Page 1 of 68 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES Date: 10/ 31/ 2005 MEMORANDUM SUBJECT: Imazaquin and its Salts: HED Chapter of the Tolerance Reassessment Eligibility Decision ( TRED) Document. PC Codes 128840, 128848 & 129023; DP Barcode: D302939 Regulatory Action: Tolerance Reassessment Eligibility Decision ( TRED) Risk Assessment Type: Single Chemical Aggregate FROM: Susan Stanton, Environmental Scientist Reregistration Branch 3 Health Effects Division ( 7509C)

AND John Doherty, Toxicologist Danette Drew, Chemist Seyed Tadayon, Chemist Reregistration Branch 3 Health Effects Division ( 7509C)

THROUGH: William Donovan, Branch Senior Scientist Reregistration Branch 3 Health Effects Division ( 7509C)

TO: Craig Doty, Chemical Review Manager Special Review Branch SRRD ( 7508C) Page 2 of 68 Table of Contents 1.0 Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.0 Ingredient Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 2.1 Summary of Registered Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 2.2 Structure and Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 2.3 Physical and Chemical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 3.0 Metabolism Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 3.1 Comparative Metabolic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 3.2 Nature of the Residue in Foods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 3.2.1. Description of Primary Crop Metabolism . . . . . . . . . . . . . . . . . . . . . . . 15 3.2.2 Description of Livestock Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . 16 3.2.3 Description of Rotational Crop Metabolism, including identification of major metabolites and specific routes of biotransformation . . . . . . . . . . 17 3.3 Environmental Degradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 3.4 Tabular Summary of Metabolites and Degradates . . . . . . . . . . . . . . . . . . . . . . . 18 3.5 Toxicity Profile of Major Metabolites and Degradates . . . . . . . . . . . . . . . . . . . 20 3.6 Summary of Residues for Tolerance Expression and Risk Assessment . . . . . . . . 20 3.6.1 Tabular Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 3.6.2 Rationale for Inclusion of Metabolites and Degradates . . . . . . . . . . . . . 21 4.0 Hazard Characterization/ Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 4.1 Hazard Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 4.1.1. Database Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 <IP_ADDRESS>. Studies available and considered . . . . . . . . . . . . . . . . . . . . . . 21 <IP_ADDRESS>. Mode of action, metabolism and toxicokinetic data . . . . . . . . 22 <IP_ADDRESS>. Sufficiency of studies/ data . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 4.1.2. Toxicological effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 4.1.3. Dose response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 4.1.4. FQPA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 4.1.5. Acute Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 4.1.6. Sub chronic/ Chronic and Other Toxicity . . . . . . . . . . . . . . . . . . . . . . . . 25 4.2 FQPA Hazard Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 4.2.1 Adequacy of the Toxicity Data Base . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 4.2.2 Evidence of Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 4.2.3 Developmental Toxicity Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 4.2.4 Reproductive Toxicity Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 4.2.5 Additional Information from Literature Sources . . . . . . . . . . . . . . . . . . 30 4.2.6 Pre and/ or Postnatal Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 <IP_ADDRESS> Determination of Susceptibility . . . . . . . . . . . . . . . . . . . 30 <IP_ADDRESS> Degree of Concern Analysis and Residual Uncertainties for Page 3 of 68 Pre and/ or Post natal Susceptibility . . . . . . . . . . . . . . . . 31 4.3 Recommendation for a Developmental Neurotoxicity Study . . . . . . . . . . . . . . . 31 4.3.1 Evidence that supports requiring a Developmental Neurotoxicity study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 4.3.2 Evidence that supports not requiring a Developmental Neurotoxicity study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 4.3.3 Rationale for the UF DB ( when a DNT is recommended) . . . . . . . . . . . . . 31 4.4 Hazard Identification and Toxicity Endpoint Selection . . . . . . . . . . . . . . . . . . . 31 4.4.1 Acute Reference Dose ( aRfD)  Females age 13 49 . . . . . . . . . . . . . . . . 31 4.4.2 Acute Reference Dose ( aRfD)  General Population . . . . . . . . . . . . . . . 31 4.4.3 Chronic Reference Dose ( cRfD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 4.4.4 Incidental Oral Exposure ( Short and Intermediate Term) . . . . . . . . . . . . 33 4.4.5 Dermal Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 4.4.6 Dermal Exposure ( Short, Intermediate and Long Term) . . . . . . . . . . . . 34 4.4.7 Inhalation Exposure ( Short, Intermediate and Long Term) . . . . . . . . . . 35 4.4.8 Margins of Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 4.4.9 Recommendation for Aggregate Exposure Risk Assessments . . . . . . . . 36 4.4.10 Classification of Carcinogenic Potential . . . . . . . . . . . . . . . . . . . . . . . . . 36 4.5 Special FQPA Safety Factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 4.6 Endocrine disruption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 5.0 Public Health Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 5.1 Incident Reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 5.2 Other . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 6.0 Exposure Characterization/ Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 6.1 Dietary Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 6.1.1 Residue Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 6.1.2 Chronic Dietary Exposure and Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 6.2 Water Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 6.3 Residential ( Non Occupational) Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . 46 6.3.1 Residential Handler Exposures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 <IP_ADDRESS> Residential Handler Exposure Scenarios . . . . . . . . . . . . . 47 <IP_ADDRESS> Data and Assumptions For Residential Handler Exposure Scenarios . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 <IP_ADDRESS> Residential Handler Exposure and Risk Estimates . . . . . 48 6.3.2 Residential Postapplication Exposures . . . . . . . . . . . . . . . . . . . . . . . . . . 50 <IP_ADDRESS> Residential Postapplication Exposure Scenarios . . . . . . . 50 <IP_ADDRESS> Data & Assumptions for Residential Postapplication Exposure Scenarios . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 <IP_ADDRESS> Residential Postapplication Exposure and Risk Estimates 53 6.3.3 Other ( Spray Drift, etc.) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Page 4 of 68 7.0 Aggregate Risk Assessments and Risk Characterization . . . . . . . . . . . . . . . . . . . . . 54 7.1 Acute Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 7.2 Short Term Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 7.3 Intermediate Term Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 7.4 Long Term Aggregate Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 7.5 Cancer Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 8.0 Cumulative Risk Characterization/ Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 9.0 Occupational Exposure/ Risk Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 10.0 Data Needs and Label Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 10.1 Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 10.2 Residue and Product Chemistry Deficiencies . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 10.3 Occupational and Residential Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 References: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 Page 5 of 68 1.0 Executive Summary The Health Effects Division ( HED) of EPA's Office of Pesticide Programs has evaluated the toxicity and exposure data bases for the pesticide active ingredient imazaquin, including its ammonium and monosodium salts, and has conducted a human health risk assessment in support of the Tolerance Reassessment Eligibility Decision ( TRED) for this active ingredient.

Use Information Imazaquin is an imidazolinone herbicide which controls weeds by inhibiting the synthesis of specific amino acids ( valine, leucine & isoleucine) necessary for plant growth. It is registered as a pre plant, preemergence and early postemergence herbicide for use on soybeans, primarily across the central Midwest from Kentucky to Illinois and across the mid South in Arkansas, Louisiana and Mississippi. It is also registered for pre and postemergence weed control on ornamentals and warm season turfgrass in both residential and non residential settings. The turf and ornamental uses are concentrated across the southern U. S. because of imazaquin's lack of selectivity on cool season grasses.

Toxicology Hazard: The available toxicity data on imazaquin are adequate to assess the chemical's hazard potential. Technical imazaquin has low ( category III/ IV) acute toxicity via the oral, dermal and inhalation routes of exposure. It is non irritating to the eye ( category IV) and only mildly irritating to the skin. Imazaquin did not cause dermal sensitization in the guinea pig.

Overall, imazaquin appears to cause subchronic and chronic toxicity only at higher doses, with few clinical signs identified in rats, mice, dogs or rabbits. Toxicity was similar in both male and female test animals, with the dog being the most sensitive species to imazaquin exposure. The most commonly observed clinical sign in the chronic studies was decreased body weight, which was seen in both mice and dogs. In the chronic dog study, additional effects were noted at the LOAEL of 125 mg/ kg/ day, including slight anemia indicated by changes in hematology parameters, changes to clinical chemistry and skeletal muscle myopathy at necropsy in both sexes. No effects were observed at the highest dose tested ( 500 mg/ kg/ day) in the rat combined chronic toxicity/ carcinogenicity study; nor were systemic effects seen at the highest dose tested ( 1000 mg/ kg/ day) in the rabbit 21 day dermal toxicity study.

The database is considered adequate to characterize any potential pre and/ or post natal risk to infants and children. Additional studies are not required. In the developmental study in rats, treatment related effects on fetal body weight and reduced ossification were observed, but only at the dose where maternal toxicity occurred. No treatment related effects on fetuses were seen in the rabbit developmental toxicity study; and in the rat reproductive study, no toxicity in either the parents or offspring was noted at the highest dose tested. Based on these studies, there is no indication of increased susceptibility of fetuses or offspring to imazaquin. Since there is no Page 6 of 68 increased risk to infants and children and no residual uncertainty, the special FQPA Safety Factor may be reduced to 1X.

No evidence of neurotoxicity was observed in any study. Based on the weight of evidence, a developmental neurotoxicity ( DNT) study is not required for imazaquin.

No evidence of carcinogenicity was seen in mice or rats, and imazaquin was non mutagenic in available mutagenicity tests. Mice were dosed up to 600 mg/ kg/ day for 18 months, and rats were fed up to 500 mg/ kg/ day for 2 years without any evidence of a treatment related increased incidence of tumors. Imazaquin was non mutagenic in the Ames test and demonstrated negative responses in the in vitro cell transformation assay, a cytogenetics study with HGPRT in Chinese hamster cells and an unscheduled DNA synthesis assay.

Toxicity Endpoint/ Dose Selection: A chronic reference dose ( cRfD) of 0.25 mg/ kg/ day was established for imazaquin, based on the NOAEL of 25 mg/ kg/ day in the dog chronic toxicity study and an uncertainty factor of 100 ( 10x for interspecies extrapolation and 10x for intraspecies variation). Effects seen at the LOAEL included body weight loss, clinical chemistry/ hematology differences, slight anemia and skeletal muscle myopathy. Body weight decreases occurred in the first 4 weeks of the study; and the hematology data from the earliest assessment at 13 weeks indicated statistically significant changes in hematology parameters, raising concern that the anemia effects of imazaquin may occur within a short or intermediate time frame. Therefore, the NOAEL of 25 mg/ kg/ day from this study was selected to assess oral, dermal and inhalation exposures of short, intermediate and long term duration. An acute reference dose ( aRfD) was not established, since an endpoint attributable to a single exposure was not identified from the available database.

Residue Chemistry A tolerance has been established under 40 CFR § 180.426 for residues of imazaquin in or on soybeans at 0.05 ppm. The available residue chemistry data are adequate to support the existing tolerance and to assess human dietary exposure to imazaquin from the consumption of treated food commodities. The residue of concern in soybeans for tolerance enforcement and risk assessment purposes is imazaquin, per se. Based on the findings of the livestock metabolism studies, where livestock were dosed at 94x ( ruminant) and 68x ( poultry) the maximum theoretical dietary burden, HED has determined that 40 CFR § 180.6( a)( 3) is applicable to imazaquin; there is no reasonable expectation of finite residues in ruminants or poultry. Adequate analytical methods are available for the enforcement of the imazaquin tolerance.

Environmental Fate The available environmental fate data are adequate to assess the residues of concern in drinking water. Imazaquin is an imidazole compound that is highly mobile and non volatile. In terrestrial Page 7 of 68 environments it is persistent; and in aquatic environments, imazaquin is stable to hydrolysis at all pH levels.

No major degradates ( i. e., > 10 % of the applied dose) were identified in the aerobic soil metabolism study. The most significant degradation occurred in the aqueous photolysis study. The major photolytic degradates (> 10% of the applied dose), in addition to CO 2 , were 3 quinolinecarboxylic acid; 2,3 quinolinecarboxylic acid imide; 2,3 dihydro 3 imino 1H pyrrolo [ 3,4b] quinolin 1 one; and 2,3 quinolinedicarboxylic acid. Specific toxicity data are not available for these compounds; however, based on their structural similarity to the parent, the risk assessment team has concluded that they may have toxicity similar to parent imazaquin and should, therefore, be included in the dietary risk assessment. These photolytic degradates are not expected to form in drinking water from ground water sources; therefore, the residue of concern in drinking water from ground water sources is imazaquin, per se.

Dietary Exposure A chronic dietary risk assessment was conducted for imazaquin, using the Dietary Exposure Evaluation Model ( DEEM FCID, Version 2.03). Since no toxic effects attributable to a single exposure have been identified for imazaquin, an acute dietary exposure assessment was not conducted. Also, since there is no evidence that imazaquin is carcinogenic to humans, a dietary cancer assessment was not conducted.

The tier 1 chronic assessment assumed that 100% of the soybean crop is treated and that residues of imazaquin are present at the tolerance level of 0.05 ppm in all soybean commodities, including processed commodities. Drinking water was incorporated directly into the dietary assessment using the tier 1 estimated drinking water concentration for ground water generated by the SCIGROW model.

The resulting dietary exposure estimates are well below HED's level of concern ( i. e., < 100% of the cPAD). Chronic dietary exposure is estimated to be less than 1% of the cPAD for the U. S. population and all population subgroups. More than 95% of the total estimated dietary exposure is from drinking water.

Residential Exposure There is a potential for exposure in residential settings during the application process for homeowners who use products containing imazaquin on turf and ornamentals. There is also a potential for exposure of children and adults who enter residential areas previously treated with imazaquin. In both cases, the duration of exposure is expected to be short term only. As a result, short term risk assessments have been completed for both residential handler and postapplication scenarios. The routes of exposure considered in the assessments included inhalation ( residential handler exposure only), dermal ( residential handler and postapplication exposures) and incidental oral ( post application exposure for children only). Page 8 of 68 Chemical specific exposure data are not available for imazaquin. Residential handler exposure was assessed using the Pesticide Handlers Exposure Database ( PHED ver. 1.1) and data from the Outdoor Residential Exposure Task Force ( ORETF). The residential handler and postapplication assessments were conducted in accordance with the EPA's draft Standard Operating Procedures for Residential Exposure Assessments ( R SOPs) adopted December 18, 1997 and revised on February 22, 2001.

