Quizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **1** of **34** UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 **OFFICE OF CHEMICA**  **L SA FETY**  **AND POLLUTION PREVENTION**  **MEMORANDUM Date**  **: November 1**  **7 , 2011**  **SUBJECT:** Quizalofop - P - ethyl : Human Health Risk Assessment for New Uses on Sorghum, Rapeseed Crop Group 20 A, and Field Corn **PC Code:** 1287 09 **DP Barcode:** D384660 and D386678 **Decision No.:** 441518 and 443799 **Registration No. :**  352 - 541 and 352 - 542 **Petition No.:** 0E7802 and 1F7822 **Regulatory Action:** Tolerance Petition **Risk A**  **ss essment Type:**  Single Chemical / Aggregate **Case No.:** NA **T XR No.:**  NA **CAS No.:** 100646 - 51 - 3 **MRID No.:** 48273601, 48260704 and 48310101 **40 CFR:** § 180.441 **FROM:** Id eliz Negrón - Encarnación, Ph.D., Risk Assessor

Sey ed Tadayon, Chemist John Doherty , Ph.D., Toxicologist Risk Assessment Branch V Health Effects Division (7509P) Office of Pesticide Programs **THROUGH:** William Donovan, Ph.D., Chemist

Michael Metzger, Branch Chief Risk Assessment Branch V Health Effects Division (7509P) Office of Pesticide Programs **TO:** Laura Nollen, Risk Manager

Risk Management Division (RM 5; 7508 P) and Mindy Ondish, Risk Manager Risk Management Division (RM 25; 7508P)Quizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **2** of **34 Table of Contents**  1.0 Executive Summary ................................ ................................ ................................ ............. 4 2.0 HED Recommendations ................................ ................................ ................................ ....... 6 2.1 Data Deficiencies/Conditions of Registration ................................ ................................ .. 6 2.2 Tolerance Considerations ................................ ................................ ................................ . 6 2.2.1 Enforcement Anal yt ical Method ................................ ................................ .................. 7 2.2.2 International Harmonization ................................ ................................ ......................... 7 2.2.3 Recommended Tolerances ................................ ................................ ............................ 7 2.3 Label Recommendations ................................ ................................ ................................ 10 3.0 Introduction ................................ ................................ ................................ ........................ 10 3.1 Chemical Identity ................................ ................................ ................................ ........... 11 3.2 Phy sic al/Chemical Characteristics ................................ ................................ ................. 11 3.3 Pesticide Use Pattern ................................ ................................ ................................ ...... 12 3.4 Anticipated Exposure Pathway s ................................ ................................ ..................... 14 3.5 Consideration of Environmental Justice ................................ ................................ ........ 14 4.0 Hazard Characterization and Dose - Response Assessment ................................ ................ 15 4.1 Toxicology

Studies Available for Analy sis ................................ ................................ ... 15 4.2 Absorption, Distribution, Metabolism, & Elimination (ADME) ................................ ... 15 4.2.1 Dermal Absorption ................................ ................................ ................................ ..... 15 4.3 Toxicological Effects ................................ ................................ ................................ ..... 15 4.4 Safety

factor for Infants and Children (FQPA Safety Factor) ................................ ....... 16 4.4.1 Completeness of the Toxicology Database ................................ ................................ 16 4.4.2 Evidence of Neurotoxicity ................................ ................................ .......................... 16 4.4.3 Evidence of Sensitivity /Susceptibility

in the Developing or Young Animal ............. 16 4.4.4 Residual Uncertaint y in the Exposure Database ................................ ......................... 19 4.5 Toxicity

Endpoint and Point of Departure Selections ................................ .................... 19 4.5.1 Dose - Response Assessment ................................ ................................ ....................... 19 4.5.3 Cancer Classification and Risk Assessment Recommendation ................................ .. 20 4.5.4 Summary

of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment ................................ ................................ ................................ ................................ 22 5.0 Dietary

Exposure and Risk Assessment ................................ ................................ ............ 23 5.1 Metabolite/Degradate Residue Profile ................................ ................................ ........... 23 5.1.1 Summary

of Plant and Animal Metabolism Studies ................................ .................. 23 5.1.3 Residues of Concern Summary and Rationale ................................ ........................... 23 5.2 Food Residue Profile ................................ ................................ ................................ ...... 24 5.3 Water Residue Profile ................................ ................................ ................................ .... 27 5.4 Di etary

Risk Assessment ................................ ................................ ................................ 27 5.4.1 Description of Residue Data Used in Dietary Assessment ................................ ......... 27 5.4.2 Percent Crop Treated Used in Dietary Assessment ................................ .................... 28 5.4.3 Acute Dietary

Risk Assessment ................................ ................................ ................. 28 5.4.4 Chronic Dietary

Risk Assessment ................................ ................................ .............. 28 5.4.5 Cancer Dietary

Risk Assessment ................................ ................................ ................ 28 5.4.6 Summary

Table ................................ ................................ ................................ ........... 28 6.0 Residential (Non - Occupational) Exposure/Risk Characterization ................................ .... 29 6.5 Spray

Drift ................................ ................................ ................................ ...................... 29Quizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **3** of **34** 7.0 Aggregate Exposure/Risk Characterization ................................ ................................ ....... 29 8.0 Cumulative Exposure/Risk Characterization ................................ ................................ ..... 29 9.0 Occupational Exposure/Risk Characterization ................................ ................................ .. 30 10.0 References ................................ ................................ ................................ .......................... 31 Appendix A. Toxicology Profile and Executive Summaries ................................ ....................... 31 Appendix A. Toxicology Profile and Executive Summaries ................................ ....................... 32 A.1 Toxicology

Data Requirements ................................ ................................ ...................... 32 A.2 Toxicity

Profiles ................................ ................................ ................................ ............. 33Quizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **4** of **34 1.0**  **Executive Summary BACKGROUND**  : Quizalofop ethyl is a selective herbicide used for the control of annual and perennial grasses in crop - and non - croplands. Presently , quizalofop ethyl is registered for uses on canola, crambe, cotton, dry beans, dry

and succulent peas, lentils, mint, snap beans, soy bean, sugar beets, barley , flaxseed , sunflower and wheat. This document addresses petitions from DuPont and Interregional Research Project No. 4 ( IR - 4 ) for the registration of Assure ® II Her bicide (EPA Reg. No. 352 - 541) Herbicide, (0.88 lb ai /gal emulsifiable concentrate) for use on sorghum, rapeseed crop group 20 A (except flaxseed), and corn. The Assure ®Her bicide product formulation contains 10.3% quizalofop - P - ethyl as the sole active ingredient, which is the R - enantiomer, while the previously registered quizalofop ethyl is a 50 - 50 racemic mixture of R and S - enantiomers. HED has determined that the toxicol ogical profiles of the racemic mixture and that of R - enantiomer are sufficientl y similar, and the available data on the former are adequate to support registration of products containing the enriched R - enantiomer. Tolerances are established under 40 CFR § 180.441(a)(1) for the combined residues of quizalofop ethyl and quizalofop, all expressed as quizalofop ethyl in/on agricultural commodities except as listed in Section (a)(3), under §180.441(a)(2) for the combined residues of quizalofop ethyl, quizalofop, and quizalofop methyl, all expressed as quizalofop ethyl, for egg, fat, meat, meat by products, milk and milk fat, and under §180.441(a)(3) for the combined residues of quizalofop - P - ethyl ester, quizalofop - P acid , and the S - enantiomers of the ester and the acid, expressed as quizalofop - P - ethyl ester, for sugar beet, canola, cotton, lentil, peppermint and spearmint. Under PP # 0E7802, IR - 4 is proposing to amend quizalofop ethyl tolerance expressions under 40 CFR part 180.441. E.I . du Pont de Nemours & Company (Dupont) is proposing to amend the label of Assure ® II herbicide to include uses on herbicide - tolerant field corn containing the aryloxyalkanoate dioxygenase - 1 gene (DAS - 40278 - 9 ) and in propagation of corn seed containing DAS - 40278 - 9. The proposed uses are postemergence applications to field and seed corn containing the quizalofop - resistant trait at a maximum seasonal rate of 0.083 lb ai/A. The proposed preharvest interval (PHI) is 30 day s for forage; a PHI for corn grain or stover is not specifie d. The IR - 4 is proposing to amend the label of Assure ® II herbicide to include uses on sorghum grain containing the DuPontTM I NZENTM AII Herbicide Tolerance Trait and on rapeseed subgroup 20A, except flaxseed . The proposed uses are postemergence applicat ions to sorghum at a maximum seasonal rate of 0.138 lb ai/A, and postemergence applications to rapeseed subgroup 20A at a maximum seasonal rate of 0.124 lb ai/A. The proposed preharvest intervals (PHI s) are 30 day s for sorghum forage, 45 day s for sorghum grain and stover, and 60 day s for rapeseed subgroup 20A. **HAZARD ASSESSMENT** : Quizalofop ethyl has low acute toxicities via the oral, dermal, and inhalation routes. It is not an eye or dermal irritant nor a skin sensitizer. Following oral administration, quizalofop ethyl is rapidl y absorbed and excreted via urine and feces. Liver is the target organ as evidenced b y increased liver weight and histopathological changes in the liver.Quizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **5** of **34** There were no effects observed in oral toxicity studies that could be attributable to a single - dose exposure. Hence, a dose and endpoint have not been selected for assessment of acute exposure. Similarly , there was no observed toxicity in a dermal subchronic study at the highest dose tested (above the limit dose) so no dermal risk assessment is needed. Inhalation toxicity studies for occupational exposure assessment are waived based on the low exposure expected by the current and proposed use patterns. A chronic reference dose (cRfD) was established based on a combined chron ic toxicity /carcinogenicity

