Document ID: EPA-HQ-OPP-2007-0672-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-08-22T04:00Z

COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE  (1/1/2006)

EPA Registration Division contact: [insert name and telephone number
with area code]

INSTRUCTIONS:  Please utilize this outline in preparing tolerance
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TEMPLATE:

Bayer CropScience

[Insert petition number]

	EPA has received a pesticide petition ([7E7224]) from Bayer
CropScience, 2 T.W. Alexander Drive, P.O. Box 12014, 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.

(Options (pick one)

	1. by establishing a tolerance for residues of

	2. to establish an exemption from the requirement of a tolerance for

	mefenpyr-diethyl,
1-(2,4-dichlorophenyl)-4,5-dihydro-5-methyl-1H-pyrazole-3,5-dicarboxylic
acid, diethyl ester and its 2,4-dichlorophenyl-pyrazoline metabolites in
or on the raw agricultural commodity soybean, seed at 0.02 parts per
million (ppm), soybean, forage at 0.1 parts per million (ppm), soybean,
hay at 0.1 parts per million (ppm),and canola, seed at 0.02 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
the 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 mefenpyr-diethyl in plants
(barley) is well understood. Identified metabolic pathways are
substantially similar in plants and animals (goat, rat and hen). EPA has
determined that mefenpyr-diethyl parent and its three
2,4-dichlorophenyl-pyrazoline metabolites are the residue of concern for
tolerance setting purposes. 

	2. Analytical method.  A practical analytical method utilizing gas
chromatography and a mass selective detector (GC/MSD) is available for
detecting and measuring levels of mefenpyr-diethyl and its
2,4-dichlorophenylpyrazoline containing metabolites in plant material.
The limit of quantitation (LOQ) was validated at 0.01 mg/kg (ppm) in
wheat and barley grain, 0.05 mg/kg (ppm) in wheat and barley straw and
wheat hay, and 0.1 ppm in wheat forage. 

An analytical method for the determination of mefenpyr-diethyl and its
metabolites in beef liver is also available using GC/MSD. The limit of
quantification (LOQ) for both mefenpyr-diethyl and its metabolites is
0.05 ppm 

	3. Magnitude of residues. Six field rotational crop trials were
conducted to measure the magnitude of total mefenpyr-diethyl residues in
soybeans and corn grown as a rotational crop following the use of AE
F107892 00EC23 A1 as an emulsifiable concentrate (EC) containing 23 g
ai/L mefenpyr-diethyl. A single broadcast spray application was made to
a target crop of wheat or bare soil at rates ranging from 0.080 to 0.082
lb ai/A (0.089 to 0.092 kg ai/ha). After harvesting or destroying the
wheat crop, corn was planted at a nominal 90-day (80-83 days) or 270-day
(266-273) plant-back interval (PBI) and the soybeans were planted at a
nominal 90-day PBI (80-124 days) following the application to wheat or
bare soil. Single control samples and duplicate treated samples of the
raw agricultural commodities (RACs) of corn forage, corn grain, corn
stover, soybean forage, soybean hay, and soybean seed were collected at
normal commercial harvest. The only exception to this was for the corn
trial conducted in Kansas, where, due to animal damage; only one grain
sample was harvested from the control and one grain sample from each of
the treated plots.

The residues of mefenpyr-diethyl and its 2,4-dichlorophenylpyrazoline
containing metabolites were quantitated by gas chromatography- mass
spectrometry GC/MS. The individual analyte residues were converted to
mefenpyr-diethyl molar equivalents. The limit of quantitation (LOQ) for
each analyte was 0.10 ppm for soybean and corn forage, stover and hay
and 0.010 ppm for corn grain and soybean seed.

The total mefenpyr residue was less than the LOQ for corn forage, corn
grain, corn stover, soybean forage, and soybean hay. The total mefenpyr
residue was less than the LOQ for two of three trials for soybean seed
and ranged from 0.02 to 0.03 ppm in the seed in the other trial. 