The Margin of Exposure ( MOE) of concern for residential exposures is 100. The combined dermal and inhalation MOEs for residential handlers range from 1,700 ( homeowners applying liquid concentrates to turf using a hose end sprayer) to 15,400 ( homeowners applying liquid concentrates to ornamentals with a hand held pump). Postapplication MOEs for adults range from 430 ( high contact turf scenario, i. e., " jazzercize") to 12,500 ( mowing turf). The combined postapplication dermal and incidental oral ( including hand to mouth, object to mouth and incidental soil ingestion exposures) MOE for children playing on treated turf is 260. The residential handler and postapplication exposure MOEs are all greater than 100 and are, therefore, not of concern.

Aggregate Risk Short and long term ( chronic) aggregate risk assessments were conducted for imazaquin. The short term assessment considered both dietary ( food + water) and residential exposures. The long term assessment considered dietary exposure only, since the current uses of imazaquin are not expected to result in long term residential exposure. An intermediate term aggregate assessment was not conducted, since the current uses of imazaquin are not expected to result in exposures of this duration. Also, since an endpoint attributable to a single exposure was not identified for imazaquin, an acute aggregate assessment was not conducted.

The results of the deterministic, tier 1 dietary assessment indicate that the chronic aggregate exposure to imazaquin from food and water is well below HED's level of concern, with estimated exposures representing < 1% of the cPAD for the U. S. population and all population subgroups, including infants and children. When the chronic dietary exposure is combined with short term residential exposure, the resulting short term aggregate risk estimates for adults and children are also below HED's level of concern. The MOE of concern for short term aggregate risk is 100. Since the estimated short term aggregate risk MOEs for adults and children ( toddlers) are 340 and 257, respectively, short term aggregate risk is not considered to be of concern for imazaquin.

Occupational Exposure An occupational exposure assessment is not required to reassess tolerances under FQPA; since this risk assessment is being conducted solely for tolerance reassessment purposes, an occupational exposure assessment has not been conducted.

Conclusions/ Risk Characterization Page 9 of 68 Imazaquin is a relatively low toxicity pesticide whose potential routes of exposure include food, drinking water and residential areas. Under the conditions of its current use, estimated health risks to the general population are below HED's level of concern. Estimated aggregate risk MOEs from the consumption of food and drinking water and from exposure to the pesticide in residential settings exceed 100 for all populations, including infants and children, and, therefore, are not of concern.

The aggregate risk assessment for imazaquin is a screening level assessment which is based on high end residential and dietary exposure estimates. Residues in food are assumed to be present at the maximum tolerance level, and 100% of the soybean crop is assumed to be treated with imazaquin. The drinking water assessment utilizes values generated by models using modeling parameters which are designed to provide conservative, health protective, high end estimates of drinking water concentrations. The residential exposure assessment is conducted in accordance with HED's residential SOPs, which also provide conservative, screening level estimates of exposure. In addition, the short term aggregate assessment for adults assumes that dietary, residential handler and residential postapplication exposures occur simultaneously over a short period of time ( 1 to 30 days), which, although possible, is unlikely.

Finally, the aggregate risk assessment includes estimated risks from dermal exposure to imazaquin. As discussed in section 4.4.6 ( Dermal Exposure ( Short, Intermediate and Long Term)), the decision to conduct a dermal assessment was based on highly conservative assumptions that may be revisited for future imazaquin risk assessments. If estimates of dermal exposure were excluded from the aggregate assessment, estimated aggregate exposure and risk for both children and adults, while already below HED's level of concern, would be even lower.

For these reasons, HED has a high level of confidence that this screening level aggregate assessment for imazaquin does not underestimate human health risks from the currently registered uses of imazaquin.

2.0 Ingredient Profile Imazaquin [ ±  2( 4,5 Dihydro 4 methyl 4( 1 methylethyl) 5 oxo 1H imidazol 2 yl) 3 quinolinecarboxylic acid] is a broad spectrum, pre plant, preemergence or postemergence herbicide belonging to the imidazolinone class of pesticides. It controls weeds by inhibiting the synthesis of specific amino acids ( valine, leucine & isoleucine) necessary for plant growth. Imazaquin is formulated as an acid, ammonium salt or sodium salt and registered for food use on soybeans, as well as non food use on warm season turfgrass and ornamentals in both residential and non residential settings. Applications in residential settings may be made by both commercial applicators and homeowners. Page 10 of 68 2.1 Summary of Registered Uses The registered imazaquin formulation types include water dispersible granule ( WDG), wettable powder ( WP), emulsifiable concentrate ( EC) and soluble concentrate ( SC). The active ingredient ( as acid equivalent) in the end use products ranges from 0.71% to 70%. On soybeans, a maximum of 0.25 lb. acid equivalent ( ae)/ acre may be applied per year using ground or aerial equipment. The maximum single application rate is 0.125 lb. ae/ acre. All product labels indicate a pre harvest interval ( PHI) of 90 days for soybeans. Imazaquin may be applied to turf and ornamentals at up to 0.5 lb. ae/ acre by commercial applicators and up to 0.38 lb. ae/ acre by homeowners. The Restricted Entry Interval ( REI) for agricultural uses is 12 hours.

A tabular summary of the registered uses of imazaquin is presented in Table 2.1.

TABLE 2.1. Directions For Use of Imazaquin Application Timing ° Application Type Max. Single Application Rate Max. Seasonal Rate Max. No. Applications/ cc & yr Restrictions SOYBEANS Pre plant, Preemergence, Postemergence, Early Postemergence ° Broadcast, Soil Incorporated ° Ground, Aerial 0.125 lb ae/ A 0.25 lb ae/ A ( EPA Reg. No. 241 292) 2 ° 90 day preharvest interval ° Do not graze or feed treated soybean forage, hay, or straw to livestock ° Do not apply through any type of irrigation system. ° Rotational/ plant back crop restriction. ° Geographic restrictions.

TURFGRASS ( RESIDENTIAL AND NON RESIDENTIAL)/ ORNAMENTALS Preemergence, Postemergence ° Ground broadcast ° Spot Application 0.375  0.5 lb. ae/ A 0.375  0.5 lb. ae/ A 1 to 2 ° Do not apply aerially. ° Do not graze or feed clippings of treated turfgrass. ° Do not apply through any type of irrigation system. Page 11 of 68 N N H N OH O O CH 3 CH( CH 3 ) 2 N N H N O O O CH 3 CH( CH 3 ) 2 NH 4 + 2.2 Structure and Nomenclature TABLE 2.2. Imazaquin ( and its Salts) Nomenclature Chemical Structure Common name Imazaquin Molecular Formula C17H17N3O3 Molecular Weight 311.34 IUPAC name ( RS) 2( 4 isopropyl 4 methyl 5 oxo 2 imidazolin 2 yl) quinoline 3 carboxylic acid CAS name ±  2( 4,5 Dihydro 4 methyl 4( 1 methylethyl) 5 oxo 1H imidazol 2 yl) 3 quinolinecarboxylic acid CAS Registry Number 81335 37 7 PC Code 128848 Chemical Class Imidazolinone Chemical structure Common name Imazaquin, ammonium salt IUPAC name ( RS) 2( 4 isopropyl 4 methyl 5 oxo 2 imidazolin 2 yl) quinoline 3 carboxylic acid, monoammonium salt CAS name 2[ 4,5 dihydro 4 methyl 4( 1 methylethyl) 5 oxo 1H imidazol 2 yl] 3 quinolinecarboxylic acid, monoammonium salt CAS # 81335 47 9 PC Code 128840 TABLE 2.2. Imazaquin ( and its Salts) Nomenclature Page 12 of 68 N N H N O O O CH 3 CH( CH 3 ) 2 Na + Chemical structure Common name Imazaquin, sodium salt IUPAC name ( RS) 2( 4 isopropyl 4 methyl 5 oxo 2 imidazolin 2 yl) quinoline 3 carboxylic acid, monosodium salt CAS name 2[ 4,5 dihydro 4 methyl 4( 1 methylethyl) 5 oxo 1H imidazol 2 yl] 3 quinolinecarboxylic acid, monosodium salt CAS # 81335 46 8 PC Code 129023 End use products ( EPs):

End use products ( EPs) Formulation1,2 Product Name There are twelve active end use products ( EPs) containing imazaquin for use on soybeans. Seven of the products contain the imazaquin acid, four contain the ammonium salt of imazaquin, and one contains the sodium salt of imazaquin. All products are registered to BASF Corp. Additionally, there are three SLN registrations.

Imazaquin ( PC Code 128848)

241 3063 70% WDG Scepter ® 70 DG Herbicide 241 361 5.4% SC Detail ® Herbicide 241 369 35% WDG Imazaquin/ Imazathapyr DG 241 376 1.9% EC Steel ® Herbicide 241 407 2.8% EC Backdraft   Herbicide 241 408 70% WP Backdraft   CP 241 415 1.7% SC Backdraft   SL Herbicide LA010010 70% WDG Scepter ® 70 DG Herbicide MS010011 2.8% EC Backdraft   Herbicide MS020002 1.7% SC Backdraft   SL Herbicide Ammonium salt of imazaquin ( PC Code 128840)

241 307 4.72% EC ( 4.48% ae) TRI SCEPT ®

241 289 17.3% SC ( 16.4% ae) Scepter ®

241 292 17.3% SC ( 16.4% ae) Scepter ®

241 327 3.65% SC ( 3.46% ae) Squadron ® TABLE 2.2. Imazaquin ( and its Salts) Nomenclature Page 13 of 68 Sodium salt of imazaquin ( PC Code 129023)

241 321 5.61% SC ( 5.24% ae) Scepter O. T ®

There are five active end use products ( EPs) containing imazaquin for use on turf and ornamentals. One of the products contains the imazaquin acid and four contain the ammonium salt of imazaquin. All are registered to BASF Corp., except one, which is registered to Ambrands.

Imazaquin ( PC Code 128848)

241 303 17.3% SC Image ® 1.5 LC Herbicide Ammonium salt of imazaquin ( PC Code 128840)

241 319 70% WDG ( 66.4% ae) Image ® 70 DG 241 326 0.79% SC ( 0.75% ae) Timeout   Grass Growth Regulator and Weed Killer 241 352 0.75% SC ( 0.71% ae) Timeout ® Plus Herbicide 73342 4 3.3% SC ( 3.14% ae) Image ® Herbicide Consumer Concentrate 1 WDG  water dispersiable granule; SC  soluble concentrate; EC  emulsifiable concentrate; WP = wettable powder 2 ae = acid equivalent 3 The registrant has indicated that the only product currently being marketed for use on soybeans is Scepter 70 DG ( EPA Reg. No. 241 306). However, all products with active registrations are presented in this document.

2.3 Physical and Chemical Properties TABLE 2.3 Physicochemical Properties of Imazaquin Parameter Value Reference Melting point 219 224 ° C ( decomposes) MRID 00146197; PP# 5F3273, RCB # 1265, 1/ 9/ 86, A. Smith pH 4.6 at 25 ° C Density, bulk density, or specific gravity 0.39 g/ mL untapped; 0.43 g/ mL tapped Water solubility at 25 ° C 60 ppm Solvent solubility g/ 100 mL Acetone 0.30 DMF 6.80 DMSO 15.9 Ethanol 0.30 Heptane 0.02 Methanol 0.50 Methylene chloride 1.36 Toluene 0.04 Vapor pressure < 2 x 10 8 mm Hg at 45 ° C TABLE 2.3 Physicochemical Properties of Imazaquin Parameter Value Reference Page 14 of 68 Dissociation constant, pKa 3.8 Octanol/ water partition coefficient 2.2 at 22 ° C UV/ visible absorption spectrum Not available 3.0 Metabolism Assessment 3.1 Comparative Metabolic Profile Imazaquin is rapidly absorbed and excreted by the rat following oral administration. In the rat metabolism study, essentially all ( 102%) of the administered radioactivity was recovered within 48 hours of treatment. The majority ( 94%) was recovered in the urine, with 4% recovered in the feces and 4% recovered in the cage wash. Twenty four hours after treatment, residual radioactivity was detected in the liver ( 0.025 ppm) and kidney ( 0.17 ppm); however, by 48 hours, the concentration in all tissues was at or below the limit of detection ( 0.01 ppm). Analysis of urine collected 24 and 48 hours after treatment showed that 99.7% of the recovered radioactivity was unchanged parent compound, indicating that imazaquin is poorly metabolized in the rat.

The results of ruminant and poultry metabolism studies suggest that imazaquin may also be poorly metabolized in other animal species. In the ruminant metabolism study, total radioactive residues ( TRR) were nondetectable in milk (< 0.01 ppm) and all tissues (< 0.05 ppm) of lactating goats following oral administration of [ 14C] imazaquin for seven consecutive days. Similarly, in the poultry metabolism study, TRR were nondetectable (< 0.05 ppm) in egg white, egg yolk, muscle, liver, kidney, skin and fat of laying hens following oral administration of [ 14C] imazaquin for seven consecutive days. The TRR in urine and feces were not measured in these studies; however, the lack of radioactive residues in milk and animal tissues suggests that imazaquin is rapidly absorbed and excreted in livestock, as it is in the rat.

The results of soybean and corn metabolism studies indicate that imazaquin is much more extensively metabolized in plants. Soybean metabolism studies using both carboxyl and benzene labeled imazaquin indicate that imazaquin is extensively degraded and reincorporated into native plant constituents. TRRs in soybean seed and mature hulls were all < 0.05 ppm. The TRR on mature foliage ranged from 0.05 to 0.66 ppm. Total radioactivity from 1 month up to maturity was similar between the carboxyl and benzene labeled imazaquin, indicating that loss of CO 2 from the carboxylic acid moiety is not a major degradation route. The residues were not chemically identified; however, characterization of the protein portion of the soybean seed indicates that a significant amount of the TRR had been reincorporated into naturally occurring protein components. Characterization of radioactivity on foliage and straw indicates the presence of several metabolites ( each < 0.01 to 0.02 ppm), with no parent compound present.

A field corn metabolism study indicates that imazaquin is extensively degraded in mature plant commodities. The proposed metabolic pathway of imazaquin applied to corn is as follows: ( i) Page 15 of 68 direct conjugation of the parent chemical; ( ii) hydroxylation of the parent chemical to its 5 hydroxy metabolite ( CL 343,684) followed by conjugation; and ( iii) degradation of the imidazoline ring system to quinoline 2,3 dicarboxylic acid ( CL 263,875) followed by conjugation. Plant residues, although substantive in the early growth stages, are comprised of a variety of metabolites which decline in content to < 0.01 ppm in mature field corn commodities.

