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.
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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.

a. 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.

b. 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.

c. 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) 
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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 
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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 
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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 TM, 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 
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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 
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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 postnatal 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 
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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).