UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460 **OFFICE OF CHEMICA**  **L SA FETY**  **AND POLLUTION PREVENTION**  **MEMORANDUM Date**  **:** March 5 , 2014 **SUBJECT:** Clomazone : Human Health Risk Assessment for New Uses in/on Brassica, H ead

and S tem , S ubgroup 5A; Rhubarb; and Pea, Southern (IR - 4 Petition 2E8136) **PC Code:** 125401 **DP Barcode:** D410435 **Decision No.:** 473594 **Registration No. :**  279 - 3052 **Petition No .:**  2E8136 **Regulatory Action:** Section 3 Registration **Risk A**  **ss essment Typ**  **e :**  Single Chemical Aggregate **Case No.:** 7203 **T XR No.:**  NA **CAS No.:** 81777 - 89 - 1 **MRID No.:** NA **40 CFR:** 180.425 **FROM:** Jessica Kidwell, Risk Assessor

Kelly O’Rourke, O ccupational/R esidential Exposure Assessor Su san V . Hummel, Chemist Bonnie Cropp - Kohl l ig ian, Dietary Assessor Angela Howard, PhD, DABT, Toxicologist Risk Assessment Branch 4 Health Effects Division (7509P) **THROUGH:** Elissa Reaves , Branch Chief

Risk Assessment Branch 4 Health Effects Division (7509P) **TO:** Sidney

Jackson , PM Barbara Madden , Team Leader Risk Integration, Minor Use and Emergency Response Branch Registration Division (7505P) The Registration Division (RD) requested that the Health Effects Division (HED) conduct a human health risk assessment for the proposed new use of clomazone on B rassica , head and stem, subgroup 5A, rhubarb and pea , southern . This document provides the Health Effect Division’s (HED’s) human health risk assessment for clomazone.CL OMAZONE/125401 Human Health Risk Assessment D410435

Page **2** of **49 1.0**  **Executive Summary** ................................ ................................ ................................ ........... 4 **2.0 HED Recommendations**  ................................ ................................ ................................ .... 7 **2.1 Data Deficiencies/Conditions of Registration**  ................................ ........................... 7 **2.2 Tolerance Considerations**  ................................ ................................ .......................... 8 **2.2.1 Enforcement Analytical Method**  ................................ ................................ ............... 8 **2.2.2 Internatio**  **nal Harmonization** ................................ ................................ ..................... 8 **2.2.3 Recommended Tolerances**  ................................ ................................ ......................... 8 **2.2.4 Revisions to Petitioned**  **- For Tolerances**  ................................ ................................ .... 9 **2.3 Label Recommendations**  ................................ ................................ ............................ 9 **2.3.1 Recommendations from Residue Reviews**  ................................ ................................ 9 **2.3.2 Recommendations from Occupational Assessment**  ................................ ................. 9 **2.3.3 Recommendations from Residential Assessment**  ................................ ..................... 9 **3.0 Introduction**  ................................ ................................ ................................ ........................ 9 **3.1 Chemical Identity**  ................................ ................................ ................................ ....... 9 **3.2 Physical/Chemical Characteristics**  ................................ ................................ .......... 10 **3.3 Pesticide Use Pattern**  ................................ ................................ ................................ 10 **3.4 Anticipated Exposure Pathways**  ................................ ................................ .............. 11 **3.5 Consideration of Environmental Justice**  ................................ ................................ 12 **4.0 Hazard Characterization and Dose**  **- Response Assessment**  ................................ .......... 12 **4.1 Toxicology Studies Available for Analysis**  ................................ ............................. 12 **4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)**  ......................... 12 **4.3 Toxicological Effects**  ................................ ................................ ................................ . 13 **4. 4**  **Safety factor for Infants and Children (FQPA Safety Factor)** ............................. 14 **4.4.1 Completeness of the Toxicology Database**  ................................ .............................. 14 **4.4.2 Evidence of Neurotoxicity**  ................................ ................................ ........................ 14 **4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal**  ........ 14 **4.4.4 Residual Uncertainty in the Exposure Database**  ................................ ................... 15 **4.5 Toxicity Endpoint and Point of Departure Selections**  ................................ ........... 15 **4.5.1 Dose**  **- Response Assessment**  ................................ ................................ ...................... 15 **4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment**  ..... 16 **4.5.3 Cancer Classification and Risk Assessment Recommendation**  ............................ 16 **4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk**  **Assessment** ................................ ................................ ................................ ............................... 16 **5.0 Dietary Exposure and Risk Assessment**  ................................ ................................ ......... 19 **5.1 Metabolite/Degradate**  **Residue Profile** ................................ ................................ .... 19 **5.1.1 Summary of Plant and Animal Metabolism Studies**  ................................ ............. 19 **5.1.2 Summary of Environmental Degradation**  ................................ .............................. 19 **5.1.3 Comparison of Metabolic Pathways**  ................................ ................................ ....... 20 **5.1.4 Residues of Concern Summary and Rationale**  ................................ ...................... 20 **5.2 Food Residue Profile**  ................................ ................................ ................................ 21 **5.3 Water Residue Profile**  ................................ ................................ .............................. 22 **5.4 Dietary Risk Assessment**  ................................ ................................ .......................... 23 **5.4.1 Description of Residue Data Used in Dietary**  ................................ ......................... 23 **Assessment** ................................ ................................ ................................ ............................... 23 **5.4.2 Percent Crop**  **Treated Used in Dietary Assessment** ................................ .............. 23 **5.4.3 Acute Dietary Risk Assessment**  ................................ ................................ ............... 24CL OMAZONE/125401 Human Health Risk Assessment D410435

Page **3** of **49 5.4.4**  **Chronic Dietary Risk Assessment** ................................ ................................ ........... 24 **5.4.5 Cancer Dietary Risk Assessment**  ................................ ................................ ............. 24 **5.4.6 Summary Table**  ................................ ................................ ................................ ......... 24 **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  ............................. 24 **6.1 Spray Drift**  ................................ ................................ ................................ ................. 24 **6.2 Resident**  **ial Bystander Postapplication Inhalation Exposure** ............................... 25 **7.0 Aggregate Exposure/Risk Characterization**  ................................ ................................ .. 25 **7.1 Acute Aggregate Risk**  ................................ ................................ ............................... 25 **7.2 Short**  **- Term Aggregate Risk**  ................................ ................................ .................... 26 **7.3 Intermediate**  **- Term Aggregate Risk**  ................................ ................................ ........ 26 **7.4 Chronic Aggregate Risk**  ................................ ................................ ........................... 26 **7.5 Cancer Aggregate Risk**  ................................ ................................ ............................ 2 6 **8. 0**  **Cumulative Exposure/Risk Characterization** ................................ ............................... 26 **9.0 Occupational Exposure/Risk Characterization**  ................................ ............................ 26 **9.1 Short**  **- Term Handler Risk**  ................................ ................................ ....................... 26 **9.2 Post**  **- Application Risk**  ................................ ................................ ............................... 27 **9. 2.1**  **Dermal Postapplication Risk** ................................ ................................ ................... 28 **9.2.2 Inhalation Postapplication Risk**  ................................ ................................ .............. 28 **10.0 References**  ................................ ................................ ................................ ......................... 29 **Appendix A. Toxicology Profile and Executive Summaries**  ................................ .................. 30 **Appendix B. Physical/Chemical Properties** ................................ ................................ ............. 48 **Appendix C**  **. Review of Human Research** ................................ ................................ ................ 49CL OMAZONE/125401 Human Health Risk Assessment D410435

Page **4** of **49 1.0**  **Executive Summary** Clomazone is an herbicide used for pre - emergence control of weeds (annual grasses and broad leaves ) . It is registered for use on snap beans, succulent peas, cabbag e, cotton, cucurbits, pepper, mint, rice, soy

beans, sugarcane, and tuberous & co rm vegetables (except potato). Tolerances for clomazone on these commodities are published in 40 CFR 180.425, including cabbage at 0.1 ppm . Clomazone products are formulated as emulsifiable concentrates and microencapsulated formulations. FMC Corporation has proposed a new use of the active ingredient (a.i.) clomazone on Brassica, head and stem, subgroup 5A ; rhubarb ; and southern peas. The proposed uses will be added to the Command ® 3ME formulated end use product label containing 31.1% clomazone (EPA Reg. # 279 - 3158 ). Command ® 3ME is a micro - encapsulated formulation designed to use water as its mode of dispersion, whil e remaining in an encapsulated state. Command ® 3ME is proposed to be applied pre - plant, pre - emergent, or earl y post - emergent to Brassica , head and stem, subgroup 5A, rhubarb and southern peas using groundboom spray equipment at rates of 0.25 - 0.5, 1.5 an d 0.50 pounds ai per acre (lb ai/A), respectivel y. A maximum of 1 application is allowed per season. T he current application requests adding Brassica, head and stem, subgroup 5A; R hubarb; and P ea, Southern; to the label for Command 3ME, and proposes the following tolerances. Brassica, stem and head subgroup 5A 0.1 ppm Rhubarb 0.3 ppm Pea, Southern, succulent seed 0.05 ppm Pea, Southern, dry

seed 0.05 ppm Pea, Southern, hay 0.05 ppm At the same time, there is a request to revoke the toler ance for cabbage at 0.1 ppm, since cabbage will be covered b y the new tolerance for Brassica , head and stem, subgroup 5A. There is a potential for acute and chronic dietary e xposures, as well as for short - term occupational exposure to clomazone during mix ing, loading, application, and post - application activities. The clomazone label requires occupational handlers to wear long sleeved shirts, long pants, chemical resistant gloves, shoes, and socks. There are no residential uses of clomazone. Toxicology Th e existing toxicological database is comprised of studies conducted with clomazone in the rat, mouse, rabbit and the dog. The primary target of clomazone is the liver, with hepatocellular cy tomegal y noted in th e chronic rat and mouse studies, hepatocellular necrosis in the chronic mouse study

and increased liver weight observed in s ubchronic and chronic studies. There was one 28 - day

dermal toxicity

study in rats that showed no effects up to the limit dose. There were no effects up to the limit dose in the c hronic dog study . No inhalation toxicity studies were submitted, and the 28 - day subchronic inha lation study was waived.CL OMAZONE/125401 Human Health Risk Assessment D410435

Page **5** of **49** Clomazone has low acute toxicity (Category

III and IV) via the oral, dermal and inhalation routes. It is non - irritating to the eyes an d mildly irritating to the skin. It is not a dermal sensitizer. No neurotoxicity

studies with clomazone are available. B ased on a WOE approach, the HASPOC concluded that a neurotoxicity battery is not required for clomazone at this time (see discussion in Section 4.3). There is no quantitative or qualitative evidence of susceptibility in the developmental toxicity

study in rabbit s or in the 2 - generation reproduction toxicity study in rats . Although qualitative susceptibility was observed in the developmental toxicity study in rats, the concern is low since there are clear NOAEL s and LOAELs in the study and th is study

was used for risk assessment , and, therefo re, is protective of the developmental effects . Clomazone is absorbed, extensively metabolized by

the liver and rapidly

excreted in urine and feces, in rats, following oral administration. The absorption and elimination is almost complete with 97% of the radioactivity excreted within 168 hours. There is no concern for mutagenicity . In the rat carcinogenicity study, there was no evidence of carcinogenicity . The mouse carcinogenicity study was inadequate to determine carcinogenic activity due to the lack of adverse effects at the highest dose tested. Despite the inadequacy of the mouse carcinogenicity study , EPA has determined that an additional mouse carcinogenicity study is not needed and that the rat chronic/carcinogenicity study will be adequate for asses sing c hronic risk, including cancer. This finding is based u pon the following conclusions: (1) the rat is more sensitive than the mouse for the chronic assessment ; (2) the consistent effect in rats (decreased body weight and increased liver weight) has bee n used as the point of departure (POD) for the chronic assessment; (3) a new mouse study would onl y use doses well above the current POD for the chronic assessment; and (4) even if new mouse study i dentified positive carcinogenicity

effects, that finding w ould not result in the adoption of a quantitative linear assessment of cancer risk due to the negative carcinogenicity finding in the rat study

and the lack of a positive finding for genotoxicity . Dose Response Assessment Toxicological endpoints were selected for dietary and occupational exposure scenarios. An acute reference dose (aRfD) of 1.0 mg/kg/day was established for females 13 - 49 ye ars old based on a point of departure (POD) of 100 mg/kg/day from a developmental toxicity study in the rat. An uncertainty factor (UF) of 100 (10 - fold for interspecies extrapolation and 10 - fold for intraspecies variability) was applied to the NOAELto derive the RfD. The lowest observed adverse effect level (LOAEL) from this developmental study was 300 mg/kg/day based on indications of delayed ossification. The Food Quality Protection Act (FQPA) Safet y Factor (SF) was reduced to 1X. An acute endpoint was not identified for the U.S. general population. T he chronic reference dose (cRfD) of 0.84 mg/kg/day was estab lished based on a POD of 84.4 mg/kg/day

from several co - critical studies (a 2 - ye ar chronic/carcinogenicity study in rats, a 90 - day oral toxicity

study in rats and a 2 - generation reproduction toxicity study in rats). An UF of 100 (10 - fold for interspecies e xtrapolation and 10 - fold for intraspecies variability) was applied to the POD to derive the cRfD. The FQPA SF was reduced to 1X. Thus, the chronic population adjusted dose (cPAD) was also 0.84 mg/kg/day . A POD for dermal exposure was not selected because n o dermal or s ys temic toxicity was observed in rats following repeated dermal application at the limit dose for 28 day s. A short - term inhalation exposure POD (100 mg/kg/day)CL OMAZONE/125401 Human Health Risk Assessment D410435

Page **6** of **49** was selected from a developmental toxicity study in rats. Based on the use pattern, only a short term inhalation exposure scenario is applicable. Dietary Exposure and Risk A cute and chronic aggregate dietary ( food and drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity

Intake Database (DEEM - FCID) Version 3.16 . Both the acute and chronic assessments are highl y conservative and incorporated tolerance level residues, assumed 100% crop treated and used default processing factors. Screening - level Tier I mo deling was used to estimate drinking water concentrations. T he acute dietary

risk estimate at the 95 th percentile of exposure utilized 3.0 % of the acute population adjusted dose (aPAD) for females 13 - 49 years old. This is the only population subgroup f

or which an acute endpoint was selected. The acute dietary risk estimate for females 13 - 49 years old is not of concern. The c hro nic dietary

risk estimates are ≤3.6% of the chronic population adjusted dose (cPAD) for all population subgroups. All Infants < 1 year of age is the most highly exposed subgroup, utilizing 3.6 % of the cPAD, while the general US population utilizes 1.4 % of the cPAD. The chronic dietary

risk estimates are not of concern. EPA has concluded that the chronic PAD for clomazone will be protective of an y cancer risk posed by clomazone . Additionally , EPA is relying on the chronic dietary exposure assessment to evaluate cancer risk. Residential Non
- Cancer Risks Currently , there are no registered or proposed residential uses for clomazone . Aggregate Risk In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. Currentl y, there are no registered or proposed residenti al uses for clomazone, therefore, short - and intermediate term aggregate risk assessments are not required. In examining acute and chronic aggregate risk, HED has assumed that the only pathway of exposure relevant to the acute and chronic time frames is di etary

exposure. Therefore, the acute and chronic aggregate risk is comprised of exposures to clomazone residues in food and drinking water and is equivalent to the acute and chronic dietary

risk estimates. Both the acute and chronic dietary risk estimates are well below HED’s level of concern for the general population and all population subgroups. EPA has concluded that the chronic PAD for clomazone will be protective of any cancer risk posed b y clomazone .CL OMAZONE/125401 Human Health Risk Assessment D410435

Page **7** of **49** Occupational Risks The occupational handler exposure and risk estimates indicate that the short - term inhalation MOEs are not of concern to HED (i.e., MOEs > 1 00) without a respirator. A respirator is not required on the label. P ost - application dermal exposure and risk estimates were not evaluated as toxicity was not observed up to the limit dose in a dermal toxicity study , and no developmental or reproductive toxicity was seen in the database. T he restricted entry interval (REI) is based on the acute toxicity of clomazone technical material. Clomazone is classified as a Toxicity Category IV for acute dermal toxicity , primary eye and skin irritation. Therefore, a 12 - hour REIunder 40 CFR 156.208 (c) (2) (i) is required . The 12 - hour REI, which currently appears on the Command ® 3M label, is adeq

uate for the proposed uses. Based on the Agency 's current practices, a quantitative non - cancer occupational post - application inhalation exposure assessment was not performed for clomazone at this time. If new policies or procedures are put into place, th e Agency may revisit the need for a quantitative occupational post - application inhalation exposure assessment for clomazone . Human Studies Review This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from PHED 1.1 and the AHETF database, are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 1

. **2.0 HED**  **Recommendations** HED recommends for the proposed tolerance, with corrections specified below, and for the associated amended use. The current tolerance expression is in accord with our current guidance on tolerance expressions. The field trials for clomazone on broccoli, rhubarb, and southern p eas are adequate. The enforcement anal yt ical method is adequate. The residue data are supported b y available storage stability data. HED concludes that there are no risk issues. Specific tolerance recommendations are discussed in section 2.2. Label rec ommendations are discussed in section 2.3. **2.1 Data Deficiencies/Conditions of Registration**  Toxicology : None.

