UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                      OFFICE OF
                                                            CHEMICAL SAFETY AND
\* MERGEFORMAT
                                                           POLLUTION PREVENTION

MEMORANDUM

Date:		March 5, 2014

SUBJECT:	Clomazone: Human Health Risk Assessment for New Uses in/on Brassica, Head and Stem, Subgroup 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 Assessment Type:  Single Chemical Aggregate
Case No.:  7203
TXR No.:  NA
CAS No.:  81777-89-1
MRID No.:  NA
40 CFR:  180.425

FROM:	Jessica Kidwell, Risk Assessor
		Kelly O'Rourke, Occupational/Residential Exposure Assessor
		Susan V. Hummel, Chemist
		Bonnie Cropp-Kohlligian, 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 Brassica, 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.

 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	International 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	24
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	Residential 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	26
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	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, cabbage, cotton, cucurbits, pepper, mint, rice, soybeans, sugarcane, and tuberous & corm 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[(R)] 3ME formulated end use product label containing 31.1% clomazone (EPA Reg. #279-3158). Command[(R)] 3ME is a micro-encapsulated formulation designed to use water as its mode of dispersion, while remaining in an encapsulated state. Command[(R)] 3ME is proposed to be applied pre-plant, pre-emergent, or early 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 and 0.50 pounds ai per acre (lb ai/A), respectively. A maximum of 1 application is allowed per season.

The current application requests adding Brassica, head and stem, subgroup 5A; Rhubarb; and Pea, 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 tolerance for cabbage at 0.1 ppm, since cabbage will be covered by the new tolerance for Brassica, head and stem, subgroup 5A.

There is a potential for acute and chronic dietary exposures, as well as for short-term occupational exposure to clomazone during mixing, 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

The 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 cytomegaly noted in the chronic rat and mouse studies, hepatocellular necrosis in the chronic mouse study and increased liver weight observed in subchronic 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 chronic dog study. No inhalation toxicity studies were submitted, and the 28-day subchronic inhalation study was waived.

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. It is not a dermal sensitizer. No neurotoxicity studies with clomazone are available. Based 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 rabbits 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 NOAELs and LOAELs in the study and this study was used for risk assessment, and, therefore, 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 assessing chronic risk, including cancer. This finding is based upon 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 point of departure (POD) for the chronic assessment; (3) a new mouse study would only use doses well above the current POD for the chronic assessment; and (4) even if new mouse study identified positive carcinogenicity 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.
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 years 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 NOAEL to 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) Safety Factor (SF) was reduced to 1X. An acute endpoint was not identified for the U.S. general population. The chronic reference dose (cRfD) of 0.84 mg/kg/day was established based on a POD of 84.4 mg/kg/day from several co-critical studies (a 2-year 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 extrapolation 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 no dermal or systemic toxicity was observed in rats following repeated dermal application at the limit dose for 28 days. A short-term inhalation exposure POD (100 mg/kg/day) 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

Acute 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 highly conservative and incorporated tolerance level residues, assumed 100% crop treated and used default processing factors. Screening-level Tier I modeling was used to estimate drinking water concentrations.

The 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.

The chronic 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 any 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. Currently, there are no registered or proposed residential 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 dietary 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 by clomazone.

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 > 100) without a respirator.  A respirator is not required on the label.

Post-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.  The 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 REI under 40 CFR 156.208 (c) (2) (i) is required. The 12-hour REI, which currently appears on the Command[(R)] 3M label, is adequate 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, the 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.

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 peas are adequate.  The enforcement analytical method is adequate. The residue data are supported by available storage stability data.

HED concludes that there are no risk issues. Specific tolerance recommendations are discussed in section 2.2. Label recommendations are discussed in section 2.3.

2.1	Data Deficiencies/Conditions of Registration

Toxicology: None.
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. Briefly, samples are acid hydrolyzed, hexane extracted, Na2CO3 washed, and cleaned-up with a Florisil column. The resulting samples are analyzed by gas chromatography (GC) using a nitrogen phosphorus detector (NPD) or mass spectrometer (MS). The limit of quantitation (LOQ) 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 analytical 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 MRLs for residues of clomazone on any commodity. Canada has not established MRLs for the commodities in this petition.