B. Toxicological Profile

	1. Acute toxicity.  The acute oral LD50 of mefenpyr-diethyl is greater
than 5,000 mg/kg in both rats and mice. The acute rat dermal LD50 is
greater than 4,000 mg/kg, and the acute rat inhalation LC50 (4-hour) is
greater than 1.32 mg/L. Mefenpyr-diethyl is slightly irritating to the
eyes of rabbits. It is not irritating to rabbit skin in a standard
dermal irritation study but was a weak dermal sensitizer in a guinea pig
maximization study. Evidence of photo-irritation, but no
photosensitization, was observed in other studies with guinea pigs.
Mefenpyr-diethyl was classified as TOXICITY CATEGORY IV for acute oral
toxicity and skin irritation, and TOXICITY CATEGORY III for acute
dermal, inhalation toxicity, and eye irritation. 

	2. Genotoxicity. No evidence of genotoxicity was observed in a battery
of studies including Salmonella and E. coli bacterial gene mutation
assays, an HGPRT gene mutation assay in Chinese hamster cells, a mouse
micronucleus assay, an in vitro chromosome aberration assay, and an in
vitro unscheduled DNA synthesis assay. 

	3. Reproductive and developmental toxicity. Two rat developmental
toxicity studies have been conducted with mefenpyr-diethyl. In the first
study, Wistar rats were administered mefenpyr-diethyl by gavage at dose
levels of 0 and 1,000 mg/kg body weight/day on gestation days 7 to 16.
The fetuses were delivered by cesarean section on gestation day 21 and
evaluated for external, visceral and/or skeletal anomalies. No maternal
or developmental effects were noted in this study. Thus, the NOEL for
maternal and developmental effects was considered to be 1,000 mg/kg
bodyweight. In the second study, Wistar rats were again administered
mefenpyr-diethyl by gavage at dose levels of 0 and 1,000 mg/kg body
weight/day on gestation days 7 to 16, but the dams were then allowed to
deliver normally and the offspring were evaluated for up to 44-days
post-partum. No maternal effects were observed in this study. There was
a marginal decrease in the body weight of the offspring at birth and
during lactation but no other changes in physical, functional, or
behavioral endpoints were observed. 

In a rabbit developmental toxicity study, mefenpyr-diethyl was
administered by gavage to Himalayan rabbits at dose levels of 0, 40,
100, and 250 mg/kg body weight/day on gestation days 6 to 18. The
highest dose tested was toxic to both dams and embryos, as evidenced by
a decreased food and water consumption, decreased maternal body weights,
abortions, and increased incidences of intrauterine death. No
morphological effects on the offspring were noted. The NOEL for maternal
and embryonic toxicity was considered to be 100 mg/kg body weight.

A 2-generation reproduction study was conducted in Wistar rats fed diet
containing mefenpyr-diethyl at dietary concentrations of 0, 200, 1,000,
and 5,000 ppm for 70-days then continuously through successive
generations. Effects observed at 5,000 ppm consisted of decreased food
consumption, decreased body weight gain, increased spleen weights and
increased splenic hematopoiesis in the parental animals, and decreased
body weights in the pups during lactation. No effects on reproductive
parameters were noted. Thus, the overall study NOEL for both parents and
the progeny was considered to be 1,000 ppm, equivalent to a mean daily
substance intake of 57.3 and 76 mg/kg bodyweight for the males and
females, respectively. 

	4. Subchronic toxicity.  In a 90-day feeding study, mefenpyr-diethyl
was administered to Wistar rats at concentrations of 0, 100, 500, 2,500,
and 7,500 ppm in the diet. Based on slight reduction in body weight at
7,500 ppm and minimal to slight anemia at 2,500 and 7,500 ppm, the NOEL
was considered to be 500 ppm, equivalent to a mean daily test substance
intake of 42 mg/kg body weight.

In a 90-day feeding study in beagle dogs, mefenpyr-diethyl was
administered in the diet at concentrations of 0, 400, 2,000, and 10,000
ppm. Effects observed at 10,000 ppm included decreased food consumption
and body weight gain, increased liver weights, anemia, and alterations
in several clinical chemistry parameters. There were no
histopathological changes. Increased liver weight and increases in two
serum enzymes were noted at 2,000 ppm. Thus, the NOEL was considered to
be 400 ppm, equivalent to a mean daily test substance intake of 15 mg/kg
body weight.