In the environment, imazaquin is stable to anaerobic soil metabolism and hydrolysis; however, significant degradation occurs by aqueous photolysis. Based on a submitted study, the major photolytic degradates, in addition to CO 2 , were 3 quinolinecarboxylic acid, 2,3 quinolinecarboxylic acid imide, 2,3 dihydro 3 imino 1H pyrrolo[ 3,4b] quinolin 1 one, and 2,3 quinolinedicarboxylic acid. There were 18 unidentified minor degradates.

3.2 Nature of the Residue in Foods 3.2.1. Description of Primary Crop Metabolism The qualitative nature of the residue in plants is understood for the use of imazaquin on soybeans. Available plant metabolism data for imazaquin are summarized below:

Soybean: Soybean metabolism studies were conducted in Florida and New Jersey using postemergence and pre plant incorporated treatment methods. Both sites used carboxyl labeled imazaquin as the test substance. The New Jersey site also used benzene labels; however, not all of the benzene results were submitted. Diisopropyl amine salt of imazaquin was applied to all test plots at a rate of 0.38 lb ai/ A ( 1.5x). For the post emergence trials, the test substance was applied at the trifoliate leaf stage. For the pre plant incorporated trials, the test substance was applied to the soil and incorporated 2 inches. Plants were harvested at intervals of one week to 6.5 months, dividing the more mature samples into fodder, hulls, and seed.

For preplant application the soybean seed had total radioactivity residue ( TRR) of 0.01 to 0.02 ppm ( 14C carboxyl label) and 0.03 ppm ( 14C benzene label). The foliage had radioactivity at 0.43 to 0.50 ppm at one month; 0.05 ppm to 0.09 ppm at 2 months; and 0.07 ppm to 0.12 ppm in mature foliage. The mature hulls had TRR at 0.04 ppm.

For early postemergence application soybean seed had TRR of 0.01 ppm to 0.05 ppm ( 14Ccarboxyl label) and 0.04 ppm ( 14C benzene label). The TRR on foliage was 0.24 to 0.60 ppm at one month and 0.19 to 0.66 ppm in mature foliage.

Total radioactivity from 1 month up to maturity was similar between the carboxyl and benzene labeled imazaquin, indicating that loss of CO 2 from the carboxylic acid moiety is not a major degradation route, since residues from the carboxyl label should be considerably lower in that case. Page 16 of 68 The residues were not chemically identified; however, some characterization involving the carboxyl label was accomplished by solvent fractionation of the activity and isolation of the protein portion of the seed. HED determined that the characterization was adequate to show that imazaquin was extensively degraded and reincorporated into native plant parts.

The characterization of radioactivity on foliage or straw was not presented in the study report. At a preregistration conference on 3/ 10/ 83, the registrant indicated that the methanol soluble activity of straw contained 8 metabolites ( each < 0.01 to 0.02 ppm) and the foliage contained at least 11 metabolites, with no parent compound present.

Corn: Metabolism data were submitted for the petition for a temporary tolerance of imazaquin on corn. HED determined that for the purposes of a temporary tolerance on corn, the nature of residue in corn is the parent compound ( D216732, W. Wassell, 2/ 11/ 97). A brief description of the methodology and results of the corn metabolism study follows:

Following a single preplant incorporated ( PPI) or preemergence ( PRE) application of [ 14C] imazaquin to field corn plants at 0.5 lb ae/ A ( 4x the proposed maximum application rate), the total radioactive residues ( expressed as imazaquin equivalents) were 0.045 0.585 ppm in/ on forage, 0.012 0.024 ppm in/ on silage, 0.018 0.033 ppm in/ on fodder, and 0.007 0.016 ppm in/ on grain. The bulk of residue characterization and identification were conducted on immature forage samples ( 15 and 30 DAT) since this commodity contained the highest levels of radioactivity. Following extraction and HPLC analyses,

79 95% of TRR in forage were characterized/ identified. The principal component identified was the parent imazaquin which accounted for

23 34% of the TRR in forage. The metabolites, 5 hydroxy imazaquin ( CL 343,684) and quinoline 2,3 dicarboxylic acid ( CL 263,875) were also qualitatively identified in the aqueous fractions of corn forage. The remainder of the characterized radioactivity consisted of several metabolite regions ( designated as Metabolites A through I) mostly comprising < 10% of the TRR, except for Metabolite F which comprised

21% of TRR ( 0.125 ppm) in 15 DAT PPI forage. Further analytical work to isolate and identify the polar Metabolite F was not successful, but HPLC analysis of the isolated fraction characterized the metabolite to be multi component in nature.

The proposed metabolic pathway of imazaquin applied to corn is as follows: ( i) direct conjugation of the parent chemical; ( ii) hydroxylation of the parent chemical to its 5 hydroxy metabolite ( CL 343,684) followed by conjugation; and ( iii) degradation of the imidazoline ring system to quinoline 2,3 dicarboxylic acid ( CL 263,875) followed by conjugation. Plant residues, although substantive in the early growth stages, are comprised of a variety of metabolites which decline in content to < 0.01 ppm in mature field corn commodities.

3.2.2 Description of Livestock Metabolism The available ruminant metabolism study indicates that the total radioactive residues were nondetectable in milk, liver, kidney, muscle and fat of lactating goats following oral administration Page 17 of 68 of [ 14C] imazaquin at 0.25 and 0.75 ppm for seven consecutive days; the limits of detection were < 0.01 ppm for milk and < 0.05 ppm for tissues. The poultry metabolism study indicates that the total radioactive residues were also nondetectable (< 0.05 ppm) in egg white, egg yolk, muscle, liver, kidney, skin and fat of laying hens following oral administration of [ 14C] imazaquin at 0.25 and 0.75 for seven consecutive days.

3.2.3 Description of Rotational Crop Metabolism, including identification of major metabolites and specific routes of biotransformation A confined rotational crop residue study was conducted using phenyl 14C labeled imazaquin mixed with quinoline 13C labeled. The chemical, formulated as the ammonium salt of imazaquin, was applied to soil at the rate of 0.19 lbs ai/ A and incorporated 2 inches. Soybeans were planted and grown to maturity, at about 4.5 months. Winter wheat was planted 3 months after treatment and spring wheat and field corn were planted 8.5 months after treatment. Carrots and lettuce were also planted 9.5 months after treatment. TRRs ranged from < 0.01 ppm to 0.07 ppm. The maximum TRR observed in the study was in winter wheat straw ( 0.07 ppm). Sixty percent of the wheat straw residue was extractable. The extractable residue was separated on HPLC into 7  9 unknown compounds, each at a level below 0.01 ppm. No residues were identified in the rotational crop study.

3.3 Environmental Degradation Imazaquin is an imidazole compound that is highly mobile ( median K oc = 17.5) and non volatile ( vapor pressure < 2E 8 torr). In terrestrial environments it is persistent ( aerobic t 1/ 2 = 7 months, anaerobic t 1/ 2 = stable). In aquatic environments, imazaquin is stable to hydrolysis at all pH levels. No aquatic metabolism data are available for imazaquin.

The most significant degradation occurred in the aqueous photolysis study, in which the half life was < 1 day at all pHs. The major photolytic degradates, in addition to CO 2 , were 3 quinolinecarboxylic acid ( 14% of the applied amount), 2,3 quinolinecarboxylic acid imide ( 21%), 2,3 dihydro 3 imino 1H pyrrolo[ 3,4b] quinolin 1 one ( 12.6%), and 2,3 quinolinedicarboxylic acid (> 30%). There were 18 unidentified minor (< 10%) degradates.

No major degradates were identified in the aerobic soil metabolism study. The primary degradate resulting from aerobic soil metabolism, in addition to CO 2 , was ( 2[( 1 carbamoyl 1,2 dimethylpropyl carbamoyl] 3 quinolinecarboxylic acid; however, this compound reached a maximum of only 7.6% of the applied amount. Up to six other minor, unidentified compounds accounted for 11 to 14% of the applied amount. Page 18 of 68 N N H N OH O O CH 3 CH( CH 3 ) 2 N N H N OH O O CH 3 CH( CH 3 ) 2 OH N OH O O OH 3.4 Tabular Summary of Metabolites and Degradates Table 3.4. Tabular Summary of Metabolites and Degradates Chemical Name Commodity Percent TRR ( PPM)

Structure Matrices  Major Residue (> 10% TRR) Matrices  Minor Residue (< 10% TRR)

Imazaquin ( CL 252,214)

2[ 4,5 dihydro 4 methyl 4( 1 methylethyl) 5 oxo 1H imidazol 2 yl] 3 quinolinecarboxylic acid soybean

corn ( immature forage) 34

Rotational Crops

Ruminant

Poultry

Rat 94 ( urine)

Water

5 Hydroxy imazaquin ( CL 343,684)

2[ 4,5 dihydro 4 methyl 4( 1 methylethyl) 5 oxo 1H imidazol 2 yl] 5 hydroxy 3 quinolinecarboxylic acid soybean

corn ( immature forage) qualitative only qualitative only Rotational Crops

Ruminant

Poultry

Rat

Water

( CL 263,875)

2,3 quinoline dicarboxylic acid soybean

corn ( immature forage) qualitative only qualitative only Rotational Crops

Ruminant

Poultry

Rat

Water > 30*  Table 3.4. Tabular Summary of Metabolites and Degradates Chemical Name Commodity Percent TRR ( PPM)

Structure Matrices  Major Residue (> 10% TRR) Matrices  Minor Residue (< 10% TRR)

Page 19 of 68 N O OH N NH NH O N NH O O ( CL 75, 947)

3 quinolinecarboxylic acid soybean

corn

Rotational Crops

Ruminant

Poultry

Rat

Water 14*

2,3 dihydro 3 imino 1H pyrrolo [ 3,4b] quinolin 1 one soybean

corn

Rotational Crops

Ruminant

Poultry

Rat

Water 13*

2,3 quinolinecarboxylic acid imide soybean

corn

Rotational Crops

Ruminant

Poultry

Rat

Water 21*

* percent of total applied ( not % TRR) Soybean; MRIDs 131563, 131546, 147012 42874001 ; 0.38 lb ai/ A ( 1.5x); preplant, early post emergent Corn: MRID 43671601; 0.5 lb ae/ A ( 4x); preplant, early preemergent Goats; MRID 147012; 0.75 ppm; 94X MTDB; 7 days Hens; MRID 147012; 0.75 ppm; 68X MTDB; 7 days Rotational Crops; MRID 147012; wheat, corn, lettuce, carrot; 0.75x, applied to bare soil; 3 8.5 months PBI Page 20 of 68 3.5 Toxicity Profile of Major Metabolites and Degradates Based on submitted studies, there are no major metabolites of imazaquin identified in plants and animals. The major degradates that could potentially be found in drinking water include 3 quinolinecarboxylic acid, 2,3 quinolinecarboxylic acid imide, 2,3 dihydro 3 imino 1H pyrrolo [ 3,4b] quinolin 1 one, and 2,3 quinolinedicarboxylic acid. Specific toxicity data are not available for these compounds; however, based on their structural similarity to the parent, the risk assessment team has concluded that they may have toxicity similar to parent imazaquin and should be included in the dietary risk assessment.

3.6 Summary of Residues for Tolerance Expression and Risk Assessment 3.6.1 Tabular Summary Table 3.6. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants Primary Crop imazaquin, per se imazaquin, per se Rotational Crop imazaquin, per se imazaquin, per se Livestock1 Ruminant NA NA Poultry NA NA Drinking Water from Surface Water Sources imazaquin 3 quinolinecarboxylic acid 2,3 quinolinecarboxylic acid imide 2,3 dihydro 3 imino 1Hpyrrolo 3,4b] quinolin 1 one 2,3 quinolinedicarboxylic acid NA Drinking Water from Ground Water Sources imazaquin, per se NA 1 HED has determined that 40 CFR § 180.6( a)( 3) is applicable to imazaquin; there is no reasonable expectation of finite residues in ruminants or poultry. Page 21 of 68 3.6.2 Rationale for Inclusion of Metabolites and Degradates The nature of the residue in plants is adequately understood for the use of imazaquin on soybeans. Based on the trace levels of radioactivity found in the soybean seed from an exaggerated application rate, the apparent extensive degradation of imazaquin into plant constituents, and the livestock grazing/ feeding prohibition of forage, straw and hay on current labels, the residue of concern for both risk assessment and tolerance enforcement is imazaquin, per se.

Tolerances for imazaquin residues in livestock commodities need not be established as a result of the current label use on soybeans, based on the absence of detectable residues in eggs, milk, and livestock tissues from the available animal metabolism studies and the absence of detectable residues in the submitted magnitude of residue studies in livestock feedstuffs. Similarly, since there is no expectation of finite residues in livestock commodities, they need not be included in the dietary risk assessment.

The major degradates that could potentially be found in drinking water from surface water sources include 3 quinolinecarboxylic acid, 2,3 quinolinecarboxylic acid imide, 2,3 dihydro 3 imino 1H pyrrolo[ 3,4b] quinolin 1 one, and 2,3 quinolinedicarboxylic acid. Specific toxicity data are not available for these compounds; however, based on their structural similarity to the parent, the risk assessment team has concluded that they may have toxicity similar to parent imazaquin and should, therefore, be included in the dietary risk assessment. These photolytic degradates are not expected to form in drinking water from ground water sources; therefore, the residue of concern in drinking water from ground water sources is imazaquin, per se.

4.0 Hazard Characterization/ Assessment 4.1 Hazard Characterization 4.1.1. Database Summary <IP_ADDRESS>. Studies available and considered A complete battery of acceptable toxicity studies was available and considered. Acute studies included oral and inhalation toxicity studies in the rat; dermal toxicity, primary eye and dermal irritation studies in rabbits; and a dermal sensitization study with guinea pigs. Subchronic dermal toxicity was assessed in a 21 day dermal study in rabbits. Subchronic and chronic feeding studies included rat 90 day and chronic toxicity/ carcinogenicity studies, a dog chronic study and a mouse carcinogenicity study. Developmental toxicity was assessed in both rats and rabbits, and reproductive and offspring toxicity were assessed in a rat reproductive study. The absorption, distribution and excretion of imazaquin was successfully assessed in a rat metabolism study. Several genetic toxicity studies were available to demonstrate that imazaquin was not mutagenic. A single special study to assess for possible thyroid function effects of imazaquin was also Page 22 of 68 available. No special neurotoxicity studies were available, and these are not considered necessary to assess the hazard of imazaquin to humans.

