Document ID: EPA-HQ-OPP-2015-0014-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-04-06T04:00Z

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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

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

Syngenta Crop Protection, LLC

Petition #4F8323

	EPA has received a pesticide petition (4F8323) from Syngenta Crop
Protection, LLC, 410 Swing Road, Greensboro, NC 27409 requesting,
pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act
(FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180

	1. by establishing a tolerance for residues of

	Mefenoxam: methyl N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-DL-alaninate
in or on the raw agricultural commodity Rapeseed Crop Subgroup 20A at
0.05 parts per million (ppm). EPA has determined that the petition
contains data or information regarding the elements set forth in section
408 (d)(2) of  FDDCA; however, EPA has not fully evaluated the
sufficiency of the submitted data at this time or whether the data
supports granting of the petition. Additional data may be needed before
EPA rules on the petition.

A. Residue Chemistry

	1. Plant metabolism. [The metabolism of mefenoxam is adequately
understood for the purpose of the proposed tolerance.]

	2. Analytical method. [Canola: The analytical method used was Novartis
Crop Protection Method 456-98, “Confirmatory Analytical Method for the
Enantioselective Determination of Residues of Parent Metalaxyl
(CGA-48988) or Mefenoxam (CGA-329351) in Crop Substrates by Chiral High
Performance Liquid Chromatography with Mass Spectrometric Detection”,
March 1999, MRID 44976201.

	3. Magnitude of residues. [Complete residue data to support the
requested tolerances have been submitted. The requested tolerances are
adequately supported by previously submitted studies. In support of the
requested tolerances, Syngenta has conducted the necessary trials in
accordance with the requirements of the EPA Residue Chemistry Guidelines
860.1500 to determine the magnitude of residue of mefenoxam in or on
requested commodities.]

B. Toxicological Profile

1. Acute toxicity. [The toxicological endpoints for mefenoxam are
discussed in B.4. of the Federal Register Notice of July 25, 1997, (62
FR 40084) (FRL-5726-4). The acute toxicity profile can be summarized as
follows:

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

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

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

Primary eye irritation study in rabbit shows mefenoxam as severely
irritating. Primary dermal irritation study in rabbit shows mefenoxam as
slightly irritating. Skin sensitization studies in guinea pigs
(maximization and Buehler Test) show mefenoxam is not a sensitizer.]

2. Genotoxicty. [The toxicological endpoints for mefenoxam are discussed
in B.4. of the Federal Register Notice of July 25, 1997, (62 FR 40084).
The genotoxicity profile can be summarized as follows:

In vitro gene mutation test: Ames test-negative.

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

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

gene mutation in mouse lymphoma cells-negative; reverse mutation in
saccharomyces cerevisiae-negative.

In vitro chromosomal aberration tests: Chinese hamster bone marrow
cytogenetic test-negative. DNA repair study in rat
hepatocytes-negative.]

3. Reproductive and developmental toxicity. [The toxicological endpoints
for mefenoxam are discussed in B.4. of the Federal Register Notice of
July 25, 1997, (62

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

Teratology study in rats with a maternal no observed adverse effect
level (NOAEL) of 10 mg/kg based on reduced body weight (bwt) gain.  The
fetuses remained entirely unaffected at the highest dose tested (HDT),
250 mg/kg.

Teratology study in rabbits with a maternal NOAEL of 150 mg/kg based on
bwt loss. The developmental NOAEL was greater than or equal to the HDT,
300 mg/kg.

Three-generation reproduction study in rats with a NOAEL of 1,250 ppm,
which was the HDT.  The treatment had no effect on reproduction or
fertility.

Dominant lethal study in mouse-negative. ]

4. Subchronic toxicity. [The toxicological endpoints for mefenoxam are
discussed in B.4. of the Federal Register Notice of July 25, 1997, (62
FR 40084). The subchronic toxicity profile can be summarized as follows:

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

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

based on liver changes.

A 90-day subchronic dietary toxicity study in dogs with a NOAEL of 250
ppm based on changes in blood biochemistry and hematology indicative of
functional liver changes.

A 21-day dermal toxicity study in rats with a NOAEL equal to or higher
than the limit dose of 1,000 mg/kg. No local or systemic signs of
toxicity were found.

A 6-month dietary toxicity study in dogs with a NOAEL of 250 ppm based
on changes in blood biochemistry indicative of hepatocellular damage.]

5. Chronic toxicity. [The toxicological endpoints for mefenoxam are
discussed in B.4. of the Federal Register Notice of July 25, 1997, (62
FR 40084). The chronic toxicity profile can be summarized as follows:

A 24-month combined chronic toxicity/carcinogenicity study conducted in
rats with a NOAEL of 250 ppm based on liver changes. No evidence of
oncogenicity was seen.

