Document ID: EPA-HQ-OPP-2010-0267-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-06-23T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE

PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: Kathryn Montague 703-305-1243

Bayer CropScience LLC

PP# 9F7679

EPA has received a pesticide petition (9F7679) from Bayer CropScience
LLC, 2 T. W. Alexander Drive, Research Triangle Park, NC 27709
proposing, 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. by
establishing a tolerance for residues of the herbicide safener,
mefenpyr-diethyl including its metabolites and degradates. Compliance
with the tolerance levels specified is to be determined by measuring
residues of mefenpyr-diethyl
((RS)-1-(2,4-dichlorophenyl)-5-methyl-2-pyrazoline-3,5-dicarboxylic
acid) and its dichlorophenylpyrazoline metabolites] in or on the raw
agricultural commodity [sorghum, grain] at [0.01] parts per million
(ppm); [sorghum, forage] at [0.1] ppm; [sorghum, stover] at [0.05] ppm;
[grass, hay] at [0.05] ppm; and [grass, forage] at [1.5] 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 nature of mefenpyr-diethyl residues in plants
and livestock is

adequately understood. The residues of concern are combined residues of
mefenpyr-diethyl, also

known as
1-(2,4-dichlorophenyl)-4,5-dihydro-5-methyl-1H-pyrazole-3,5-dicarboxylic
acid,

diethyl ester and its 2,4-dichlorophenyl-pyrazoline metabolites.

2. Analytical method. An enforcement method for plants has been
developed and

radiovalidation and independent laboratory validation (ILV) conducted.
The EPA has concluded

that this method is suitable for food tolerance enforcement of
mefenpyr-diethyl and its 2,4-

dichlorophenyl-pyrazoline metabolites.

M-36Ü357-Ü1-1

3. Magnitude of residues. The appropriate number of residue trials was
conducted in

sorghum and grasses in the appropriate locations in the United States to
support the requested

tolerances on the sorghum and grass commodities. Specifically, twelve
field trials were

conducted to measure the magnitude of total mefenpyr-diethyl residues
in/on sorghum forage,

grain, and stover or grass hay and forage following two foliar spray
applications of HUSKIE

herbicide to sorghum or grass. Residues of mefenpyr-diethyl and
2,4-dichlorophenyl-pyrazoline

metabolites were quantified in the harvested matrices (sorghum grain,
forage and fodder as well

as grass hay and grass forage) following a postemergence application of
Huskie Herbicide.

The highest average field trial (HAFT) total mefenpyr-diethyl residue in
sorghum forage

harvested at a 0-day PHI was 1.1 ppm (maximum residue 1.2 ppm); There
were no total

mefenpyr-diethyl residues greater than the LOQ (0.10 ppm) in sorghum
forage harvested at

either a target 7-day PHI or at ECH. There were no total
mefenpyr-diethyl residues greater than

the LOQ (0.01 ppm) in sorghum grain. The HAFT total mefenpyr-diethyl
residue in sorghum

stover was 0.06 ppm (maximum residue 0.06 ppm). The total
mefenpyr-diethyl residue

decreased with time in sorghum early forage but could not be assessed in
ECH forage, grain, or

stover due to residues being below the LOQ.

The HAFT total mefenpyr-diethyl residue in grass forage harvested at a
0-day PHI was 1.4 ppm

(maximum residue 1.4 ppm). The HAFT total mefenpyr-diethyl residue in
grass forage harvested

at a 7-day PHI was 1.2 ppm (maximum residue 1.2 ppm). No residues
greater than the LOQ of

0.05 ppm were observed in any of the hay samples harvested at a target
30-day PHI.

B. Toxicological Profile

The Agency published complete reviews of the safety of mefenpyr-diethyl
in the ‘Final Rule’

published in the Federal Register April 30, 2003 (Volume 68, Number 83,
Pages 23038-23046),

and in the Federal Register December 10, 2008 (Volume 73, No. 238, pages
74972- 74979).

EPA has evaluated the available toxicity data and considered its
validity, completeness, and

reliability as well as the relationship of the results of the studies to
human risk. EPA has also

considered available information concerning the variability of the
sensitivities of major

identifiable subgroups of consumers, including infants and children.

1. Acute toxicity. Mefenpyr-diethyl has low acute toxicity by the oral,
dermal, and

inhalation routes of exposure. It is not a dermal irritant but is a
slight dermal sensitizer and ocular

irritant.

2. Genotoxicty. Mefenpyr-diethyl did not show any genotoxic potential.

3. Reproductive and developmental toxicity. Developmental toxicity was
not observed in

the rat at the limit dose (1,000 milligrams/kilogram/day (mg/kg/day))
but was observed in the

rabbit (abortions) at the same dose level producing maternal toxicity.
Mefenpyr-diethyl did not

induce any signs of reproductive toxicity or neurotoxic potential. The
developmental toxicity

studies in rats and rabbits, as well as the reproductive toxicity study
in rats, did not demonstrate

any prenatal or postnatal sensitivity. There was no evidence of
reproductive toxicity following

exposure via the diet at concentrations of 0, 200, 1000, and 5000 ppm
for two generations. There

is a lack of evidence of neurotoxicity in any study on mefenpyr-diethyl
and therefore there is no

concern for neurotoxicity resulting from exposure to mefenpyr-diethyl.

