OFFICE OF PREVENTION, PESTICIDES, AND TOXIC SUBSTANCES UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 MEMORANDUM DATE: 22 JUN 2005 SUBJECT: Revised as per 30 day Error Only Registrant Comments. Sethoxydim: HED Chapter of the Reregistration Eligibility Decision ( RED) Document. PC Code 121001, DP Barcode D318165.

Regulatory Action: Phase 2 Reregistration Action Risk Assessment Type: Single Chemical, Aggregate FROM: William H. Donovan, Ph. D., Chemist and Risk Assessor Kimyata Morgan, Ph. D., Toxicologist Wade Britton, Industrial Hygenist Reregistration Branch 3 ( RRB3)/ Health Effects Division ( HED) ( 7509C)

THRU: Danette Drew, Branch Senior Scientist RRB3/ HED ( 7509C)

TO: James Parker, Chemical Review Manager Reregistration Branch 1 Special Review and Registration Division ( SRRD) ( 7508C)

Attached is HED's preliminary human health risk assessment conducted for the purposes of issuing a Reregistration Eligibility Decision ( RED) for sethoxydim. The residue chemistry and risk assessment was provided by William Donovan ( RRB3), the occupational/ residential exposure assessment by Wade Britton ( RRB3), the hazard characterization by Kimyata Morgan ( RRB3), the dietary analyses by David Soderberg and Nancy Dodd, and the drinking water assessment by William Eckel of the Environmental Fate and Effects Division ( EFED). Page 2 of 71 Table of Contents 1.0 EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.0 PHYSICAL/ CHEMICAL PROPERTIES CHARACTERIZATION . . . . . . . . . . . . . . . . 9 2.1 Chemical Identity and Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 2.2 Physical and Chemical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 2.3 Physical/ Chemical Properties Characterization . . . . . . . . . . . . . . . . . . . . . . . . . 10 3.0 HAZARD CHARACTERIZATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 3.1 Hazard Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 3.2 FQPA Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 3.3 Recommendation of a Developmental Neurotoxicity Study . . . . . . . . . . . . . . . . 21 3.4 Hazard Identification and Toxicity Endpoint Selection . . . . . . . . . . . . . . . . . . . 21 3.5 Special FQPA Safety Factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 3.6 Endocrine Disruption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 4.0 EXPOSURE ASSESSMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 4.1 Summary of Proposed/ Registered Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 4.2 Dietary Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 4.2.1 Residue Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 4.2.2 Dietary Exposure Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 <IP_ADDRESS>Acute Dietary Exposure Analysis . . . . . . . . . . . . . . . . . . . . . . . . 39 <IP_ADDRESS>Chronic Dietary Exposure Analysis . . . . . . . . . . . . . . . . . . . . . . 41 4.3 Water Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 4.4 Residential Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 4.4.1 Non Occupational ( Residential) Handler Exposure and Risk . . . . . . . . . 43 4.4.2 Non Occupational ( Residential) Postapplication Exposure and Risk . . . 44 <IP_ADDRESS> Non Occupational Risk Characterization . . . . . . . . . . . . . . . . . . 45 4.4.3 Non Occupational Off Target Exposure and Risk . . . . . . . . . . . . . . . . . 46 <IP_ADDRESS>Recreational . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 <IP_ADDRESS> Spray Drift . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 <IP_ADDRESS> Exposure from Use of Tobacco  Health Risk Assessment . . . . . 47 5.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION . . . . . . . 48 5.1 Acute Aggregate Risk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 5.2 Short Term Aggregate Risk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 5.3 Chronic Aggregate Risk Assessment ( Food and Drinking Water) . . . . . . . . . . . 50 6.0 CUMULATIVE RISK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 Page 3 of 71 7.0 OCCUPATIONAL EXPOSURE/ RISK PATHWAY . . . . . . . . . . . . . . . . . . . . . . . . . . 52 7.1 Occupational Handler Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 7.2 Occupational Postapplication Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 7.3 Incidents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 8.0 DATA NEEDS/ LABEL REQUIREMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 8.1 Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 8.2 Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56 9.0 TOLERANCE REASSESSMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 10.0 APPENDIX  Names and Structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 10.1 Names and Structures of Sethoxydim and Some Metabolites/ Analytes . . . . . . . 61 10.2 Toxicology Data Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 10.3 Non critical Toxicology Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Page 4 of 71 1.0 EXECUTIVE SUMMARY Sethoxydim is a selective, systemic, postemergence herbicide used for the control of annual and perennial grass weeds in broadleaf crops. Sethoxydim is a member of the cyclohexenone class of pesticides ( Fundamentals of Pesticides, 4th Edition, G. Ware, 1994). The other members of this class include cycloxydim, clethodim, and tralkoxydim.

Tolerances are currently established ( 40 CFR § 180.412) for residues of sethoxydim and its metabolites on a variety of agricultural commodities at levels ranging from 0.2 ppm to 75.0 ppm. Permanent tolerances are also established in/ on the meat and fat of cattle, goats, hogs, horses, poultry, and sheep at 0.2 ppm; meat byproducts of cattle, goats, hogs, horses, and sheep at 1.0 ppm ( 2.0 ppm in meat byproducts of poultry); eggs at 2.0 ppm, and milk at 0.5 ppm. The tolerance expression for plant and livestock commodities includes the combined residues of sethoxydim and its metabolites containing the 2 cyclohexen 1 one moiety ( calculated as the herbicide) as specified in 40 CFR § 180.412.

Sethoxydim is currently registered on agricultural crops such as various fruits, tree nuts, vegetables and herbs, as well as non agricultural sites, including ornamentals and flowering plants, recreational areas, rights of way, along fences and hedgerows, and public and commercial buildings/ structures ( non agricultural outdoors).

Hazard Assessment The toxicity database for sethoxydim is complete and there are no datagaps. The acute toxicity data indicate that sethoxydim is minimally toxic ( Category III) via oral, dermal, and inhalation routes of exposure. It is neither irritating to the eye nor the skin ( Category IV).

The database on sethoxydim indicates that the liver is a major target for this chemical. In the chronic toxicity study ( dogs), there were significantly increased absolute and relative liver weights accompanied by supportive clinical chemistry and histopathology. Dose related clinical chemistry abnormalities were observed in both sexes and included increased alkaline phosphatase and ALT and decreased albumin and cholesterol synthesis. Dose related histopathologic lesions were found in the liver, spleen, and bone marrow. A mild hepatocellular cytoplasmic alteration was found in low ( 1/ 6), mid ( 3/ 6), and high ( 6/ 6) doses in males, and in the mid ( 1/ 6) and high( 6/ 6) doses in females. In addition, adverse liver effects were also observed via the oral route in another species ( mice) and via another route of exposure ( inhalation) in rats.

Dose Response Assessment and Food Quality Protection Act ( FQPA) Decision On December 2, 2004, the HED Risk Assessment Review Committee ( RARC) revisited the need for a developmental neurotoxicity study for sethoxydim. During that meeting, the RARC concurred with the risk assessment team that the evidence does not support the need for a Page 5 of 71 developmental neurotoxicity study; noting that the clinical signs observed at the high dose are likely to be a high dose phenomena. Additionally, the RARC recommended that the " tail abnormalities" be classified as adverse developmental malformations in the prenatal developmental study in rats and 2 generation reproductive study in rats ( see Hazard Characterization section 3.1 for full discussion). Given these findings, the RARC recommended to waive the requirement for a developmental neurotoxicity study. The FQPA factor is reduced to 1X.

The HIARC concluded that the degree of concern was low for pre and/ or postnatal toxicity resulting from exposure to sethoxydim and determined that the special FQPA SF can be reduced ( 1X) since there are no residual uncertainties for pre and/ or postnatal toxicity.

A rat developmental study was used to select the dose and endpoint for establishing the acute RfD ( aRfD) of 1.8 mg/ kg/ day. The acute RfD ( aRfD) was calculated by dividing the No Observed Adverse Effect Level ( NOAEL) of 180 mg/ kg/ day from this study by an uncertainty factor ( UF) of 100 [ 10X for interspecies extrapolation and 10X for intraspecies variation]. The Lowest Observed Adverse Effect Level ( LOAEL) for this study ( 650 mg/ kg/ day) was based on filamentous tail and lack of tail due to the absence of sacral and/ or caudal vertebrae, and delayed ossification in the hyoids, vertebral centrum and/ or transverse processes, sternebrae and/ or metatarsals, and pubes in pups. This RfD is applicable to the general U. S. population, including infants and children. As the acute Population Adjusted Dose ( aPAD) is equal to the aRfD divided by the FQPA SF ( 1X), then the aPAD is equal to the aRfD ( 1.8 mg/ kg/ day).

The mouse combined chronic toxicity/ carcinogenicity study was used to select the dose and endpoint for establishing the cRfD of 0.14 mg/ kg/ day and because the FQPA SF is 1X, the cPAD is also 0.14 mg/ kg/ day. The NOAEL of 14 mg/ kg/ day and the LOAEL of 41.2 mg/ kg was based on early onset of liver effects including hepatocellular hypertrophy and fatty degeneration. A 100 fold uncertainty factor ( 10X interspecies and 10X intraspecies) was applied.

Sethoxydim is not a likely human carcinogen based on lack of evidence of carcinogenicity in rats and mice; therefore, a dietary cancer exposure analysis was not conducted.

HIARC did not identify dermal toxicity endpoints because no dermal or systemic toxicity was seen following repeated dermal applications of sethoxydim at the limit dose to rabbits, in addition there is no concern for pre natal toxicity in rabbits and a low level of concern for pre natal toxicity in rats. A dermal absorption factor is not required since quantification of non cancer risks is not required.

A rat developmental study was used to select the dose and endpoint for short term incidental oral exposure. The basis for the endpoint was the maternal NOAEL of 180 mg/ kg/ day and maternal LOAEL of 650 mg/ kg/ day based on irregular gait observed in dams on the first day of dosing. Intermediate term incidental oral exposure not anticipated; therefore, no endpoint was selected. Page 6 of 71 A rat 28 day inhalation study was used for dose and endpoint selection of 0.3 mg/ L ( 81 mg/ kg/ day). The LOAEL of 2.4 mg/ L ( 651 mg/ kg/ day) was based on liver weight, clinical chemistry ( bilirubin) and histology. The dose/ endpoint is derived from a study conducted via the appropriate route of concern and used for all inhalation exposure durations.

Residential Exposure Estimates Homeowners who apply sethoxydim to ornamental gardens and turf may be exposed for shortterm ( up to 30 days) durations via the dermal and inhalation routes. Short term postapplication exposures to children may result from incidental oral contact via hand to mouth activities with treated turf. The HED HIARC did not identify dermal toxicity endpoints for sethoxydim, therefore, only exposure from inhalation ( adult handlers) and incidental ingestion ( children) were assessed. Inhalation risk was estimated using the NOAEL of 81 mg/ kg/ day from a 28 day rat inhalation study. The NOAEL was based upon increased liver weight, clinical chemistry ( increased total serum bilirubin), and liver histopathology. The risk for postapplication toddler short term incidental ingestion ( hand to mouth, turf to mouth, soil to mouth) was estimated using the NOAEL of 180 mg/ kg/ day from a rat developmental toxicity study.

HED's level of concern, in this instance, is an margin of exposure ( MOE) = 100 ( 10x inter species extrapolation, and 10x intra species variation) for all residential population groups. MOEs estimated for residential handlers range from 1.4E+ 6 to 1.6E+ 6. MOEs estimated for short term postapplication incidental ingestion range from 26,000 for hand to mouth incidental exposures to 7.6E+ 6 for soil ingestion incidental exposures. The resulting MOEs are above the target MOE of 100 and, therefore, are not of concern to HED.

Dietary Exposure Estimates Sethoxydim acute and chronic dietary exposure assessments were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database ( DEEMFCID   , Version 1.33), which incorporates consumption data from USDA's Continuing Surveys of Food Intakes by Individuals ( CSFII), 1994 1996 and 1998. The acute and chronic analyses are limited refined dietary risk assessments. The acute assessment used tolerance level residues for most crops but limited refinement was obtained through the incorporation of field trial data and experimental processing factors for some of the crops expected to be more highly associated with dietary exposure to sethoxydim. For the chronic analysis, tolerance level residues were used for crops and anticipated residue estimates were used for meat and milk. The acute analyses used the maximum percent crop treated provided by BEAD and the chronic analyses used the average percent crop treated. The acute and chronic dietary analyses for sethoxydim show that the estimated risks from acute and chronic dietary exposure to sethoxydim are below the Agency's level of concern (< 100%) for the US population and all population subgroups. From the chronic analysis, the cPAD was 2.7% for the general US population and 7.5% for all infants (< 1 year old). From the acute analysis, the exposure at the 99.9th percentile ( 99.9th percentile used because the assessment incorporated estimates of percent crop treated, field trial data and some experimental Page 7 of 71 processing data) was 5.3% of the aPAD for the general US population and 9.2% of the aPAD for children 1 2 years old and also children 3 5 years old ( the two most highly exposed population subgroups).

Drinking Water Exposure Estimates EFED provided the Estimated Drinking Water Concentrations ( EDWCs) for sethoxydim and all its degradates based on modeling results assuming the maximum use rate for any crop registered for sethoxydim use. The maximum single use rate is 0.47 lb active ingredient per acre ( lb ai/ A). The maximum seasonal use rate is 1.875 lb ai/ A, consisting of four applications at 0.47 lb ai/ A, with a retreatment interval ( RTI) of 14 days. The surface water estimates were calculated using the linked FIRST simulation models. For surface water, the acute ( peak) value for total sethoxydim residues was 130 ppb, and the chronic ( annual average) value for total sethoxydim residues was 16 ppb. The acute and chronic groundwater EDWCs of 1.5 ppb for total residues was estimated using the SCIGROW model. Both surface and groundwater values represent upper bound conservative estimates for concentrations that might be found in surface water and groundwater due to the use of sethoxydim.

Aggregate Exposure Scenarios and Risk Conclusions Human health aggregate risk assessments have been conducted for the following exposure scenarios: acute and chronic aggregate exposure ( food + drinking water), and short term aggregate exposure ( food + drinking water + residential). A cancer aggregate risk assessment was not performed because sethoxydim shows no evidence of carcinogenicity. For short and intermediate term aggregate exposure/ risk assessments, the inhalation exposures estimated for adult handlers cannot be combined with dietary exposure due to lack of common toxicity via the oral ( neurotoxicity) and inhalation ( hepatotoxicity) routes of exposure. Intermediate and longterm residential exposure was neither expected nor assessed. No quantification of dermal exposure is required for any time period.

Acute Aggregate The partially refined acute dietary exposure ( food only) estimates are below HED's level of concern (< 100% aPAD) at the 99.9th exposure percentile for the general U. S. population ( 5.2% of the aPAD) and all other population subgroups. The most highly exposed population subgroups were Children 1 2 years old and Children 3 5 years old, both at 9.2 % of the aPAD. The EDWCs generated by EFED are less than HED's calculated DWLOCs for acute exposure to sethoxydim in drinking water. Therefore, the acute aggregate risk associated with the registered uses of sethoxydim does not exceed HED's level of concern for the general U. S. population or any population subgroups.

