Document ID: EPA-HQ-OPP-2015-0030-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-05-20T04:00Z

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

EPA Registration Division contact: Susan Lewis; (703)305-7090

Interregional Research Project Number 4 (IR-4)

Petition 4E8337

	EPA has received a pesticide petition (4E8337) from Interregional
Research Project No. 4 (IR-4), 500 College Road East, Suite 201 W,
Princeton, NJ 08540 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 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 artichoke at 0.1 parts per million (ppm); asparagus at 0.25
ppm; peppermint, tops at 0.25 ppm; spearmint, tops at 0.25 ppm; teff,
grain at 0.25 ppm; teff, forage at 1.00 ppm; teff, hay at 0.30 ppm;
teff, straw at 0.10 ppm; vegetable, bulb, group 3-07 at 0.10 ppm;
vegetable, fruiting, group 8-10 at 0.10 ppm; fruit, citrus, group 10-10
at 0.10 ppm; fruit, pome, group 11-10 at 0.10 ppm; fruit, stone, group
12-12 at 0.10 ppm; caneberry subgroup 13-07A at 0.10 ppm; bushberry
subgroup 13-07B at 0.10 ppm; fruit, small vine climbing, subgroup
13-07F, except fuzzy kiwi fruit at 0.10 ppm; berry, low growing,
subgroup 13-07G at 0.10 ppm; nut, tree, group 14-12 at 0.10 ppm; oilseed
group 20 at 0.20 ppm; grain, cereal forage group 16 at 1.0 ppm; grain,
cereal, hay, group 16 at 0.30 ppm; grain cereal, stover, group 16 at
0.80 ppm; and grain, cereal, straw, group 16 at 3.0 ppm.

In addition, upon approval of the aforementioned tolerances, IR-4
requests 1) to modify the existing tolerance for banana from 0.20 ppm to
0.10 ppm and 2) to remove the following established tolerances: 
vegetable, bulb group 3 at 0.10 ppm; vegetable, fruiting, group 8 at
0.10 ppm; fruit, citrus, group 10 at 0.10 ppm; fruit, pome, group 11 at
0.10 ppm; fruit, stone, group 12 at 0.10 ppm; berry group 13 at 0.10
ppm; borage at 0.10 ppm; grape at 0.10 ppm; caneberry subgroup 13A at
0.10 ppm; nut, tree group 14 at 0.10 ppm; pistachio at 0.10 ppm; pummelo
at 0.10 ppm; kiwi fruit at 0.10 ppm; canola at 0.10 ppm; crambe, seed at
0.10 ppm; flax, seed at 0.10 ppm; rapeseed, seed at 0.10 ppm;; okra at
0.10 ppm; safflower seed at 0.10 ppm; salal at 0.10 ppm; cotton,
undelinted seed at 0.20 ppm; sunflower seed at 0.10 ppm; strawberry at
0.10 ppm; juneberry at 0.10 ppm; lingonberry at 0.10 ppm; mustard, seed
at 0.10 ppm; barley bran at 0.80 ppm; barley, flour at 0.80 ppm; corn,
field, forage at 0.20 ppm; corn, sweet, forage at 0.20 ppm, corn, sweet,
kernel plus cob with husk removed at 0.10 ppm; grain, cereal, forage,
fodder and straw group 16, except corn and sorghum; forage at 1.0 ppm;
grain, cereal, forage, fodder and straw, group 16, hay at 0.30 ppm;
grain, cereal, forage, fodder and straw, group 16, stover at 0.30 ppm;
grain, cereal, forage, fodder and straw, group 16, except rice; straw at
0.10 ppm; grain, cereal, group 15 at 0.10 ppm; grain, cereal, stover at
0.80 ppm; grain, cereal, straw at 3.0 ppm; millet, flour at 0.80 ppm;
oat, flour at 0.80 ppm; rice, straw at 1.0 ppm; rye, bran at 0.80 ppm;
rye, flour at 0.80 ppm; sorghum, forage at 0.20 ppm; sorghum, sweet at
0.10 ppm; wheat, bran at 0.80 ppm; wheat, flour at 0.80 ppm; wheat, germ
at 0.80 ppm; wheat, middlings at 0.80 ppm; and wheat, shorts at 0.80
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 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 asparagus treated
with 2 broadcast application to the soil (after clean harvest) at an
interval of 20 (± 2) days with the last application 5 days before
harvesting emergent spears.  Carfentrazone-ethyl formulated as Aim EC or
Aim EW Herbicide was applied at 0.03 lbs ai/A per application using a
spray solution of approximately 10 to 40 gallons of water per acre.