study in rats. Mutagenicit y studies conducted on quizalofop ethyl did not demonstrate evidence of mutagenic potential. The Cancer Peer Review Committee determined that quizalofop ethyl should be classified as Category D (not c lassifiable as to human carcinogenicity) . As such, a cancer risk assessment was not conducted. Developmental studies in rats and rabbits and a two - generation reproduction study in rats showed no evidence (qualitative or quantitative) for increased suscep tibility following in utero and/or pre/post - natal exposure to quizalofop eth yl . The toxicity database is adequate in terms of endpoint and dose response information to characterize the potential for prenatal or postnatal risk to infants and children. Base d on the above data, the 10x Food Quality Protection Act Safet y Factor (FQPA SF) to account for enhanced sensitivity of infants and children has been reduced to 1x. HED has confidence that the risk assessment conducted with no additional safety factor wil l provide a reasonable certainty of no harm to the safet y of infants and children. The available toxicology

data are sufficient to assess the critical exposure scenarios and for endpoint and dose - response evaluation. Due to the adequacy of data, the comb ined uncertaint y factor (UF) of 100x was used for the risk assessment (10x for intraspecies variation and 10x for interspecies extrapolation). Since there is no additional UF, margin of exposure (MOE) greater than 100 are considered to represent risks bel ow HED’s level of concern (LOC). **OCCUPATIONAL RISK** : A separate memo was issued to address the occupational risk of quizalofop ethyl to pesticide handlers and post - application workers. As noted above, no doses or endpoints for dermal or inhalation expos ure were selected or needed . Therefore, a quantitative estimate of occupational risk was not determined. The acute toxicity categories are IV for both routes of exposure, and a 12 - hour re - entry interval (REI) was established under the worker protection s tandard (WPS). **RESIDENTIAL RISK** : Quizalofop ethyl has no registered homeowner or ornamental uses and none are being proposed. **DIETARY RISK :**  An acute dietary risk assessment was not performed, as an acute endpoint was not identified in the hazard assess ment. Similarly no cancer risk assessment was needed , as quizalofop ethyl was not classifiable with regard to carcinogenicity . A chronic dietary

exposure assessment was conducted using the Dietary Exposure Evaluation Model - Food Consumption Intake Datab ase (DEEM - FCID  , ver.2.03). The inputs used were (i) tolerance level residues for all commodities, (ii) 100 percent crop treated (%CT), (iii) DEEMTM ver. 7.78) default processing factors, and (iv) drinking water numbers generated b y Pesticide Root Zone Mo del - Exposure Anal ys is and Modeling S ys tem (PRZM - EXAMS) using the maximum application rate per season for quizalofop ethyl on dry peas in Michigan. UnderQuizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **6** of **34** this scenario, children (1 - 2 years) were found to have the maximum chronic dietary risk at 29% of the chronic population adjusted dose (cPAD). This is well below HED’s level of concern of 100% of cPAD. **AGGREGATE RISK :**  Aggregate risk estimates take into account dietary and non - dietary residential sources of exposure. As there are no registered or proposed uses of quizalofop that would result in non - dietary residential exposure, the aggregate risk estimates are equivalent to the chronic dietary

risk estimates discussed above and are below HED’s le vel of concern. In summary , this risk assessm ent indicates that adding field corn, sorghum and the rapeseed subgroup 20A , to the existing uses of quizalofop - P - ethyl , w ill not pose a health risk to humans. **2.0 HED**  **Recommendations** HED can recommend the registration and tolerance for the use of quizalofop - P - ethyl on field corn, sorghum and the rapeseed subgroup 20A . Additional data needs are outlined in section 2.1 below. The specific tolerance recommendations are discussed in 2.2, and label modifications are discussed in section 2.3 **2.1 Data Deficiencies/Conditions of Registration**  HED has examined the residue chemistry database for quizalofop ethyl. Pending submission of the items requested in the residue chemistry chapter (D 39 5630 , I. Negron, 15 Nov2011 ), there are no residue chemistry

issues that would preclude granting a registration for the proposed uses on corn, sorghum and rapeseed, subgroup 20A (except flaxseed) and the establishment of the correspond ing tolerances. Inaddition to the items described below, HED expects to receive the report on the storage stability of the field corn samples and it corresponding processed commodities. **2.2 Tolerance Considerations** 

• The proposed tolerance level for corn forage and grain is 0.01 ppm. However, by using the OECD calculator the appropriate tolerance level for co rn forage and grain is 0.02 ppm. A revised tolerance should be proposed.

• The petitioner proposed separate tolerances in/on the individual commodities of the rapeseed subgroup 20A, except flaxseed [borage seed, crambe seed, gold of pleasure seed, cuphea seed, echium seed, hare’s ear mustard seed, lesquerella seed, lunaria seed, meadowfoam seed, milkweed seed, mustard seed, oil radish seed, popp y seed, rapeseed, sesame seed, and sweet rocket seed] at 1.0 ppm . The recommended tolerance differs since the residues levels were scaled to reflect theQuizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **7** of **34** proposed use pattern and a toleranc e was estimated by using the OECD calculator. Therefore, for the proposed use pattern a subgroup tolerance in/on rapeseed subgroup 20A, except flaxseed should be proposed at 1.5 ppm. Also, a tolerance of 2.0 ppm is recomm ended for rapeseed, subgroup 20A, meal , except flaxseed .

• The proposed tolerance level for sorghum stover is 0.35 ppm. However, by using the OECD calculator the appropriate tolerance level for sorghum stover is 0.3 ppm. A revised tolerance should be proposed.

• The proposed toler ances should be revised to reflect the correct commodity defi nitions as specified in the residue chemistry chapter . **2.2.1 Enforcement Analytical Method**  860.1340 Residue Anal yt ical Methods

• After reviewing Morse Method Meth - 147 against the Tolerance Method Validation (TMV) Review Checklist, provided the solvent exchange modification made b y the ILV laboratory is incorporated into the final method, the analytical method data satisfy

the requirements. A TMV b y ACB will not be necessary. **2.2.2 International Harmonization**  No Codex MRL s have been established for residues of quizalofop ethyl. Canadian MRL s have been established for residues of quizalofop ethyl and quizalofop in/on oriental mustard seeds (condiment ty

pe and oil seed t ype), and rap eseeds (canola), the onl y crops included in the subject petition, at 0.05 ppm. The US tolerance can not be harmonized with the Canadian MRL for the commodities of the Rapeseed, subgroup 20A. No Mexican MRL s have been established for an y of the requested crops. **2.2.3 Recommended Tolerances**  Field Corn , Sorghum and Rapeseed Subgroup 20A (except flaxseed ) The OECD MRLcalculator (March 2011 version) was utilized for determining appropriate tolerance levels for RACs. An adequate number of field trials at ~1x the proposed use rate are available to recommend tolerances for corn (forage, grain, and stover) and sorghum (forage, grain, stover and aspirated grain fractions). Individual tolerances for each member of the Rape seed Subgroup 20A are no longer required. Canola seed is the representative commodity of crop subgroup 20A for which a tolerance is established in the 40 CFR §180.441(a)(3). Pending revi sion of 40 CFR §180.441(a)(3), separate tolerance s for canola seed and canola meal shouldQuizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **8** of **34** be removed. N ew tolerance s w ere determined for the rapeseed subgroup 20A and the meal process ed commodity by adjusting for differences between the proposed and study application rate s . Th ese new tolerance s should be included in the r evised 40 CFR § 180.441 (a)( 1 ) . HED recommends the amendment of the tolerances in 40 CFR part 180.441 by combining the tables for sections (a)(1) and (a)(3) into one table under section (a)(1), and by removing section (a)(3). Also, the tolerance expression s under section (a)(1), (a)(2) and (c) can be modified as follows: Section (a)(1): “ Tolerances are established for residues of the herbicide quizalofop ethyl, including its metabolites and degradates, in or on the commodities in the table bel ow. Compliance with the tolerance levels specified below is to be determined by measuring only those quizalofop ethyl residues convertible to 2 - methoxy- 6 - chloroquinoxaline, expressed as the stoichiometric equivalent of quizalofop ethyl, in or on the commod ity .” S ection (a)(2): “ Tolerances are established for residues of the herbicide quizalofop ethyl, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only those quizalofop ethyl residues convertible to quizalofop (2 - [4 - (6 - chloroquinoxalin - 2 - yl oxy )phenoxy]propanoic acid), expressed as quizalofop, in or on the commodity . ” S ection (c): “ Tolerances with regional registrations. Tole rances with regional registration are established for residues of the herbicide quizalofop ethyl, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determine d by measuring only

those quizalofop ethyl residues convertible to 2 - methoxy - 6 - chlor oquinoxaline, expressed as the stoichiometric equivalent of quizalofop ethyl, in or on the commodity . ” The petitioner should submit a revised section F reflecting the reco mmended tolerances and commodity

definitions presented in Table 2.2.3 . These new tolerances should be includ ed in the revised 40 CFR § 180.441 (a)(1 ).Quizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **9** of **34 Table 2.2.3. Tolerance Summary for**  **Quizalofop -**  **P -**  **ethyl Comm**  **odity Established/Proposed** 

**Tolerance (ppm) Recommended** 

**Tolerance (ppm) Comments** 

**Correct Commodity Definition** Corn, forage 0.01 0.02 Corn, field, forage Corn, grain 0.01 0.02 Corn, field, grain Corn, stover 0.03 0.03 Corn, field, stover Canola, seed 1 1.0 Remove Gold of Pleasure, seed 1.0 Not needed Borage, seed 1.0 Not needed Crambe, seed 1.0 Not needed Cuphea, seed 1.0 Not needed Echiuim, seed 1.0 Not needed Hare’s ear mustard, seed 1.0 Not needed Lesquerella, seed 1.0 Not needed Lunaria, seed 1.0 Not needed Meadow foam, seed 1.0 Not needed Milkweed, seed 1.0 Not needed Mustard, seed 1.0 Not needed Oil Radish, seed 1.0 Not needed Poppy, seed 1.0 Not needed Rapeseed 1.0 Not needed Sesame, seed 1.0 Not needed Sweet Rocket, seed 1.0 Not needed Canola, meal 1, 2 1.5 R emove Rapeseed subgroup 20A, meal , except flaxseed 2 -- 2.0 Gold of Pleasure, meal 1.5 Not needed Crambe, meal 1.5 Not needed Rapeseed , subgroup 20A, except flaxseed 3 -- 1.5 Sorghum, grain 0.2 0.20 Sorghum, grain, grain Sorghum, forage 0.2 0.20 Sorghum, grain, forage Sorghum, stover 0.35 0.30 Sorghum, grain, stover Sorghum, aspirated grain 1.0 1.0 Sorghum, grain, aspirated grain fractions 1 Established under 40 CFR §180.441(a)(3). 2 The available canola processing data was translated to the rapeseed subgroup 20A to calculate and propose a tolerance for rapeseed , subgroup 20A, meal. 3 Canola seed is a member of crop subgroup 20A. Pending revision of 40 CFR §180.441(a)(3), the established separate toleranc e s for canola seed and canola meal may be removed.Quizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **10** of **34 2.3**  **Label Recommendations** 860.1200 Directions for Use The following changes are recommended in the draft label of Assure ® II herbicide:

• The application rate on the supplemental label for field corn and sorghum is presented in terms of “oz product/A.” The label should be amended to read “fl. oz product/A”.