Chronic Aggregate Page 8 of 71 The partially refined chronic dietary exposure ( food only) estimates are below HED's level of concern (< 100% cPAD) for the general U. S. population ( 2.7% of the cPAD) and all other population subgroups. The most highly exposed population subgroup is All Infants (< 1 year old), at 7.5% of the cPAD. The EDWCs generated by EFED are less than HED's calculated DWLOCs for acute exposure to sethoxydim in drinking water. Therefore, the chronic aggregate risk associated with the registered uses of sethoxydim does not exceed HED's level of concern for the general U. S. population or any population subgroups.

Short Term Aggregate The short term exposures to Children ( 1 2 years old) result in MOE's that are greater than 100 and are not of concern. Likewise, chronic dietary exposures are less than HED's level of concern. An aggregate risk analysis was conducted by combining chronic dietary exposure with residential incidental oral exposures [ hand to mouth, object to mouth, and soil ingestion] for children 1 2 years old. Based on the aggregate food and residential exposures, short term DWLOCs were calculated for comparison the surface and ground water EDWC values. The EDWCs generated by EFED are less than HED's calculated DWLOCs for short term exposure to sethoxydim in drinking water. Therefore, the short term aggregate risks associated with the registered uses of sethoxydim do not exceed HED's level of concern for Children 1 2 years old.

Occupational Exposure Estimates Sethoxydim is currently registered for use on agricultural crops such as various fruits, tree nuts, vegetables and herbs, as well as non agricultural sites, including ornamentals and flowering plants, recreational areas, rights of way, along fences and hedgerows, and public and commercial buildings/ structures ( non agricultural outdoors). The potential for occupational exposure to sethoxydim exists in a variety of exposure scenarios. Which include the handling of sethoxydim during mixing, loading, and applying processes ( i. e. mixer/ loaders, applicators, flaggers, and mixer/ loader/ applicators) and a potential for postapplication worker exposure from entering into areas previously treated with sethoxydim. Short term and intermediate term exposures ( 1 to 6 months) may occur, however, long term exposures ( greater than 6 months) are not expected. The HED HIARC did not identify dermal toxicity endpoints for sethoxydim, therefore, only inhalation exposures were estimated. The risk for inhalation exposures was estimated using the NOAEL of 81 mg/ kg/ day from a 28 day rat inhalation study. Estimated MOEs range from 2,400 to 3.2E+ 7. The resulting MOEs are above the target MOE of 100 ( 10x inter species extrapolation, 10x intraspecies variation) and, therefore, are not of concern to HED.

2.0 PHYSICAL/ CHEMICAL PROPERTIES CHARACTERIZATION 2.1 Chemical Identity and Structure Page 9 of 71 S H 3 C CH3 OH CH 3 O N O CH 3 IUPAC Name: ( ± ) ( EZ) 2( 1 ethoxyiminobutyl) 5[ 2( ethylthio) propyl] 3 hydroxycyclohex 2 enone CAS Name: ( ± )  2[ 1( ethoxyimino) butyl] 5[ 2( ethylthio) propyl] 3 hydroxy 2 cyclohexen 1 one CAS Registry No.: 74051 80 2 Chemical Class: cyclohexenone herbicide Empirical Formula: C 17 H 29 NO 3 S Molecular Structure:

Sethoxydim 2.2 Physical and Chemical Properties of Sethoxydim Table 2.2.1. Physical and Chemical Properties of Sethoxydim Property Description Color brown Physical state viscous liquid Odor garlic like Boiling Point > 130

C at 6 x 10 1 mm Hg Density, bulk density, or specific gravity 1.058 specific gravity at 20

C Solubility Water at 25

C: 2.57 x 10 2 at pH 5, 4.39 x 10 3 at pH 7; organic solvents ( methanol, n octanol, ethyl acetate, n hexane, toluene, xylene, and olive oil) at 20

C: freely soluble (> 10 3 g/ 100 mL).

Vapor pressure 1.6 x 10  7 mm Hg at 25

C Dissociation constant pKa is 4.6 at pH 4.5 and 25

C Octanol/ water partition coefficient Kow is 3.26 x 10 3 at pH 5; 45.1 at pH 7 pH 3.95 at 20

C Table 2.2.1. Physical and Chemical Properties of Sethoxydim Property Description Page 10 of 71 Stability stable at normal temperatures ( 24

C) and in the presence of metals ( zinc or iron powder); unstable at elevated temperatures ( 54

C) and in the presence of sunlight.

Sethoxydim is a racemate [ designated ( ± ) ] of geometrical isomers [ designated ( E) and ( Z)].

2.3 Physical/ Chemical Properties Characterization Technical sethoxydim is a liquid. It is soluble in water and most organic solvents.

3.0 HAZARD CHARACTERIZATION 3.1 Hazard Profile The database for sethoxydim is complete and there are no data gaps. The scientific quality of the database for sethoxydim is relatively high and the toxicity profile can be characterized for all effects.

The acute toxicity data indicate that sethoxydim is minimally toxic ( Category III) via oral, dermal, and inhalation routes of exposure. It is neither irritating to the eye nor the skin( Category IV).

The database on sethoxydim indicates that the liver is a major target for this chemical. In the chronic toxicity study ( dogs), there were significantly increased absolute and relative liver weights accompanied by supportive clinical chemistry and histopathology. Dose related clinical chemistry abnormalities were observed in both sexes and included increased alkaline phosphatase and ALT and decreased albumin and cholesterol synthesis. Dose related histopathologic lesions were found in the liver, spleen, and bone marrow. A mild hepatocellular cytoplasmic alteration was found in low ( 1/ 6), mid ( 3/ 6), and high ( 6/ 6) doses in males, and in the mid ( 1/ 6) and high( 6/ 6) doses in females. In addition, adverse liver effects were also observed via the oral route in another species ( mice) and via another route of exposure ( inhalation) in rats.

HIARC concluded that there was low concern for pre and/ or postnatal toxicity resulting from exposure to sethoxydim. There was evidence of qualitative susceptibility in the developmental rat study with the occurrence of more severe effects in the fetuses ( delayed ossification and tail abnormalities) than in the maternal animals ( irregular gait and decreased activity). However, these effects were only observed at a high dose. A single tail anomaly was seen in the F1b offspring of the two generation reproduction rat study ( 1/ 344 pups). The developmental toxicity study in rabbits did not exhibit either quantitative or qualitative susceptibility. The special FQPA safety factor is reduced to 1X. Page 11 of 71 There is no evidence of neurotoxicity. The clinical signs following sethoxydim exposure in the prenatal developmental toxicity study in the rat were irregular gait, decreased activity, excessive salivation, and anogenital staining. These effects were only observed in animals receiving very high doses of sethoxydim ( 650 mg/ kg/ day and 1000 mg/ kg/ day). Irregular gait was observed in 12/ 24 dams at 650 mg/ kg/ day and 10/ 10 dams at 1000 mg/ kg/ day on the first day of dosing, after 3 doses the signs began to dissipate. Decreased activity was noted in 1/ 34 dams at 650 mg/ kg/ day and in 4/ 10 dams at 1000 mg/ kg/ day and reversed after several days. Excessive salivation was noted in 23/ 34 dams at 650 mg/ kg/ day and 10/ 10 dams at 1000 mg/ kg/ day. Anogenital staining was documented in 13/ 34 dams at 650 mg/ kg/ day and 7/ 10 dams at 1000 mg/ kg/ day. All clinical signs reported were transient, with the exception of the anogenital staining which did not reverse. Because the clinical signs occurred shortly after dosing, only occurred at very high treatment doses ( over one half the limit dose) and were transitory, it is unlikely that the signs observed are the result of a primary systemic effect on the nervous system but, rather, are reflective of the general toxicity at the high dose. It should be noted that clinical signs indicative of nervous system effects were not observed in any other standard toxicity study for sethoxydim. Although none of these other studies dosed up to 650 and 1000 mg/ kg/ day, a MTD was reached because of evidence of other toxicities ( e. g., liver effects or body weight reductions).

There were no developmental effects seen in the rat and rabbit prenatal studies indicative of an effect on the nervous system. The main effect seen in the rat and rabbit prenatal studies was an increased incidence of fetal skeletal variations due to delayed ossification. In the rat prenatal study, tail abnormalities ( filamentous tail or lack of a tail) were noted. These abnormalities were observed at a very low incidence ( 10 fetuses in 7 litters, 650 mg/ kg bw day) and at high treatment doses ( 650 and 1000 mg/ kg/ day). In the 2 generation reproduction study in rat, a tail anomaly ( short, thread like tail, no anal opening, hindlimbs curved toward central midline) was found in one pup in the F2b generation ( 1/ 344 total pups; in 1/ 4 litters). Tail abnormalities are sometimes thought to relate to CNS malformations; however, in this case, these tail abnormalities are not likely to be the result of a primary neurotube effect. In the rat prenatal study, there is no description of any effect on neural tube derived structures. Furthermore, the class of compounds, cyclohexones, do not demonstrate neurotoxicity or developmental malformations of the nervous system. In addition the acute risk assessment is based on the results of the rat developmental toxicity study and is protective of these effects.

Therefore, after a weight of evidence examination of all the toxicological studies available in the database, the requirement for a developmental neurotoxicity study is waived. The FQPA safety factor is reduced to 1X.

Neither local nor systemic toxic effects were observed in the 21 day dermal toxicity study in rabbits indicating that there is a low level of concern for toxicity via the dermal route of exposure. The acute inhalation toxicity study demonstrated that sethoxydim induced hepatotoxicity similar to that observed by oral routes of exposure. In a 4 week inhalation toxicity study with sethoxydim, toxicity based on increased liver weight accompanied by alterations in clinical chemistry ( increased bilirubin) and liver histopathology at the highest dose tested ( 651 mg/ kg/ day) Page 12 of 71 was observed.

Sethoxydim is classified as " not a likely human carcinogen". No increase in any tumors were found in carcinogenicity studies in rats or mice. No specific signs of immunotoxicity were indicated by any of the guideline studies.

There was no evidence that sethoxydim induces any endocrine disruption. Furthermore, all mutagenicity studies are negative and there is no mutagenicity concern. Sethoxydim is rapidly excreted and tissue accumulation is negligible. No significant differences in pharmacokinetic parameters were seen among dosing groups or between sexes.

Acute Toxicity: The acute toxicity database for sethoxydim is considered complete for acute oral, acute dermal, acute inhalation, dermal and eye irritation, and dermal sensitization. Sethoxydim has a low order of toxicity via the oral, dermal, and inhalation routes of exposure ( Category III). It is neither irritating to the eye nor the skin ( Category IV). It is not an eye or skin irritant. Based on the lack of sensitization of guinea pigs treated with the formulation ( Poast), the requirement for a dermal sensitization study in guinea pigs was waived. The acute toxicity data for sethoxydim are summarized below in Table 3.1.1.

Table 3.1.1 Acute Toxicity Profile for Sethoxydim Guideline No. Study Type MRIDs # Results Toxicity Category 870.1100 Acute Oral Rats 00045847 LD50 = M: 3125 mg/ kg F: 2676 mg/ kg III 870.1200 Acute Dermal Rats 00045848 LD50 = > 5000 mg/ kg III 870.1300 Acute Inhalation Rats 00045849 LC50 = M: 6.03 m/ L F: 6.28 m/ L Aerosol composed of NP 55 ( 25%), DMSO ( 75%). III 870.2400 P r i m a r y E y e Irritation Rabbits 00045850 No Irritation IV 870.2500 P r i m a r y S k i n Irritation Rabbits 00045851 No Irritation IV 870.2600 Dermal Sensitization Guinea pigs 00045852 Study waived based on lack of sensitization in guinea pigs treated with the formulation ( Poast).

Table 3.1.2 Subchronic, Chronic, and Other Toxicity Profile Page 13 of 71 Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 870.3100a 90 Day oral toxicity rodents ( rats) 00045859 ( 1978)/ Acceptable/ Doses: 0, 33, 100, 300, 900, 2700 ppm ( M: 0, 2, 7, 20, 60, 196 mg/ kg/ day; F: 0, 2, 7, 21, 66, 201 mg/ kg/ day) Males: NOAEL = 60, LOAEL = 196 mg/ kg/ day Females: NOAEL = 66, LOAEL = 201 mg/ kg/ day, based on decreases in body weight, body weight gain, and food efficiency.

870.3100b 90 Day oral toxicity rodents ( mice) 00045858 ( 1978)/ Acceptable/ Doses: 0, 100, 300, 900, 2700 ppm ( M: 0, 15, 46, 137, 374 mg/ kg/ day F: 0, 17, 53, 164, 486 mg/ kg/ day) Males: NOAEL = 46, LOAEL = 137 mg/ kg/ day Females: NOAEL = 53, LOAEL = 164 mg/ kg/ day, based on increased liver weight and histopathological evidence of hepatocellular hypertrophy.

870.3150 90 Day oral toxicity ( nonrodents dogs) 00045860 ( 1980)/ Unacceptable/ Doses: 0, 120, 600, 3000 ppm ( M: 0, 4, 19, 89 mg/ kg/ day; F: 0, 3, 17, 86 mg/ kg/ day) Males & Females: NOAEL not identified, LOAEL = 3.4 mg/ kg/ day, based on possible treatmentrelated clinical findings of cystitis of urinary bladder.

870.3200 21 Day dermal toxicity ( rabbits) 41987203 ( 1991)/ Acceptable/ Doses: 0, 40, 200, 1000 mg/ kg/ day. Males & Females: NOAEL = 1000 mg/ kg/ day ( HDT), LOAEL not established. No localized or systemic effects.

870.3250 90 Day dermal toxicity NA NA 870.3465 4 Week inhalation toxicity ( rat) 44021202 ( 1993)/ Acceptable/ Doses: 0, 0.04, 0.3, and 2.4 mg/ L Males & Females: NOAEL = 0.3 mg/ L ( 81mg/ kg/ day), LOAEL of 2.4 mg/ L ( 651 mg/ kg/ day), based on increased liver weight, clinical chemistry ( increased total serum bilirubin), and liver histopathology.

870.3700a Prenatal developmental toxicity ( rats) 43092902 ( 1993)/ Acceptable/ Doses: 0, 50, 180, 650, 1000 mg/ kg/ day Maternal: NOAEL = 180 mg/ kg/ day, LOAEL = 650 mg/ kg/ day, based on irregular gait, decreased activity, excessive salivation, and anogenital staining.

