Document ID: EPA-HQ-OPP-2013-0056-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2013-02-27T05:00Z

<EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING OF PESTICIDE
PETITION >

EPA Registration Division contact: Sidney Jackson (703) 305-7610 

Interregional Research Project Number 4 (IR-4)

Pesticide Petition Number: 2E8136

	EPA has received a pesticide petition, 2E8136, from IR-4 Project
Headquarters, 500 College Road East, Suite 201W, Princeton, NJ, 08540
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 clomazone,
2-[(2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone in or on the
raw agricultural commodity Brassica, head and stem, subgroup 5A at 0.10
parts per million (ppm); Rhubarb at 0.30 ppm; Pea, Southern, succulent
seed at 0.05 ppm;  Pea, Southern, dry seed at 0.05 ppm; and Pea,
Southern, hay at 0.05 ppm.  In addition, IR-4 is proposing that upon
approval of the petitioned-for tolerance on brassica, stem and head
subgroup 5A, the previously established tolerance on cabbage at 0.10 ppm
is removed.  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 support granting of the
petition. Additional data may be needed before EPA rules on the
petition.

<A. Residue Chemistry>

<	1. Plant metabolism. The metabolism of clomazone in plants is
adequately understood.  The metabolism of clomazone has been studied in
both monocotyledonous (corn) and dicotyledonous (soybeans) plant
species.  The residue of significance is the parent compound, clomazone.
 This picture is consistent with plant metabolism studies in other
species (cotton, sweet potatoes and tobacco), all of which have
exhibited a similar metabolic pathway with the residue of significance
being clomazone.>

<	2. Analytical method. There is a practical analytical method for
detecting and measuring levels of clomazone in or on raw agricultural
commodities with a limit of detection that allows monitoring of food for
residues at or above the levels proposed in this tolerance.  Samples are
analyzed using an analytical method consisting of an acid reflux, a C18
solid phase extraction (SPE), a Florisil SPE clean-up followed by gas
chromatography (GC)-mass selective detection (MSD).  The limit of
quantitation (LOQ) of the method is 0.05 ppm.  The limit of detection
(LOD) is 0.01 ppm.

>

<	3. Magnitude of residues. Clomazone was applied at the maximum label
rates for broccoli, rhubarb and southern pea was in trials at the
appropriate EPA regions.  The RACs were harvested at the appropriate
growth stages. The subsequent analyses of the RACs and processed parts
determined that the residues of clomazone would not exceed the
established and proposed tolerances.

Broccoli:

IR-4 conducted a residue study consisting of eight crop field trials,
located in EPA Region 1 (NY, one trial), Region 6 (TX, one trial),
Region 10 (CA; five trials), and Region 12 (OR, one trial) to determine
the magnitude of the residue of clomazone in/on broccoli after Command
3ME (3.0 lb/gal Mcap) application.  At each test location, one broadcast
application of clomazone (3.0 lb/gal Mcap) was made to the soil surface,
less than 48 hours before transplanting broccoli, at 0.24-0.25 lb ai/A
(0.27-0.28 kg ai/ha).  The applications were made in a spray volume of
20.0-35.6 gal/A (187-333 L/ha of water), and did not include an adjuvant
in the spray mixture.  Broccoli flower head and stem RAC samples were
harvested at 52-120 days after treatment (DAT).  The results from these
trials show that maximum residues of clomazone were below the lowest
level of method validation (LLMV, <0.03 ppm) in/on all 16 broccoli
flower head and stem RAC samples harvested 52 to 120 days after one
pre-plant treatment of clomazone (3.0 lb/gal Mcap) at 0.24-0.25 lb
ai/A/season.