1 http://www.epa.gov/pesticides/science/handler - exposure - data.html and http://www.epa.gov/pesticides/science/post - app - exposure - data.htmlCL OMAZONE/125401 Human Health Risk Assessment D410435

Page **8** of **49** Residue Chemistry : None. Occupational Assessment: None. **2.2 Tolerance Considerations**  **2.2.1 Enforcement Analytical Method**  Adequate enforcement methods are available for the determination of the residues of clomazone in plants. Briefl y, samples are acid h ydrol yz ed, hexane extracted, Na2 CO 3 washed, and cleaned up with a Florisil column. The resulting samples are anal yz ed b y gas chromato graph y (GC) using a nitrogen phosphorus detector (NPD) or mass spectrometer (MS). The limit of quantitation (L OQ) for this method is 0.05 ppm. A confirmatory procedure (GC/MS - SIM) is available (Method I, PAM II). Clomazone was determined in broccoli using the anal yt ical method adapted from method FMC No. ACG 124. The LOQ (determined as the LLMV) was 0.03 ppm for broccoli and rhubarb; and 0.05 ppm in southern pea commodities . The calculated LOQ and LOD, respectively , were 0.01850 and 0.006168 ppm in broccoli ; 0.0394 and 0.0131 ppm in rhubarb. The residue data were gathered with an adequate data collection method. **2.2.2 International Harmonization**  There are no CODEX MRL s for residues of clomazone on any commodity. Canada has not established MRL s for the comm odities in this petition. **2.2.3 Recommended Tolerances**  HED recommends for the proposed tolerance s , with corrections specified below in Table 2.2.3 , and for the associated amended use. The current tolerance expression is in accord with our current guidanc e on tolerance expressions. When the tolerance for residues of clomazone on Brassica, head and stem, subgroup 5A is established, the tolerance on cabbage should be revoked. **Table 2.2.3**  **. Tolerance Summary for**  **Clom azone (**  **§ 180.4**  **25) Comm**  **odity Established/Proposed** 

**Tolerance (ppm) Recommended** 

**Tolerance (ppm) Comments** 

**Correct Commodity Definition** Brassica, stem and head subgroup 5 A 0.1 0.10 Brassica, head and stem, subgroup 5A. Tolerance changed to add a significant figure. Rhubarb 0.3 0.30 Tolerance changed to add a significant figure. Pea, Southern, succulent seed 0. 0 5 0. 0 5 Pea, Southern, dry seed 0. 0 5 0.05 Pea, Southern, hay 0. 0 5 0.05 Cowpea, hay and Cowpea, forage. Southern pea hay is a very minor feed, but cow

pea is a type of southern pea.CL OMAZONE/125401 Human Health Risk Assessment D410435

Page **9** of **49 2.2.4**  **Revisions to Petitioned -**  **For Tolerances** Revisions are recommended to petitioned - for tolerances for consistent naming of commodities, and to add a significant figure . The recommended changes are documented in Table 2.2.3 above. Tolerances are being established for cowpea, forage, and cowpea, hay , rather than southern pea hay , because cowpea is a ty pe of southern pea. **2.3 Label Recommendations**  **2.3.1 Recommendations from Residue Reviews**  No label revisions are required; however, it should be noted that while the proposed maximum use rate on rhubarb is 1 application at 1.5 lb ai/A at dormancy , the submitted field trial data for rhubarb would support a second application at 1.0 lb ai/A a minimum of 50 day s after the first application. If a second application on rhubarb is desired, the petitioner should submit an amended petition to reflect this proposed use . **2.3.2 Recommendations**  **from Occupational Assessment** None. **2.3.3 Recommendations f**  **rom Residential**  **Assessment** There are no resid ential uses proposed with this petition. **3.0 In**  **troduction 3.1**  **Chemical Identity** T he chemical structure and nomenclature of the active ingredient , clomazone, are presented below in Table 3.1.CL OMAZONE/125401 Human Health Risk Assessment D410435

Page **10** of **49 Table 3.1 Test Compound Nom**  **enclature**

Chemical Structure

Em pirical Formula C 12 H 14 ClN O 2 Common Name Clomazone Com pany experimental name FMC 57020 IUPAC name 2 - (2 - chlorobenzyl) - 4,4 - dimethylisoxazolidin - 3 - one CAS Name 2 - [(2 - chlorophenyl)methyl] - 4,4 - dimethyl - 3 - isoxazolidinone CAS Registry Number 8 1777 - 89 - 1 End - use product/EP Command ME, EPA Reg. . No. 279 - 3158 Chemical Class Isoxazolone Known Impurities of Concern none **3.2 Physical/Chemical Characteristics**  T he phy sicochemical properties are presented in Appendix C. Clomazone is very soluble in water and a number of organic solvents used with pesticides. Its vapor pressure is relativel y high ( 1.44 x 10 - 4 mm Hg ), indicating a potential concern for inhalation . T he octanol/water partition coefficient indicates affini ty for organic solvents over water, indicating a potential for bioaccumulation. **3.3 Pesticide Use Pattern**  As summarized in Table 3.3 , applications of Command ® 3ME (EPA Reg. #279 - 3158) to pre plant, pre - emergent, or early post - emergent Brassica , rhubarb and southern peas are proposed using groundboom spray

equipment at rates of 0.25, 1.5 and 0.50 pounds ai per acre (lb ai/A), respectivel y. A maximum of 1 application is allowed per season. Clomazone products are formulated as emulsifiable concentrates and microencapsulated formulations. Applications are usually made as a single or split (2) pre - plant, or early post - emergence broadcast applications. Aerial and chemigation application are prohibited on the Command® label. See Section 2.3 for recommended modifications to the proposed label.CL OMAZONE/125401 Human Health Risk Assessment D410435

Page **11** of **49 Table**  **3 .**  **3 . Summary of Directions for Use of**  **Clomazone Applic.**  **Timing, Type, and Equip.**  **Form ulation** 

**[EPA Reg. No.] Applic.** 

**Rate (lb ai/A)**  **Max. No.**

**Applic. per**  **Season Max.** 

**Seasonal Applic. Rate**  **(lb ai/A) PHI** 

**(days) Use Directions and** 

**Limitations Brassica**  **, Head & Stem , Subgroup 5A; Direct Seeded Cabbage; Transplant Broccoli**  Broadcast application at pre - emergence using groundboom Micro encapslated (3 lb/gal) [279 - 3158] 0.25 1 0.25 1 Not Specified Use as a soil applied

treatment prior to weed emergence . **Transplant Cabbage** Broadcast application at pre - emergence using groundboom Micro encapslated (3 lb/gal) [279 - 3158] 0.25 - 0.5 1 0.50 1 Not Specified Use lower rate on

coarse soils and higher rate on fine soils. Use as a soil applied treatment prior to weed emergence . **Rhubarb** Broadcast application prior to leaf emerg ence using groundboom Micro encapslated (3 lb/gal) [279 - 3158] 1.5 1 1.5 1 Not Specified Apply to dormant

rhubarb.

**Peas, Southern** Broadcast application at pre - emergence using groundboom Micro encapslated (3 lb/gal) [279 - 3158] 0.50 1 0.50 1 Not Specified Use as a soil applied

treatment prior to weed emergence .

1 Not specifically detailed in Section B of the petition but clearly intended given the specified maximum single application rate and number of applications for the subject vegetable crops. **3.4 Anticipated Exposure Pathways**  The Registration Division has requested an assessment of human health risk to support the proposed new use of clomazone . Humans may be exposed to clomazone in food and drinking water, since application may result in clomazone reaching surface and ground water sources of drinking water. There are no residential uses of clomazone, so there is not likely to be exposure in residential or non - occupational settings. In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during app lication. There is a potential for post - application exposure for workers re - entering treated fields.CL OMAZONE/125401 Human Health Risk Assessment D410435

Page **12** of **49** Risk assessments have been previousl y prepared for the existing uses of clomazone . This risk assessment considers all of the aforementioned exposure pathways based on the proposed new uses of clomazone , but also considers the existing uses as well, particularl y for the dietary exposure assessment . **3.5 Consideration of Environmental Ju**  **stice** Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf . As a part of every

pesticide risk assessment, OPP considers a large variet y of consumer subgrou ps according to well - established procedures. In line with OPP policy , HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized by subgroups based on age, season of the ye ar, ethnic group, and region of the country . Additionally , OPP is able to assess dietary

exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non - dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to by standers and farm workers as well as lif estyle and traditional dietary patterns among specific subgroups. **4.0 Hazard Characterization and Dose**  **- Response Assessment**  **4.1 Toxicology Studies Available for Analysis**  The toxicology

database for clomazone is adequate to support the currently registered uses. Exposure to clomazone is expected via the oral, dermal and inhalation routes. A route - specific dermal study

was submitted, but no subchronic inhalation study has been submitted. The Hazard and Science Policy Council (HASPOC) recentl y revi ewed clomazone ( TXR No. 0056801 ). B ased on a WOE approach considering all available hazard and exposure information, the HASPOC concluded that a neurotoxicity battery (acute and subchronic), a 28 - day inhalation toxicity

study , a chronic/carcinogenicity study in the mouse, and an immunotoxicity

study are not required at this time. **4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)**  Clomazone is absorbed, extensively metabolized by

the liver and rapi dly

excreted in urine and feces in rats following oral administration. Analysis of the metabolic products showed the presence of parent compound and sixteen identifiable metabolites. The majority of theseCL OMAZONE/125401 Human Health Risk Assessment D410435

Page **13** of **49** products were eliminated in the urine and the feces within 24 hours with the predominant route of excretion being the urine. The quantities of metabolites varied with the dose regimen, sex and route of administration, but were the same qualitatively both in the urine and the feces in all groups. A total of 75 - 85% of the administered dose was recovered for all routes and doses after the first 24 hours , except in females in the single high dose group, where the total recovery was only 48% compared to males (75%). The total recovery after 48 hours was generall y comparable between all groups and sexes and ranged from 91 - 100%. **4.2.1 Dermal Absorption**  There was no evidence of sy stemic toxicity at the limit dose in a 28 day dermal toxicity clomazone study

in rats, however dermal irritation was observed in dosed females at increased inci dence and/or severity over controls. A dermal absorption study is not needed. **4.3 Toxicological Effects**  The primary

target of clomazone is the liver, with hepatocellular cy tomegaly noted in the chronic rat and mouse studies (chronic mouse study deemed unacceptable due to maximum tolerated dose (MTD) not achieved), hepatocellular necrosis in the chronic mouse study and increased liver weight observed in s ubchronic and chronic studies. Clomazone has low acute toxicity (Category III and IV) via the oral, dermal and inhalation routes. It is non - irritating to the eyes and mildly

irritating to the skin. Itis not a dermal sensitizer. No neurotoxicity studies with clomazone are available. The HASPOC, based on a WOE approach, concluded that a neurotoxicity

battery is not required for clomazone at this time. This approach considered all of the available hazard and exposure information including: 1) the lack of evidence for clinical signs of neurotoxicity

or neuropathology

in adult animals in subchronic and chro nic studies; 2) liver is the target organ for clomazone, not the neurological sy stem; 3) clomazone is absorbed and rapidl y excreted in rats with 97% of the radioactivity excreted within 168 hours; and 4) the POD and endpoint for chronic dietary risk assess ment is based on liver effects in rats which appear to be the most sensitive endpoint ( TXR No. 0056801) . There is no quantitative or qualitative evidence of susceptibility in the developmental toxicity study in rabbit s or in the 2 - generation reproduction t oxicity study in rats . In the developmental toxicity study in rats, delayed ossification occurred at doses that produced maternal effects (chromorhinorrhea and abdominogenital staining). Although qualitative susceptibility was observed in the developmental toxicity

study in rats, the concern is low since there are clear NOAELs and LOAELs and this study

was used for risk assessment , and, therefore, is protective of the developmental effects . There is no concern for mutagenicity . In the rat carcinogenicity study , there was no evidence of carcinogenicity . The mouse carcinogenicity study was inadequate to determine carcinogenic activity due to the lack of adverse effects at the highest dose tested. Despite the inadequacy of the mouse carcinogenicity study , EP A has determined that an additional mouse carcinogenicity study is not needed and that the rat chronic/carcinogenicity study will be adequate for assessing c hronic risk, including cancer. This finding is based u pon the following conclusions: (1) the rat is more sensitive than the mouse for the chronic assessment ; (2) the consistent effect in rats (decreased body weight and increased liver weight) has been used as the POD for the chronicCL OMAZONE/125401 Human Health Risk Assessment D410435