• The proposed grazing restrictions are impractical for field corn and sorghum and should be removed from the product label.

• The sup plemental label for field corn should specify the PHI for corn grain and stover, and the concentration of either crop oil concentrate or nonionic surfactant. These parameters should reflect those used in the crop field trials. **3.0 In**  **troduction** Dupont has submitted a label amendment for Assure ® II herbicide (EPA Reg. No. 352 - 541) to include uses on corn seed containing DAS - 40278 - 9 and field corn containing DAS - 40278 - 9. The Interregional Research Project No. 4 (IR - 4) is proposing to amend the label of Assure ® II herbicide to include uses on sorghum grain containing the DuPontTM INZENTM AII Herbicide Tolerance Trait and on rapeseed subgroup 20A, except flaxseed [borage, crambe, gold of pleasure (Camelina), cuphea, echium, hare’s ear mustard, lesquerella, lunaria, meadowfoam, milkweed, mustard seed, oil radish, poppy seed, rapeseed (canola), sesame, and sweet rocket]. Assure ® herbicide contains quizalofop - P - ethyl as the sole ai, which is an R - enantiomer of quizalofop ethyl. Chemically , quizalofop ethyl is a racemic mixture containing R - and S enantiomers and the former is the pesticide active component. Quizalofop ethyl is a selective preplant, pre - and postemergence herbicide registered for the control of annual and perennial grasses on noncrop and on cro p land areas. The chemical structure of quizalofop - P - ethyl is presented in Table 3. 1 and its phy sicochemical properties are presented in Table 3.2 .Quizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **11** of **34 3.1**  **Chemical Identity Table 3.1 Test Compound Nom**  **enclature** Chemical structure

N N Cl O O C H 3 O O C H 3 Common name Quizalofop - P - ethyl Company experimental name Not provided IUPAC name ethyl (R) - 2 - [4 - ((6 - chloroquinoxalin - 2 - yl)oxy)phenoxy]propanoate CAS name (2R) - 2 - [4 - [(6 - chloro - 2 - quinoxalinyl)oxy]phenoxy]propanoic acid, ethyl ester CAS registry number 100646 - 51 - 3 End - use product (EP) 0.88 lb ai /gal EC formulation (EPA Reg. No. 352 - 541) **3.2 Physical/Chemical Characteristics**  **TABLE 3.2**  **Physicochem ical Properties of the Technical Grade Test Compound**  **Quizalofop -**  **P -**  **Ethyl.** Parameter Value Reference Melting point 76.0 - 77.0  C (pure form) CB Nos. 5852 & 5853, 3/29/90, W. Hazel pH 6.6 (1% aqueous slurry) Density 1.35 g/cm3 at 20  C (pure form) Water solubility 0.4 ppm (20  C) Solvent solubility acetone benzene carbon disulfide chloroform cyclohexanone dichloromethane dimethyl sulfoxide ethanol n - hexane methanol tetrahydrofuran toluene xylene g/L at 20 oC 650 680 660 1350 440 1970 200 22 5 22 1160 430 360 Vapor pressure 8.3 x 10 - 10 mm Hg (20  C) Dissociation constant, pKa Not applicable Octanol/water partition coefficient log P OW = 4.66 UV/visible absorption spectrum Not availableQuizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **12** of **34 3.3**  **Pesticide Use Pattern** The petitioner has submitted a Section B along with draft specimen supplemental labeling for the 0.88 lb ai / gal EC formulation of quizalofop - P - ethyl (Assure ® II Herbicide; EPA Reg. No. 352 - 541). IR - 4 is proposing a label amendment for this product to add new uses on sorghum grain containing the DuPontTM INZENTM AII Herbicide Tolerance Trait and rapeseed subgroup 20A, except flaxseed . The currently registered EPA label, dated 4/14/2010, was obtained from PPL S. The currently

registered uses include canola, crambe, cotton, crops grown for seed, eucal yptus, dry beans (including Chickpea), dry and succulent peas, flaxseed , hy brid poplar plantings, lentils, mint (spearmint and peppermint), pineapple, ryegrass grown for seed, snap beans, soy beans, sugar beets, sunflowers, and noncrop areas. DuPont C rop P rotection is also requesting the addition of genetically modified f

ield corn (containing DAS - 40278 - 9) to the label of Assure ® II Herbicide; EPA Reg. No. 352 - 541. T he use patterns for the proposed new uses are presented in Table 3 .3 .Quizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **13** of **34 Table 3.3 Summary of Directions for Use of**  **Quizalofop -**  **P -**  **ethyl Formulation. 1**  Applic. Timing, Type, and Equip. Form.

[EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per Season Max.

Seasonal Applic. Rate (lb ai/A) RTI

(days) PHI

(days) Use Directions and

Limitations **Field Corn containing DAS -**  **40278 -**  **9**

Postemergence, Broadcast foliar application by ground 0.88 lb ai

/gal EC [352 - 541] 0.034 -

0.083 2 0.083 NS 2 30 (forage) 3 For use in propagation of

corn seed containing DAS 40278 - 9 and quizalofop tolerant field corn containing DAS - 40278 - 9. Applications may be made to emerged corn that is at the V2 through V6 stage of development. Applications must include either a crop oil concentrate or a non - ionic surfactant. Aerial application is prohibited. The grazing of livestock on treated corn or harvesting forage within 30 days of application is prohibited. **Sorghum, grain containing the DuPontTM INZENTM AII Herbicide Tolerance Trait** Postemergence, Broadcast application by ground or air 0.88 lb ai

/gal EC [352 - 541] 0.034 -

0.083 2 0.138 NS 2 30 (forage) 4 45 (grain and stover) Applications must include

either a crop oil concentrate or a non - ionic surfactant. **Rapeseed Subgroup 20A, Except Flaxseed**  **, Seed [includes Borage, Cram** **be, Cuphea, Echium, Gold of Pleasure ( Camelina**  **), Hare’s ear mustard, Lesquerella, Lunaria, Meadowfoam**  **, Milkweed, Mustard seed, Oil Radish, Poppy seed, Rapeseed (Canola), Sesam**  **e, and Sweet Rocket]**  Postemergence, Broadcast application by ground or air 0.88 lb ai

/gal EC [352 - 541] NS NS 0.124 7 60 Applications must include either a crop oil concentrate or a non - ionic surfactant. 1 G eneral use directions, restrictions, and precautions were obtained from the currently registered label for Assure ® II Herbicide (EPA Reg. No. 352 - 541), dated April 14, 2010 2 NS = Not specified 3 The supplemental labeling indicates that a 30 - day PHI is proposed for forage; a PHI for corn grain or stover is not specified. The currently registered label indicates that the grazing of livestock in treated areas or feeding of forage, hay, or straw fro m the treated crops to livestock is prohibited. 4 The Section 3 label describes the crop rotation restrictions as required.Quizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **14** of **34 3.4**  **Anticipated Exposure Pathways** The Registration Division has requested an assessment of human health risk to support the proposed new use of quizalofop - P - eth yl on s orghum, rapeseed sub group 20 A, and field corn. Humans may

be exposed to quizalofop - P - ethyl in food and drinking water, since quizalofop - P ethyl may be applied directly

to growing crops and appli cation may result in quizalofop - P - ethyl reaching surface and ground water sources of drinking water. There are no residential uses of quizalofop - P - ethyl , so there is not likely to be exposure in residential or non - occupational settings. In an occupationa l setting, applicators may be exposed while handling the pesticide prior to application, as well as during application. There is a potential for post - application exposure for workers re - entering treated fields. Risk assessments have been previousl y prepared for the existing uses of quizalofop - P - ethyl . This risk assessment considers all of the aforementioned exposure pathways based on the proposed new uses of quizalofop - P - ethyl , but also considers the existing uses as well, particularl y for the dietary exposure assessment. **3.5 Consideration of Environmental Justice**  Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Ac tions to Address Environmental Justice in Minority Populations and L ow - Income Populations," ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf . As a part of every

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

expos ure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non - dietary exposures based on home use of pesticide products and associated risks for adult applicators and for t oddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that con sider exposure to by standers and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.Quizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **15** of **34 4.0**  **Hazard Characterization and Dose -**  **Response Assessment** This section was adapted from Quizalofop -P- ethyl : Human Health Ri sk Assessment for New Uses on Barley, Flaxseed , Sunflower and W

heat. , p repared b y S. Oonnithan, dated August 10, 2006 for D310869 . T he series 870.7800 immunotoxicity screen study was the only new t oxicity study submitted and reviewed since 2006 . **4.1 Toxicology Studies Available for Analysis**  Studies Considered:

• Developmental studies in rats and rabbits. • Subchronic - 28 - day

dermal study

in rats, 90 - day

oral toxicity in rats and dogs. • Chronic toxicity

studies in dogs and rats, carcinogenicity studies in rats and mice. Repro/Developmental - 2 - generation reproduction study in rats and developmental studies in rats and rabbits. • Other - Mutagenicity

screens , Immunotoxicity screening **4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)**  Metabolism study

in rats showed that following oral administration, quizalofop ethyl is readil y absorbed from the gastrointestinal tract and is excreted rapidly via urine and feces. The major met abolite of quizalofop ethyl is the corresponding acid, which is metabolized further. According to W. Phang, the metabolism study has several deficiencies and the study is classified as SUPPLEMENTARY (TXR # 006487, 12/3/87) . **4.2.1 Dermal Absorption**  T he results of a dermal absorption study in rats (MRID 00146679) indicated that with a10 - hour exposure at doses of 0.19, 1.9, or 19 mg/rat, the percent of absorption was 8.38, 3.27, and 2.9 % of the applied dose, respectively . A dermal absorption factor is not applicable since dermal risk assessments are not required. **4.3 Toxicological Effects**  Liver is the target organ as evidenced b y increased liver weight and histopathological changes in the liver. Developmental studies in rats and rabbits and a two - generation reproduction study in rats showed no evidence (qualitative or quantitative) for increased susceptibility following in utero and/or pre/post - natal exposure to quizalofop ethyl. Quizalofop ethyl does not appear to be a neurotoxic chemi cal since no treatment - related effects on brain weight or histopathology of the nervous s ys tem were observed in studies that measure these endpoints. The Cancer Peer Review Committee determined that quizalofop ethyl should be classified as Category D (not classifiableQuizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **16** of **34** as to human carcinogenicity). Mutagenicity studies conducted on quizalofop ethyl did not demonstrate evidence of mutagenic potential. **4.4 Safety factor for Infants and Children (FQPA Safety Factor)**  The database is adequate in terms of endpoint and dose - response information to characterize the potential for pre - or post - natal exposure to infants and children. There is no evidence of increased susceptibility

following in utero exposure in rat or rabb it developmental toxicity studies and pre - /post - natal exposure in a two - generation reproduction study in rats. There are no concerns and no resid

ual uncertainties for pre - and postnatal toxicity . Quizalofop ethyl does not appear to be a neurotoxic chemic al based on a weight - of - evidence consideration. Based on the available data, the 10x FQPA SF to account for enhanced sensitivity of infants and children (as required b y FQPA) was reduced to 1x. The HED has conf idence that the risk assessment conducted wi th no additional safet y factor will provide a reasonable certainty of no harm to the safet y of infants and children. **4.4.1 Completeness of the Toxicology Database**  Adequacy

of the Toxicity

Datab ase: The toxicology database for quizalofop ethyl is adequate for FQPA consideration. The following studies are available:

- Developmental toxicity

studies in rats and rabbits (acceptable).

- Two generation reproduction study in rats (acceptable). **4.4.2 Evidence of Neurotoxicity**  Although no neurotoxicity studies were available, the HED determined that quizalofop ethyl does not appear to be a neurotoxic chemical. There were no treatment - related effects on brain weight or histopathology

of the nervous s ys tem seen in studies that measured these endpoints. There was no evidence of effects on functional development observed in a postnatal segment of the reproduction study

in rats. **4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal**  **Developmental Toxicity:** In a developmental toxicity study , Quizalofop ethyl technical (99.1%, ai) was administered to pregnant JCL :SD rats (20 - 24/dose) b y gavage in 2 m L/kg of 0.5% carboxy

methy lcellulose at dose levels of 0, 30, 100, or 300 mg/kg bw/day from gestation day s 6 through 15. The study was conducted in two segments; one segment in which rats were sacrificed on GD 21, and the other in which rats were allowed to deliver. The nursing subgroups were maintained for three additional weeks.Quizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **17** of **34** For maternal toxicity , there were no deaths, abor tions, or clinical signs observed in treated and control rats. Decreased body weight gains and food consumption were observed in 100 - and 300 - mg/kg/day

treated rats. Increased liver weights were observed in 300 mg/kg/day treated rats. Decreased average number of corpora lutea per litter was observed at 100 mg/kg/day and increased rate of implantation was observed at 100 and 300 mg/kg/day . Under the conditions of the study, the maternal LOAEL is 100 mg/kg bw/day, based on decreased body weight gains and food consumption. The maternal NOAEL is 30 mg/kg bw/day . For developmental toxicity, statistically significant increase of skeletal variations (mostly fourteenth rib variety ) was observed in fetuses in the 300 mg/kg/day group. The biological significa nce of the increase in the number of ribs in these fetuses was questionable since the skeletal examination of the nursing groups revealed no abnormality in the frequency

of appearance of 14th - rib variety among the 8 - week old. Apparently, these 14th - rib s might have fused with the vertebral arches and disappeared in the course of postnatal growth. No significant abnormality was seen in the visceral examination. The developmental toxicity study in the rat is classified acceptable/guideline and satisfi es the guideline requirement (OPPTS 870.3700; OECD 414). In another developmental toxicity study , quizalofop ethy

l technical (99.1%, a.i.) was administered to pregnant NSW rabbits (16/dose) by gavage at dose levels of 0, 7, 20, or 60 mg/kg bw/day from g estation day s 7 through 19. On GD 29, fetuses were delivered with cesarean section from the surviving females prior to sacrifice. Decreased body weight gains and food consumption were observed in the 60 mg/kg group during the dosing period (gestation day s 7 - 20). During the post treatment period (GDs 20 - 29), the mean body weight gain was significantly elevated compared to the control. No other significant treatment - related effects were reported. In the range - finding study , decreased bod y weight gains an d food consumption was observed in the 75 mg/kg group. In creased incidence of abortion was observed in 60 and 75 mg/kg groups compared to the control. Under conditions of the study , the maternal L OAEL is 60 mg/kg bw/day , based on decreased bod y weight ga ins and food consumption. The maternal NOAEL is 20 mg/kg bw/day . No evidence of developmental toxicity was observed in the range - finding and the final developmental toxicity

studies. The developmental NOAEL is 60 mg/kg bw/day (HDT) **.** The developmental toxicity

study in the rabbit is classified acceptable/guideline and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414). **Reproductive Toxicity:** Ina two - generation reproduction study , INY - 6202 (quizalofop 99.1% a.i.) was administered to Crl:CD Sprague - Dawley rats (23/sex/dose) in the diet at dose levels of 0, 25, 100, or 400 ppm (equivalent to 0, 1.25, 5.0, or 20 mg/kg bw/day , respectivel y). After 70 day s on test, the F 0 generation was bred to produce F 1a and F 1b litters. At weaning, randomly selected F 1a rats were fed diets containing INY - 6202 for 80 day s and then mated to produce F 2a and F 2b litters. After litter production, ten rats per sex per dose in the F 0 and F 1a generations had r eproductive tissues examined. Ten F 2b weanlings per sex per dose were subjected to gross pathological examination. Those from the control and high - dose (400 ppm) groups were subjected to complete microscopic examination. For parental toxicity , signific ant decreases of body weight and body

weight gains were observed in both F 0 and F 1a males and F 1a females at 400 ppm compared to the control. NoQuizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **18** of **34** treatment - related deaths or clinical observations were observed in the parental rats. The LOAEL of parental s ys temic toxicity is 400 ppm (equivalent to 20 mg/kg bw/day), based on decreased bod y weights and body weight gains. The NOAEL is 100 ppm (equivalent to 5.0 mg/kg bw/day

). For offspring toxicity, pup body weights at the high - dose (40 0 ppm) were significantly lower than controls in F 1a and F 1b pups from birth throughout lactation, and F 2a and F 2b pup weights were significantly

reduced starting at day

7 and day 4, respectively . Significantly increased absolute and relative liver wei ghts were observed in the F 2b weanlings of both sexes at 100 and 400 ppm. Increased relative kidney and heart weights were also observed at 400 ppm compared to the control. Mean relative spleen weight was decreased at 400 ppm. Histopathological exami nation of hepatocy

tes from F 2b weanlings revealed distinct eosinophilic granular cy toplasm and decreases in cy toplasmic basophilia and glycogen accumulation in the 100 and 400 ppm groups. Previously HED had established a LOAEL at 100 ppm based on increa sed incidence of eosinophilic changes in the liver of F2 weanlings. However, the HED later questioned the biological significance of these findings and stated that this endpoint in adults (eosinophilic changes) would not be considered appropriate for u se in the regulation of quizalofop ethy

l (TXR# 012373, J. Rowland, 10/24/1997). The study author stated that hepatocy tes had distinct eosinophilic changes and were considered indicative of proliferation of the smooth endoplasmic reticulum. Therefore , the LOAEL of offspring toxicity is revised to 400 ppm (20 mg/kg bw/day) based on decreased pup weights. The NOAEL is 100 ppm (5 mg/kg bw/day ). For reproductive toxicity , a significantly lower percentage of pups born alive were observed in the F 1a and F 2 a litters of the 400 ppm group. Fertility rates were comparable in all groups of both generations except the low - dose F 0 males and females, which had significantl y reduced fertility

rates when compared to the control at the first mating. All pregnant fem ales successfull y delivered live pups and maintained their litters until weaning. Clinical observation of the offspring showed an increased incidence of hematomas in the F 1b pups at 25, 100, and 400 ppm and F 2a pups at 100 and 400 ppm. However, the in creased incidence of hematomas was not considered a reproductive effect because it was not dose - related, and was not consistently

observed in all generations and in other studies. The reproductive L OAEL is 400 ppm (20 mg/kg bw/day), based on decreased percentage of pups born alive. The reproductive NOAEL is 100 ppm (5 mg/kg bw/day). This study is acceptable/guideline and satisfies the guideline requirement for a 2 - generation reproductive study (OPPTS 870.3800; OECD 416). **Additional Information fro m Literature Sources:**  No additional relevant toxicity studies from published literature were identified. **Pre -**  **and/or Postnatal Toxicity and Determination of Susceptibility:** There is no evidence of increased qualitative or quantitative susceptibility fo llowing in utero and/or pre/post - natal exposure in the developmental toxicities in rats and rabbits and two - generation reproduction study in rats. **Degree of Concern Analysis and Residual Uncertainties for Pre and/or Post -**  **natal Susceptibility:**  There are no concerns and no residual uncertainties for pre - and postnatal toxicity .Quizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **19** of **34 Recommendation for a Developmental Neurotoxicity Study:**  The HED has determined that a developmental neurotoxicity study is not required based on the lack of evidence of neurotox icity

