**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: 2E8**  **136** EPA has received a pesticide petition, **2E81 36**  **,** 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 **0.1 0**  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 **0.0 5 ppm**  **. In addition, IR** **- 4 is proposing that upon approval of**  **the petitioned**  **- for tolerance on**  **brassica, stem and head subgroup 5A, the pr**  **evious ly established**  **tolerance on**  **cabbage** at **0.1 0**  **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 underst**  **ood. 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 oth**  **er 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 o**  **f 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 C 18**  **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.** 2 3. Magnitude of residues. **C lomazone**  **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 determin**  **ed 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 f**

**lower 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). T he 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 ea**  **ch 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 clo mazone in/on**  **southern pea after Command 3ME (3.0 lb/gal Mcap)** 3

**application. Pre -**  **emergent b roadcast 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/o**  **r tolerances of clomazone: An acute oral rat study with an LD**  **50 of 2,077 mg/kg**  **(males) and 1,369 mg/kg (females). An acute rabbit dermal study with an LD 50**  **of > 2,000 mg/kg. An acute rat inhalation study with LC**  **50 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); cla**  **stogenicity 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 co**  **nducted 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 NOA EL 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** 4

**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 NOAE**  **L 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 tes**  **ted. 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 d ogs 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 stu**  **dy 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 dos e.**  **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. Clomaz**  **one 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 toxicologi**  **cal 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 st** **udies demonstrated that clomazone has low acute toxicity**  **via the oral, dermal and inhalation route of exposure, an overall absence of** 5

**genotoxicity, and does not cause reproductive toxicity, developmental toxicity or carcinogenicity.**  8. Endocrine disrup tion

. **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, t**  **hat 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 pot**  **ential 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). Aggreg**  **ate 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 estab lished 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 pota to 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 t**  **he 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 19**  **94 -**  **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**6

**Adjusted Dose (cPAD). Three proposed tolerances for residues of clomazon**  **e 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 diet**  **ary 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 f actor 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 R** **eference 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 stu**  **dy 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 r** **isk 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 sur face 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 Concent ration (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 estima** **tion 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 c**  **hemistry. 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**7

**and C), the expression of cumulative human health eff ects 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 toxicol**  **ogy data, it is estimated that the acute dietary exposure (food plus drinking water) at the 95**  **th 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 10**  **0% 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 resul** **t 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 infan ts**  **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 95**  **th percentile for the ‘All**  **infants’ U.S. p opulation 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 populatio**  **n 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** 8

**drinking water) exposure to clomazone residues from proposed head & stem brassica subgroup 5A, rhubarb, and southern peas, as well as all other existing**  **cl omazone**  **- 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).**