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


MEMORANDUM


Date: November 17, 2011

SUBJECT:	Quizalofop-P-ethyl:  Human Health Risk Assessment for New Uses on Sorghum, Rapeseed Crop Group 20 A, and Field Corn
 
PC Code:  128709
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 Assessment Type: Single Chemical / Aggregate 
Case No.: NA
TXR No.: NA
CAS No.: 100646-51-3
MRID No.: 48273601, 48260704 and 48310101
40 CFR: § 180.441


FROM:		Ideliz Negrón-Encarnación, Ph.D., Risk Assessor
		Seyed 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)




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 Analytical Method	7
2.2.2	International Harmonization	7
2.2.3	Recommended Tolerances	7
2.3	Label Recommendations	9
3.0	Introduction	10
3.1	Chemical Identity	10
3.2	Physical/Chemical Characteristics	11
3.3	Pesticide Use Pattern	11
3.4	Anticipated Exposure Pathways	14
3.5	Consideration of Environmental Justice	14
4.0	Hazard Characterization and Dose-Response Assessment	15
4.1	Toxicology Studies Available for Analysis	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 Uncertainty 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	Dietary 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	29
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	33

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, soybean, 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 (R) II Herbicide (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 (R)Herbicide 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 toxicological profiles of the racemic mixture and that of R-enantiomer are sufficiently 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 byproducts, 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(R) 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 days for forage; a PHI for corn grain or stover is not specified.  

The IR-4 is proposing to amend the label of Assure(R) II herbicide to include uses on sorghum grain containing the DuPont(TM) INZEN(TM) AII Herbicide Tolerance Trait and on rapeseed subgroup 20A, except flaxseed.  The proposed uses are postemergence applications 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 (PHIs) are 30 days for sorghum forage, 45 days for sorghum grain and stover, and 60 days 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 rapidly absorbed and excreted via urine and feces.  Liver is the target organ as evidenced by increased liver weight and histopathological changes in the liver.
 
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 chronic toxicity/carcinogenicity study in rats.  Mutagenicity 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 classifiable 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 susceptibility following in utero and/or pre/post-natal exposure to quizalofop ethyl. 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.  Based on the above data, the 10x Food Quality Protection Act Safety 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 will provide a reasonable certainty of no harm to the safety 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 combined uncertainty 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 below 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 exposure 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 standard (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 assessment.  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 Database (DEEM-FCID, ver.2.03).  The inputs used were (i) tolerance level residues for all commodities, (ii) 100 percent crop treated (%CT), (iii)  DEEM(TM) ver. 7.78) default processing factors, and (iv) drinking water numbers generated by Pesticide Root Zone Model-Exposure Analysis and Modeling System (PRZM-EXAMS) using the maximum application rate per season for quizalofop ethyl on dry peas in Michigan.  Under 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 level of concern.  

In summary, this risk assessment indicates that adding field corn, sorghum and the rapeseed subgroup 20A, to the existing uses of quizalofop-P-ethyl, will 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 (D395630, I. Negron, 15Nov2011), 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 corresponding tolerances.  In addition 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 corn 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, poppy seed, rapeseed, sesame seed, and sweet rocket seed] at 1.0 ppm.  The recommended tolerance differs since the residues levels were scaled to reflect the proposed use pattern and a tolerance 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 recommended 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 tolerances should be revised to reflect the correct commodity definitions as specified in the residue chemistry chapter.



2.2.1	Enforcement Analytical Method

860.1340 Residue Analytical Methods

	::	After reviewing Morse Method Meth-147 against the Tolerance Method Validation (TMV) Review Checklist, provided the solvent exchange modification made by the ILV laboratory is incorporated into the final method, the analytical method data satisfy the requirements.  A TMV by ACB will not be necessary. 


2.2.2	International Harmonization

No Codex MRLs have been established for residues of quizalofop ethyl.  Canadian MRLs have been established for residues of quizalofop ethyl and quizalofop in/on oriental mustard seeds (condiment type and oil seed type), and rapeseeds (canola), the only 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 MRLs have been established for any of the requested crops.  