Rhubarb:

IR-4 conducted a residue study consisting of eight crop field trials
located in EPA Region 5 (MI, two trials at one site) and Region 12 (OR,
six trials at three sites), to determine the magnitude of the residue of
clomazone in/on rhubarb after Command 3ME (3.0 lb/gal Mcap) application.
 At each test location, two broadcast applications of clomazone (3.0
lb/gal Mcap) were made; the first at 1.49-1.66 or 0.96-1.14 lb ai/A, and
the second at 0.98-1.10 or 0.75-0.85 lb ai/A, for total seasonal rates
of 2.49-2.76 or 1.71-1.99 lb ai/A/season, respectively (2.79-3.09 or
1.91-2.23 kg ai/ha/season).  Retreatment intervals were 44-63 days.  The
applications were made in spray volumes of 19.59-45.65 gal/A (183-427
L/ha of water), and did not include an adjuvant in the spray mixture. 
Rhubarb petioles RAC samples were harvested at 41-44 days after
treatment (DAT).  The results from these trials show that following two
applications of clomazone (3.0 lb/gal Mcap) totaling either 2.49-2.76 or
1.71-1.99 lb ai/A/season, the maximum clomazone residues were 0.180 and
0.076 ppm, respectively, in/on rhubarb RAC samples (n=8 each rate)
harvested 41 to 44 days after the last application.

Southern pea:

IR-4 conducted a residue study consisting of five crop field  trials
located in EPA Region 2 (SC), Region 4 (TN) and Region 6 (TX) to
determine the magnitude of the residue of clomazone in/on southern pea
after Command 3ME (3.0 lb/gal Mcap) application.  Pre-emergent broadcast
applications (to the ground) were used at all field sites and were
targeted at 0.5 lbs a.i./A.  Two samples of peas and two samples of pea
plants with pods, in two separate harvest intervals (mature succulent
pea plants with pods/succulent pea seed and mature dry pea plants with
pods/dry pea seed) were collected from each plot.  The results from
these trials show that the maximum residue in succulent pea seed and a
62 to 77 day PHI was <0.05 ppm from all field trials.  The maximum
residue in plants and pods (fresh) and a 62 to 77 day PHI were less than
the LLMV of 0.05 ppm.  The maximum residue in plants and pods (dry) and
a 77 to 91 day PHI were less than the LLMV of 0.05 ppm.  The maximum
residue in dry pea seed and a 77 to 91 day PHI was <0.05 ppm from all
field trials.  Residues detected in all control samples (A, B (succulent
pea seed), E, F (plants with pods (fresh), I, J (dry seed), and M, N
(plants with pods (dry)) were analyzed and found to be <0.05 ppm in
clomazone.  

>

<B. Toxicological Profile>

<	1. Acute toxicity.  The following mammalian toxicity studies were
conducted with clomazone technical (unless noted otherwise) to support
registrations and/or tolerances of clomazone:  An acute oral rat study
with an LD50 of 2,077 mg/kg (males) and 1,369 mg/kg (females).  An acute
rabbit dermal study with an LD50 of > 2,000 mg/kg.  An acute rat
inhalation study with LC50 of 4.85 mg/L/4 hr.  A dermal irritation study
in rabbits which showed minimal irritation to rabbit skin.  An eye
irritation study in the rabbit which showed practically no irritation to
eyes of rabbits.  A dermal sensitization study in the guinea pig which
demonstrated no sensitization.  Acute delayed neurotoxicity - clomazone,
and its known metabolites, are not structurally related to any known
neurotoxic substances.>

<	2. Genotoxicty. Clomazone is negative in the following genotoxicity
tests:  Bacterial reverse mutation test (Ames Assay); clastogenicity
test in mammalian cells (CHO/HGPRT Mutation Assay); unscheduled DNA
synthesis in mammalian cells and mammalian bone marrow chromosomal
aberration test.  

>

<	3. Reproductive and developmental toxicity. A two-generation
reproductive study was conducted in rats with a parental systemic NOAEL
of 1,000 ppm (equivalent to 50 mg/kg/day) based on decreased maternal
body weight, maternal body weight gain and food consumption at the LOAEL
of 2,000 ppm (equivalent to 100 mg/kg/day), and a progeny systemic NOAEL
of 1,000 ppm (50 mg/kg/day) based on decreased pup body weight at 2,000
ppm.  The reproductive NOAEL is greater than 200 mg/kg/day.