2.2.3	Recommended Tolerances

HED recommends for the proposed tolerances, 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 guidance 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 Clomazone (§ 180.425)
                                   Commodity
                     Established/Proposed Tolerance (ppm)
                          Recommended Tolerance (ppm)
                                   Comments
                         Correct Commodity Definition
Brassica, stem and head subgroup 5A
                                      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
                                     0.05
                                     0.05

Pea, Southern, dry seed
                                     0.05
                                     0.05

Pea, Southern, hay
                                     0.05
                                     0.05
Cowpea, hay and Cowpea, forage.  Southern pea hay is a very minor feed, but cowpea is a type of southern pea.

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 type 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 days 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 from Residential Assessment

There are no residential uses proposed with this petition.

3.0	Introduction

3.1	Chemical Identity

The chemical structure and nomenclature of the active ingredient, clomazone, are presented below in Table 3.1.

Table 3.1  Test Compound Nomenclature
Chemical Structure

Empirical Formula
C12H14ClNO2
Common Name
Clomazone
Company 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
81777-89-1
End-use product/EP
Command ME, EPA Reg.. No. 279-3158
Chemical Class
Isoxazolone
Known Impurities of Concern
none

3.2	Physical/Chemical Characteristics

The physicochemical 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 relatively high (1.44 x 10 [-4] mm Hg), indicating a potential concern for inhalation. The octanol/water partition coefficient indicates affinity for organic solvents over water, indicating a potential for bioaccumulation.

3.3	Pesticide Use Pattern

As summarized in Table 3.3, applications of Command(R) 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), respectively. 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(R) label. See Section 2.3 for recommended modifications to the proposed label.

Table 3.3.  Summary of Directions for Use of Clomazone
Applic. Timing, Type, and  Equip.
Formulation
[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 emergence 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 application. There is a potential for post-application exposure for workers re-entering treated fields.

RISK ASSESSMENTS HAVE BEEN PREVIOUSLY 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, particularly for the dietary exposure assessment.

3.5	Consideration of Environmental Justice

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 Low-Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.  As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups 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 analyzed and categorized by subgroups based on age, season of the year, 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 bystanders and farm workers as well as lifestyle 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) recently reviewed clomazone (TXR No. 0056801).  Based 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 rapidly 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 these 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 generally comparable between all groups and sexes and ranged from 91-100%.

 4.2.1	Dermal Absorption

There was no evidence of systemic 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 incidence 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 cytomegaly 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 subchronic 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.  It is 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 chronic studies; 2) liver is the target organ for clomazone, not the neurological system; 3) clomazone is absorbed and rapidly excreted in rats with 97% of the radioactivity excreted within 168 hours; and 4) the POD and endpoint for chronic dietary risk assessment 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 rabbits or in the 2-generation reproduction toxicity 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, EPA has determined that an additional mouse carcinogenicity study is not needed and that the rat chronic/carcinogenicity study will be adequate for assessing chronic risk, including cancer. This finding is based upon 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 only use doses well above the current POD for the chronic assessment; and (4) even if new mouse study identified positive carcinogenicity 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 database 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. Based on the results of the available toxicity studies, there is no evidence for neurotoxicity or immunotoxicity.

4.4.1	Completeness of the Toxicology Database

The toxicology database for clomazone is complete.  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) recently reviewed clomazone (TXR No. 0056801).  HASPOC, based on a WOE 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 time.

4.4.2	Evidence of Neurotoxicity

There are no acute or subchronic neurotoxicity studies available for clomazone. There was no evidence of neurotoxic effects in any animals in available subchronic, chronic, reproductive or developmental toxicity studies. Based 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 of Sensitivity/Susceptibility in the Developing or 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.  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.