in the submitted studies. **4.4.4 Residual Uncertainty in the Exposure Database**  Based on the available data, the 10x FQPA SF to account for enhanced sensitivity of infants and children (as required b y FQPA) was reduced to 1x. The HED has confidence that the risk assessment conducted with no additional safety factor will provide a reasonable certainty of no harm to the safet y of infants and children. **4.5 Toxicity Endpoint and Point of Departure Selections**  **4.5.1 Dose**  **- Response Assessment**  **Acute Reference Dose (aRfD) :** There were no effects observed in oral toxicity studies that could be attributable to a single dose (exposure). In addition, there is no developmental or reproductive toxicity

of concern for quizalofop ethyl. Therefore, no appropriate endpoint or dose that is approp riate for assessing acute risk has been selected for quizalofop ethyl. **Chronic Reference Dose (cRfD):** In a combined chronic toxicity /carcinogenicity

study in rats; (MRID No.: 00146682), NC - 302 (quizalofop ethyl, 99.1%, a.i.) was administered to Sprague Dawley CD rats (50/sex/dose) at dose levels of 0, 25, 100, or 400 ppm (0, 0.9, 3.7, or 15.5 mg/kg/day

for males and 0, 1.1, 4.6, or 18.6 mg/kg/day for females, respectively) in their diet for 104 weeks. The re were no significant treatment - related clinical signs. Body weights and food consumption were comparable among the dosed and control groups. The hematological values showed a trend of mild anemia or red blood cell destruction in the 100 ppm males early in the study and in the 400 ppm females late in the study . Clinical chemistry examination showed a significantl y elevated alkaline phosphatase level in the 400 ppm males at all intervals and in the 400 ppm females at Week 101. Significant increases in liver weights were observed in the 400 ppm males and females at all intervals. Gross pathology showed an increased numbers of liver masses in the 100 and 400 ppm males and females. Histopathology showed an increased incidence of generalized hepatocy tic enlargement in the 400 ppm males and cy toplasmic eosinophilia of the centrilobular hepatocy tes in the 400 ppm group of both sexes. In creased incidence of slight/minimal centrilobular enlargement of the liver was observed in the 100 ppm and 400 ppm males and females. The LOAEL is 100 ppm (3.7 mg/kg/day for males and 4.6 mg/kg/day for females) based on increased incidence of centrilobular enlargement of the liver in both sexes and mild anemia in the males. The NOAEL is 25 ppm (0.9 mg/kg/day f or males a nd 1.1 mg/kg/day

for females). The combined chronic toxicity /carcinogenicity study

in the rat is classified acceptable/guideline and satisfies the guideline requirement for a chronic toxicity /carcinogenicity s tudy

(OPPTS 870.4300; OECD 453).Quizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **20** of **34** Dose and Endpoint for Establishing the cRfD: 0.9 mg/kg/day (NOAEL) based on increased incidence of centrilobular enlargement of the liver in both sexes and mild anemia in the males at 3.7 mg/kg/day

(L OAEL). Uncertainty Factor(s): 100 (10x for interspecies extrapol ation and 10x for intra - species variations). Comments about Study

/Endpoint/Uncertainty Factor: The selected dose/endpoints are appropriate for the route and duration of exposure. cRfD = 0.9 mg/kg (NOAEL) = 0.009 mg/kg/day

100 (UF ) **Incidental Oral Exposure:** Quizalofop ethyl is not registered for residential uses. Based on this use pattern (low exposure), there is no incidental oral exposure; therefore, no short - term (1 - 30 day s) and intermediated - term (1 - 6 months) end points were selected and no risk assessments are required. **Dermal Exposure: (All Durations):** There was no dermal or sy stemic toxicity identified in a 21 - day dermal toxicity study in rabbits. The NOAEL was 2000 mg/kg/day at the maximum dose tested (MDT). No appropriate endpoint was identified . Therefore, a risk assessment via this route is not required. Furthermore, no endpoints from the available data suggest that a dermal risk assessment should be done by extrapolating from an oral NOAEL, in order to be protective of effects not typ icall y measured in dermal toxicity studies. The results of a dermal absorption study in rats (MRID 00146679) indicated that with a 10 - hour exposure at doses of 0.19, 1.9, or 19 mg/rat, the percent of absorption was 8.38, 3.27, and 2.9% of the applied dose, respectivel y. A dermal absorption factor i s not applicable since dermal risk assessments are not required. **Inhalation Exposure (All Durations):** The LC 50 value for quizalofop ethyl is 4.8 - 5.8 mg/L which place it Toxicity C ategory IV indicative of low acute inhalation toxicity . For longer exposu re durations, b ased on a comparison of inhalation and oral points of departure for a series of 89 pesticides, and on the maximum inhalation exposure expected from occupational and residential uses of quizalofop - P - ethyl, HED concludes that an inhalation tox icity study on quizalofop - P ethyl is unlikely

to result in a point of departure indicating risks of concern. Therefore, a risk assessment via this route of exposure is not required. **Margins of Exposure:** For residential and occupational exposures, no ri sk assessments are required. **4.5.3 Cancer Classification and Risk Assessment Recommendation**  Quizalofop ethyl is classified as category D (Not classifiable as to human carcinogenicity).Quizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **21** of **34 Carcinogenicity Study in Rats**  See the discussion on cRfD under section 4.3 Discussion of Tumor Data: Neoplastic histopathology showed an increased incidence of benign and malignant liver cell tumors in both sexes with a significant dose - related trend for hepatocellular carcinoma in females. However, no increase of liver hy perplasia or adenoma was seen. The Registrant asked the tumor pathology data to be re - evaluated by the Environmental Pathology Laboratory (EPL) and the findings were revised as follows (a) an increased number of adenomas in all groups and (b) a reduction in the number of carcinomas in the mid - and high - dose groups. The HED Carcinogenicity Peer Review Committ ee subsequentl y concluded that quizalofop ethyl did not appear to be associated with an increase in liver carcinoma in female CR - SD rats (TXR# 007983, W. Phang, 6/11/1987). **Carcinogenicity Study in Mice** Ina carcinogenicity study (MRID 00146684), NC - 302 (quizalofop ethyl, 99%, a.i.) was administered to CD - 1 mice (70/sex/dose) at dose levels of 0, 2, 10, 80, or 320 ppm (equivalent to 0, 0.3, 1.4, 11.4 or 45.7 mg/kg/day by a standard conversion factor) in diet for 78 weeks. Two subgroups of animals (10/sex/dose) were designated as satellite groups for interim sacrifices at weeks 26 and 52. There was a significant trend toward s decreased survival in the males with a significant lower survival seen at 320 ppm compared to controls. Female survival was comparable in the dosed and control groups. Increased body weights, hematology

and clinical chemistry

parameters were observe d in the 80 - and 320 - ppm groups. A statisticall y significant decrease in testicular weight was noted at the terminal sacrifice in males that received 320 ppm. Increased incidences of bilateral testicular atrophy were observed at 80 and 320 ppm. In bot h sexes of 80 and 320 - ppm treated mice, hepatotoxicity was evident with enlarged and dark livers along with histopathology

observations. The NOAEL was 10 ppm (1.4 mg/kg/day ) and the LOAEL was 80 ppm (11.4 mg/kg/day

) based on increased incidence of bila teral testicular atrophy , enlarged liver and histopathology

findings indicative of hepatotoxicity in the liver. The carcinogenicity study in the mouse is classified acceptable/guideline and satisfies the guideline requirement for a carcinogenicity

study ( OPPTS 870.4200; OECD 4531). Discussion of Tumor Data: Increased incidences of ovarian tumors in females and liver tumors in males were observed at the high - dose onl y. The EPA Carcinogenicity Peer Review Committee reevaluated the study and determined th at the tumor incidence of ovarian stromal tumors in female mice was not significantl y elevated and was not considered a compound related effect based on historical control data and the absence in findings of hy perplasia of the ovary , signs of endocrine activity related to ovarian function, and dose - response relationship with respect to the incidences observed. The Committee also diminished the weight of evidence for an effect of test material to produce liver tumors based on the historical control dat a and the lack of increased incidences of liver adenoma and liver hy perplasia. Also, the liver tumors observed in this study did not occur in a strictl y dose - related manner, they were seen only at the high dose level which exceeded a MDT level.Quizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **22** of **34** Adequacy of the Dose Levels Tested: The Cancer Peer Review Committee has determined that the highest dose tested in males exceeded a MDT level based on increased mortality rate (TXR# 007983, W. Phang, 6/11/1987). **Mutagenicity:** The Cancer Peer Review Committee determined that mutagenicity studies did not demonstrate mutagenic potential for quizalofop ethy l (TXR# 007983, W. Phang, 6/11/1987). Results are summarized as follows: negative for recombinant assays using B. subtilis M - 45 and H - 17, negative for revision assays using E. coli WP2 and S. typhimurium TA1535, TA1537, TA1538, TA98, TA100 strains, negative for chromosome aberration in the CHO cells, and negative for unscheduled DNA synthesis (UDS). **4. 5**  **. 4**  **Summary of Points of Departure and Toxicity Endpoints Used in Human Risk**  **Assessment Table 4.5.**  **4 .1 Summary of Toxicological Doses and Endpoints for**  **Quizalofop -**  **P -**  **ethyl for Use in Dietary and**  **Non -**  **Occupational Hum an Health Risk Assessments**  **Exposure/ Scenario**  **Point of**

**Departu re**  **Uncertainty/FQPA**

**Safety Factors RfD, PAD,** 

**Level of Concern for**  **Risk Assessment**  **Study and Toxicological Effects** Ac ute Dietary

– all populations No appropriate endpoint was identified. There were no effects observed in oral toxicity studies

that could be attributed to a single - dose exposure. Chronic Dietary (All Populations) NOAEL=