<IP_ADDRESS>. Mode of action, metabolism and toxicokinetic data Mode of Action. The mode of action of imazaquin in plants involves the inhibition of the synthesis of specific amino acids ( valine, leucine and isoleucine) necessary for plant growth. Valine, leucine and isoleucine are essential amino acids in humans, meaning that they are not synthesized in the mammalian body and must be obtained from food sources. Since they are not synthesized in mammals, the mechanism of herbicidal action of imazaquin is not operative in mammals and not applicable to humans.

Metabolism. The toxicokinetic data for imazaquin indicate that it is rapidly absorbed and excreted by the rat following oral administration. In the rat metabolism study, essentially all ( 102%) of the administered radioactivity was recovered within 48 hours of treatment. The majority ( 94%) was recovered in the urine, with 4% recovered in the feces and 4% recovered in the cage wash. Twenty four hours after treatment, residual radioactivity was detected in the liver ( 0.025 ppm) and kidney ( 0.17 ppm); however, by 48 hours, the concentration in all tissues was at or below the limit of detection ( 0.01 ppm). Analysis of urine collected 24 and 48 hours after treatment showed that 99.7% of the recovered radioactivity was unchanged parent compound, indicating that imazaquin is poorly metabolized in the rat.

<IP_ADDRESS>. Sufficiency of studies/ data The toxicity studies with imazaquin are considered to be sufficient to evaluate the various parameters for which they were designed.

4.1.2. Toxicological effects Imazaquin demonstrated low acute toxicity in oral and inhalation studies in rats with LD 50 and LC 50 values of > 5000 mg/ kg and > 5.5 mg/ L, respectively . It also demonstrated low toxicity in rabbits via the dermal route with a dermal LD 50 of > 2000 mg/ kg. In primary dermal and eye irritation studies in rabbits, the chemical was only mildly irritating and non irritating, respectively. Imazaquin was not a dermal sensitizer in guinea pigs.

Overall, imazaquin appears to demonstrate subchronic and chronic toxicity only at higher doses, with few clinical signs identified in rats, mice, dogs or rabbits. Toxicity was similar in both male and female test animals. The dog was the most sensitive species to exposure to imazaquin.

The most common clinical sign observed in the chronic studies was decreased body weight in the dog and mouse. In the chronic dog study, weight loss, slight anemia indicated by changes in hematology parameters, changes to clinical chemistry and skeletal muscle myopathy at necropsy in both sexes were noted at the LOAEL of 125 mg/ kg/ day ( 5000 ppm). Decreases in body weight in Page 23 of 68 male and female mice in the carcinogenicity study are the basis for the LOAEL of 600 mg/ kg/ day. In the rat combined chronic toxicity/ carcinogenicity study, the LOAEL was not established as there were no effects observed at the highest dose administered ( 10,000 ppm or 500 mg/ kg/ day).

No indications of systemic toxicity were noted in the 21 day dermal toxicity study in rabbits, and the NOAEL was established as 1000 mg/ kg/ day ( the highest dose tested). The only dermal lesion was observed in one high dose rabbit with slight dermal erythema at the treated site for a limited period of time.

In prenatal developmental toxicity studies, maternal toxicity in the rat was indicated by two deaths and adverse clinical signs observed when imazaquin was administered by gavage at 2000 mg/ kg/ day. These clinical signs included salivation, stained genital area, ocular discharge, rough haircoat and lethargy. In rat fetuses, treatment related effects on body weight and reduced ossification were observed at 2000 mg/ kg/ day. Maternal toxicity in rabbits was demonstrated by decreased weight gain at 500 mg/ kg/ day ( the highest dose tested). There were no treatmentrelated development effects in rabbit fetuses at the 500 mg/ kg/ day dose.

Imazaquin did not adversely affect reproductive parameters or cause systemic toxicity or developmental effects in rats over three generations, and the NOAEL for both parental and offspring toxicity was $ 10,000 ppm [ 870 938 mg/ kg/ day in males and 947 1051 mg/ kg/ day in females].

Mice were dosed up to 600 mg/ kg/ day ( 4000 ppm) for 18 months, and rats were fed up to 500 mg/ kg/ day ( 10,000 ppm) for 2 years without any evidence of a treatment related increased incidence of tumors. Imazaquin was non mutagenic in the Ames test, and negative responses were also demonstrated in the in vitro cell transformation assay, a cytogenetics study with HGPRT in Chinese hamster cells and an unscheduled DNA synthesis assay.

Evidence of specific neurotoxicity or immunotoxicity was not observed in any study.

A special non guideline study to assess thyroid function in male rats fed imazaquin for up to 92 days at concentrations of 100 or 5000 ppm ( 4.98 or 254.4 mg/ kg/ day, respectively) demonstrated an approximately 2 fold increase in adjusted TSH ( thyroid stimulating hormone) with a corresponding decrease in total serum T 4 at the highest dose tested ( 254 mg/ kg/ day). Minimal to moderate thyroid follicular cell hypertrophy was also observed only at the highest dose. Thus, imazaquin, at higher doses, may have some endocrine effects; however, these may be due to a secondary effect of altered hepatic metabolizing capacity. Page 24 of 68 4.1.3. Dose response The most common effect observed was decreased body weight, which was observed in the dog at 125 mg/ kg/ day, in the mouse at 600 mg/ kg/ day and the rabbit at 500 mg/ kg/ day. These doses were the highest doses tested in each species, so that dose response information was not further investigated. In addition to the body weight effect, adverse signs were observed in the chronic dog feeding study, but only at the highest test dose. These included a slight anemia, changes in clinical chemistry parameters and skeletal muscle myopathy. No effects on body weight were observed at the highest doses tested in the rat subchronic and chronic studies, although decreased body weight was noted at the high dose in the special study for assessment of thyroid function.

4.1.4. FQPA The database is considered adequate to characterize any potential pre and/ or post natal risk to infants and children. Additional studies are not required. Neither the rat nor rabbit prenatal developmental toxicity studies nor the rat multi generation reproduction study demonstrated increased sensitivity of the fetuses or the offspring to imazaquin. Therefore, since there is no increased risk to infants and children and no residual uncertainty, the special FQPA Safety Factor may be reduced to 1X.

4.1.5. Acute Toxicity Imazaquin's acute toxicity profile is presented below in Table 4.1.5.

Table 4.1.5 Acute Toxicity Profile  Imazaquin Guideline No. Study Type MRID( s) Results Toxicity Category 870.1100 Acute oral [ rat] 00132576 LD50 = > 5000 mg/ kg IV 870.1200 Acute dermal [ rabbit] 00132576 LD50 > 2000 mg/ kg III 870.1300 Acute inhalation [ rat] 00146199 > 5.5 mg/ L ( 4 hours) III 870.2400 Acute eye irritation [ rabbit] 00132576 Non irritating IV 870.2500 Acute dermal irritation [ rabbit] 00132576 Mildly irritating IV 870.2600 Skin sensitization [ guinea pig] 00146200 Negative  not a sensitizer N/ A Page 25 of 68 4.1.6. Sub chronic/ Chronic and Other Toxicity Table 4.1.6 Subchronic, Chronic and Other Toxicity Profile  Imazaquin Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results 870.3100 90 Day oral toxicity ( rat) 00131553 ( 1983) Acceptable/ guideline M& F: 0, 20, 80, 400 or 800 mg/ kg/ day 0, 250, 1000, 5000 or 10,000 ppm NOAEL: 800 mg/ kg/ day LOAEL: not established 870.3150 90 Day oral toxicity No study. See chronic dog study below.

870.3200 21/ 28 Day dermal toxicity ( rabbit) 00146204 ( 1985) Acceptable/ guideline M& F: 0, 250, 500 or 1000 mg/ kg/ day Systemic NOAEL = 1000 mg/ kg/ day LOAEL = not established Dermal NOAEL = 1000 mg/ kg/ day LOAEL = Not established ( no effects at highest dose tested)

870.3250 90 Day dermal toxicity No study and not required.

870.3465 90 Day inhalation toxicity ( species) No study and not required.

870.3700a Prenatal developmental ( rat) 00131552 ( 1983) Acceptable/ guideline 0, 250, 500 or 2000 mg/ kg/ day Maternal NOAEL = 500 mg/ kg/ day LOAEL = 2000 mg/ kg/ day, based on salivation, alopecia, lethargy, flaccidity and 2/ 25 deaths Developmental NOAEL = 500 mg/ kg/ day LOAEL = 2000 mg/ kg/ day, based on sl. decrease in fetal weight and reduced ossification.

870.3700b Prenatal developmental in ( rabbit) 00147011 ( 1984) Acceptable/ guideline 0, 100, 250, or 500 mg/ kg/ day Maternal NOAEL = 250 mg/ kg/ day LOAEL = 500 mg/ kg/ day based on decreased weight gain. Developmental NOAEL $ 500 mg/ kg/ day ( no effects seen at highest dose) LOAEL = not identified Table 4.1.6 Subchronic, Chronic and Other Toxicity Profile  Imazaquin Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results Page 26 of 68 870.3800 Reproduction and fertility effects ( rat) 00147016 ( 1985) Acceptable/ guideline 0, 92 97, 431 483 or 870 938 mg/ kg/ day ( M) 0, 99 108, 498 525 or 947 1051 mg/ kg/ day ( F) 0, 1000, 5000 or 10,000 ppm ( M and F) Parental/ Systemic NOAEL$ 870 938 mg/ kg/ day ( M)

$ 947 1051 mg/ kg/ day ( F) LOAEL = not identified Reproductive NOAEL $ 870 938 mg/ kg/ day ( M)

$ 947 1051 mg/ kg/ day ( F) LOAEL = not identified Offspring NOAEL $ 870 938 mg/ kg/ day ( M)

$ 947 1051 mg/ kg/ day ( F) LOAEL = not identified 870.4100b Chronic toxicity ( dog) 00138972 ( 1984) Acceptable/ guideline M& F: 0, 5, 25 or 125 mg/ kg/ day 0, 200, 1000 or 5000 ppm NOAEL = 25 mg/ kg/ day LOAEL = 125 mg/ kg/ day, based on decreased body weight gain, skeletal muscle myopathy, elevated clinical chemistry values ( ALT, AST, LDH, CPK) and decreased hematology values ( RBC, Hgb, Hct, MCV and MCH)

870.4200 Carcinogenicity ( rat) See combined toxicity/ carcinogenicity study in rats below 870.4300 Carcinogenicity ( mouse) 00146206 ( 1985) Acceptable/ guideline M& F: 0, 38, 150 or 600 mg/ kg/ day ( estimated by calculation) 0, 250, 1000 or 4000 ppm NOAEL = 150 mg/ kg/ day ( MF) LOAEL = 600 mg/ kg/ day, based on decreased body weight gain in females and males no evidence of carcinogenicity in mice 870.4300 Combined chronic toxicity/ carcinoge nicity ( rat) 00146205 ( 1985) Acceptable/ guideline M& F: 0, 50, 250 or 500 mg/ kg/ day 0, 1000, 5000 or 10,000 ppm NOAEL $ 500 mg/ kg/ day ( no effects at highest dose tested). LOAEL = not identified no evidence of carcinogenicity in rats Gene Mutation 870.5100 ( Ames test) 00131549 ( 1982) Minimum Non mutagenic Cytogenetics 870.5300 ( in vitro cell transformation) 00147018 ( 1984) Acceptable Negative Table 4.1.6 Subchronic, Chronic and Other Toxicity Profile  Imazaquin Guideline No./ Study Type MRID No. ( year)/ Classification / Doses Results Page 27 of 68 Cytogenetics 870.5375 ( HGPRT in Chinese hamster) 00147017 ( 1985) Acceptable Negative Other mechanism 870.5550 ( unscheduled DNA synthesis) 00147019 ( 1984) Acceptable/ guideline Negative 870.6200a Acute neurotoxicity screening battery No study and not required.

870.6200b Subchronic neurotoxicity screening battery No study and not required.

870.6300 Developmental neurotoxicity No study and not required.

870.7485 Metabolism and pharmacokinetics ( rat) 00131550 ( 1983) Acceptable/ Nonguideline 0 or 12 mg/ kg 94% recovered in urine and 3.94% in the feces with 3.75% recovered in the cage washings. Total recovery  102%. Only parent ( 99.7%) was detected in the urine.

870.7600 Dermal penetration No study and not required.

Special studies 90 day thyroid function ( rats) 42054601 ( 1991) Acceptable/ Nonguideline 0, 100 and 5000 ppm or 4.98 and 245.4 mg/ kg/ day. NOAEL = 4.98 mg/ kg/ day LOAEL = 245.4 mg/ kg/ day, based on slight decrease in body weight with a 20% decrease in body weight gain and increase in TSH ( up to 2 fold) accompanied by a decrease in serum total T4 and a slight decrease in serum T3.

4.2 FQPA Hazard Considerations 4.2.1 Adequacy of the Toxicity Data Base Page 28 of 68 Data are adequate for evaluation of effects resulting from in utero and post natal exposure to imazaquin. Relevant studies include both rat and rabbit prenatal developmental toxicity studies and the rat multi generation reproduction study.

4.2.2 Evidence of Neurotoxicity No behavioral alterations or evidence of neuropathological effects were observed in any of the available guideline studies with rats, rabbits or dogs. There are no series 870.6200 ( acute or subchronic) neurotoxicity screen studies or an 870.6300 developmental neurotoxicity screen study, and these studies are not being required, since there is no evidence that imazaquin is neurotoxic and other systemic toxicity occurs only at higher doses. The presence of salivation in the dams in the rat prenatal developmental toxicity study was not considered a primary neurotoxic response.

4.2.3 Developmental Toxicity Studies Developmental Toxicity in Rats EXECUTIVE SUMMARY: In a prenatal developmental toxicity study ( 1983, MRID 00131552), 25 presumed pregnant Crl: CD ® ( SD) BR rats per group were administered 0, 250, 500, or 2000 mg/ kg/ day of AC 252,214 ( 89.4% a. i.; Lot No. AC 4325 96 in corn oil) by gavage on gestation days ( GD) 6 15, inclusive. On GD 20, the dams were sacrificed and cesarian sectioned. All fetuses were weighed, sexed and examined for external malformations/ variations. Approximately one third of the fetuses were examined for visceral malformations/ variations by the Wilson technique. The remaining fetuses were processed for skeletal examination.