4.4.4	Residual Uncertainty in the Exposure Database

Since the dietary and non-dietary exposure estimates were based on several conservative assumptions, HED does not believe that the exposure estimates are underestimated.  The acute and chronic dietary assessments conducted with DEEM-FCID were screening level analyses. The assessments utilized tolerance values and 100% crop treated was assumed for all commodities.  The DEEM analysis also assumed that all drinking 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 analysis 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 Departure 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 <IP_ADDRESS> and <IP_ADDRESS>. Toxicological endpoints were selected for dietary/drinking water and occupational exposure scenarios. An acute reference dose (RfD; 1.0 mg/kg/day) for assessment 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 for the acute dietary (females 13-49 years 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 adult 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 populations) 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 oral exposure scenario was not selected. A point of departure (POD) for dermal exposure was not selected because no systemic toxicity was observed in rats following repeated dermal application at the highest dose tested for 28 days. 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 the developmental toxicity study. This study was selected because the duration of the exposure in this study is appropriate for the short-term endpoint. Based 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. Since there are no residential uses of clomazone, only aggregate exposure from food and water is required. A dermal endpoint was not selected. Because only 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 Assessment 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 chronic risk, including cancer. This finding is based upon 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 only use doses well above the current POD for the chronic assessment; and (4) even if new mouse study identified positive carcinogenicity 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 factors, 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.

Table <IP_ADDRESS>  Summary of Toxicological Doses and Endpoints for Clomazone for Use in Dietary Human Health Risk Assessments
                              Exposure/ Scenario
                              Point of Departure
                        Uncertainty/FQPA Safety Factors
                RfD, PAD, Level of Concern for Risk Assessment
                        Study and Toxicological Effects
Acute Dietary
(General Population including infants and children)
An endpoint was not selected for the general population because no adverse effect in adult animals was identified that resulted from a single exposure. A risk assessment is not required for this population subgroup.
                                 Acute Dietary
                         (Females 13  -  49 years old)
                             NOAEL = 100 mg/kg/day
                                   UFA= 10x
                                    UFH=10x
                                  FQPA SF= 1x
                           Acute 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
                                   UFA= 10x
                                    UFH=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 was 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-Generation 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)
The 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 human exposures.  NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use of a short-term study for long-term risk assessment.  UFDB = to account for the absence of key data (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 <IP_ADDRESS> Summary of Toxicological Doses and Endpoints for Clomazone for Use in Occupational Human 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
UFA= 10x
UFH=10x

Occupational LOC for MOE = 100
Developmental Toxicity Study - Rat
(MRID 00150291)
Maternal LOAEL = 300 mg/kg/day based on chromorhinorrhea and abdominogenital staining in maternal animals.
Cancer (oral, dermal, inhalation)
The 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 human exposures.  NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use of a short-term study for long-term risk assessment.  UFDB = to account for the absence of key data (i.e., lack of a critical study).  MOE = margin of exposure.  LOC = level of concern.  N/A = not applicable.

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 soybeans, corn, cotton, sweet potatoes, tomatoes and bell peppers, and alfalfa, HED concludes that the nature of the residue in plants is adequately understood. The major metabolite was 2-chlorobenzyl alcohol. The postulated major route of metabolism of clomazone in plants is hydroxylation 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-chlorobenzaldehyde reduces to the alcohol or is oxidized to the carboxylic acid.  The alcohol, the carboxylic acid, and the isoxazolidinone metabolites form glycosides and/or amino acid conjugates. Minor pathways include hydroxylation of clomazone to form monohydroxylated and possibly 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 livestock 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 adequately understood.  The 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 hydrolysis 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 days, depending on soil type. Carbon dioxide is the major degradate. Under anaerobic conditions, clomazone readily degrades (t1/2: 13 days) to (N-[(2-chlorophenol)methyl]-3-hydroxy-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 moderately 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 days in an Iowa silty clay loam and 17 days in a Louisiana silt loam. In both studies, parent clomazone was not detected below 6 inches. Degradates were analyzed for but were not detected (detection limit: 0.01 ppm). It is not clear what factor most contributed to the 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 metabolism 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, especially 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 soybeans, corn, cotton, sweet potatoes, tomatoes and bell peppers, and alfalfa. The major metabolite was 2-chlorobenzyl alcohol. The postulated major route of metabolism of clomazone in plants is hydroxylation 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-chlorobenzaldehyde reduces to the alcohol or is oxidized to the carboxylic acid.  The alcohol, the carboxylic acid, and the isoxazolidinone metabolites form glycosides and/or amino acid conjugates.  Minor pathways include hydroxylation of clomazone to form monohydroxylated and possibly dihydroxylated metabolites.

