the highest exposure is based on the
“belly grinder” application method and results in a margin of
exposure (MOE) below HED’s LOC.  Intermediate-term inhalation exposure
is not expected.    Children’s incidental oral exposure
(hand-to-mouth, object-to-mouth, and ingestion of soil was assessed for
both short-term and intermediate-term.  Total exposure for short-term
and intermediate-term resulted in MOEs that are below HED’s LOC (i.e.,
an MOE < 100).  

Aggregate Risk

Acute Aggregate Risk: An acute dietary endpoint was not identified. 
Therefore, an acute aggregate risk assessment was not conducted.  

Chronic Aggregate Risk: Results of the chronic dietary assessment
indicate that the general U.S. population and all other population
subgroups have exposure and risk estimates below HED’s LOC.  The
chronic dietary exposure estimates are 26% of the cPAD for the general
U.S. population and 58% of the cPAD for the highest exposed population
subgroup, children 1-2 years of age. 

Short-Term Aggregate Risk: Combined exposure from inhalation, incidental
oral, dietary food, and water risk estimates are taken into account. 
Risk from dermal exposure was not included since no dermal hazard was
identified.  Adult residential short-term inhalation exposure estimate
and children’s postapplication incidental oral exposure scenarios were
assessed.  All short-term MOEs were greater than 100; therefore, the
short-term aggregate risk estimates do not exceed HED’s LOC for adults
or children.  

Intermediate-Term Aggregate Risk: Combined exposure from incidental
oral, dietary food, and water risk estimates are taken into account. 
Risk from dermal exposure is not considered since no dermal hazard was
identified.  Intermediate-term residential handler (adult) exposure is
not expected because of the intermittent and seasonal use pattern. 
Children’s residential exposure (postapplication oral exposure) was
assessed.  The intermediate-term aggregate MOEs are all greater than
100, risk estimates do not exceed HED’s LOC for children.  

Long-Term Aggregate Risk: There is potential for chronic exposure via
dietary (food and water) exposure.  Refer to Chronic Dietary
Exposure/Risk. 

Cancer Risk: Mefenoxam is classified as “not likely to be carcinogenic
to humans;” therefore, an aggregate cancer assessment was not
conducted.

Occupational Exposure and Risk

Chemical-specific handler exposure data were not submitted in support of
this registration.  Occupational handlers may be exposed during mixing,
loading, and application of mefenoxam using aerial, chemigation, and
groundboom equipment.  All handler scenarios resulted in MOEs greater
than HED’s LOC.  The inhalation risk estimates to handlers are not of
concern to HED for any of the handler scenarios.

Occupational postapplication exposure can occur via the dermal and/or
inhalation route.  Dermal exposure during postapplication activities is
not considered because applicable dermal endpoints were not identified. 
Based on the Agency's current practices, a quantitative occupational
postapplication inhalation exposure assessment was not performed for
mefenoxam at this time.  If new policies or procedures are put into
place, the Agency may revisit the need for a quantitative occupational
postapplication inhalation exposure assessment for mefenoxam.

Because primary eye irritation testing has placed mefenoxam in Toxicity
Category I, an interim 48-hour restricted entry interval (REI) is
required under WPS for Agricultural Pesticides.

Regulatory Recommendations and Recommendations for Tolerances

Provided revised Sections B (OPPTS 860.1200) and F (OPPTS 860.1550) are
submitted, HED recommends for a conditional registration and permanent
tolerances for the requested uses of mefenoxam on members of the bulb
and green onion subgroups, spinach, snap beans, and bushberry subgroup,
and caneberry subgroup.  Additional data are needed as conditions of
registration as outlined below and in Section 10.0.

Note to PM:   SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1   SEQ CHAPTER \h
\r 1 The petitioner should note for future submissions that the
tolerance expression for mefenoxam includes the L-enantiomer, and
therefore, analytical methods should include determination of both the
D- and L-enantiomers.  

Based on the tolerance expressions recommended by HED (HED RARC Report,
W. Britton, 02/14/2007 and HED Metalaxyl/Mefenoxam Registration Review,
DP#368461, N. Dodd, 04/13/2010) and to be consistent with Codex, the
tolerance expression for mefenoxam should be revised according to
HED’s Interim Guidance on Tolerance Expressions (S. Knizner,
05/27/2009) to state:

“Tolerances are established for residues of mefenoxam, including its
metabolites and degradates, in or on the commodities in the table below.
 Compliance with the tolerance levels specified below is to be
determined by measuring only metalaxyl (methyl
N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-DL-alaninate).”

Tolerances for residues of mefenoxam are recommended as follows: 

Bean, snap, succulent	0.20 ppm

Caneberry subgroup 13-07A	0.70 ppm

Bushberry subgroup 13-07B	2.0 ppm

Onion, bulb, subgroup 3-07A	3.0 ppm

Onion, green, subgroup 3-07B	10 ppm

Spinach	10 ppm

 

In the absence of supporting crop field trial data, HED recommends
against expanding the registered foliar uses of the 4 lb ai/gal EC and
SL formulations on head and leaf lettuce to include spinach or any other
members of the leafy vegetables (except Brassica) crop group.

Note to PM: When the recommended tolerance on Bushberry subgroup 13-07B
is established, the tolerance for lingonberry should be removed.

The following must be provided prior to a tolerance being established or
registration allowed:

 860.1200 Directions for Use

A revised Section B must be submitted reflecting the following changes
to the proposed use directions.

Onions:

Since the WP label for bulb onions indicates a maximum of 0.4 lb
ai/A/season of foliar-applied mefenoxam, the proposed use directions for
the 4 lb ai/gal EC and SL formulations should be revised to reflect the
following maximum seasonal rate for bulb onion: “Do not exceed the
equivalent of 1.0 lb ai/A per crop of soil-applied and 0.4 lb ai/A per
crop of foliar-applied mefenoxam-containing products.”

The proposed use directions for the 5% WP formulation should be revised
to reflect the following maximum seasonal rates: (1) for bulb onion,
“Do not exceed the equivalent of 1.0 lb ai/A per crop of soil-applied
and 0.4 lb ai/A per crop of foliar-applied mefenoxam-containing
products”; and (2) for green onion, “Do not exceed the equivalent of
1.0 lb ai/A per crop of soil-applied and 0.3 lb ai/A per crop of
foliar-applied mefenoxam-containing products.”

Leafy Vegetables/Spinach:

The proposed labels for Leafy Vegetables and Spinach Only must be
revised.  The 3-day PHI for spinach can be applied only to application
types and rates supported by the 3-day PHI data (i.e., soil application
at 1.0 lb ai/A/season and foliar application at 0.25 lb ai/A/season).  
Soil application of the EC formulation can be translated to the SL
formulation.  Based on the available data for spinach at the proposed
3-day PHI, the proposed use directions for Spinach Only should be
revised to specify soil surface application of the EC or SL formulations
and foliar directed or broadcast spray applications of the WP
formulation, and to specify the following maximum seasonal rates: “Do
not exceed the equivalent of 1.0 lb ai/A per crop of soil-applied
mefenoxam containing products at planting and 0.25 lb ai/A of
foliar-applied mefenoxam containing products.”  The proposed changes
to the existing Leafy Vegetables section of the existing labels to
establish a 3-day PHI for spinach should be removed.

For the 4 lb ai/gal EC and SL formulations, spinach and all other
members of the leafy vegetables except Brassica crop group, except head
and leaf lettuce, must be removed from the use directions for Part 2 of
the proposed label; the reference to Part 2 of the label that appears in
Part 1 should be revised accordingly. 

On the 5% WP formulation label, the statement referring to a 21-day PHI
for spinach should be removed.

The proposed use directions for all three products must be amended to
specify that no adjuvants may be added to spray mixtures for foliar use
on spinach.

When HED approved the registered use of the 4 lb ai/gal EC formulation
on head and leaf lettuce (DP# 324493, L. Cheng, 03/17/2006), certain
label revisions were required which have not been made.  These revisions
also apply to the label for the 4 lb ai/gal SL formulation.   As
previously required under DP# 324493, Part 1 of the labels for the 4 lb
ai/gal EC and SL formulations should be revised to specify that no more
than one soil-directed application may be made, and Part 2 should be
revised to specify a maximum of 4 foliar-directed applications.

Snap Beans: 

The proposed use directions for the 5% WP formulation must be revised to
specify a maximum of two applications per season at 0.1 lb
ai/A/application and to reflect the following maximum seasonal rate for
snap bean: “Do not exceed the equivalent of 0.5 lb ai/A per crop of
soil-applied mefenoxam containing products at planting and 0.2 lb ai/A
per crop of foliar-applied mefenoxam-containing products.”

The proposed use directions for the 5% WP formulation must be revised to
propose a 7-day PHI.  Four of eight field trials have a 7-day PHI and
four have a 6-day PHI.

The proposed use directions must be amended to specify that no adjuvants
may be added to spray mixtures for foliar use on snap beans.

Caneberries:

The proposed use directions for the 4 lb ai/gal EC and SL formulations
for the caneberry subgroup must be revised to specify a maximum of one
soil application per season at 1.8 lb ai/A and to reflect the following
maximum seasonal rate: “Do not exceed the equivalent of 1.8 lb ai/A
per crop of soil-applied and 0.2 lb ai/A per crop of foliar-applied
mefenoxam-containing products for a maximum seasonal application rate of
2.0 lb ai/A.”

To clarify the use pattern for established plantings specified in Part 2
of the labels for the 4 lb ai/gal EC and SL formulations, the use
directions should be revised to indicate that applications are to be
directed toward the base of the plants.

The proposed use directions for the 5% WP formulation must be revised to
specify a maximum of two foliar applications per season at 0.1 lb
ai/A/application and to reflect the following maximum seasonal rate:
“Do not exceed the equivalent of 1.8 lb ai/A per crop of soil-applied
and 0.2 lb ai/A per crop of foliar-applied mefenoxam-containing products
for a maximum seasonal application rate of 2.0 lb ai/A.”

For all three products, bromberre must be corrected to brombeere and
nectaberry must be corrected to nectarberry.

The proposed use directions for all three products must be amended to
specify that no adjuvants may be added to spray mixtures for foliar use
on caneberries.

Bushberries: 

The following berries are not members of bushberry subgroup 13-07B and
must be removed from the crops listed under the bushberry subgroup on
the labels for the 4 lb ai/gal EC and SL formulations: bilberry,
bearberry, cloudberry, muntries, and partridgeberry.

To clarify the use pattern for established plantings specified in Part 2
of the labels for the 4 lb ai/gal EC and SL formulations, the use
directions should be revised to indicate that applications are to be
directed toward the base of the plants.

For both products, hostaberry must be corrected to jostaberry.

When the proposed use on bushberries is registered for the 4 lb ai/gal
EC and SL formulations, the separate use directions for lingonberries
may be removed from the labels. 

860.1550 Proposed Tolerances

Based on the tolerance expressions recommended by HED in the
metalaxyl/mefenoxam registration review, and to be consistent with
Codex, the tolerance expression proposed by IR-4 under PP#9E7591 must be
revised (HED RARC Report, W. Britton, 02/14/2007).  The tolerance
expression should be stated as follows:

Tolerances are established for residues of mefenoxam, including its
metabolites and degradates, in or on the commodities in the table below.
 Compliance with the tolerance levels specified below is to be
determined by measuring only metalaxyl [methyl
N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-DL-alaninate].

The proposed tolerances for snap bean and the caneberry subgroup are too
high; tolerances should be established at 0.20 ppm for snap bean and
0.70 ppm for caneberry subgroup 13-07A.

The proposed tolerance for spinach is too low; a tolerance should be
established at 10 ppm.

In conjunction with establishment of the proposed tolerance for the
bushberry subgroup, the mefenoxam tolerance for lingonberry can be
removed.

The proposed tolerance for the caneberry subgroup must be revised to
reflect the correct commodity definition: “Caneberry subgroup
13-07A.”

The following data are required as a condition of registration:

TOXICOLOGY

870.6200 Neurotoxicity Battery (Acute and Subchronic Studies) 

The acute and subchronic neurotoxicity screening battery is required to
fulfill current 158 data requirements. 

870.7800 Immunotoxicity Study 

An immunotoxicity study is required to fulfill current 158 data
requirements. 

RESIDUE CHEMISTRY

860.1500 Crop Field Trials

To fulfill geographic distribution requirements for caneberry subgroup
13-07A, an additional field trial must be conducted in Zone 5
(raspberry) or Zone 6 (blackberry).  The required trial should include
additional sampling intervals to assess residue decline. 

Environmental Justice Considerations

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

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures. 
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by the USDA under the Continuing
Survey of Food Intake by Individuals (CSFII) and are used in pesticide
risk assessments for all registered food uses of a pesticide.  These
data are analyzed and categorized by subgroups based on age, season of
the year, ethnic group, and region of the country.  Additionally, OPP is
able to assess dietary exposure to smaller, specialized subgroups and
exposure assessments are performed when conditions or circumstances
warrant.  Whenever appropriate, non-dietary exposures based on home use
of pesticide products and associated risks for adult applicators and for
children, youths, and adults entering or playing on treated areas
postapplication are evaluated.  Further considerations are currently in
development as OPP has committed resources and expertise to the
development of specialized software and models that consider exposure to
bystanders and farm workers as well as lifestyle and traditional dietary
patterns among specific subgroups.

Review of Human Research

This risk assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical.  These studies, which comprise PHED, have been determined to
require a review of their ethical conduct, have received that review,
and have been determined to be ethical.

2.0	Ingredient Profile  TC \l1 "2.0  Ingredient Profile 

Mefenoxam is a systemic fungicide which is absorbed through the leaves,
stems, and roots of plants.  Mefenoxam inhibits protein synthesis in
fungi.  Mefenoxam belongs to the phenylamide class of systemic
fungicides that are effective against soil-borne diseases caused by
Pythium and Phytophthora and foliar diseases caused by the Phycomycetes
(downy mildews).   Other phenylamides are furalaxyl, benalaxyl, and
oxadixyl.  Mefenoxam may enter the environment through use as foliar,
soil, or seed treatments for agricultural crops or as a treatment in the
residential environment.  

Mefenoxam and metalaxyl have the same empirical formula. Metalaxyl
merely includes a near equal amount of both enantiomers (optical isomers
whose molecular structures have a mirror-image relationship to each
other), whereas, mefenoxam includes mainly the R-enantiomer.  Due to
this relationship between mefenoxam and metalaxyl, toxicology and
residue chemistry data for metalaxyl have been used to better understand
the toxicity and chemistry of mefenoxam.  

2.1	Summary of Proposed Uses

  TC \l2 "2.1  Summary of Registered/Proposed Uses 

IR-4 has submitted proposed amended use directions for three products
registered to Syngenta: a 4 lb ai/gal EC formulation, Ridomil Gold® EC
(EPA Reg. No. 100-801; label dated 07/07/2009); a 4 lb ai/gal SL
formulation, Ridomil Gold® SL (EPA Reg. No. 100-1202; label dated
07/30/2009); and a 5% WP formulation, Ridomil Gold®/Copper (EPA Reg.
No. 100-804; label dated 07/30/2009).  The 5% WP formulation is an MAI
product containing 5% mefenoxam and 60% copper hydroxide.  

For the 4 lb ai/gal EC and SL formulations, the petitioner is proposing
to: (1) expand the registered use on onions to include additional crops
that are now included in the bulb vegetable crop group 3-07; (2) reduce
the preharvest interval (PHI) for spinach from 21 to 3 days; (3) expand
the registered foliar use of the 4 lb ai/gal EC and SL formulations on
head and leaf lettuce to cover all members of the leafy vegetables
group; (4) add new uses on the caneberry subgroup; and (5) expand the
registered use on blueberries to cover the bushberry subgroup.  For the
5% WP formulation, the petitioner is proposing to: (1) expand the
registered use on onions to include additional crops that are now
included in the bulb vegetable crop group 3-07; (2) reduce the PHI for
spinach from 21 to 3 days; (3) add new uses on snap beans; and (4) add
new uses on the caneberry subgroup.  

The proposed use directions for the EC and SL formulations are divided
into two parts on the labels: “Part 1: Soil-Injected or
Soil-Incorporated Applications” and “Part 2: Soil Directed and Other
Foliar Applications.”  