Maternal Toxicity: Two animals in the high dose group were found dead, one each on GDs 16 and 17. Clinical signs in these animals included salivation after dosing, stained genital area and fur, rough coat, ocular discharge, and lethargy; no abnormalities were found at necropsy. Salivation ( dams affected/ mean severity score) after dosing was observed in all treated groups with low ( 18/ 1.33), mid ( 14/ 1.44), and high ( 25/ 1.84) dose groups, respectively. Urogenital staining was seen in 8 high dose animals. Maternal body weight was similar between the treated and control groups throughout the study. Maternal food consumption was not measured. Gross necropsy was unremarkable. The maternal toxicity LOAEL for AC 252,214 is 2000 mg/ kg/ day based on death and clinical signs of toxicity. The NOAEL is 500 mg/ kg/ day. Note: The salivation was not considered a specific neurotoxic response, and there was no dose response between the low and mid dose groups; therefore, this effect was not included in the LOAEL.

Developmental Toxicity: At cesarean section, the number of corpora lutea, number of implantations per dam, implantation efficiency, live fetuses per litter, and fetal sex ratios were similar between the treated and control groups. Pregnancy rate was 84% for the high dose group and 88 92% for the control, low, and mid dose groups. Mean fetal body weight at the high dose Page 29 of 68 was significantly less than that of the controls. No dose or treatment related external or visceral malformations/ variations were observed. Reduced ossification of fetuses in the high dose group was evident as indicated by a significantly greater number of litters containing fetuses with reduced or not ossified skull, hyoid, sternebrae, and metacarpals. The developmental toxicity LOAEL for AC 252,214 in rats is 2000 mg/ kg/ day, based on decreased fetal body weight and reduced ossification. The NOAEL is 500 mg/ kg/ day.

This study is classified as Acceptable/ Guideline and satisfies the guideline requirement for a developmental toxicity study [ OPPTS 870.3700 ( 83 3a)] in rats. This study was conducted prior to implementation of current guidelines.

Developmental Toxicity in Rabbits EXECUTIVE SUMMARY: In a developmental toxicity study ( 1984, MRID 00147011), 19 inseminated New Zealand white rabbits per group were administered 0, 100, 250, or 500 mg/ kg/ day of AC 252,214 ( 89.4% a. i.; Lot No. AC 4325 96) by gavage on gestation days ( GD) 6 18, inclusive. A 0.5% aqueous methylcellulose solution was used as the vehicle. On GD 29, all surviving does were sacrificed and subjected to gross examination. All fetuses were weighed and examined for external, visceral, and skeletal malformations/ variations. The brain was examined by a mid coronal slice.

Maternal toxicity: One high dose animal was found dead on GD 11; necropsy findings of hemorrhage and congestion in the internal organs, hyperemia of the kidney, and accentuation of the lobular pattern of the liver were inconclusive of a treatment related effect. Other deaths and one abortion by several treated and control animals were incidental to treatment. No clinical signs of toxicity were observed in any doe. Absolute maternal body weight was similar between the treated and control groups throughout the study. Body weight gain by the high dose group was significantly reduced ( p # 0.05; 13%) during the treatment interval. The most pronounced effect on body weight was during GD 6 12 when the high dose group had a weight loss ( 25 g) compared to a weight gain by the controls (+ 50 g). Maternal food consumption was not measured. Gross necropsy was unremarkable. The maternal toxicity LOAEL is 500 mg/ kg/ day based on decreased body weight gain. The maternal toxicity NOAEL is 250 mg/ kg/ day.

Developmental toxicity: At cesarean section, no treatment related effects were seen for the number of corpora lutea, number of implantations and resorptions per dam, post implantation loss, number of live fetuses per litter, and fetal sex ratio. The number of fetuses( litters) examined in the control, low, mid, and high dose groups was 85( 14), 66( 14), 66( 12), 71( 13), respectively. Mean fetal body weight was similar between the treated and control groups. No dose or treatment related external, visceral, or skeletal malformations/ variations were observed in any fetus. The developmental toxicity LOAEL in rabbits is not identified and the developmental toxicity NOAEL is $ 500 mg/ kg/ day. Page 30 of 68 This study is classified as Acceptable/ Guideline and satisfies the guideline requirement for a developmental toxicity study [ OPPTS 870.3700 ( 83 3b)] in rabbits. This study was conducted prior to implementation of current guidelines.

4.2.4 Reproductive Toxicity Study EXECUTIVE SUMMARY: In a three generation reproduction study ( 1985, MRID 00147016), AC 252,214 ( 87.9% a. i.; Lot No. AC 4325 23) was administered in the diet to 12 male and 24 female CD rats per group at concentrations of 0, 1000, 5000, or 10,000 ppm. The premating interval for the F 0 parental animals was 69 days. Each parental generation was mated for the first time at approximately 100 days old. Two litters were produced in each generation. Doses for the parental animals were 0, 92.1 97.2, 430.7 483.4, and 869.5 938.1 mg/ kg/ day, respectively, for males and 0, 99.1 107.5, 497.5 525.4, and 947.3 1050.9 mg/ kg/ day, respectively, for females.

Parental Systemic Toxicity: No treatment related deaths or clinical signs of toxicity occurred during the study. Premating body weight, body weight gain and food consumption by adult animals of all generations were not affected by treatment. Differences from control values were sporadic, not dose related and not consistent over time. No treatment related gross lesions were observed at necropsy. The parental systemic toxicity LOAEL for AC 252,214 in rats is not identified. The NOAEL is $ 10,000 ppm ( 869.5 938.1 and 947.3 1050.9 mg/ kg/ day for males and females, respectively).

Reproductive and Developmental Toxicity: Mating and fertility indices were not affected by treatment of any generation during production of both litters. Estrous cycles and sperm parameters were not evaluated; number of days to mating, gestation length, and gestation index were not given. The reproductive toxicity LOAEL for AC 252,214 in male and female rats was not identified. The reproductive toxicity NOAEL is $ 10,000 ppm ( 869.5 938.1 and 947.3 1050.9 mg/ kg/ day for males and females, respectively).

No differences were noted between the treated and control groups of any generation for number of pups/ litter or offspring survival during lactation. Offspring body weight during lactation was similar between the treated and control groups of all litters and generations. The offspring toxicity LOAEL for AC 252,214 in rats is not identified. The offspring toxicity NOAEL is $ 10,000 ppm ( 869.5 938.1 and 947.3 1050.9 mg/ kg/ day for males and females, respectively).

This study is classified as Acceptable/ Guideline and satisfies the guideline requirement for a reproductive toxicity study [ OPPTS 870.3800 ( 83 4)] in rats. Although no systemic or reproductive toxicity was observed at any dose, the highest dose approximated the limit dose of 1000 mg/ kg/ day. This study was conducted prior to the implementation of the current guidelines.

4.2.5 Additional Information from Literature Sources Page 31 of 68 No additional information on the toxicity of imazaquin was identified in the open literature.

4.2.6 Pre and/ or Postnatal Toxicity <IP_ADDRESS> Determination of Susceptibility There is no indication of increased susceptibility of fetuses or offspring to imazaquin in the developmental or reproductive toxicity studies. In the developmental study in rats, treatmentrelated effects on body weight and reduced ossification were observed, but only at the dose where maternal toxicity occurred. No treatment related effects on fetuses were seen in the rabbit developmental toxicity study; and in the rat reproductive study, no toxicity in either the parents or offspring was noted at the highest dose tested.

<IP_ADDRESS> Degree of Concern Analysis and Residual Uncertainties for Pre and/ or Post natal Susceptibility There is no concern and there are no residual uncertainties for pre and/ or postnatal susceptibility.

4.3 Recommendation for a Developmental Neurotoxicity Study 4.3.1 Evidence that supports requiring a Developmental Neurotoxicity study There is no evidence that supports requiring a developmental neurotoxicity study with imazaquin.

4.3.2 Evidence that supports not requiring a Developmental Neurotoxicity study The available data on the toxicity of imazaquin do not support the recommendation for a developmental neurotoxicity study. Prenatal exposure did not cause any obvious nervous system malformations. No clinical signs suggestive of neurotoxicity were reported in any of the chronic studies conducted in mice, rats and dogs.

4.3.3 Rationale for the UFDB ( when a DNT is recommended)

Not applicable. A developmental neurotoxicity study is not recommended.

4.4 Hazard Identification and Toxicity Endpoint Selection 4.4.1 Acute Reference Dose ( aRfD)  Females age 13 49 An endpoint attributable to a single exposure was not identified from the available database. Page 32 of 68 4.4.2 Acute Reference Dose ( aRfD)  General Population An endpoint attributable to a single exposure was not identified from the available database.

4.4.3 Chronic Reference Dose ( cRfD)

Study Selected: Chronic toxicity dog OPPTS: 870.4100b MRID No.: 00138972 EXECUTIVE SUMMARY: In a chronic toxicity study ( 1984, MRID 00138972), AC 252,214 ( Imazaquin, 87.9% a. i., Lot No. AC 4325 23) was administered in the diet to eight beagle dogs/ sex/ dose levels of 0 ( controls), 200, 1000 or 5000 ppm for one year. Using a food factor of 0.025, corresponding concentrations were 0, 5, 25, or 125 mg/ kg bw/ day, respectively.

One high dose male dog was sacrificed in a moribund condition at week 23 because of decreased appetite, weight loss, and inactivity. Necropsy did not indicate the cause of death. Clinical signs including dermal lesions were observed in all animals and did not appear to be treatment related. Several dogs were diagnosed with Demodex mange, which could have been the cause of the dermal lesions.

Mean body weight was consistently lower ( 8 18%) in the high dose males during the first 20 weeks of the study. After week 20, the body weights increased until they were similar to controls. Correspondingly, mean body weight gain was decreased ( 25%) in the first 12 weeks. High dose females had a decrease in mean body weight ( 10 15%) throughout the study. Lowand mid dose males had occasional slight weight loss that was not consistent throughout the study. The low dose females had a mean body weight slightly below the controls throughout the study but the mid dose values displayed no dose trend and varied between being higher and lower than the controls. Food consumption in high dose males was decreased ( 8 23%) but was comparable and greater than controls after approximately week 24. This value was decreased due to the low amount of food consumed by the one high dose male sacrificed at week 23. Food consumption by the high dose females decreased slightly ( 6 8%) during weeks 4 10 but then was similar to that of controls throughout the remainder of the study.

High dose males and females had a statistically significant decrease in the hematology parameters typically associated with anemia. Animals had decreases in the red blood cell count ( RBCs), hemoglobin ( Hgb), hematocrit ( Hct), mean corpuscular volume ( MCV), mean corpuscular hemoglobin ( MCH) and an occasional decrease in mean corpuscular hemoglobin concentration ( MCHC) at weeks 13, 26 and 52. The decreases in these parameters support a slight, transient microcytic, hypochromic anemia that was improving by week 52. Increased nucleated red blood cells ( nRBC's) (> 2 nRBC/ 100 cells in field) were observed in 3/ 8, 4/ 7 and 4/ 7 high dose males at weeks 13, 26 and 52, respectively. Increased nRBC's were observed in the high dose females at weeks 13, 26 and 52 in 2/ 8, 4/ 8 and 4/ 8 animals, respectively. High dose males had a Page 33 of 68 statistically significant increase in the serum aspartate transferase ( AST or SGOT), serum alanine transferase ( AST or SGPT), lactate dehydrogenase ( LDH) and creatine phosphokinase ( CPK) values at all time points. High dose females also were observed to have significant or at least increased values at all timepoints. At necropsy, mean liver to body weight ratio was statistically increased in the high dose male ( 1.2x) and female ( 1.3x). The mean liver weight and liver tobrain weight ratios were increased but were not statistically significant. Hepatic lesions were not observed. A degenerative skeletal muscle myopathy was observed in the high dose males ( 7/ 7) and females ( 3/ 8) versus none identified in the controls. This finding was characterized by a loss of striation, increased eosinophils and the presence of mononuclear inflammatory cells. Bone marrow hypercellularity was observed only in the high dose males ( 2/ 8) and females ( 4/ 8) as an increase in hematopoietic cells in the bone marrow. This finding is consistent with a regenerative anemia. The LOAEL for Imazaquin is 5000 ppm ( 125 mg/ kg bw/ day) based on a treatment related decrease in body weight; a slight, microcytic, hypochromic anemia; skeletal muscle myopathy and clinical chemistry changes. The NOAEL is 1000 ppm ( 25 mg/ kg bw/ day).

This chronic study in dogs is Acceptable/ Guideline and satisfies the guideline requirements for a chronic toxicity study in dogs. [ OPPTS 870.4100b, OECD 452].

Dose and Endpoint for establishing cRfD: Chronic NOAEL of 25 mg/ kg/ day ( 1000 ppm), based on body weight loss, clinical chemistry/ hematology differences, slight anemia and the presence of skeletal muscle myopathy at a dose of 125 mg/ kg/ day ( 5000 ppm).

Uncertainty Factor ( UF): 100; includes 10x for interspecies extrapolation and 10x for intraspecies variation.

Comments about Study/ Endpoint/ UF: The duration of dosing and the endpoint are appropriate for this scenario. The special 92 day study ( 1991, MRID No.: 42054601) to assess for thyroid effects of imazaquin, which demonstrated a NOAEL and LOAEL of 4.98 ( or 5) and 245.4 mg/ kg/ day, respectively, based on slight body weight decrease and increases in TSH accompanied by decreases in T4 and T3, was not selected for the NOAEL for the cRfD, because the NOAEL of 5 mg/ kg/ day for this study is an artefact of dose spacing. The magnitude of the effects of imazaquin at 245.4 mg/ kg/ day in the special thyroid study was considered relatively small, so that HED believes the thyroid and body weight effects would not be present at a dose of 25 mg/ kg/ day. In addition, all other NOAELs for imazaquin from the available subchronic and chronic studies are much higher than 25 mg/ kg/ day. Finally, the selected NOAEL of 25 mg/ kg/ day based on the dog chronic feeding study is well below the dose at which the thyroid effects were seen and should be protective of any potential thyroid effects of imazaquin.

Chronic RfD = 25 mg/ kg/ day = 0.25 mg/ kg/ day 100 4.4.4 Incidental Oral Exposure ( Short and Intermediate Term) Page 34 of 68 Study Selected: Dog Chronic Feeding Study. OPPTS: 870.4100b MRID No.: 00147011 EXECUTIVE SUMMARY: See above under cRFD.

Dose and Endpoint: NOAEL of 25 mg/ kg/ day based on decreased body weight, changes in hematology indicating anemia and changes in clinical chemistry parameters.