4. Chronic toxicity. Repeat exposure via the dermal route did not induce
any treatmentrelated

effects at dose levels up to and including the limit dose. Repeated
exposure studies via

the oral route demonstrated that the target organs are the liver and
hematopoietic system in dogs,

mice, and rats. Mefenpyr-diethyl was negative for carcinogenicity in
rats and mice, and classified

as ``not likely to be carcinogenic to humans.''

5. Animal metabolism. Metabolism studies indicate that mefenpyr-diethyl
is rapidly

metabolized, widely distributed, and primarily excreted via the urine
and feces during the first 24

hours.

7. Metabolite toxicology. The metabolic profile for mefenpyr-diethyl
appears to be

substantially similar in plants, animals and the environment. The
primary identified metabolites

in rats, ruminants, poultry, plants and the environment are the three 2,
4-dichlorophenylpyrazolone

metabolites which are included in the risk assessment and for tolerance
setting

purposes.

C. Aggregate Exposure

1. Dietary exposure. Assessments were conducted to evaluate potential
risks due to

chronic and acute dietary exposure of the U.S. population and selected
population subgroups to

residues of mefenpyr-diethyl and its two 2,4-dichlorophenyl-pyrazoline
metabolites. These

assessments included current and proposed uses of mefenpyr-diethyl.

, Version 2.14), which is

licensed to Bayer, was used to estimate the chronic and acute dietary
exposure. This software

uses the food consumption data from the 1994-1998 USDA Continuing
Surveys of Food Intake

by Individuals (CSFII 1994-1998).

No appropriate endpoint attributable to a single exposure (dose) was
identified from oral

toxicity studies in the database. Therefore, an acute dietary endpoint
was not selected and

an acute dietary risk assessment was not conducted.

The cRfD was established based on increased liver weights in the chronic
dog study. The

LOAEL for this study was 260 mg/kg/day (M/F) with a NOAEL = 51.0
mg/kg/day. This

study is supported by the chronic rat study, which shows a similar NOAEL
(48

mg/kg/day). Application of the normal 100X uncertainty factor results in
a cRfD/cPAD

of 0.51 mg/kg/day. Results from the chronic dietary exposure analysis
described below demonstrate a reasonable certainty of no harm to the
overall U.S. population or any population

subgroup from the proposed use of mefenpyr-diethyl on sorghum and grass
grown for

seed.

i. Food.  The tier 1 chronic risk assessment was conducted using the
results of

field trials conducted at maximum label application rates and the
shortest pre-harvest

intervals on the proposed label. No adjustments were made to account for
dissipation of

residues during storage, transportation from the field to the consumer,
washing or

peeling. Therefore, the actual dietary exposure will be less than that
presented here.

The chronic dietary exposure estimated the percent of the chronic
reference dose (cRfD)

for the overall US population and various subpopulations. In this
analysis, total exposure

was less then 1% of the chronic RfD for the US Population and all
population subgroups.

Therefore, the chronic exposure estimates are below EPA's level of
concern for the

overall U.S. population as well as all subpopulations.

ii. Drinking water. EPA’s Tier 1 EDWCs for surface and ground water
were generated

using FIRST and SCIGROW, respectively. Based on the results of these
simulations,

μg/L for use in the human-health risk

assessment. Potential water residues are included in the dietary
exposure calculated

above.

D. Cumulative Effects

EPA has not made a common mechanism of toxicity finding for
mefenpyrdiethyl

and any other substances and mefenpyr-diethyl does not appear to produce
a toxic

metabolite produced by other substances. Therefore, EPA has not assumed
that

mefenpyr-diethyl has a common mechanism of toxicity with other
substances. 

E. Safety Determination

1. U.S. population. Using the conservative exposure assumptions
described

above and based on the completeness of the toxicity data, it can be
concluded that

aggregate exposure to residues of mefenpyr-diethyl presents a reasonable
certainty of no

harm. No appropriate endpoint attributable to a single exposure (dose)
was identified

from oral toxicity studies in the database. Therefore, an acute dietary
endpoint was not

selected and an acute dietary risk assessment was not conducted.

The chronic assessment indicated that exposure from residues in crops
utilized

<1% of the chronic RfD for the U. S. Population when food and water are
included. EPA

generally has no concerns for exposures below 100% of the cRfD. An
aggregate

assessment for the proposed uses for mefenpyr-diethyl demonstrates that
there is a

reasonable certainty that no harm will result to the US Population from
these uses of

mefenpyr-diethyl.

2. Infants and children. FFDCA section 408 provides that EPA shall apply
an

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摧槓<	㜀$␸䠀$摧槓<ᰀtoxicological database for mefenpyr-diethyl
is complete for FQPA purposes and there are

no residual uncertainties for pre-/post-natal toxicity for
mefenpyr-diethyl. Based on the

available toxicity data the Special FQPA Safety Factor can be reduced to
1x.

Based on the exposure assessments described above and on the
completeness and

reliability of the toxicity data, it can be concluded that the dietary
exposure from the

proposed uses for mefenpyr-diethyl consumes <1% of the cRfD for all
subpopulations.

Thus, it can be concluded that there is a reasonable certainty that no
harm will result from

aggregate exposure to mefenpyr-diethyl residues.

F. International Tolerances

No Codex, Canadian, or Mexican maximum residue limits (MRLs) are

established for residues of mefenpyr-diethyl and metabolites in crop or
livestock

commodities.