The proposed changes to the crops or use patterns from those which
appear on the accepted labels are highlighted in Table 2.1.1.

Table 2.1.1.  Summary of Directions for Use of Mefenoxam.

Applic. Timing, Type, and Equipment1	Formulation

[EPA Reg. No.]	Applic. Rate 

(lb ai/A)	Max. No. Applic. per Season	Max. Seasonal Applic. Rate

(lb ai/A)	PHI

(days)	Use Directions and Limitations2

Onions3: Dry Bulb including Garlic, Onions (dry bulb), Shallots (dry
bulb); and Green including Green eschalots, Green onions, Green
shallots, Japanese bunching onions, Leeks, Spring onions, Scallions. 
Including hybrids, cultivars, and varieties of these.  Other Dry Bulb
Crops: Great-headed Garlic, Serpent Garlic, Lily Bulb, Chinese Onion
Bulb, Pearl Onion, Potato Onion Bulb.  Other Green Bulb Crops: Chive
(fresh leaves), Chinese Chive (fresh leaves), Hosta Elegans, Fritillaria
(leaves), Kurrat, Lady’s Leek, Beltsville Bunching Onion, Onion
(fresh), Macrostem Onion, Tree Tops Onion, Welsh Onion (tops), Shallot
(fresh leaves)

Preplant incorporated (broadcast or band)

At planting

Soil spray (broadcast or band)	4 lb/gal EC

[100-801]

4 lb/gal SL

[100-1202]	0.25-0.50	Not specified	1.0 soil + 0.5 foliar applied (dry
bulb)

1.0 soil + 0.3 foliar applied  (green)	Not specified	Part 1: Apply in
water or liquid fertilizer.  For preplant incorporated application,
mechanically incorporate in the top 2 inches of soil.   For banded
applications, use a 7-inch band.

Postemergence

Foliar	5% WP

[100-804]	0.1	4

(dry bulb and seed)

3

(green)	0.4	10

(dry bulb)

7

(green)	Begin applications when conditions are favorable for disease,
but before infection; continue at a 14-day RTI.  Use of a suitable
spreader-sticker is recommended.

Leafy Vegetables (Except Brassica): Celery, Endive (Escarole), Lettuce
(Head and Leaf), Parsley, Rhubarb, Spinach, Swiss chard.  Additional
Leafy Vegetable Crops: Amaranth, Arugula, Cardoon, Celtuce, Chervil,
Chinese Celery, Chrysanthemum (edible-leaved), Chrysanthemum (garland),
Corn salad, Cress (garden), Cress (Upland), Dandelion, Dock (Sorrel),
Florence Fennel (finochio), Orach, Purslane (garden), Purslane (winter),
Radicchio (red chicory), Spinach (New Zealand), and Spinach (vine)

Preplant incorporated (broadcast or band)

At planting

Soil spray (broadcast or band) 	4 lb/gal EC

[100-801]

4 lb/gal SL

[100-1202]	0.50-1.0	Not specified	1.0 soil + 0.4 foliar applied (all
except spinach)

1.0 soil + 0.25 shank to soil or 0.4 foliar applied  (spinach)	7

(all except spinach)

3

(spinach)	Part 1: Apply in water or liquid fertilizer.  For preplant
incorporated application, mechanically incorporate in the top 2 inches
of soil.   For banded applications, use a 7-inch band.  

Postemergence

Foliar	4 lb/gal EC

[100-801]

4 lb/gal SL

 [100-1202]	0.063-0.125	Not specified	1.0 soil + 0.4 foliar applied 	74

(all except spinach)

3

(spinach)	Part 2: Apply only in a tank mix with other fungicides, when
conditions are favorable for disease; continue at a 14-day RTI.  

Spinach only

Shank injections

Soil	4 lb/gal EC

[100-801]

4 lb/gal SL

 [100-1202]	0.125	2	1.0 soil + 0.25 shank to soil or 0.4 foliar applied
3	Part 1: Apply in addition to preplant incorporated or at-planting soil
spray applications5, 21 days after planting or first cutting; a second
application may be made after the next cutting at a 21-day retreatment
interval.  

Postemergence

Foliar	5% WP

[100-804]	0.125	2	Not specified	3	Apply 21 days after preplant or
at-planting application of the 4 lb/gal EC formulation at 0.5-1 lb ai/A
or immediately after each repeated cutting.  Make 1-2 applications at a
14-day RTI; avoid late season applications.

Snap Beans

Postemergence

Foliar	5% WP

[100-804]	0.1	4	0.4	6	Begin applications at onset of disease; continue
at a 7-day RTI.

Caneberry (Blackberry and Raspberry) Subgroup: Blackberry, Raspberry
(Red and Black), Wild Raspberry Cultivars, Including hybrids, cultivars,
and varieties of these.

Subgroup includes Andean Blackberry, Arctic Blackberry, Bingleberry,
Black Satin Berry, Boysenberry, Bromberre, California Blackberry,
Cherokee Blackberry, Chesterberry, Cheyenne Blackberry, Common
Blackberry, Coryberry, Darrowberry, Dewberry, Dirksen Thornless Berry,
Evergreen Blackberry, Himalayaberry, Hullberry, Lavacaberry, Loganberry,
Lowberry, Lucretiaberry, Mammoth Blackberry, Marionberry, Mora, Mures
Deronce, Nectaberry, Northern Dewberry, Olallieberry, Oregon Evergreen
Berry, Phenomenalberry, Rangeberry, Ravenberry, Rossberry, Shawnee
Blackberry, Southern Dewberry, Tayberry, Youngberry, Zarzamora

At planting

Soil spray (broadcast or band)	4 lb/gal EC

[100-801]

4 lb/gal SL

[100-1202]	1.8	1

(implied)	3.6

soil applied	45	Part 1: New plantings: For banded applications, use an
18-inch band

Postemergence

Soil spray (band)

1.8	Not specified

	Part 2: Established plantings: Apply in a 3-ft band over the row before
plants start to grow in the spring.

Postemergence

Foliar	5% WP

[100-804]	0.1	4	3.6 soil + foliar applied	0	Begin applications when
conditions are favorable for disease, but before infection; continue at
a 7-day RTI.

Bushberry Subgroup: Blueberries (High and Low Bush), Currants,
Elderberry, Gooseberry, Highbush Cranberry, Including hybrids,
cultivars, and varieties of these.

 Other Bushberries in Subgroup: Aronia Berry, Highbush Blueberry,
Lowbush Blueberry, Bearberry, Bilberry, Buffalo Currant, Chilean Guava,
Cloudberry, Black Currant, Red Currant, Elderberry, European Barberry,
Gooseberry, Highbush Cranberry, Edible Honeysuckle, Huckleberry,
Hostaberry, Juneberry, Lingonberry, Muntries, Native Currant,
Partridgeberry, Salal, Sea Buckthorn.

At planting

Soil spray (broadcast or band)	4 lb/gal EC

[100-801]

4 lb/gal SL

[100-1202]	1.8	1

(implied)	3.6

soil applied	0	Part 1: Application is to be made to new plantings.  For
banded applications, use an 18-inch band.

Post-planting

Soil spray (band)

1.8	1

	Part 2: New plantings: After initial at-planting application, reapply
once during a period favorable for root rot.

Postemergence

Soil spray (band)

1.8	2

	Part 2: Established plantings: Apply in a 3-ft band over the row before
plants start to grow in the spring.  Re-apply once during the period
most favorable for root rot.

1	Information pertaining to equipment type appears on the accepted
labels; use of ground, aerial, and irrigation equipment is approved for
all products.  Ground applications are to be made in ≥20 gal/A of
water, and aerial applications are to be made in ≥3 gal/A of water.

2	For the proposed and registered labels for the 4 lb/gal EC and SL
formulations, Part 1 = Soil-Injected or Soil-Incorporated Applications
and Part 2 = Soil Directed and Other Foliar Applications.  RTI =
Retreatment interval.

3	The proposed and accepted labels for the 5% WP formulation also list
onions grown for seed. 

4	For the 4 lb/gal SL formulation, Section B reflects foliar use on all
leafy vegetables listed; on the Data Package Label, the proposed use is
listed for head and leaf lettuce and spinach.  The registered labels for
both products reflect foliar use on head and leaf lettuce only.

5	This statement appears on the 4 lb/gal EC label only; use directions
for the 4 lb/gal SL state: Shank in 21 days after planting or after the
first cutting.

The enantiomeric relationship between mefenoxam and metalaxyl is the
basis for bridging residue chemistry data between the two active
ingredients: mefenoxam and metalaxyl have the same empirical formula,
yet mefenoxam primarily consists of one optical isomer, whereas
metalaxyl includes approximately equal amounts of both optical isomers.

Mefenoxam may be applied prior to planting, at-planting, or shortly
after new plantings, at application rates ranging from 0.125 lb ai/A to
1.8 lb ai/A.  Handlers may apply mefenoxam using groundboom, aerial, and
chemigation equipment, as summarized in Table 2.1.2.

Table 2.1.2.  Proposed Use Pattern for Mefenoxam.

Crop	Treatment Type/Target of Application	Application Equipment	Maximum
Application Rate 

(lb ai/A)	Treatment Interval	Preharvest Interval

Ridomil Gold® SL Fungicide, EPA Reg. No. 100-1202, SL 45.3% ai

Bushberry 

(Subgroup 13-07B)	Soil-Injection, Soil-Incorporation,

Foliage	Groundboom	1.8	0-14 days

(Applied 

At-Planting)	0 days

Caneberry 

(Subgroup 13-07A)	Soil-Injection, Soil-Incorporation,

Foliage	Groundboom	1.8	0-14 days

(Applied 

At-Planting)	45 days

Spinach	Soil-Injection, Soil-Incorporation,

Foliage	Groundboom,

Aerial,

Chemigation	0.125	14-21 days	3 days

Bulb Vegetables

(Crop Group 3-07)	Soil-Injection, Soil-Incorporation,

Foliage	Groundboom,

Aerial,

Chemigation	0.50	0-14 days

(Applied Preplant or

At-Planting)	Not Specified

Ridomil Gold® EC Fungicide, EPA Reg. No. 100-801, EC 49% ai

Bushberry 

(Subgroup 13-07B)	Soil-Injection, Soil-Incorporation,

Foliage	Groundboom	1.8	0-14 days

(Applied 

At-Planting)	0 days

Caneberry 

(Subgroup 13-07A)	Soil-Injection, Soil-Incorporation,

Foliage	Groundboom	1.8	0-14 days

(Applied 

At-Planting)	45 days

Spinach	Soil-Injection, Soil-Incorporation,

Foliage	Groundboom,

Aerial,

Chemigation	0.125	14-21 days	3 days

Bulb Vegetables

(Crop Group 3-07)	Soil-Injection, Soil-Incorporation,

Foliage	Groundboom,

Aerial,

Chemigation	0.50	0-14 days

(Applied Preplant or

At-Planting)	Not Specified

Table 2.1.2.  Proposed Use Pattern for Mefenoxam.

Crop	Treatment Type/Target of Application	Application Equipment	Maximum
Application Rate 

(lb ai/A)	Treatment Interval	Preharvest Interval

Ridomil Gold®/Copper Fungicide, EPA Reg. No. 100-804, WP (WSP) 5% ai

Caneberry 

(Subgroup 13-07A)	Ground, Foliage	Groundboom	0.1	7 days	0 days

Edible Podded Beans	Ground, Foliage	Groundboom	0.1	7 days	6 days

Bulb Vegetables

(Crop Group 3-07)	Ground, Foliage	Groundboom,

Aerial,

Chemigation	0.1	14 days	10 days (bulb)

7 days (green)

Spinach	Ground, Foliage	Groundboom,

Aerial,

Chemigation	0.1	14 days	3 days

2.2	Structure and Nomenclature

The chemical structure and nomenclature of the technical grade of
mefenoxam is shown in Table 2.2.

 

(R)-2-[(2,6-dimethylphenyl)-methoxyacetylamino]-propionic acid methyl
ester

Empirical Formula:	C15H21NO4

Common Name	Mefenoxam

Company Experimental Name	CGA-329351

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

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

CAS Number	70630-17-0

2.3	Physical and Chemical Properties

The physicochemical properties of the technical grade of mefenoxam are
shown in Table 2.3.

Table 2.3.  Physicochemical Properties of Mefenoxam.

Parameter	Value1	Reference

Boiling point/range	>270ºC (PAI)	DP #223261, L. Kutney, 04/24/1996

pH	5-6 at 25°C (1% aqueous dispersion; TGAI)

	Density	1.125 g/cm3 (20°C; TGAI)

	Water solubility	26 g/L (25°C; PAI)

	Solvent solubility	Completely miscible in acetone, dichloromethane,
ethyl acetate, methanol, N-octanol, and toluene; 59 g/L in N-hexane at
25°C (TGAI).

	Vapor pressure	3.3 x 10-3 (25°C; PAI)

	Dissociation constant, pKa	None in 1-10 pH range (PAI)

	Octanol/water partition coefficient, Log(KOW)	1.71 at 25°C (TGAI)

	UV/visible absorption spectrum	Not available

	1  TGAI = Technical grade of the active ingredient; PAI = Purified
active ingredient.

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” (DP#274784, C. Christensen, 06/14/2001).

3.0	Hazard Characterization/Assessment

References: 

Effect of metalaxyl on heart rate in rats: role of alpha
1-adrenoreceptors.  Naidu, K.A. and Radhakrishnamurty, R., 1989. J.
Toxicol. Environmental Health, 26 (2): 203-207.

Metalaxyl induced bradycardia in rats: mediated by
alpha-adrenoreceptors.  Naidu, K.A. and Radhakrishnamurty, R., 1988. J.
Toxicol. Environmental Health, 23 (4): 495-498.

3.1	Hazard and Dose-Response Characterization

  TC \l2 "3.1  Hazard and Dose-Response Characterization 

Mefenoxam is an acylalanine systemic fungicide which controls certain
diseases caused by members of the Oomycete class of fungi.  The
fungicidal effects are caused by inhibition of protein synthesis in
fungi.  Mefenoxam is the R-enantiomer of the racemic mixture, metalaxyl,
which contains about 50% each of the R- and S-enantiomers.   In 1997,
HED conducted a side-by-side comparison of the available toxicity data
for mefenoxam and metalaxyl and concluded that mefenoxam has similar
toxicity to that of metalaxyl (TXR 0012380, DP#222895 and DP#234224,
HIARC Report 11/04/1997). Therefore, metalaxyl data may be used to
support the registration of mefenoxam.

3.1	Toxicology Studies Available for Analysis

The available toxicity data are sufficient for selecting toxicity
endpoint and points of departure for risk assessment purposes.	Data from
the following studies conducted with either mefenoxam or metalaxyl were
used to evaluate the hazard potential of mefenoxam.

Data from the following studies were used to evaluate the hazard
potential of mefenoxam:

Acute - oral, dermal, inhalation, eye irritation, skin irritation,
dermal sensitization;

Subchronic - dermal 21-day rat; oral 90-day rat, oral 28-day rat, oral
90-day dog;

Chronic - oral rat and dog;

Carcinogenicity - rat and mouse

Reproductive/developmental - oral developmental rabbit and rat;
2-generation reproductive rat; and

Other - oral  mouse cancer study, mutagenicity screens, rat metabolism
and pharmacokinetic; dermal penetration.

3.2	Adsorption, Distribution, Metabolism, and Elimination

Metalaxyl was rapidly absorbed, distributed, metabolized, and eliminated
in rats under all dosing regimens.  Within 48 hours following treatment,
96.3% of the administered dose was eliminated in the urine and feces in
48 hours following treatment.  The majority (63.5%) was recovered in the
urine.  Results indicated that ether and ester bonds of metalaxyl are
hydrolyzed to form N-(2,6-dimethylphenyl)-N-(methoxyacetyl) alanine and
N-(2,6-dimethylphenyl)-hydroxyacetamide. Urine fractions treated with
glucuronidase showed similar patterns to urine not treated with enzyme
indicating that metabolites are excreted as unconjugated or glucuronide
conjugate products.   Fecal metabolites were not characterized in the
study beyond comparison of chromatograms for urine and feces. 