A developmental toxicity study in rats dosed with 100, 300 and 600
mg/kg/day by gavage was conducted. A maternal NOAEL of 100 mg/kg/day was
determined based on decreased locomotion, genital staining and runny
eyes observed at the two highest dose groups. The fetal developmental
NOAEL of 100 mg/kg/day was determined based on increased incidence of
delayed ossification at the LOAEL of 300 mg/kg/day. This study also
determined that clomazone was negative for teratogenicity at all dose
levels tested.

A developmental toxicity study in rabbits given doses of 30, 240 and 700
mg/kg/day by gavage was conducted. The maternal NOAEL of 240 mg/kg/day
was determined based on decreased body weight observed at the LOAEL of
700 mg/kg/day, and the fetal developmental NOAEL was 700 mg/kg/day, the
highest dose tested in this study. This study was negative for
teratogenicity at all doses tested.

In all of the reproductive and developmental studies, the reproductive
and developmental NOAELs were equal to or greater than the parental
NOAELs, thus indicating that clomazone does not pose any higher risks to
infants or children.

>

<	4. Subchronic toxicity. In a 90-day feeding study in rats, the NOAEL
was 2,000 ppm (equivalent to 200 mg/kg/day) based on treatment-related
increase in the absolute and relative liver weights in the 2 highest
dose groups.

 

In a 90-day feeding study in mice, the NOAEL was 2,000 ppm (equivalent
to 300 mg/kg/day) based on a treatment-related increase in the absolute
and relative liver weights and histopathological changes in hepatocytes
in the two highest dose levels.>

<	5. Chronic toxicity. A 12-month feeding study in dogs with a NOAEL of
500 ppm (14.0 mg/kg/day for males; 14.9 mg/kg/day for females) based on
increased blood cholesterol levels as a sign of liver toxicity and
increased liver weights at 2,500 ppm.

In a 24-month combined chronic/carcinogenicity feeding study in rats,
the NOAEL was 2000 ppm for males (equivalent to 84.4 mg/kg/day) and
females (equivalent to 112.9 mg/kg/day), the highest dose tested. 

In a 24-month carcinogenicity feeding study in mice, no carcinogenic
effects were observed at any tested dose.

Clomazone is classified as a “not likely human carcinogen” based on
the lack of carcinogenic response in rats and mice and the lack of
mutagenic concern.>

<	6. Animal metabolism. The metabolism of clomazone in animals is
adequately understood.  Clomazone degrades rapidly and extensively in
rats, goats and poultry to a variety of metabolites which were readily
excreted from the body via excreta.

>

<	7. Metabolite toxicology. No clomazone-related metabolite residues are
identified as being of toxicological concern; the residue of
significance is the parent compound, clomazone, which was thoroughly
investigated in a full battery of studies including acute, subchronic,
genotoxicity, chronic, carcinogenicity reproductive and developmental
studies.  These studies demonstrated that clomazone has low acute
toxicity via the oral, dermal and inhalation route of exposure, an
overall absence of genotoxicity, and does not cause reproductive
toxicity, developmental toxicity or carcinogenicity.>

<	8. Endocrine disruption. No specific tests were conducted with
clomazone to determine whether clomazone may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or may cause other endocrine effects.  It should be noted, however, that
the chemistry of clomazone is unrelated to that of any compound
previously identified as having estrogenic or other endocrine effects. 
Additionally, a standard battery of required studies was conducted. 
These studies included an evaluation of the potential effects of
clomazone on reproduction and development, and an evaluation of the
pathology of the endocrine organs following repeated dose or long-term
exposure. No endocrine effects were noted in any of these studies.>