Page **14** of **49** assessment; (3) a new mouse study would onl y use doses well above the c urrent POD for the chronic assessment; and (4) even if new mouse study identified positive carcinogenicit y effects, that finding would not result in the adoption of a quantitative linear assessment of cancer risk due to the negative carcinogenicity finding in the rat study

and the lack of a positive finding for genotoxicity . **4.4 Safety factor for Infants and Children (FQPA Safety Factor)**  The chemical risk assessment team has recommended that the FQPA Safety Factor (SF) be reduced to 1X. The toxicity dat abase for clomazone is adequate for a hazard evaluation and is considered adequate to evaluate risks to infants and children. Acceptable developmental toxicity studies in the rat and rabbit and an acceptable reproduction study in the rat are available . Bas ed on the results of the available toxicity studies, there is no evidence for neurotoxicity or immunotoxicity . **4.4 .1**  **Completeness o**  **f the**  **Toxicology Database** The toxi cology database for clomazone is complete. Exposure to clomazone is expected via the oral, dermal, and inhalation rout es. A route - specific dermal study was submitted, but no subchronic inhalation s tudy has been submitted. The Hazard and Science Policy Council (HASPOC) recentl y reviewed clomazone ( TXR No. 0056801 ). HASPOC, based on a WO E approach considering all available hazard and exposure information concluded that the acute and subchronic neurotoxicity studies, the subchronic inhalation study , the carcinogenicity study in mice and the immunotoxicity study are not required at this tim e. **4.4.2 Evidence of N**  **eurotoxicity** There are no acute or subchronic neurotoxicity studies available for clomazone. There was no evidence of neurotoxic effects in an y animals in available subchronic, chronic, reproductive or developmental toxicity

studies. B ased on a WOE approach , the HASPOC concluded that the acute and subchronic neurotoxicity studies are not required at this time ( TXR No. 0056801) . **4.4.3 Evidence**  **o f Sensitivity/Su**  **sceptibility in the Developing o r Young Animal**  There was no evidence of increased quantitative or qualitative susceptibility in the prenatal developmental toxicity study in rabbits or in the reproductive toxicity study in rats with clomazone . Inthe developmental toxicity study in rats, delayed ossification occurred at doses that produced maternal effects (chromo rhinorrhea and abdominogenital staining). Although qualitative susceptibility

was observed in the developmental toxicity study in rats, the concern is low since there are clear NOAELs and LOAELs and this study was used for risk assessment and, therefore, i s protective of the developmental effects .CL OMAZONE/125401 Human Health Risk Assessment D410435

Page **15** of **49 4.4.4**  **Residual Uncertainty in the Exposure Datab**  **ase** Since the dietary

and non - dietary

exposure estimates were based on several conservative assumptions, HED does not believe that the exposure estimates are und erestimated. The acute and chronic dietary

assessments conducted with DEEM - FCID were screening level anal ys es. The assessm ents utilized tolerance values and 100% crop treated was assumed for all commodities. The DEEM analy sis also assumed that all drinki n g water will contain clomazone at the highest EDWC levels modeled by EFED for ground water or surface water. For these reasons it can be concluded that the DEEM - FCID anal ys is does not underestimate risk from acute or chronic exposure to acetochlor. Similarly, HED does not believe that the non - dietary occupational exposures are underestimated because they are also based on conservative assumptions, including maximum application rates, and standard values for unit exposures and acreage treated/amount handled. **4.5 Toxicity Endpoint and Point of**  **D eparture Selections**  **4.5.1 Dose**  **- Response Assessment**  The detailed description of the toxicity studies used for selecting toxicity endpoints and points of departure for various exposure scenarios are presented in the appendix. The specific toxicity endpoints and PODs are presented in Tables 4.5.4.1 and 4.5.4.2. Toxicological endpoints were selected for dietary

/drinking water and occupational exposure scenarios. An acute reference dose (RfD; 1.0 mg/kg/day) for a ssessment of food and drinking water exposure to females age 13 - 49 , was selected from a developmental toxicity study in rats (NOAEL = 100 mg/kg/day). The endpoint of delayed ossification identified in the developmental toxicity study in rats was chosen fo r the acute dietary

(females 13 - 49 ye ars of age) endpoint because it was considered to be an adverse effect in the developing animal and results from a single exposure. An endpoint was not selected for the general population because no adverse effect in ad ult animals was identified that resulted from a single exposure. A chronic RfD (0.84 mg/kg/day) was selected from the co critical studies of the chronic/carcinogenicity study in rats, the subchronic toxicity study in rats and the 2 - generation reproduction toxicity study in rats. The endpoint of decreased body weight, body weight gain, food consumption and in increased absolute and relative liver weight in females and increased absolute liver weight in males was chosen for the chronic dietary (all population s) endpoint because the duration of the exposure in this study is appropriate for a chronic dietary

endpoint and these effects represent the most sensitive endpoint. There are no residential uses of clomazone, therefore, an endpoint for the incidental o ral exposure scenario was not selected. A point of departure (POD) for dermal exposure was not selected because no sy stemic toxicity was observed in rats following repeated dermal application at the highest dose tested for 28 day s. Additionally , there are no quantitative sensitivities or uncertainties with clomazone to warrant an oral study for use in the dermal assessment. Therefore, a dermal assessment is not required. No inhalation toxicity studies were available for the short - term and intermediate - term inhalation scenarios. The HASPOC met on September 19, 2013, to discuss the need for a subchronic inhalation study for clomazone (TXR No. 0056801 ). The decision was made that the data requirement for this study can be waived. A short - term inhalation exposure POD (100 mg/kg/day) was selected from the developmental toxicity study in rats. The endpoint of chromorhinorrhea and abdominogenital staining was selected from theCL OMAZONE/125401 Human Health Risk Assessment D410435

Page **16** of **49** developmental toxicity

study . This study

was selected because the duration of the exposur e in this study is appropriate for the short - term endpoint. B ased on the use pattern, an intermediate term inhalation exposure scenario is not required. **4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment**  When there are potential residential exposures to the pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal and inhalation exposures. S ince there are no residential uses of clomazone , only aggregate exposure from food and water is required . A dermal endpoint was not selected. Because onl y inhalation exposure/risk was estimated in this assessment, combining risk from other routes of exposure (e.g. dermal) is not relevant. **4.5.3 Cancer Classification and Risk Ass**  **essment Recommendation** In the rat carcinogenicity study , there was no evidence of carcinogenicity. The mouse carcinogenicity

study was inadequate to determine carcinogenic activity due to the lack of adverse effects at the highest dose tested. Despite the inadequacy of the mouse carcinogenicity study , EPA has determined that an additional mouse carcinogenicity study is not needed and that the rat chronic/carcinogenicity study will be adequate for assessing c hronic risk, including cancer. This finding is ba sed u pon the following conclusions: (1) the rat is more sensitive than the mouse for the chronic assessment ; (2) the consistent effect in rats (decreased body weight and increased liver weight) has been used as the POD for the chronic assessment; (3) a new mouse study

would onl y use doses well above the current POD for the chronic assessment; and (4) even if new mouse study identified positive carcinogenicit y effects, that finding would not result in the adoption of a quantitative linear assessment of cancer risk due to the negative carcinogenicity

finding in the rat study

and the lack of a positive finding for genotoxicity . **4. 5**  **. 4**  **Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment**  The points of departure, uncertainty facto rs, and toxicity endpoints are presented in the following tables. No endpoint is selected for dermal exposure scenarios. No hazard was identified at the maximum dermal dose tested.CL OMAZONE/125401 Human Health Risk Assessment D410435

Page **17** of **49 Table 4**  **.5. 4**  **. 1**  **Summary of Toxicological Doses and Endpoints for Clom**  **azone for Use in Dietary Hum**  **an Health Risk Assessments**  **Exposure/ Scenario**  **Point of**

**Departure Uncertainty/FQPA** 

**Safety Factors RfD, PAD,** 

**Level of Concern for**  **Risk Assessment**  **Study and Toxicological Effects** Ac ute Dietary ( General Population including infants and children) An endpoint was not selected for the general population because no adverse effect in adult animals

wa s identified that resulted from a single exposure. A risk assessment is not required for this population subgroup. Ac ute Dietary ( Females 13

– 49 years old) NOAEL =

1 00 mg/kg/day UF A= 10x

UF H =10x FQPA SF= 1x Ac ute RfD =

1 .0 mg/kg/day aPAD = 1 .0 mg/kg/day Developmental Toxicity Study - Rat

(MRID 00150291 ) Developmental LOAEL = 300 mg/kg/day based on indications of delayed ossification in the form of either partial ossification or the absence of the manubrium, sternebrae 3 - 4, xiphoid, caudal vertebrae, and meta - carpals. Chronic Dietary (All Populations) NOAEL =

84.4 mg/kg/day UF A= 10x

UF H =10x FQPA SF= 1x Chronic RfD

= 0.84 mg/kg/day cPAD = 0.84 mg/kg/day **Two Year Chronic Toxicity Study**
**–**

**Rats** (MRID 00132586 ) NOAEL = 84.4/112.9 mg/kg/day, males/females (highest dose tested) LOAEL wa s not attained **Co -**  **critical 90 -**  **day Oral Rat Study** (MRID 00132586) NOAEL = 135.2/160.9 mg/kg/day, males/females LOAEL = 273/319.3 mg/kg/day, males/females, based on decreased body weight, body weight gains, food consumption and increased absolute and relative liver weights in females and increased absolute liver weights in males. **Co -**  **critical 2 -**  **Generat ion Reproduction**  **Toxicity Study** (MRID 00151108) Parental NOAEL = 50 mg/kg/day Parental LOAEL = 100 mg/kg/day based on statistically significantly decreased body weight & body weight gain during pre - mating, and decreased body weight during gestation & lactation M & F. In addition, decreased food consumption in females and hydronephritic kidneys in males. Cancer (oral, dermal, inhalation) T he chronic endpoint is protective against any effects resulting from long - term exposure to clomazone. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant humanCL OMAZONE/125401 Human Health Risk Assessment D410435

Page **18** of **49** exposures. NOAEL = no ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short - term study for long - term

risk assessment. UF DB = to account for the absence of key dat a (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. **Table 4.5. 4**  **.2 Summary of Toxicological Doses and Endpoints for Clom**  **azone for Use in Occupational Hum**  **an Health Risk Assessments**  **Exposure/ Scenario**  **Point of**

**Departure Uncertainty** 

**Factors Level of Concern** 

**for Risk Assessment**  **Study and Toxicological Effects** Dermal Short and Intermediate Term No hazard identified
Inhalation Short - Term

(1 - 30 days) NOAEL=

100 mg/kg/day UF A= 10x

UF H =10x Occupational

LOC for MOE = 100 Developmental Toxicity Study - Rat

(MRID 00150291 ) Mate rnal LOAEL = 300 mg/kg/day based on chromorhinorrhea and abdominogenital staining in maternal animals. Cancer (oral, dermal, inhalation) T he chronic endpoint is protective against any effects resulting from long - term exposure to clomazone. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine ris k associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short - term study for long - term

risk assessment. UF DB = to acc ount for the absence of key data (i.e., lack of a cr itical study). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.CL OMAZONE/125401 Human Health Risk Assessment D410435

Page **19** of **49 5.0**  **Dietary Exposure and Risk Assessment 5.1**  **Metabolite/Degradate Residue Profile 5.1.1**  **Summary of Plant and Animal Metabolism Studies** Based on metabolism studies on soy beans , corn, cotton, sweet potatoes , tomatoes and bell peppers , and alfalfa , HED concludes that the nature of the residue in plants is adequatel y understood. The major metaboli te was 2 - chlorobenzyl alcohol. The postulated major route of metab olism of clomazone in plants is hydrox yl ation of the methylene bridge carbon of clomazone to form the carbinolamide; decomposition of the unstable intermediate, the carbinolamide, to form the isoxazolidinone moiety and 2 - chlorobenzaldehyde. 2 - chlorobenzal deh yde reduces to the alcohol or is oxidized to the carbox yl ic acid. The alcohol, the carbox yl ic acid, and the isoxazolidinone metabolites form gl ycosides and/or amino acid conjugates. Minor pathway s include hydrox yl ation of clomazone to form monohydrox yl ated and possib ly dihydroxylated metabolites. Based on low levels of these metabolites found in crops, the residue of concern for regulatory and risk assessment purposes in plants is clomazone per se (PP#8E3628, M. J. Nelson, 4/22/92). As there are no liv estock feed stuffs currently associated with Brassica , rhubarb, or southern peas, issues pertaining to the nature of the residue in livestock are not germane to this petition. The nature of the residue in plants and livestock is adequatel y understood. Th e residue of concern is clomazone per se as specified in 40 CFR 180.425. **5.1.2 Summary of Environmental Degradation**  Vapor phase transport and microbial degradation appear to be the major routes of dissipation in the environment. Clomazone is stable to hydrol ys is in acidic, neutral, and alkaline solutions and does not photodegrade in either water or on soil. In soil, clomazone is metabolized under aerobic conditions with half

- lives ranging from 28 - 173 day s, depending on soil ty pe. Carbon dioxide is the m ajor degradate. Under anaerobic conditions, clomazone readil y degrades (t 1/2 : 13 day s) to (N - [(2 - chlorophenol)methyl] - 3 - hydrox y - 2,2 - dimethyl propanamide), which persists under anaerobic conditions. Clomazone has a moderately high vapor pressure of 1.44 x 10 - 4 mmHg and a high water solubility of 1100 mg/L. Considering its Henry ’s Law Constant of 4.14 x 10 - 8 atm - m 3 /mol, clomazone is expected to remain in the water column as opposed to volatilizing. However, in the terrestrial environment, clomazone may volatilize from soil. Clomazone is moderatel y mobile with Kd ’s ranging from 1.5 to 7.4 (lower in sandy soils) and Koc ’s from 139 to 608. In the field, Command 3 ME applied to bare soil at a rate of 1.25 lbs. a.i./A dissipated with a half - life of 139 day s in an I owa silty clay loam and 17 day s in a Louisiana silt loam. In both studies, parent clomazone was not detected below 6 inches. Degradates were anal yz ed for but were not detected (detection limit: 0.01 ppm). It is not clear what factor most contributed to theCL OMAZONE/125401 Human Health Risk Assessment D410435

Page **20** of **49** difference in dissipation rates at these sites, but one possibility might be that the conditions at the Louisiana site favored volatilization. Also a possibility is different soil metabolism rates in the two soils, as exemplified in the aerobic soil m etabolism study . Based on laboratory and field data, clomazone is not likely to contaminate ground water, however surface water contamination through runoff, spray

drift, and vapor phase transport is possible. In surface water, clomazone will exist in the dissolved phase and bound to suspended particulates and sediment, and may persist with half

- lives ranging from 1.5 - 2.5 months. The degradate N - [(2 - chlorophenol) methyl] - 3 - hydroxy - 2,2 - dimethyl propanamide may be found in surface water and will persist, espe ciall y under anaerobic conditions ( Clomazone Summary Document: Registration Review: Initial Docket. January