Developmental: NOAEL = 180mg/ kg/ day, LOAEL = 650 mg/ kg/ day, based on 21 22% decrease in fetal weights, filamentous tail and lack of tail due to the absence of sacral and/ or caudal vertebrae, and delayed ossification in the hyoids, vertebral centrum and/ or transverse processes, sternebrae and/ or metatarsals, and pubes. Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results Page 14 of 71 870.3700b Prenatal developmental toxicity ( rabbits) 43092901 ( 1993)/ Acceptable/ Doses: 0, 80, 160, 320, 400 mg/ kg/ day Maternal: NOAEL = 320 mg/ kg/ day, LOAEL = 400 mg/ kg/ day, based on 37% reduction in body weight gain without significant differences in group mean body weights, and decreased food consumption during dosing Developmental: NOAEL 320 mg/ kg/ day, LOAEL = 400 mg/ kg/ day ( HDT), based on an increase in the incidence of incompletely ossified 6th sternebrae.

870.3800 Reproduction and fertility effects ( rats) 41510606, 43366401 ( 1983)/ Acceptable/ Doses: 0, 150, 600, 3000 ppm ( 0, 7.5, 30, 150 mg/ kg/ day) Systemic: NOAEL > 150 mg/ kg/ day, LOAEL not established Reproductive: NOAEL > 150 mg/ kg/ day, LOAEL > 150 mg/ kg/ day Offspring: NOAEL = 30 mg/ kg/ day, LOAEL = 150 mg/ kg/ day, based on decreased pup weight in F2b during lactation.

870.4100a Chronic toxicity ( rodents) NA; see 870.4300 NA 870.4100b Chronic toxicity ( dogs) 00152669 ( 1984)/ Acceptable/ Doses: 0, 300, 600, or 3600 ppm. ( Overall time weighted average doses were 0, 9, 18, and 110 mg/ kg/ day, respectively, for males and 0, 9, 20, and 129 mg/ kg/ day, respectively, for females.) Males: NOAEL = 17.5 mg/ kg/ day, LOAEL = 110 mg/ kg/ day Females: NOAEL = 20 mg/ kg/ day, LOAEL = 129 mg/ kg/ day, based on increase hemosiderosis in the spleen and depressed myeloid erythropoiesis in the sternal bone marrow, increased absolute and relative liver weights, increased alkaline phosphatase and ALT levels.

870.4200a Carcinogenicity ( rats) N/ A; see 870.4300 N/ A 870.4200b Carcinogenicity ( mice) 00100527 ( 1981)/ Acceptable/ Doses: 0, 40, 120, 360, or 1080 ppm ( equivalent to 0, 5, 14, 41, or 134 mg/ kg / day for males and 0, 5, 15, 44, or 143 mg/ kg / day for females) Males: NOAEL = 14 mg/ kg/ day, LOAEL = 41 mg/ kg/ day, based on early onset of liver effects including hepatocellular hypertrophy and fatty degeneration in male mice.

No evidence of carcinogenicity. Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results Page 15 of 71 870.4300 Combined Chronic/ carcinogenicity ( rats) MRID # 43939101 ( 1995)/ Acceptable/ Doses: 0, 264, 1000, or 3000 ppm ( 0, 12, 48, and 143 mg/ kg/ day for males and 0, 17, 66, 204 mg/ kg/ day for females) Male: NOAEL = 12 mg/ kg/ day, LOAEL = 48 mg/ kg/ day, based on liver toxicity ( centrilobular hepatocellular hypertrophy).

Females: NOAEL = 66 mg/ kg/ day, LOAEL = 204 mg/ kg/ day, based on decreased body weight, body weight gain, liver toxicity ( centrilobular hepatocellular hypertrophy), and lung lesions ( heart failure cells and interstitial fibrosis).

No evidence of carcinogenicity.

870.5100 Bacterial reverse mutation 00153604/ Acceptable/ Negative.

870.5100 Bacterial reverse mutation 41885904/ Acceptable/ Concentrations 313 to 5000 ug/ plate Negative.

870.5100 Bacterial reverse mutation 41915901/ Acceptable/ Concentrations 312 to 5000 ug/ mL Negative.

870.5300 In vitro mammalian cell gene mutation 00155130/ Unacceptable/ highest dose tested 5000 ug/ mL Negative.

870.5300 In vitro mammalian cell gene mutation 41421301/ Acceptable/ Concentrations 500 to 5000 ug/ mL Negative.

870.5300 In vitro mammalian cell gene mutation 00130710/ Acceptable/ highest dose tested 10,000 mg/ kg Negative.

870.5300 In vitro mammalian cell gene mutation 00138950/ Acceptable/ Negative.

870.5550 Unscheduled DNA synthesis ( rat hepatocyte cells) 41885905/ Acceptable/ Concentrations 10 to 507 ug/ mL Negative. Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results Page 16 of 71 870.5915 In vivo sister chromatid exchange ( chinese hamster bone marrow) 41475206/ Acceptable/ Dose: 0, 0.5, 1.67, 5 g/ kg Negative.

870.6200a Acute neurotoxicity screening battery ( rats) N/ A N/ A 870.6200b Subchronic neurotoxicity screening battery ( rats) N/ A N/ A 870.6300 Developmental neurotoxicity ( rats) N/ A N/ A 870.7485 Metabolism and pharmacokinetics ( rats) 00045868 ( 1980)/ Acceptable/ Excretion is extremely rapid and tissue accumulation is negligible, assuming DMSO vehicle does not affect excretion or storage of NP 55, 78.% excreted into urine and 20.1% in feces.

870.7485 Metabolism and pharmacokinetics ( rats) 00153605 ( 1985)/ Acceptable/ Administration of radioactively labeled NP 55 yielded 0.8% radioactivity in urine identified as hydroxymetabolites represented by 6 OH M2SO2 & 2 other metabolites found by mass spectrometry were MSO and M1SO.

870.7600 Dermal penetration N/ A N/ A 3.2 FQPA Hazard Considerations 3.2.1 Adequacy of the Toxicity Data Base The toxicology database for sethoxydim is complete and there are no datagaps. Acceptable developmental toxicity studies have been performed in rats and rabbits. In addition, an acceptable 2 generation reproduction study has also been performed in rats. A subchronic neurotoxicity study is being submitted and will be evaluated upon submission. Acute and developmental Page 17 of 71 neurotoxicity studies were not required.

3.2.2 Evidence of Neurotoxicity There is no evidence of neurotoxicity in the database. Historically, the HIARC met on March 19, 2003 and concluded that " there is a concern for developmental neurotoxicity resulting from exposure to Sethoxydim" and recommended that this study be conducted based on " irregular gait and delayed ossification in the developmental rat study and developmental ( tail) abnormalities that were observed in the rat developmental toxicity study and in F1a and F1b offsprings in the 2 generation reproduction studies." In accordance with the 2002 OPP Guidance Document on Determination of the Appropriate FQPA Safety Factor( s) in Tolerance Assessment, the HIARC concluded that a Database Uncertainty Factor of 10X is required for lack of a subchronic and developmental neurotoxicity studies ( TXR 0051694).

On December 2, 2004, the HED RARC revisited the need for a developmental neurotoxicity study for sethoxydim. During that meeting, the RARC concurred with the risk assessment team that the evidence does not support the need for a developmental neurotoxicity study; noting that the clinical signs observed at the high dose are likely to be a high dose phenomena. Additionally, the RARC recommended that the " tail abnormalities" be classified as adverse developmental malformations in the prenatal developmental study in rats and 2 generation reproductive study in rats ( see Hazard Characterization section 3.1for full discussion). Given these findings, the RARC recommended to waive the requirement for a developmental neurotoxicity study and reduced the database uncertainty factor to 1X.

3.2.3 Developmental Toxicity Study The rat developmental toxicity study ( 1993, MRID 43092902) demonstrated a maternal NOAEL and LOAEL of 180 and 650 mg/ kg/ day, respectively, based on irregular gait, decreased activity, excessive salivation and anogenital staining. The developmental NOAEL and LOAEL were 180 and 650 mg/ kg/ day, respectively, based on 21 22% decrease in fetal weights, filamentous tail and lack of tail due to the absence of sacral and/ or caudal vertebrae, and delayed ossification in the hyoids, vertebral centrum and/ or transverse processes, sternebrae and/ or metatarsals, and pubes. The rabbit developmental toxicity study ( 1993, MRID 43092901) demonstrated a maternal NOAEL and LOAEL of 320 and 400 mg/ kg/ day, respectively, based on a 37% reduction in body weight gain and decreased food consumption during dosing. The rabbit developmental NOAEL and LOAEL were 320 and 400 mg/ kg/ day, respectively, based on an increase in the incidence of incompletely ossified 6th sternebrae.

Developmental Rat Study Executive Summary: Pregnant CD ® rats received doses of 0 ( vehicle control), 50, 180, 650, and 1000 mg/ kg/ day by gavage between gestation days 6 and 15. Satellite dams were included in all but the 180 mg/ kg/ day dose, and the 1000 mg/ kg/ day group consisted entirely of satellites. Page 18 of 71 Fetuses carried by satellite dams were not examined. The dams were sacrificed on gestation day 20, and their uteri and ovaries were examined. The fetuses were examined for external, visceral, and skeletal anomalies.

There were no deaths in any group. Clinical signs, seen mostly in the 650 and 1000 mg/ kg/ day dams, included irregular gait and decreased activity which reversed after several days; and excessive salivation and anogenital staining which did not reverse. Biologically significant decreases in maternal body weights ( 12 15%, compared to controls) were seen only in the 1000 mg/ kg/ day satellite group. No compound related gross lesions were found. The LOAEL for maternal toxicity is 650 mg/ kg/ day based on irregular gait, decreased activity, excessive salivation, and anogenital staining. The NOAEL for maternal toxicity is 180 mg/ kg/ day.

There were no resorptions, abortions, premature births, or dead fetuses. The number of corpora lutea, implantation sites, resorptions, and viable fetuses, as well as mean litter sizes and sex ratios were similar for all groups. External and skeletal anomalies, including filamentous tail and lack of tail due to the absence of sacral and/ or caudal vertebrae, were dose related, but visceral anomalies were not. The LOAEL for developmental toxicity is 650 mg/ kg/ day based on 21 22% decrease in fetal weights, filamentous tail and lack of tail due to the absence of sacral and/ or caudal vertebrae, and delayed ossification in the hyoids, vertebral centrum and/ or transverse processes, sternebrae and/ or metatarsals, and pubes. The NOAEL for developmental toxicity is 180 mg/ kg/ day.

This study is Acceptable Guideline, and satisfies the requirement 83 3a for a Developmental Toxicity study in rats. Satellite dams were added at the 650 and 1000 mg/ kg/ day level "... to clarify maternal effects seen in pilot studies." There was no mention of what these effects were, or what was learned from the satellite animals.

Developmental Rabbit Study Executive Summary: Sethoxydim ( 96.8% a. i., Lot # NS 9203) was administered in 1% aqueous carbosymethylcellulose to groups of 15 pregnant New Zealand White rabbits by gavage at dose levels of 0, 80, 160, 320 or 400 mg/ kg/ day from gestation day 6 through 18 ( gestation day 0 was the day of mating). Animals were sacrificed on gestation day 30 and uteri were examined for live fetuses and intra uterine deaths. Fetuses were weighed and examined for external, visceral and skeletal alterations.

Body weight gains were reduced during the dosing period in comparison to control values by 37% for the 400 mg/ kg/ day dose group without significant differences in group mean body weights. Food consumption values were similarly decrease in the highest dose group ( by 10 25%) during dosing. The LOAEL for maternal toxicity is 400 mg/ kg/ day based on based on decreases in body weight gain and food consumption. The NOAEL for maternal toxicity is 320 mg/ kg/ day. Page 19 of 71 There was an apparently dose related increase in the incidence of incompletely ossified 6th sternebrae ( 1/ 13, 4/ 12, 3/ 15, 6/ 13 and 9/ 13 litters in the 0, 80, 160, 320 and 400 mg/ kg/ day groups, respectively), and the incidence of this variation at the highest dose level was outside the reported historical range ( average incidence is 35.1% of litters ranging from 0 57.1%). However, the incidence of all other skeletal ossifications variations was not increased in a dose related manner. The LOAEL for developmental toxicity is 400 mg/ kg/ day based on an increase in the incidence of incompletely ossified 6th sternebrae. The NOAEL for developmental toxicity is 320 mg/ kg/ day.

This study is Acceptable Guideline and satisfies the requirement for a guideline series § 83 3b developmental toxicity study in rabbits.

Two Generation Reproduction Study Rat Executive Summary: In a 2 generation reproduction study ( MRID 41510606), NP 55 ( sethoxydim technical, 96.86 % a. i., Lot # KK 1240) was administered to 13 male and 26 female/ group/ dose F 0 Charles River CD rats at dose levels of 0, 7.5, 30 or 150 mg/ kg/ day. The F 0 animals produced 2 litters ( F 1a and F 1b). The F 1b animals produced 2 litters ( F 2a and F 2b). Clinical signs, body weights, reproductive parameters, necropsy and histopathology data were obtained from parental animals and/ or offspring.

There were no indications of systemic toxicity in the F 0 parental animals. In the F 1 dams in the 150 mg/ kg/ day group, maternal body weights were slightly decreased during the F 2a and F 2b gestation and lactation periods ( 8 10%), with no concomitant effect on food consumption. The 150 mg/ kg/ day F 2b pups had a decrease in body weight of up to  13% by lactation day 21. Malformations were only observed in one F 1b ( 1/ 244 total pups in litter) and two F 2b pups ( 2/ 344 total pups in litter). In the F 1b litter, cleft palate was observed in one high dose pup. In the F 2b litter, one high dose pup had a thread like tail, no anal opening, malformed hindlimb, malpositioned kidneys and another high dose pup had cleft lip, cleft palate and microphthalmia. There were no dose related gross or microscopic lesions, or developmental variations ( cannibalism complicated the evaluation).

Parental Systemic Toxicity NOAEL > 150 mg/ kg/ day Parental Systemic Toxicity LOAEL > 150 mg/ kg/ day Offspring/ Developmental Toxicity NOAEL = 30 mg/ kg/ day Offspring/ Developmental Toxicity LOAEL = 150 mg/ kg/ day based on decreased pup body weight in F1a, F1b, and F2b during lactation.

Reproductive Toxicity NOAEL > 150 mg/ kg/ day Reproductive Toxicity LOAEL > 150 mg/ kg/ day Page 20 of 71 The study is Acceptable Guideline and satisfies the requirement for a guideline series 83 4 Reproduction study in rats.

The HIARC determined that the Parental Systemic Toxicity NOAEL is > 150 mg/ kg/ day ( HDT) and that the LOAEL could not be established, based on the endpoints of 8 10% decreased in body weight seen at 150 mg/ kg/ day is not considered adverse ( LOEL but not LOAEL is established). The Reproductive Toxicity NOAEL/ LOAEL > 150 mg/ kg/ day ( HDT). The Offspring Toxicity NOAEL is 30 mg/ kg/ day, the LOAEL is 150 mg/ kg/ day, based on decreased pup body weight of 11 13% in F1a, F1b, and F2b during lactation.

3.2.5 Additional Information from Literature Search A literature search did not reveal studies with sethoxydim that would impact risk assessment.