<C. Aggregate Exposure>

<	1. Dietary exposure. A short-term aggregate exposure assessment was
conducted to determine the total exposure for someone who would be
exposed to sulfentrazone residues from both dietary and non-dietary
routes over a short-term period (i.e. 1-7 days).  Aggregate exposure to
sulfentrazone was evaluated for two separate products (crop herbicide
and residential lawn/turf herbicide).  Exposure from these two uses
occurred by multiple routes (dietary, dermal and incidental ingestion). 
Aggregation is conducted for dietary and non-dietary residential
exposures and it is to represent reasonable conditions of exposure. The
aggregate exposure estimates for all adults, adult females and toddlers
were less than 100% of the PAD.>

<	i. Food. Permanent tolerances were established under 40 CFR §180.425
for residues of clomazone in/on commodity succulent snap bean , cabbage
, cottonseed , cucumber, succulent peas, peppers, peppermint tops,
pumpkins, rice grain, soybeans, spearmint tops, summer squash, winter
squash, sweet potato roots, snap beans, sugar (from cane), vegetable
cucurbit group 9, vegetable tuberous and corm except potato, subgroup
1D.  Various feedstuffs from cotton, soybeans and sugarcane may be fed
to animals, thus exposure of humans to residues might result if such
residues carry through to meat, milk, poultry or eggs.  However, no
tolerances were proposed for meat, milk, poultry or eggs since no
detectable residues from clomazone were found in animal feed items from
these crops. In conducting this dietary risk assessment, EPA made
conservative Tier 1 assumptions, i.e., 100% of crops treated contain
clomazone residues at the level of the established tolerances. 
Accordingly, Tier 1 acute and chronic dietary exposure assessments on
clomazone were conducted using the Dietary Exposure Evaluation Model
software with the Food Commodity Intake Database (DEEM-FCID ™, Version
2.14), which uses food consumption data from the U.S. Department of
Agriculture’s Continuing Surveys of Food Intakes by Individuals (CSF
II) from 1994-1996 and 1998.  Overall dietary exposure to clomazone was
expressed in mg/kg/day and was calculated as a percent of the Acute
Population Adjusted Dose (aPAD) or Chronic Population Adjusted Dose
(cPAD).

Three proposed tolerances for residues of clomazone in/on head & stem
brassica subgroup 5A (0.10 ppm), rhubarb (0.25 ppm), and southern peas
(0.05 ppm for Southern succulent, seed/hay and 0.06 for Southern, dry
seed) were incorporated into the DEEM (Dietary Exposure Evaluation
Model) residue file for dietary exposure assessments. 

The Acute Reference Dose (aRfD) of 1.0 mg/kg/day was established for the
“All infants” subgroup (most sensitive) based on a developmental
toxicity study in rats with a fetal developmental NOAEL of 100
mg/kg/day. An uncertainty factor of 100 was applied to the NOAEL to
derive the aRfD. A FQPA safety factor of 1X is applied for acute dietary
risk assessment since fetal and maternal sensitivity was the same. Thus,
the aPAD is equivalent to the aRfD of 1.0 mg/kg/day.  

The Chronic Reference Dose (cRfD) was established at 0.84 mg/kg/day.
This cRfD is based on a 24-month combined chronic/carcinogenicity rat
study with a NOAEL of 84.4 mg/kg/day. The uncertainty factor of 100 was
applied to the NOAEL to derive cRfD. The toxicological study database
relative to pre- and post-natal effects for infants and children is
complete (See Section B.3) and indicates that infants and children are
not more sensitive than adults. Thus, the FQPA safety factor was 1X and
was applied for chronic dietary risk assessment. Thus, the cPAD is
equivalent to the cRfD of 0.84 mg/kg/day.>

<	ii. Drinking water. No monitoring data are currently available for
clomazone, so a Tier I drinking water assessment was conducted to
represent drinking water exposure.  For surface water, the Tier I EPA
screening model FIRST (FQPA Index Reservoir Screening Tool v 1.1.1)
model was used to estimate clomazone drinking water exposure relevant
for dietary risk assessment.  The maximum acute and chronic Estimated
Environmental Concentration (EEC) from FIRST was 24.66 ppb and 3.62 ppb
respectively.  Using the Tier 1 screening model SCI-GROW2, the ground
water EEC for clomazone was 0.47 ppb, which was considered appropriate
for both acute and chronic EEC.  