2007. EPA - HQ - OPP - 2006 - 0013) . **5.1.3 Comparison of Metabolic Pathways**  Plant metabolism studies are available for soy beans , corn, cotton, sweet potatoes , tomatoes and bell peppers , and alfalfa. The major metaboli te was 2 - chlorobenz ylalcohol. The postulated major route of metabolism of clomazone in plants is hydrox yl ation of the methylene bridge carbon of clomazone to form the carbinolamide; decom position of the unstable intermediate, the carbinolamide, to form the isoxazolidinone moiety and 2 - chlorobenzaldehyde. 2 - chlorobenzaldeh yde reduces to the alcohol or is oxidized to the carbox yl ic acid. The alcohol, the carbox yl ic acid, and the isoxazolid inone metabolites form gl ycosides and/or amino acid conjugates. Minor pathway s include hydrox yl ation of clomazone to form monohydrox yl ated and possibly dihydroxylated metabolites. A rat metabolism study

is available for clomazone. Sixteen metabolites i ncluding the parent compound were identified. The predominant metabolites were the isoxazolidinone metabolites ( FMC 87010 (4’,5’ - dihydrodiol - 5 - hydrox y - 2 - (2 - chlorophenyl)methyl - 4,4 - dimethyl - 3 - isoxazolidinone), FMC 83918 (4’,5’ - di hydrox y - 2 - (2 - chlorophenyl)m eth yl - 4,4 - dimethyl - 3 - isoxazolidinone) an d FMC 60217 (5’ - hydrox y - 2 - (2 - chlorophen yl )meth yl - 4,4 - dimethyl - 3 - isoxazolidinone ). The predominant route of excretion was in the urine. **5.1.4 Residues of Concern Summary and Rationale**  Based on metabolism studies on soy beans, corn, cotton, sweet potatoes, tomatoes and bell peppers, and alfalfa, HED concludes that the nature of the residue in plants is adequatel y understood. The residue of concern in plants is clomazone per se as specifi ed in 40 CFR 180.425. The residue of concern in ruminants and poultry is clomazone per se , although the current petition does not include any livestock feeds. Very low residues were reported in rotational crops. The residue of concern in rotational crop s is clomazone per se . The residue of concern in drinking water was discussed at a Metabolism SARC meeting on 9/12/2000, and was determined to include clomazone per se, and the major environmental degradate FMC 65317 (N - [(2 - chlorophen yl )meth yl ] - 3 - hydrox y - 2 ,2 - dimethyl propanamide ) (Kramer, G & Kidwell, J. 10/2/00; D268905) .CL OMAZONE/125401 Human Health Risk Assessment D410435

Page **21** of **49 Table 5.1.4**  **Summary of Metabolites and Degradates to be included in th e Risk**  **Assessment and Tolerance Expression**  Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants Primary Crop Clomazone Clomazone

Rotational Crop Clomazone Clomazone Livestock Ruminant Clomazone Clomazone

Poultry Clomazone Clomazone Drinking Water Clomazone + FMC 65317 * Not Applicable * FMC 6531 7 = N - [(2 - chlorophenyl)methyl] - 3 - hydroxy - 2,2 - dimethyl propanamide **5 .2**  **Food Residue**  **Profile** Residue data are adequate to support the proposed new uses. Adequate metabolism and rotational crop data were submitted in support of earlier petitions. Adequate fiel d trial data were submitted. The field trials reflected the proposed use pattern , and adequate geographic representation . The field trial data were collected using an adequate anal yt ical method; and the data were properl y supported by storage stability d ata. Samples were analyzed for clomazone, per se, which is the residue of concern. Residues were within the proposed tolerances of 0.10, 0.3 ppm, and 0.05 ppm for clomazone in or on Brassica , head and stem, subgroup 5A, rhubarb, and southern pea commodit ies, respectivel y. No adjuvants were added in any of the field trials. No processing data were needed for the proposed new uses. Broccoli: Following one preplant application of the 3 lb ai/gal ME formulation of clomazone at 0.24 - 0.25 lb ai/A, residues o f clomazone in/on broccoli flower head and stem harvested at a 52 - to 120 - day

PHI were all <LOQ (<0.03 ppm). Brassica , head and stem, subgroup 5A: There are 2 representative commodities for Brassica, head and stem, subgroup 5A, broccoli or cauliflower, and cabbage. The broccoli residue data are discussed above. A tolerance has been established for residues of clomazone on cabbage at 0.1 ppm (PP#4E 4311, N. Dodd, D199086, 04/17/95, MRID 43077301 ) . Command 4EC was applied at 0.5 lb ai/A as a single broadcast application in at least 10 gallons of water per acre, using ground equipment before seeding or transplanting cabbage. Clomazone is incorporat ed to a depth of 1 inch or less. Residues were reported to be non - quantifiable at less than 0.1 ppm except in one sample in which interferences were noted, and the limit of quantitation was 0.17 ppm. Rhubarb : Following two foliar broadcast applications of the 3 lb ai/gal ME formulation of clomazone at 2.49 - 2.76 (~1.7

– 1.8x) and 1.71 - 1.99 lb ai/A (~1.1

– 1.3x), respectively , residues of clomazone (and per trial averages) in/on rhubarb petioles harvested at a 41 - to 44 - day PHI were <0.03 - 0.180 (<0.033 - 0.1 14) and <0.03 - 0.076 (<0.03 - 0.062) ppm.CL OMAZONE/125401 Human Health Risk Assessment D410435

Page **22** of **49** Southern Peas : Following one pre - emergent broadcast application of the 3 lb ai/gal ME formulation of clomazone at 0.484 - 0.501 lb ai/A, residues of clomazone in/on shelled succulent pea and fresh plants with pods and shelled dry pea and dry

plants with pods and harvested at a 62 - to 77 - day

and 77 - to 91 - day

PHIs, respectively , were all <LOQ (<0.05 ppm). **TABLE 5.2. Summ ary of Residue Data from** **Field Trials with Clom**  **azone.** Commodity Analyte Total Rate (lb ai/A) PHI

(days) Residue Levels (ppm) 1

n Sample Min. Sample Max. LAFT 2 HAFT 2 Median Mean Std . Dev. Broccoli Clomazone 0.24 - 0.25 52 - 120 8 <0.03 <0.03 <0.03 <0.03 0.03 0.03 N/A Rhubarb Petioles Clomazone 2.49 - 2.76 41 - 44 4 <0.03 0.180 <0.033 0.114 0.046 0.060 0.038 1.71 - 1.99 4 <0.03 0.076 <0.03 0.062 0.044 0.045 0.017 Shelled Succulent Pea Clomazone 0.484 - 0.501 62 - 77 4 <0.05 <0.05 <0.05 <0.05 0.05 0.05 N/A Pla nts With Pods, Fresh 4 <0.05 <0.05 <0.05 <0.05 0.05 0.05 N/A Shelled Dry Pea 77 - 91 4 <0.05 <0.05 <0.05 <0.05 0.05 0.05 N/A Pla nts with Pods, Dry 4 <0.05 <0.05 <0.05 <0.05 0.05 0.05 N/A 1 Except for sample min/max, values reflect per trial averages; n = no . of field trials . N/A = Not applicable. 2 LAF T = lowest average field trial; HAFT = highest average field trial. **5.3 Water Residue Profile**  The drinking water residues used in the dietary risk assessment were provided by the Environmental Fate and Effects Division (EFED) in the following memorand a : “ Clomazone: Drinking Water Exposure Assessment for Proposed New Uses for Brassica (Head and Stem Subgroup 5A), Southern Peas, and Rhubarb ” ( Both memoranda under D 408878 by J. L in and dated 7/23/13 or 9/24/13 ) . These estimated drinking water concentrations (EDWCs) were incorporated directl y into this dietary assessment in the DEEM - FCID into the food categories “water, direct, all sources” and “water, indirect, all sources.” EFED generated the surface water ED WCs using FQPA Index Reservoir Screening Tool ( FIRST) and the Tier 1 Rice model. Ground water EDWCs were generated using Pesticide Root Zone Model for Ground Water (PRZM - GW) and Screening Concentration In GROund Water ( SCI - GROW ) . EDWCs were derived based on the maximum registered/proposed use rate (1.5 lb ai/A existing for tuberous and corm vegetables and proposed for rhubarb) and the maximum registered use rate on rice (dry - seeded 0.8 lb ai/A). The Tier 1 Rice model (dry- seeded scenario) produced the hi ghest EDWCs for both acute and chronic at 550 ppb and this estimate was used in both the acute and chronic dietary risk assessments.CL OMAZONE/125401 Human Health Risk Assessment D410435

Page **23** of **49 Table**  **5.3 . EDWCs for the Clom**  **azone Human Health Risk Assessment Source (Tier: Model)**  **Maximum Annual Rate Acute**  **E DWC**  **(μg/L) Chronic** 

**EDWC (μg/L)**  Surface Water (Tier 1: FIRST) 1.5 lb ai/A 89.2 12.8 Surface Water (Tier 1: Rice Model) 1 0.8 lb ai/A (dry - seeded scenario) 2 **550** Ground Water (Tier 1: PRZM - GW) 1.5 lb ai/A 85.7 77.4 Ground Water (Tier 1: SCI - GROW) 1.5 lb ai/A 0.0338 1 Calculates the water - column exposure expected on the day of application to a flooded rice paddy, accounting only for sorption to sediment as a dissipation process. No other degradation processes, such as hydrolysis, photolysis, or metabolism are conside red. Hence, this exposure modeling is inclusive of all of the residues of concern (parent plus FMC 65317). 2 Clomazone used in dry - seeded rice culture is subject to dissipation (volatilization and aerobic metabolism) after application but prior to floo ding; however, significant levels of the metabolite FMC 65317 are not expected to form during this interval under these aerobic conditions. The potential dissipation of the parent after application but prior to flooding was accounted for in the calculated concentration/use rate for clomazone (0.707 lb ai/A) used in the Tier 1 Rice Model. [Reviewer Note: The maximum registered use rate for clomazone on wet - seeded rice (0.6 lb ai/A) is less than that used in the Tier 1 Rice Model.] The drinking water models and their descriptions are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/ . **5.4 Dietary Risk Assessment**  Clomazone acute and chronic dietary exposure assessments were conducted using the DEEM FCID, Version 3.16, which incorporates 2003 - 2008 consumption data from USDA’s NHANES/WWEIA. This software uses 2003 - 2008 food consumption data from the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey , What We Eat in America, (NHANES/WWEIA). The anal ys es were conducted for the proposed Section 3 uses of clomazone on Brassica , head and stem (Subgroup 5A), rhubarb, and southern pea. This memorandum was reviewed b y two peer reviewers o f the DE SAC , per DESAC SOP 2012.1. Both the acute and chronic assessments are highl y conservative and incorporated tolerance level residues, assumed 100% crop treated and used default processing factors. Screening - level Tier I modeling was used to estim ate drinking water concentrations. **5.4.1 Description of Residue Data Used in Dietary Assessment**  Both the acute and chronic assessments incorporated tolerance level residues and used default processing factors. **5.4.2 Percent Crop Treated Used in**  **Dietary Assessment** The acute and chronic assessments are based on the assumption that 100% of all commodities with tolerances will be treated.CL OMAZONE/125401 Human Health Risk Assessment D410435

Page **24** of **49 5.4.3**  **Acute Dietary Risk Assessment** T he acute dietary

risk estimate at the 95 th percentile of exposure utilized 3.0 % of the acute population adjusted dose (aPAD) for females 13 - 49 years old. This is the only population subgroup for which an acute endpoint was selected. The acute dietary risk estimate for females 13 - 49 years old is not of concern. **5.4.4 Chr**  **onic Dietary Risk Assessment** The c hro nic dietary

risk estimates are ≤3.6% of the chronic population adjusted dose (cPAD) for all population subgroups. All Infants < 1 year of age is the most highly exposed subgroup, utilizing 3.6 % of the cPAD, while the g eneral US population utilizes 1.4 % of the cPAD. The chronic dietary

risk estimates are not of concern. **5.4.5 Cancer Dietary Risk Assessment**  EPA has concluded that the chronic PAD for clomazone will be protective of any cancer risk posed by clomazone . Add itionally , EPA is relying on the chronic dietary exposure assessment to evaluate cancer risk. **5.4.6 Summary Table**  **Table 5.4.6. Summary of Dietary (Food and Drinking Water)**  **Exposure and Risk for Clom azone.**  **Population Subgroup Acute Dietary**  **(95th Percentile)**  **Chronic Dietary Cancer**  **Dietary Exposure**  **(m g/kg/day)**  **% aPAD*** **Dietary Exposure**  **(m g/kg/day)**  **% cPAD*** **Dietary Exposure**  **(m g/kg/day)**  **Risk** General U.S. Population

N/A N/A 0.0 11624 1. 4 **All Infants (<1 year old) 0.02**  **9942 3.**  **6**

N/A N/A Children 1 - 2 years old 0.01 6899 2.0 Children 3 - 5 years old 0.01 4233 1. 7 Children 6 - 12 years old 0.0 10243 1. 2 Youth 13 - 19 years old 0.00 8475 1 .0 Adults 20 - 49 years old 0.0 11576 1. 4 Adults 50 - 99 years old 0.0 11451 1. 4 **Fem ales 13**  **- 49 years**  **old 0.0**  **30050 3.0**  0.0 11536 1. 4 **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  Currently , there are no registered or proposed residential uses for clomazone. **6.1 Spray Drift**  Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularl y the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application method s (e.g., groundboom andCL OMAZONE/125401 Human Health Risk Assessment D410435

Page **25** of **49** airblast) emplo yed for clomazone **.** The Agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call - Inissued by

EPA), EPA Regional Offices and State L ead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency ’s Spray Drift website for more information). 2 The Agency is also taking means to qualitatively and qualitatively

address s pray

drift as a potential source of exposure in risk assessments for pesticides through existing programs such as Ag Drift and chemical specific properties of pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently . **6.2 Residential Bystander Postapplication Inhalation Exposure**  Based on the Agency 's current practices, a quantitative post - application inhalation exposure assessment was not performed for clomazone at this time primarily because of the low acute inhalation toxicity

(Toxicity Category IV). However, volatilization of pesticides may be a source of post - application inhalation exposure to indiv iduals nearb y pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received th e SAP’s final report on March 2, 2010 3 . The Agency is in the process of evaluating the SAP report and may , as appropriate, develop policies and procedures to identify the need for and, subsequently , the way to incorporate post - application inhalation expos ure into the Agency's risk assessments. If new policies or procedures are developed, the Agency may revisit the need for a quantitative post - application inhalation exposure assessment for clomazone . **7.0 Aggregate Exposure/Risk Characterization**  In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to qu antitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. **7.1 Acute Aggregate Risk**  In examining acute aggregate risk, HED has assumed that the only pathway of exposure relevant to the acute time frame is dietary exposure. Therefore, the acute aggregate risk is comprised of exposures to clomazone residues in food and drinking water and is equivalent t o the acute dietary risk estimates summarized in Table 5.4.6 in Section 5.4.3. The acute dietary risk estimates are well below HED’s level of concern for the general population and all population subgroups.