3.2.6 Pre and/ or Postnatal Toxicity <IP_ADDRESS> Determination of Susceptibility HIARC concluded that there was evidence of qualitative susceptibility in the developmental rat study with the occurrence of more severe effects in the fetuses ( delayed ossification and tail abnormalities) than the maternal animals ( irregular gait). The developmental toxicity study in the rabbits did not exhibit either quantitative of qualitative susceptibility. In the two generation study, there is evidence of qualitative susceptibility indicated by tail anomaly in F 2b offspring ( based on evidence of qualitative susceptibility, see degree of concern analysis and residual uncertainties for pre and/ or post natal susceptibility below).

<IP_ADDRESS> Degree of Concern Analysis and Residual Uncertainties for Pre and/ or Post natal Susceptibility Since there is evidence of increased susceptibility of the young following exposure to sethoxydim in the rat developmental study, the HIARC performed a Degree of Concern Analysis to: 1) determine the level of concern for the effects observed when considered in the context of all available toxicity data; and 2) identify any residual uncertainties after establishing toxicity endpoints and traditional uncertainty factors to be used in the risk assessment of this chemical. If residual uncertainties are identified, HIARC examines whether these residual uncertainties can be addressed by a special FQPA safety factor and, if so, the size of the factor needed. The results of the HIARC Degree of Concern analysis for sethoxydim are presented as follows:

The degree of concern is low for the fetal effects in the developmental rat study since the fetal anomalies were seen only at the high dose ( 650 mg/ kg/ day) which is closer to the Limit Dose ( 1000 mg/ kg/ day), they were seen in the presence of maternal toxicity ( irregular gait) and clear NOAELs/ LOAELs were established for maternal and developmental toxicities. Additionally, the Page 21 of 71 HIARC concluded at that time that the level of concern was low for the effects observed in the 2 generation reproductive study because the LOAEL for offspring toxicity was based on a conservative determination of a minimal response ( 1/ 344 pups in F 2b generation).

The HIARC concluded that the degree of concern was low for pre and/ or postnatal toxicity resulting from exposure to sethoxydim and determined that the special FQPA SF can be removed ( 1X) since there are no residual uncertainties for pre and/ or postnatal toxicity.

3.3 Recommendation of a Developmental Neurotoxicity Study 3.3.1 Evidence that supports requiring a Developmental Neurotoxicity Study None.

3.3.2 Evidence that supports not requiring a Developmental Neurotoxicity Study Based on the results seen in the prenatal developmental toxicity study in rats and 2 generation reproduction study in rats, there was no evidence of neurotoxicity. All clinical signs reported in the rat prenatal developmental toxicity study occurred shortly after dosing, only occurred at very high treatment doses ( over one half the limit dose) and were transitory. It is unlikely that the clinical signs observed are the result of a primary systemic effect on the nervous system but, rather, are reflective of the general toxicity at the high doses. There were no developmental effects seen in the rat and rabbit prenatal studies indicative of an effect on the nervous system. There is no description of any effect on neural tube derived structures ( see full description in Hazard Characterization section 3.1).

<IP_ADDRESS> Rationale for the UFDB ( when a DNT is recommended)

Given the findings above ( section 3.3.2), a database uncertainty factor is not needed.

3.4 Hazard Identification and Toxicity Endpoint Selection 3.4.1 Acute Reference Dose ( aRfD) Females age 13 49 and general population Study selected: The prenatal developmental study in rats was used to select the dose and endpoint for establishing the aRfD of 1.8 mg/ kg/ day for the general population including infants and children. The FQPA SF is 1X, the aPAD is also 1.8 mg/ kg/ day. For this population, the endpoint used the maternal NOAEL of 180 mg/ kg/ day and maternal LOAEL of 650 mg/ kg/ day based on irregular gait, decreased activity, excessive salivation, and anogenital staining observed in dams on the first day of dosing. A 100 fold uncertainty factor ( 10X interspecies and 10X intraspecies) was Page 22 of 71 applied.

A rat developmental study was used to select the dose and endpoint for establishing the aRfD of 1.8 mg/ kg/ day for subpopulation group females 13 50, and because the FQPA SF is 1X, the aPAD is also 1.8 mg/ kg/ day. The LOAEL of 650 mg/ kg/ day was based on filamentous tail and lack of tail due to the absence of sacral and/ or caudal vertebrae, and delayed ossification in the hyoids, vertebral centrum and/ or transverse processes, sternebrae and/ or metatarsals, and pubes in pups. The fetal anomalies are presumed to occur following a single dose in utero and, thus, this endpoint would be applicable to females 13 50 years of age. A 100 fold uncertainty factor ( 10X interspecies and 10X intraspecies) was applied.

Acute Reference Dose ( aRfD)  GENERAL POPULATION Executive Summary: See summary section 3.2.3 Dose and Endpoint for Establishing aRfD: Maternal NOAEL = 180 mg/ kg/ day based on based on irregular gait at 650 mg/ kg/ day ( LOAEL).

Uncertainty Factor ( UF): 100 ( 10X for interspecies extrapolation and 10X for intraspecies variations) was applied.

Comments about Study/ Endpoint/ Uncertainty Factor: Irregular gait was observed in 12/ 34 dams on the first day of dosing and thus is appropriate for this risk assessment.

Acute Reference Dose ( aRfD)  FEMALES 13 49 Executive Summary: See summary section 3.2.3 Dose and Endpoint for Establishing aRfD: Developmental NOAEL = 180 mg/ kg/ day based on filamentous tail and lack of tail due to the absence of sacral and/ or caudal vertebrae, and delayed ossification in the hyoids, vertebral centrum and/ or transverse processes, sternebrae and/ or metatarsals, and pubes at a LOAEL = 650 mg/ kg/ day.

Uncertainty Factor ( UF): 100 ( 10X for interspecies extrapolation and 10X for intraspecies variations) was applied.

Comments about Study/ Endpoint/ Uncertainty Factor: The fetal anomalies are presumed to occur Acute RfD ( GENERAL POPULATION) = 180 mg/ kg ( NOAEL) = 1.8 mg/ kg 100 ( UF) Page 23 of 71 after a single dose in In Utero and are thus appropriate for this population of concern.

3.4.3 Chronic Reference Dose ( cRfD)

Study Selected: The mouse combined chronic toxicity/ carcinogenicity study was used to select the dose and endpoint for establishing the cRfD of 0.14 mg/ kg/ day and because the FQPA SF is 1X, the cPAD is also 0.14 mg/ kg/ day. The NOAEL of 14 mg/ kg/ day and the LOAEL of 41.2 mg/ kg/ day was based on early onset of liver effects including hepatocellular hypertrophy and fatty degeneration. A 100 fold uncertainty factor ( 10X interspecies and 10X intraspecies) was applied.

MRID No.: 43939101 ( 1995)

Executive Summary: In a combined chronic toxicity/ carcinogenicity study ( MRID 00100527) NP 55 ( sethoxydim technical, 95.4% a. i., lot # PN 1 2) was administered to 60 BDF1 mice/ sex/ dose in the diet at concentrations of 40, 120, 360, or 1080 ppm ( equivalent to 4.48, 13.77, 41.16, or 134.46 mg/ kg bw/ day for males and 4.85, 14.86, 44.33, or 142.85 mg/ kg bw/ day for females) for 24 months. A group of 90 males and 90 females administered the vehicle ( acetone) treated food served as the control. Additional groups of 10/ mice/ sex/ dose were sacrificed at 12 months.

There were no compound related effects on clinical signs or mortality. The final body weight and body weight gain of male mice in the 1080 ppm group were reduced by 10% and 21%, respectively, compared with the control group. Mean body weights and body weight gains of females were unaffected by treatment. Both absolute and relative liver weights were significantly increased ( by 115 138%) at the 24 month sacrifice in males and females in the 1080 ppm group. Increases were also observed in males and females ( relative weight only) in this group at the 12 month interim sacrifice. At the 24 month terminal sacrifice, increases in liver weight correlated with clinical chemistry parameters of elevated alanine aminotransferase and aspartate aminotransferase activities and the microscopically observed lesions including hepatocellular hypertrophy in males in the 1080 ppm group ( all p< 0.01). Focal granulomatous inflammation, fatty degeneration, and hemosiderin deposition were also observed in the livers of males in the 1080 ppm group ( all p< 0.01). Fatty degeneration of the liver was present in 87% of males in the 1080 ppm group and 1% of males in the control group. The incidences of fatty degeneration ( p< 0.05) and hemosiderin deposition ( non significant) in the liver were also elevated in males in the 360 ppm group, although the increased incidences ( 7 8%) were small compared with incidences ( 0 1%) in the control group. Only the incidence of fatty degeneration of the liver was Acute RfD ( FEMALES 13 49) = 180 mg/ kg ( NOAEL) = 1.8 mg/ kg 100 ( UF) Page 24 of 71 significantly elevated in female mice in the 1080 ppm group at 24 months ( control, 7%; 1080, 20%; p< 0.01).

The LOAEL for NP 55 for systemic toxicity is 360 ppm in the diet ( 41.2 mg/ kg/ day) based on early onset of liver effects including hepatocellular hypertrophy and fatty degeneration in male mice. The NOAEL is 120 ppm in the diet ( 13.8 mg/ kg/ day).

This chronic/ carcinogenicity study in the mouse is Acceptable/ Guideline and satisfies the guideline requirement for a chronic/ carcinogenicity study OPPTS 870.4300); OECD 453] in mice. Although data on the homogeneity, concentration, and stability of the test material in the diet were not included with the present report, acceptable data are available from related studies.

Dose and Endpoint for Establishing cRfD: NOAEL of 14.0 mg/ kg/ day for male mice based on early onset of liver effects including hepatocellular hypertrophy and fatty degeneration at a LOAEL of 41.2 mg/ kg/ day.

Uncertainty Factor( s): 100 ( 10X for interspecies extrapolation and 10X for intraspecies variations) was applied.

Comments about Study/ Endpoint/ Uncertainty Factor: Appropriate route and duration for the chronic RfD. The liver toxicity is the primary effect of concern. The endpoint selection is supported by the chronic/ carcinogenicity study in rat where liver toxicity ( centrilobular hepatocellular hypertrophy) was seen at a comparable LOAEL ( 48 mg/ kg/ day in male rats.

3.4.4 Incidental Oral Exposure ( Short Term)

Short Term ( 1 30 days)

Study Selected: A rat developmental study was used to select the dose and endpoint for shortterm incidental oral exposure. The basis for the endpoint was the maternal NOAEL of 180 mg/ kg/ day and maternal LOAEL of 650 mg/ kg/ day based on irregular gait observed in dams on the first day of dosing.

MRID No: 43092902 ( 1993)

Executive Summary: See summary section 3.2.3 Chronic RfD = 14mg/ kg/ day ( NOAEL) = 0.14 mg/ kg/ day 100 ( UF) Page 25 of 71 Dose and Endpoint for Risk Assessment: Maternal NOAEL = 180 mg/ kg/ day based on based on irregular gait and excessive salivation at 650 mg/ kg/ day ( LOAEL).

Comments about Study/ Endpoint: The maternal effects are appropriate for the population ( infants and children) of concerns since irregular gait was observed in 12/ 34 dams on the first day of dosing, peaking on gestation day 8 ( i. e., after 3 doses). This is appropriate for this exposure period of concern.

Intermediate Term ( 1 6 Months)

Study Selected: No study selected. Intermediate term exposure not anticipated.

3.4.5 Dermal Absorption Dermal Absorption Factor: The HIARC concluded that calculation of a dermal absorption factor is not required because a dermal assessment is not required for sethoxydim ( see below; section 3.4.6).

3.4.6 Dermal Exposure ( Short, Intermediate, and Long Term)

The HIARC concluded that for all durations of dermal exposure, quantification of non cancer risk is not required based on the following factors:

° No dermal or systemic toxicity was seen following repeated dermal applications at the limit dose ( 1000 mg/ kg/ day) in rabbits.

° There is no concern for pre natal toxicity in rabbits. Although there is a concern for developmental effects in rats, they occurred in the presence of maternal toxicity at a high dose ( 650 mg/ kg/ day), which is close to the limit Dose ( 1000 mg/ kg/ day).

3.4.7 Inhalation Exposure ( Short and Intermediate Term)

Study Selected: A rat 28 day study was used for dose and endpoint selection with a NOAEL of 0.3 mg/ L ( 81 m/ kg/ day) and a LOAEL of 2.4 mg/ L ( 651 mg/ kg/ day) which was based on liver weight, clinical chemistry ( bilirubin) and histology. The dose/ endpoint is derived from a study conducted via the appropriate route of concern and used for all inhalation exposure durations.

MRID No: 44021202 ( 1993)

Executive Summary: In a 28 day toxicity study ( MRID 44021202), sethoxydim ( 96.8%; batch Page 26 of 71 no. NS 9212) was administered by inhalation ( nose only) to 5 Wistar rats/ sex/ dose at aerosol analytical concentrations of 0.04, 0.3, and 2.4 mg/ L. The control group received filtered air only and the sethoxydim was administered as received from the sponsor. Exposures were 6 hours/ day, 5 days/ week, for a total of 21 exposures. The mass median aerodynamic diameter ( ± geometric standard deviation) for Groups 1, 2, and 3 were 0.8 ± 3.7 µ m, 1.4 ± 1.8 µ m, and 1.5 ± 2.4 µ m, respectively.

No animals died prior to terminal sacrifice. Clinical signs included nasal irritation ( bloody crust formation on the nose) in all mid and high dose rats, salivation during and after exposure in highdose rats, and fur stained with the test substance at the high dose throughout most or all of the study. Body weights and body weight gains were similar to controls ( food consumption was not reported). Clinical chemistry analysis revealed a significant increase in total serum bilirubin high dose males ( 164% of controls; p

0.05) and females ( 239% of controls; p

0.02), although these levels are not considered to be toxicologically significant. There were no treatment related findings at necropsy, but microscopic examination showed an increased incidence of slight ( grade 2) centrilobular hepatocyte swelling in high dose males ( 5/ 5 vs. 1/ 5 for controls; p< 0.05). The absolute and relative ( to terminal body weight) liver weights were increased 14 16% for both sexes ( p

0.05 or 0.01 for females and for relative weight in males). The liver weight increases in both sexes and the microscopic changes in males are general adaptive responses of the liver to a xenobiotic and are not considered adverse effects. A slight increase was also seen in kidney weights of high dose males ( 6 8%, NS) and females ( 12 13%, p< 0.05 for absolute weight), but it was unclear if this effect was treatment related due to a lack of histopathological correlates.

Under the conditions of this one month study, the LOAEL was 2.4 ( 651 mg/ kg/ day) based on increased liver weight, clinical chemistry ( increased total serum bilirubin), and liver histopathology. The NOAEL was 0.3 mg/ L ( 81 mg/ kg/ day), for both male and female rats.

This 28 day study was conducted appropriately and is Acceptable/ Non Guideline.

