Document ID: EPA-HQ-OPP-2011-0428-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2011-07-06T04:00Z

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

>

<EPA Registration Division contact: [Bethany Benbow (703) 347-8072]>

<>

<FMC Corporation, 1735 Market Street, Philadelphia, PA 19103>

<[1F7839]>

<	EPA has received a pesticide petition (1F7839) from FMC
Corporation,1735 Market street, Philadelphia, PA 19103, 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 180.515 by establishing
a tolerance for residues of carfentrazone-ethyl
(ethyl--2-dichloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1
H-1,2,4-triazol-1-yl]-4-fluorobenzene-propanoate) and the metabolite
carfentrazone-ethyl chloropropionic acid (α,
2-dichloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-tri
azol-1-yl]-4-fluorobenzenepropanoic acid)] in or on the raw agricultural
commodity [Crop Group 18 Non-grass animal feed (forage, fodder, straw
and hay): alfalfa, forage at 5 ppm; alfalfa, hay at 18 ppm; alfalfa,
seed at 10 ppm;  clover, forage at 5 ppm; clover, hay at 18 ppm;
clover, seed at 10 ppm 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 carfentrazone-ethyl in plants
is adequately understood.  Corn, wheat, radish and soybean metabolism
studies with carfentrazone-ethyl have shown uptake of material into
plant tissue with no significant movement into grain, root or seeds. 
All four plants extensively metabolized carfentrazone-ethyl and
exhibited a similar metabolic pathway.  The residues of concern are the
combined residues of carfentrazone-ethyl and carfentrazone-ethyl-
chloropropionic acid.>

<	2. Analytical method. There is a practical analytical method for
detecting and measuring levels of carfentrazone-ethyl and its metabolite
in or on food with a limit of quantitation that allows monitoring of
food with residues at or above the levels set or proposed in the
tolerances.  The analytical enforcement method for carfentrazone-ethyl
was used with minor modification that eliminated several clean-up and
derivatization steps that was required for GC/MSD but not for
LC/MS/MS.  The analytical method for carfentrazone-ethyl involves
separate analyses for parent and its metabolite.  The parent is
analyzed by evaporation and reconstitution of the sample prior to
analysis by LC/MS/MS GC/ECD.  The metabolite samples were refluxed in
the presence of acid and cleaned up with solid phase extraction prior to
analysis by LC/MS/MS.

>

<	3. Magnitude of residues. The magnitude of the residue of
carfentrazone-ethyl and its major metabolites in/on Crop Group 18
(non-grass animal feed) representative crops alfalfa and clover treated
with Spartan Charge Herbicide were determined.  Forage/hay plots were
treated with one or two applications of carfentrazone-ethyl for a
cumulative application of 0.04 lbs ai/A. Applications to each treated
plot in this study were made using a spray solution of approximately 10
GPA. Each field trial followed one of three treatment types: single
dormant application, single stubble application or split dormant and
stubble applications. Seed plots were treated with one application of
carfentrazone-ethyl at a rate of 0.04 lbs ai/A. At maturity, seed plots
were treated with carfentrazone-ethyl at a rate of 0.06 lbs ai/A as a
harvest aid for seed samples. RAC for each crop were harvested at the
appropriate time and subsequent analyses determined that the residues of
carfentrazone-ethyl and its metabolites would not exceed the proposed
tolerances. 

B. Toxicological Profile>

<	1. Acute toxicity.  Carfentrazone-ethyl demonstrates low oral, dermal
and inhalation toxicity.  The acute oral LD50 value in the rat was
greater than 5000 mg/kg, the acute dermal LD50 value in the rat was
greater than 4000 mg/kg and the acute inhalation LC50 value in the rat
was greater than 5.09 mg/L/4h.  Carfentrazone-ethyl is non-irritating to
rabbit skin and minimally irritating to rabbit eyes.  It did not cause
skin sensitization in guinea pigs.  An acute neurotoxicity study in the
rat had a systemic NOAEL of 500 mg/kg based on clinical signs and
decreased motor activity levels; the NOAEL for neurotoxicity was greater
than 2000 mg/kg (highest dose tested) based on the lack of neurotoxic
clinical signs or effects on neuropathology.>

<	2. Genotoxicty. Carfentrazone-ethyl did not cause mutations in the
Ames assay with or without metabolic activation.  There was a positive
response in the Chromosome Aberration assay without activation but a
negative response with activation.  The Mouse Micronucleus assay (an in
vivo test which also measures chromosome damage), the CHO/HGPRT forward
mutation assay and the Unscheduled DNA Synthesis assay were negative. 
The overwhelming weight of the evidence supports the conclusion that
Carfentrazone-ethyl is not genotoxic.>