3.3	Toxicological Effects

The database for mefenoxam/metalaxyl indicates that the major target
organ is the liver.  Liver effects observed in oral studies in rats,
mice, and dogs include increased liver enzymes (alanine
amino-transferase, aspartate amino-transferase, alkaline phosphatase),
increased incidence of pathological observations in the liver
(hepatocyte hypertrophy, vacuolation of hepatocytes, fatty infiltration)
and increased liver weights (both relative and absolute).  In guideline
studies, the dog appears to be the most sensitive species.  

Metalaxyl has been classified as "not likely to be carcinogenic in
humans" based on the results of carcinogenicity study in mice and the
combined chronic toxicity and carcinogenicity study in rats (HED Cancer
Peer Review Committee, 12/31/1985). Based on the classification of
metalaxyl, mefenoxam is also considered "not likely to be a human
carcinogen."  Mutagenicity studies do not indicate increased mutagenic
potential following exposure to metalaxyl and mefenoxam.

In developmental toxicity studies with mefenoxam in rats, no
developmental toxicity was observed. In the rat and rabbit developmental
toxicity studies, in which the test animals were administered metalaxyl
by gavage, both rat and rabbit dams exhibited clinical signs (ataxia,
body tremors, reduced activity, and righting reflex ) at  >250 mg/kg for
rats and >500 mg/kg for rabbits. The database does not indicate any
reproductive toxicity. The data demonstrates no increased susceptibility
in the young animals following prenatal and postnatal exposures. 

In gavage studies with metalaxy in rats and rabbits, clinical signs of
ataxia, tremors, hypoactivity, and prostrate behavior were observed at
relatively high doses ((150 mg/kg/day). These clinical signs generally
would lead to consideration o f possible neurotoxic potential for a
pesticide. However, Naidu and Radhakrishnamurty (1988, 1989) have shown
that metalaxyl at doses (250 mg/kg/day caused sustained bradycardia
which led to cardiac arrest in rats.  The authors observed clinical
signs similar to those observed in guideline gavage studies such as
tremors, loss righting reflex, ataxia, and hypnosis.   Naidu and
Radhakrishnamurty (1988, 1989) also demonstrated that
acetylcholinesterase activity in brain and heart were not affected
(plasma acetylcholinesterase activity was not measured). The
metalaxyl-induced bradycardia was blocked in rats pretreated with either
a nonselective alpha-adrenoreceptor antagonist (phentolamine) or an
alpha 1-adrenoreceptor antagonist (prazosin).   Pretreatment with an
alpha 2-adrenoreceptor antagonist (yohimbine) did not change the
decreased heart rate observed with metalaxyl treatment.  The function of
alpha-adrenoreceptors is to constrict the walls of blood vessels.  This
constriction of blood vessel walls can result in bradycardia; blockage
of the alpha-adrenoreceptors by the antagonists prevents the
constriction and prevents the metalaxyl-induced bradycardia. 

Based on this evidence, it is possible that the clinical signs observed
at relatively high doses in guideline studies ((150 mg/kg/day) with
metalaxyl and mefenoxam result from the bradycardia mediated through
alpha-adrenoreceptors and do not result from neurotoxicity (HIARC
Report, 05/17/2000).

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

Based on the hazard and exposure data, the mefenoxam risk assessment
team has recommended that the FQPA Safety Factor be reduced to 1X for
the reasons described below. 

3.4.1	Completeness of the Toxicology Database

The toxicity database for mefenoxam is complete except for
immunotoxicity, acute neurotoxicity, and subchronic neurotoxicity
testing. Recent changes to 40 CFR Part 158 require acute and subchronic
neurotoxicity testing (OPPTS Guideline 870.6200), and immunotoxicity
testing (OPPTS Guideline 870.7800) for pesticide registration. However,
the existing data are sufficient for endpoint selection for
exposure/risk assessment scenarios, and for evaluation of the
requirements under the FQPA.  The available studies do not indicate
potential for immunotoxicity as evidenced by lack of effects seen in the
spleen, thymus, or hematologica parameters. Also, metalaxyl/mefenoxam do
not belong to a class of compounds (e.g., the organotins, heavy metals,
or halogenated aromatic hydrocarbons) that would be expected to be toxic
to the immune system. With respect to neurotoxicity, clinical signs of
ataxia, tremors, hypoactivity, and prostrate behavior were observed at
relatively high doses ((150 mg/kg/day) in the studies where metalaxyl
was administered by gavage only. As discussed in Section 3.3, the
clinical signs observed at relatively high doses ((150 mg/kg/day) by
gavage dosing with metalaxyl and mefenoxam were unlikely neurotoxically
mediated, but rather resulted from the bradycardia mediated through
alpha-adrenoreceptors. The endpoints selected for risk assessment are
considered adequately protective of prenatal and/or postnatal toxicity;
therefore, an additional database uncertainty factor is not needed to
account for potential immunotoxicity or neurotoxicity.

3.4.2	Evidence of Neurotoxicity

In rat and rabbit developmental studies clinical signs (ataxia, body
tremors, reduced activity, and righting reflex) were observed in
maternal animals. These clinical signs are not likely due to
neurotoxicity as discussed above. Therefore, there is no need for a
developmental neurotoxicity study or additional UFs to account for
neurotoxicity.

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

There is no evidence that mefenoxam results in increased susceptibility
from in utero exposure to rats or rabbits in the prenatal developmental
studies or exposure to young rats in the 2–generation reproduction
study.

3.4.4	Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure data base.  The
dietary exposure assessments (food and water), which employed
tolerance-level resides and high-end estimates of EDWCs, are
conservative and high-end assessments.  They do not underestimate the
potential dietary exposures.  Exposures are unlikely to be
underestimated because the calculated residential risks represent
conservative estimates of exposure because maximum application rates are
used to define residue levels.

3.5	Dose Response Assessment

The mefenoxam/metalaxyl risk assessment team selected the most sensitive
and protective endpoints from the database to employ in the risk
assessment.  An appropriate endpoint was identified for the chronic
dietary exposure scenario but not for acute dietary exposure, and
appropriate endpoints were selected for occupational scenarios following
inhalation exposures.  Short- and intermediate-term residential exposure
scenarios are anticipated, and appropriate endpoints were selected.

3.6	Toxicity Endpoints and Points of Departure Selections

Table 3.6 summarizes the toxicological endpoints for mefenoxam for human
health risk assessments.  The toxicity endpoints and points of departure
were previously selected by HED (HIARC Report, 05/17/2000).  These
selections are still valid for no new toxicity studies have been
submitted since that time. 

Table 3.6.  Summary of Toxicological Doses and Endpoints for Mefenoxam
for Use in Human Health Risk Assessments.

Exposure

Scenario	Point of Departure	Uncertainty/FQPA Safety Factors	RfD, PAD,
Level of Concern for Risk Assessment	Study and Toxicological Effects

Acute Dietary	None. No appropriate endpoint attributable to a single
dose was identified. 

Table 3.6.  Summary of Toxicological Doses and Endpoints for Mefenoxam
for Use in Human Health Risk Assessments.

Exposure

Scenario	Point of Departure	Uncertainty/FQPA Safety Factors	RfD, PAD,
Level of Concern for Risk Assessment	Study and Toxicological Effects

Chronic Dietary

(All Populations)	NOAEL= 7.41 mg/kg/day	UFA=10X

UFH=10X

FQPA SF=1X	Chronic RfD = 0.074 mg/kg/day

cPAD = 0.074 mg/kg/day	6 Month Feeding (Metalaxyl) Study in Dog

MRID no. 00071598 

LOAEL = 39 mg/kg/day, based on increased liver weights and clinical
chemistry (alkaline phosphatase).

Incidental Ingestion, Short-Term 

(1 - 30 days)	NOAEL = 50 mg/kg/day	UFA=10X

UFH=10X

FQPA SF=1X	MOE = 100 (Residential) 

MOE = NA (Occupational)	Developmental Toxicity in Rat (Metalaxyl) 

MRID no. 43800393

LOAEL = 250 mg/kg/day, based on clinical signs of toxicity including
post-dosing convulsions.  

Incidental Ingestion, Intermediate-Term

(1 – 6 months)	NOAEL = 7.41 mg/kg/day 	UFA=10X

UFH=10X

FQPA SF=1X	MOE = 100 (Residential) 

MOE = NA (Occupational)	6 Month Feeding (Metalaxyl) Study in Dog

MRID no. 00071598 

LOAEL = 39 mg/kg/day, based on increased liver weights and clinical
chemistry (alkaline phosphatase).

Dermal, Short-and Intermediate Term	No endpoint was identified.  No
systemic toxicity was seen at the limit dose (1000 mg/kg/day) in a
21-day dermal rabbit toxicity study (Metalaxyl).  MRID No. 00072394. a

Inhalation, 

Short-Term

	NOAEL = 50 mg/kg/day b 	UFA=10X

UFH=10X

FQPA SF=1X	MOE = 100 (Residential) 

MOE = 100 (Occupational)	Developmental Toxicity in Rat (Metalaxyl) 

MRID no. 43800393

LOAEL = 250 mg/kg/day, based on clinical signs of toxicity including
post-dosing convulsions.  

 Inhalation, Intermediate-Term

	NOAEL = 7.41 mg/kg/day b 	UFA=10X

UFH=10X

FQPA SF=1X	MOE = 100 (Residential) 

MOE = 100 (Occupational)	6 Month Feeding (Metalaxyl) Study in Dog

MRID no. 00071598 

LOAEL = 39 mg/kg/day, based on increased liver weights and clinical
chemistry (alkaline phosphatase).

Cancer (oral, dermal, inhalation)	Classification: “not likely to be
carcinogenic to humans.”

* UF =  100 (10X for interspecies and 10X for intraspecies differences),
FQPA SF = 1X, MOE = margin of exposure, NA = not applicable

a Dermal absorption factor of 35% will be used for conversion from oral
to dermal route (TXR. No. 014165, A. Lowit, 05/17/00)

b Absorption of 100% will be assumed in route to route conversion

3.7	Recommendation for Combining Routes of Exposure for Risk Assessment

For short- term exposure, the incidental oral and inhalation toxicity
endpoints were the same, and similar situation also existed for
intermediate-term exposure. Exposures to residues from food, drinking
water, and residential pesticide uses should be aggregated.

3.8	Endocrine Disruption

 tc \l2 "3.4 Endocrine Disruption 

As required under FFDCA section 408(p), EPA has developed the Endocrine
Disruptor Screening Program (EDSP) to determine whether certain
substances (including pesticide active and other ingredients) may have
an effect in humans or wildlife similar to an effect produced by a
“naturally occurring estrogen, or other such endocrine effects as the
Administrator may designate.”  The EDSP employs a two-tiered approach
to making the statutorily required determinations. Tier 1 consists of a
battery of 11 screening assays to identify the potential of a chemical
substance to interact with the estrogen, androgen, or thyroid (E, A, or
T) hormonal systems.  Chemicals that go through Tier 1 screening and are
found to have the potential to interact with E, A, or T hormonal systems
will proceed to the next stage of the EDSP where EPA will determine
which, if any, of the Tier 2 tests are necessary based on the available
data. Tier 2 testing is designed to identify any adverse endocrine
related effects caused by the substance, and establish a dose-response
relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA is issuing test orders/data
call-ins for the first group of 67 chemicals, which contains 58
pesticide active ingredients and 9 inert ingredients.  This list of
chemicals was selected based on the potential for human exposure through
pathways such as food and water, residential activity, and certain
post-application agricultural scenarios.  This list should not be
construed as a list of known or likely endocrine disruptors.

Mefenoxam is not among the group of 58 pesticide active ingredients on
the initial list to be screened under the EDSP.  Under FFDCA Sec. 408(p)
the Agency must screen all pesticide chemicals.  Accordingly, EPA
anticipates issuing future EDSP test orders/data call-ins for all
pesticide active ingredients. 

For further information on the status of the EDSP, the policies and
procedures, the list of 67 chemicals, the test guidelines and the Tier 1
screening battery, please visit our website:    HYPERLINK
"http://www.epa.gov/endo/"  http://www.epa.gov/endo/ .

4.0	Public Health and Pesticide Epidemiology Data  TC \l1 "4.0  Public
Health and Pesticide Epidemiology Data  

No data are available at this time.

5.0	Dietary Exposure/Risk Characterization  TC \l1 "5.0  Dietary
Exposure/Risk Characterization 

References:

Mefenoxam Memo: Summary of Analytical Chemistry and Residue Data. 
DP#371307, N. Dodd, 06/30/2010.

Mefenoxam HED RARC Report, W. Britton, 02/14/2007.

Mefenoxam. HED MARC Issues Memo, DP#268454, N. Dodd, 10/17/2000.

Mefenoxam. HED   SEQ CHAPTER \h \r 1 MARC Decision Memo, DP#269910, N.
Dodd, 10/27/2000.

5.1	Summary of Proposed Uses   TC \l2 "5.1  Summary of Proposed Uses 

Section 2.1 provides a use profile table, along with a summary of
directions for proposed used of mefenoxam.

5.2	Dietary Exposure/Risk Pathway tc \l2 "5.2 Dietary Exposure/Risk
Pathway 

5.2.1	Metabolism in Primary Crops tc \l3 "5.2.1 Metabolism in Primary
Crops  

The nature of the residue in plants is adequately understood for
mefenoxam, based on metalaxyl metabolism studies.  The metalaxyl
metabolism studies on potato, grape, and lettuce indicate that metalaxyl
is taken up, translocated, and extensively metabolized by plants. 
Metabolism involves oxidation of a ring-methyl group to the alcohol and
then the carboxylic acid, hydroxylation of the phenyl group, hydrolysis
of the methyl ester and methyl ester bonds, and N-dealkylation.  The
major residues were: metalaxyl in potato tubers and grapes; metalaxyl,
CGA-94689 (free and conjugated), and possibly CGA-100255, CGA-62826, and
CGA-108905 in potato foliage; and metalaxyl and CGA-94689 (free and
conjugated) in grape leaves and lettuce.  Glucose conjugates of
CGA-94689, CGA-100255, CGA-62826, CGA-107955, CGA-37734, and CGA-67869
have been found.  For the chemical names and structures of identified
metabolites, see Appendix C.

Metabolites can be separated into four classes, those containing a: (i)
2,6-DMA moiety; (ii) HMMA moiety; (iii) Ring-OH moiety; and (iv) benzoic
acid moiety.   The only HMMA metabolite found in primary plant
commodities is CGA-94689 (free and conjugated).

5.2.2	Metabolism in Livestock tc \l3 "5.2.2 Metabolism in Livestock 

  SEQ CHAPTER \h \r 1 

The nature of the residue in livestock is adequately understood for
mefenoxam, based on metalaxyl goat and hen metabolism studies. 
Metalaxyl in ruminants may be hydrolyzed to the ester alcohol and the
acid alcohol which may in turn be N-dealkylated.  Alternatively,
oxidation can lead to either benzylic alcohol or phenolic compounds. 
The major residues in milk were fatty acid conjugates of CGA-67869, and
the major residues in tissues were CGA-107955, CGA-94689, and CGA-67869;
some metabolites may have been conjugated with glucuronic acid.  

In poultry, metalaxyl is hydrolyzed to either the benzylic alcohol
CGA-94689 or the ester alcohol CGA-67869; subsequently, the hydroxy
metabolite CGA-94689 is converted to the sulfate P4 and CGA-67869 is
converted to the fatty acid conjugate U3 or the acid alcohol CGA-107955;
and CGA-107955 is subsequently hydrolyzed to the benzylic alcohol.  The
predominant metalaxyl metabolites in poultry are the disubstituted free
acid form (P1) of CGA-94689 (isomer B), the sulfuric acid conjugate of
CGA-94689 (isomer B), the disubstituted free acid form (P2) of CGA-94689
(isomer A), CGA-107955, and a fatty acid conjugate of P1 and P2. 
Metalaxyl was isolated only in whole egg.  For the chemical names and
structures of identified metabolites, see Appendix C.