Dose/ Endpoint for Risk Assessment: NOAEL is 0.3 mg/ L ( 81 mg/ kg/ day) based on liver weight, clinical chemistry ( bilirubin) and histology ( LOAEL is 2.4 mg/ L = 651 mg/ kg/ day).

Comments about Study/ Endpoint: The dose/ endpoint is derived from a study conducted via the appropriate route of concern. The HIARC determined that this study could be used for all durations, however, an additional Uncertainty Factor of 3X is required when assessing risk due to long term exposure (> 6 months) since there is evidence of progression of liver toxicity over time ( 14 16%) demonstrated in studies conducted via the oral route.

3.4.8 Margins of Exposure The target MOE for occupational short, intermediate, and long term dermal exposure/ risk assessment was not quantified. No endpoint selected. No systemic effect at limit dose ( 1000 Page 27 of 71 mg/ kg/ day).

The target MOE of 100 for occupational short, intermediate term inhalation exposure/ risk assessments includes 100X ( 10X for interspecies extrapolation and 10X for intraspecies variations).

No long term exposure anticipated; however, for reference, the target MOE of 300 for occupational long term inhalation exposure/ risk assessments includes the conventional 100X ( 10X for interspecies extrapolation and 10X for intraspecies variations) and an additional 3X based on concern for the progression of hepatic toxicity following long term exposures as demonstrated in oral studies.

The target MOE of 100 for residential short term incidental oral and inhalation exposure/ risk assessments includes the conventional 100X ( 10X for interspecies extrapolation and 10X for intraspecies variations).

No long term exposure anticipated; however, for reference, the target MOE of 300 for residential long term inhalation exposure risk assessments includes the conventional 100X ( 10X for interspecies extrapolation and 10X for intraspecies variations), and a 3X because of the concern for progression of hepatic toxicity following long term exposure as demonstrated in oral studies.

Table 3.4.8 Margins of Exposure Route/ Duration Short Term ( 1  30 days) Intermediate Term ( 1  6 months) Long Term (> 6 months)

Occupational ( Worker) Exposure Dermal N/ A N/ A N/ A Inhalation 100 100 N/ A Residential ( Non Dietary Exposure)

Oral 100 N/ A N/ A Dermal N/ A N/ A N/ A Inhalation 100 N/ A N/ A N/ A = Not applicable 3.4.9 Recommendation for Aggregate Exposure Risk Assessments As per 1996 FQPA, when there are potential residential exposures to the pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal and inhalation Page 28 of 71 exposures. For short term aggregate risk assessments, oral and inhalation exposures can not be aggregated because of a lack of a common toxic endpoint across the exposure routes. Long term aggregate exposures are not anticipated. No quantification of dermal risk assessments are required for any time period. A cancer aggregate risk assessment was not performed because sethoxydim shows no evidence of carcinogenicity.

3.4.10 Classification of Carcinogenic Potential Sethoxydim is characterized as " not likely" to be a human carcinogen based on the lack of increased tumor incidence in the rat and mouse carcinogenicity studies.

Table 3.4.10 Summary of Toxicological Doses and Endpoints for Sethoxydim Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF* and Level of Concern for Risk Assessment Study and Toxicological Effects Acute Dietary ( Females 13 50 years of age and including infants and children) NOAEL = 180 mg/ kg/ day UF = 100 Acute RfD = 1.8 mg/ kg/ day FQPA SF = 1X aPAD = acute RfD FQPA SF = 1.8 mg/ kg/ day Rat Developmental Toxicity Developmental LOAEL = 650 mg/ kg/ day based on decreased fetal body weight, tail abnormalities, delayed ossification.

Acute Dietary ( General population ) NOAEL = 180 mg/ kg/ day UF = 100 Acute RfD = 1.8 mg/ kg/ day FQPA SF = 1X aPAD = acute RfD FQPA SF = 1.8 mg/ kg/ day Rat Developmental Toxicity Maternal LOAEL = 650 mg/ kg/ day based on irregular gait that was observed in 12/ 34 dams on the first day of dosing.

Chronic Dietary ( All populations) NOAEL= 14 mg/ kg/ day UF = 100 Chronic RfD = 0.14 mg/ kg/ day FQPA SF = 1X cPAD = chronic RfD FQPA SF = 0.14 mg/ kg/ day Mouse Carcinogenicity Study LOAEL = 41 mg/ kg/ day based on liver hypertrophy and fatty degeneration.

Short Term Incidental Oral ( 1 30 days) NOAEL= 180 mg/ kg/ day Residential LOC for MOE = 100 Occupational = NA Rat Developmental Toxicity Maternal LOAEL = 650 mg/ kg/ day based on irregular gait that was observed in 12/ 34 dams on the first day of dosing.

Short, Intermediate, and Long Term Dermal Dermal ( or oral) study NOAEL= NA Residential LOC for MOE = NA Occupational LOC for MOE NA Quantification of dermal exposure risk assessment is not required because of lack of dermal & pre natal toxicity in rabbits, and the low dermal absorption physical & chemical properties of sethoxydim. Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF* and Level of Concern for Risk Assessment Study and Toxicological Effects Page 29 of 71 Short Term Inhalation ( 1 to 30 days) Inhalation study NOAEL= 81 mg/ kg/ day Residential LOC for MOE = 100 Occupational LOC for MOE = 100 28 day rat inhalation LOAEL = 651 mg/ kg/ day based on increased liver weight, clinical chemistry ( increased total serum bilirubin), and liver histopathology.

Intermediate Term Inhalation ( 1 to 6 months) Inhalation study NOAEL= 81 mg/ kg/ day Residential LOC for MOE = 100 Occupational LOC for MOE = 100 28 day rat inhalation LOAEL = 651 mg/ kg/ day based on increased liver weight, clinical chemistry ( increased total serum bilirubin), and liver histopathology.

Long Term Inhalation (> 6 months) Inhalation study NOAEL= 81 mg/ kg/ day Residential LOC for MOE = 300 Occupational LOC for MOE = 300 28 day rat inhalation LOAEL = 651 mg/ kg/ day based on increased liver weight, clinical chemistry ( increased total serum bilirubin), and liver histopathology.

Cancer ( oral, dermal, inhalation) " Not likely human carcinogen" based on the lack of evidence of carcinogenicity in rats and mice.

3.5 Special FQPA Safety Factor On July 16, 2002 and December 17, 2002, the HIARC evaluated the potential for increased susceptibility of infants and children from exposure to Sethoxydim as required by the Food Quality Protection Act ( FQPA) of 1996 according to the 2002 OPP 10x Guidance Document. The HIARC concluded that the degree of concern was low for pre and/ or postnatal toxicity resulting from exposure to sethoxydim and determined that the special FQPA SF can be removed ( 1X) since there are no residual uncertainties for pre and/ or postnatal toxicity based on the following evidence:

° In the developmental rat study, the fetal anomalies were seen only at the high dose ( 650 mg/ kg/ day) which is close to the limit dose ( 1000 mg/ kg/ day), and they were observed in the presence of maternal toxicity ( irregular gait).

° Clear NOAELs/ LOAELs were established for maternal and developmental toxicities in the rat developmental study.

° In the 2 generation reproductive study, the LOAEL for offspring toxicity was based on a conservative determination of a minimal response. Page 30 of 71 3.6 Endocrine Disruption EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances ( including all pesticide active and other ingredients) " may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate." Following recommendations of its Endocrine Disruptor and Testing Advisory Committee ( EDSTAC), EPA determined that there was a scientific basis for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC's recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program ( EDSP). In the available toxicity studies on sethoxydim, there was no estrogen, androgen, and/ or thyroid mediated toxicity.

When additional appropriate screening and/ or testing protocols being considered under the Agency's EDSP have been developed, sethoxydim may be subjected to further screening and/ or testing to better characterize effects related to endocrine disruption.

4.0 EXPOSURE ASSESSMENT 4.1 Summary of Proposed/ Registered Uses Sethoxydim, (+) 2[ 1( ethoxyimino) butyl] 5[ 2( ethylthio) propyl] 3 hydroxy 2 cyclohexen 1 one, is a member of the cyclohexenone class of herbicides. Sethoxydim is a systemic, postemergence herbicide which controls annual and perennial grass weeds in broadleaf crops. Sethoxydim is an acetyl CoA carboxylase ( fatty acid synthesis) inhibitor. Sethoxydim inhibits mitosis.

Poast ® Herbicide ( EPA Reg. No. 7969 58) is an emulsifiable concentrate which contains 18% sethoxydim and 82% inerts. The formulation contains 1.5 lbs active ingredient/ gal.

Tolerances are currently established ( 40 CFR § 180.412) for combined residues of sethoxydim and its metabolites on a variety of agricultural commodities at levels ranging from 0.2 ppm to 75.0 ppm. Tolerances are also currently established for secondary residues in meat, fat, and meat byproducts of cattle, goats, hogs, horses, poultry, and sheep at 0.2 ppm ( except 2.0 ppm in poultry, mbyp); eggs at 2.0 ppm, and milk at 0.05 ppm. The tolerance expression for plant and livestock commodities includes the combined residues of sethoxydim and its metabolites containing the 2 cyclohexen 1 one moiety ( calculated as the herbicide) as specified in 40 CFR Page 31 of 71 § 180.412. Page 32 of 71 Table 4.1 Summary of Sethoxydim Use Directions Crop Minimum Time From Application to Harvest ( PHI) (# of days) Maximum Rate Per Acre Per Application ( lb ai/ acre) Maximum Rate Per Acre Per Season ( lb ai/ acre)

Alfalfa, birdsfoot trefoil, and sanfoin ( dried) 14 0.47 1.2 Alfalfa, birdsfoot trefoil, and sanfoin ( undried) 7 0.47 1.2 Apricot 25 0.47 0.94 Artichoke, Globe 7 0.47 0.94 Asparagus 1 0.47 0.94 Avacado ( nonbearing) 365 0.47 1.4 Beans ; Dry, Succulent 30 15 0.47 0.75 Beet ( Garden) 60 0.47 0.94 Blueberry 30 0.47 0.94 Brassica ( Crop Group 5*) 30 0.28 0.56 Bulb Vegetables ( Crop Group 3*) 30 0.28 0.84 Caneberries ( Crop Subgroup 13A*) 45 0.47 0.94 Canola/ Crambe/ Rapeseed 60 0.47 0.94 Carrot 30 0.47 0.94 Cherries ( sweet and sour) 25 0.47 0.94 Christmas tree farms n/ a 0.47 0.56 Citrus ( Crop Group 10*) 15 0.47 1.9 Clover 7 ( before grazing, feeding, or cutting for undried forage) 0.47 1.2 Clover hay 20 ( before grazing, feeding, or cutting for dry hay) 0.47 1.2 Corn ( Poast ® protected field corn) 60 ( grain or fodder) 45 ( forage and silage) 0.28 0.56 Table 4.1 Summary of Sethoxydim Use Directions Crop Minimum Time From Application to Harvest ( PHI) (# of days) Maximum Rate Per Acre Per Application ( lb ai/ acre) Maximum Rate Per Acre Per Season ( lb ai/ acre)

Page 33 of 71 Corn ( Poast ® protected sweet corn) 45 ( grain or fodder) 30 ( fresh sweet corn or forage and silage) 0.28 0.56 Cotton 40 0.47 1.4 Cranberry 60 0.47 0.94 Curcubits ( Crop Group 9*) 14 0.28 0.56 Date ( nonbearing) 365 0.47 1.4 Deciduous trees, Nonfood Crop Areas, Fallow Land n/ a 0.47 n/ a Fescue ( tall) n/ a 0.47 n/ a Fig ( nonbearing) 365 0.47 1.4 Flax 75 0.28 0.75 Fruiting Vegetables ( Crop Group 8*) 20 0.28 0.84 Grape 50 0.47 0.94 Head and Petiole Type Vegetables ( Crop Subgroup 4B*) 30 0.28 0.56 Horseradish 60 0.47 0.94 Leafy Vegetables ( Crop Group 4*) 15 0.28 0.56 Lentil 50 0.47 0.75 Lingonberry, Salal, Juneberry 45 0.47 0.94 Mint 20 0.47 0.94 Nectarine 25 0.47 0.94 Non bearing food crops n/ a 0.47 0.56 Nursery plantings n/ a 0.47 0.56 Table 4.1 Summary of Sethoxydim Use Directions Crop Minimum Time From Application to Harvest ( PHI) (# of days) Maximum Rate Per Acre Per Application ( lb ai/ acre) Maximum Rate Per Acre Per Season ( lb ai/ acre)

Page 34 of 71 Olives ( nonbearing) 365 0.47 1.4 Orchard floor middles n/ a 0.09 0.09 Ornamentals n/ a 0.47 0.56 Peach 25 0.47 0.94 Peanut 40 0.28 0.47 Peas, Dry Succulent 30 15 0.47 0.47 0.75 Pistachio 15 0.47 1.9 Plum ( nonbearing) 365 0.47 1.4 Pome fruits ( Crop Group 11*) 14 0.47 1.4 Pomegranate ( nonbearing) 365 0.47 1.4 Potatoes, Field Sweet ( East US) Sweet ( West US) 30 30 60 0.47 0.47 0.28 0.94 0.94 0.94 Prune ( nonbearing) 365 0.47 1.4 Rights of way n/ a 0.47 0.56 Roadsides n/ a 0.47 0.56 Safflower 30 0.47 0.94 Set Aside Conservation Land n/ a 0.47 1.4 Soybean 75 0.47 0.94 Strawberry 7 0.47 0.47 Sugar beet 60 0.47 0.94 Sunflower 70 0.47 0.47 Tobacco 42 0.28 0.75 Table 4.1 Summary of Sethoxydim Use Directions Crop Minimum Time From Application to Harvest ( PHI) (# of days) Maximum Rate Per Acre Per Application ( lb ai/ acre) Maximum Rate Per Acre Per Season ( lb ai/ acre)

Page 35 of 71 Tree Nuts ( Crop Group 14) 15 0.47 1.9 Tuberous and Corm Vegetables ( Crop Subgroup 1C*) 30 0.47 0.94 Turf/ lawns n/ a 0.47 0.56 Wildflowers n/ a 0.47 0.56 * Crop groups referenced from Code of Federal Regulations ( CFR) 40 Part 180.41.

4.2 Dietary Exposure/ Risk Pathway Reference: Sethoxydim. Reregistration Eligibility Decision ( RED). Summary of Analytical Chemistry and Residue Data, DP Barcode D318169, William Donovan, 22 JUN 2005.

4.2.1 Residue Profile Nature of the Residue  Plants and Livestock The metabolism of sethoxydim in plants is adequately understood, based on adequate metabolism studies which are available on soybeans, tomatoes, and sugar beets. Sethoxydim is rapidly metabolized in plants to a multitude of cyclohexenone derivatives including the corresponding sethoxydim sulfoxide ( MSO), sethoxydim sulfone ( MSO2), their hydroxylated and desethoxylated analogs, and oxazole compounds. Very little (

0.5%) sethoxydim ( MS) is left unmetabolized.