A rat metabolism study is available for clomazone. Sixteen metabolites including the parent compound were identified. The predominant metabolites were the isoxazolidinone metabolites (FMC 87010 (4',5'-dihydrodiol-5-hydroxy-2-(2-chlorophenyl)methyl-4,4-dimethyl-3-isoxazolidinone), FMC 83918 (4',5'-di hydroxy-2-(2-chlorophenyl)methyl-4,4-dimethyl-3-isoxazolidinone) and FMC 60217 (5'-hydroxy-2-(2-chlorophenyl)methyl-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 soybeans, corn, cotton, sweet potatoes, tomatoes and bell peppers, and alfalfa, HED concludes that the nature of the residue in plants is adequately understood.  The residue of concern in plants is clomazone per se as specified 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 crops 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-chlorophenyl)methyl]-3-hydroxy-2,2-dimethyl propanamide) (Kramer, G & Kidwell, J. 10/2/00; D268905).

Table 5.1.4  Summary of Metabolites and Degradates to be included in the 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 65317 = 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 field 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 analytical method; and the data were properly supported by storage stability data.  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 commodities, respectively. 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 of 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#4E4311, 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 incorporated 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 (<0.033-0.114) and <0.03-0.076 (<0.03-0.062) ppm.

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.  Summary of Residue Data from  Field Trials with Clomazone.
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
Plants 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
Plants 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]  LAFT = 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 memoranda: "Clomazone:  Drinking Water Exposure Assessment for  Proposed New Uses for Brassica (Head and Stem Subgroup 5A), Southern Peas, and Rhubarb" (Both memoranda under D408878 by J. Lin and dated 7/23/13 or 9/24/13). These estimated drinking water concentrations (EDWCs) were incorporated directly 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 EDWCs 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 highest EDWCs for both acute and chronic at 550 ppb and this estimate was used in both the acute and chronic dietary risk assessments.

Table 5.3.  EDWCs for the Clomazone Human Health Risk Assessment
Source (Tier: Model)
                              Maximum Annual Rate
                                     Acute
                                     EDWC
                                    (ug/L)
                                    Chronic
                                     EDWC
                                    (ug/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 considered.  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 flooding; 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 analyses 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 by two peer reviewers of the DESAC, per DESAC SOP 2012.1.  Both the acute and chronic assessments are highly conservative and incorporated tolerance level residues, assumed 100% crop treated and used default processing factors.  Screening-level Tier I modeling was used to estimate 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.

5.4.3	Acute Dietary Risk Assessment

The 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	Chronic Dietary Risk Assessment

The chronic 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.

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. Additionally, 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 Clomazone.
                              Population Subgroup
                                 Acute Dietary
                               (95th Percentile)
                                Chronic Dietary
                                     Cancer

                          Dietary Exposure (mg/kg/day)
                                    % aPAD*
                                Dietary Exposure
                                  (mg/kg/day)
                                    % cPAD*
                                Dietary Exposure
                                  (mg/kg/day)
                                      Risk
 General U.S. Population
                                      N/A
                                      N/A
                                    0.011624
                                      1.4

 All Infants (<1 year old)

                                    0.029942
                                      3.6
                                      N/A
                                      N/A
 Children 1-2 years old

                                    0.016899
                                      2.0

 Children 3-5 years old

                                    0.014233
                                      1.7

 Children 6-12 years old

                                    0.010243
                                      1.2

 Youth 13-19 years old

                                    0.008475
                                      1.0

 Adults 20-49 years old

                                    0.011576
                                      1.4

 Adults 50-99 years old

                                    0.011451
                                      1.4

 Females 13-49 years old
                                    0.030050
                                      3.0
                                    0.011536
                                      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 particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed 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-In issued by EPA), EPA Regional Offices and State Lead 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).   The Agency is also taking means to qualitatively and qualitatively address spray 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 individuals nearby 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 the SAP's final report on March 2, 2010.  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 exposure 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 quantitative 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 to 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.

78.2 Short-Term Aggregate Risk

Currently, there are 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 for all population subgroups.