In a 90-day feeding study in NMRI mice, mefenpyr-diethyl was
administered in the diet at concentrations of 0, 100, 500, 2,500, and
7,500 ppm. Effects noted at 7,500 ppm included decreased food
consumption and body weight gain, slight anemia, alterations in several
hematology and clinical chemistry parameters, slightly increased spleen
weights, and markedly increased liver weights. Histopathological
evaluation revealed hepatocellular hypertrophy in the liver, and
increased hemosiderin deposits and compensatory hematopoiesis in the
spleen. Effects noted at 2,500 ppm included decreased weight gain, minor
alterations in several clinical pathology parameters, slight increases
in liver weights, and hepatocellular hypertrophy. The NOEL for this
study was considered to be 500 ppm, equivalent to a mean daily substance
intake of 89 mg/kg body weight.

In a subchronic dermal toxicity study, mefenpyr-diethyl was applied to
Wistar rats at dose levels of 0, 100, 300, and 1,000 mg/kg body weight
for six hours per day, 5-days a week, for a total of 21-days over a
period of 30-days. Based on slight anemia observed among the females at
1,000 mg/kg body weight, the NOEL was considered to be 300 mg/kg
bodyweight. 

	5. Chronic toxicity. A 2-year feeding chronic toxicity/carcinogenicity
study was conducted in Wistar rats with mefenpyr-diethyl at dietary
concentrations of 0, 40, 200, 1,000, and 5,000 ppm. No evidence of
carcinogenicity was observed in this study. Based on slight reductions
in female body weights and slight anemia in both sexes at 5,000 ppm, the
NOEL was considered to be 1,000 ppm, equivalent to a mean daily
substance intake of 48 and 60 mg/kg bodyweight in males and females,
respectively.

A 2-year carcinogenicity study was conducted in NMRI mice with
mefenpyr-diethyl at dietary concentrations of 0, 20, 100, 500, and 2,500
ppm. No evidence of carcinogenicity was observed in this study. Slight
but consistently reduced body weights and slight increases in liver
weight were noted in male mice at 2,500 ppm. Hepatocellular hypertrophy
was noted in both sexes at 2,500 ppm, in male mice only at 500 ppm, and
in a few males at 100 ppm. Hematology, serum biochemistry and urinalysis
parameters were unaffected. Because of the low incidence and severity of
the hepatocellular hypertrophy at 100 ppm, the NOAEL for this study was
considered to be 500 ppm, equivalent to a mean daily intake of 71 and 92
mg/kg body weight (Male and female mice).

A 1-year feeding study was conducted in beagle dogs with
mefenpyr-diethyl at dietary concentrations of 0, 60, 300, 1,500, and
7,500 ppm. There was a slight decrease in food consumption in males at
7,500 ppm, but body weights were unaffected. Other effects at this dose
level consisted of slight anemia, a slight increase in platelet count,
alterations in several clinical chemistry parameters, moderately to
markedly increased liver weights, slightly increased thyroid weights,
slightly decreased prostate weights, and minimal intrahepatic
cholestasis. The NOEL for this study was considered to be 1,500 ppm,
equivalent to a mean daily test substance intake of 55 mg/kg body
weight. 

	6. Animal metabolism. The metabolism of mefenpyr-diethyl in poultry is
adequately understood. Laying hens were fed the compound at a level
approximately 5-times the worst case dietary burden for 14-days. Low
levels of residues of mefenpyr-diethyl were detected in fat, and low
levels of residues of mefenpyr-diethyl and its
2,4-dichlorophenylpyrazoline containing metabolites were detected in
liver and eggs.

The metabolism of mefenpyr-diethyl in ruminants is also adequately
understood. A lactating goat was dosed with the compound at a level
approximately 56-times the worst case dietary burden for 7-days. Low
levels of residues of mefenpyr-diethyl and/or its
2,4-dichlorophenylpyrazoline containing metabolites were detected in
kidney, liver, fat, and milk. 

Based on the results observed in these metabolism studies, secondary
residues in animal commodities are not expected to be of concern in
terms of dietary risk to consumers. 

	7. Metabolite toxicology. N-A Remove 

	8. Endocrine disruption. No special studies have been conducted to
investigate the potential of mefenpyr-diethyl to induce estrogenic or
other endocrine effects.  However, no evidence of estrogenic or other
endocrine effects have been noted in any of the standard toxicology
studies that have been conducted with this product and there is no
reason to suspect that any such effects would be likely. 