The metabolism of sethoxydim in ruminants is adequately understood. In a lactating goat fed 14Cring labeled sethoxydim sulfoxide ( 14C MSO), sethoxydim sulfoxide ( MSO) was oxidized to the corresponding sulfone ( MSO2). Desethylation with subsequent methylation at the sulfur atom also occurred. The major residues in milk and kidney were MSO and MSO2. The major residues in liver were MSO2 and MS.

The metabolism of sethoxydim in poultry is adequately understood. In one study, laying hens were dosed with 14C ring labeled sethoxydim sulfoxide; the major residues in eggs, muscle, fat, skin, and liver were MSO and MSO2. In a second poultry metabolism study, 10 laying hens were dosed with 14C ring labeled sethoxydim; the major residues were MSO and MSO2 in muscle and liver, and MSO and MS in fat. Page 36 of 71 The residues to be included in the tolerance expression and in the risk assessment for plant and livestock commodities are the combined residues of sethoxydim and its metabolites ( see Appendix for stuctures) containing the 2 cyclohexen 1 one moiety ( calculated as the herbicide) as specified in 40 CFR § 180.412.

Residue Analytical Methods Plants and Livestock Commodities Adequate enforcement methodology ( gas liquid chromatography with flame photometric detection [ GLC/ FPD] in the sulfur mode) is available [ BASF Wyandotte Corporation's ( BWC's) Method No. 30, 3/ 15/ 82; MRID 44864501; Method I, PAM II] to enforce the tolerance expression in plant and livestock commodities.

Multiresidue Methods Multiresidue data for sethoxydim, sethoxydim sulfoxide ( MSO), and 5 hydroxy sethoxydim sulfone ( 5 OH MSO2) have been submitted. Protocols A and B are not applicable; protocols C, D, and E were tested. Sethoxydim and its metabolites are not recovered or are not likely to be recovered by FDA multiresidue methods.

Storage Stability Adequate storage stability data are available to support all registered uses except safflower oil. Storage stability data for sethoxydim, MSO, and 5 OH MSO2 in safflower oil ( or another oil) stored frozen for one year are needed since storage stability data for sethoxydim residues in oil have not previously been submitted.

Crop Field Trial Data No monitoring data were used. Field trial data have been used.

Currently, the residues included in the tolerance expression for plant and livestock commodities are the combined residues of sethoxydim and its metabolites ( see Appendix for stuctures) containing the 2 cyclohexen 1 one moiety ( calculated as the herbicide) as specified in 40 CFR § 180.412. Because sethoxydim metabolism is similar in plant and animal tissues, resulting in formation of many cyclohexenone derivatives, and there is no data allowing differentiation of the toxicity of these species ( R. Loranger, D246356, 27 MAY 1998), the sethoxydim risk assessment team determined that the existing tolerance expression is appropriate. Moreover, a common moiety analytical method which quantitates all compounds containing the 2 cyclohexen 1 one moiety was used to collect residue data. This method was successfully validated by EPA labs. Accordingly, the sethoxydim risk assessment team also determined that the appropriate residues of concern for risk assessment purposes are the combined residues of sethoxydim and its metabolites containing the 2 cyclohexen 1 one moiety, calculated as the herbicide. Page 37 of 71 Residue Analytical Methods Plants and Livestock Commodities Adequate enforcement methodology ( gas liquid chromatography with flame photometric detection [ GLC/ FPD] in the sulfur mode) is available [ BASF Method No. 30; Method I, PAM II] to enforce the tolerance expression in plant and livestock commodities. Method 30 is a common moiety method, where residues are determined as 3[ 2( ethylsulfonyl) propyl] pentanedioic acid dimethyl ester ( DME) and its 3 hydroxy derivative, 3[ 2( ethoxysulfonyl) propyl] 3 hydroxypentanedioic acid dimethyl ester ( DME OH), respectively. Sethoxydim and its metabolites are oxidized and then derivatized to DME and DME OH, respectively. The limit of quantitation for each analyte is 0.05 ppm sethoxydim equivalents.

Processed Food/ Feed The reregistration requirements for magnitude of the residue in the processed food/ feed commodities have been fulfilled.

Confined Accumulation in Rotational Crops HED ( D189273, G. Kramer, 8/ 3/ 93) reviewed a confined rotational crop study ( Accession # 42825) and a limited field accumulation study ( MRID 41510612). The limited field study used soybeans treated with 14C ring labeled sethoxydim at 0.9 or 1.0 lb ai/ A and cotton treated at 0.5 lb ai/ A as primary crops. ( The proposed rate on herbs is 0.56 lb ai/ A/ season.) The rotational crops included root crops, leafy vegetables, and small grains. Total radioactive residues ( TRRs) were < 0.005 0.01 ppm with some exceptions: 0.05 ppm in sorghum forage at a plantback interval of 30 days ( 0.5 lb ai/ A application rate); 0.02 ppm in winter wheat forage and 0.05 ppm in winter wheat straw at a plantback interval of 134 days ( 1 lb ai/ A application rate); and 0.024 ppm in spring wheat grain and 0.06 ppm in spring wheat straw at a plantback interval of 283 days ( 0.5 lb ai/ A application rate). Approximately 60% of the TRR is expected to be in the form of sethoxydim metabolites ( based on soybean and alfalfa studies). Residues in all the limited field accumulation trials were below the limit of quantitation of the enforcement method ( 0.1 0.2 ppm) for all RACs at all plantback intervals. Since residues in rotational crops were expected to be below the limit of quantitation of the method, HED concluded that tolerances were not required at that time for rotational crops planted greater than 30 days after the primary crop is treated with sethoxydim.

The limited field accumulation study indicated that residues were below the limit of quantitation ( 0.1 or 0.2 ppm LOQ) of the enforcement method in all rotational crop RACs at all plantback intervals. Since residues in rotational crops are expected to be below the limit of quantitation of the method, tolerances are not required for rotational crops planted greater than 30 days after the primary crop is treated with sethoxydim.

A plantback restriction of at least 30 days should be added to the label. Page 38 of 71 Meat, Milk, Poultry, and Eggs Dairy cattle and poultry feeding studies are available. Based on the feeding study results and the dietary burden calculations, secondary residues in livestock commodities may be expected as a result of livestock ingesting feedstuffs derived from crops which may be treated with sethoxydim. Permanent tolerances are established ( 40 CFR § 180.412) for residues of the herbicide sethoxydim and its metabolites containing the 2 cyclohexen 1 one moiety in meat and fat of cattle, goats, hogs, horses, poultry, and sheep at 0.2 ppm; meat byproducts of cattle, goats, hogs, horses, and sheep at 1.0 ppm ( 2.0 ppm in meat byproducts of poultry); eggs at 2.0 ppm, and milk at 0.5 ppm. The existing sethoxydim permanent tolerances on livestock commodities are adequate.

International Harmonization A comparison of Canadian and Mexican MRLs with recommended US tolerances for sethoxydim is provided in Table 4.2.1. The Canadian tolerances on various legume vegetables are significantly less than those needed to cover residues in the U. S. The Mexican MRLs are based on the U. S. tolerance levels.

Table 4.2.1. Comparison of Canadian and Mexican MRLs with Recommended US Tolerances.

Crop US Tolerance ( ppm) Canada MRL ( ppm) Mexico MRL ( ppm)

Alfalfa ( hay & forage) 40  40 Pea, dry 40  40 Lentils 30 30 30 Peanut 25  25 Tomato paste 4 15 4 Soybean 16 5 16 Pea, succulent 10 10 10 Bean, dry 20 10

Strawberry 10 10 10 Sunflower 7 7

Brassica vegetables 5  5 Cotton, seed 5  5 Raspberry 5 5

Bean, succulent 15 5

Curcurbit vegetables 4  4 Crop US Tolerance ( ppm) Canada MRL ( ppm) Mexico MRL ( ppm)

Page 39 of 71 Fruiting vegetables 4  4 Leafy vegetables 4  4 Blueberry 4 4

Potato 4 4 4 Tomato 4 4 4 Artichoke 5 2

Cabbage 4 2 4 Cantaloupe 4 2 4 Cranberrry 2.5 2

Eggplant 4 2 4 Mustard 4 2 4 Mustard greens 4 2 4 Spinach 4 2 4 Celery 4 1 4 Cucumber 4 1 4 Lettuce 4 1 4 Pumpkin 4 1 4 Squash 4 1 4 Bulb vegetables 1   1 Grape 1   1 Citrus fruit 0.5   0.5 Asparagus 4 0.5

Broccoli 4 0.5 4 Corn 0.5 0.5

Pepper 4 0.5 4 Flax 5 0.2

Onion 1 0.2 1 Turnip   0.2 1 Crop US Tolerance ( ppm) Canada MRL ( ppm) Mexico MRL ( ppm)

Page 40 of 71 Apple 0.2   0.2 Carrot 1 0.1   4.2.2 Dietary Exposure Analyses The sethoxydim dietary exposure assessment was conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database ( DEEM FCID   , Version 1.3), which incorporates consumption data from USDA's Continuing Surveys of Food Intakes by Individuals ( CSFII), 1994 1996 and 1998. The 1994 1996, and 1998 data are based on the reported consumption of more than 20,000 individuals over two non consecutive survey days. Foods " as consumed" ( e. g., apple pie) are linked to EPA defined food commodities ( e. g. apples, peeled fruit  cooked; fresh or N/ S; baked; or wheat flour  cooked; fresh or N/ S, baked) using publicly available recipe translation files developed jointly by USDA/ ARS and EPA. Consumption data are averaged for the entire U. S. population and within population subgroups for chronic exposure assessment, but are retained as individual consumption events for acute exposure assessment.

For chronic exposure and risk assessment, an estimate of the residue level in each food or foodform ( e. g., orange or orange juice) on the food commodity residue list is multiplied by the average daily consumption estimate for that food/ food form. The resulting residue consumption estimate for each food/ food form is summed with the residue consumption estimates for all other food/ food forms on the commodity residue list to arrive at the total average estimated exposure. Exposure is expressed in mg/ kg body weight/ day and as a percent of the cPAD. This procedure is performed for each population subgroup.

For acute exposure assessments, individual one day food consumption data are used on an individual by individual basis. The reported consumption amounts of each food item can be multiplied by a residue point estimate and summed to obtain a total daily pesticide exposure for a deterministic ( Tier 1 or Tier 2) exposure assessment, or " matched" in multiple random pairings with residue values and then summed in a probabilistic ( Tier 3/ 4) assessment. The resulting distribution of exposures is expressed as a percentage of the aPAD on both a user ( i. e., those who reported eating relevant commodities/ food forms) and a per capita ( i. e., those who reported eating the relevant commodities as well as those who did not) basis. As stated above, for acute and chronic assessments, HED is concerned when dietary risk exceeds 100% of the PAD. The DEEM FCID   analyses estimate the dietary exposure of the U. S. population and 32 population subgroups.

<IP_ADDRESS> Acute Dietary Exposure Analysis Reference: Sethoxydim. Acute Dietary Exposure Assessment for Section 3 Registration Actions, DP Barcode D292905, David Soderberg, 11 AUG 2003. Page 41 of 71 This acute assessment used tolerance level residues for most of the crops but limited refinement was obtained through the incorporation of field trial data and experimental processing factors for some of the crops expected to be more highly associated with dietary exposure to sethoxydim. Specifically, field trial data were incorporated for apples, pears and other pome fruits, grapes, oranges, potatoes, strawberries, peaches, succulent green peas, succulent green beans, and succulent lima beans. Empirical processing data for apples, grapes, tomatoes, potatoes and oranges were also used. The processing data for orange juice was also translated to other citrus juices. Percent crop treated information was available for most crops and was used wherever possible to refine the assessment. Tolerance level residues were used for meat, poultry, milk and eggs.

With the refinements incorporated in this assessment, the acute dietary analyses for sethoxydim show that the estimated risks from acute dietary exposure to sethoxydim are below the Agency's level of concern (< 100% aPAD) for the US population and all population subgroups listed in Table <IP_ADDRESS>. Exposure at the 99.9th percentile was 5.3% of the aPAD for the general US population, and 9.2% of the aPAD for children aged 1 2 years, and also children aged 3 5 years, the two most highly exposed population subgroup.

Table <IP_ADDRESS>. Results of Acute Dietary Exposure Analysis Population Subgroup aPAD ( mg/ kg/ day) 95th Percentile 99th Percentile 99.9th Percentile Exposure ( mg/ kg/ day) % aPAD Exposure ( mg/ kg/ day) % aPAD Exposure ( mg/ kg/ day) % aPAD General U. S. Population 1.8 0.028 1.6 0.052 2.9 0.096 5.3 All Infants (< 1 year old) 1.8 0.058 3.2 0.089 5.0 0.133 7.4 Children 1 2 years old 1.8 0.068 3.8 0.098 5.4 0.165 9.2 Children 3 5 years old 1.8 0.051 2.8 0.077 4.3 0.165 9.2 Children 6 12 years old 1.8 0.033 1.8 0.052 2.9 0.118 6.6 Youth 13 19 years old 1.8 0.021 1.2 0.036 2.0 0.078 4.3 Adults 20 49 years old 1.8 0.016 0.91 0.029 1.6 0.072 4.0 Females 13 49 years old 1.8 0.016 0.90 0.028 1.5 0.074 4.1 Table <IP_ADDRESS>. Results of Acute Dietary Exposure Analysis Population Subgroup aPAD ( mg/ kg/ day) 95th Percentile 99th Percentile 99.9th Percentile Exposure ( mg/ kg/ day) % aPAD Exposure ( mg/ kg/ day) % aPAD Exposure ( mg/ kg/ day) % aPAD Page 42 of 71 Adults 50+ years old 1.8 0.016 0.87 0.028 1.6 0.063 3.5 <IP_ADDRESS> Chronic Dietary Exposure Analysis Reference: Sethoxydim. Acute and Chronic Dietary Exposure Assessments for Section 3 Registration Actions, DP Barcode D289880, Nancy Dodd, 06 MAY 2003.

Sethoxydim chronic dietary exposure assessments were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database ( DEEM FCID   , Version 1.3), which incorporates consumption data from USDA's Continuing Surveys of Food Intake by Individuals ( CSFII), 1994 1996 and 1998. The chronic DEEM FCID   analysis used mean consumption ( 3 day average) data and gave the results listed in Table 6. The chronic analysis ( limited refined dietary risk assessment) used tolerance level residues for all crops, percent crop treated for many crops, and anticipated residues for meat and milk. The most highly exposed population subgroup is infants, at 7.5 % of the cPAD. The results of this analysis indicate that the chronic dietary risk ( food only) associated with existing uses of sethoxydim is below the Agency's level of concern (< 100% cPAD) for the general U. S. population and all population subgroups listed in Table <IP_ADDRESS>.

Table <IP_ADDRESS>. Results of Chronic Dietary Exposure Analysis for Sethoxydim.