2 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm 3 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htm lCL OMAZONE/125401 Human Health Risk Assessment D410435

Page **26** of **49 7.2**  **Short -**  **Term Aggregate Risk** Currently , there ar e no registered or proposed residential uses for clomazone, therefore, a short term aggregate risk assessment is not required. **7.3 Intermediate**  **- Term Aggregate Risk**  Currently , there are no registered or proposed residential uses for clomazone, therefore, an intermediate - term aggregate risk assessment is not required. **7.4 Chronic Aggregate Risk**  In examining chronic aggregate risk, HED has assumed that the only pathway of exposure relevant to the chronic time frame is dietary exposure. Therefore, the chronic aggregate risk is comprised of exposures to clomazone residues in food and drinking water and is equivalent to the chronic dietary

risk estimates summarized in Table 5.4.6 in Section 5.4.4. The chronic risk estimates are below HED’s level of concern f or all population subgroups. **7.5 Cancer Aggregate Risk**  E PA has concluded that the cPAD is protective of any cancer risk clomazone poses to humans. As noted above, chronic dietary exposure is 3.6 % of the cPAD for the highest exposed population subgroup . **8.0 Cumulative Exposure/Risk Characterization**  Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity , EPA has not made a common mechanism of toxicity finding as to clomazone and an y other substances and clomazone does not appear to produce a toxic metabolite produced b y other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that clomazone has a common mechanism of toxicity with other subst ances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by

EPA’s Office of Pesticide Programs concerning co mmon mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/. **9.0 Occupational Exposure/Risk Characterization**  **9.1 Short**  **- Term**  **Handler Risk** HED uses the term handlers to describe those individuals who are involved in the pesticide application process. Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handle r exposure is expected from the proposed uses on Brassica , rhubarb and southern peas . The quantitativeCL OMAZONE/125401 Human Health Risk Assessment D410435

Page **27** of **49** exposure/risk assessment developed for occupational handlers is based on the following scenarios: 1) Mixing/loading liquids for groundboom applications; and 2) Applying spray s via groundboom equipment. Summary of Occupational Handler Non - Cancer Exposure and Risk Estimates As summarized in Table 9.1 , the occupational handler exposure and risk estimates indicate that the short - term inhalation MOEs are not of co ncern to HED (i.e., MOE > 1 00 ) with out the use of a respirator . Onl y exposure from use on rhubarb was quantitatively assessed because it s higher application rate is considered to be protective of the proposed uses on Brassica and Southern pea. **Table 9.**  **1. Short**  **- Term** **Occupational Handler Non -**  **Cancer Exposure and Risk Estimates for Clom azone**  **Exposure Scenario Crop or** 

**Target Inhalation** 

**Unit Exposure**  **(μg/lb ai) 1**  **Maximum**

**Application Rate**  **2 Area Treated or** 

**Am ount**  **Handled Daily 3**  **Inhalation (LOC = 100)**  **Baseline Dose**  **(m g/kg/day)**  **4 MOE**  **5** Mixer /Load er Mixing/loading liquid formulation for groundboom application Rhubarb 0.219 1.5 lb ai/A 80 0.00033 300,000 Appl icator Groundboom application of liquid formulation Rhubarb 0.34 1.5 lb ai/A 80 0.00051 200,000 1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ; Level of mitigation: no respirator. 2 Based on registered or proposed label (Reg. No. 279 - 3158). 3 Exposure Science Advisory Council Policy #9.1. 4 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/ μg) × Application Rate (lb ai/acre) × Area

Treated or Amount Handled (A/day) ÷ BW (80 kg). 5 Inhalation MOE = I nhalation NOAEL (100 mg/kg/day) ÷ I nhalation Dose (mg/kg/day). **9.2 Post**  **- Application**  **Risk** HED uses the term post - application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re entry exposure). Such exposures may occur wh en workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Post - application exposure levels vary over time and depend on such things as the ty pe of activity , the nature of the crop or target that was treated, the ty pe of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatl y reduce the potential for post - application exposure.CL OMAZONE/125401 Human Health Risk Assessment D410435

Page **28** of **49 9.2.1**  **Dermal Postapplication Risk** P ost - application dermal exposure and risk estimates were not evaluated as toxicity was not observed up to the limit dose in a dermal toxicity study , and no developmental or reproductive toxicity was seen in the database. Restricted Entry

Interval T he restricted entry

interval (REI) is based on the acute toxicity of clomazone technical material. Clomazone is classified in Toxicity Category IV for acute dermal toxicity , primary eye and skin irritation. Therefore, a 12 - hour REI under 40 CFR 156.208 (c) (2) (i) is required . The 12 - hour REI , which currently

appears on the Command ® 3M label, is adequate for the proposed uses. **9.2.2 Inhalation Postapplication Risk**  Based on the Agency 's current practices, a quantitative post - application inhalation exposure assessment was not performed for clomazone at this time primarily because of the low acute inhalation toxicity

(Toxicity Category IV). However, there are multiple potential sources of post - appli cation inhalation exposure to individuals performing post - application activities in previously

treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 4 . The Agenc y is in the process of evaluating the SAP report as well as available post - application inhalation exposure data generated b y the ARTF and may , as appropriate, develop policies and procedures, to identify the need for and, subsequently , the way

to incorporate occupational post - application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post - application inhalation exposure assessment for clomazone . Although a quantitative occupational post - application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pestic ides outdoors is likely to result in higher exposure than post - application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post - application inhalation exposure scenarios.

4 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlCL OMAZONE/125401 Human Health Risk Assessment D410435

Page **29** of **49 10.0**  **References** Cropp - Kholligian, B. 12/6/2013. D410437. Clomazone. Acute and Chronic A ggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment s for Proposed New Uses on Brassica , Head and Stem (Subgroup 5A), Rhubarb, and Southern Pea. Humme l, S . , 9 / 5 /2013, D410436 . “ Clomazone. PP#2E8136. Brassica , Head and Stem, Subgroup 5A; Rhubarb; and Pea, Southern. Summary of Anal yt ical Methods and Residue Data. ” EPA Memorandum. Kramer, G . and Kidwell, J . , 10/2/20 00 . D268905. “Ad Hoc RED Metabolism Assessment Review Committee (MARC) Meeting of 9/12/00. Clomazone. Residues of Concern in Drinking Water.” EPA Memorandum. Lin, J. 7/23/2013. D408878. Clomazone: Drinking Water Exposure Assessment for Proposed New Uses for Brassica (Head and S tem, Subgroup 5A), Southern Peas, and Rhubarb. Lin, J. 9/24/2013. D408878. Clomazone: Drinking Water Exposure Assessment for Proposed New Uses for Brassica (Head and Stem, Subgroup 5A), Southern Peas, and Rhubarb. Update. O’Rourke, K. 1 2 / 17 /2013. D410438 . Clomazone. Occupational and Residential Exposure Assessment for a Proposed Use on Brassica , Rhubarb and Southern Peas. EPA Memorandum. Rury , K . 1/8/2014 . TXR No. 0056801 . “Clomazone: Summary of Hazard and Science Policy Council (HASPOC) Meeting of September 19, 2013: Recommendations on the need for multiple studies.” EPA Memorandum datedCL OMAZONE/125401 Human Health Risk Assessment D410435

Page **30** of **49 A**  **ppendix A**  **. Toxicology Profile and Executive Summaries**  **A.1 Toxicology Data Requirements**  The requirements (40 CFR 158.340) for food use for Clomazone are in Table 1. Use of the new guideline numbers does not imply that the ne w (1998) guideline protocols were used. **Study Technical**  **Required Satisfied**  870.1100 Acute Oral Toxicity 870.1200 Acute Dermal Toxicity 870.1300 Acute Inhalation Toxicity 870.2400 Primary Eye Irritation 870.2500 Primary Dermal Irritation 870.2600 Dermal Sensitization yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 Oral Subchronic (rodent) 870.3150 Oral Subchronic (nonrodent) 870.3200 21/28 - Day Dermal 870.3250 90 - Day

Dermal 870.3465 90 - Day

Inhalation yes yes yes no yes yes

no yes

- no* 870.3700a Developmental Toxicity (rodent) 870.3700b Developmental Toxicity (nonrodent) 870.3800 Reproduction yes yes yes yes

yes yes 870.4100a Chronic Toxicity (rodent) 870.4100b Chronic Toxicity (nonrodent) 870.4200a Oncogenicity (rat) 870.4200b Oncogenicity (mouse) 870.4300 Chronic/Oncogenicity yes yes yes yes yes yes

yes

- no* yes 870.5100 Mutagenicity

—Gene Mutation - bacterial 870.5300 Mutagenicity

—Gene Mutation - mammalian 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations 870.5xxx Mutagenicity

—Other Genotoxic Effects yes yes yes yes yes

yes yes

- 870.6100a Acute Delayed Neurotoxicity (hen) 870.6100b 90 - Day

Neurotoxicity (hen) 870.6200a Acute Neurotoxicity Screening Battery (rat) 870.6200b 90 - Day

Neurotoxicity Screening Battery (rat) 870.6300 Develop. Neurotoxicity no no no no no -

-

- *

- *

- 870.7485 General Metabolism 870.7600 Dermal Penetration 870.7800 Immunotoxicity yes no yes yes

no no* Special Studies for Ocular Effects Ac ute Oral (rat) Subchronic Oral (rat) Six - mo nth Oral (dog) no

* Waived at HASPOC September 19, 2013 ( TXR No. 0056801 )CL OMAZONE/125401 Human Health Risk Assessment D410435

Page **31** of **49 A.2**  **Toxicity Profiles**  **Table 1. Acute Toxicity Profile**
**– Clomazone**  **Guideline No. Study Type [species]**  **MRID(s) Results**  **a Toxicity**  **Category** 870.1100 Ac ute oral [rat] 00117121 LD 50 2077.0 mg/kg

– 1369.0 mg/kg III 870.1200 Ac ute dermal [rabbi t] 00117122 LD 50 > 2 000 mg/kg I II 870.1300 Ac ute inhalation [rat] 00117123 LC 50 =6.52 mg/L

– 4.23 mg/L IV
870.2400 Ac ute eye irritation [rabbit] 00117124 Almost non - irritating at 1 hour in washed and unwashed eyes I II
870.2500 Ac ute dermal irritation [rabbit] 00117125 Minimally irritating at 24 and 72 hours I II 870.2600 Skin sensitization [guinea pig] 00117126 Non - sensitizer NA **Table A.2.2 Subchronic, Chronic and Other Toxicity Profile**  **- Clomazone**  **Guideline No.**  **Study Type MRID**  **No. (year)/ Classification /Doses**  **Results** 870.3100 90 - Day oral toxicity

rodents 00132586 (1982)

Males: 0, 1.4, 6.9, 34.5, 68.2, 135.2, 273, 552.2 mg/kg/day Females: 0, 1.6, 8.2, 41.9, 83.4, 160.9, 319.3, 629.4 mg/kg/day NOAEL = 135.2/160.9 mg/kg/day, males/females LOAEL = 273/319.3 mg/kg/day, males/females, based on decreased body weight, body weight gains, food consumption and increased absolute and relative liver weights in females and increased absolute liver weights in males Acceptable/Guideline 870.3100 90 - Day oral toxicity

mouse 00132585 (1983)

0, 3, 15, 75, 150, 300, 600, 1200 mg/kg/day NOAEL  1200 mg/kg/day (limit dose) LOAEL >1200 mg/kg/day Acceptable/guideline 870.3200 28 - Day dermal

toxicity rats 46021101 (2003 )

0 or 1000 mg/kg/day sy stemic NOAEL = 1000 mg/kg/day. sy stemic LOAEL = Not established Acceptable/Guideline 870.3700a Prenatal

developmental in rodents 00150291 (1984)

0, 100, 300, 600 mg/kg/day (gavage) Maternal NOAEL = 1 00 mg/kg/day. Maternal LOAEL = 3 00 mg/kg/day based on chromorhinorrhea and/or abdominogenital staining. D evelopmental toxicity NOAEL = 1 00 mg/kg/day D evelopmental toxicity LOAEL = 3 00 mg/kg/day based on indications of delayed ossification in the form of either partial ossification or the absence of the manubrium, sternebrae 3 - 4, xiphoid, caudal vertebrae, and meta - carpals. Acceptable/GuidelineCL OMAZONE/125401 Human Health Risk Assessment D410435

Page **32** of **49 Table A.2.2**  **Subchronic, Chronic and Other Toxicity Profile -**  **Clomazone Guideline**  **No. Study Type**  **MRID No. (year)/**  **Classification /Doses Results**  870.3700b Prenatal

developmental in (New Zealand White) ra bbits 00133220 (1982)

0, 30, 240, 1000/700 mg/kg/day Maternal NOAEL = 240 mg/kg/day LOAEL = 700 mg/kg/day based on effects seen at 1000 mg/kg/day, which included mortality, abortions, decreased body wt. gain, and decreased defecation or no feces Developme ntal NOAEL  700 mg/kg/day (HDT) LOAEL > 700 mg/kg/day Acceptable/Guideline 870.3800 Two - Generation

Reproduction and fertility effects (CD) rats 00151108 (1984)

0, 5, 50, 100, 200 mg/kg/day Parental NOAEL = 50 mg/kg/day Parental LOAEL = 100 mg/kg/day based on statistically significantly decreased body wt. & body wt. gain during pre - mating, and decreased body wt. during gestation & lactation M & F. In addition decreased food consumption in females and hydro nephritic kidneys in males. Develop mental NOAEL = 50 mg/kg/day Developmenta l LOAEL = 100 mg/kg/day based on decreased body weight in F2a and F2b litters Acceptable/Guideline 870.4100b Chronic toxicity

dogs 00150290 (1984)

Males: 0, 19, 94, 487, 1038 mg/kg/day Females: 0, 21, 106, 502, 1012 mg/kg/day NOAEL  1038/1012 mg/kg/day, males/females (HDT) LOAEL >1038/1012 mg/kg/day Acceptable/Guideline 870.4200 Chronic

toxicity/Carcinogeni city rat s 00132586 (1984)

Males: 0, 0.9, 4.3, 21.5, 42.9, 84.8 mg/kg/day Females: 0, 1.1, 5.5, 27.8, 56.5, 112.9 mg/kg/day NOAEL = 84.4/112.9 mg/kg/day, males/females (highest dose tested) LOAEL not attained Not carcinogenic to rats Acceptable/Guideline 870.4300 Carcinogenicity

mice 00132585, 00132587,

00144244 (1983) 0 , 3, 15, 75, 150, 300 mg/kg/day NOAEL = 300 mg/kg/day (highest dose tested) LOAEL = >300 mg/kg/day N o evidence of carcinogenicity Una cceptable/Guideline 870.5100 Gene Mutation

(Salmonella typhimurium and Escherichia coli reverse gene mutation assay) 00142238 (1984)

FMC 65361 (>98%) 3 - chloropivaloyl chloride (starting material in the clomazone manufacturing process) Starting material FMC 65361 caused a positive mutagenic response in tester strain TA100 both in the absence and presence of microsomal activation. Acceptable/Guideline 870.5100 Gene Mutation

(Salmonella typhimurium and Escherichia coli reverse gene mutation assay) 00142243 (1984)

FMC 57090 hydroxamic acid, an intermediate in the manufacturing process for clomazone technical In the absence of reported cytotoxicity, the test article [FMC 57090 (intermediate)] increased (more than doubling) the frequency of histidine prototrophy ( his + ) in both base substitution strains TA1535 and TA100 under both non - activation and activation ( + S9) cultures in a dose - responsive manner at 5000 and 10,000 μg/plate, i.e., a positive response. Acceptable/Guideline 870.5100 Gene Mutation