C. Aggregate Exposure.  The aggregate exposure assessment includes
dietary exposure through food and drinking water and in residential
settings, but does not include occupational exposure. .

	1. Dietary exposure. There are no acute toxicity concerns with
mefenpyr-diethyl. No acute endpoint was identified; therefore, no acute
risk is expected

Therefore, only chronic exposures are being addressed here. 

	i. Food. Potential dietary exposures from food under the proposed
tolerances were estimated using the DEEM-FCID (ver. 2.16). For the
purposes of this risk assessment, Bayer CropScience has made the
conservative assumption that 100% of all wheat, barley, canola, and
soybean commodities will contain residues of mefenpyr-diethyl and that
all of those residues will be at the proposed tolerance level. Thus,
this estimate resulted in a gross overestimation of actual human
exposure. Metabolite profiles were similar following oral and dermal
exposures, with the route of metabolism being hydrolysis of the two
carboxylic acid ester groups, and decarboxylation of one of the
carboxylic acid groups resulting in the aromatization of the
heterocyclic ring. 

	ii. Drinking Water.  In the publication of permanent tolerances for
wheat and barley EPA published an estimation of theoretical
concentrations in drinking water (FR Vol 68, No. 83, 30-Apr-2003, p
23042). The Agency used the FQPA Index Reservoir Screening Tool (FIRST)
to produce estimates of pesticide concentrations in an index reservoir. 
The screening concentration in ground water (SCI-GROW2) model was used
to predict pesticide concentrations in shallow ground water. The
Estimated Environmental Concentrations for a single application of
mefenpyr-diethyl at an exaggerated rate of 0.090 kg/hectare (ha) (0.080
lb/acre) resulted in the peak and chronic concentrations of combined
parent and metabolites of 5 parts per billion (ppb) and 3 ppb,
respectively for surface water and 4 ppb for ground water. As the use
rate in soybeans and canola will be only 60 g/ha, the above drinking
water assumptions are still valid. Residues in drinking water at 4 ppb
were included in the DEEM-FCID calculation. 

	2. Non-dietary exposure. Mefenpyr-diethyl is not registered for uses on
any sites that would result in residential exposure.  

D. Cumulative Effects

	In the Federal Register (68 FR 83, p 23042) EPA stated they do not have
available data to determine whether mefenpyr-diethyl has a common
mechanism of toxicity with other substances or how to include this
pesticide in a cumulative risk assessment.  Unlike other pesticides for
which EPA has followed a cumulative risk approach based on a common
mechanism of toxicity, 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. A Reference Dose value (RfD) of 0.57 mg/kg body
weight/day is appropriate for chronic dietary risk assessments of
mefenpyr-diethyl. This RfD is based on the 2-year rat chronic toxicity
study in which the NOEL was 1,000 ppm, equivalent to 57.3 mg/kg body
weight for males, and a 100-fold safety factor to account for
interspecies extrapolation and intraspecies variation. Under the
conservative (worst-case) dietary exposure assumption described above,
chronic dietary exposures will utilize only 0.03% of the RfD for the
general U.S. population. There is generally no concern for exposures
below 100% of the RfD since it represents the level at or below which no
appreciable risks to human health is posed. Thus, there is reasonable
certainty that no harm will result to the U.S. population in general
from aggregate exposure to mefenpyr-diethyl residues. 

	2. Infants and children. There is no indication from the toxicological
data that infants and children may be more susceptible to mefenpyr
diethyl than adults.  In the Federal Register (68 FR 83, p 23402) EPA
confirmed that no additional safety factor is needed.  Therefore the
proposed RfD of 0.57 mg/kg/day can be used for this population subgroup
as well. Under the conservative (worst-case) dietary exposure assumption
described above, chronic dietary exposures will utilize only 0.06% of
the RfD for the Children 1-2 population subgroup. This estimate would,
in all likelihood, be significantly lower if an adjustment for actual
percent of crop treated was considered. 

F. International Tolerances

	Tolerances are established for various crops in a number of countries
ranging from e.g. 0.01 ppm in cereal grains in Australia to e.g. 0.5 ppm
in corn in Belarus.