2.2.3	Recommended Tolerances

Field Corn, Sorghum and Rapeseed Subgroup 20A (except flaxseed)

The OECD MRL calculator (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 Rapeseed 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 revision of 40 CFR §180.441(a)(3), separate tolerances for canola seed and canola meal should be removed.  New tolerances were determined for the rapeseed subgroup 20A and the meal processed commodity by adjusting for differences between the proposed and study application rates. These new tolerances should be included in the revised 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 expressions 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  below. 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 commodity."  

Section (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."

Section (c): "Tolerances with regional registrations. Tolerances 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 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 commodity."

The petitioner should submit a revised section F reflecting the recommended tolerances and commodity definitions presented in Table 2.2.3.  These new tolerances should be included in the revised 40 CFR § 180.441 (a)(1).















Table 2.2.3.   Tolerance Summary for Quizalofop-P-ethyl
                                   Commodity
                     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
                                       
Meadowfoam, 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
                                    Remove
                                       
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 tolerances for canola seed and canola meal may be removed.











2.3	Label Recommendations

860.1200 Directions for Use

The following changes are recommended in the draft label of Assure(R) 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 supplemental 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	Introduction
	
Dupont has submitted a label amendment for Assure(R) 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(R) II herbicide to include uses on sorghum grain containing the DuPont(TM) INZEN(TM) 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[(R)] 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 crop land areas.

The chemical structure of quizalofop-P-ethyl is presented in Table 3.1 and its physicochemical properties are presented in Table3.2.










3.1	Chemical Identity

Table 3.1  Test Compound Nomenclature
Chemical structure
                                       
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 Physicochemical 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/cm[3] 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 POW = 4.66

UV/visible absorption spectrum
Not available

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(R) 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 DuPont(TM) INZEN(TM) AII Herbicide Tolerance Trait and rapeseed subgroup 20A, except flaxseed.  The currently registered EPA label, dated 4/14/2010, was obtained from PPLS.  The currently registered uses include canola, crambe, cotton, crops grown for seed, eucalyptus, dry beans (including Chickpea), dry and succulent peas, flaxseed, hybrid poplar plantings, lentils, mint (spearmint and peppermint), pineapple, ryegrass grown for seed, snap beans, soybeans, sugar beets, sunflowers, and noncrop areas. DuPont Crop Protection is also requesting the addition of genetically modified field corn (containing DAS-40278-9) to the label of Assure(R) II Herbicide; EPA Reg. No. 352-541. The use patterns for the proposed new uses are presented in Table 3.3.

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 DuPont(TM) INZEN(TM) 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, 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]
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] General use directions, restrictions, and precautions were obtained from the currently registered label for Assure(R) 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 from the treated crops to livestock is prohibited.  
[4] The Section 3 label describes the crop rotation restrictions as required.



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-ethyl on sorghum, rapeseed subgroup 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 application 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 occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application.  There is a potential for post-application exposure for workers re-entering treated fields.  

Risk assessments have been previously prepared for the existing uses of 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, particularly for the dietary exposure assessment.  


3.5	Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.  As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated.  Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.






4.0	Hazard Characterization and Dose-Response Assessment

This section was adapted from Quizalofop-P-ethyl:  Human Health Risk Assessment for New Uses on Barley, Flaxseed, Sunflower and Wheat., prepared by S. Oonnithan, dated August 10, 2006 for D310869.  The series 870.7800 immunotoxicity screen study was the only new toxicity 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 readily absorbed from the gastrointestinal tract and is excreted rapidly via urine and feces.  The major metabolite 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

The 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 by 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 chemical since no treatment-related effects on brain weight or histopathology of the nervous system were observed in studies that measure these endpoints.  The Cancer Peer Review Committee determined that quizalofop ethyl should be classified as Category D (not classifiable 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 rabbit developmental toxicity studies and pre-/post-natal exposure in a two-generation reproduction study in rats.  There are no concerns and no residual uncertainties for pre- and postnatal toxicity.  Quizalofop ethyl does not appear to be a neurotoxic chemical 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 by 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 safety of infants and children. 