0.9 mg/kg/day UF A= 10 x

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

= 0.009 mg/kg/day cPAD = 0.009 mg/kg/day Chronic toxicity/Carcinogenicity study in

rats. LOAEL = 3.7 mg/kg/day based on increased incidence of centrilobular enlargement of the liver in both sexes and mild anemia in males. Incidental Oral No endpoint was selected as no residential uses are under registration. Dermal

– all durations No appropriate endpoint was identified and a risk assessment via this route is not required. Inhalation

– all durations No appropriate endpoint was identified and a risk assessment via this route is not required. Cancer (oral, dermal, inhalation) Category D . Not classifiable as to human carcinogenicity. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose .Quizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **23** of **34 5.0**  **Dietary Exposure and Risk Assessment 5.1**  **Metabolite/Degradate Residue Profile 5.1.1**  **Summary of Plant and Animal Metabolism Studies** The qualitative nature of the residue in plants is a dequatel y understood based on previously submitted plant metabolism studies with soy bean, cotton, tomatoes, potatoes, and sugar beets. The metabolis m studies indicate that quizalofop ethyl does not accumulate but is rapidly hydrol yz ed at the ethyl ester to f orm quizalofop acid. The acid then undergoes cleavage of the enol ether linkage between the phen yland quinoxalinyl rings and/or cleavage of the ether linkage between the isopropanoic group and the phen ylring to form phenols. Metabolism studies with soy beans demonstrated that the racemic mixture of quizalofop ethyl and the resolved R enantiomer, quizalofop - P - ethyl have nearl y identical pathways ( DP# 182751, J. Stokes, 7/15/93). To support the current petition to uses on genetically modified corn, a metabolism study in geneticall y modified corn containing the AAD - 1 gene was submitted. The petitioner proposed that the metabolism of quizalofop - P - ethylester proceeds from the ester to the acid and continues through incorporation of the radiolabeled carbon into natural plant constituents, such as lignin and cellulose. The nature of the residue in livestock is adequately understood based on metabolism studies with goats and poultry . The studies indicate that quizalofop ethyl is metabolized in livestock via hydrol ys is to quizalofop acid which then undergoes methylation to form quizalofop methyl ester. No phenols were detected in either the goat or hen matrices, indicating that cleavage of the ether linkages of quizalo fop does not occur. In hens quizalofop - P acid is utilized in fatty chain elongation to form quizalofop - p entanoic acid. Refer to section 4.2 for a brief description of metabolism studies in rats. **5.1.3 Residues of Concern Summary and Rationale**  **Nature of the Residue in Plants** : The qualitative nature of the residue in plants is adequatel y understood based on previously submitted plant metabolism studies with soy bean, cotton, tomatoes, p otatoes, sugar beets, barley , flaxseed , sunflower and wheat . In addition, adequate metabolism studies with geneticall y modified field corn were submitted to support the proposed new uses. For the risk assessment, HED has determined that the residues of concern in plant commodities are quizalofop - P - ethyl , it metabolite quizalofop - P acid , and the S - enantiomers of both compounds, each expressed as quizalofop - P - ethyl

. **Nature of the Residue i n Animals**  : The qualitative nature of the residue in livestock is adequatel y understood based on metabolism studies with goats and poultry . The studies indicated that quizalofop ethyl is metabolized in livestock via hydrol ys is to quizalofop acid which the n undergoes methylation to form quizalofop methyl ester. No phenols were detected in either goat or hen commodities, indicating that cleavage of the ether linkages of quizalofopQuizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **24** of **34** does not occur. The residues of concern in livestock commodities are quizalo fop ethyl, quizalofop methyl, and quizalofop acid, expressed as quizalofop ethyl. **Nature of the Residue in Rotational Crops** : In a confined accumulation study , [Phenyl 14 C] - and [quinoxaline 14 C] - quizalofop ethyl treated soils were aged 30 and 62 day s bef ore planting with the rotational crops red beets, lettuce, wheat, peanuts, and cotton. The petitioner has characterized and identified over 50% of the residue in each of the rotational crops from the phenyl - and quinoxaline - labeled quizalofop eth ylsoil treatment and has confirmed the hydrol ys is of the ethyl ester, and the cleavage of the enol and ether linkage metabol ic pathway s. The data support a 120 - day plant - back interval. The nature of the residue in rotational crops is adequatel y under stood and is the same as identified above for tomatoes, cotton seed, soy beans, and sugar beet s. The residues of concern are quizalofop ethyl and its acid metabolite (D219672 and D222000, Griffith, F. D, 1/26/1996). **Table 5.1.4 Summary of Metabolites and Degrada tes to be included in the Risk Assessment and**  **Tolerance Expression** Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants Primary Crop Quizalofop - P - ethyl , quizalofop - P , and the S enantiomers of both, expressed as quizalofop ethyl Quizalofop - P - ethyl , quizalofop - P , and the S enantiomers of both, expressed as quizalofop ethyl Rotational Crop Quizalofop ethyl and quizalofop Not Applicable. Livestock Ruminant Quizalofop ethyl, quizalofop methyl, and quizalofop acid, expressed as quizalofop ethyl Quizalofop ethyl, quizalofop methyl, and quizalofop acid, expressed as quizalofop ethyl Poultry Drinking Water Quizalofop ethyl and quizalofop acid Not Applicable **5 .2**  **Food Residue**  **Profile Crop Field Trials:**  The submitted residue data for field corn commodities (forage, grain, and stover) are tentativel y considered to be adequate, pending submission of storage stability data demonstrating the stability of quizalofop - P - ethyl and quizalofop acid in/on field cor n forage, grain, and stover. The number and locations of crop field trials are in accordance with OCSPP Guideline 860.1500. The field trials reflect the proposed use pattern. The maximum t otal quizalofop - P - ethyl residues [sum of quizalofop - P - ethyl and quizalofop acid residues (as parent equivalents)] were <0.02 ppm in/on forage and grain and <0.022 ppm in/on stover. Using the OECD MRLcalculator, the recommended tolerances are 0.02, 0.02, and 0.03 ppm in/on corn forage, grain, and stover, respectivel y. The forage and grain recommendations are higher than the tolerance levels proposed by the petitioner and the stover recommendation is identical to the tolerance level proposed by the petitioner.Quizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **25** of **34** The submitted residue data for sorghum commodities (forage, grain, and stover) are adequate to satisfy data requirements. The sorghum field trials reflected the maximum proposed application rates and the proposed PHI s. The maximum t otal quizalofop - P - ethyl residues [sum of quizalofop - P - ethyl and quizalofop acid r esidues (as parent equivalents)] were <0.180 ppm in/on forage, <0.158 ppm in/on grain, and <0.266 ppm in/on stover. Using the OECD MRLcalculator, the recommended tolerances are 0.20, 0.20, and 0.30 ppm in/on sorghum forage, grain, and stover, respectivel y. These recommendations are identical to the tolerance levels proposed b y the petitioner for sorghum forage and grain. The tolerance level recommendation for sorghum stover is slightly

lower than the level (0.35 ppm) proposed by the petitioner. No resi due data were submitted to support the proposed use on mustard seed and other members of the rapeseed subgroup 20A, except flaxseed . The available field trial data for canola seed, the representative crop of the rapeseed subgroup 20A, may be translated to support the proposed uses on mustard seed and other members of the rapeseed subgroup 20A, except flaxseed . These data are adequate to fulfill data requirements and reflect ~0.8 - 1.5x the maximum proposed seasonal application rate for the EC formulation wi th 38 - to 74 - day PHI . The data for 0.8x and 1.5x was analyzed to recommend a tolerance that may support use of the 0.88 lb ai /gal EC formulation. **Table 5.2. Summ ary of Residues from the Crop Field Trials with**  **Quizalofop -**  **P -**  **ethyl .**  **Crop Matrix Applic.**  **Rate (lb ai/A)**  **PHI**

**(days) Residues (ppm** **)**

**n Me**  **an Std.** 

**Dev. HAFT**  **1 Min.**  **Max. Field Corn containing DAS**  **- 40278**  **- 9**  **(Proposed Use: 0.083 lb ai/A total application rate, 30 -**  **day PHI for forage; plus adjuvant) 2**  Corn, field, early forage 0.078 - 0.088 32 - 47 24 0.02 --- <0.02 <0.02 <0.02 Corn, field, forage 44 - 83 24 0.02 --- <0.02 <0.02 <0.02 Corn, field, grain 79 - 144 25 0.02 --- <0.02 <0.02 <0.02 Corn, field, stover 79 - 144 25 0.02 --- <0.022 <0.02 <0.022