Population Subgroup cPAD ( mg/ kg/ day) Exposure ( mg/ kg/ day) % cPAD General U. S. Population 0.14 0.004 2.7 All Infants (< 1 year old) 0.14 0.010 7.5 Children 1 2 years old 0.14 0.009 6.8 Children 3 5 years old 0.14 0.008 5.5 Children 6 12 years old 0.14 0.005 3.5 Youth 13 19 years old 0.14 0.003 2.4 Adults 20 49 years old 0.14 0.003 2.1 Females 13 49 years old 0.14 0.003 2.1 Table <IP_ADDRESS>. Results of Chronic Dietary Exposure Analysis for Sethoxydim.

Population Subgroup cPAD ( mg/ kg/ day) Exposure ( mg/ kg/ day) % cPAD Page 43 of 71 Adults 50+ years old 0.14 0.003 2.2 4.3 Water Exposure/ Risk Pathway Reference: Sethoxydim Drinking Water Assessment ( Tier 1) for Reregistration Eligibility Decision, DP Barcode: D312559, William Eckel, 07 FEB 2005 The Metabolism Assessment Review Committee ( MARC) discussed residues of the herbicide sethoxydim in water on May 14, 1998 ( R. Loranger, D246356, 27 MAY 1998). The predominant degradates in soil are the sulfoxide and sulfone derivatives of the parent ( MSO and MSO2) ( see Appendix for structures). These degradates are expected to be found in water along with M1S and M2S. Toxicology data for the four degradates expected in water are not available. In the absence of such data, the MARC concluded that these degradates should be considered as having comparable toxicity as the parent. Therefore, for risk assessment purposes the " total sethoxydim residues" in water should be used instead of the levels for only parent sethoxydim.

Little if any monitoring data are available for sethoxydim to determine its concentration in drinking water sources. The USGS Pesticide National Synthesis Project ( http:// ca. water. usgs. gov/ pnsp/ ) did not include sethoxydim ( nor any of its degradates) in its list of pesticides for laboratory analysis of ground water and surface water samples. Therefore, modeling estimates were used to quantify possible drinking water exposure.

Surface water  Surface water assessment used a Tier 1 model called FIRST, or FQPA Index Reservoir Screening Tool, a simulation model based on a high runoff scenario ( Mississippi cotton) with a storm two days after application. The modeling was performed using the maximum number of applications ( four) and maximum application rate of 0.47 pounds ( 2.5 pints) active ingredient per acre, assuming a 14 day RTI. A default percent cropped area factor ( PCA) of 87% was used for the surface water assessment. This means that it was assumed that sethoxydimtreated crops were grown on 87% of the acres of land in the modeled watershed. This is the highest PCA for any watershed in the continental U. S., and is used as a default value for minor crops. Lower PCA values could have been applied for the major crops on which sethoxydim is used ( soybeans, cotton, and corn). However, because there is such a great variety of uses, it is likely that there is usage on major and minor crops in the same watershed, so the crop specific PCA may not be applicable. EDWCs are proportional to the PCA used. The FIRST model results for total sethoxydim residues are in Table 4.3.

Ground water  The EDWC for ground water was estimated by the SCI GROW model, version 2.3. The results of the model for acute and chronic scenarios ( Table 4.3) are 1.5 ppb for parent Page 44 of 71 sethoxydim plus degradates when assuming a maximum use rate of 1.875 lb ai/ A per year.

Table 4.3. Estimated Concentrations of Total Sethoxydim Residues in Drinking Water.

Chemical Surface Water ( ppb) Groundwater ( ppb)

Acute Chronic Acute and Chronic Sethoxydim 130 16 1.5 4.4 Residential ( Non Occupational) Exposure/ Risk Pathway The following non occupational assessment was extracted from the HED ORE chapter for sethoxydim ( W. Britton. DP318167, 6/ 22/ 05).

Sethoxydim is registered for residential ( consumer) use on ornamentals and flowering plants, recreational areas, and buildings/ structures ( outdoor). Homeowners who apply sethoxydim to ornamental gardens and turf may be exposed for short term durations via the dermal and inhalation routes. In addition, short term postapplication exposures may result from incidental oral exposures ( children only) due to contact with sethoxydim treated turf in public ( recreational) and residential settings.

Use instructions on product labeling for residential applications suggest only spot treatment, which is not considered by HED to result in consequential exposures. However, because no recommendation against broadcast lawn use appears on product labeling, it is assumed that such a use could occur and, therefore, an assessment of residential postapplication turf exposure was performed. No endpoint was selected for intermediate term incidental ingestion exposures which are considered unlikely. This decision is based upon the frequency ( no more than twice per year) and method of application ( spot treatment) specified by product labeling. The HED HIARC did not identify a dermal endpoint of concern for sethoxydim. Therefore, only exposure from inhalation ( adult handlers) and incidental ingestion ( children, postapplication) were assessed.

Inhalation risk was estimated using the NOAEL of 81 mg/ kg/ day from a 28 day rat inhalation study. The NOAEL was based upon increased liver weight, clinical chemistry ( increased total serum bilirubin), and liver histopathology. The risk for short term postapplication toddler incidental ingestion ( hand to mouth, turf to mouth, soil to mouth) was estimated using the NOAEL of 180 mg/ kg/ day from a rat developmental toxicity study. This NOAEL was based upon was based on irregular gait observed in the dams on the first day of dosing HED's level of concern, in this instance, is an MOE = 100 ( 10x inter species extrapolation, and 10x intra species variation) for all residential population groups. MOEs estimated for handlers range from 1.4E+ 6 to 1.6E+ 6. MOEs estimated for short term postapplication incidental ingestion range from 26,000 for hand to mouth incidental exposures to 7.6E+ 6 for soil ingestion Page 45 of 71 incidental exposures. The resulting MOEs are above the target MOE of 100 and, therefore, are not of concern to HED.

4.4.1 Non Occupational ( Residential) Handler Exposure and Risks As previously mentioned, sethoxydim exposure to residential handlers may occur. Residential handler scenarios assessed for sethoxydim are as follows:

° Inhalation exposure from mixing/ loading/ applying liquids for low pressure handwand application ° Inhalation exposure from mixing/ loading/ applying liquids for backpack sprayers ° Inhalation exposure from mixing/ loading/ applying liquids for garden hose end sprayers ( spot treatment)

Residential ( non occupational) handler risks range from 1.4E+ 6 to 1.6E+ 6 and, therefore, do not exceed HED's level of concern. Results from exposure and risk calculations are presented in Table 4.4.1.

A series of assumptions and exposure factors served as the basis for completing the residential handler risk assessments. Each assumption and factor is detailed in the HED ORE chapter. In addition to these factors, unit exposure values were used to calculate handler risk estimates. These unit exposure values were taken from the Pesticide Handlers Exposure Database ( PHED) and Outdoor Residential Exposure Task Force ( ORETF) studies. The handler assessment was conducted for application on turf and ornamental gardens at the maximum application rate of 0.47 lb ai/ A.

Table 4.4.1: Short term Exposures and Risks for Residential ( Non occupational) Handlers Exposure Scenario ( Scenario #) Inhalation Unit Exposure ( Ug/ lb ai) 1 Crop2 Application Rate3 Daily Area Treated4 Inhalation Dose ( mg/ kg/ day) 5 Inhalation MOE6 Mixer/ Loader/ App Mixing/ Loading/ Applyi ng Liquids for Low Pressure Handwand application ( 1) 30 Ornamentals, Flowering Plants, Turf/ Lawn 0.02 lb ai per gallon 5 Gallons per day 0.000049 1600000 Mixing/ Loading/ Applyi ng Liquids for Backpack sprayer application ( 2) 30 Ornamentals, Flowering Plants, Turf/ Lawn 0.02 lb ai per gallon 5 Gallons per day 0.000049 1600000 Mixing/ Loading/ Applyi ng Liquids for Garden hose end sprayer( ORETF  conventional) application ( 2) 17 Ornamentals, Flowering Plants, Turf/ Lawn 0.47 lb ai per acre 0.5 Acres per day 0.000057 1400000 1Baseline inhalation unit exposures represent no respirator. Values are reported in the PHED Surrogate Exposure Guide dated August 1998 or are Page 46 of 71 from data submitted by the Outdoor Residential Exposure Task Force dated May 2000. 2Crops and use patterns are from various sources including LUIS and labels. 3Application rates are based on maximum values found in various sources including LUIS and various labels. In most scenarios, a range of maximum application rates is used to represent the range of rates for different crops/ sites/ uses. Most application rates upon which the analysis is based are presented as lb ai/ A. In some cases, the application rate is based on applying a solution at concentrations specified by the label ( i. e., presented as lb ai/ gallon). 4Amount treated is based on the area or gallons that can be reasonably applied in a single day for each exposure scenario of concern based on the application method and formulation/ packaging type. ( Standard EPA/ OPP/ HED values). 5Inhalation dose ( mg/ kg/ day) = [ unit exposure ( ug/ lb ai) * 0.001 mg/ g unit conversion * Inhalation absorption ( 100%) * Application rate ( lb ai/ acre or lb ai/ gallon) * Daily area treated ( acres or gallons)] / Body weight ( 70 kg). 6Inhalation MOE = NOAEL ( 81 mg/ kg/ day) / Daily Inhalation Dose. Target Inhalation MOE is 100.

4.4.2 Non Occupational ( Residential) Postapplication Exposure and Risks HED uses the term postapplication to describe exposures to individuals that occur as a result of being in an environment that has been previously treated with a pesticide. Sethoxydim can be used in areas that can be frequented by the general population including residential areas ( i. e. home lawns). As previously mentioned, there is potential for dermal ( adults and children) and incidental oral exposure ( children) following the application of sethoxydim.

The HED Standard Operating Procedures for Residential Exposure Assessments ( Draft, December 18, 1997) were used as a guideline for performing the residential postapplication assessment, along with interim changes to these SOPs which were adopted by the HED Exposure Science Advisory Council regarding standard values, including, for turf transferrable residues, turf transfer coefficients and hand to mouth activities ( Policy 11, February 22, 2001). While toddler short term incidental oral exposures are estimated, it should be recognized that these estimates are conservative in nature due to the application method specified by product labeling ( spottreatment While only spot treatment is specified, no recommendation against broadcast lawn use appears on product labeling and, therefore, it is assumed that this could occur. The HED SOPs for Residential Exposure Assessments that pertain to turf uses were adopted based upon the results and determinations made from studies involving broadcast lawn applications. The spottreatment method of application specified for sethoxydim is intermittent in nature and should reduce the likelihood of exposure.

Again, HIARC did not identify a dermal endpoint of concern for sethoxydim and, because inhalation is considered negligible for postapplication exposure, only toddler incidental oral exposures were assessed. Postapplication risk scenarios assessed for sethoxydim are as follows:

Toddler

° Hand to Mouth Activity on Turf ° Object to Mouth Activity on Turf ° Incidental Soil Ingestion MOEs for all toddler postapplication risk scenarios ( short term) are not a risk of concern ( i. e. MOE less than 100). Results are presented in Tables <IP_ADDRESS>, <IP_ADDRESS>, and <IP_ADDRESS>.

<IP_ADDRESS> Non Occupational ( Residential) Postapplication Risk Page 47 of 71 Characterization.

The exposure estimates generated are based on some upper percentile ( i. e., maximum application rate, day zero residues, surface area and hand to mouth activity) assumptions and are, therefore, considered to be representative of central to high end exposures. The uncertainties associated with this assessment stem from the use of an assumed amount of pesticide available from turf, and assumptions regarding transfer of chemical residues, and hand to mouth activity, as well as, the exposures expected from a spot treatment application as specified by product labeling. This is considered to represent Tier 1 assessment. If a Tier 1 assessment indicates a potential concern, a more detailed exposure assessment is warranted, possibly including chemical specific or sitespecific data. exposure assessment is warranted, possibly including chemical specific or sitespecific data.

Table <IP_ADDRESS>: Short term Oral Hand to Mouth Exposure and Risk for Children from Treated Lawns Exposure Scenario For mula tion Applicat ion Rate ( lbai/ A) Percent ai dislodgea ble TTR1 (

g/ cm2 ) Surface Area ( cm2) Hand to Mouth ( events/ hr) Extracti on by Saliva Exposur e Time ( hrs/ day) Body Weight ( kg) Daily Dose2 ( mg/ kg / day) MOE3 Hand to Mouth ( using 5% defalt) Spr ay 0.47 5 % 0.26 20 20 50% 2 15 0.007 26000 1 Turf Transferrable Residue ( ug/ cm2) = Application rate ( lb ai/ A) x Fraction of ai Available x 4.54E+ 8 ug/ lb x 2.47E 8 A/ cm2 2 Daily Dose = ( Turf Transferrable Residue ( ug/ cm2) x Extraction by Saliva x Hand Surface Area ( cm2/ event) x Frequency ( events/ hr) x 1E 3 mg/ ug x ET ( hrs/ day)] / [ Body Weight ( kg)] 3 MOE = Short Term Oral NOAEL ( 180 mg/ kg/ day) / Daily Dose.

Table <IP_ADDRESS>: Short term Oral Object to Mouth ( Turfgrass) Exposure and Risk for Children from Treated Lawns Exposure Scenario Formulation Application Rate ( lbai/ A) Percent ai dislodgeable TTR1 (

g/ cm2) Surface Area Mouthed ( cm2/ day) Body Weight ( kg) Daily Dose2 ( mg/ kg/ day) MOE3 Object to Mouth ( turf) Spray 0.47 20 % 1.05 25 15 0.0018 100000 1Grass residue ( ug/ cm2) = [ Application Rate ( lbs ai/ A) x Fraction of ai Available x 4.54E+ 8 ug/ lb x 2.47E 8 A/ cm2] 2 Daily Dose = [ Grass reside ( ug/ cm2) x Surface Area Mouthed ( cm2/ day) x 1E 3 mg/ ug] / [ Body Weight ( kg)] 3 MOE = Short Term Oral NOAEL ( 180 mg/ kg/ day) / Daily Dose.

Table <IP_ADDRESS>: Short term Exposure and Risk for Children from Ingestion of Soil Exposure Scenario Formulation Application Rate ( lbai/ A) Fraction of ai available Soil Residue1 (

g/ g) Ingestion Rate ( mg/ day) Body Weight ( kg) Daily Dose2 ( mg/ kg/ day) MOE3 Soil Ingestion Spray 0.47 100% 3.5 100 15 2.4E 05 7600000 1 Soil residue ( ug/ g) = [ Application Rate ( lbs ai/ A) x Fraction of ai Available x 4.54E+ 8 ug/ lb x 2.47E 8 A/ cm2 x 0.67 cm3/ g soil] 2 Daily Dose = [ Soil reside ( ug/ g) x Ingestion rate ( mg/ day) x 1E 6 g/ ug] 3 MOE = Short Term Oral NOAEL ( 180 mg/ kg/ day) / Daily Dose.