4.4.1	Completeness of the Toxicology Database

Adequacy of the Toxicity Database:  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 system 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) by gavage in 2 mL/kg of 0.5% carboxymethylcellulose at dose levels of 0, 30, 100, or 300 mg/kg bw/day from gestation days 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. 

For maternal toxicity, there were no deaths, abortions, 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 significance 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-ribs 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 satisfies the guideline requirement (OPPTS 870.3700; OECD 414). 

In another developmental toxicity study , quizalofop ethyl 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 gestation days 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 days 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 body weight gains and food consumption was observed in the 75 mg/kg group.  Increased incidence of abortion was observed in 60 and 75 mg/kg groups compared to the control.  Under conditions of the study, the maternal LOAEL is 60 mg/kg bw/day, based on decreased body weight gains 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:  In a 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, respectively).  After 70 
days on test, the F0 generation was bred to produce F1a and F1b litters.  At weaning, randomly 
selected F1a rats were fed diets containing INY-6202 for 80 days and then mated to produce F2a 
and F2b litters.  After litter production, ten rats per sex per dose in the F0 and F1a generations had 
reproductive tissues examined.  Ten F2b 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, significant decreases of body weight and body weight gains were observed in both F0 and F1a males and F1a females at 400 ppm compared to the control.  No 
treatment-related deaths or clinical observations were observed in the parental rats.    The 
LOAEL of parental systemic toxicity is 400 ppm (equivalent to 20 mg/kg bw/day), based on 
decreased body 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 (400 ppm) were significantly lower 
than controls in F1a and F1b pups from birth throughout lactation, and F2a and F2b pup weights 
were significantly reduced starting at day 7 and day 4, respectively.  Significantly increased 
absolute and relative liver weights were observed in the F2b 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 
examination of hepatocytes from F2b weanlings revealed distinct eosinophilic granular 
cytoplasm and decreases in cytoplasmic basophilia and glycogen accumulation in the 100 and 
400 ppm groups.  Previously HED had established a LOAEL at 100 ppm based on increased 
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 use in the regulation of 
quizalofop ethyl (TXR# 012373, J. Rowland, 10/24/1997).  The study author stated that 
hepatocytes 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 F1a and F2a litters of the 400 ppm group.  Fertility rates were comparable in all groups of both generations except the low-dose F0 males and females, which had significantly reduced fertility rates when compared to the control at the first mating.  All pregnant females 
successfully delivered live pups and maintained their litters until weaning.  Clinical observation 
of the offspring showed an increased incidence of hematomas in the F1b pups at 25, 100, and 
400 ppm and F2a pups at 100 and 400 ppm.  However, the increased 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 LOAEL 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 from 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 following 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. 

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 
neurotoxicity 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 by 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 safety 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 appropriate 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.  There 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 significantly 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 hepatocytic enlargement in the 400 ppm males and 
cytoplasmic eosinophilia of the centrilobular hepatocytes in the 400 ppm group of both sexes. Increased 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 for males and 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 study (OPPTS 
870.4300; OECD 453). 

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 (LOAEL). 

Uncertainty Factor(s): 100 (10x for interspecies extrapolation 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 days) 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 systemic 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 typically 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, respectively.  A dermal absorption factor is not applicable since dermal risk assessments are not required. 

Inhalation Exposure (All Durations):  The LC50 value for quizalofop ethyl is 4.8-5.8 mg/L which place it Toxicity Category IV indicative of low acute inhalation toxicity.  For longer exposure durations, based 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 toxicity 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 risk 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). 

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 hyperplasia 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 Committee subsequently 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 

In a 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 towards 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 observed in the 80- and 320-ppm groups.  A statistically 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 both 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 bilateral 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 only.  The EPA Carcinogenicity Peer Review 
Committee reevaluated the study and determined that the tumor incidence of ovarian stromal 
tumors in female mice was not significantly elevated and was not considered a compound-
related effect based on historical control data and the absence in findings of hyperplasia 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 
data and the lack of increased incidences of liver adenoma and liver hyperplasia.  Also, the liver tumors observed in this study did not occur in a strictly dose-related manner, they were seen 
only at the high dose level which exceeded a MDT level.