7.5	Cancer Aggregate Risk

EPA 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.

6.0 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 any other substances and clomazone does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that clomazone has a common mechanism of toxicity with other substances. 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 common 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/.

7.0 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 handler exposure is expected from the proposed uses on Brassica, rhubarb and southern peas.  The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenarios:
   1) Mixing/loading liquids for groundboom applications; and
   2) Applying sprays 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 concern to HED (i.e., MOE > 100) without the use of a respirator.  Only exposure from use on rhubarb was quantitatively assessed because its 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 Clomazone
                               Exposure Scenario
                                Crop or Target
                    Inhalation Unit Exposure (μg/lb ai)[1]
                          Maximum Application Rate[2]
                    Area Treated or Amount Handled Daily[3]
                                  Inhalation
                                  (LOC = 100)

                                   Baseline

                              Dose (mg/kg/day)[4]
                                    MOE[5]
                                 Mixer/Loader
         Mixing/loading liquid formulation for groundboom application
                                    Rhubarb
                                     0.219
                                      1.5
                                    lb ai/A
                                      80
                                    0.00033
                                    300,000
                                  Applicator
                 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) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre) x Area Treated or Amount Handled (A/day) / BW (80 kg).
5	Inhalation MOE = Inhalation NOAEL (100 mg/kg/day) / Inhalation 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 when 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 type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical's degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post-application exposure.

9.2.1	Dermal Postapplication Risk

Post-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
The 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[(R)] 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-application 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. The Agency is in the process of evaluating the SAP report as well as available post-application inhalation exposure data generated by 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 pesticides 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.

10.0	References

Cropp-Kholligian, B. 12/6/2013. D410437. Clomazone. Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for Proposed New Uses on Brassica, Head and Stem (Subgroup 5A), Rhubarb, and Southern Pea.

Hummel, S., 9/5/2013, D410436. "Clomazone.  PP#2E8136.  Brassica, Head and Stem, Subgroup 5A; Rhubarb; and Pea, Southern.  Summary of Analytical Methods and Residue Data."    EPA Memorandum.

Kramer, G. and Kidwell, J., 10/2/2000. 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 Stem, 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. 12/17/2013. 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 dated

Appendix 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 new (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
Acute Oral (rat)
Subchronic Oral (rat)
Six-month Oral (dog)
no

[*]Waived at HASPOC September 19, 2013  (TXR No. 0056801 )

A.2	Toxicity Profiles

Table 1.   Acute Toxicity Profile  -  Clomazone

Guideline No.

Study Type [species]

MRID(s)

Results a

Toxicity Category

870.1100

Acute oral [rat]

00117121

     LD50 2077.0 mg/kg  -  1369.0 mg/kg

III

870.1200

Acute dermal [rabbit]

00117122

LD50 >2000 mg/kg

III

870.1300

Acute inhalation [rat]

00117123

LC50 =6.52 mg/L  -  4.23 mg/L

IV

870.2400

Acute eye irritation [rabbit]

00117124

Almost non-irritating at 1 hour in washed and unwashed eyes

III

870.2500

Acute dermal irritation [rabbit]

00117125

Minimally irritating at 24 and 72 hours

III

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
systemic  NOAEL =  1000 mg/kg/day.
systemic LOAEL = Not established

Acceptable/Guideline
870.3700a

Prenatal developmental in rodents

00150291 (1984)
0, 100, 300, 600 mg/kg/day (gavage)

Maternal NOAEL = 100 mg/kg/day.
Maternal LOAEL = 300 mg/kg/day based on chromorhinorrhea and/or abdominogenital staining.
Developmental toxicity NOAEL = 100 mg/kg/day Developmental toxicity 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.
Acceptable/Guideline
870.3700b

Prenatal developmental in (New Zealand White) rabbits
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
Developmental 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.
Developmental NOAEL = 50 mg/kg/day
Developmental 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/Carcinogenicity
rats

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
No evidence of carcinogenicity

Unacceptable/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 ug/plate, i.e., a positive response.