A 24-month oncogenicity study conducted in mice with a NOAEL of 250 ppm
based on liver changes. No evidence of oncogenicity was seen.]

6. Animal metabolism. [The rat and goat rapidly metabolize and excrete
via the same metabolic pathways as plants. Urinary metabolites are
polar, primarily gucuronide and other conjugates. The parent compound is
not retained in animal tissues nor secreted in milk.]

7. Metabolite toxicology. [Metabolites are considered to be of equal or
less toxicity than the parent material]

8. Endocrine disruption. [Mefenoxam does not belong to a class of
chemicals known or suspected of having adverse effects on the endocrine
system. Furthermore, supporting developmental toxicity studies in rats
and rabbits, and a reproduction study in rats gave no indication of any
effects on endocrine function related to development and reproduction.
Subchronic and chronic treatment did not induce any morphological
changes in endocrine organs and tissues.]

C. Aggregate Exposure

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

evaluations were made for mefenoxam using the using the Dietary Exposure
Evaluation Model (DEEM-FCID™ Version 3.16) from Exponent, which
utilizes consumption data from the USDA NHANES “What We Eat in
America” survey, 2003-2008. Established tolerances for mefenoxam
and/or metalaxyl were used for all existing uses, as well as proposed
tolerances for the Oilseed Crop Group 20. Percent of crop treated values
were conservatively estimated based upon economic, pest, and competitive
pressures. Drinking water estimates were selected using the higher of
the estimated drinking water concentrations (EDWCs) for surface and
ground water.]

i. Food. [Acute Exposure. Acute dietary exposure assessments were not
performed since the EPA was has not established an acute endpoint of
concern for mefenoxam.

Chronic Exposure. The mefenoxam chronic dietary (food only) risk
assessment was performed for all population subgroups with a chronic
reference dose (cRfD) of 0.074 mg/kg-bw/day based on a six-month feeding
study in dogs with a no observed adverse effect level (NOAEL) of 7.4
mg/kg-bw/day and an uncertainty factor of 100X. The 100X safety factor
includes intra- and inter-species variations. No additional FQPA safety
factor was applied. For the purpose of aggregate risk assessment, the
exposure values were expressed in terms of margin of exposure (MOE),
which was calculated by dividing the NOAEL by the exposure for each
population subgroup. In addition, exposure was expressed as a percent of
the reference dose (%RfD). Chronic (food only) exposure to the U.S.
population resulted in a MOE of 654 (15.3% of the cRfD of 0.074
mg/kg-bw/day). The most exposed sub-population was children (1-2 years
old) with a MOE of 267 (37.5% of the cRfD). Since the benchmark MOE for
these assessments was 100 and since EPA generally has no concern for
exposures above the benchmark or below 100% of the reference dose,
Syngenta believes that there is a reasonable certainty that no harm will
result from dietary (food only) exposure to residues arising from the
current and proposed tolerances and label amendments for mefenoxam.

Cancer. Based on the classification of metalaxyl, mefenoxam is also
considered “not likely to be a human carcinogen”. Therefore, no
cancer risk assessment was performed for mefenoxam.]

ii. Drinking water. [The Estimated Drinking Water Concentrations (EDWCs)
of mefenoxam were determined using Tier l SCI-GROW (version 2.3), which
estimates pesticide concentrations in ground water and Tier II
PRZM/EXAMS (PE version 5.0) which estimates pesticide concentrations in
surface water. The application and use parameters for the proposed use
on oilseeds, crop group 20 were modeled along with the currently
registered uses to identify the highest EDWCs. The currently registered
use on citrus based on a treatment rate of 3.0 lbs ai/A, with 2
applications at an interval of 60 days was determined to be the crop
driver. For ground water, the SCI-GROW model provided a chronic EDWC of
1.72 ppb for mefenoxam. For surface water, employing the FL citrus
standard PRZM scenario, the PRZM/EXAMS output provided a chronic EDWC of
22.9 ppb for mefenoxam. This surface water EDWC has not been adjusted
for Percent Cropped Area. Since the surface water EDWC exceeds the
ground water EDWC, the surface water chronic exposure value will be used
for risk assessment purposes and considered protective for any ground
water concentration concerns.

Drinking water estimates were incorporated directly into the dietary
exposure assessment along with the food exposure using the higher of the
estimated drinking water concentrations (EDWCs) for surface water (22.9
ppb). Chronic drinking water exposure to the U.S. population resulted in
a MOE of 15,433 (0.6% of the cRfD of 0.074 mg/kg-bw/day). The most
exposed sub-population was infants <1 year old with a MOE of 5,985 (1.7%
of the cRfD). Since the benchmark MOE for these assessments was 100 and
since EPA generally has no concern for exposures above the benchmark or
below 100% of the reference dose, Syngenta believes that there is a
reasonable certainty that no harm will result from drinking water
exposure to residues arising from all current and proposed uses for
mefenoxam.]