(Salmonella 00142242 (1983)

FMC 57090 (99%), In the absence of reported cytotoxicity, the test article [FMC 57090 (intermediate)] increased (2 toCL OMAZONE/125401 Human Health Risk Assessment D410435

Page **33** of **49 Table A.2.2**  **Subchronic, Chronic and Other Toxicity Profile -**  **Clomazone Guideline**  **No. Study Type**  **MRID No. (year)/**  **Classification /Doses Results**  typhimurium reverse gene mutation assay) hydroxamine acid, an

intermedi ate in the manufacturing process for clomazone. 3.5 fold) in the frequency of histidine prototrophy ( his + ) both base substitution strains TA1535 and TA100 under both in the presence or absence of S9 activation. Metabolic activation system was not characterized. Therefore, under the conditions of this assay, the mutagenic potential cannot be ascertained . Unacceptable 870.5100 Gene Mutation

(Salmonella typhimurium reverse gene mutation assay) 00142244 (1984)

FMC 22896 (>98%) 3 - chloropivalic acid, an intermediate in the manufacturing process for clomazone FMC 22896 (intermediate) was positive for mutagenicity in the base substitution strains TA100 and TA1535 in the absence of overt cytotoxicity. Acceptable 870.5100 Gene Mutation

(Salmonella typhimurium and Escherichia coli reverse gene mutation assay) 00150292 (1984)

FMC 57020 (clomazone, 93.4% a.i.) The test article (technical) was assayed up to cy totoxic concentrations (5000 μg/plate), but in no instance were appreciably increased number of revertants to histidine prototrophy ( his + ) found in any of the tester strains, either in the presence or absence of metabolic activation. Accep table/Guideline 870.5375 Cy

togenetics In vitro mammalian cell cytogenetic assay in CHO cells 00144187 (1984)

FMC 57090 (98%) hydroxamic acid, an intermediate in the manufacturing process for clomazone technical The test article [FMC 57090 (intermediate)] did not induce a significant increase in presumed mutant colonies over control when assayed up to the limit of solubility (700 - 800 μg/mL). Acceptable 870.5395 Cy

togenetics In vivo rat 00133222 (1982) Technical was negative. The incidence of aberrations and the aberrations/cell were not significantly increased. Acceptable 870.5550 Other Effects

In vitro UDS assay in primary rat hepatocytes 00133223 (1983)

FMC 57020 (clomazone, 88.8%) Clomazone was tested up to cytotoxicity (relative toxicity at 0.10 μL/mL was 88.6%), but in no cultures treated with test article was a significant increase in mean net nuclear counts indicative of UDS recorded. Acceptable 870.7485 Metabolism and

pharmacokinetics 00142234, 00142233 (1984) Clomazo ne is extensively metabolized by the liver and excreted in the urine and feces within 24 hours. Sixteen metabolites, including the parent, were identified; and the predominant route of excretion was in urine. AcceptableCL OMAZONE/125401 Human Health Risk Assessment D410435

Page **34** of **49 A.3**  **Hazard Identification and Endpoint Selection A.3.1**  **Acute Reference Dose (aRfD) -**  **Females age 13 -**  **49 Study Selected:**  Developmental Toxicity in Rats **MRID No.:** 00150291 **Dose and Endpoint for Risk Assessment:** NOAEL= 100 mg/kg/day based on delayed ossification observed at the LOAEL of 300 mg/kg/day . **Comments about Study/Endpoint/Uncertainty Factors:** The skeletal anomalies observed in this study are presumed to occur after a single dose (acute exposure) and are appropriate for females 13 - 49 years old because they occur in utero . The total UF is 100 (10X for interspecies uncertainty factor and 10X for intraspecies variability). The FQPA safet y factor of 1X is applicable for acute dietary risk assessment. Th erefore, the aPAD is equivalent to the aRfD of 1.0 mg/kg/day .

**Acute RfD (Females 13 -**  **49 years old) = (NOAEL) 100 mg/kg**  **= 1.0 mg/kg/day (UF) 100**  **A.3.2 Acute Reference Dose (aRfD)**  **- General Population including**  **Infants and Children** A dose and endpoint were not selected for this population group because there were no effects observed in oral toxicology studies including maternal toxicity in the developmental toxicity studies in rats and rabbits that are attributa ble to a single exposure (dose). A risk assessment is not required for this population subgroup. **A.3.3 Chronic Reference Dose (cRfD) Study Selected:**  2 - year chronic/carcinogenicity study in rats; 90 - day oral toxicity

study in rats; 2 - generation reproduc tion toxicity study in rats. **MRID No.:** 00132586; 00132586; 00151108 **Dose and Endpoint for Risk Assessment:** NOAEL= 84.4 mg/kg/day based on decreased body weight, body weight gain, food consumption and in increased absolute and relative liver weight in females and increased absolute liver weight in males observed at the LOAEL of 273/319.3 mg/kg/day

in males and females, respectivel y. **Comments about Study/Endpoint/Uncertainty Factors:** The NOAEL of 84.4 mg/kg/day from the rat chronic carcinogenicity study was selected as the POD and supported by the co critical studies of the 90 - day oral toxicity

study and the 2 - generation reproduction toxicity study . The 90 - day

oral toxicity

study had a NOAEL of 160.9 mg/kg/day in females and a LOAEL of 319.3 mg/kg/day in females, based on decreased body weight, body weight gains, and food consumption and increased absolute and relative liver weights in females. In the 2 - generation reproductive toxicity

study , the parental NOAEL = 50 mg/kg/day with a LOAEL = 100 mg/kg/day

based on statistically

significantl y decreased body weight and body weight gain during pre - mating and decreased body weight during gestation and lactation in males and females, a statisticall y significant decrease in food consumption in females and hydro - nephritic kidney s in males. T he NOAEL in the 2 - generation reproduction toxicity study is lower (50CL OMAZONE/125401 Human Health Risk Assessment D410435

Page **35** of **49** mg/kg/day) than the NOAELfrom the 2 - ye ar rat study (84.4 mg/kg/day), however, the NOAEL from the 2 - ye ar study was selected due to the longer duration of the study and the fact that the difference in the dose is due to the difference in the calculated food intake between the two studies. The 2 - year rat study used actual consumption data (measured weekly) whereas the 2 - generation study used the standard food conversion values to estimate consumption. The total UF is 100 (10X for interspecies variability and 10X for intraspecies variability). **Chronic RfD (General Population) = (NO**  **AEL) 84.4 mg/kg = 0.84 mg/kg**  **(UF) 100 A.3.4**  **Incidental Oral Exposure (Short -**  **and Intermediate -**  **Term)** There are no residential uses of clomazone and therefore, no endpoints were selected for this exposure scenario. **A.3.5 Dermal Exposure (Short**  **- Term**  **)** No hazard was identified for quantification of risk following dermal exposure. In a 28 - day dermal toxicity

study (MRID 46021101), no s ys temic toxicity was seen following repeated dermal application of clomazone technical (9 2.7% ai) to the hair - clipped, intact skin of ten Sprague - Dawley

CD rats/sex/dose at dose levels of 0 or 1000 mg/kg bw/day (limit dose) for 6 hours/day , 5 day s/week during a 28 - day period. Additionally , there are no quantitative sensitivities or uncertaint ies with clomazone to warrant an oral study for use in the dermal assessment. Therefore, a dermal assessment is not required. **A.3.6 Inhalation Exposure (Short**  **- Term)**  **Study Selected:** Developmental Toxicity Study in Rats **MRID No.:** 00150291 **Dose and Endpoint for Risk Assessment:**  100 mg/kg/day based on a NOAEL of 100 mg/kg/day , based on chromorhinorrhea and abdominogenital staining at the maternal LOAEL of 300 mg/kg/day . **Comments about Study/Endpoint/Uncertainty Factors:** In the absence of a route - specific study , the oral developmental toxicity study in rats was selected and a 100% absorption factor was applied. The duration of this study is appropriate for this exposure scenario. The total UF is 100 (10X for interspecies variability and 10X for intraspecies variability). **A.3.7 Inhalation Exposure (Intermediate**  **- Term)**  **Study Selected:** 2 - year chronic/carcinogenicity study in rats; 90 - d ay oral toxicity

study in rats; 2 - generation reproduction toxicity study in rats. **MRID No.:** 00132586; 00132586; 00151108 **Dose and Endpoint for Risk Assessment:** NOAEL= 84.4 mg/kg/day based on decreased body weight, body weight gain, food consumption and in increased absolute and relative liver weight in females and increased absolute liver weight in males observed at the LOAELof 273/319.3 mg/kg/day

in males and females, respectivel y.CL OMAZONE/125401 Human Health Risk Assessment D410435

Page **36** of **49 Comments about Study/Endpoint/Uncertainty Factors:**  In the absence of a route - specific study , the co - critical oral studies were selected and a 100% absorption factor was app lied. The duration of these studies is appropriate for this exposure scenario. The total UF is 100 (10X for interspecies variability

and 10X for intraspecies variability). **A.4 Executive Summaries**  **A.4.1 Subchronic Toxicity**  **870.3100 90**  **- Day Oral**  **Toxicity**
**— Rat**  In a subchronic toxicity

study (MRID 00132586) FMC 57020 Technical (Purity 91.4 %, Reference E1756 - 146)was administered to 120 rats/sex/dose in the diet at concentrations of 0, 20, 100, 500, 1000, 2000, 4000, or 8000 ppm. These concentration s resulted in mean concentrations of 0, 1.4, 6.9, 34.5, 68.2, 135.2, 273.0, or 552.2 mg/kg/day (males), and 0, 1.63, 8.2, 41.9, 83.4, 160.9, 319.3, or 629.4 mg/kg/day (females) for up to 15 weeks. Interim sacrifices consisting of 10 rats/sex/group were c onducted at 30 and 60 days and blood determinations and gross necrops y (tissues not saved) were performed on these rats. The final sacrifice consisted of 20 rats/sex/group, with hematological anal ys is, urinaly sis, gross necrops y, and histopathological eva luation conducted. In addition, during the recovery phase of study for the 4000 and 8000 ppm groups, 5 rats/sex/group were sacrificed at 30, 60 and 90 days of recovery . The toxic effects of this substance did not manifest themselves as overt clinical si gns at an y time during the study. The survival rate for this study was 100 % for all groups, control and treated. Decreased mean body weights (87 - 95% of control) among males and females fed 8000 ppm achieved statistical significance (p < 0.01) througho ut the study when compared with the respec tive control groups. Mean overall body weight gain for males and females was 84 and 75 %, (no statistical anal ys is performed) respectivel y of the control group means. Females fed 4000 ppm had a mean overall body weight gain that was 86 % of the control mean and had significantl y decreased (p < 0.01) mean absolute body weights (92 - 96 % of control) at several of the weekl y weighings. The effects on body weight at the two highest doses were considered biologicall y significant adverse manifestations of test - substance exposure. Food consumption and food efficiency were also decreased among males and females at 8000 ppm. Males had significantly (p < 0.05 or 0.01) decreased food consumption (92 - 96% of control) thro ughout much of the exposure period. Females also had significantly (p < 0.01) decreased food consumption values that ranged from 86 - 90% of control values throughout most of the study

period. Overall food efficiency at this dietary

level was decreased f

or males (84 %) and females (85 %) compared to the respective control groups. Hematological analy sis of animals treated with the test substance revealed no untoward effects. Plasma analy sis for clinical chemistry changes related to test substance exposur e revealed a statistically

significant (p < 0.01) increase in plasma cholesterol levels among males and females fed 8000 ppm (55 - 77 %) and females fed 1000 (67 %) and 4000 ppm (44 %). A clear concen tration - effect relationship was observed in both sexes.CL OMAZONE/125401 Human Health Risk Assessment D410435

Page **37** of **49** Among males and females fed 4000 and 8000 ppm, absolute mean liver weights, liver to body weight ratios, and liver to brain weight ratios were increased significantl y (p < 0.01) compared to the respective control groups. Mean liver weights were also significantly increased among males and females fed 2000 ppm. However, onl y the 8000 ppm groups were observed to have signifi cantly increased incidences (p < 0.05 or 0.01) of microscopic lesions in the liver compared to the control group. These lesions were characterized as minimal or mild megalocy tosis of centrilobular hepatocy

tes. Since histopathology was not conducted at 4000 ppm but assumption could be made that at 4000 ppm some megalocy tosis may have occurred. Because animals fed lower concentrations of the test diet had no histopatho logical correlates, it is unclear if these liver weight changes are of toxicological significance. Following 3 months of recovery the absolute and relative liver weights of 4000 and 8000 ppm groups were comparable to c ontrols. **Under the conditions of this study, the LOAEL was 4000 ppm (273.0 and 319.3 mg/kg/day for males and females, respectively), based on changes in body weight, body weight gain,**  **food consumption and increased absolute and relative liver weights in f emales and absolute**  **liver weights in males. The NOAEL was 2000 ppm (135.2 and 160.9 mg/kg/day for males and females, respectively).**  This subchronic oral toxicity study is classified as **Acceptable/Guideline** and satisfies the guideline requirement for a subchronic oral toxicity study **[OPPTS 870.3100 (§82 -**  **1b)]** in rats. **870.3100 90**  **- Day Oral Toxicity** 
**— Mouse**  In a combined subchronic and oncogenicity study (MRID 00132585, 0013287 and 00144244) clomazone (88.8%, a.i.) was administered to 120 CD - 1 mice/sex/dose in diet at dose levels of 0, 20, 100, 500, 1000, 2000, 4000 or 8000 ppm (equivalent to 0, 3, 15, 75, 150, 300, 600 or 1200 mg/kg/day

for males and females) for 3 to 24 months. In the subchronic phase of the study (MRID 00144244) 10 mice/sex/dose at 30 and 60 day s and 20 mice/sex/dose at 90 day s, were randomly selected for hematology

and gross and histopathology . Animals sacrificed at 90 day s from the 0, 20, 500, 2000 or 8000 ppm were evaluated histopathologically . Following evaluation of organ wt. data from the 90 - day sacrifice, the remaining animals from the 4000 and 8000 ppm groups were removed from the study , sacrificed and examined. During the oncogenicity phase of the study