For conservatism (over estimation of potential exposure via drinking
water), the predicted acute EEC for surface water (24.66 ppb) and
predicted chronic EEC for surface water (3.62 ppb) from FIRST were
incorporated in the DEEM dietary assessment modeling.>

<	2. Non-dietary exposure. Since clomazone is registered for use on food
crops only, no assessments are required for non-dietary or
non-occupational exposure.>

<D. Cumulative Effects. Clomazone is an isoxazolidinone herbicide.  No
other registered chemical exists in this class of chemistry.  Therefore,
given clomazone’s unique chemistry, low acute toxicity, the absence of
genotoxic, carcinogenicity, developmental or reproductive effects, and
low exposure potential (see Sections A and C), the expression of
cumulative human health effects with clomazone and other natural or
synthetic pesticides is not anticipated.>

<E. Safety Determination>

<	1. U.S. population. Using the conservative Tier 1 assumptions
described in Section C., based on the completeness and reliability of
the toxicology data, it is estimated that the acute dietary exposure
(food plus drinking water) at the 95th percentile general U.S.
population comprises <0.1% of the aPAD.  For general U.S. population,
the chronic dietary exposure from the registered and pending uses of
clomazone comprises <0.1% of the cPAD. These conservative estimates
include exposure to clomazone from tolerance-level residues in/on head &
stem brassica subgroup 5A, rhubarb, and southern peas.  The EPA
generally has no concern for exposures below 100% of the PAD (aPAD/cPAD)
because it represents the level at or below which daily aggregate
dietary exposure over a lifetime will not pose any unacceptable risks to
human health.  It is concluded that there is a reasonable certainty that
no harm will result from aggregate exposure to residues of clomazone,
including all anticipated dietary exposure.>

<	2. Infants and children. The toxicological study database for pre- and
post-natal effects for mammals is complete (See Section B.3) and
indicates that infants and children are not more sensitive than adults.
Therefore, no extra uncertainty factor is warranted and the FQPA safety
factor was reduced to 1X to derive cPAD (i.e. 0.84 mg/kg/day) for
chronic dietary risk assessment to infants and children as well as
adults. Furthermore, the NOAEL of 84.4 mg/kg/day in the 24-month rat
feeding study which was used to calculate the cRfD (0.84 mg/kg/day) is
already lower than the fetal developmental NOAEL (i.e. 100 mg/kg/day)
from the rat developmental studies.  

Using the conservative Tier 1 assumptions described in Section C. and
based on the completeness and reliability of the toxicology data, it is
estimated that the acute dietary exposure (food plus drinking water) at
the 95th percentile for the ‘All infants’ U.S. population subgroup
comprises 0.51% of the aPAD (most sensitive sub-population).  

Using the Tier 1 assumptions described in Section C., it is estimated
that aggregate dietary (food plus drinking water) exposure to clomazone
comprises 0.1% of cPAD for the “All infants” subgroup (< 1 year old)
and “Non-nursing infants” subgroup.  Clomazone comprises <0.1% of
the cPAD for the “Nursing infant”, children 1-6 years old, and
children 7-12 years old subgroups.  In addition, for “All infants”
and children population subgroups, the percent of the cPAD comprised by
these pending head & stem brassica subgroup 5A, rhubarb, and southern
peas uses are negligible (i.e., equal to or less than 0.1% of the cPAD).

Based on the above information, it is concluded that there is reasonable
certainty that no harm will result to infants, children or adults from
dietary (food plus drinking water) exposure to clomazone residues from
proposed head & stem brassica subgroup 5A, rhubarb, and southern peas,
as well as all other existing clomazone-treated human dietary food
sources.>

<F. International Tolerances. There are EU maximum residue limits for
residues of clomazone in/on broccoli (0.01 ppm), rhubarb (0.01 ppm), and
peas (dry, fresh with and without pod 0.01 ppm).>

<>

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