**Sorghum grain containing the DuPontTM INZENTM AII Herbicide Tolerance Trait**  **(Proposed Use: 0.138 lb ai/A total application rate, 30**  **- day PHI for forage and 45**  **- day PHI for grain and stover;**  **plus adjuvant)** Sorghum, forage 0.136 - 0.145 25 - 32 13 0.112 0.019 <0.169 <0.104 <0.180 Sorghum, grain 29 - 49 12 0.111 0.014 <0.149 <0.104 <0.158 Sorghum, stover 42 - 56 13 0.129 0.040 <0.212 <0.104 <0.266 **Rapeseed Subgroup 20A, Except Flaxseed, Seed 3, 4**  **(Proposed Use: 0.124 lb ai/A total application rate, 60**  **- day PHI; plus adjuvant)**  Canola, seed 0.094 38 - 74 9 0.19 0.21 0.65 <0.05 0.7 Canola, seed 0.188 38 - 74 9 0.39 0.46 1.5 <0.05 1.5 1 HAFT = highest - average - field - trial. 2 Except for sample min/max, values reflect per trial averages; n = no. of field trials. For calculation of median, mean, and standard deviation, the LOQ (0.01 ppm) was used for any results reported as ND (0.003 ppm) or between the LOD and LOQ. 3 Canola data available from a previous petition (PP#5F4545/FAP#6H5737; DP#s 220476, 220478, 220480, F. Griffith, 2/21/96) 4 The Rapeseed Subgroup 20A includes Borage, Crambe, Cuphea, Echium, Gold of Pleasure ( Camelina ), Hare’s ear mustard, Lesquerella, Lunaria, Meadowfoam, Milkweed, Mustard seed, Oil Radish, Poppy seed, Rapeseed (Canola), Sesame, and Sweet Rocket.Quizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **26** of **34 Processing Studies:**  Adequate processing data for corn have been submitted, pending submission of storage stability data demonstrating the stability of quizalofop - P - ethyl and quizalofop acid in/on field corn processed commodities. Tolerances for the processed commodities of corn are not needed for the purpose of this petition based on the results of processing trials which showed that residues of quizalofop - P - ethyl and quizalofop acid (as parent equivalents) were <LOQ in/on field corn grain RAC (treatment at ~2x the proposed maximum seasonal rate), and in field corn processed commodities (starch, refined oil (wet and dry milling), meal, grits, flour, and AGF). The registrant explained that ph yt otoxicity concerns preclude corn processing studies at higher treatment rates. Ad equate processing data for sorghum have been submitted. The processing data indicate that total quizalofop - P - ethyl residues concentrate in sorghum AGF. Based on the processing factor, 3.4x, and the HAFT for sorghum grain, 0.149 ppm, expected residues in sorghum AGF following treatment at 1x would be 0.507 ppm. Because this value is greater than the recommended 0.2 - ppm tolerance for sorghum grain, a tolerance is needed for total quizalofop - P ethyl residues in/on sorghum, grain, aspirated grain fractions. A tolerance of 1.0 ppm would be appropriate. No new processing data were submitted in support of the label amendment request to expand the use of quizalofop on rapeseed meal that would cover the rapeseed subgroup 20A, except flaxseed) . Acceptable proc essing data were previously submitted and reviewed for canola seed, the representative crop of subgroup 20A, under PP# 5F4545/FAP# 6H5737 (DP#s 220476, 220478, and 220480, F. Griffith, 2/21/96). Based on the available canola processing data, a tolerance f

or canola meal was established at 1.5 ppm; a tolerance was not required for refined oil. The canola processing data was used to recommend a tolerance for the rapeseed, meal of 2.0 ppm by adjusting for the proposed application rate. **Rotational Field Tr ials:**  The available confined/field rotational crop data indicate that a 120 - day plant back interval (PBI) is required for all crops other than those with registered uses. **Storage Stability:** The storage duration of the samples of the submitted crop field trial studies with sorghum are supported by adequate storage stability data of the residues of concern. However, storage stability data for quizalofop P - ethyl and quizalofop acid in/on field corn and processed commodities are not currently available. The petitioner indicated that a storage stability study is in progress. Storage stability data for quizalofop ethyl and quizalofop in/on various matrices, including cotton, so ybean, and wheat c ommodities, have been submitted previously . The available wheat storage stability data are tentativel y considered adequate to support submitted crop field trial on corn. Storage stability data were not provided for the corn processed commodities and are required to support the processing studies. When the storage stability study on corn is submitted, the adequacy of the storage stabilit y data will be re evaluated.Quizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **27** of **34 Milk, Meat, Poultry and Eggs:**  Adequate ruminant and poultry feeding studies were submitt ed previously . These studies indicate that tolerances are needed for livestock commodities to support the current and proposed uses of quizalofop - P - ethyl. The maximum reasonable dietary burdens (MRDBs) of quizalofop - P - ethyl to livestock have been re - calc ulated using the registered and proposed uses. Based on the calculated MRDBs, the established tolerances are adequate for all livestock commodities. **5.3 Water Residue Profile**  The Agency

does not have monitoring data available to perform a quantitative drinking water risk assessment for quizalofop - P - eth yl at this time. A Tier II drinking water assessment prepared by the Environmental Effects and Fate Division (EFED) is summarized below (S. Wente, 07/19/2011, D384661). A Tier II drinking water assessment of surface water was performed based on Index Reservoir settings, using the linked PRZM - EXAMs models. The sorghum application scenario was used to predict an estimated drinking water concentration (EDWC) of 2.006 ppb for chronic exposure. For ground wat er sources, the SCI GROW model was used to predict an EDWC of 1.29 ppb for chronic exposure. Since the surface water concentration was the highest, the chronic dietary risk assessment was conducted assuming a residue of 0.002 ppm for all water sources (dire ct and indirect). The EDWCs obtained by these two models are summarized in Table 5.3. **Table 5.3. Drinking Water EDWCs for Quizalofop ethyl** Model Used Chronic (parts/billion) PRZM/EXAMs 2.006 SCIGROW 1.29 **5.4 Dietary Risk Assessment**  **5.4.1 Description of Residue Data Used in Dietary Assessment**  An acute dietary

exposure assessment was not prepared because an endpoint attributable to a single oral dose was not identified from the toxicity studies of quizalofop ethyl; therefore, an aRfD was not established. A chronic dietary

risk assessment was conducted using the Dietary Exposure Evaluation Model

- Food Consumption Intake Database (DEEM - FCID  , ver. 2.03). DEEMTM - FCID in corporates the food consumption data from the USDA’s Continuing Survey s of Food Intakes by Individuals (CSFII; 1994 - 1996 and 1998). The chronic anal ys is incorporated tolerance level re sidues for all commodities and 100 %CT was assumed. DEEMTM (ver 7.78) d efault processing factors were assumed when applicable. The assessment included existing food uses as well as the newly

proposed tolerances to be established for Section 3 uses on barley , wheat, sunflower and flaxseed , as well as the PRZM - EXAMs modeled chronic surface water point estimate generated based on the MIdry pea application scenario. Table 5.4.6 summarizes theQuizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **28** of **34** dietary exposures and the corresponding %cPADs for the population subgroups ( D 395387 , S. Tadayon, 10/25/2011 ). **5.4.2 Percent Crop Treat**  **ed Used in Dietary Assessment** The chronic anal ys is was based 100 %CT for all food commodities. **5.4.3 Acute Dietary Risk Assessment**  No acute endpoint has been identified; therefore, an acute dietary assessment was not performed. **5.4.4 Chronic Dietary**  **Risk Assessment** The chronic anal ys is was based on conservative assumptions (tolerance level residues and 100 %CT) for food commodities . A modeled drinking water estimate was used is the assessment. The drinking water assessment of surface water was performed to assess drinking water exposure for quizalofop - P - eth ylin support of field corn and sorghum. Since the drinking water estimate wa s generated using the site/scenario which produced the highest estimated surface water concentration, and since conservative assumptions were used for food, HED concludes that the exposure estimates provided in this document are highl y conservative and is not likely to underestimate risk. The chronic dietary

risk estimates are  29 % cPAD and are therefore below HED’s level of concern (children 1 - 2 years old were the most highly exposed population). **5.4.5 Cancer Dietary Risk Assessment**  Quizalofop - P - ethyl was classified as "not likel y" to be a human carcinogen, therefore no cancer assessment was needed . **5.4.6 Summary Table**  The chronic dietary

risk estimates are  29 % cPAD (See Table 5.4.6) and are therefore below HED’s level of concern (children 1 - 2 years old were the most highl y exposed population). **Table 5.4.6 Summary of Chronic Dietary Exposure and Risk for**  **Quizalofop -**  **P -**  **ethyl (drinking water included)** Population Subgroup cPAD (mg/kg/day) Chronic Exposure (mg/kg/day) %cPAD General U.S. Population

0.009 0.001025 11 All Infants (< 1 year old) 0.002477 28 **Children 1 -**  **2 years old 0.002636**  **29** ***** Children 3 - 5 years old 0.002315 26 Children 6 - 12 years old 0.001590 18 Youth 13 - 19 years old 0.000978 11 Adults 20 - 49 years old 0.000803 9 Adults 50+ years old 0.000685 8 Females 13 - 49 years old 0.000767 9 ***** Children 1 - 2 years old were the most highly exposed populationQuizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **29** of **34 6.0**  **Residential (Non -**  **Occupational) Exposure/Risk Characterization** Quizalofop - P - ethyl doesn’t have either proposed or registered residential uses. **6. 5**  **Spray Drift** Spray drift is alway s a potential source of exposure to residents nearby to spraying operations. This is particularly

the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application metho d employ ed for quizalofop - P ethyl . The Agency

has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency ’s Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labe ling. The Agency has completed its evaluation of the new database submitted by

the Spray

Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy

on how to appropriatel y apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied b y air, orchard airblast and ground hydraulic methods. After the policy

is in place, the Agency

may impose further refinements in spray drift management practices to reduce off - target drift with specific products wi th significant risks associated with drift. **7.0 Aggregate Exposure/Risk Characterization**  Since quizalofop ethyl has no registered or proposed residential uses which would result in residential exposures, the chronic dietary exposure anal ys is incorporating e xposures from food and drinking water, presented in Table 5.4.6 represents the aggregate chronic risk assessment . **8.0 Cumulative Exposure/Risk Characterization**  Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common m echanism of toxicity , EPA has not made a common mechanism of toxicity finding as to quizalofop - P - ethyl and any other substances and quizalofop - P - ethyl does not appear to produce a toxic metabolite produced b y other substances. For the purposes of this tole rance action, there fore, EPA has not assumed that quizalofop - P - eth yl has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumu lative effects of such chemicals, see the policy statements released b y EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.Quizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **3 0**  of **34 9.0**  **Occupational Exposure/Risk Characterization** A separate memorandum summarizes HED's assessment of the occupational exposure and risks of use of quizalofop eth yl as an herbicide (D392851, S. Tadayon, 9/1/2011). Since no short term dermal and inhalation toxicity endpoints were identified for estimating the occupational exposures to handlers and post - application workers, no quantitative risks were calculated. HED has no concerns for occupational exposures associated with the proposed uses. Quizalofop ethyl has a 12 - hour (REI) established under the WPS and its acute toxicity categories are IV for both dermal and inhalation routes of exposures. **Occupational/Commercial Postapplication Inhalation Section** Based on the Agency 's current practices, a quantitative post - application inhalation exposure assessment was not performed for quizalofop - P - ethyl at this time primarily because of the low acute inhalation toxicity