2. Non-dietary exposure. [The use of mefenoxam on residential turf may
result in short- or intermediate-term exposures to selected subgroups. A
short-term inhalation toxicological endpoint of 50 mg/kg-bw/day was
selected based upon the no observed adverse effect level (NOAEL) from a
dev tox study in rats, with an uncertainty factor of 100X, which
includes intra- and inter-species variations; no additional FQPA safety
factor was applied. An intermediate-term inhalation toxicological
endpoint of 7.41 mg/kg-bw/day was selected based upon the no observed
adverse effect level (NOAEL) from a 6-month feeding study in the dog,
with an uncertainty factor of 100X, which includes intra- and
inter-species variations; no additional FQPA safety factor was applied.
Exposure values were expressed in terms of margin of exposure (MOE),
which was calculated by dividing the NOAEL by the exposure for each
subgroup. Residential exposure risk assessments were performed for use
of mefenoxam formulated as Subdue GR, Subdue WSP, and Subdue MAXX for
residential turf). Assessments were also performed for exposure due to
off-site drift of agricultural products. Application of mefenoxam by
residents is allowed; therefore residential handler exposure assessments
are required. Adults 13+ years old had a short-term residential MOE of
501,974 (hose-end sprayer; liquid concentrate); children 1-6 years old
had MOEs of 4,786 (hand-to-mouth; liquid concentrate). Since the
Benchmark MOE for this assessment was 100 and since the EPA generally
has no concern for exposures above the Benchmark MOE, Syngenta believes
that there is a reasonable certainty that no harm will result from
short- and intermediate-term residential exposure to residues arising
from all current and proposed uses of mefenoxam.]

D. Cumulative Effects

[Cumulative Exposure to Substances with a Common Mechanism of Toxicity.
Section 408(b)(2)(D)(v) requires that, when considering whether to
establish, modify, or revoke a tolerance, the Agency consider
“available information” concerning the cumulative effects of a
particular pesticide’s residues and “other substances that have a
common mechanism of toxicity”. The EPA does not have, at this time,
available data to determine whether mefenoxam has a common mechanism of
toxicity with other substances or how to include this pesticide in a
cumulative risk assessment. For the purposes of this tolerance action,
the EPA has not assumed that mefenoxam has a common mechanism of
toxicity with other substances.]

E. Safety Determination

1. U.S. population. [Using the conservative assumptions described above,
and based on the completeness and reliability of the toxicity data, the
short- and intermediate-term aggregate exposure calculations for all
current and proposed uses of mefenoxam provided MOEs of 4,238 and 628,
respectively, for the U.S. population. The chronic aggregate exposure
calculation for all current and proposed uses of mefenoxam provided a
MOE of 627 (15.9% of the cRfD 0f 0.074 mg/kg-bw/day) for the U.S.
population. Since the aggregate MOEs exceed the Benchmark MOE of 100,
Syngenta believes that there is a reasonable certainty that no harm will
result from aggregate exposure to residues arising from all current and
proposed uses of mefenoxam, including anticipated dietary exposure from
food, water, and all other types of non-occupational residential
exposures.]

2. Infants and children. [Using the conservative assumptions described
above, and based on the completeness and reliability of the toxicity
data, the short- and intermediate-term aggregate exposure calculations
for all current and proposed uses of mefenoxam provided MOEs of 1,286
and 261, respectively, for children 1-2 years old. The chronic aggregate
exposure calculation for all current and proposed uses of mefenoxam
provided a MOE of 260 (38.4% of the cRfD 0f 0.074 mg/kg-bw/day) for
children 1-2 years old. Since the aggregate MOEs exceed the Benchmark
MOE of 100, Syngenta believes that there is a reasonable certainty that
no harm will result from aggregate exposure to residues arising from all
current and proposed uses of mefenoxam, including anticipated dietary
exposure from food, water, and all other types of non-occupational
residential exposures.]

F. International Tolerances

[There are no Codex MRLs established for residues of mefenoxam in any
plant or animal commodity. Codex MRLs have been established for
metalaxyl, the racemic fungicide mixture containing the active isomer
mefenoxam, in a number of commodities including asparagus, avocado,
broccoli, Brussels sprouts, cabbage, cacao, carrot, cauliflower, cereal
grains, citrus, cotton seed, cucumbers, grapes, hops, lettuce, melons,
onions, peanuts, peas (succulent), peppers, pome fruits, potatoes,
raspberries, soybeans, spices, spinach, squash, sugar beet, sunflower
seed, and tomatoes.]

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