MOE = 100 Comments about Study/ Endpoint/ UF: Body weight shows an apparent decrease in the first 4 weeks. The hematology data from the earliest assessment time at 13 weeks indicate statistically significant changes in both hematology parameters to indicate a concern that the anemia effects of imazaquin may occur within the time frame for short and intermediate term incidental oral exposure.

4.4.5 Dermal Absorption A dermal penetration study is not available for imazaquin. When the NOAEL of 1000 mg/ kg/ day from the rabbit 21 day dermal toxicity study ( 1985, MRID No.: 00146204) is compared with the maternal LOAEL of 500 mg/ kg/ day for body weight effects in the rabbit oral prenatal developmental toxicity study ( 1984, MRID No.: 00174011), an upper bound estimate of 50% dermal absorption is made. It is noted that a LOAEL from the rabbit oral study is being compared with a NOAEL from a dermal study when LOAELs for both studies should normally be compared. However, since no LOAEL for the rabbit dermal study was established, the highest dose tested ( 1000 mg/ kg/ day) is being compared to give a conservative estimate, based on the possibility that toxicity may develop at doses slightly higher than the NOAEL. This conservative estimate of 50% dermal absorption should be used to assess imazaquin dermal exposure and risk.

4.4.6 Dermal Exposure ( Short, Intermediate and Long Term)

Study Selected: Chronic toxicity dog OPPTS: 870.4100b MRID No.: 00138972 EXECUTIVE SUMMARY: MRID 00138972 see chronic RfD.

Dose and Endpoint for establishing cRfD: Chronic NOAEL of 25 mg/ kg/ day ( 1000 ppm), based on body weight loss, clinical chemistry/ hematology differences, slight anemia and the presence of skeletal muscle myopathy at a dose of 125 mg/ kg/ day ( 5000 ppm).

Uncertainty Factor ( UF): 100 Page 35 of 68 Comments about Study/ Endpoint/ UF: 50% dermal absorption should be assumed for risk assessment purposes. The chronic oral toxicity NOAEL of 25 mg/ kg/ day in dogs ( refer to chronic dietary RfD above for executive summary), based on weight loss, slight anemia and myopathy at 125 mg/ kg/ day, is appropriate for the short, intermediate or long term intervals. The chronic dog study demonstrated indications of anemia at the week 13 assessment time, and the time to onset of this condition is not known and may well be within the short and intermediate term exposure intervals. Because there were no systemic or dermal effects at the highest dose tested in the 21 day dermal toxicity study ( 1985, MRID No.: 00146204) with rabbits that demonstrated a NOAEL of 1000 mg/ kg/ day, this route specific study was not selected for dermal risk assessment. In addition, the dog study demonstrated anemia as a critical endpoint and the rabbit may not be susceptible to this condition.

Ordinarily, when there is no toxic effect of concern demonstrated in the rabbit 21 day dermal study at the limit dose ( 1000 mg/ kg/ day) and there are no indications of developmental, reproductive or neurotoxicity, a dermal exposure assessment is not deemed necessary. In this case, a dermal endpoint is being selected for imazaquin, because effects noted in the chronic dog study suggest that the dog may be more sensitive to imazaquin than the rabbit, especially with regard to the induction of anemia. Although there are no studies available to confirm this ( such studies comparing oral toxicity in one species to dermal toxicity in the rabbit are not generally conducted or required), HED is making the highly conservative assumption that the dog is the most sensitive species for the purpose of this screening level risk assessment. HED is also making the assumption that effects noted in the dog study at 13 weeks could occur within a short term ( i. e., 4 week) time frame. Again, there are no data to confirm this assumption, and considering the slight and transient nature of the toxic effects seen at 13 weeks, this assumption may also be considered highly conservative. Therefore, dermal exposure assessments based on this endpoint may be considered screening level only; and the risk assessment team leaves open the option to reconsider the need for a dermal risk assessment in future risk assessments for imazaquin.

4.4.7 Inhalation Exposure ( Short, Intermediate and Long Term)

Study Selected: Chronic toxicity dog ( long term) OPPTS: 870.4100b MRID No.: 00138972 EXECUTIVE SUMMARY: See cRFD above.

Dose and Endpoint for establishing cRfD: Chronic NOAEL of 25 mg/ kg/ day ( 1000 ppm), based on body weight loss, clinical chemistry/ hematology differences, slight anemia and the presence of skeletal muscle myopathy at a dose of 125 mg/ kg/ day ( 5000 ppm).

Uncertainty Factor ( UF): 100 Comments about Study/ Endpoint/ UF: 100% absorption of the inhaled imazaquin in the atmosphere should be assumed for risk assessment purposes. The chronic oral toxicity NOAEL Page 36 of 68 of 25 mg/ kg/ day in dogs ( refer to chronic dietary RfD above for executive summary), based on weight loss, slight anemia and myopathy at 125 mg/ kg/ day, is appropriate for the short, intermediate or long term intervals. The chronic dog study demonstrated indications of anemia at the week 13 assessment time and the time to onset of this condition is not known and may well be within the short and intermediate term exposure intervals.

4.4.8 Margins of Exposure The Margins of Exposure ( MOEs) of concern for occupational and residential exposure risk assessments are as follows:

Route of Exposure Duration of Exposure Short Term ( 1 30 Days) Intermediate Term ( 1 6 Months) Long Term (> 6 Months)

Dermal 100 100 100 Inhalation 100 100 100 For occupational and residential dermal and inhalation exposure risk assessments ( all exposure durations), a MOE of 100 is required. The MOE is based on the conventional uncertainty factor of 100X ( 10X for intraspecies variation and 10X for interspecies extrapolation).

4.4.9 Recommendation for Aggregate Exposure Risk Assessments All oral, dermal and inhalation exposures can be aggregated, as the toxic endpoints selected to assess oral, dermal and inhalation risks are based on common effects in dogs ( i. e., body weight effects, anemia and blood chemistry changes).

4.4.10 Classification of Carcinogenic Potential Imazaquin has not been reviewed by the HED Carcinogenicity Assessment Review Committee or its predecessors. However, no evidence of carcinogenicity was seen in rats or mice and the mutagenicity and genetic toxicity studies do not indicate a concern for mutagenicity. Page 37 of 68 Table 4.4. Summary of Toxicological Doses and Endpoints for Imazaquin for Use in Human Risk Assessments 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 49) Not Applicable Not Applicable No appropriate acute endpoint identified for this population ( i. e., no toxic effect attributable to a single dose identified).

Acute Dietary ( general population) Not Applicable Not Applicable No appropriate acute endpoint identified for this population ( i. e., no toxic effect attributable to a single dose identified).

Chronic Dietary ( all populations) NOAEL = 25 mg/ kg/ day UF = 100 cRfD = 0.25 FQPA SF = 1 X cPAD = cRfD FQPA SF cPAD = 0.25 mg/ kg/ day Chronic toxicity  dog LOAEL = 125 mg/ kg/ day, based on weight loss, slight anemia, evidence of skeletal muscle myopathy and supporting hematology/ clinical chemistry differences Incidental Oral  all durations. NOAEL = 25 mg/ kg/ day FQPA SF = 1 X MOE of concern = 100 ( Residential and Occupational) Same as above.

Dermal  all durations. NOAEL = 25 mg/ kg/ day FQPA SF = 1 X MOE of concern = 100 ( Residential and Occupational)

Assume 50% dermal absorption. Same as above.

Inhalation  all durations NOAEL = 25 mg/ kg/ day FQPA SF = 1X MOE of concern = 100 ( Residential and Occupational)

Assume 100% absorption. Same as above.

Cancer ( oral, dermal, inhalation) Classification: No evidence of carcinogenicity in mice or rats. Page 38 of 68 UF = uncertainty factor, FQPA SF = Special FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose ( a = acute, c = chronic) RfD = reference dose, MOE = margin of exposure * Refer to Section 4.5 Page 39 of 68 4.5 Special FQPA Safety Factor The imazaquin risk assessment team evaluated the potential for increased susceptibility of infants and children from exposure to imazaquin as required by the Food Quality Protection Act ( FQPA) of 1996 according to the 2002 OPP 10x Guidance Document. Based on the hazard data, the team concluded that the special FQPA SF can be reduced to 1X, since there are no concerns and no residual uncertainties for pre and/ or postnatal toxicity based on the following evidence.

° Neither the rat nor rabbit prenatal developmental toxicity studies demonstrated developmental toxicity at doses lower than maternal toxicity. In rabbits, there was no developmental toxicity at the highest dose tested. In the rats, developmental toxicity was demonstrated at the same dose demonstrating maternal toxicity, and this dose was twice the limit dose for acceptable prenatal developmental toxicity testing.

° The rat multi generation reproduction study did not demonstrate either systemic, reproductive or offspring toxicity at the highest dose tested, which was near the limit dose.

The imazaquin risk assessment team evaluated the quality of the exposure data; and, based on these data, recommended that the special FQPA SF be reduced to 1x. This recommendation is based on the following:

° The dietary food exposure assessment utilizes tolerance level residues and 100% crop treated ( CT) information for all commodities. By using these screening level input parameters, chronic exposures/ risks will not be underestimated.

° The dietary drinking water assessment utilizes values generated by models and associated modeling parameters which are designed to provide conservative, health protective, highend estimates of drinking water concentrations.

° The residential exposure assessment is conducted in accordance with HED's residential SOPs, which provide conservative, screening level estimates of exposure. By using these SOPs, residential exposures will not be underestimated.

4.6 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 Page 40 of 68 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 with imazaquin, there was no evidence of estrogen or androgen mediated toxicity. Imazaquin, at higher doses, was demonstrated to increase thyroid stimulating hormone ( TSH) and to have associated decreased in T4 and T3. However, the dose level at which these changes were noted is much higher (~ 10 fold) than the current reference dose for risk assessment. Therefore, the risk assessment should be protective of the observed endocrine/ thyroid effects.

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

5.0 Public Health Data Reference: Review of Imazaquin Incident Reports, DP Barcode: D321563, Jerome Blondell, 10/ 12/ 2005 5.1 Incident Reports There have been no reports of serious human poisoning associated with the use of imazaquin. There have been a few reports of dermal symptoms ( primarily skin irritation, itching and rash) from exposure during the application process or from postapplication exposure. The lack of serious incidents further supports HED's characterization of imazaquin as a low toxicity pesticide with little potential for acute effects. The available incident data for imazaquin are summarized below:

I. OPP Incident Data System Incident# 7203 1: A pesticide incident occurred in 1998, when a man accidentally got the product on his back and legs. He reported skin irritation. No further information on the disposition of the case was reported.

Incident# 7205 1: A pesticide incident occurred in 1998, when a child played in an area that was treated with the product the previous week. The child reported a rash. No further information on the disposition of the case was reported. Page 41 of 68 Three minor cases involving skin reactions and a legal suit that did not provide specific information on the symptoms or exposure were not included in the summary above. Note that including the three minor cases, there were a total of five cases involving skin irritation or rash.

II. Poison Control Center Data  1993 through 2001 There were 58 reports of exposure to imazaquin from 1993 through 2003. However, just 25 of these reports received follow up to determine medical outcome and just 10 of the 25 had symptoms related to their exposure. The primary symptoms reported were dermally related, primarily irritation, itching and rash.

III. California Data  1982 through 2002 No reports of imazaquin poisoning were reported in California from 1982 through 2003.

IV. National Pesticide Information Center On the list of the top 200 chemicals for which NPIC received calls from 1984 1991, inclusively, imazaquin was not reported to be involved in human incidents.

V. NIOSH SENSOR Out of 5,899 reported cases from 1998 2003, none involved imazaquin.

VI. Scientific Literature No scientific literature was found concerning human poisoning or other adverse effects from exposure to imazaquin.

5.2 Other Imazaquin is not included in the Agricultural Health Survey ( AHS) Applicator questionnaire and is not on the current National Health and Nutrition Examination Survey ( NHANES) list.

6.0 Exposure Characterization/ Assessment 6.1 Dietary Exposure/ Risk Pathway 6.1.1 Residue Profile Reference: Imazaquin. Tolerance Reassessment Eligibility Decision ( TRED). Summary of Analytical Chemistry and Residue Data; DP Barcode 302944; D. Drew; 10/ 6/ 05. Page 42 of 68 Nature of the Residue The nature of the residue in plants is adequately understood for the use of imazaquin on soybeans. Based on the trace levels of radioactivity found in the soybean seed from an exaggerated application rate, the apparent extensive degradation of imazaquin into plant constituents, and the livestock grazing/ feeding prohibition of forage, straw and hay on current labels, the residue of concern for the use of imazaquin on soybeans is imazaquin, per se. If additional uses of imazaquin are proposed, then additional metabolism data may be required.

The nature of residue in livestock is adequately understood for the use of imazaquin on soybeans. Based on the results of the animal metabolism studies where livestock were dosed at 94x ( ruminant) and 68x ( poultry) the maximum theoretical dietary burden ( based on the feeding of soybean seed), there is no reasonable expectation of finite imazaquin residues to occur in meat, milk, poultry, and eggs ( Category 3 of 40 CFR § 180.6( a)) as a result of the use pattern on soybean. Additionally, soybean seed samples had no detectable residues (< 0.05 ppm), when treated at up to 8X the maximum application rate of imazaquin; and forage, hay, and straw are restricted as feed items. HED considers the feeding restrictions to be enforceable, and therefore acceptable, since soybeans are grown only for seed and the feed items remain under the control of the grower. If additional uses or additional field studies result in detectable residues in feedstuffs, then additional animal metabolism studies may be required.

Magnitude of the Residue A tolerance has been established under 40 CFR § 180.426 for imazaquin in or on soybeans at 0.05 ppm. In crop field trials conducted on soybeans using pre plant incorporated and post emergence treatments with diisoproyl amine salt of imazaquin at rates of 0.25 lb ae/ A ( 1x) to 2 lb ae/ A ( 8x; one trial), residues of imazaquin were < 0.05 ppm in all samples including seeds, foliage, and straw. Forage and hay samples were not collected. Processing studies are not required, because residues were not detected in soybean samples treated at 8x the maximum application rate.

Residues of imazaquin are stable for up to 24 months on frozen soybean and corn. The storage duration of the crop field trial soybean samples from harvest to analysis was not provided.