Metalaxyl metabolites in livestock can be separated into four classes,
those containing a: (i) 2,6-DMA moiety; (ii) HMMA moiety; (iii) Ring-OH
moiety; and (iv) benzoic acid moiety.   Residues containing the 2,6-DMA
moiety accounted for up to approximately 50% of the residues in ruminant
tissues.  Residues containing the HMMA moiety accounted for 34% of the
residues in goat kidney and 12-14% of the residues in goat muscle and
fat.

Conclusions: HED originally concluded that the mefenoxam residues to be
regulated for the tolerance expression and for dietary assessments would
be (R)- and (S)-2-[(2,6-dimethylphenyl)-methoxyacetylamino]-propionic
acid methyl ester, its metabolites containing the 2,6-DMA moiety, and
CGA-94689  SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r
1 , each expressed as mefenoxam equivalents.

HED has subsequently determined that: (1) the residue to be regulated
(in the tolerance expression) in plant and livestock commodities is (R)-
and (S)-2-[(2,6-dimethylphenyl)-methoxyacetylamino]-propionic acid
methyl ester; (2) the current/reassessed tolerance levels should be
retained; (3) for risk assessment, the residues of concern in plant and
livestock commodities are metalaxyl/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; and (4) the available
residue chemistry data can be used and factors may be employed to
estimate the total residues of concern in dietary risk assessments (HED
RARC Report, W. Britton, 02/14/2007).

5.2.3	Analytical Methodology  tc \l3 "5.2.3 Analytical Methodology 

The residue analytical methods available for enforcement of tolerances
in crop commodities are common moiety methods which determine residues
of metalaxyl/mefenoxam and metabolites that are convertible to 2,6-DMA. 
These methods include: (1) Method I in PAM, Vol. II (Method AG-348)
which determines residues in plant commodities using GLC/AFID; and (2)
Method AG-395 (sent to FDA for inclusion in PAM, Vol. II as Method III),
an improved version of Method AG-348, which determines residues in plant
commodities using GLC/NPD.  

Neither Method AG-348 nor Method AG-395 distinguish between the R- and
S-enantiomers of metalaxyl/mefenoxam; however, a chiral LC/MS method,
Method 456-98, for the enantioselective determination of the D- and
L-enantiomers of metalaxyl in crops has been adequately validated by
ACB/BEAD, and a revised version of the method has been submitted for
inclusion in PAM, Vol. II.  

HED has determined that the 2,6-DMA common moiety residue analytical
methods available for tolerance enforcement and used for data collection
will not adequately recover all of the metalaxyl/mefenoxam residues of
concern in the current tolerance expressions.  While these methods are
adequate to recover residues of metalaxyl/mefenoxam, they will not
adequately recover metabolites containing the HMMA moiety and may not
adequately recover all metabolites containing the 2,6-DMA moiety with
the certainty needed to set legal limits, nor are they likely to recover
metabolites containing the Ring-OH moiety or the benzoic acid moiety. 
As a result, in addition to the changes to the tolerance expression and
the residues of concern for risk assessment addressed above, HED
determined that: 1) the multiresidue method PAM, Vol. I Section 302
(Protocol D), which completely recovers metalaxyl/mefenoxam (>80%
according to FDA PESTDATA) is an adequate enforcement method for the
determination of metalaxyl/mefenoxam in plant and livestock commodities;
and (2) all future metalaxyl/mefenoxam magnitude of the residue data
should include (a) analysis for residues of parent only using the
multiresidue method PAM, Vol. I Section 302 (Protocol D) in order to
establish more appropriate tolerance levels; and (b) analysis with a
2,6-DMA common moiety method and recovery data for parent, CGA-62826,
and CGA-94689 in order to refine dietary risk assessments (HED RARC
Report, W. Britton, 02/14/2007).

Conclusions: The available and submitted residue analytical methods data
are adequate to satisfy data requirements for this petition.  Adequate
methodology is available for tolerance enforcement purposes for the
residue of concern in crop commodities, mefenoxam, as determined by HED
(HED RARC Report, W. Britton, 02/14/2007).  These methods include Method
456-98 and PAM multiresidue method Protocol D.  

HED notes that although samples from the submitted crop field trials
were analyzed using a 2,6-DMA common moiety method, recovery data were
provided for parent only.  No recovery data were provided for
metabolites CGA-62826, and CGA-94689 as requested in the HED decision to
refine dietary risk assessments (HED RARC Report, W. Britton,
02/14/2007); such recovery data should be submitted with future
petitions.

HED notes that the method used for determination of residues of
mefenoxam in snap beans and caneberries did not include determination of
the L-enantiomer, which is included in the tolerance expression. 
However, the ratio of D-enantiomer to L-enantiomer in mefenoxam products
is >90% (DP# 223261, L. Kutney, 04/24/1996).  Therefore, the lack of
analysis for the L-enantiomer would not significantly affect the residue
results for snap bean and caneberry.    SEQ CHAPTER \h \r 1   SEQ
CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 The petitioner should note for
future submissions that the tolerance expression for mefenoxam includes
the L-enantiomer, and therefore, as stated above, analytical methods
should include determination of both the D- and L-enantiomers.  

Samples of crop commodities from the submitted crop field trials were
analyzed for residues of mefenoxam or for combined residues of
mefenoxam, metalaxyl, and metabolites convertible to 2,6-DMA using
adequate data collection methods.  Given concerns regarding the adequacy
of the residue analytical methods to determine metalaxyl/mefenoxam
residues of concern in plant and animal commodities, factors derived
from available residue chemistry data were used, as appropriate, to
estimate total metalaxyl/mefenoxam residues of concern for dietary risk
assessments.

5.2.4	Pesticide Metabolites and Degradates of Concern  tc \l3 "5.2.4
Pesticide Metabolites and Degradates of Concern 

Previously, HED concluded that the mefenoxam residues to be regulated
for the tolerance expression and for dietary assessments would be as
follows (MARC Metabolism Assessment Review Committee, 10/27/2000):

In plants: (R)- and
(S)-2-[(2,6-dimethylphenyl)-methoxyacetylamino]-propionic acid methyl
ester, its metabolites containing the 2,6-DMA moiety, and one metabolite
containing the HMMA moiety,
N-(2-hydroxymethyl-6-methylphenyl)-N-(methoxyacetyl)alanine methyl ester
(CGA-94689)  SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1   SEQ CHAPTER \h
\r 1 , each expressed as mefenoxam equivalents.

In livestock: (R)- and
(S)-2-[(2,6-dimethylphenyl)-methoxyacetylamino]-propionic acid methyl
ester, its metabolites containing the 2,6-DMA moiety, and its
metabolites containing the HMMA moiety  SEQ CHAPTER \h \r 1   SEQ
CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 ,
N-(2-hydroxymethyl-6-methylphenyl)-N-(methoxyacetyl)alanine methyl ester
(CGA-94689)  SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1   SEQ CHAPTER \h
\r 1 , each expressed as mefenoxam equivalents.

In rotational crops: (R)- and
(S)-2-[(2,6-dimethylphenyl)-methoxyacetylamino]-propionic acid methyl
ester, its metabolites containing the 2,6-DMA moiety, and one metabolite
containing the HMMA moiety,
N-2-hydroxymethyl-6-methylphenyl)-N-(methoxyacetyl)alanine methyl ester
(CGA-94689)  SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1   SEQ CHAPTER \h
\r 1 , each expressed as mefenoxam equivalents, except that
2-[(methoxyacetyl)(2-methoxy-1-methyl-2-oxoethyl)amino]-3-methylbenzoic
acid (CGA-108905, which contains the HMMA moiety) would also be included
in the risk assessment for cereal grain rotational crops and
N-(3-hydroxy-2,6-dimethylphenyl)-N-(methoxyacetyl)alanine methyl ester
(CGA-100255, which contains the Ring-OH moiety) would be included in the
risk assessment for leafy vegetables (Brassica and non-Brassica). 

The mefenoxam risk Assessment team recommends the residues to be
regulated for the tolerance expression be modified to include residues
of metalaxyl/mefenoxam and the residues of concern for dietary risk
assessments are metalaxyl/mefenoxam, its metabolites containing the
2,6-DMA moiety, HMMA moiety, Ring-OH moiety, and benzoic acid moiety
(HED RARC Report, W. Britton, 02/14/2007).

Table 5.2.4.  Summary of Metabolites and Degradates to be included in
the Risk Assessment and Tolerance Expression.

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plants	Primary and Rotational Crops	Metalaxyl/mefenoxam Metabolites
containing the 2,6-DMA (2,6-dimethylalanine) moiety

Metabolites containing the HMMA (2-hydroxymethyl-6-methylaniline) moiety

Metabolites containing the Ring-OH (ring hydroxylated dimethylaniline)
moiety	Metalaxyl/mefenoxam

Livestock	Ruminant and Poultry	Metalaxyl/mefenoxam

Metabolites containing the 2,6-DMA (2,6-dimethylalanine) moiety

Metabolites containing the HMMA (2-hydroxymethyl-6-methylaniline) moiety

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

5.2.5	Drinking Water Profile 

rom Tier II surface water modeling are not expected to exceed 108.9
μg/L for the 1 in 10 year daily peak concentration, 36.7 μg/L for the
1 in 10 year annual concentration, and 25.9 μg/L for the 30 year annual
average concentration.  Metalaxyl/mefenoxam residue concentrations from
Tier I ground water modeling is not expected to exceed 1.72 μg/L. 
However, it should be mentioned that the maximum metalaxyl concentration
in registrant-sponsored ground water monitoring studies was 3.0 μg/L.

Table 5.2.5.  Summary of Estimated Surface Water and Ground Water
Concentrations for 

Metalaxyl/Mefenoxam.

	Metalaxyl/Mefenoxam

	Surface Water Conc., ppb a	Ground Water Conc., ppb b

Acute	108.9	1.72

a From the Tier II PRZM-EXAMS-Index Reservoir model.  Input parameters
are based on the scenario for Florida citrus crops.

b From the SCI-GROW model assuming a maximum seasonal use rate of 6 lb
ai/A, a Koc of 409, and a half-life of 400 days.

5.2.6	Food Residue Profile 

HED has concluded that the established tolerances for metalaxyl will be
adequate to support the use of mefenoxam on the same crops provided that
(1) the use rates for mefenoxam are one-half the rate of metalaxyl; (2)
mefenoxam applications are made in the same way as for metalaxyl; and
(3) the labels restrict the use of both pesticides concurrently on the
same crop (DP#223261, L. Kutney, 04/24/1996).

Onion, Bulb, Subgroup 3-07A and Onion, Green, Subgroup 3-07B

No residue data were provided in support of the proposed expansion of
the registered use of mefenoxam on bulb and green onions to support the
new bulb onion subgroup 3-07A and the green onion subgroup 3-07B.  The
proposed/registered use of mefenoxam on bulb and green onions is
supported by adequate crop field trial data for metalaxyl on these
crops, reflecting a variety of use patterns, which were summarized in
the Metalaxyl Registration Standard dated 6/22/87.  The available data
were re-assessed for the Residue Chemistry Chapter of the Metalaxyl RED
where it was concluded that no additional data were needed for dry bulb
or green onion.  Because bulb onion is the representative commodity of
the bulb onion subgroup, and green onion is the representative commodity
of the green onion subgroup, HED has no objections to expanding the
registered use to cover the members of the crop subgroups provided the
revisions requested under Section 860.1200 are made.  The available data
for bulb and green onion will support tolerances of 3.0 ppm for onion,
bulb subgroup 3-07A, and 10 ppm for the onion, green, subgroup 3-07B,
respectively

Spinach

The submitted field trial residue data for spinach, as summarized in
Table 5.2.6.1, are adequate to support the proposed reduction of PHI
from 21 days to 3 days treated with a soil application of the EC or SL
formulation followed by foliar application of the WP formulation.  The
submitted crop field trial data will support a reduction in PHI for
spinach treated with this combination of products only.  Additional
field trial data reflecting foliar application of EC and SL formulations
to spinach with a 3-day PHI would be required to support a reduction in
PHI for the proposed foliar uses of the 4 lb ai/gal EC and SL
formulations on spinach.  Based on current Agency policy, data for the
WP formulation cannot support EC or SL foliar applications with short
PHIs, and EC data cannot be translated to SL for foliar applications
with short PHIs.  No data supporting metalaxyl/mefenoxam foliar
application of an SL formulation on leafy vegetables was found.

Table 5.2.6.1.  Summary of Residue Data from Field Trials with
Mefenoxam.

Crop matrix	Total Applic. Rate  (lb ai/A)	PHI (days)	Residue Levels
(ppm)1

	n	Min.	Max.	HAFT 2	Median	Mean	Std. Dev.

SPINACH (proposed use for 5% WP = 1.0 lb ai/A soil + 0.25 lb ai/A foliar
for 1.25 lb ai/A total application rate; 3-day PHI; proposed use for 4
lb ai/gal EC and SL = 1.0 lb ai/A soil + 0.4 lb ai/A foliar for 1.4 lb
ai/A total application rate; 3-day PHI)

Spinach leaves 	1.21-1.25	2-4	18	1.47	6.19	5.85	3.07	3.26	1.34

1  Combined residues of mefenoxam, metalaxyl, and metabolites
convertible to 2,6-DMA.

2  HAFT = Highest Average Field Trial.

In conjunction with this request, IR-4 has submitted revised use
directions for the 4 lb ai/gal EC and the SL formulations indicating
that they wish to expand the registered foliar uses on head and leaf
lettuce for one or both products to include all members of the leafy
vegetables crop group.  

The representative crops for the leafy vegetables (except Brassica
vegetables) crop group are celery, head lettuce, leaf lettuce, and
spinach.  

In the absence of supporting crop field trial data, HED recommends
against expanding the registered foliar uses of the 4 lb ai/gal EC and
SL formulations on head and leaf lettuce to include spinach or any other
members of the leafy vegetables (except Brassica vegetables) crop group.
 To expand the registered foliar uses of the 4 lb ai/gal EC and SL
formulations on head and leaf lettuce to include all members of the
leafy vegetables (except Brassica vegetables) crop group, data
reflecting foliar uses of the EC and SL formulations on spinach and
celery reflecting the proposed use rate and PHI must be submitted or
referenced.   If spinach is to have a 3-day PHI while the others in the
crop group have a 7-day PHI, spinach would have to be excluded from the
crop group tolerance and have its own tolerance.

Samples were analyzed for combined residues of mefenoxam and metabolites
convertible to 2,6-DMA using an acceptable method, and adequate storage
stability data are available to support the study.

The submitted field trial data, reflecting combined residues of
mefenoxam/metalaxyl and metabolites convertible to 2,6-DMA, would
support a tolerance of 8.0 ppm and a reduced PHI of 3 days for spinach
treated with a soil application of the EC or SL formulation followed by
foliar application of the WP formulation.  However, because the
submitted data are not representative of all registered uses of
mefenoxam on spinach, HED recommends against establishing a reduced
tolerance for mefenoxam on spinach.  The existing established tolerance
of 10 ppm for spinach, is appropriate.  

Snap Bean

The submitted field trial residue data for snap bean summarized in Table
5.2.6.2 and are adequate for risk assessment and tolerance assessment. 
Adequate concurrent storage stability data were submitted to support the
study.  Samples were initially analyzed for residues of mefenoxam using
an acceptable chiral LC/MS method, and selected samples were re-analyzed
for combined residues of mefenoxam/metalaxyl and metabolites convertible
to 2,6-DMA using an acceptable GC/MS method.  Calculation of combined
residues in remaining crop samples using a 1.8X conversion factor was
approved by the HED Chemistry Science Advisory Council (ChemSAC). 
ChemSAC agreed that parent + metabolites to parent ratios could be used
to estimate residue levels for risk assessments in snap beans, with the
provision that these ratios would not necessarily be correct/adequate
for these commodities for future risk assessments if refinements were
necessary. The submitted field trial data, reflecting residues of
mefenoxam, will support the proposed tolerance of 0.20 ppm for snap bean
(ChemSAC Minutes, 02/25/2009).

Table 5.2.6.2.  Summary of Residue Data from Field Trials with
Mefenoxam.

Crop matrix1	Total Applic. Rate  (lb ai/A)	PHI (days)	Residue Levels
(ppm)

	n	Min.	Max.	HAFT2	Median	Mean	Std. Dev.