4.4.3 Non Occupational Off Target Exposure and Risk Page 48 of 71 <IP_ADDRESS> Recreational Uses Sethoxydim may be used on turf at recreational use sites and, therefore, may result in postapplication exposure to adults and children involved in recreational activities. Exposures to adults and children from the use of sethoxydim at recreational use sites are assumed to be the same as those assessed for residential use sites. In lieu of this, a separate exposure assessment was not included.

<IP_ADDRESS> Other ( Spray Drift, etc.)

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for sethoxydim. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices. On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/ labeling. The Agency has completed its evaluation of the new data base submitted by the Spray Drift Task Force, a membership of U. S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off target drift with specific products with significant risks associated with drift.

<IP_ADDRESS> Exposure from Use of Tobacco  Health Risk Assessment In assessing exposure through use of tobacco, HED has assumed that the greatest exposure to sethoxydim would come from cigarettes. Further, HED has assumed that the average U. S. smoker smokes 15 cigarettes per day. ( Pierce, J. P., et al. 1989. Tobacco Use in 1986  Methods and Basic Tabulations from Adult Use of Tobacco Survey. U. S. Dept. of Health and Human Services Publication Number OM90 2004. Office on Smoking and Health, Rockville, Maryland.) Based on the field trial data provided on tobacco, combined residues of sethoxydim and metabolites ranged from 0.26  22.62 ppm in/ on six samples of cured tobacco leaves. An average residue of 1.49 ppm of sethoxydim and its metabolites were used to make cigarettes. The results of the tobacco pyrolysis study for total radioactive residues ( TRR) recovered was 19% and 30% for main stream and side stream smoke, respectively, thus approximately total for sethoxydim and its metabolites is 0.73 ppm ( 1.49 ppm x 49%). Since this is a composited sample of main stream and side stream smoke, it greatly exaggerates the actual exposure to the smoker, whose primary route of exposure is via main stream smoke. HED has further assumed that 100% of the pesticide residue on the tobacco is inhaled and 100% inhaled is absorbed ( i. e., that none of the residue is exhaled along with the smoke). These assumptions result in an extreme overestimate of actual likely exposure. With the assumptions regarding residue levels and smoking frequency, and assuming an average body weight of 70 kg, HED estimates that exposure to sethoxydim will not exceed 0.00016 mg/ kg/ day for males [ 0.73 µ g/ g cigarette × 1 g/ cigarette × 15 cigarettes/ day × 1 Page 49 of 71 mg/ 1000 µ g ÷ 70 kg body weight = 0.00016 mg/ kg/ day] and 0.00018 mg/ kg/ day for females ( 60 kg body weight).

The inhalation NOAEL is 81 mg/ kg/ day ( all durations) and is based on a 28 day inhalation study in the rat. HED has not examined intermediate or long term exposure to sethoxydim via tobacco due to the severity and quantity of health effects associated with the use of tobacco products. Based on the inhalation NOAEL, the short term MOE for sethoxydim exposure from the use of tobacco is estimated to be greater than 100 ( males: 81mg/ kg/ day ÷ 0.00016 mg/ kg/ day = 500,000; females: 81 mg/ kg/ day ÷ 0.00018 mg/ kg/ day = 440,000). This is a highly conservative value for the reasons stated above. This risk is below HED's level of concern for all population subgroups.

5.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION Aggregate exposure / risk assessments were performed for the following scenarios: acute and chronic aggregate exposure ( food + drinking water) and short term aggregate exposure ( residential + food + drinking water). A cancer aggregate risk assessment was not performed because sethoxydim is not carcinogenic.

Since HED does not have reliable ground and surface water monitoring data, water modeling data were used to compare with Drinking Water Levels of Comparsion ( DWLOCs). A DWLOC is a theoretical upper limit on a pesticide's concentration in drinking water in light of total aggregate exposure to a pesticide in food, drinking water, and through residential uses, when applicable. A DWLOC will vary depending on the toxicity endpoint, drinking water consumption, body weights, and pesticide uses. Different population subgroups will have different DWLOCs. HED uses DWLOCs in the risk assessment process to assess potential concern for exposure associated with pesticides in drinking water. DWLOC values are not regulatory standards for drinking water.

To calculate DWLOCs, the dietary food estimates ( from DEEM FCID   ) were subtracted from the PAD value to obtain the maximum water exposure level. DWLOCs were then calculated using the standard body weights and drinking water consumption figures: 70kg/ 2L ( US Population; Adults 20 49; Adults 50+), 60 kg/ 2L ( Youth 13 19; Females 13 49), and 10kg/ 1L ( all Infants and Children).

5.1 Acute Aggregate Risk Assessment ( Food and Drinking Water)

The acute aggregate risk assessment takes into account exposure estimates from dietary consumption of sethoxydim ( food and drinking water).

The limited refined acute dietary exposure ( food only) estimates are below HED's level of concern (< 100% aPAD) at the 99.9th exposure percentile for the general U. S. population ( 5.2 % Page 50 of 71 of the aPAD) and all other population subgroups. The most highly exposed subpopulations were children aged 1 2 and children aged 3 5 years, both at 9.2% of the aPAD. The EDWCs generated by EFED are less than HED's calculated DWLOCs for acute exposure to sethoxydim. Table 5.1 summarizes the acute aggregate exposure estimates to sethoxydim residues.

Table 5.1. Acute DWLOC Calculations for Sethoxydim.

Population Subgroup Acute Scenario aPAD mg/ kg/ day Acute Food Exp mg/ kg/ day Max Acute Water Exp mg/ kg/ day1 Ground Water EDWC ( ppb) 2 Surface Water EDWC ( ppb) 2 Acute DWLOC (

g/ L) 3 General U. S. Population 1.8 0.096 1.704 1.5 130 5.96e+ 04 All Infants (< 1year) 1.8 0.133 1.667 1.5 130 1.67e+ 04 Children 1 2 years 1.8 0.165 1.635 1.5 130 1.64e+ 04 Children 3 5 years 1.8 0.165 1.635 1.5 130 1.64e+ 04 Children 6 12 years 1.8 0.118 1.682 1.5 130 1.68e+ 04 Youth 13 19 years 1.8 0.078 1.722 1.5 130 5.17e+ 04 Adults 20 49 years 1.8 0.072 1.728 1.5 130 6.05e+ 04 Females 13 49 years 1.8 0.074 1.726 1.5 130 5.18e+ 04 Adults 50+ years 1.8 0.063 1.737 1.5 130 6.08e+ 04 1 Maximum acute water exposure ( mg/ kg/ day) = [( acute PAD ( mg/ kg/ day)  acute food exposure ( mg/ kg/ day)]. 2 The crop producing the highest level was used. 3 Acute DWLOC(

g/ L) = [ maximum acute water exposure ( mg/ kg/ day) x body weight ( kg)] [ water consumption ( L) x 10 3 mg/

g]

5.2 Short Term Aggregate Risk Assessment The short term aggregate risk assessment estimates risks likely to result from 1 30 day exposures to sethoxydim residues from food, drinking water, and residential pesticide uses. High end estimates of the residential exposure are used in the short term assessment, and average values are used for food and drinking water exposures. Page 51 of 71 Short term aggregate risk assessments were not calculated for adult handlers because oral and inhalation endpoints lack a common toxicity endpoint. Further, no dermal exposure risk assessment is required because there is no dermal or systemic toxicity following repeated dermal exposure, susceptibility in rabbits is not a concern, and low dermal absorption physical and chemical properties. Short term aggregate risk assessments are required for children/ toddlers because there is a potential for oral postapplication exposure resulting from the residential uses of sethoxydim. The short term residential exposure potential for sethoxydim for children/ toddlers can be found in Table 5.2. The children/ toddlers 1 2 years of age scenario was chosen because it was the highest estimated food exposure and thus, also protective of children 3 5 years of age. As the MOEs are greater than 100, the short term aggregate risks are below HED's level of concern. For surface and ground water, the estimated average concentrations of sethoxydim are less than HED's calculated DWLOCs for sethoxydim in drinking water as a contribution to shortterm aggregate exposures. Therefore, HED concludes with reasonable certainty that residues of sethoxydim in drinking water do not contribute significantly to the short term aggregate human health risks at the present time.

Table 5.2. Short Term Aggregate DWLOCs for Sethoxydim Population Subgroup NOAEL ( mg/ kg/ day) Target MOE 1 Target Maximum Exposure 2 ( mg/ kg/ day) Estimated Food Exposure ( mg/ kg/ day) Estimated Residential Exposure ( mg/ kg/ day) Allowable Water Exposure 3 ( mg/ kg/ day) Groundw ater EDWC (

g/ L) 4 Surface water EDWC (

g/ L) 4 DWLOC 5 ( µ g/ L)

Short term: Children ( 1 2 years old) 180 100 1.8 0.0095 0.0088 1.7817 1.5 16 1.78e+ 04 1 The short term target MOE for sethoxydim includes the standard intra and inter species uncertainty factors as well as the FQPA uncertainty safety factor of 10X. 2 Target Max Exposure = NOAEL / Target MOE 3 Maximum Water Exposure ( mg/ kg/ day) = Target Maximum Exposure ( mg/ kg/ day)  Aggregate Food and Residential Exposure ( mg/ kg/ day). 4 Estimate for the highest use rate was chosen. 5 DWLOC ( µ g/ L) = Max. water exposure ( mg/ kg/ day) x body wt ( kg) ÷ [( 10 3 mg/ µ g) * water consumed daily ( L/ day)]. HED standard body weight: All Infants/ Children, 10 kg. HED standard daily drinking rate: 1 L/ day for children.

5.3 Chronic Aggregate Risk Assessment ( Food and Drinking Water)

The chronic aggregate risk assessment takes into account average exposure estimates from dietary consumption of sethoxydim ( food and drinking water).

The partially refined chronic dietary exposure estimates are below HED's level of concern (< 100% cPAD) for the general U. S. population ( 2.7% of the cPAD) and all population subgroups. The most highly exposed population subgroup is Infants (< 1 year old), at 7.5 % of the cPAD. The EDWCs generated by EFED are less than HED's calculated chronic DWLOCs for chronic exposure to sethoxydim in drinking water. Therefore, the chronic aggregate risk associated with the proposed use of sethoxydim does not exceed HED's level of concern for the general U. S. population or any population subgroups. Table 5.3 summarizes the chronic aggregate exposure estimates to sethoxydim residues. Page 52 of 71 Table 5.3. Chronic DWLOC Calculations for Chronic Exposure to Sethoxydim.

Population Subgroup Chronic Scenario cPAD mg/ kg/ day Chronic Food Exp mg/ kg/ day Max Chronic Water Exp mg/ kg/ day1 Ground Water EDWC ( ppb) 2 Surface Water EDWC ( ppb) 2 Chronic DWLOC (

g/ L) 3 U. S. Population 0.14 0.0038 0.1362 1.5 16 4.77e+ 03 All Infants (< 1year) 0.14 0.0105 0.1295 1.5 16 1.30e+ 03 Children 1 2 years 0.14 0.0095 0.1305 1.5 16 1.31e+ 03 Children 3 5 years 0.14 0.0077 0.1323 1.5 16 1.32e+ 03 Children 6 12 years 0.14 0.0049 0.1351 1.5 16 1.35e+ 03 Youth 13 19 years 0.14 0.0033 0.1367 1.5 16 4.10e+ 03 Adults 20 49 years 0.14 0.0030 0.1370 1.5 16 4.80e+ 03 Females 13 49 years 0.14 0.0030 0.1370 1.5 16 4.11e+ 03 Adults 50+ years 0.14 0.0031 0.1369 1.5 16 4.79e+ 03 1Maximum Chronic Water Exposure ( mg/ kg/ day) = [ Chronic PAD ( mg/ kg/ day)  Chronic Dietary Exposure ( mg/ kg/ day)] 2The crop producing the highest level was used. 3 Chronic DWLOC(

g/ L) = [ maximum chronic water exposure ( mg/ kg/ day) x body weight ( kg)] [ water consumption ( L) x 10 3 mg/

g] Page 53 of 71 6.0 CUMULATIVE RISK 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 sethoxydim and any other substances and sethoxydim 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 sethoxydim 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 PATHWAY The following occupational assessment was extracted from the HED ORE chapter for sethoxydim ( W. Britton. DP312565, 3/ 30/ 05).

Sethoxydim is a selective, systemic, post emergent herbicide used for the control of annual and perennial grass weeds in broadleaf crops. Registered use sites for sethoxydim include agricultural crops such as various fruits, tree nuts, vegetables and herbs, as well as non agricultural sites, including ornamental and flowering plants, recreational areas, rights of way, along fences and hedgerows, and public and commercial buildings/ structures ( outdoor). Sethoxydim is formulated for occupational use as a liquid product.

The potential for occupational exposure to sethoxydim exists in a variety of exposure scenarios. Such scenarios include the handling of sethoxydim during mixing, loading, and applying processes ( i. e. mixer/ loaders, applicators, flaggers, and mixer/ loader/ applicators) and a potential for postapplication worker exposure from entering into areas previously treated with sethoxydim. Short term ( 1 to 30 days) and intermediate term exposures ( 1 to 6 months) may occur, however, long term exposures ( greater than 6 months) are not expected.

The HED HIARC did not identify dermal toxicity endpoints for sethoxydim, therefore, occupational handlers were assessed for both short and intermediate term inhalation exposures only. Inhalation risk was estimated using the inhalation endpoint NOAEL from a 28 day rat study ( NOAEL = 81 mg/ kg/ day), based upon increased liver weight, clinical chemistry ( increased total serum bilirubin), and liver histopathology. HED's level of concern for occupational inhalation exposure is an MOE of 100 ( 10x for inter species extrapolation, 10x for intra species variation). In accordance with HED's Exposure Science Advisory Council ( SAC) policy, exposure data from the Pesticide Handlers Exposure Database ( PHED) Version 1.1 as presented in PHED Surrogate Exposure Guide ( 8/ 98) were used with other HED default values for acres treated per day, body Page 54 of 71 weight, and the level of personal protective equipment to assess the handler exposures.

7.1 Occupational Handler Handler inhalation exposure and risk were assessed for the following scenarios:

Mixer/ Loaders:

( 1) Liquids for Aerial Applications ( 2) Liquids for Groundboom Applications ( 3) Rights of Way Sprayer Applications Applicators:

( 4) Aerial Spray Applications ( 5) Groundboom Spray Applications ( 6) Rights of Way Sprayer Applications Flaggers:

( 7) Flagging for Aerial Spray Applications Mixer/ Loader/ Applicators:

( 8) Liquids for Low Pressure Handwand Sprayer ( 9) Liquids for Backpack Sprayer ( 10) Liquids for High Pressure Handwand Sprayer ( 11) Liquids for Handgun ( lawn) Sprayer ( ORETF)

The MOEs range from 2,400 for Mixing/ Loading/ Applying Liquids for High Pressure Handwand Application to 3.2E+ 7 for Mixing/ Loading/ Applying with a Handgun Sprayer. The resulting MOEs are above the target MOE of 100 and, therefore, are not a risk concern. A summary of the MOEs estimated for handlers are presented in Table 7.1.1.