10 animals/sex/group were sacrificed at 6, 12, and 18 months for blood and histopathological evaluations. At terminal sacrifice (24 months) blood parameters were evaluated for 10 animals /sex/dose and a complete histopathological examination was performed on all animals. Tests for concentration, homogeneity and stability

of the test material in the diet were all within acceptable limits. There were no compound related effects between treated and control group for any time period for either clinical observations, mortality , body weight change, food consumption, hematology an d/or clinical chemistry

values.CL OMAZONE/125401 Human Health Risk Assessment D410435

Page **38** of **49** Absolute and relative liver weights were increased in males and females at several time points and dose levels. Statistically significant (p<0.01) increases were recorded for both sexes at 90 day s at 4000 and 8000 ppm for a bsolute liver weight (23 - 33%), liver to body weight (20 - 36%), and liver to brain weight ratios (20 - 36%). Hepatocellular cy tomegal y was observed at 8000 ppm in 11 of 20 males. Histopathology of 4000 ppm group was not performed. In the absence of o ther s ys temic toxicity findings, increased liver weights and cellular hy pertrophy are considered adaptive changes and has no toxicological significance. Therefore, there were no adverse effects at the high dose of 2000 ppm in the carcinogenicity study. NOAEL  8000 ppm ( 1200 mg/kg/d; L imit Dose) in the 3 month mouse feeding study . LOAEL was not established. NOAEL  2000 ppm (300 mg/kg/d) oncogenicity study (24 months). LOAEL was not established. Administration of FMC 57020 for up to 2 - ye ars did not result in a statistically significant increase in the incidence of neoplastic lesions. Dosing was not considered adequate based on the lack of a toxic effect on the animals. CLASSIFICATION : The subchronic phase of the study was classified as **Acceptable/Guideline** and satisfies the guideline requirement for a subchronic oral toxicity study **[OPPTS 870.3100]** in mice . The oncogenicity phase of the study in mice is classified as **Unacceptable/Guideline** and does not satisfy

the guideline requirement for an oncogenicity study **[ OPPTS 870.4**  **200b]** in mice because dosing was not adequate. **870.3150 90**  **- Day Oral Toxicity** 
**— Dog**  This requirement is satisfied by a chronic dog study

(MRID 00150290). **870.3200 28**  **- D**  **ay Dermal Toxicity**
**– Rat**  In a 28 - day

dermal toxicity

study (MRID 46021101), Clomazone Technical (92.7% a.i.; Reference # PL01 - 0346) was applied directly to the hair - clipped intact skin of 10 Sprague Dawley CD rats/sex/dose at dose levels of 0 or 1000 mg/k g bw/day (limit dose) for 6 hours/day , 5 day s/week during a 28 - day period. No treatment - related effects were observed in mortality, clinical signs, dermal effects, body weight, body weight gain, food consumption, ophthalmoscopic examination, hematology , c linical chemistry , organ weights, or macroscopic pathology . Epidermal hyperplasia and focal erosion of the epidermis in the treated and untreated skin and hy

perkeratosis in the untreated skin were observed in the dosed females at increased incidence and/o r severity over controls. Additionally , hy perplasia in the epidermis was observed in all dosed and control males; however, severity was increased from minimal to mild in both the treated and untreated skin. Abdominal skin (distant from the application si te) was not affectedCL OMAZONE/125401 Human Health Risk Assessment D410435

Page **39** of **49** indicating a lack of s ys temic effect. The Sponsor stated that similar findings on treated skin and untreated skin near the application site was most likely due to diffusion of the compound beneath the bandage. The study pathologist s tated that the changes observed to the skin were adaptive changes due to minimal irritation of the test material and that these changes were expected to be fully reversible. The reviewers concur that the test compound resulted in only minimal skin irritat ion and did not consider this an adverse effect. This study

is classified as **Acceptable/Guideline** and does sat isfy the guideline requirement **[OPPTS 870.3200]** for a 28 - day dermal toxicity

study in rats. The LOAEL was not observed; however, the compound was tested at the limit dose (1,000 mg/kg). **870.3465 90**  **- Day Inhalation** 
**– Rat**  The HASPOC waived the requirement for this study on September 19, 2013 (Rury , 2013). **870.3700a Prenatal Developmental Toxicity Study -**  **Rat** In a prenatal developmental toxicity study in the rat (MRID 00150291) one - hundred assumed pregnant Sprague - Dawley rats were divided into four groups of 25 and orally gavaged with either 100, 300 or 600 mg/kg of test material from day s 6 - 15 of gestation. One additional group served a vehicle control group and received onl y corn oil. Dams were sacrificed on day 20 of gestation and necropsied. Half the viable fetuses were examined for skeletal effects using a modification of the Wilson technique and half examined for visceral effects. Standard s tatistical anal ys es were conducted on 13 of 15 parameters covering both dams and fetuses. There were no compound related deaths. Non - treatment related deaths were associated with esophageal or lung puncture during the administration of compound. Clinical signs were observed onl y in dams receiving 300 and 600 mg/kg/d. Signs seen at 300 mg/kg/d consisted of chromorhinorrhea and/or abdominogenital staining in 4/24 dams. Signs seen at 600 mg/kg in 23/23 dams were abdominogenital staining, decreased locomotion and/or chromorhinorrhea. Body weight gain in dams was decreased, but not statistically significant, at 600 mg/kg/d on day s 6 - 15 [ - 5.7%], 15 - 20 [ - 9.0%] and 0 - 20 [ - 7.2%]. Food consumption in dams at 600 mg/kg/d was however, meaningfull y decreased onl y on day s 6 - 13. [ - 12 %; p< 0.05]. Fetal body weights were decreased onl y for females at 600 mg/kg/d [ - 6.6%; p< 0.05] with male body weights [ - 3.3%] and total live fetal body

weights [ - 5.0%] being generally comparable to controls and not statistically significant. Minor malformation of the thoracic vertebrae was statisticall y s ignificant at 600 mg/kg when reported on a fetal incidence basis. In dications of delayed ossification in the form of either partial ossification or the absence of the following bones were repo rted as statistically significant either on a litter or a fetal basis at 300 or 600 mg/kg: manubrium, sternebrae 3 - 4, xiphoid, caudal vertebrae, and meta - carpals. The fetal/litter incidences for sternebrae 3 - 4, at 300 and 600 mg/kg/day

were 2.8%/17.4% and 4.7%/22.7%, respectively , compared to 0%/0% in the controls. Normal variations were reported for sternebrae 2 and 5 at 300 and 600 mg/kg. All other reported values for both dams and fetuses were comparable to controls.CL OMAZONE/125401 Human Health Risk Assessment D410435

Page **40** of **49 The maternal NOAEL is 100 mg/kg.**  **The maternal LOAEL is 300 mg/kg based on chromorhinorrhea and/or abdominogenital staining. The developmental NOAEL is 100**  **mg/kg. The developmental LOAEL is 300 mg/kg based on indications of delayed ossification**  **in the form of either partial ossification or the absence of the manubrium,**  **sternebrae 3 -**  **4, xiphoid, caudal vertebrae, and meta -**  **carpals.** This developmental toxicity study in the rat is classified **Acceptable/Guideline** and satisfies the guideline requirement for a developmental toxicity study **[ OPPTS**  **870.3700a (§83 -**  **3)]** in the rat. **870.3700b Prenatal Developmental Toxicity Study -**  **Rabbit** In a prenatal developmental toxicity study in the rabbit (MRID 00133220) four groups of assumed pregnant New Zealand white rabbits comprised of 18 animals per group were administered FMC 57020 in doses of either 30, 240 or 1000 mg/kg (reduced to 700 mg/kg on day 13 - 18 of gestation) from day s 6 - 18 of gestation. An additional group served as control and received only

the vehicle carboxy - methyl - cellulose. All animals we re sacrificed on day 29 of gestation. Compound related toxicity at the high dose tested (HDT; 1000/700 mg/kg) included 3 deaths, and 3 abortions all after day 18. [animals dying were not animals aborting]. Net body mean weight gain [i.e. maternal body w eight at day

29 minus the weight of the gravid uterus] for controls and treated groups was +87; +160; - 60 and - 85 grams respectivel y with the HDT being statistically

significant [ - 85 grams; p<0.05]. Mean weight of the gravid uteri were comparable between dose groups ranging from 340 - 361 grams. Mean maternal body weight gain for day s 6 - 18 of gestation from controls to the HDT was +155; +219; +96 and - 300 grams respectivel y. Ataxia was also reported for 2 animals in the HDT as well as red vaginal discharge in 4 rabbits 3 of which aborted. Decreased or no defecation was also observed at 1000/700 mg/kg more frequentl y than at the lower doses. No other significant toxicological effects were noted for dams at either 30.0 or 240 mg/kg. Examination of fetal and l itter data indicated no meaningful developmental toxicological effects for either mean fetal data at the time of laparotomy, or external, skeletal or visceral compound related effects at an y dose level. The maternal NOAEL is 240 mg/kg. The maternal L OAEL is 700 mg/kg based on the effects seen at 1000 mg/kg. (The assumption here is that the effects of maternal death, abortions, decreased body weight gain and deceased or no defecation may also have occurred at 700 mg/kg if the animals had been given this d ose of 700 mg/kg during days 6 - 18). The developmental NOAELis 700 mg/kg. The developmental LOAEL is > 700 mg/kg since no higher dose was given for the day s 13 - 18. This study

is classified as **Acceptable/Guideline** and does satisfy the guideline requirement for a developmental toxicity

study **[OPPTS 870.3700b (§83 -**  **3)]** in the rabbit.CL OMAZONE/125401 Human Health Risk Assessment D410435

Page **41** of **49 870.3800 Reproduction and Fertility Effects**  **- Rat**  In a 2 - generation reproduction study in rats (MRID 00151108) two hundred and fift y [250] male and female Charles River CD strain rats were randomly assigned into 5 groups of 25 males and 25 females per dose group and administered either 0, 100, 1000, 2000 or 4000 ppm (equivalent to 0, 5, 50, 100, or 200 mg/kg/day) of FMC 57020. There was no compound related mortality. Parental body weight in males during pre - mating was comparable to controls whereas female body weight was statistically significantly

lower [p<0.05 - p<0.01] at 2000 and 4000 ppm as earl y as 2 and 5 weeks through to copulation [8 and 11 weeks later]. Premating body w eight gain was also lower [p<0.01] for females in both generations at 2000 ppm and 4000 ppm (26%;26% and 11%;13% respectively) Maternal body weight during periods of gestation (days 0 - 20) and lactation (days 0 - 21) were lower [p<0.05 - 0.01] at 2000 and 400 0 ppm for all generation and litters. Food consumption for treated males was generall y comparable to controls during premating; however, food consumption for F O and F 1 females was generall y lower at 2000 and 4000 ppm with several occasions of statistical significance (p<0.05 - p<0.01). The onl y clinically significant observation was noted in the 4000 ppm female groups of the F O and F1 generations and consisted of urine so aked and/or yellow - brown stained fur. Reproductive performance was comparable for all generations when compared to controls with the exception of a statistically significant [p<0.05] but apparentl y aberrant decreased fertility value for the F 1 b litter at 4000 ppm. Pup survival and pup body weight values were comparable to control values for all litters during lactation with the exception of a statistically significant decrease in pup body weight values at 2000 ppm and 4000 ppm for the F 2 a and F 2 b litters. Statistically

significant increases were noted for liver to body weight ratios in both males and females of the F O generation at 4000 ppm and in liver to brain weight ratios for males at 4000 ppm. Statistically

significant increases for liver to body weight ratios were also reported for F 1 males and females in the 4000 ppm groups and females in the 2000 ppm group. However, absolute weights were not increased and histopathology was not remarkable indicating that increases may

be attributable to a combinatio n of enzy me induction and/or decreased body weight. There was also an increased incidence of dilated and distended pelvis of the kidney in the F 1 males after the F 2 b mating in the 2000 and 4000 ppm groups when compared to the control group [1/23; 2/24; 1/2 3; 6/24; 7/24 equal to 4%; 8%; 4%; 25% and 29% control to high dose respectively]. These effects were not seen after F 2 a mating. This suggests that the effects occurred as adults but not in utero effect. Histopathology was conducted on the F O and F 1 par ental animals from the control and the 4000 ppm group as well as 10 male and 10 female F1b and F2b progen y from the control and the 4000 ppm dose groups randoml y chosen from those subjected to necropsy

examination. Any

progeny which exhibited grossly

appar ent developmental anomalies were subjected to gross pathologic study and tissues retained b y the pathologist. Tissues and organs examined for histopathology included the ovaries (with corpus), prostate, seminal vesicles, testes (with epididy mides), uteri, and vagina, and all other tissues and organs appearing abnormal. All kidney s from the F 1 parental generation were also examined microscopicall y as a result of the incidence of h ydro - nephritic kidney s noted grossl y. Malformations reported were either those commonly occurring, not statistically significant and/or not dose responsive. Observations such as short, kinked and hair like tail, macrophthalmia and anophthalmia were reported as common observations. L imb abnormalities (i.e. 1 pup in theCL OMAZONE/125401 Human Health Risk Assessment D410435

Page **42** of **49** 1000 ppm group and 1 in the 4000 ppm group) and the absence of the anal opening (1 pup in the 4000 ppm group) raised concerns of teratogenicity . [NOTE: the absence of these effects in the rat teratology

resulted in the rat teratology study being audited and re - examined by outside experts]. **Parental NOAEL** is 1000 ppm equivalent to 50 mg/kg/d. **Parental LOAEL** is 2000 ppm equivalent to 100 mg/kg/d based on statistically significant decreases in premating body weight and body

weight gain, statistically

significant decreases in body weight during gestation and lactation, a statistically significant decrease in food consumption in females and hydro - nephritic kidney s in males. **Developmental NOAEL** is 1000 ppm (50 mg/kg/d). **Developmental LOAEL** is equal to 2000 ppm (100 mg/kg/d) based on a decreased body weight in F2a and F2b litters. **Reproductive NOAEL and LOAEL** is  200 mg/kg/day . This study

is classified as **Acceptable/Guideline** and does satisfy the guideline requirements for a two - generation reproduction study **[OPPTS 870.38 00 (§83**  **- 4)]**  in the rat. **870.4100a (870.4300) Chronic Toxicity**
**– Rat**  In a chronic toxicity

/oncogenicity

study (MRID 00132586), FMC 57020 Technical (Reference E1756 - 146) was administered to 5 groups of 120 CD (Sprague - Dawley) outbred albino rats/sex for a period of up to 24 months in the diet at concentrations of 0, 20, 100, 500, 1000, or 2000 ppm. These dietary

levels resulted in mean doses of 0, 0.9, 4.3, 21.5, 42.9, or 84.8 mg/kg/day (males), and 0, 1.1, 5.5, 27.8, 56.5, or 112.9 mg/kg/day (females). After 15 weeks of treatment, 20 rats/sex/group were chosen for hematology , urinaly sis, and gross pathology to satisfy the requirements for the subchronic portion of the study ; these results are discussed in a separate DER. During the chronic phase of the study , 10 randomly selected rats/sex/group were sacrificed at 6, 12, and 18 months for blood and histopathological evaluations. At the final 24 - month sacrifice, 10 rats/sex/group were bled for hematological anal ys is and a complete histopathological evalu ation was performed on all rats. Survival was not affected by the test substance in any

of the treated groups compared to either of the control groups. No treatment - related clinical signs or alterations of body weight, food consumption, hematology or uri nal ys is parameters were observed. During the first year of treatment, males and females fed 1000 or 2000 ppm had slightly elevated total cholesterol plasma levels. Since this effect did not continue into the second year of treatment, the toxicological relevance of these alterations remains unclear. At the 3 - month sacrifice slight liver enlargement (p < 0.05, liver weight and ratio to body weight) was evident among male and female rats treated with 2000 ppm and in females treatedCL OMAZONE/125401 Human Health Risk Assessment D410435