SNAP BEAN (proposed use = 0.4 lb ai/A total application rate foliar
only; 6-day PHI)

(proposed + registered use = 0.5 lb ai/A soil + 0.4 lb ai/A foliar for
0.9 lb ai/A total application rate)

Mefenoxam

Snap Bean

(Original analysis)	0.68-0.71	6-7	16	<0.05	0.168	0.137	0.05	0.061	0.032

Combined residues of mefenoxam/metalaxyl and metabolites convertible to
2,6-DMA

Snap Bean

(Reanalysis/

calculation)	0.68-0.71	6-7	16	<0.05	0.282	0.246	0.05	0.075	0.068

1  Original analysis: samples were originally analyzed for residues of
mefenoxam.  Reanalysis/calculation: samples from the CA site were
re-analyzed for combined residues of mefenoxam/metalaxyl and metabolites
convertible to 2,6-DMA; for all other trials, the original residue
results were corrected using a conversion factor of 1.8X.

2  HAFT = Highest Average Field Trial.

Caneberry Subgroup 13-07A

The submitted field trial residue data for caneberries are not adequate
for a permanent registration but will support a conditional
registration.  The field trial locations are not in accordance with
860.1500, and no residue decline data were submitted.  To fulfill
geographic distribution requirements, one additional field trial must be
conducted in Zone 5 (raspberry) or Zone 6 (blackberry).  The required
field trial should include additional sampling intervals to assess
residue decline.  Samples were initially analyzed for residues of
mefenoxam using an acceptable chiral LC/MS method, and selected samples
were re-analyzed for combined residues of mefenoxam and metabolites
convertible to 2,6-DMA using an acceptable GC/MS method.  Calculation of
combined residues in remaining crop samples using a 1.3X conversion
factor was approved by ChemSAC.  Adequate concurrent storage stability
data were submitted to support the study.  The submitted field trial
data, reflecting residues of mefenoxam, will support a tolerance of 0.70
ppm for caneberry subgroup 13-07A.  Pending submission of the additional
required field trial data, the tolerance will be recalculated and a
revised tolerance proposal may be needed.

The study results, reflecting the original analysis for mefenoxam only
and re-analysis of the NC, NJ, and CA field trial samples for parent +
metabolites, were presented to ChemSAC with a request to use a 1.3X
conversion factor, calculated by dividing the average residues obtained
on re-analysis for each of the three trials by the average residues
obtained on original analysis, to calculate residues in the remaining
field trial samples for setting residue values for the risk assessment. 
ChemSAC agreed that parent + metabolites to parent ratios could be used
to estimate residue levels for risk assessments in caneberry, with the
provision that these ratios would not necessarily be correct/adequate
for these commodities for future risk assessments if refinements were
necessary. The results of the caneberry field trials are presented in
Table 5.2.6.3 (ChemSAC Minutes, 02/25/2009).  

Table 5.2.6.3.  Summary of Residue Data from Field Trials with
Mefenoxam.

Crop matrix1	Total Applic. Rate  (lb ai/A)	PHI (days)	Residue Levels
(ppm)

	n	Min.	Max.	HAFT2	Median	Mean	Std. Dev.

CANEBERRY (proposed use = 3.6 lb ai/A total application rate, soil +
foliar applied; 0-day PHI for foliar application)

Mefenoxam

Caneberries

(Original analysis)	1.95-2.18	0	12	0.213	0.554	0.527	0.296	0.329	0.106

Combined residues of mefenoxam/metalaxyl and metabolites convertible to
2,6-DMA

Caneberries

(Reanalysis/

calculation)	1.95-2.18	0	12	0.277	0.691	0.686	0.370	0.412	0.135

1  Original analysis: samples were originally analyzed for residues of
mefenoxam.  Reanalysis/calculation: samples from the NC, NJ, and one CA
(02-CA27) trials were re-analyzed for combined residues of
mefenoxam/metalaxyl and metabolites convertible to 2,6-DMA; for all
other trials, the original residue results were corrected using a
conversion factor of 1.3X.

 2  HAFT = Highest Average Field Trial.

Bushberry Subgroup 13-07B

No residue data were provided in support of the proposed expansion of
the registered use of mefenoxam on blueberry to support the bushberry
subgroup 13-07B.  The registered use of mefenoxam on blueberry is
supported by adequate crop field trial data for metalaxyl, and the
proposed use pattern for mefenoxam on bushberry subgroup 13-07B is
identical to the registered use on blueberry.  Because blueberry is the
representative commodity of the bushberry subgroup, HED has no
objections to expanding the registered use to cover the crop subgroup
provided the revisions requested under Section 860.1200 to the EC and SL
labels for bushberries are made.  The available data for blueberry will
support a tolerance of 2.0 ppm for the bushberry subgroup 13-07B.  The
available data were re-assessed for the Residue Chemistry Chapter of the
Metalaxyl RED which concluded that no additional data were needed for
blueberry.  A tolerance of 2.0 ppm is established for metalaxyl on
blueberry.  

Processed Food and Feed

HED does not require residue data for any processed commodities
associated with onion, legume vegetables/spinach, snap beans,
caneberries, or bushberries.  Therefore, data requirements for processed
food and feed are not relevant to this tolerance petition.

5.2.7	International Residue Limits  tc \l3 "5.2. 7 International Residue
Limits  

There are Codex MRLs for Metalaxyl-M (mefenoxam) for plant commodities
expressed as metalaxyl.  Although there are no Codex MRLs for animal
commodities, the definition for animal commodities is metalaxyl +
metabolites containing the 2,6-dimethylaniline moiety.  The Codex MRLs
for Metalaxyl-M have not been advanced to final status, pending
revocation of metalaxyl MRLs.

Codex MRLs, expressed in terms of metalaxyl for plant commodities, are
established for spinach at 0.1 and onion at 0.03 ppm.  Canadian MRLs for
mefenoxam (Metalaxyl-M) are covered by MRLs established for metalaxyl,
the unresolved isomeric mixture, which are expressed in terms of
N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-DL-alanine methyl ester,
including metabolites that can be converted to the 2,6-dimethylaniline
moiety, calculated as metalaxyl equivalents.  Canadian MRLs are
established for spinach at 10 ppm, bulb onion at 3.0 ppm, green onion at
10 ppm, bean at 0.2 ppm, raspberry at 0.2 ppm, and blueberry at 2.0 ppm.
No Mexican MRLs are established for mefenoxam or metalaxyl.  With the
adoption of the tolerance expression recommended by HED, the U.S.
tolerance expression will be in harmonization with Codex MRLs but not
with PMRA MRLs (HED RARC Report, W. Britton, 02/14/2007).

5.3	Dietary Exposure and Risk TC \l2 "5.3  Dietary Exposure and Risk 

Reference:	

Mefenoxam Chronic Aggregate Dietary (Food and Drinking Water) Exposure
and Risk Assessment for the Section 3 Registration Action on Snap Bean
(Succulent) and the Caneberry Subgroup 13-07A, Expanded Uses on the Bulb
Onion Subgroup 3-07A, the Green Onion Subgroup 3-07B, and the Bushberry
Subgroup 13-07B, and Amended Use on Spinach, DP#371309, N. Dodd,
07/02/2010.

5.3.1	Acute Dietary

 tc \l3 "5.3.1 Acute Dietary 

There was no indication of an adverse effect attributable to a single
dose.  An acute reference dose (aRfD) was not established; therefore an
acute dietary risk assessment was not performed. 

5.3.2	Chronic Dietary

 tc \l3 "5.3.2 Chronic Dietary 

A refined chronic aggregate dietary (food and drinking water) exposure
and risk assessment was conducted using the Dietary Exposure Evaluation
Model DEEM-FCID™, Version 2.03 which uses food consumption data from
the U.S. Department of Agriculture’s Continuing Surveys of Food
Intakes by Individuals (CSFII) from 1994-1996 and 1998 for all existing
and proposed new food uses of metalaxyl/mefenoxam.  In this assessment,
it was assumed that residues were present at tolerance levels in plant
commodities for both direct use tolerances for metalaxyl/mefenoxam and
indirect or inadvertent tolerances for metalaxyl.  Additional factors
were applied to certain plant commodities to address concerns regarding
the adequacy of the residue analytical method to determine total
residues of concern in plant and animal commodities.  This concern was
raised during the review of method validation data required for
reregistration which were submitted with a previous petition.  HED used
data from metabolism studies on goats and hens to estimate conservative
levels of metalaxyl/mefenoxam in livestock commodities for upper bound
dietary risk assessment purposes. 

DEEM default processing factors were generally used except for those
cases in which the tolerances were specifically established for
processed commodities such as fruit juices, dried apricot, processed
potato and tomato commodities; therefore processing factors were set to
1.  Additionally, a 1X processing factor for fruit juices was used based
on available grape metabolism data (including total radioactive residues
in both grapes and grape juice) and supporting.data on metalaxyl apple,
orange, and metalaxyl/mefenoxam grape processing data.  These data
indicate that total metalaxyl/mefenoxam residues of concern in fruit
juices are not expected to exceed those estimated in/on the associated
fruits.  Average PCT estimates were available from a SLUA for mefenoxam
(dated 05/05/2009) and for metalxyl (dated 04/07/2009).  Average PCT
information for mefenoxam was incorporated into the dietary assessment
since it showed higher estimates than metalaxyl, with the exception of
pumpkins where there was no PCT estimate for mefenoxam.  The 1 in 10
year annual estimated surface water concentration of 36.7 ug/L from the
Tier II PRZM-EXAMS model was used to assess contributions from drinking
water.  

Given concerns regarding the adequacy of the residue analytical methods
to determine metalaxyl/mefenoxam residues of concern in plant and animal
commodities, HED has approved the use of factors, as appropriate,
derived from available residue chemistry data, to estimate total
metalaxyl/mefenoxam residues of concern for dietary risk assessments
(HED RARC Report, W. Britton, 02/14/2007).  A detailed discussion of
concerns regarding the analytical method and of the factors applied to
assess the total residues of concern is provided in (DP# 371309, N.
Dodd, 06/17/2010).  Factors were applied to the current/reassessed
tolerance levels used in the chronic dietary risk assessment to account
for all residues of concern.  Estimated factors were as follows: for
leafy commodities (4X), fruit and vegetable commodities (no additional
factor), grain, seed (including dried beans), and nut commodities (25X)
(with the exception of flour cereal grains), snap bean (succulent)
(1.8X), caneberries (1.3X).  For snap bean (succulent) and caneberries,
the factors used were determined by ChemSAC; the factors are based on
the ratio of combined residues of mefenoxam/metalaxyl and metabolites
convertible to 2,6-DMA to residues of mefenoxam (ChemSAC Minutes,
02/25/2009). 

  

Results of the chronic dietary assessment indicate that the general U.S.
population and all other population subgroups have exposure and risk
estimates below HED’s LOC.  The DEEM chronic dietary exposure estimate
is 26% of the cPAD for the general U.S. population, and 58% of the cPAD
for the highest exposed population subgroup, children 1-2 years of age. 

Table 5.3.  Summary of Dietary (Food and Drinking Water) Exposure and
Risk for Mefenoxam/Metalaxyl.1

Population Subgroup	Acute Dietary	Chronic Dietary	Cancer

	Dietary Exposure (mg/kg/day)	% aPAD	Dietary Exposure

(mg/kg/day)	% cPAD	Dietary Exposure

(mg/kg/day)	Risk

General U.S. Population	NA	0.018848	26	NA	NA

All Infants (< 1 year old)

0.020147	27

Children 1-2 years old

0.042959	58

Children 3-5 years old

0.041014	55

Children 6-12 years old

0.027915	38

Youth 13-19 years old

0.017987	24

Adults 20-49 years old

0.015700	21

Adults 50+ years old

0.013914	19

Females 13-49 years old

0.014792	20

 1	The population subgroup with the highest estimated chronic dietary
(food + drinking water) exposure and risk is indicated by bold text.

5.3.3	Cancer Dietary tc \l3 "5.3.3 Cancer Dietary 

Metalaxyl has been classified as “not likely to be a human
carcinogen” based on the results of a carcinogenicity study in mice
and the combined chronic toxicity and carcinogenicity study in rats. 
Based on the classification of metalaxyl, mefenoxam is also considered
“not likely to be a human carcinogen,” and an assessment of cancer
risk was not conducted.

5.3.4	Anticipated Residues and Percent Crop Treated (PCT) Information tc
\l3 "5.3.4 Anticipated Residues and Percent Crop Treated (%CT)
Information  

Reference: 

Mefenoxam Screening Level Usage Analysis, 05/05/2009.

Metalaxyl Screening Level Usage Analysis, 04/07/2009.

The chronic assessment was based on the assumption of tolerance level
residues in plant commodities for both direct use tolerances for
metalaxyl/mefenoxam and indirect or inadvertent tolerances for
metalaxyl.  Additional factors were applied to certain plant commodities
to address concerns regarding the adequacy of the residue analytical
method to determine total residues of concern in plant and animal
commodities.  HED used data from metabolism studies on goats and hens to
estimate conservative levels of metalaxyl/mefenoxam in livestock
commodities for upper bound dietary risk assessment purposes. 

Average PCT estimates were available from a SLUA for mefenoxam (dated
05/05/2009) amd a SLUA for metalaxyl (dated 04/07/2009).  Average PCT
information for mefenoxam was incorporated into the dietary assessment
since it showed higher estimates than metalaxyl, with the exception of
pumpkins where there was no PCT estimate for mefenoxam, as summarized in
Table 5.3.4.

Table 5.3.4.  Percent Crop Treated Comparison for Mefenoxam.*

Commodity	Average Percent Crop Treated Data	Commodity	Average Percent
Crop Treated Data

Almonds	<1	Lemons	5

Apples	<1	Lettuce	10

Artichokes	5	Onions	30

Asparagus	10	Oranges	5

Avocados	<2.5	Peaches	<1

Beans, green	10	Peanuts	<1

Blueberries	<1	Peas, green	<2.5

Broccoli	10	Peppers	15

Cabbage	10	Potatoes	20

Caneberries	15	Pumpkins	<2.5*

Cantaloupes	10	Raspberries	20

Carrots	35	Rice	<1

Cauliflower	5	Soybeans	10

Celery	5	Spinach	55

Cherries	<1	Squash	10

Cotton	5	Strawberries	10

Cucumbers	10	Sugar beets	<1

Dry Beans/Peas	<1	Sweet corn	<1

Garlic	15	Tangerines	10

Grapefruit	5	Tomatoes	15

Grapes	<1	Walnuts	<1

Honeydew	5	Watermelons	15

* Mefenoxam Screening Level Usage Analysis, 05/05/2009.

6.0	Residential Exposure  TC \l1 "6.0  Residential Exposure  

Reference:	

Mefenoxam. Human Health Risk Assessment for Proposed Uses on Succulent
Shelled Beans and Turnip Greens. DP#325137, Myron Ottley, 05/31/2007.

No residential uses are being requested at this time.  However,
mefenoxam products are currently registered for use on residential turf
and ornamentals as well as recreational turf such as golf courses and
athletic fields.  While no residential uses are subject to this current
petition, the FQPA requires that all existing non-occupational exposures
be considered for aggregate risk to the general population.  The
products registered for residential uses that could result in
non-occupational exposure include a granular, a wettable powder, and two
emulsifiable concentrates for use on fruit and nut trees, ornamentals,
and turf.  

EPA Reg. No.		Product name                (% ai)			Formulation

 100-793 		Subdue® MAXX® EC    (46.6%)		Emulsifiable Concentrate

 100-794 		Subdue® MAXX® GR    (0.97%)		Granular

 100-795 		Subdue® MAXX® WSP (45.0%)		WP in Water-soluble Packets

 100-796		Subdue® MAXX® EC    (22.0%)		Emulsifiable Concentrate 

Registered residential uses may result in short-term (1-30 days) to
intermediate-term (1-6 months) exposures; however, based on current use
patterns, long-term exposure (6 or more months of continuous exposure)
to mefenoxam is not expected.  Exposure may occur to adults from
handling the pesticide, and to both adults and children from contact
with treated areas following application.  Toxicity endpoints have been
identified for use in assessing risks from short- and intermediate-term
inhalation exposure to residential handlers, and short- and
intermediate-term incidental ingestion exposure to children. 
Non-occupational (i.e., residential) handler and postapplication
exposures are assessed below for the two major mefenoxam products on
turf which are considered to represent the reasonable upper-bound
residential exposure potential: Subdue® MAXX® EC (46.6%), and Subdue®
MAXX® GR (0.97%).

