EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE 

PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

Interregional Research No. 4, Rutgers, The State University of New Jersey, 500 College 

Road East, Suite 201-W, Princeton, NJ 08540

PP# 5E8402

EPA has received a pesticide petition (PP# 5E8402) from Interregional Research Number 

4 (IR-4), Rutgers, The State University of New Jersey, 500 College Road East, Suite 201-

W, 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 tolerances for residues of clomazone, 2-(2-chlorophenyl)methyl-4,4-

dimethyl-3-isoxazolidinone in or on the raw agricultural commodity asparagus at 0.05 

parts per million (ppm); and vegetable soybean (edamame) at 0.05 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 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 

asparagus in trials at the appropriate EPA regions. The RACs were harvested at the 

appropriate growth stages. The subsequent analyses of the RACs determined that the 

residues of clomazone would not exceed the established and proposed tolerances. IR-4 is 

requesting that existing data from snap beans, succulent peas, and soybeans be used for 

extrapolation for vegetable soybean (edamame).

B. Toxicological Profile

 1. Acute toxicity. The following mammalian toxicity studies were conducted with 
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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. 
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 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. Based on the available toxicity data, the EPA has established 

an acute reference dose (aRfD) for clomazone of 1.0 mg/kg/day for females 13-49 years 

old. The aRfD is based on a developmental no observed adverse effect level (NOAEL) of 

100 mg/kg/day from a developmental toxicity study in the rat and an uncertainty factor of 

100. The Food Quality Protection Act (FQPA) Safety Factor (SF) of 1X is applicable for 

acute dietary risk assessment. The acute population adjusted dose (aPAD) is equivalent to 

the aRfD of 1.0 mg/kg/day. An aRfD was not established for the U.S. general population, 
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including infants and children, because a dose and endpoint attributable to a single 

exposure were not identified from the available oral toxicity studies, including maternal 

toxicity in the developmental toxicity studies. 

The chronic reference dose (cRfD) of 0.84 mg/kg/day was determined on the basis of a 2-

year combined toxicity/carcinogenicity study in rats, a 90-day oral toxicity study in rats, 

and a 2-generation reproduction toxicity study in rats. The NOAEL of 84.4 mg/kg/day 

(HDT) from the 2-year chronic toxicity/carcinogenicity rat study was selected and an 

uncertainty factor of 100 was applied. The FQPA SF of 1X is applicable for chronic 

dietary risk assessment. The chronic population adjusted dose (cPAD) is equivalent to the 

cRfD of 0.84 mg/kg/day. 

Acute and chronic aggregate dietary (food and drinking water) exposure and risk 

assessments were conducted using the Dietary Exposure Evaluation Model - Food 

Commodity Intake Database (DEEM-FCID) Version 3.18, which incorporates food 

consumption data from the U.S. Department of Agriculture’s (USDA) National Health 

and Nutrition Examination Survey/“What We Eat in America” (NHANES/WWEIA) 

dietary survey from 2003-2008. For both analyses, conservative assumptions were made 

including tolerance-level residues, 100% crop treated, DEEM default processing factors, 

and screening-level modeling of drinking water concentrations. Both the acute and 

chronic dietary risk estimates are well below EPA’s level of concern for the general 

population and all population subgroups. 

 i. Food. Permanent tolerances have been established under 40 CFR §180.425 for 

residues of clomazone in/on commodities including succulent snap bean, head and stem 

Brassica subgroup 5A, cottonseed, cowpea forage and hay, cucumber, southern peas, 

succulent peas, peppers, peppermint tops, pumpkins, rhuharb, rice grain and straw, 

soybeans, spearmint tops, summer squash, winter squash, sweet potato roots, 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. The proposed tolerance for residues of clomazone in/on asparagus (0.05 ppm) was 

incorporated into the DEEM residue file. In conducting this dietary risk assessment, EPA 

made conservative assumptions, i.e., 100% of crops treated contained clomazone residues 

at the level of the established tolerances, and default processing factors were used. 

Clomazone acute and chronic dietary exposure assessments were conducted using the 

DEEM-FCIDVersion 3.18, which incorporates 2003-2008 food consumption data from 

USDA’s NHANES/WWEIA. Based on the consumption data, EPA concluded that it is 

most appropriate to report risk for the following population subgroups: the general U.S. 

population, all infants (<1 year old), children 1-2, children 3-5, children 6-12, youth 13-

19, adults 20-49, females 13-49, and adults 50-99 years old. Overall dietary exposure to 

clomazone was expressed in mg/kg/day and as a percent of the aPAD or cPAD. 

A conservative acute dietary exposure analysis was performed for females 13-49; the 
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only population subgroup for which an acute endpoint was selected. An acute drinking 

water residue of 550 ppb (the most conservative surface water estimate) was used in the 

assessment. The acute exposure estimate for females 13-49 utilized 3.0% of the aPAD at 

the 95th percentile for clomazone, which is below EPA’s level of concern (<100% 

aPAD). 

A conservative chronic dietary exposure analysis was performed for the general U.S. 

population and various population subgroups. A chronic drinking water residue of 550 

ppb (the most conservative surface water estimate) was used in the assessment. The 

highest chronic exposure estimate was for the population subgroup of all infants (<1 year 

old), which utilized 3.6% of the cPAD for clomazone. The results show that for all 

populations, the exposures are below EPA’s level of concern (<100% cPAD). 

 ii. Drinking water. No monitoring data are currently available for clomazone, so a 

screening-level drinking water assessment was conducted to represent drinking water 

exposure. Estimated drinking water concentrations (EDWCs) were derived based on the 

maximum registered use rate (1.5 lb ai/A existing for tuberous and corm vegetables and 

rhuharbs) and the maximum registered use rate on rice (dry-seeded 0.8 lb ai/A). The 

surface water EDWCs were generated using FQPA Index Reservoir Screening Tool 

(FIRST) and the Tier 1 Rice Model. Conservative acute and chronic surface water 

concentrations were both estimated at 550 ppb using the Tier 1 Rice Model. The 

groundwater EDWCs were generated using Pesticide Root Zone Model for Ground 

Water (PRZM-GW) and Screening Concentration In GROund Water (SCI-GROW). 

Conservative acute and chronic groundwater concentrations were estimated at 85.7 and 

77.4 ppb, respectively, using PRZM-GW. As a conservative estimate, the highest 

EDWCs for both acute and chronic exposures at 550 ppb were incorporated in the dietary 

risk assessments. 

 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. As described in Section C, an aRfD or aPAD was not

established for the U.S. general population and thus no acute dietary exposure was 

estimated. Using the conservative assumptions described in Section C., and based on the 

completeness and reliability of the toxicology data, it is estimated that the aggregate 

chronic dietary (food plus drinking water) exposure for the U.S. general population from 

the registered and pending uses of clomazone comprises 1.4% of the cPAD. The EPA 
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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. 

As described in Section C, an aRfD or aPAD was not established for infants and children 

and thus no acute dietary exposure was estimated. 

Using the conservative assumptions described in Section C., it is estimated that aggregate 

chronic dietary (food plus drinking water) exposure to clomazone comprises 3.6% of the 

cPAD for all infants (< 1 year old), 2.0% of the cPAD for children 1-2 years old, 1.7% of 

the cPAD for children 3-5 years old, and 1.2% of the cPAD for children 6-12 years old. 

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 use on asparagus, as well as all other 

existing clomazone-treated human dietary food sources.

F. International Tolerances 

There are no international maximum residue levels (MRLs) established for clomazone on 

asparagus or vegetable soybean (edamame).