<	3. Reproductive and developmental toxicity. Carfentrazone-ethyl is not
considered to be a reproductive or a developmental toxin.  In the
2-generation reproduction study, the NOEL for reproductive toxicity was
greater than 4000 ppm (greater than 323 to greater than 409 mg/kg/day). 
In the developmental toxicity studies, the rat and rabbit maternal NOELs
were 100 mg/kg/day and 150 mg/kg/day, respectively.  The developmental
NOEL for the rabbit was greater than 300 mg/kg/day, which were the
highest dose tested and for the rat the NOEL was 600 mg/kg/day based on
increased litter incidences of thickened and wavy ribs at 1250
mg/kg/day.  These two findings (thickened and wavy ribs) are not
considered adverse effects of treatment but related delays in rib
development which are generally believed to be reversible.>

<	4. Subchronic toxicity. Ninety-day feeding studies were conducted in
mice, rats and dogs with Carfentrazone-ethyl.  The NOEL for the mouse
study was 4000 ppm (571 mg/kg/day), for the rat study was 1000 ppm (57.9
mg/kg/day for males; 72.4 mg/kg/day for females) and for dogs was 150
mg/kg/day.  A 90-day subchronic neurotoxicity study in the rat had a
systemic NOEL of 1000 ppm (59.0 mg/kg/day for males; 70.7 mg/kg/day for
females) based on decreases in body weights, body weight gains and food
consumption at 10,000 ppm; the neurotoxicity NOEL was greater than
20,000 ppm (1178.3 mg/kg/day for males; 1433.5 mg/kg/day for females)
which was the highest dose tested.>

<	5. Chronic toxicity. Carfentrazone-ethyl is not carcinogenic to rats
or mice.  A 2-Year Combined Chronic Toxicity/Oncogenicity study in the
rat was negative for carcinogenicity and had a chronic toxicity NOEL of
200 ppm (9 mg/kg/day) for males and 50 ppm (3 mg/kg/day) for females
based on red fluorescent granules consistent with porphyrin deposits in
the liver at the 500 and 200 ppm levels, respectively.  An 18 Month
Oncogenicity study in the mouse had a carcinogenic NOEL that was greater
than 7000 ppm (>1090 mg/kg/day for males; >1296 mg/kg/day for females)
based on no evidence of carcinogenicity at the highest dose tested.  A
1-Year Oral Toxicity study in the dog had a NOEL of 50 mg/kg/day based
on isolated increases in urine porphyrins in the 150 mg/kg/day group
(this finding was not considered adverse).

Using the Guidelines for Carcinogen Risk Assessment, carfentrazone-ethyl
should be classified as Group AE@ for carcinogenicity  -- no evidence of
carcinogenicity -- based on the results of carcinogenicity studies in
two species.  There was no evidence of carcinogenicity in an 18-month
feeding study in mice and a 2-year feeding study in rats at the dosage
levels tested.  The doses tested are adequate for identifying a cancer
risk.  Thus, a cancer risk assessment is not necessary.>

<	6. Animal metabolism. The metabolism of carfentrazone-ethyl in animals
is adequately understood. Carfentrazone-ethyl was extensively
metabolized and readily eliminated following oral administration to
rats, goats, and poultry via excreta.  All three animals exhibited a
similar metabolic pathway.  As in plants, the parent chemical was
metabolized by hydrolytic mechanisms to predominantly form
carfentrazone-ethyl-chloropropionic acid, which was readily excreted.>

<	7. Metabolite toxicology. [NA ]>

<	8. Endocrine disruption. An evaluation of the potential effects on the
endocrine systems of mammals has not been determined; however, no
evidence of such effects was reported in the chronic or reproductive
toxicology studies described above.  There was no observed pathology of
the endocrine organs in these studies.  There is no evidence at this
time that carfentrazone-ethyl causes endocrine effect.>

<C. Aggregate Exposure>

<	1. Dietary exposure. Based on the available toxicity data, the EPA has
established a Reference Dose (RfD) and cPAD for carfentrazone-ethyl of
0.03 mg/kg/day.  This is based on a 2-year chronic
toxicity/carcinogenicity study in rats with a threshold No-Observed
Effect Level (NOEL) of 3 mg/kg/day and an uncertainty factor of 100.  In
support of the proposed harvest-aid application the Agency conducted
acute and chronic dietary risk assessments.  For both analysis 100%
crop-treated, default processing factors and modeled drinking water
estimates resulting from the highest registered proposed application
rate of 0.4 lbs ai/acre, tolerance- level residues for livestock, fish,
shellfish, cereal grains and cotton commodities were made.  Using the
above assumptions, the resulting acute and chronic exposure estimates
were aPAD <1% and cPAD <89% respectively.>