6.1	Residential Handler Exposure TC \l2 "6.1	Residential Handler
Exposure 

Residential handler exposure has been assessed for two formulations of
mefenoxam: an emulsifiable concentrate, Subdue® MAXX® EC, which is
used at a maximum rate of 0.015 lb ai/1000 ft2; and, a granular,
Subdue® MAXX® GR, which also is used at a maximum rate of 0.015 lb
ai/1000 ft2. 

 

The five scenarios used were: (1) Granular Bait Dispersed by Hand, (2)
Belly Grinder-Granular Open Pour- Mixer/Loader/Applicator (MLAP), (3)
Push Type Granular Spreader (MLAP), (4) Mixer/Loader/Applicator
Liquid–Low-Pressure Handwand, and (5) Garden Hose-End Sprayer.

Residential handlers may be exposed on a short-term basis. 
Intermediate-term handler exposure (more than 30 days of continuous
exposure) is not expected.  The method used for estimating residential
applicator exposure is believed to produce a central tendency to
high-end estimate of exposure.  All exposure scenarios for short-term
inhalation result in MOEs that do not trigger HED's LOC.   Exposure and
risk for residential applicators are summarized in Table 6.1.

Table 6.1.  Inhalation Exposure and Risk Estimates for Non-Occupational
Lawn Applicators.

PHED Scenario

Selected from Draft SOP for Residential Exposure Assessments	Application
Rate	Area Treated

per day	Unit Exposure

(mg/lb ai)	PHED

Data

Confidence	Short-term Daily Inhalation Dose 1

(mg/kg/day)	Short-Term

 MOE 2

1. Granular Bait Dispersed by Hand	0.015 lb ai/1000 ft2	1000 ft2	0.47 3
Medium	0.00012	430,000

2. Belly Grinder Granular Open Pour (Mix, Load,  Apply)	0.65 lb ai/acre
0.5 acres	0.062 3	High	0.00033	150,000

3. Push Type Granular (Mix Load, and Apply)	0.65 lb ai/acre	0.5 acres
0.00091 4	High	0.0000049	10,000,000

4. Mixer/loader/applicator Liquid/Low-pressure Handwand	0.015 lb ai/1000
ft2	1000 ft2	0.03 3	Medium	0.0000075	6,700,000

5. Garden hose-end sprayer	0.65 lb ai/acre	0.5 acres	0.016 4	Low
0.000087	570,000

1	Daily Dose =[Application Rate (lb ai/A) x Acres Treated (A/day) x Unit
Exposure(mg/lb ai handled) x Absorption Factor (100%)]/Body Weight (60
kg).

2	MOE = NOAEL/ Daily Dose.  Short-term Inhalation NOAEL=50 mg/kg/day.

3	PHED unit exposure value from Draft SOPs for Residential Exposure
Assessments (December 18, 1997).

4	Data from Outdoor Residential Exposure Taskforce (MRID 449722-01).

6.2	Residential Postapplication Exposure

 TC \l2 "6.2	Residential  Postapplication Exposure 

Short- and intermediate-term oral endpoints were identified for use in
assessing children’s   SEQ CHAPTER \h \r 1 postapplication exposure
that may occur through children’s incidental oral ingestion of
residues of mefenoxam on treated turf (hand-to-mouth, object-to-mouth,
and ingestion of soil).  However, because no acute oral endpoint was
identified, “episodic” (single dose) ingestion of granules by
children was not assessed.  Based on the Agency's current practices, a
quantitative residential postapplication inhalation exposure assessment
was not performed for mefenoxam at this time.  If new policies or
procedures are put into place, the Agency may revisit the need for a
quantitative residential postapplication inhalation exposure assessment
for mefenoxam.

Dermal exposure is not assessed because appropriate dermal toxicity
endpoints were not identified.  Chronic exposure is not expected for any
mefenoxam use pattern.

The short- and intermediate-term MOEs for children from oral
hand-to-mouth activities on treated lawns are 5,200 and 1,600,
respectively.  The short- and intermediate-term MOEs for children from
oral object-to-mouth (turfgrass) from treated lawns are 22,000 and
3,200, respectively.  The short- and intermediate-term MOEs for children
from incidental ingestion of soil from treated lawns are 1,500,000 and
230,000, respectively.  Both short-term and intermediate-term MOEs are
above 100 and, therefore, are not of concern to HED.

It should be noted that FQPA requires residential exposures that could
reasonably be expected to occur on the same day to be combined and
compared to the appropriate toxicity endpoint.  For non-occupational
scenarios, the three scenarios that would reasonably be expected to
occur on the same day are children’s incidental ingestion of residues
on turf from hand-to-mouth activities, object-to-mouth (turfgrass) and
ingestion of soil.  These daily exposures, when combined, total 0.012
mg/kg/day (short-term) and 0.0071 (intermediate-term).  When the
combined short-term exposure is compared to the short-term NOAEL (50
mg/kg/day), the MOE = 4,200.  When the combined intermediate-term
exposure is compared to the intermediate-term NOAEL (7.4 mg/kg/day), the
MOE = 1000.  Therefore, the combined exposures anticipated for
residential scenarios are not of concern to HED.

Table 6.2.1  Oral Hand-To-Mouth Exposure and Risk for Children from
Treated Lawns.

Application Rate

 (lb ai/A)	Fraction of ai Available	Turf Transferable Residue1

(ug/cm2)	Exposure Time 

(hrs/day)	Extraction by Saliva	Hand Surface Area (cm2/event)	Frequency

(events/ hr)	Body Weight

(kg)	 Daily Dose2

(mg/kg/day)	Short-Term

MOE3	Int-Term

MOE3

0.65	0.05	0.36	2	0.5	20	20 (ST) 

9.5 (IT)	15	0.010 (ST)

0.0046 (IT)	5,200	1,600

1	Turf Transferable Residue (µg/cm2) = Application rate (lb ai/A) x
Fraction of ai Available x 4.54x108 ug/lb x 2.47x10-8 A/cm2.

2	Daily Dose = (Turf Transferable Residue (ug/cm2) x Extraction by
Saliva x Hand Surface Area (cm2/event) x Frequency (events/hr) x 1x10-3
mg/ µg  x  ET (hrs/day)] / [Body Weight (kg)].

3	Short-/Intermediate-Term Oral MOE = Short- (50 mg/kg/day) &
Intermediate-Term (7.4 mg/kg/day) Oral NOAEL/Daily Dose.

Table 6.2.2.  Exposure and Risk for Children from Object-To-Mouth
(Turfgrass) from Treated Lawns. 

Application Rate

 (lb ai/A)	Fraction of ai Available	Grass

Residue1 

(ug/cm2)	Mouthing Rate

(cm2/day)	Body 

Weight

(kg)	 Daily Dose2

(mg/kg/day)	Short-Term MOE3	Intermediate-Term MOE3

0.65	0.2	1.4	25	15	0.0023	22,000	3,200

1	Grass residue (µg/cm2) = [Application Rate (lb ai/A) x Fraction of ai
Available x 4.54x108 ug/lb x 2.47x10-8 A/cm2].

2	Daily Dose = [Grass reside (µg/cm2) x mouthing rate (cm2/day) x
1x10-3 mg/µg] / [Body Weight (kg)].

3	Short-/Intermediate-Term Oral MOE = Short- (50 mg/kg/day) &
Intermediate-Term (7.4 mg/kg/day) Oral NOAEL/Daily Dose.

Table 6.2.3.  Exposure and Risk for Children from Ingestion of Soil from
Treated Lawns. 

Application Rate

 (lb ai/A)	Fraction of ai Available	Soil

Residue1 

(ug/g)	Ingestion Rate

(g/day)	Body 

Weight

(kg)	 Daily Dose2

(mg/kg/day)	Short-Term MOE3	Intermediate-Term MOE3

0.65	1.0	4.5	100	15	0.000033	1,500,000	230,000

1	Soil residue (µg/g) = Application Rate (lb ai/A) x Fraction of ai
Available x 4.54x108 ug/lb x 2.47x10-8 A/cm2 x 0.67 cm3/g soil.

2	Daily Dose = [Soil reside (ug/g) x Ingestion rate (mg/day) x 1E-6
g/ug] / [Body Weight (kg)].

3	Short-/Intermediate-Term Oral MOE = Short- (50 mg/kg/day) &
Intermediate-Term (7.4 mg/kg/day) Oral NOAEL/Daily Dose. 

6.3	Residential Bystander Postapplication Inhalation Exposure

 TC \l2 "6.3	Residential Bystander  Postapplication Inhalation Exposure 

Based on the Agency's current practices, a quantitative postapplication
inhalation exposure assessment was not performed for mefenoxam at this
time.  However, volatilization of pesticides may be a potential source
of postapplication inhalation exposure to individuals nearby to
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.  The Agency received the SAP’s final report on
March 2, 2010 ( HYPERLINK
"http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html"
http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ) and is
in the process of evaluating the SAP report.  The Agency may, as
appropriate, develop policies and procedures to identify the need for
and, subsequently, the way to incorporate postapplication inhalation
exposure into the Agency's risk assessments.  If new policies or
procedures are put into place, the Agency may revisit the need for a
quantitative postapplication inhalation exposure assessment for
mefenoxam.

6.4	Recreational TC \l2 "6.4	Recreational 

Mefenoxam may be used on turf at recreational use sites and, therefore,
may result in postapplication exposure to adults and children involved
in recreational activities.  Exposure to adults and children from the
use of mefenoxam at recreational use sites are assumed to be the same as
those assessed for residential use sites and, therefore, a separate
recreational exposure assessment was not included.  Residential turf
exposure assessment result in what are considered upper bound risk
estimates.  Therefore, it is not expected that the upper bound
residential exposure scenario would occur on the same day as an upper
bound recreational exposure scenario.  Exposures from these two exposure
scenarios are not aggregated.  Rather, the residential risk estimate
should serve as an upper bound for both residential and recreational
exposure.

6.5	Other (Spray Drift, etc.)

 TC \l2 "6.5	Other (Spray Drift, etc.) 

Spray drift is always a potential source of exposure to residents nearby
to spraying operations.  This is particularly the case with aerial
application, but, to a lesser extent, could also be a potential source
of exposure from the ground application method employed for mefenoxam. 
The Agency has been working with the Spray Drift Task Force, EPA
Regional Offices, and State Lead Agencies for pesticide regulation and
other parties to develop the best spray drift management practices.  The
Agency is now requiring interim mitigation measures for aerial
applications that must be placed on product labels/labeling.  The Agency
has completed its evaluation of the new data base submitted by the Spray
Drift Task Force, a membership of U.S. pesticide registrants, and is
developing a policy on how to appropriately apply the data and the
AgDRIFT computer model to its risk assessments for pesticides applied by
air, orchard airblast, and ground hydraulic methods.  After the policy
is in place, the Agency may impose further refinements in spray drift
management practices to reduce off-target drift and risks associated
with aerial as well as other application types where appropriate.  Note
that mefenoxam is directly applied to residential turf and does not
result in exposures of concern.  It is unlikely that spray drift would
result in a higher potential for risk of exposure than the scenarios
already assessed.

7.0	Aggregate Risk Assessments and Risk Characterization  TC \l1 "7.0 
Aggregate Risk Assessments and Risk Characterization 

Aggregate risk considers total exposure to mefenoxam through different
pathways of exposure.  Risk estimates are aggregated because it is
assumed that these exposures may occur over the same time period.  The
identification of the same endpoint for exposures that may occur over
the same time period (although via different routes) enables risk via
different routes to be aggregated.

The same endpoint and NOAEL for short-term inhalation and incidental
oral exposure was identified from a developmental toxicity study in rats
with mefenoxam (clinical signs of toxicity including post-dosing
convulsions, NOAEL=50 mg/kg/day).  Likewise, the same endpoint and NOAEL
for intermediate-term inhalation and incidental oral exposure and
chronic dietary exposure (increased liver weight and clinical chemistry
changes, NOAEL=7.41 mg/kg/day) was identified from a 6-month dog study. 
Therefore, short-term, intermediate-term and chronic risk estimates can
be aggregated in this risk assessment.

7.1	Acute Aggregate Risk TC \l2 "7.1	Acute Aggregate Risk 

No endpoint attributable to a single dose was identified.  Therefore, an
acute aggregate risk assessment was not conducted.

7.2	Short-Term Aggregate Risk TC \l2 "7.2	Short-Term Aggregate Risk 

Short-term exposure occurs over 1-30 days.  Short-term aggregate risk is
made up of the combined exposure from inhalation, incidental oral,
dietary food, and water risk estimates.  

Risk from dermal exposure was not included because no dermal hazard was
identified.  For adult residential short-term exposure (males and
females), the inhalation exposure estimate for the belly grinder
application scenario was used because it was the scenario resulting in
the highest handler exposure (0.00033 mg/kg/day).  For an estimate of
children’s residential exposure, the postapplication incidental oral
exposure scenario was used.  Children’s combined exposure from all
incidental oral sources (residential turf) is 0.01233 mg/kg/day.

Because the short-term aggregate MOEs are all greater than 100, risk
estimates do not exceed HED’s LOC for adults or children.  Results are
presented in Table 7.2.

Table 7.2.  Short-Term Aggregate Risk Calculations.		

Population	Short-Term Scenario

	NOAEL

mg/kg/day	LOC1	Average Food

& Water

Exposure

mg/kg/day	Residential Exposure2

mg/kg/day	Aggregate MOE

(food and

residential)3

Adult Males	50	100	0.018848	0.00033	2600

Adult Females	50	100	0.014792	0.00033	3300

Children 1-2 years	50	100	0.042959	0.01233	900

Children 3-5 years	50	100	0.041014	0.01233	940

1	100X = 10X interspecies and 10X intraspecies uncertainty factors.

2	Residential Exposure = [Oral exposure + Inhalation Exposure]. 
Mefenoxam. Human Health Risk Assessment for Proposed Uses on Succulent
Shelled Beans and Turnip Greens. Myron Ottley, 05/31/2007.

3	Aggregate MOE = NOAEL / (Avg Food & Water Exposure + Residential
Exposure).

7.3	Intermediate-Term Aggregate Risk TC \l2 "7.3	Intermediate-Term
Aggregate Risk 

Intermediate-term exposure occurs from 30 days to six months. 
Intermediate-term aggregate risks are made up of the combined exposure
from incidental oral, dietary, and drinking water risk estimates.  

Risk from dermal exposure is not considered because no dermal hazard was
identified.  Intermediate-term residential handler (adult) exposure is
not expected because of the intermittent and seasonal use pattern.  For
an estimate of children’s residential exposure, the postapplication
oral exposure scenario was used.  Children’s combined exposure from
all residential incidental oral sources is 0.006933 mg/kg/day. 

Because the intermediate-term aggregate MOEs are all greater than 100,
risk estimates do not exceed HED’s LOC for adults or children. 
Results are presented in Table 7.3. 



Table 7.3.  Intermediate-Term Aggregate Risk Calculations.

Population	Intermediate-Term Scenario

	NOAEL

mg/kg/day	LOC1	Average Food & Water

Exposure

mg/kg/day	Residential Exposure2

mg/kg/day	Aggregate MOE

(food and

residential)3

Children 1-2 years	7.4	100	0.042959	0.006933	1000

Children 3-5 years	7.4	100	0.041014	0.006933	1000

1	100X = 10X interspecies and 10X intraspecies uncertainty factors.

2	Residential Exposure = [Oral exposure + Inhalation Exposure]. 
Mefenoxam. Human Health Risk Assessment for Proposed Uses on Succulent
Shelled Beans and Turnip Greens. Myron Ottley, 05/31/2007.

3	Aggregate MOE = NOAEL / (Avg Food & Water Exposure + Residential
Exposure).

7.4	Chronic Aggregate Risk tc \l2 "7.4	Chronic Aggregate Risk 

Chronic exposure occurs continuously for more than six months.  Chronic
aggregate risk is made up of the combined exposure from dietary and
drinking water risk estimates.  Based on the Agency's current practices,
a quantitative postapplication inhalation exposure assessment was not
performed for mefenoxam at this time.  Incidental oral exposure was not
included as it is not expected to occur over the long-term duration. 