No studies pertaining to magnitude of the residue in eggs, milk and meat were submitted. Several raw agricultural and processed commodities of soybean may be utilized as livestock feed items; however, based on the results of the animal metabolism studies discussed above, there is no reasonable expectation of finite imazaquin residues occurring in livestock commodities as a result of the soybean use. Therefore, HED has determined that feeding studies are not required at this time. HED reserves the right to request livestock feeding studies in the future if additional uses on crops with livestock feed items are proposed for registration. Page 43 of 68 Rotational Crops In a confined rotational crop study, soybeans were planted in soil treated with 14C labeled imazaquin and 13C labeled quinoline ( approx. 1.5x maximum single application rate) and grown to maturity, about 4.5 months. Winter wheat was planted 3 months after treatment, and spring wheat and field corn were planted 8.5 months after treatment. Carrots and lettuce were also planted 9.5 months after treatment. The total radioactive residue ( TRR) were below 0.01 ppm in RACs, except in corn fodder ( 0.02 ppm) and in winter wheat straw ( 0.07 ppm). Sixty percent of the wheat straw residue was extractable and further characterized. The extractable residue was separated on HPLC into 7  9 unknown compounds, each at a level below 0.01 ppm.

A field accumulation in rotational crop study for corn planted following soybeans was submitted in order to support the reduction of the corn plant back interval to 9.5 months, instead of the 11 months that was in place at the time. Imazaquin was applied at a rate of 0.125 lb ae/ A in both pre plant incorporation and post emergence stages ( 0.25 lbs ae/ A total). Soybeans were grown to maturity and harvested. Corn was planted 281 334 days ( 9.3 to 11 months) after final imazaquin treatment. Corn samples, after planting, were harvested at 40 41days for forage, 60 93 days for early silage, 84 110 days for late silage, and 111 181 days for grain and foddler. No detectable imazaquin residues were detected, i. e. all sample detections were < 0.05 ppm. Based on the submitted confined accumulation and field accumulation in rotational crop studies, HED was in favor of the proposed label amendment to reduce the plant back interval from eleven months to nine and a half months for corn.

Currently, labels specify PBIs from 3 to 11 months for most rotated crops. PBIs greater than 11 months are specified for some rotated crops, presumably because of phytotoxicity concerns. Based on the plant back intervals ( PBIs) used in the confined accumulation study and field accumulation study, where no residues of imazaquin were detected, the rotational crop restrictions on the current labels are adequate. If the registrant desires reduced rotational crop plant back intervals, additional field accumulation in rotational crops data should be submitted.

Analytical Methods Method M 1410 has been accepted for tolerance enforcement purposes and is included in PAM, Vol II as Method I. The gas chromatography method uses acidic water and methanol in the extraction process and has a limit of quantitation ( LOQ) of 0.05 ppm. The previous analytical methods ( M 1283 and M 1245) were replaced by Method M 1410 because the analysis of freezer stability samples using Methods M 1283 and M 1245 showed that extraction with ethyl acetate only extracted about 50% of the residue. The crop field samples were analyzed using Methods M 1283 and M 1245; however, the fortification results indicated acceptable recovery.

Imazaquin has not been tested for recovery via FDA Multiresidue Protocols ( PAM Vol. I), and it is unknown whether it is recoverable by these methods. Page 44 of 68 Residue Chemistry Deficiencies/ Regulatory Recommendations A tolerance of 0.05 ppm has been established under 40 CFR § 180.426 for residues of imazaquin in or on soybeans. HED supports this tolerance, provided the following deficiencies and data gaps are resolved:

° The storage duration of the crop field trial soybean samples from harvest to analysis was not provided and should be submitted. Storage stability studies indicate that residues of imazaquin are stable on soybeans for up to 24 months of frozen storage.

° Multiresidue method data were not submitted. The registrant should submit data pertaining to the recovery of imazaquin via FDA Multiresidue Protocols ( PAM Vol. I).

° Residue data were not provided for soybean forage and hay; however, these data are not required provided current label restrictions prohibiting the grazing and feeding of forage, straw and hay to livestock are maintained.

6.1.2 Chronic Dietary Exposure and Risk Reference: Imazaquin Chronic Dietary Exposure Assessment for the Reregistration Eligibility Decision, DP Barcode: D302943, Susan Stanton, 10/ 20/ 05 A chronic dietary risk assessment was conducted for imazaquin, using the Dietary Exposure Evaluation Model ( DEEM FCID, Version 2.03), which uses food consumption data from the USDA's Continuing Surveys of Food Intakes by Individuals ( CSFII) from 1994 1996 and 1998. Since no toxic effects attributable to a single ( i. e., acute) exposure have been identified for imazaquin, an acute dietary exposure assessment was not conducted. Also, since there is no evidence that imazaquin is carcinogenic to humans, a dietary cancer assessment was not conducted.

The tier 1 chronic assessment assumed that 100% of the soybean crop is treated and that residues of imazaquin are present at the tolerance level of 0.05 ppm in all soybean commodities, including processed commodities. Drinking water was incorporated directly into the dietary assessment using the tier 1 estimated drinking water concentration for ground water generated by the SCIGROW model ( See sec. 6.2, below). As discussed in section 3.6.2 ( Rationale for Inclusion of Metabolites and Degradates), the residue of concern in surface water consists of parent imazaquin and its photolytic degradates; whereas, the residue of concern in groundwater consists of parent imazaquin only. The SCI GROW groundwater estimate was selected for risk assessment purposes, because this estimate of parent imazaquin only was higher than the PRZM EXAMS model estimates of imazaquin and its photolytic degradates in surface water.

The resulting dietary exposure estimates are well below HED's level of concern ( i. e., < 100% of the cPAD) for the overall U. S. population and all population subgroups. Using the DEEM FCID Page 45 of 68 software, chronic dietary exposure is estimated at 0.000677 mg/ kg/ day for the U. S. population ( 0.3% of the cPAD) and 0.002208 mg/ kg/ day ( 0.9% of the cPAD) for infants less than 1 year old, the population subgroup with the highest estimated chronic dietary exposure to imazaquin.

More than 95% of the total estimated dietary exposure is from drinking water. Estimated exposure and risk from food, drinking water and combined food and drinking water are summarized below in Table 6.1 for the U. S. population and population subgroups.

Table 6.1. Summary of Chronic Dietary Exposure and Risk for Imazaquin1 Population Subgroup Food Only Drinking Water Only Food + Drinking Water Exposure ( mg/ kg/ day) % cPAD Exposure ( mg/ kg/ day) % cPAD Exposure ( mg/ kg/ day) % cPAD General U. S. Population 0.000024 0.01 0.000653 0.3 0.000677 0.3 All Infants (< 1 year old) 0.000066 0.03 0.002142 0.9 0.002208 0.9 Children 1 2 years old 0.000053 0.02 0.000970 0.4 0.001023 0.4 Children 3 5 years old 0.000052 0.02 0.000908 0.4 0.000960 0.4 Children 6 12 years old 0.000036 0.01 0.000627 0.3 0.000663 0.3 Youth 13 19 years old 0.000023 0.01 0.000472 0.2 0.000496 0.2 Adults 20 49 years old 0.000019 0.01 0.000610 0.2 0.000629 0.3 Adults 50+ years old 0.000015 0.01 0.000642 0.3 0.000657 0.3 Females 13 49 years old 0.000018 0.01 0.000608 0.2 0.000626 0.3 1The values for the population with the highest estimated exposure are bolded.

6.2 Water Exposure/ Risk Pathway Reference: Drinking Water Assessment for Imazaquin and its Salts; K. Moore; June 21, 2005, as amended on September 27, 2005.

Potential concentrations of imazaquin and its monoammonium and monosodium salts in drinking water were assessed by the Environmental Fate and Effects Division ( EFED) through an evaluation of surface water and groundwater monitoring data and modeling. Because all three compounds dissociate in water to form the carboxylate anion, they were treated concurrently in the assessment.

Imazaquin's primary use is as a broad spectrum herbicide on soybeans. The turf and ornamental use patterns were also considered in EFED's assessment. Surface and groundwater monitoring data were available from the United States Geological Survey ( USGS) National Water Quality Assessment ( NAWQA) Program and from an additional USGS study on pesticide concentrations Page 46 of 68 in high use areas in the Midwest. Maximum concentrations of imazaquin in the monitoring data reviewed were 4.89 : g ae/ L in surface water and 0.098 : g ae/ L in groundwater. Because the monitoring studies reviewed are short term or not targeted to detect imazaquin, they are not likely to capture peak concentrations. Modeling was used, therefore, to predict the most conservative concentrations, with monitoring data used to confirm that modeling results are reasonable. Estimated Environmental Concentrations ( EECs) in surface water were modeled using PRZM 3.12/ EXAMS 2.98.04, and ground water concentrations were modeled using SCIGROW ( version 2.3).

At the time of EFED's original assessment, no degradates of concern had been identified and only the parent compounds were assessed. HED subsequently determined that the major surface water degradates should also be considered in the risk assessment. Therefore, EFED repeated the surface water modeling for the most vulnerable scenario, turf, with an updated photolysis half life that incorporated these degradates. The updated, total residue half life was calculated by performing first order linear regression on the log transformed sum total of imazaquin plus each of the four major degradates at each sampling point. Since these degradates are not expected to form in ground water, the ground water EECs include the parent compounds only. The surface and ground water modeling results are presented in Table 6.2. Note that all concentrations reported in this assessment are in acid equivalents ( ae).

Table 6.2. Imazaquin EECs 1 Surface water ( PRZM / EXAMS) 2 Groundwater ( SCIGROW) 3 Crop Scenario Acute ( Peak) Chronic ( Annual average) Acute & Chronic Soybeans 1.8 µ g ae/ L 0.4 µ g ae/ L 3.8 µ g ae/ L Ornamental 1.9 µ g ae/ L 1.0 µ g ae/ L 15.6 µ g ae/ L Turf  1 app. 15.2 µ g ae/ L 5.0 µ g ae/ L 15.6 µ g ae/ L Turf  1 app. 4 16.0 µ g ae/ L 6.7 µ g ae/ L 15.6 µ g ae/ L Turf  2 app. 20.0 µ g ae/ L 7.6 µ g ae/ L 31.1 µ g ae/ L Turf  2 app. 4 21.8 µ g ae/ L 11.6 µ g ae/ L 31.1 µ g ae/ L 1 All EECs are for parent compound only, unless otherwise specified.

2 From the PRZM EXAMS  Index Reservoir model. Input parameters are based on maximum application rates, an aerobic soil metabolic half life of 630 days ( 3 times the reported value), an anaerobic soil metabolic half life of " stable", an aerobic aquatic degradation half life of 1260 days ( no data available  2 times the aerobic soil metabolic half life), an anaerobic aquatic degradation half life of " stable", an aqueous photolysis half life of 0.9 days, a hydrolysis half life of " stable", vapor pressure of < 2 x 10 8 and a median Koc of 17.5 ml/ g. A percent cropped area ( PCA) adjustment factor of 0.41 was assumed for soybeans. 3 From the SCI GROW model. Input parameters based on maximum application rates, an aerobic soil metabolic half life of 210 days and a median KOC of 17.5 ml/ g. 4 The surface water EECs include parent imazaquin and its major degradates. The ground water EECs include parent compound only. Page 47 of 68 The highest imazaquin concentration was estimated for groundwater, based on 2 applications to turf at 0.5 lbs. ae/ acre. This value ( 31.1 ppb/ 0.031 ppm) was used as a point estimate to assess exposure to imazaquin from drinking water in the dietary assessment.

6.3 Residential ( Non Occupational) Exposure/ Risk Pathway Reference: Imazaquin: Residential Exposure Assessment and Recommendations for the Tolerance Reassessment Eligibility Decision ( TRED); DP Barcode: D302942; Seyed Tadayon; 10/ 06/ 2005 Imazaquin may be used in residential settings on turfgrass and ornamentals, including turfgrass and ornamentals on golf courses. The residential use of imazaquin is limited to outdoor applications. There is a potential for short term ( 1 to 30 days in duration) non occupational exposure in residential settings during the application process for homeowners who use products containing imazaquin. There is also a potential for short term exposure of children and adults entering areas that have been treated with imazaquin. As a result, short term risk assessments have been completed for both residential handler and postapplication exposure scenarios. Due to the episodic nature of imazaquin applications, intermediate and long term exposures are not anticipated and, therefore, have not been assessed.

6.3.1 Residential Handler Exposures The Agency uses the term " handlers" to describe those individuals who are involved in the pesticide application process ( i. e., the mixing, loading or applying of pesticides). The agency believes that there are distinct tasks related to applications and that exposures can vary depending on the specifics of each task. Residential handler exposures are assessed somewhat differently than occupational handler exposures by the Agency, as described below:

° Residential handler exposure scenarios are considered to be of short term duration only, due to the episodic nature of homeowner applications;

° A tiered approach based on increasing levels of personal protective equipment ( PPE) is not used in residential handler risk assessments. Homeowner handler assessments assume that individuals are wearing shorts, short sleeved shirts, socks and shoes.

° Homeowner handlers are expected to complete all tasks associated with the use of a pesticide product, including mixing/ loading, if needed, and the application;

° Label directions and application rates for residential ( i. e., homeowner) products serve as the basis for exposure and risk calculations, rather than commercial label rates and directions for use; and Page 48 of 68 ° Area/ volumes of spray or chemical used in the risk assessment are based on HED guidance specific to residential use patterns.

<IP_ADDRESS> Residential Handler Exposure Scenarios Residential handler exposure is likely during the use of imazaquin on turf and ornamentals in a variety of outdoor environments. The anticipated use patterns and current labeling indicate several major residential exposure scenarios based on the types of equipment and techniques that can potentially be used to make imazaquin applications. The quantitative exposure/ risk assessment developed for residential handlers is based on the following scenarios:

Mixer/ Loader/ Applicators:

( 1) Liquid Concentrate: Hose end Sprayer  Turf Application ( 2) Liquid Concentrate: Hand Held Pump Sprayer  Ornamentals/ Shade Tree Application ( 3) Liquid Concentrate: Ready to Use Sprayer  Turf Application <IP_ADDRESS> Data and Assumptions For Residential Handler Exposure Scenarios A series of assumptions served as the basis for the handler risk assessments. The assumptions used in the risk assessment calculations are detailed below:

° Both dermal and inhalation short term exposures may occur during the handling of imazaquin in residential settings. Dermal and inhalation exposures were each assessed, based on the NOAEL of 25 mg/ kg/ day from the dog chronic toxicity study. For the dermal assessment, 50% dermal absorption of imazaquin was assumed; for the inhalation assessment, 100% absorption of inhaled imazaquin in the atmosphere was assumed.