(Toxicity Category III and IV), low vapor p ressure (8.3 x 10 - 10 mm Hg ), and the low proposed use rate (0.83 lb ai/A). However, there are multiple potential sources of post - application inhalation exposure to individuals performing post - application activities in previously

treated fields. These pote ntial sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available post - application inhalation exposure data generated b y the Agricultural Reentry Task Force and may , as appropriate, develop policies and procedures, to identify the need for and, subsequently , the way to incorporate occupational post - applicat ion inhalation exposure into the Agency 's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post - application inhalation exposure assessment for quizalofop - P - ethyl.Quizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **31** of **34 10.0**  **References Risk Assessments**  Quizalofop -P- ethyl : Human health risk assessment for new uses on barley, flaxseed , sunflower and wheat , D310869, S. Oonnithan, 08/10/2006. **Dietary Exposure Memorandum**  Quizalofop -P- ethyl. Chronic dietary exposure assessment to support section 3 registration for use on corn, rapeseed and sorghum , D395387, 10/25/2011. **Drinking Water Memoranda** Drinking water exposure for quizalofop -P- ethyl in support of propagation of herbicide - tolerant field corn and sorghum , D384 661, S.P. Wente, 07/19/2011. **Residue Chemistry Data Review** Quizalofop -P- ethyl. Petition for Registration of New Use on Corn (PP#1F7822) and Sorghum Grain, and Rapeseed Subgroup 20A, Except Flaxseed (PP#0E7802). Summary of Analytical Chemistry and Resid

ue Data. , D 395630 , I. Negrón - Encarnación , 15 /Nov/2011 . **Occupational and Residential Exposure Assessment** Quizalofop -P- ethyl: Occupational Risk Assessment for the Proposed Uses on Corn, Sorghum, Grain, and Rapeseed Subgroup 20A (except Flaxseed ) seed, D392851, S. Tadayon, 09/10/2011.Quizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **32** of **34 A**  **ppendix A**  **. Toxicology Profile and Executive Summaries**  **A.1 Toxicology Data Requirements**  The requirements (40 CFR 158.340) for non food and food uses for quizalofop - P - eth ylare below. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used. **Study Technical**  **Required Satisfied**  870.1100 Acute Oral Toxicity ................................ ....................... 870.1200 Acute Dermal Toxicity ................................ .................. 870.1300 Acute Inhalation Toxicity ................................ .............. 870.2400 Primary Eye Irritation ................................ .................... 870.2500 Primary Dermal Irritation ................................ .............. 870.2600 Dermal Sensitization ................................ ...................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 Oral Subchronic (rodent) ................................ ............... 870.3150 Oral Subchronic (nonrodent) ................................ ......... 870.3200 21 - Day

Dermal ................................ .............................. 870.3250 90 - Day

Dermal ................................ .............................. 870.3465 90 - Day

Inhalation ................................ .......................... yes yes no no no yes

yes yes

--

-- 870.3700a Developmental Toxicity (rodent) ................................ ... 870.3700b Developmental Toxicity (nonrodent) ............................. 870.3800 Reproduction ................................ ................................ . yes yes yes yes

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

yes yes yes yes 870.5100 Mutagenicity

— Gene Mutation - bacterial ..................... 870.5300 Mutagenicity

— Gene Mutation - ma mmalian ................ 870.5375 Mutagenicity

— Structural Chromosomal Aberrations in CHO cells ................................ ................................ ..................... 870.5500. Bacterial DNA damage or repair test (recombinant assay in B. subtilis ). 870.5550 Mutagenicity

— Unscheduled DNA synthesis ................. yes

-- yes yes yes yes

-- yes ye s yes 870.6100a Acute Delayed Neurotoxicity (hen) ............................... 870.6100b 90 - Day

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

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

-

-

-

- 870.7485 General Metabolism ................................ ...................... 870.7600 Dermal Penetration ................................ ........................ 870.7800 Immunotoxicity ................................ ............................. yes no Conditionally yes no yesQuizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **33** of **34 A.2**  **Toxicity Profiles Table A.2.1 Acute Toxicity Profile of Quizalofop ethyl.**  OPPTS Guidelin e Study Type MRID Results Toxicity Category 870.1100 Ac ute oral toxicity / rat 00146669 LD 50 = 1670 mg/kg (M) 1480 mg/kg (F) III 870.1200 Ac ute dermal toxicity / rat 00146670 LD 50 => 5000 mg/kg IV 870.1300 Ac ute inhalation toxicity / rat 00146674 LC 50 = 4.8 - 5.8 mg/L IV 870.2400 Primary eye irritation / rabbit 00146671 Not an irritant IV 870.2500 Primary dermal irritation /

rabbit 00146672 Negative IV 870.2600 Dermal sensitization /

guinea pig 00146673 Non - Sensitizer -- **Table A.2.2 Subchronic, Chronic and Other Toxicities Profile for Quizalofop ethyl.**  Guideline No./ Study T ype/ MRID Nos.

Doses/Classification Results 1 870.3100 Subchronic Oral

- Rat 00128216 (1982)

(0, 40, 128, 1280 ppm) M: 0, 2.6, 8.4, 82.9 mg/kg/day F: 0,3.0, 9.7, 93.6 mg/kg/day Acceptable/Guideline NOAEL=8.4/9.7 (M/F) mg/kg/day LOAEL= 89.2/93.6 (M/F) mg/kg/day based on decreased body weight gains, increased liver weight and centrilobular liver cell enlargement. 870.3150 Subchronic Oral

- Dog 00127969 (1982)

(0, 25, 100, 400 ppm) 0, 0.63, 2.5, 10 mg/kg (M/F) (by a standard conversion factor) Acceptable/Guideline NOAEL= 2.5 mg/kg/day LOAEL= 10 mg/kg/day based on increased incidence of testicular atrophy. 870.3200 28 - Day dermal toxicity - Rabbit 00146677 (1983)

0, 125, 500, 2000 mg/kg/day (M/F) Acceptable/Guideline NOAEL= 2000 mg/kg/day (highest dose tested [HDT]) 870.3700a Prenatal, developmental - Rat 00128206 (1983)

0, 30, 100, 300 mg/kg/day (GD 2 6 - 15) Acceptable/Guideline Maternal: NOAEL= 30 mg/kg/day; LOAEL= 100 mg/kg/day based on decreased body weight gains and food consumption. Developmental: NOAEL= 300 mg/kg/day (HDT). 870.3700b Prenatal developmental

- NZW Rabbit 3 40370502 (1985)

0, 7, 20, 60 mg/kg/day (GD 7 - 19) Range - finding study 0, 7, 25, 60, 75 mg /kg/day (GD 7 - 19), Acceptable/Guideline Maternal: NOAEL= 20 mg/kg/day, LOAEL= 60 mg/kg/day based on decreased body weight gains and food consumption. Developmental: NOAEL= 60 mg/kg/day (HDT). 870.3800 Reproduction and fertility effects

- Rat 00153351 (1985), 40242502

(1987) (0,25, 100, 400 ppm) 0, 1.25, 5.0, 20 mg/kg/day (M/F) (by a standard conversion factor) Acceptable/Guideline Parental/Systemic **:** NOAEL= 5 mg/kg/day; LOAEL= 20 mg/kg/day based on decreased body weight and body weight gains. Reproducti ve **:** NOAEL=5 mg/kg/day; LOAEL= 20 mg/kg/day based on decreased percentage of pup bornQuizalofop - P - ethyl Human Health Risk Assessment DP No. 384660 and 386678

Page **34** of **34 Table A.2.2 Subchronic,**  **Chronic and Other Toxicities Profile for Quizalofop ethyl.** Guideline No./ Study T ype/ MRID Nos.

Doses/Classification Results 1 alive. Offspring **:** NOAEL=5 mg/kg/day; LOAEL= 20 mg/kg/day based on decreased pup w eights. 870.4200a Chronic Toxicity/ Carcinogenicity

- Rat 00146682 (1985)

(0, 25, 100, 400 ppm) 0, 0.9, 3.7, 15.5 mg/kg/day (M) 0, 1.1, 4.6, 18.6 mg/kg/day (F) Acceptable/guideline NOAEL= 0.9/1.1 mg/kg/day (M/F), LOAEL= 3.7/4.6 mg/kg/day based on increased incidence of centrilobular enlargement of the liver in both sexes and mild anemia in males. Increased incidence, with dose - related trend, of hepatocellular carcinomas in females o nly. Cancer classification: Category D (not classifiable as to human carcinogenicity) 870.4100b Chronic toxicity

- dog 00146683(1985)/40242501

(1987) (0, 25, 100, 400 ppm) 0, 0.625, 2.5, 10 mg/kg/day (M/F) (by a standard conversion factor) Acceptable/Guideline NOAEL=10 mg/kg/day (HDT).

870.4200b Carcinogenicity

- mo use 00146684 (1985)

(0, 2, 10, 20, 80, 320 ppm) 0, 0.3, 1.4, 11.4, 45.7 mg/kg/day (by a standard conversion factor) Acceptable/Guideline NOAEL=1.4 mg/kg/day; LOAEL=11.4 mg/kg/day based on increased incidence of bilateral testicular atrophy, enlarged liver and histopathology finding indicative of hepatotoxicity in the liver. Increased incidences of ovarian tumors in females and liver tumors in males at the high dose. Cance r classification: Category D (not classifiable as to human carcinogenicity) 870.7485 Metabolism See metabolism section for

details. Acceptable/Guideline See metabolism section for details. 870,7800. Immunotoxicity screen. 48500401(2011)

0, 10, 100, 300, or 600 ppm (0, 2, 20, 55, or 103 mg/kg/day. Acceptable/Guideline. No evidence of immunotoxicity.

1. LOAEL = Lowest observed adverse effect level, NOAEL = No observed adverse effect level. 2 . GD = Gestation Day 3. NZW = New

Zealand White Rabbits