Chronic residential handler (adult) exposure is not expected based on
the use pattern.  Based on the Agency's current practices, a
quantitative postapplication inhalation exposure assessment was not
performed for mefenoxam at this time.  Finally, postapplication oral
exposure to children is not expected over the chronic time period. 
Chronic aggregate risk estimates are based on food and drinking water
exposures only.

Results of the chronic aggregate risk assessment indicate that risk
estimates do not exceed HED’s LOC for adults or children.  Results are
presented in Table 5.3.

7.5	Cancer Risk tc \l2 "7.5	Cancer Risk 

Based on the classification of metalaxyl, mefenoxam is considered “not
likely to be a human carcinogen.”  Therefore, an aggregate cancer risk
assessment is not needed.

8.0	Cumulative Risk Characterization/Assessment  TC \l1 "8.0  Cumulative
Risk Characterization/Assessment 

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

9.0	Occupational Exposure/Risk Pathway  TC \l1 "9.0  Occupational
Exposure/Risk Pathway 

Reference: 

Mefenoxam.  Occupational and Residential Exposure Assessment for
Proposed Use on Caneberries (Subgroup 13-07A), Bushberries (Subgroup
13-07B), Bulb Vegetables (Crop Group 3-07), Edible Podded Beans, and
Spinach. DP#371308, Nancy J. Tsaur, 05/25/2010.

Mefenoxam may be applied using groundboom, aerial, or chemigation
equipment.  There is potential for exposure to mefenoxam during mixing,
loading, and applying activities.  Handler exposure is expected to be
short- or intermediate-term based on information provided on the
proposed label.  Chronic exposure (greater than or equal to 6 months of
continuous exposure) is not expected.

9.1	Occupational Handler

There is a potential for exposure to mefenoxam during mixing, loading,
and application activities.  An exposure/risk assessment was performed
using applicable endpoints selected by HED and affirmed by the risk
assessment team (HIARC Report, 04/11/2000).  Handler’s exposure and
risk were estimated for the following scenarios: (1) mixer/loader: open
mixing liquid for aerial; (2) mixer/loader: open mixing wettable powder
in water-soluble bag for aerial and chemigation; (3) aerial application
of liquid: closed cockpit; (4) flagging for aerial applications; (5)
mixer/loader: open mixing  liquid for groundboom; (6) mixer/loader: open
mixing wettable powder in water-soluble bag for groundboom; and (7)
groundboom application of liquid: open cab.

Chemical-specific handler exposure data were not submitted in support of
this registration.  It is HEDs policy to use data from the PHED version
1.1 as presented in PHED Surrogate Exposure Guide (8/98) to assess
handler exposures for regulatory actions when chemical-specific
monitoring data are not available (HED ExpoSAC SOP No. 7, dated
01/28/1999).

Short- and intermediate-term dermal toxicity endpoints were not
identified because no systemic toxicity was seen at the limit dose in a
21-day dermal toxicity study in rabbits.  Although a long-term dermal
endpoint was identified, long-term exposure (( 180 days) is not
expected.  Therefore, a dermal risk assessment was not conducted. 
Inhalation toxicity endpoints of concern were identified for all
durations of exposure.  However, because long-term exposures are not
anticipated, only short- and intermediate-term inhalation risks were
assessed.

To determine the short-term inhalation exposure risks, daily inhalation
exposures (assuming

100% absorption) were compared to the NOAEL of 50 mg/kg/day from a
developmental study in rats (endpoint: clinical signs including
post-dosing convulsions).  For short-term exposures, the MOEs range from
4,000 (mixer/loader: open mixing liquid for aerial and chemigation
application) to 1,300,000 (aerial application, liquid).  These risk
estimates are not of concern HED.  

To determine intermediate-term risks, daily inhalation exposures
(assuming 100% absorption) were compared to the NOAEL of 7.4 mg/kg/day
from a six-month oral study in dogs (endpoint: increased liver weights
and clinical chemistry).  The MOEs range from 680 (mixer/loader: open
mixing liquid for aerial and chemigation application) to 220,000 (aerial
application, liquid).  These risk estimates are not of concern to HED.

Summaries of the inhalation risk estimates for occupational handlers are
included in Table 9.1.  The maximum application rate for each exposure
scenario is presented as the worst case scenario. The inhalation risks
to handlers are not of concern to HED for any of the handler scenarios. 

Table 9.1.  Short- and Intermediate-Term Occupational Handler Exposure
and Risk for Mefenoxam.

Exposure Scenario	Crop or Target	App Ratea

(lb ai/A)	Acres Treated Dailyb	Baseline Inhalation Unit Exposurec

(µg/lb ai)	Short-Term Dose

(mg/kg/day)

Inhalationd	Intermediate-Term Dose

(mg/kg/day)

Inhalatione	Short-Term MOE

Inhalationf	Intermediate-Term MOE

Inhalationg

Mixer/Loader

Mixing/Loading

Liquids for

Groundboom Applications (PHED)	Bushberry

(Subgroup 13-07B)

Caneberry

(Subgroup 13-07A)	1.8	80	1.2	0.00288	0.00247	17,000	3,000

	Spinach	0.125	80	1.2	0.0002	0.000171	250,000	43,000

	Bulb Vegetables

(Crop Group 3-07)	0.5	80	1.2	0.0008	0.000686	63,000	11,000

	Edible

Podded Beans	0.10	80	1.2	0.00016	0.000137	310,000	54,000

Mixing/Loading Liquids for

Aerial and Chemigation Applications (PHED)	Bushberry

(Subgroup 13-07B)

Caneberry

(Subgroup 13-07A)	1.8	350	1.2	0.0126	0.0108	4,000	690

	Spinach	0.125	350	1.2	0.000875	0.00075	57,000	9,900

	Bulb Vegetables

(Crop Group 3-07)	0.5	350	1.2	0.0035	0.003	14,000	2,500

	Edible

Podded Beans	0.10	350	1.2	0.0007	0.0006	71,000	12,000

Mixing/Loading Wettable Powders (Water Soluble Packets) for

Groundboom Applications (PHED)	Bushberry

(Subgroup 13-07B)

Caneberry

(Subgroup 13-07A)	1.8	80	0.24	0.000576	0.00049	87,000	15,000

	Spinach	0.125	80	0.24	0.00004	0.000034	1,300,000	220,000

	Bulb Vegetables

(Crop Group 3-07)	0.5	80	0.24	0.00016	0.000137	310,000	54,000

	Edible

Podded Beans	0.10	80	0.24	0.000032	0.0000274	1,600,000	270,000

Mixing/Loading Wettable Powders (Water Soluble Packets) for

Aerial and Chemigation Applications (PHED)	Bushberry

(Subgroup 13-07B)

Caneberry

(Subgroup 13-07A)	1.8	350	0.24	0.00252	0.00216	20,000	3,000

	Spinach	0.125	350	0.24	0.000175	0.00015	290,000	49,000

	Bulb Vegetables

(Crop Group 3-07)	0.5	350	0.24	0.0007	0.0006	71,000	12,000

	Edible

Podded Beans	0.10	350	0.24	0.00014	0.00012	360,000	62,000

Applicator

Applying Sprays via

Groundboom Equipment (PHED)	Bushberry

(Subgroup 13-07B)

Caneberry

(Subgroup 13-07A)	1.8	80	0.74	0.001776	0.00152	28,000	4,900

	Spinach	0.125	80	0.74	0.000123	0.000106	410,000	70,000

	Bulb Vegetables

(Crop Group 3-07)	0.5	80	0.74	0.000493	0.000423	100,000	18,000

	Edible 

Podded Beans	0.10	80	0.74	0.0000987	0.0000846	510,000	88,000

Applying Sprays via

Aerial Equipment (PHED)	Bushberry

(Subgroup 13-07B)

Caneberry

(Subgroup 13-07A)	1.8	350	0.068	0.000714	0.000612	70,000	12,000

	Spinach	0.125	350	0.068	0.0000496	0.0000425	1,000,000	170,000

	Bulb Vegetables

(Crop Group 3-07)	0.5	350	0.068	0.000198	0.00017	250,000	44,000

	Edible 

Podded Beans	0.10	350	0.068	0.0000397	0.000034	1,300,000	220,000

Flagger

Applying Sprays via

Groundboom Equipment (PHED)	Bushberry

(Subgroup 13-07B)

Caneberry

(Subgroup 13-07A)	1.8	350	0.35	0.00368	0.00315	14,000	2,300

	Spinach	0.125	350	0.35	0.000255	0.000219	200,000	34,000

	Bulb Vegetables

(Crop Group 3-07)	0.5	350	0.35	0.00102	0.000875	49,000	8,500

	Edible 

Podded Beans	0.10	350	0.35	0.000204	0.000175	240,000	42,000

a	Application Rates based on proposed uses on label for mefenoxam
products: Ridomil Gold® SL (EPA Reg. No. 100-1202), Ridomil Gold® EC
(EPA Reg. No. 100-801), and Ridomil Gold® Copper (EPA Reg. No.
100-804).

b	Exposure Science Advisory Council Policy No. 9.1.

c	Unit Exposures based on PHED Version 1.1.

d	Short-Term Inhalation Dose (mg/kg/day) = daily unit exposure (mg/lb
ai)  x application rate (lb ai/acre) x acres treated / body weight (60
kg).  Body weight = 60 kg due to the maternal toxicity in a
developmental study.

e	Intermediate-Term Inhalation Dose (mg/kg/day) = daily unit exposure
(mg/lb ai)  x application rate (lb ai/acre) x acres treated / body
weight (70 kg).  

f	Short-Term Inhalation MOE = NOAEL (50 mg/kg/day) / inhalation daily
dose (mg/kg/day).  Level of concern = 100.

g	Intermediate-Term Inhalation MOE = NOAEL (7.4 mg/kg/day) / inhalation
daily dose (mg/kg/day).  Level of concern = 100.

The minimum level of PPE for handlers is based on acute toxicity for the
end-use products.  RD is responsible for ensuring that PPE listed on the
label is in compliance with WPS.

  tc \l2 "9.1	Occupational Handler  

9.2	Occupational Postapplication

 tc \l2 "9.2	Occupational Postapplication 

Occupational postapplication exposure can occur via the dermal and/or
inhalation route.  Based on the Agency's current practices, a
quantitative occupational postapplication inhalation exposure assessment
was not performed for mefenoxam at this time.  However, there are
multiple potential sources of postapplication inhalation exposure to
individuals performing postapplication activities in previously treated
fields.  These potential sources include volatilization of pesticides
and resuspension of dusts and/or particulates that contain pesticides. 
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. 
The Agency received the SAP’s final report on March 2, 2010 ( 
HYPERLINK
"http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html" 
http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ) and is
in the process of evaluating the SAP report as well as available
postapplication inhalation exposure data generated by the Agricultural
Reentry Task Force.  The Agency may, as appropriate, develop policies
and procedures to identify the need for and, subsequently, the way to
incorporate occupational postapplication inhalation exposure into the
Agency's risk assessments.  If new policies or procedures are put into
place, the Agency may revisit the need for a quantitative occupational
postapplication inhalation exposure assessment for mefenoxam.

Dermal exposure during postapplication activities is not considered
because applicable dermal endpoints were not identified.  Therefore, a
risk assessment for postapplication activities with mefenoxam-treated
crops is not necessary.  However, because primary eye irritation testing
has placed mefenoxam in Toxicity Category I, an interim 48-hour
restricted entry interval (REI) is required under the Worker Protection
Standard.Appendix A:	Toxicity Profile   TC \l1 "Appendix A:  Toxicity
Profile 

Table A.1.  Summary for Toxicology Data Requirements for Mefenoxam and
Metalaxyl.

Test	Technical

	Required	Satisfied

870.1100    Acute Oral Toxicity	

870.1200    Acute Dermal Toxicity	

870.1300    Acute Inhalation Toxicity	

870.2400    Primary Eye Irritation	

870.2500    Primary Dermal Irritation	

870.2600    Dermal Sensitization		yes

yes

yes

yes

yes

yes	yes 

yes

yes

yes

yes

870.3100    Oral Subchronic (rodent)	

870.3150    Oral Subchronic (nonrodent)	

870.3200    21-Day Dermal	

870.3465    90-Day Inhalation		Yes

Yes

Yes

No

	Yes

Yes

Yes

No

870.3700a  Developmental Toxicity (rodent)	

870.3700b  Developmental Toxicity (nonrodent)	

870.3800    Reproduction		Yes

Yes

Yes	Yes

Yes

Yes

870.4100a  Chronic Toxicity (rodent)	

870.4100b  Chronic Toxicity (nonrodent)	

870.4200a  Oncogenicity (rat)	

870.4200b  Oncogenicity (mouse)	

870.4300    Chronic/Oncogenicity		Yes

Yes

Yes

Yes	Yes

Yes

Yes

Yes

870.5100    Mutagenicity—Gene Mutation - bacterial	

870.5300    Mutagenicity—Gene Mutation - mammalian	

870.5xxx    Mutagenicity—Structural Chromosomal Aberrations	

870.5xxx    Mutagenicity—Other Genotoxic Effects		Yes

Yes

Yes

Yes	Yes

Yes

Yes

Yes

870.6100a  Acute Delayed Neurotox. (hen)	

870.6100b  90-Day Neurotoxicity (hen)	

870.6200a  Acute Neurotox. Screening Battery (rat)	

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

870.6300    Develop. Neuro		No

No

Yes

Yes

No	N/A

N/A

No

No

NA

870.7485    General Metabolism	

870.7600    Dermal Penetration		Yes

No	Yes

Yes

870.7800    Immunotoxicity screening 	Yes	No



Table A.2.  Mefenoxam and Metalaxyl Toxicity Profile.

Guideline No.	Study Type	MRID No. (Year)/ Classification/Doses	Results

870.3100	28 Day oral toxicity—rats (gavage)	43800390 Mefenoxam or
Metalaxyl

Acceptable/Non-guideline

1, 10, 50, 150, 300 mg/kg/day 	Mefenoxam

NOAEL= 300 mg/k/day (HTD)a. 

LOAEL could not be established.

Metalaxyl

NOAEL = 50 mg/kg/day

LOAEL = 150 mg/kg/day based on minimal extramedullary hematopoeisis of
the spleen and hepatocellulary hypertrophy. 

	28-Day oral toxicity—rats

(Dietary)	42800391 Mefenoxam

Acceptable/Non-guideline

0, 500, 3000, & 6000 ppm (M: 0, 42.68, 257.1, or  534.2 mg/kg/day. F: 0,
47.47, 363.3, or  649.8 mg/kg/day)	NOAEL= 6000 ppm (M: 534.2 mg/kg/day;
F:649.8 mg/kg/day) ( HTD)

LOAEL could not be established.

870.3100	90-Day oral—rats	43823202 Mefenoxam

Acceptable

0, 25, 50, 250, 625, 0r 1250 ppm (M: 0, 1.72, 3.50, 16.8, 44.8, or 90.5
mg/kg/day.  F: 0, 1.86, 3.71, 17.9, 49.2, or 95.0 mg/kg/day)	NOAEL =
44.8 mg/kg/day; 

LOAEL = 90.5 mg/kg/day based on increased hepatocyte hypertrophy,
increased lymphocytic infiltration of liver.

00084110  Metalaxyl

0, 50, 250, or 1250 ppm (0, 3.4, 17,  or 83 mg/kg/day)	NOAEL =17
mg/kg/day

LOAEL= 83 mg/kg/day based on slightly reduced food consumption in males
and minimally increased liver cell hypertrophy

870.3150	90-Day dietary feeding—dogs

	43800392 Mefenoxam

Acceptable

0, 50, 125, 250, 1250 ppm (M:  0, 1.57, 4..07, 7.25, 38.6 mg/kg/day.

F: 0, 1.56, 4.33, 7.93, 39.46 mg/kg/day)	3 -Month

NOAEL = 7.25 mg/kg/day

LOAEL= 38.6 mg/kg/day based on slightly increased alk. phos and
increased abs and rel liver weights in both sexes.