° No chemical specific exposure data for imazaquin were available for use in the residential handler exposure assessment. Therefore, HED used standard unit exposure values derived from studies conducted by the Outdoor Residential Exposure Task Force ( ORETF) to estimate handler exposure and risk.

° HED always considers the maximum application rates allowed by labels in its risk assessments. If additional information, such as average or typical rates, is available, these values also may be used to allow risk managers to make a more informed risk management decision. Average/ typical application rates were not available for the residential uses of imazaquin. Therefore, the maximum homeowner application rates were assumed.

° Residential risk assessments are based on estimates of what homeowners would typically treat, such as the size of a lawn. The estimates used for the imazaquin assessment were taken from HED's Exposure Science Advisory Committee Policy 12: Recommended Page 49 of 68 Revisions To The Standard Operating Procedures For Residential Exposure Assessment, which was completed on February 22, 2001; and on professional judgement. The daily volumes handled and area treated that were assumed for each residential scenario are provided in Table <IP_ADDRESS>.

<IP_ADDRESS> Residential Handler Exposure and Risk Estimates Dermal and inhalation potential exposures for residential handlers were calculated as follows:

Exposure Dose ( mg/ kg/ day) = UE x AR x A x AB BW Where: UE = unit exposure from ORETF study data ( mg/ lb ai or µ g/ lb ai) AR = maximum application rate ( lb ai/ acre or lb ai/ gal) A = maximum area treated ( acres/ day or gal/ day) AB = absorption value ( Dermal absorption = 50%; inhalation absorption = 100%) BW = body weight ( 70 kg)

For handler short term exposure, the margin of exposure ( MOE) was calculated as follows:

Inhalation MOE = NOAEL ( 25 mg/ kg/ day) Inhalation Exposure Dose Dermal MOE= NOAEL ( 25 mg/ kg/ day) Dermal Exposure Dose MOE TOTAL = 1 ( 1/ Dermal MOE ) + ( 1/ Inhalation MOE)

The dermal and inhalation exposures were combined for the imazaquin handler risk assessment, because exposure is expected via both routes and the toxicity endpoints for the dermal and inhalation routes of exposure are the same. The resulting dermal, inhalation and combined residential handler risk estimates are presented in Table <IP_ADDRESS> below. Page 50 of 68 Table <IP_ADDRESS>: Imazaquin Short Term Residential Handler Exposure and Risks Estimates Exposure Scenario Target Application Ratea Area Treated Dailyb Dermal Unit Exposure ( mg/ lb ai) Inhalation Unit Exposure ( Ug/ lb ai) Dermal Dose d ( mg/ kg/ day) Inhalation Dose e ( mg/ kg/ day) MOE ( HED's level of concern = 100)

Dermalf Inhalation g Dermal +

Inhalation h Mixer/ Loader/ Applicator Mixing/ Loading/ Applying Liquid Concentrates with Hose End Sprayer ( Residential ORETF data) ( 1) Turf 0.38/ A 0.5 acre 11 17 0.015 0.000046 1,700 550,000 1,700 Mixing/ Loading/ Applying Liquid Concentrates with a Hand Held Pump ( ORETF ) sprayer( 2) Ornamental s 0.006 lb ai/ gal 1 gal 38 2.7 0.0016 0.0000002 15,400 125,000,000 15,400 Applying Ready to Use sprayer ( ORETF)( 3) Turf 0.006 lb ai/ gal 1 gal 54 19 0.0023 0.0000016 11,000 15,625,000 11,000 a Application rates are the maximum application rates determined from EPA registered labels for imazaquin.

b Amount handled per day values are EPA estimates.

c Attire is short sleeve shirt, short pants, and no gloves and no respirator.

d Dermal Dose = application rate x area treated x dermal unit exposure x % DA ( 50) ÷ 70 e. Inhalation Dose = application rate x area treated x inhalation unit exposure ÷ 70 f. Dermal MOE = NOAEL ( 25mg/ kg/ day) / dermal daily dose ( mg/ kg/ day),

g. Inhalation MOE = NOAEL ( 25 mg/ kg/ day) / inhalation daily dose ( mg/ kg/ day)

h MOE TOTAL = 1 ( 1/ Dermal MOE ) + ( 1/ Inhalation MOE) Page 51 of 68 MOEs of less than 100 indicate exposures of risk concern. Since all of the estimated combined dermal/ inhalation MOEs for residential handlers of imazaquin are well above 100, the estimated exposures do not exceed the Agency's level of concern for risk assessments in non occupational settings.

6.3.2 Residential Postapplication Exposures <IP_ADDRESS> Residential Postapplication Exposure Scenarios Individuals of varying ages can potentially be exposed to imazaquin when they are in areas that have been previously treated. Postapplication exposure scenarios were developed for each residential setting where imazaquin can be used. The scenarios assessed include:

Residential Adults: These individuals are members of the general population that are exposed to chemicals by engaging in activities at their residences ( e. g., on their lawns) and also in areas not limited to their residence ( e. g., golf courses or parks) previously treated with a pesticide. These kinds of exposures are attributable to a variety of activities and are usually addressed by HED in risk assessments by considering a representative activity as the basis for the exposure calculation.

Residential Children: Children are members of the general population that can also be exposed at their residences ( e. g., on lawns and other residential turfgrass areas). These kinds of exposures are attributable to a variety of activities such as playing outside. Toddlers have been selected as the sentinel ( representative) children's population for turf. Children are addressed by HED in risk assessments by considering representative activities for each age group in an exposure calculation.

The SOPs For Residential Exposure Assessment define several scenarios that apply to uses specified in current imazaquin labels. The Agency used this guidance to define the adult and toddler exposure scenarios included in this postapplication exposure assessment. The assessed exposure scenarios are summarized below:

Toddlers:

C Hand to mouth activity on treated turf: Postapplication exposure among toddlers from incidental non dietary ingestion of pesticide residues on treated turf from hand to mouth transfer.

° Object to mouth activity on treated turf: Postapplication exposure among toddlers from incidental non dietary ingestion of pesticide residues on treated turf from object to mouth transfer. Page 52 of 68 C Soil ingestion activity on treated turf: Postapplication exposure among toddlers from incidental non dietary ingestion of pesticide residues from ingesting soil in a treated turf area.

° High contact activities on treated turf: Postapplication exposure among toddlers from dermal contact with treated turf.

Adults:

° High contact activities on treated turf: Postapplication exposure among adults from dermal contact with treated turf.

° Mowing turf: Postapplication exposure among adults from dermal contact with treated turf during mowing activities.

° Golf Course: Postapplication exposure among adults from dermal contact with treated turf on golf courses.

<IP_ADDRESS> Data & Assumptions for Residential Postapplication Exposure Scenarios A series of assumptions served as the basis for the residential postapplication risk assessments. Each assumption is detailed below.

° Postapplication inhalation exposures are expected to be minimal; therefore, HED considered only dermal and incidental oral exposures in the postapplication risk assessments.

° HED combines or aggregates risks resulting from exposures to individual chemicals when it is likely they can occur simultaneously based on the use pattern and the behaviors associated with the exposed population. For imazaquin, HED has combined postapplication risks for turf scenarios involving toddlers  i. e., dermal + oral risks ( handto mouth, object to mouth and soil ingestion).

° The body weight of an average adult ( 70 kilograms) is used for assessing dermal risks to adults.

° Exposures of adults and children on treated turf have been assessed using the latest Agency approaches for these scenarios, including:

< A dermal absorption value of 50% was used for estimating risk in this assessment. Page 53 of 68 < 5 percent of the application rate has been used to calculate the 0 day residue levels for assessing risks from dermal and hand to mouth exposures, since imazaquinspecific turf transferable residue ( TRR) data are not available.

< 20 percent of the application rate has been used to calculate the 0 day residue levels for assessing risks from object to mouth behaviors. A higher percent transfer has been used for object to mouth behavior because it involves a teething action believed to be more analogous to dislodgeable foliar residue ( DFR)/ leaf wash sample collection where 20 percent is also used.

< The transfer coefficients used are those presented during the 1999 Agency presentation before the FIFRA Science Advisory Panel that have been adopted in routine practice by HED.

< 3 year old toddlers are expected to weigh 15 kilograms ( representing an average weight from years one to six).

< Short term hand to mouth exposures are based on a frequency of 20 events/ hour. A surface area per event of 20 cm2 representing the palmar surfaces of three fingers is assumed.

< Saliva extraction efficiency is assumed to be 50 percent, meaning that every time the hand goes in the mouth, approximately ½ of the residues on the hand are removed.

< Object to mouth exposures are based on a 25 cm2 surface area.

< Exposure durations for turfgrass scenarios are expected to be 2 hours based on information in the Agency's Exposure Factors Handbook < Soil residues are contained in the top centimeter and soil density is 0.67 mL/ gram.

< Dermal, hand to mouth, object to mouth and soil ingestion risks are combined to represent an overall risk from exposure to treated turf.

° Postapplication residential risks are based generally on maximum application rates or values specified in the SOPs For Residential Exposure Assessment.

° The Jazzercize approach is the basis for the dermal transfer coefficients from turfgrass as described in HED's Series 875 guidelines, SOPs For Residential Exposure Assessment, and the 1999 FIFRA SAP Overview document. Page 54 of 68 <IP_ADDRESS> Residential Postapplication Exposure and Risk Estimates Short term postapplication exposures and risks for toddlers and adults based on the above assumptions are summarized in Tables <IP_ADDRESS>a and <IP_ADDRESS>b.

Table <IP_ADDRESS>a: Short Term Postapplication Residential Risk Estimates from Oral and Dermal Exposure of Toddlers to Imazaquin Exposure Scenario Route of Exposure Population Application Ratea Ave. Daily Dose ( mg/ kg/ day) MOEb Residential Turf ( High Contact Activities) Dermal Toddler 0.5 lb. a. i./ A 0.1 260 Hand to Mouth Activity on Turfd Oral 0.007 3,400 Object to Mouth Activity on Turfe 0.0019 13,400 Incidental Soil Ingestionf 0.0003 1,000,000 a Application rates represent maximum label rates from current EPA registered labels . b MOEs calculated using residues which would be found on day of treatment. MOE = NOAEL ( 25 mg/ kg/ day)/ Ave. Daily Dose ( mg/ kg/ day). An MOE of 100 represents HED's level of concern. c Dermal Dose Calculation: TTR( ug/ cm2) x 0.001 ( mg/ ug) x Transfer Coefficient ( cm2/ hr) x Exposure Time ( hr/ day) x Dermal Absorption (%) ÷ Body Weight ( kg) d Hand to mouth Dose Calculation: oral dose to child ( 1 6 year old) on the day of treatment ( mg/ kg/ day) = [ application rate ( lb ai/ acre) x fraction of residue dislodgeable from potentially wet hands ( 5%) x 11.2 ( conversion factor to convert lb ai/ acre to µ g/ cm2)] x median surface area for 1 3 fingers ( 20 cm2/ event) x hand to mouth rate ( 20 events/ hour) x exp. time ( 2 hr/ day) x 50% saliva extraction factor x 0.001 mg/: g] / bw ( 15 kg child). e Object to Mouth Activity on  Turf Dose Calculation: oral dose to child ( 1 6 year old) on the day of treatment = [ application rate ( lb ai/ acre) x fraction of residue dislodgeable ( 5%) x 11.2 ( conversion factor to convert lb ai/ acre to µ g/ cm2)] x median surface area for 1 3 fingers ( 25 cm2/ event) x hand to mouth rate ( 20 events/ hour) x 0.001 mg/: g]] / bw ( 15 kg child). f Incidental Soil ingestion  Dose Calculation: oral dose to child ( 1 6 year old) on the day of treatment ( mg/ kg/ day) = [( application rate ( lb ai/ acre) x fraction of residue retained on uppermost 1 cm of soil ( 100% or 1.0/ cm) x 4.54E+ 08 µ g/ lb conversion factor x 2.47E 08 acre/ cm2 conversion factor x 0.67 cm3/ g soil conversion factor) x 100 mg/ day ingestion rate x 1.0E 06 g/ µ g conversion factor] / bw ( 15 kg).

Note: Assumptions used in dose calculations ( e. g., transfer coefficients) are from Residential SOPs ( revised 2/ 01).

Table <IP_ADDRESS>b: Short Term Postapplication Residential Risk Estimates from Dermal Exposure of Adults to Imazaquin Exposure Scenario Route of Exposure Population Application Ratea Ave. Daily Doseb ( mg/ kg/ day) MOEc Residential Turf ( High Contact Activities)

Dermal Adult 0.5 lb. a. i./ A 0.06 430 Mowing Turf 0.002 12,500 Golf Course 0.004 6,250 a Application rates represent maximum label rates from current EPA registered labels . b Dermal Dose Calculation: TTR( ug/ cm2) x 0.001 ( mg/ ug) x Transfer Coefficient ( cm2/ hr) x Exposure Time ( hr/ day) x Dermal Absorption (%) ÷ Body Weight ( kg) c MOEs calculated using residues which would be found on day of treatment. MOE = NOAEL ( 25 mg/ kg/ day)/ Ave. Daily Dose ( mg/ kg/ day). An MOE of 100 represents HED's level of concern.

Note: Assumptions used in dose calculations ( e. g., transfer coefficients) are from Residential SOPs ( revised 2/ 01). Page 55 of 68 The Agency aggregates risk values resulting from separate postapplication exposure scenarios when it is likely they can occur simultaneously based on the use pattern and the behavior associated with the exposed population. For imazaquin, the Agency aggregated risk values ( i. e., MOEs) for postapplication exposures of toddlers associated with turf applications by combining risks from all dermal and oral exposures. The combined risks are shown below in Table <IP_ADDRESS>c.

Table <IP_ADDRESS>c: Short term ( aggregate) Toddler Risk from Turf Uses of Imazaquin Exposure Scenario Margins of Exposure ( MOEs) ( UF= 100) Dermal Oral ( Non Dietary) Total Non Dietary Riska Short term Exposures Toddler Turf: 0.5 lb ai/ A High Contact Activities 260 N/ A 260 Hand to Mouth N/ A 3400 Object to Mouth N/ A 13,400 Incidental Soil Ingestion N/ A 1,000,000 a The following formula is used to calculate total MOE values by combining the route specific MOEs: MOE total = 1/(( 1/ MOE a) + ( 1/ MOE b) +.... ( 1/ MOE n)). Where: MOE a, MOE b, and MOE n represent MOEs for each exposure route of concern.

The aggregated residential risk MOE is > 100 and is, therefore, not of concern.

6.3.3 Other ( Spray Drift, etc.)