Page **43** of **49** with 2000 ppm at the fin al 24 - month sacrifice. Clear liver effects were seen at 4000 and 8000 ppm. At other interim sacrifice time points, no significant differences were observed. Histopathological anal ys is of the livers of treated males and females revealed increased inciden ces of hepatocy

tomegaly . These increases achieved statistical significance at various time points of sacrifice, but generall y were not dose - related and often were more profound in the mid - dose groups. Therefore, the toxicological significance of this fin ding in this dose range remains obscured. **The no -**  **observed -**  **adverse -**  **effect level (NOAEL) is > 2000 ppm for males (84.4 mg/kg/day) and females (112.9 mg/kg/day) in this study. A lowest**  **- observed**  **- adverse**  **- effect level**  **(LOAEL) was not identified.** The administration of FMC 57020 Technical for up to 104 weeks did not result in a statistically significant increase in the incidence of neoplastic lesions. No treatment - related effects were observed at the highest dose tested (2000 ppm; 84.4 mg/kg/day). Inspite of the absence of s ys temic toxicity at this dose, the HIARC concluded that this dose was adequate to assess the chronic toxicity and carcinogenicity in rats. This conclusion was based on the results obtained in the 90 - day oral toxicity

(MRID 001 32586) and the two generation reproduction study in rats. In the 90 - day

study , the LOAEL was 4000 ppm (319 mg/kg/day) and the NOAELwas 2000 ppm (160 mg/kg/day) based on statistically significant decrease in body weight and body weight gain in female rats . In the two generation reproduction study (MRID 00151108), the L OAEL was 2000 ppm (100 mg/kg/day) and the NOAEL was 1000 ppm (50 mg/kg/day). This chronic study

in rats is classified as **Acceptable/Guideline** and satisfies the guideline requirement for a c hronic toxicity study **[OPPTS 870.4100a (§83 -**  **1)]** in rats. The oncogenicity phase of study in rats is classified as **Acceptable/Guideline** and satisfies the guideline requirement for a combined chronic toxicity /oncogenicity

study in rats **[OPPTS 870.4**  **3 00 (§83**  **- 2)]**  . **870.4100b Chronic Toxicity -**  **Dog** In a chronic toxicity

study (MRID 00150290) FMC 57020 (88.8% a.i.) was administered to 6/sex/dose dogs in diet at dose levels of 0, 100, 500, 2500, or 5000 ppm for one year (approximately , M: 0, 19, 94, 487, and 1038 mg/kg/day ; F: 0, 21, 106, 502, and 1012 mg/kg/day). Measures were taken of body weight, food consumption, hematology , clinical chemistry , and organ weights. At the 3 month interim sacrifice, 2/sex/dose were sacrificed. Treatment with clomazone up to 50 00 ppm had no effect on mortality , food consumption body weights and body weight gains, hematology and/or clinical chemistry and macro or micropathology

of any organs. High dose (1012 mg/kg/day) females had reduced percentage (12%) of hematocrit level at 1 month, increased platelet count at 3 (44%) and 6 (58%) months and increased eosinophil percentage (250%) at 6 months. Statistically significant increases inCL OMAZONE/125401 Human Health Risk Assessment D410435

Page **44** of **49** cholesterol levels above control values were noted for males and females of the 5000 ppm (1038 an d 1012 mg/kg/day) group at 1 and 3 months (37 to 56%), and for those in the 2500 ppm group at 3 months (females, 502 mg/kg/day increased 26%) and 12 months (males, 487 mg/kg/day increased 20%). At 12 months the levels of GGT were increased relative to controls for males of the 2500 and 5000 ppm (487 and 1038 mg/kg/day , 113% and 100%, respectively) groups and females of the 2500 ppm (502 mg/kg/day increased 106%) group. The above changes in hematology

and/or clinical chemistry parameters are within the control ranges and are not considered toxicologically relevant. A treatment related trend for higher (10 - 46%) absolute and relative liver weights at the interim and terminal sacrifices was present in males and females. Statistical significantly higher (46 %) relative liver weights occurred in males of the 5000 ppm (1038 mg/kg/day) group compared to the control group at terminal sacrifice. Relative brain weight for males in the 5000 ppm (1038 mg/kg/day) were increased (25%) when compared to controls. All macroscopic observations and microscopic lesions were considered incidental to the study and not treatment related. The changes in cholesterol values and liver weights were not reflected in morphological change upon microscopic examination of the liver. Based on the above findings, the NOAEL of 500 ppm (12.5 mg/kg/day) established earlier (see HED Doc. No. 004173) has been changed to  5000 ppm (1038 mg/kg/day for males and 1012 mg/kg/day

for females) since no s ys temic toxicity was observed at the highes t dose tested (5000 ppm). The LOAEL was not established in this study . Highest dose tested (HDT) is > limit test of 1,000 mg/kg/day . This chronic toxicity

study in the dog is classified as Acceptable/Guideline and does satisfy the guideline requirement for a chronic oral study **[OPPTS 870.4100 (§83 -**  **1(b)]** in dog. **870.4200a Carcinogenicity Study -**  **rat** See 870.4100a **870.4200b Carcinogenicity (feeding) -**  **Mouse** In a combined subchronic and oncogenicity study (MRID 00132585, 00132587 and 00144244) clomazone (88.8%, a.i.) was administered to 120 CD - 1 mice/sex/dose in diet at dose levels of 0, 20, 100, 500, 1000, 2000, 4000 or 8000 ppm (equivalent to 0, 3, 15, 75, 150, 300, 600 or 1200 mg/kg/day

for males and females) for 3 to 24 months. In the subchronic pha se of the study (MRID 00144244) 10 mice/sex/dose at 30 and 60 day s and 20 mice/sex/dose at 90 day s, were randomly selected for hematology

and gross and histopathology . Animals sacrificed at 90 day s from the 0, 20, 500, 2000 or 8000 ppm were evaluated hist opathologically . Following evaluation of organ wt. data from the 90 - day sacrifice, the remaining animals from the 4000 and 8000 ppm groups were removed from the study , sacrificed and examined. During the oncogenicity phase of the study

10 animals/sex/gro up were sacrificed at 6, 12, and 18 months for blood and histopathological evaluations. At terminal sacrifice (24 months) blood parameters were evaluated for 10 animals /sex/dose and a complete histopathological examination was performed on allCL OMAZONE/125401 Human Health Risk Assessment D410435

Page **45** of **49** animals. T ests for concentration, homogeneity and stability

of the test material in the diet were all within acceptable limits. There were no compound related effects between treated and control group for any time period for either clinical observations, mortality , body weight change, food consumption, hematology and/or clinical chemistry

values. Absolute and relative liver weights were increased in males and females at several time points and dose levels. Statistically significant (p<0.01) increases were recorded for both sexes at 90 day s at 4000 and 8000 ppm for absolute liver weight (23 - 33%), liver to body weight (20 - 36%), and liver to brain weight ratios (20 - 36%). Hepatocellular cy tomegal y was observed at 8000 ppm in 11 of 20 males. Histopathology of 40 00 ppm group was not performed. In the absence of other s ys temic toxicity findings, increased liver weights and cellular hy pertrophy are considered adaptive changes and has no toxicological significance. Therefore, there were no adverse effects at the hi gh dose of 2000 ppm in the carcinogenicity study. NOAEL  8000 ppm ( 1200 mg/kg/d; L imit Dose) in the 3 month mouse feeding study . LOAEL was not established. NOAEL  2000 ppm (300 mg/kg/d) oncogenicity study (24 months). LOAEL was not established. Adm inistration of FMC 57020 for up to 2 - ye ars did not result in a statistically significant increase in the incidence of neoplastic lesions. Dosing was not considered adequate based on the lack of a toxic effect on the animals. CLASSIFICATION : The HIARC cl assified the mouse oncogenicity study as **Unacceptable/Guideline** and does not satisfy the guideline requirement for an oncogenicity study [OPPTS 870.4200b] in mice because dosing was not adequate. Sy stemic toxicity was not observed at the highest dose test ed. HED has reevaluated the database and determined that a new mouse study

is not required because a new study would need to test at doses above 300 mg/kg/day

and the current chronic reference dose would be protective of any effects observed in mice at th ese higher doses. **870.7485 Metabolism**  **- Rat**  In a general metabolism study (MRID 00142234) ten male and ten female animals were divided into two groups of 5 males and 5 females per group and fasted for 18 hours prior to receiving either a single oral (lo w) dose of 5.0 mg/kg of radio - labeled test compound by gavage, or a single oral (high) dose of 900.0 mg/kg of radio - labeled test material b y gavage in corn oil. Total radio - activity

was approximately

20 micro curies per test animal. A third group of 5 mal es and 5 females were also fasted for 18 hours and anaesthetized with ether prior to shaving the rear leg for access to the safenous vein. 14 C FMC 57020 dissolved inCL OMAZONE/125401 Human Health Risk Assessment D410435

Page **46** of **49** de - ionized water was then injected into the vein at a dose of about 3 - 4 mg/kg and 20 mic ro curies. A last group of 5 animals per sex per dose were also fasted for 18 hours before administration of un - labeled FMC 57020 in corn oil by gavage. The animals were given food and water ad libitum for 14 day s and were dosed daily by gavage with un - la

beled FMC 57020 at a dose of 5.0 mg/kg. Rats were again fasted for 18 hours prior to being given 14 C labeled FMC 57020 by gavage at a dose of 5.0 mg/kg equivalent to 20 micro curies. After the administration of radio - active compound all animals in all groups remained of fast for an additional 6 hours prior to being returned to laboratory rat diet and were fed ad libitum. Urine and feces samples were collected at periodic intervals over 7 day s at which time the animals were sacrificed by exsanguination. Rats were then dissected and the following organs and tissues obtained for radioactive counting: brain, heart, kidney , spleen, skin, bone, leg muscle, adipose tissue, and gonads (uterus and ovaries for females; testes, prostate and seminal vesicles for males ) and carcass. Analy sis of metabolic products by HPLC, TLC, GS/MS, NMR and scintillation counting showed the presence of parent chemical and 16 identifiable metabolites. The majority of these products were eliminated in the urine and the feces within 24 h ours with the predominant route of excretion being the urine. The total amount of the administered dose recovered after the first day (24 hours) ranged between 75 - 85% for all routes and doses with the exception of females in the single high dose group whe re the total recovery was only 48 %, compared to males which was 75%. The total recovery

after 48 hours was generally comparable between all groups and ranged between 91 - 100%. The quantities of metabolites varied with the dose regimen, sex, and route of administration but were the same qualitativel y both in the urine and the feces in all groups. The observed quantitative differences between the groups can be summarized as follows: (1) excretion (48%) in the high dose was lowest in females in the 24 hour period. Examining the total weight of the excreta revealed that the amount of feces from the females was substantially suppressed in the first day. (2) the total amount of 5 - hydrox y FMC 57020 was highest in the single oral low dose group but not in the mu ltiple oral low dose group indicating the possibility of an enz yme induction effect. (3) both single oral low and high dose groups gave a high percentage of 5 - hydroxy FMC 57020 in their feces samples especiall y in the first day feces indicating the possibility of entero - hepatic circulation. This possibility was further enhanced by the fact that less than 1% of the fecal and urinary metabolites was un - metabolized parent compound. (4) it was reasonable to assume that 5 - OH FMC 57020 - conjugate formed in the liver was excreted to the gastrointestinal tract via the bile duct and this conjugate was readil y cleaved to 5 - OH FMC 57020 and excreted in the feces. (5) in the multiple oral lo w dosed group, the amounts of di - hydrox yl ated, tri - hydrox yl ated andCL OMAZONE/125401 Human Health Risk Assessment D410435

Page **47** of **49** di - hydrodiol metabolites were increased significantly , indicating that an induction effect on the mixed function oxidase (MFO) s ys tem (possibl y the cytochrome p - 450 s ys tem) had developed. The predominant metabolites included: 5 - hydrox y FMC 57020; 4', 5 - dihydroxy FMC 57020; 4', 5' - dihydrodiol - 5 - hydroxy FMC 57020; 4', 5' - dihydrodiol FMC 57020, N - [(2' - chlorophen yl ) methyl] -N - hydrox y - 2 - methyl - 2 - carbox y propanamide (FMC 87008) and a dihydro xylated derivative of FMC 57020. Metabolites were excreted both free and as conjugates. Residual 14 C in tissues was, in general, very low. Most of the tissues had residues of less than twice the background. Single oral 5.0 mg/kg (low) dose: Values higher than twice the back ground were detected in the lungs, spleen, kidney , liver, blood, skin, hair, and carcass of both sexes. The highest residue was generall y found in the hair, the organs involved in the metabolism and excretion of the compound, the live r, kidney and the blood. Single oral 900.0 mg/kg (high) dose: Residue levels higher than twice the background were detected in the same organs as the low dose. Intravenous dose: Residue levels higher than twice the background were detected in the same ti ssues as those found for oral administration. Multiple dose (14 day s): Residue values higher than twice the background were detected in the same tissues as for the single oral dose. This metabolism study

in the rat is classified **Acceptable/Guideline** and satisfies the requirements for a metabolism and pharmacokinetics study [OPPTS 870.7485 (§85 - 1) in rats. **870.7800 Immunotoxicity**  The HASPOC waived the requirement for this study on September 19, 2013 ( TXR No. 0056801, Rury , 2013).CL OMAZONE/125401 Human Health Risk Assessment D410435

Page **48** of **49 Appendix**  **B .**  **Physical/Chemical Properties Table**  **C1. Physico**  **- Chemical Properties**  **of Clom azone**  **Param eter**  **Value Reference**  Molecular Weight 239.7 Calculated Melting point/range 25 C, broad range MRID 00144241 pH 6.89 + 14 (supernatant of slurry) MRID 00144241 Density 1.187 g/mL MRID 00144241 Water solubility ( mg/L at unspecified C) 1100 mg/L MRID 00144241 Solvent solubility (mg/L at unspecified C) >200 mg/L in Tenneco 500 - 100 4.5 - 5.0 mg/L in Isopar M >90 mg/L in refined soy bean oil Infinite in dimethyl formamide Infinite in cyclohexanone MRID 00144241

Vapor pressure at 25 C 1.92 x 10 - 2 Pa (1.44 x 10 - 4 mm Hg) MRID 00144241 Dissociation constant (pKa) N/A neither acidic nor basic MRID 00144241 Octanol/water partition coefficient Log(KOW ) 350 (log p = 2.54) MRID 00144241 UV/visible absorption spectrum Not availableCL OMAZONE/125401 Human Health Risk Assessment D410435

Page **49** of **49 Appendix**  **C .**  **Review of Human Research** This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from PHED 1.1; the AHETF database; and the ARTF database, are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicab le ethics requirements. For certain studies, the ethics review may have included review b y the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 5

. The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Task Force members Health Canada, U.S. Environmental Protection Agency , and the National Agricultural Chemicals Association, released February , 1995. Agricultural Re - entry

Task Force (ARTF) data bas e (SOP #3.1)

5 http://www.epa.gov/pesticides/science/handler - exposure - data.html and http://www.epa.gov/pesticides/science/post - app - exposure - data.html