870.3200	21-Day dermal toxicity—rabbits	00072394  Metalaxyl

Acceptable 

0, 10, 100, 1000 mg/kg/day	No dermal systemic toxicity was found.

NOAEL = 1000 mg/kg/day (HTD)

870.3700	Developmental toxicity—rats	43800393  Mefenoxam

Acceptable/Guideline

0, 10, 50, 250 mg/kg/day	Maternal 

NOAEL = 50 mg/kg/day; 

LOAEL = 250 mg/kg/day based on decreased body weight gains and food
consumption (marginal effects).

Developmental 

NOAEL = 250 mg/kg/day; 

LOAEL > 250 mg/kg/day.

	Developmental toxicity—rats	00144423  (1985) Metalaxyl

Acceptable

50, 250, 400 mg/kg/day	Maternal 

NOAEL = 50 mg/kg/day; 

LOAEL = 250 mg/kg/day based on clinical signs (ataxia, body tremors,
reduce activity and righting reflex) including post-dose convulsions.

Developmental 

NOAEL = 250 mg/kg/day; 

LOAEL = 400 mg/kg/day based on

increased incidence of skeletal variations

	Developmental toxicity—rabbits	00144371, 00144372, 00148866,
00154938;  (1984);  Metalaxyl  

Acceptable 

0, 30, 150, 300 mg/kg/day	Maternal 

NOAEL = 150 mg/kg/day; 

LOAEL = 300 mg/kg/day based on decreased

body weight gain.

Developmental

 NOAEL = 300 mg/kg/day (HTD)

870.3800	2-Generation reproduction—

rats	00071600  (1980)  Metalaxyl

Acceptable 

0, 50, 250, 1250 ppm (0, 2.5, 12.5, 62.5 mg/kg/day)	Parental/Systemic 

NOAEL = 62.5 mg/kg/day (M), 12.5 mg/kg/day (F)

LOAEL > 62.5 mg/kg/day (M), = 62.5 mg/kg/day (F) based on increased
relative liver weights

Reproductive 

NOAEL = 62.5 mg/kg/day; 

LOAEL > 62.5 mg/kg/day.

Offspring 

NOAEL = 12.5 mg/kg/day; 

LOAEL = 62.5 mg/kg/day based on histopathological changes in the livers
of female pups.

	6-Month dietary Feeding—Dog

	00071598 (1981) Metalaxyl

Acceptable 

0, 25, 250, 1000 ppm

(M: 0, 1.57, 7.80, 30.63 mg/kg/day. F: 0, 1.71, 7.41, 32.36 mg/kg/day)
NOAEL = 7.80 mg/kg/day (M), 7.41 mg/kg/day (F)

 LOAEL = 30.63 mg/kg/day (M), 32.36 mg/kg/day (F) based on increased
alkaline phosphatase, increased relative and absolute liver weights.

870.4100

870.4200	Combined chronic/ Oncogenicity study—rats (2-yr)	00098481,
00132009, 00150185

(1981) Metalaxyl  

Acceptable/guideline 

0, 50, 250, 1250 ppm

(M: 1.88, 9.43, 46.6 mg/kg/day. F: 0, 2.2, 9.95, 55.0 mg/kg/day)	NOAEL =
M: 9.43 mg/kg/day (M), 9.95 mg/kg/day (F) 

LOAEL = 46.6 mg/kg/day (M), 55.0 mg/kg/day (F) based on increased serum
alanine amino-transferase and serum aspartate amino-transferase,
increased periacinar vacuolation of hepatocytes, increased absolute and
relative liver weights. No evidence of carcinogenicity

870.4200	Oncogenicity Study—mice (80 wk)

	00103354 (1981) Metalazxyl  

Acceptable/Guideline 

0, 50, 250, 1250 ppm

(M:0, 5.00, 24.85, 128.89 mg/kg/day. F: 0, 5.68, 29.59, 148.16
mg/kg/day)	NOAEL = 24.85 mg/kg/day (M), 29.59 mg/kg/day (F)

LOAEL = 128.89 mg/kg/day (M), 148.16 mg/kg/day (F) based on increased
fatty infiltration of the liver. No evidence of carcinogenicity

870.5100	Bacterial reverse gene mutation assay

	43800394  Mefenoxam

Acceptable 

20.58, 61.73, 185.19, 555.6, 1667, 5000 µg/plate	Negative

	Bacterial reverse gene mutation assay	00084113, 00154301, 00154302

Metalaxyl  

Acceptable 

25-2025 µg/plate, 20-5000 µg/plate, 10-5000 µg/plate 	Negative

870.5300	Mouse lymphoma gene mutation assay	00103362, 00154309 Metalaxyl

Acceptable 

0.125-1.0 mg/ml w/o S9 0.0625/0.5 ml\g/ml w/S9	Negative

870.5375	In-vitro mammalian cell assay (CHO cell culture)	43800395
Mefenoxam  Acceptable

15.86 -2,030 µg/ml	Negative

	Chromosome aberration (CHOcells)	43800404 Mefenoxam or its
intermediate, CA 2331 A

Acceptable

1000 µg/ml mefenoxam spiked with 1, 10, 100, 1000, 2000 pp, CA 2331
Mefenoxam spike with CA 2331 A was positive at 10 ppm or greater CA 2331
A

870.5385	In vivo cytogeneticx in hamsters	00103361, 00154307  Metalaxyl

Acceptable 

0, 595, 1190, 2380 mg/kg 	Negative

870.7485	Metabolism Study—Rats

	41664501  Metalaxyl

Acceptabl e

Low dose 1 mg/kg; high dose 200 mg/kg	Metalaxyl was readily absorbed ,
extensively metabobolized. 70-80% of the administered dose was
eliminated within 24 hours. For  females urinary elimination was the
major route of elimination, while fecal route was for males. Hydrolysis
of the ether and ester bonds was shown to be a significant metabolic
pathway.

870.7600	Dermal Penetration—Rats	001614202 Metalaxyl 

Acceptable 

1 or 10 mg/kg	30% of the applied dose was absorbed within 8 hrs. 70-80%
of the applied dose was eliminated within 72 hours. The elimination t1/2
36 & 49 hours for males and 42 and 44 hrs for 1 & 10 mg/kg,
respectively.

	Dermal penetration study—Rats	45085901 Mefenoxam (formulation as
Ridomil Gold EC (A-9408))

Acceptable 

0.0094 or 4.7 mg/cm2	% absorbed were 24.5, 35.3, 34.8 for the low dose
and 3.0, 9.3, 16.5 for 8 hrs of exposure time. A value of 35% should be
used as a dermal absorption factor (HIARC Report. 5/17/2000). 

a	In this 28-day toxicity study, the test animals were administered
mefenoxam by gavage; 

2-hours after the first dose, the animals at 150 and 300 mg/kg dose
group showed clinical signs (hypoactivity and prostration).  However,
these signs were not repeated during the study, and the relevance of
this observation could not be determined.

b	In the developmental range-finding study, 10-1000 mg/kg metalaxyl were
used.  At >500 mg/kg level, treatment-related clinical signs such as
loss of righting reflex and hindlimb dysfunction were reported.  	 

Table A.2.  Acute Toxicity for Mefenoxam.

Guideline

No.	Study Type	MRID #(S)	Results	Toxicity Category

81-1	Acute Oral	43800383	LD50(M)=1671 (1380-2024) mg/kg

LD50(F)=490 (360-666) mg/kg

LD50(both)=1269 (737-2187) mg/kg	II

81-2	Acute Dermal	43800384	LD50(M) > 2000 mg/kg

LD50(F) > 2000 mg/kg	III

81-3	Acute Inhalation	43800385	LC50(M) > 2.29 mg/L

LC50(F) > 2.29 mg/L	IV

81-4	Primary Eye  Irritation	43800386	severe to corrosive ocular
irritant	I

81-5	Primary Skin Irritation	43800387	slight dermal irritant	IV

81-6	Dermal Sensitization	43800388

43800389	maximization test - not a sensitizer

Buehler test - not a sensitizer	NA

Appendix B:	International Residue Limit Status Sheet   TC \l1 "Appendix
B:  International Residue Limit Status Sheet  

INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name: methyl
N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-D-alaninate	Common Name:

mefenoxam

(metalaxyl-M)	( Proposed tolerance

( Reevaluated tolerance

X Other - Recommended	Date: 07/28/2010

Codex Status (Maximum Residue Limits)	U. S. Tolerances

(No Codex proposal step 6 or above

(No Codex proposal step 6 or above for the crops requested	Petition
Number: PP#9E7591 

DP Barcode: D371307

Other Identifier: 

Residue definition (step 8/CXL): metalaxyl (plant); sum of metalaxyl and
metabolites containing the 2,6-dimethylaniline moiety, expressed as
metalaxyl (livestock).

Metalaxyl-M MRLs are at Step 6, pending resolution of the status of
metalaxyl CXLs. 	Reviewer/Branch: RAB4 – Nancy Dodd

	Residue definition: methyl
N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-DL-alaninate

Crop (s)	MRL (mg/kg) (Step 6)	Crop(s) 	Tolerance (ppm)

Caneberry subgroup 13-07A	0.70

Bean, snap, succulent	0.20

Spinach	0.1 (existing CXL 2 for metalaxyl)	Spinach	Remains at 10

Bushberry subgroup 13-07B	2.0

Lingonberry	Remove

Onion, bulb	0.03 (existing CXL 2 for metalaxyl)	Onion, bulb, subgroup
3-07A	3.0

Onion, green, subgroup 3-07B	10

Limits for Canada	Limits for Mexico1

X No Limits (metalaxyl MRLs apply)

( No Limits for the crops requested	X No Limits

(No Limits for the crops requested

Residue definition: Residues of the resolved isomer metalaxyl-M are
covered by MRLs established for metalaxyl, the unresolved isomeric
mixture.

N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-DL-alanine methyl ester,
including metabolites that can be converted to the 2,6-dimethylaniline
moiety, each expressed as metalaxyl equivalents

The following are metalaxyl MRLs:	Residue definition: N/A

A 2004 listing gives numerous crops for both metalaxyl and metalaxyl-M,
but without tolerance values.

Crop(s)	MRL (mg/kg)	Crop(s)	MRL (mg/kg)

Raspberry	0.2

Bean	0.2

Spinach	10

Blueberry	2

Onion, bulb	3.0

Onion, green	10

Notes/Special Instructions: S. Funk, 03/01/2010.  

1 Mexico adopts Codex MRLs or US tolerances for its export purposes.

Appendix C:	Chemical Structures   TC \l1 "Appendix C:  Chemical
Structures  

Table C.  Chemical Nomenclature and Structure of Metalaxyl/Mefenoxam and
Its Metabolites.

Parent and 2,6-DMA (2,6-dimethylaniline) Metabolites

 

Metalaxyl/Mefenoxam

CGA-48988/CGA-329351

 	CGA-62826

 	CGA-37734

 

CGA-67866

 	CGA-67867

 	CGA-67869

 

CGA-67868

 	CGA-107955

 	CGA-79353

CGA-78532

 	CGA-68124

 	CGA-68125

 

N-decanoic acid ester of

CGA-67869

 

HMMA (2-hydroxymethyl-6-methylaniline) Metabolites

 

CGA-94689

 	Fatty acid conjugates of P1/P2

 	P0

 

P1/P2

 	P4

 	N1a aglycone; benzyl alcohol of CGA-67868

 

HMMA (2-hydroxymethyl-6-methylaniline) Metabolites

 

CGA-94689

 	Fatty acid conjugates of P1/P2

 	P0

 

P1/P2

 	P4

 	N1a aglycone; benzyl alcohol of CGA-67868

 

Benzoic Acid Metabolites

 

CGA-108905

 	CGA-108906

 

	Ring OH Metabolites

 

CGA-100255

 	CGA-119857

 	N1b aglycone; phenyl ring hydroxy of CGA-67868

 

Appendix D:	Rationale for Immunotoxicity Data Requirement   TC \l2
"Appendix D: Rationale for Toxicity Data Requirement 

Guideline Number: 870.7800

Study Title:  Immunotoxicity

Rationale for Requiring the Data

This is a new data requirement under 40 CFR Part 158 as a part of the
data requirements for registration of a pesticide (food and non-food
uses). 

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional
immunotoxicity testing and is designed to evaluate the potential of a
repeated chemical exposure to produce adverse effects (i.e. suppression)
on the immune system. Immunosuppression is a deficit in the ability of
the immune system to respond to a challenge of bacterial or viral
infections such as tuberculosis (TB), Severe Acquired Respiratory
Syndrome (SARS), or neoplasia.  Because the immune system is highly
complex, studies assessing functional immunotoxic endpoints are helpful
in fully characterizing a pesticide’s potential immunotoxicity.  These
data will be used in combination with data from hematology, lymphoid
organ weights, and histopathology in routine chronic or subchronic
toxicity studies to characterize potential immunotoxic effects.  

Practical Utility of the Data

How will the data be used?

These animal studies can be used to select endpoints and doses for use
in risk assessment of all exposure scenarios and are considered a
primary data source for reliable reference dose calculation. For
example, animal studies have demonstrated that immunotoxicity in rodents
is one of the more sensitive manifestations of TCDD
(2,3,7,8-tetrachlorodibenzo-p-dioxin) among developmental, reproductive,
and endocrinologic toxicities.  Additionally, the EPA has established an
oral reference dose (RfD) for tributyltin oxide (TBTO) based on observed
immunotoxicity in animal studies (IRIS, 1997).

How could the data impact the Agency's future decision-making? 

If the immunotoxicity study shows that the test material poses either a
greater or a diminished risk than that given in the interim decision’s
conclusion, the risk assessments for the test material may need to be
revised to reflect the magnitude of potential risk derived from the new
data.

 

If the Agency does not have this data, a 10X database uncertainty factor
may be applied for conducting a risk assessment from the available
studies.

Appendix E:	Rationale for Acute and Subchronic Toxicity Data
Requirement  TC \l2 "Appendix E: Rationale for Toxicity Data Requirement

Guideline Number: 870.6200

Study Title:  Neurotoxicity Battery (Acute and Subchronic Study)

Rationale for Requiring the Data

This is a new data requirement under 40 CFR Part 158 as a part of the
data requirements for registration of a pesticide (food and non-food
uses). 

The Neurotoxicity Screening Battery (OPPTS 870.6200) is designed to
evaluate the potential adverse effects on the nervous system from
exposure to pesticide chemicals.  The Agency believes that the guideline
studies are inadequate in their assessment of behavioral effects and do
not use optimal methods to evaluate the potential toxicity to the
nervous tissue structure and function. To detect and characterize these
potential effects more fully, a battery of more sensitive testing is
required. The objective of this neurotoxicity battery testing is to
evaluate the incidence and severity of the functional and/or behavioral
effects, the level of motor activity, and the histopathology of the
nervous system. The acute neurotoxicity study is required to detect
possible effects resulting from a single exposure. The subchronic
neurotoxicity study is intended to detect possible effects resulting
from repeated or long-term exposures.

 

Practical Utility of the Data

How will the data be used?

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to the human population on the nervous system from pesticide exposure. 
These studies can provide data on a wide range of functional tests for
evaluating neurotoxicity including sensory effects, neuromuscular
effects, learning and memory and histopathology of the nervous system. 
For example, animal studies with organophosphorous chemicals have shown
neurotoxicity to be the primary toxic endpoints (e.g. cholinesterase
inhibition) of concern in rodents and non-rodents.    These animal
studies can be used to select endpoints and doses for use in risk
assessment of all exposure scenarios and are considered a primary data
source for reliable reference dose calculation. The Agency has
established an oral reference dose (RfD) for assessing dietary risks for
a number of chemicals (e.g. organophosphates and carbamates) where
neurotoxicity was the most sensitive endpoint of concern.

How could the data impact the Agency's future decision-making? 

If the acute or subchronic neurotoxicity studies show that mefenoxam
poses either a greater or a diminished risk than that given in the
interim decision’s conclusion, the risk assessment for mefenoxam may
need to be revised to reflect the magnitude of potential risk derived
from the new data.

 

If the Agency does not have this data, a 10X database uncertainty factor
may be applied when conducting a risk assessment using the currently
available studies.

 PAGE   

Page   PAGE  58  of   NUMPAGES  59