Acceptable/Guideline
870.5100

Gene Mutation
(Salmonella typhimurium reverse gene mutation assay)
00142242 (1983)
FMC 57090 (99%), hydroxamine acid, an intermediate in the manufacturing process for  clomazone.
In the absence of reported cytotoxicity, the test article [FMC 57090 (intermediate)] increased (2 to 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 cytotoxic concentrations (5000 ug/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.

Acceptable/Guideline
870.5375

Cytogenetics
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 ug/mL).

Acceptable
870.5395
Cytogenetics
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 uL/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)

Clomazone 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.

Acceptable

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 safety factor of 1X is applicable for acute dietary risk assessment.  Therefore, 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 attributable 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 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 LOAEL of 273/319.3 mg/kg/day in males and females, respectively.
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 significantly decreased body weight and body weight gain during pre-mating and decreased body weight during gestation and lactation in males and females, a statistically significant decrease in food consumption in females and hydro-nephritic kidneys in males.  The NOAEL in the 2-generation reproduction toxicity study is lower (50 mg/kg/day) than the NOAEL from the 2-year rat study (84.4 mg/kg/day), however, the NOAEL from the 2-year 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) =  (NOAEL) 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 systemic toxicity was seen following repeated dermal application of clomazone technical (92.7% 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 days/week during a 28-day period.  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.

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-day 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 LOAEL of 273/319.3 mg/kg/day in males and females, respectively.
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 applied.  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 concentrations 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 conducted at 30 and 60 days and blood determinations and gross necropsy (tissues not saved) were performed on these rats.  The final sacrifice consisted of 20 rats/sex/group, with hematological analysis, urinalysis, gross necropsy, and histopathological evaluation 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 signs at any 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) throughout 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 analysis performed) respectively 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 significantly decreased (p < 0.01) mean absolute body weights (92 - 96 % of control) at several of the weekly weighings.  The effects on body weight at the two highest doses were considered biologically 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) throughout 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 for males (84 %) and females (85 %) compared to the respective control groups.

Hematological analysis of animals treated with the test substance revealed no untoward effects.  Plasma analysis for clinical chemistry changes related to test substance exposure 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.

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 significantly (p < 0.01) compared to the respective control groups.  Mean liver weights were also significantly increased among males and females fed 2000 ppm.  However, only 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 megalocytosis of centrilobular hepatocytes.  Since histopathology was not conducted at 4000 ppm but assumption could be made that at 4000 ppm some megalocytosis 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 controls.

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 females 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 days and 20 mice/sex/dose at 90 days, were randomly selected for hematology and gross and histopathology.  Animals sacrificed at 90 days 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 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 days 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 cytomegaly was observed at 8000 ppm in 11 of 20 males.  Histopathology of 4000 ppm group was not performed.  In the absence of other systemic toxicity findings, increased liver weights and cellular hypertrophy 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; Limit 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-years 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 870.4200b] 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-Day 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/kg bw/day (limit dose) for 6 hours/day, 5 days/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, clinical chemistry, organ weights, or macroscopic pathology.  Epidermal hyperplasia and focal erosion of the epidermis in the treated and untreated skin and hyperkeratosis in the untreated skin were observed in the dosed females at increased incidence and/or severity over controls.  Additionally, hyperplasia 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 site) was not affected indicating a lack of systemic 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 stated 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 irritation and did not consider this an adverse effect.

This study is classified as Acceptable/Guideline and does satisfy 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 days 6-15 of gestation. One additional group served a vehicle control group and received only 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 statistical analyses 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 only 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 days 6-15 [-5.7%], 15-20 [-9.0%] and 0-20 [-7.2%]. Food consumption in dams at 600 mg/kg/d was however, meaningfully decreased only on days 6-13. [-12 %; p< 0.05]. Fetal body weights were decreased only 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 statistically significant at 600 mg/kg when reported on a fetal incidence basis. Indications of delayed ossification in the form of either partial ossification or the absence of the following bones were reported 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.

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 days 6-18 of gestation. An additional group served as control and received only the vehicle carboxy-methyl-cellulose. All animals were 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 weight at day 29 minus the weight of the  gravid uterus] for controls and treated groups was +87; +160; -60 and -85 grams respectively 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 days 6-18 of gestation from controls to the HDT was +155; +219; +96 and -300 grams respectively. 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 frequently 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 litter 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 any dose level.