The magnitude of the residue of carfentrazone-ethyl and its major
metabolites in/on mint treated with one broadcast application to emerged
weeds before mint break dormancy.  Carfentrazone-ethyl formulated as Aim
EC or Aim EW Herbicide was applied at 0.015 lbs ai/A to 0.03 lbs ai/A
using a spray solution of approximately 10 to 40 gallons of water per
acre.

RAC for each crop, crop group or subgroup 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 toxicant.  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 - Remove.

	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 subchronic, 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 an acute Reference Dose (RfD) for carfentrazone-ethyl of 5
mg/kg/day. The acute RfD is based on acute neurotoxicity study in rats
with a threshold NOEL of 500 mg/kg/day and an uncertainty factor of 100.
A chronic RfD for carfentrazone-ethyl was established at 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 using DEEM-FCID, ver 3.16 which incorporates consumption
data from the USDA NHANES/WWEIA; 2003-2008.  For both analysis 100%
crop-treated, DEEM default processing factors and modeled drinking water
estimates resulting from the highest registered proposed application
rate of 0.46 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 <49% respectively for the most sensitive
sub-population (non-nursing infants <1 year old).

	i. Food. The registered tolerances (40CFR 180.515) and the tolerances
proposed by IR-4 Project subject to this petition (AMENDS 40CFT180.515)
were used as dietary exposure.  

Acute dietary exposure: The most conservative acute exposure estimate
was for the population subgroup of non-nursing infants (< 1 year old),
which utilized <1% of the aPAD at the 95th percentile for
carfentrazone-ethyl. The acute drinking water residue of 160 ppb (using
groundwater as the most conservative estimate) was used in the
assessment.   The results show that for all populations, the estimated
exposures are below the Agency's level of concern (< 100% aPAD).

Chronic dietary exposure: The highest chronic exposure estimate was for
the population subgroup of non-nursing infants (<1 year old), which
utilized 49% of the cPAD for carfentrazone-ethyl. The chronic drinking
water residue of 128 ppb (using groundwater as the most conservative
estimate) was used in the assessment.   The results show that for all
populations, the exposures are below the Agency’s level of concern (<
100% cPAD).

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 49% or
less of the cPAD in subpopulations (including infants and children).

	ii. Drinking water. Groundwater estimates of 160 ppb (highest daily
value) and 128 ppb (post-breakthrough average) using the Tier I/II
ground water exposure model, PRZM-GW, exceeded the surface water
estimates (DP Barcode 389083) of 126 ppb (peak exposure) and 48 ppb
(annual average). Therefore, groundwater estimates from PRZM-GW were
incorporated directly into the a  SEQ CHAPTER \h \r 1 cute and chronic
dietary risk assessment to provide a conservative estimate.

	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 17% of the cPAD for the general US population. 
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 cRfD of 0.03 mg/kg/day is appropriate (cRfD
= cPAD) for assessing aggregate risk to infants and children.

Using the conservative exposure assumptions described above (Tier I
dietary assessment), the percent of the PAD that will be utilized by
aggregate exposure to residues of carfentrazone-ethyl for non-nursing
infants (<1 year old) would be <1% (aPAD) and 49% (cPAD), which
represent the most conservative exposure in all subpopulations.  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

h÷d

h÷d

h÷d

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

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