EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE

PETITIONS PUBLISHED IN THE FEDERAL REGISTER

Interregional Research No. 4, Rutgers, The State Un iversity 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 Jers ey, 500 College Road East, Suite 201- W, Princeton, NJ 08540 proposing, pursuant to secti on 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a (d), to am end 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 agricul tural commodity asparagus at 0.05 parts per million (ppm); and vegetable soybean (eda mame) at 0.05 ppm. EPA has determined that the petition contains data or infor mation regarding the elements set forth in section 408 (d) (2) of FDDCA; however, EPA has n ot fully evaluated the sufficiency

of the submitted data at this time or whether the d ata supports granting of the petition. Additional data may be needed before EPA rules on t he petition.

A. Residue Chemistry

1. Plant metabolism. The metabolism of clomazone in plants is adequatel y understood. The metabolism of clomazone has been s tudied in both monocotyledonous (corn) and dicotyledonous (soybeans) plant species. The residue of significance is the parent compound, clomazone. This picture is consis tent 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 detecti ng and measuring levels of clomazone in or on raw agricult ural commodities with a limit of detection that allows monitoring of food for residu es at or above the levels proposed in this tolerance. Samples are analyzed using an anal ytical 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.

3. Magnitude of residues. Clomazone was applied at the maximum label rates f or 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 establis hed and proposed tolerances. IR-4 is requesting that existing data from snap beans, succ ulent peas, and soybeans be used for extrapolation for vegetable soybean (edamame).

B. Toxicological Profile

1. Acute toxicity. The following mammalian toxicity studies were con ducted with2

clomazone technical (unless noted otherwise) to sup port registrations and/or 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 r abbits

which showed minimal irritation to rabbit skin. An eye irritation study in the rabbit which showed practically no irritation to eyes of r abbits. A dermal sensitization study in the guinea pig which demonstrated no sensitization. Acute delayed neurotoxicity - clomazone, and its known metabolites, are not struc turally related to any known

neurotoxic substances.

2. Genotoxicty. Clomazone is negative in the following genotoxicit y tests: Bacterial reverse mutation test (Ames Assay); clast ogenicity test in mammalian cells (CHO/HGPRT Mutation Assay); unscheduled DNA synthes is 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 NOAE L 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 (equival ent 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 gre ater than 200 mg/kg/day.

A developmental toxicity study in rats dosed with 1 00, 300 and 600 mg/kg/day by gavage was conducted. A maternal NOAEL of 100 mg/kg/day wa s determined based on decreased locomotion, genital staining and runny ey es 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 ter atogenicity at all dose levels tested.

A developmental toxicity study in rabbits given dos es 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 7 00 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 studie s, the reproductive and developmental NOAELs were equal to or greater than the parental N OAELs, 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 treatmen t-related increase in the absolute and relative liver weights in the 2 highest dose gr oups.

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 hepatocyte s in the two highest dose levels.3

5. Chronic toxicity. A 12-month feeding study in dogs with a NOAEL of 5 00 ppm (14.0 mg/kg/day for males; 14.9 mg/kg/day for femal es) 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 feed ing study in rats, the NOAEL was 2000 ppm for males (equivalent to 84.4 mg/kg/day) a nd 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 carc inogen” 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 adequate ly understood. Clomazone degrades rapidly and extensi vely 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 iden tified as being of toxicological concern; the residue of s ignificance is the parent compound, clomazone, which was thoroughly investigated in a f ull 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 t o determine whether clomazone may have an effect in h umans 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 clo mazone is unrelated to that of any compound previously identified as having estrogenic or other endocrine effects. Additionally, a standard battery of required studie s 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 e ffects 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 observ ed adverse effect level (NOAEL) of 100 mg/kg/day from a developmental toxicity study i n 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 establis hed for the U.S. general population,4

including infants and children, because a dose and endpoint attributable to a single exposure were not identified from the available ora l 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 rat s, a 90-day oral toxicity study in rats, and a 2-generation reproduction toxicity study in r ats. The NOAEL of 84.4 mg/kg/day (HDT) from the 2-year chronic toxicity/carcinogenic ity 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 adj usted dose (cPAD) is equivalent to the cRfD of 0.84 mg/kg/day.