The maternal NOAEL is 240 mg/kg. The maternal LOAEL 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 dose of 700 mg/kg during days 6-18).

The developmental NOAEL is 700 mg/kg. The developmental LOAEL is > 700 mg/kg since no higher dose was given for the days 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.

870.3800 Reproduction and Fertility Effects - Rat

In a 2-generation reproduction study in rats (MRID 00151108) two hundred and fifty [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 early as 2 and 5 weeks through to copulation [8 and 11 weeks later]. Premating body weight 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 4000 ppm for all generation and litters.  Food consumption for treated males was generally comparable to controls during premating; however, food consumption for FO and F1 females was generally lower at 2000 and 4000 ppm with several occasions of statistical significance (p<0.05-p<0.01). The only clinically significant observation was noted in the 4000 ppm female groups of the FO and F1 generations and consisted of urine soaked 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 apparently aberrant decreased fertility value for the F1b 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 F2a and F2b litters. Statistically significant increases were noted for liver to body weight ratios in both males and females of the FO 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 F1 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 combination of enzyme induction and/or decreased body weight. There was also an increased incidence of dilated and distended pelvis of the kidney in the F1 males after the F2b mating in the 2000 and 4000 ppm groups when compared to the control group [1/23; 2/24; 1/23; 6/24; 7/24 equal to 4%; 8%; 4%; 25% and 29% control to high dose respectively].  These effects were not seen after F2a mating.  This suggests that the effects occurred as adults but not in utero effect.  Histopathology was conducted on the FO and F1 parental animals from the control and the 4000 ppm group as well as 10 male and 10 female F1b and F2b progeny from the control and the 4000 ppm dose groups randomly chosen from those subjected to necropsy examination. Any progeny which exhibited grossly apparent developmental anomalies were subjected to gross pathologic study and tissues retained by the pathologist. Tissues and organs examined for histopathology included the ovaries (with corpus), prostate, seminal vesicles, testes (with epididymides), uteri, and vagina, and all other tissues and organs appearing abnormal. All kidneys from the F1 parental generation were also examined microscopically as a result of the incidence of hydro-nephritic kidneys noted grossly. 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. Limb abnormalities (i.e. 1 pup in the 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 kidneys 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 870.3800 (§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, urinalysis, 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 analysis and a complete histopathological evaluation 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 urinalysis 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 treated with 2000 ppm at the final 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 analysis of the livers of treated males and females revealed increased incidences of hepatocytomegaly.  These increases achieved statistical significance at various time points of sacrifice, but generally were not dose-related and often were more profound in the mid-dose groups.  Therefore, the toxicological significance of this finding 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 systemic 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 00132586) and the two generation reproduction study in rats.  In the 90-day study, the LOAEL was 4000 ppm (319 mg/kg/day) and the NOAEL was 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 LOAEL 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 chronic 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 870.4300 (§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 5000 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 in cholesterol levels above control values were noted for males and females of the 5000 ppm (1038 and 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 systemic toxicity was observed at the highest 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 phase of the study (MRID 00144244) 10 mice/sex/dose at 30 and 60 days and 20 mice/sex/dose at 90 days, were randomly selected for hematology and gross and histopathology.  Animals sacrificed at 90 days 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 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 days 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 cytomegaly was observed at 8000 ppm in 11 of 20 males.  Histopathology of 4000 ppm group was not performed.  In the absence of other systemic toxicity findings, increased liver weights and cellular hypertrophy 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; Limit 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-years 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 classified 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.  Systemic toxicity was not observed at the highest dose tested.  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 these 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 (low) 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 by gavage in corn oil. Total radio-activity was approximately 20 micro curies per test animal.

A third group of 5 males 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 in
de-ionized water was then injected into the vein at a dose of about 3-4 mg/kg and 20 micro 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 days and were dosed daily by gavage with un-labeled 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 days 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.

Analysis 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 hours 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 where 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 qualitatively 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-hydroxy FMC 57020 was highest in the single oral low dose group but not in the multiple oral low dose group indicating the possibility of an enzyme induction effect.