<	i. Food. Dietary exposure from the proposed harvest-aid application
accounts for 1.0% or less of the aPAD in subpopulations (including
infants and children).  Dietary exposure from all uses would accounts
for 89% or less of the cPAD in subpopulations (including infants and
children).>

<	ii. Drinking water. Ground water estimate of 13.4 ppb, surface water
estimates of 34.3 ppb (peak concentration) and 19.0 ppb (annual average)
were incorporated directly into the a  SEQ CHAPTER \h \r 1 cute and
chronic dietary assessment by the Agency.>

<	2. Non-dietary exposure. Non-occupational exposures to
carfentrazone-ethyl are anticipated from the lawn, turf and aquatic
applications.  The resulting MOEs were calculated to be >500,000.>

<D. Cumulative Effects>

<	EPA is also required to consider the potential for cumulative effects
of carfentrazone-ethyl and other substances that have a common mechanism
of toxicity.  EPA consideration of a common mechanism of toxicity is not
appropriate at this time since EPA does not have information to indicate
that toxic effects produced by carfentrazone-ethyl would be cumulative
with those of any other chemical compounds; thus only the potential
risks of carfentrazone-ethyl are considered in this exposure
assessment.>

<E. Safety Determination>

<	1. U.S. population. Using the conservative exposure assumptions
described and based on the completeness and reliability of the toxicity
data, the aggregate exposure to carfentrazone-ethyl will utilize less
than 1% of the aPAD and less than 32% of the cPAD for the US
subpopulations.  EPA generally has no concern for exposures below 100
percent of the aPAD or cPAD.  Therefore, based on the completeness and
reliability of the toxicity data and the conservative exposure
assessment, there is a reasonable certainty that no harm will result
from aggregate exposure to residues of carfentrazone-ethyl, including
all anticipated dietary exposure and all other non-occupational
exposures.>

<	2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of carfentrazone-ethyl,
EPA considers data from developmental toxicity studies in the rat and
rabbit and the two-generation reproduction study in the rat.  The
developmental toxicity studies are designed to evaluate adverse effects
on the developing organism resulting from pesticide exposure during
prenatal development.  Reproduction studies provide information relating
to effects on the reproductive capacity of males and females exposed to
the pesticide.  Developmental toxicity was not observed in developmental
toxicity studies using rats and rabbits.  In these studies, the rat and
rabbit maternal NOELs were 100 mg/kg/day and 150 mg/kg/day,
respectively.  The developmental NOEL for the rabbit was greater than
300 mg/kg/day, which was the highest dose, tested and for the rat was
600 mg/kg/day based on increased litter incidences of thickened and wavy
ribs.  These two findings are not considered adverse effects of
treatment but related delays in rib development, which are generally
believed to be reversible.

In a two-generation reproduction study in rats, no reproductive toxicity
was observed under the conditions of the study at 4000 ppm, which was
the highest dose tested.

FFDCA section 408 provides that EPA may apply an additional safety
factor for infants and children in the case of threshold effects to
account for pre- and post-natal toxicity and the completeness of the
database.  Based on the current toxicological data requirements, the
database relative to pre- and post-natal effects for children is
complete and an additional uncertainty factor is not warranted.  
Therefore at this time, the RfD of 0.03 mg/kg/day is appropriate for
assessing aggregate risk to infants and children.

Population Adjusted Dose (aPAD and cPAD)

Using the conservative exposure assumptions described above, the percent
of the aPAD that will be utilized by aggregate exposure to residues of
carfentrazone-ethyl for non-nursing infants (<1 year old) would be < 1%
(aPAD) and < 53% (cPAD); for children 1-6 years of age would be < 1%
(aPAD) and < 89% (cPAD), (the most highly exposed group).  Based on the
completeness and reliability of the toxicity data and the conservative
exposure assessment, there is a reasonable certainty that no harm will
result to infants and children from aggregate exposure to the residues
of carfentrazone-ethyl including all anticipated dietary exposure.>

<F. International Tolerances>

@

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B*

฀There are no established Codex Alimentarius Commission (Codex)
Maximum Residue Levels (MRLs) for carfentrazone-ethyl, in/on the
proposed commodities.>