Acute and chronic aggregate dietary (food and drink ing water) exposure and risk assessments were conducted using the Dietary Exposu re Evaluation Model - Food Commodity Intake Database (DEEM-FCID) Version 3.18, which incorporates food consumption data from the U.S. Department of Agricu lture’s (USDA) National Health and Nutrition Examination Survey/“What We Eat in Am erica” (NHANES/WWEIA) dietary survey from 2003-2008. For both analyses, conservative assumptions were made including tolerance-level residues, 100% crop treat ed, DEEM default processing factors, and screening-level modeling of drinking water conc entrations. 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 4 0 CFR §180.425 for residues of clomazone in/on commodities including s ucculent snap bean, head and stem

Brassica subgroup 5A, cottonseed, cowpea forage and hay, cu cumber, southern peas, succulent peas, peppers, peppermint tops, pumpkins, rhuharb, rice grain and straw, soybeans, spearmint tops, summer squash, winter squ ash, sweet potato roots, sugar (from cane), vegetable cucurbit group 9, vegetable tubero us and corm except potato, subgroup 1D. Various feedstuffs from cotton, soybeans and s ugarcane 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 propo sed for meat, milk, poultry or eggs

since no detectable residues from clomazone were fo und in animal feed items from these crops. The proposed tolerance for residues of cloma zone in/on asparagus (0.05 ppm) was incorporated into the DEEM residue file. In conduct ing 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 def ault processing factors were used. Clomazone acute and chronic dietary exposure assess ments 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 p opulation 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 y ears old. Overall dietary exposure to clomazone was expressed in mg/kg/day and as a perce nt of the aPAD or cPAD.

A conservative acute dietary exposure analysis was performed for females 13-49; the5

only population subgroup for which an acute endpoin t was selected. An acute drinking water residue of 550 ppb (the most conservative sur face water estimate) was used in the assessment. The acute exposure estimate for females 13-49 utilized 3.0% of the aPAD at

the 95 th percentile for clomazone, which is below EPA’s lev el of concern (<100% aPAD).

A conservative chronic dietary exposure analysis wa s performed for the general U.S. population and various population subgroups. A chro nic 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 popul ation 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 clo mazone, so a screening-level drinking water assessment was condu cted 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 f or tuberous and corm vegetables and rhuharbs) and the maximum registered use rate on ri ce (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 acu te and chronic surface water concentrations were both estimated at 550 ppb using the Tier 1 Rice Model. The groundwater EDWCs were generated using Pesticide Ro ot Zone Model for Ground Water (PRZM-GW) and Screening Concentration In GROu nd Water (SCI-GROW). Conservative acute and chronic groundwater concentr ations were estimated at 85.7 and 77.4 ppb, respectively, using PRZM-GW. As a conserv ative estimate, the highest EDWCs for both acute and chronic exposures at 550 p pb were incorporated in the dietary

risk assessments.

2. Non-dietary exposure . Since clomazone is registered for use on food cro ps only, no assessments are required for non-dietary o r non-occupational exposure.

D. Cumulative Effects. Clomazone is an isoxazolidinone herbicide. No oth er registered chemical exists in this class of chemistry. Theref ore, given clomazone’s unique chemistry, low acute toxicity, the absence of genot oxic, 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 thu s no acute dietary exposure was estimated. Using the conservative assumptions descr ibed 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 compri ses 1.4% of the cPAD. The EPA6

generally has no concern for exposures below 100% o f the PAD (aPAD/cPAD) because it represents the level at or below which daily agg regate dietary exposure over a lifetime will not pose any unacceptable risks to human healt h. 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 exposu re.

2. Infants and children . The toxicological study database for pre- and pos t-natal effects for mammals is complete (See Section B.3) a nd indicates that infants and children are not more sensitive than adults. Therefore, no e xtra 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 chil dren 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 lowe r than the fetal developmental NOAEL (i.e. 100 mg/kg/day) from the rat development al 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 Sec tion 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 cP AD for children 1-2 years old, 1.7% of the cPAD for children 3-5 years old, and 1.2% of th e cPAD for children 6-12 years old.

Based on the above information, it is concluded tha t there is reasonable certainty that no harm will result to infants, children or adults fro m 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 sourc es.

F. International Tolerances

There are no international maximum residue levels ( MRLs) established for clomazone on asparagus or vegetable soybean (edamame).