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 ethyl (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 Human Health Risk Assessments
                              Exposure/ Scenario
                              Point of Departure
                        Uncertainty/FQPA Safety Factors
                RfD, PAD, Level of Concern for Risk Assessment
                        Study and Toxicological Effects
Acute Dietary  -  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
UFA= 10x
UFH=10x
FQPA SF= 1x

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.  UFA = extrapolation from animal to human (interspecies).  UFH = 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.




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 adequately understood based on previously submitted plant metabolism studies with soybean, cotton, tomatoes, potatoes, and sugar beets.  The metabolism studies indicate that quizalofop ethyl does not accumulate but is rapidly hydrolyzed at the ethyl ester to form quizalofop acid.  The acid then undergoes cleavage of the enol ether linkage between the phenyl and quinoxalinyl rings and/or cleavage of the ether linkage between the isopropanoic group and the phenyl ring to form phenols.  Metabolism studies with soybeans demonstrated that the racemic mixture of quizalofop ethyl and the resolved R-enantiomer, quizalofop-P-ethyl have nearly identical pathways (DP# 182751, J. Stokes, 7/15/93). To support the current petition to uses on genetically modified corn, a metabolism study in genetically modified corn containing the AAD-1 gene was submitted.  The petitioner proposed that the metabolism of quizalofop-P-ethyl ester 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 hydrolysis 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 quizalofop does not occur.  In hens quizalofop-P acid is utilized in fatty chain elongation to form quizalofop-pentanoic 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 adequately understood based on previously submitted plant metabolism studies with soybean, cotton, tomatoes, potatoes, sugar beets, barley, flaxseed, sunflower and wheat.   In addition, adequate metabolism studies with genetically 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 in Animals:  The qualitative nature of the residue in livestock is adequately understood based on metabolism studies with goats and poultry.  The studies indicated that quizalofop ethyl is metabolized in livestock via hydrolysis to quizalofop acid which then 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 quizalofop does not occur.  The residues of concern in livestock commodities are quizalofop 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 days before 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 ethyl soil treatment and has confirmed the hydrolysis of the ethyl ester, and the cleavage of the enol and ether linkage metabol - ic pathways.  The data support a 120-day plant-back interval.  The nature of the residue in rotational crops is adequately under - stood and is the same as identified above for tomatoes, cotton - seed, soybeans, 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 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
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 tentatively considered to be adequate, pending submission of storage stability data demonstrating the stability of quizalofop-P-ethyl and quizalofop acid in/on field corn 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 total 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 MRL calculator, the recommended tolerances are 0.02, 0.02, and 0.03 ppm in/on corn forage, grain, and stover, respectively.  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.

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 PHIs.  The maximum total quizalofop-P-ethyl residues [sum of quizalofop-P-ethyl and quizalofop acid residues (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 MRL calculator, the recommended tolerances are 0.20, 0.20, and 0.30 ppm in/on sorghum forage, grain, and stover, respectively.  These recommendations are identical to the tolerance levels proposed by 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 residue 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 with 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.  Summary of Residues from the Crop Field Trials with Quizalofop-P-ethyl.
                                  Crop Matrix
                                 Applic. Rate
                                   (lb ai/A)
                                  PHI (days)
                                Residues (ppm)
                                       
                                       
                                       
                                       n
                                     Mean
                                   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 DuPont(TM) INZEN(TM) 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.


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 phytotoxicity concerns preclude corn processing studies at higher treatment rates.

Adequate 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 processing 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 for 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 Trials: 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, soybean, and wheat commodities, have been submitted previously.  The available wheat storage stability data are tentatively 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 stability data will be re-evaluated.


Milk, Meat, Poultry and Eggs:  Adequate ruminant and poultry feeding studies were submitted 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-calculated 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-ethyl 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 water sources, the SCIGROW 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 (direct 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).  DEEM(TM)-FCID incorporates the food consumption data from the USDA's Continuing Surveys of Food Intakes by Individuals (CSFII; 1994-1996 and 1998).  The chronic analysis incorporated tolerance level residues for all commodities and 100 %CT was assumed.  DEEM(TM) (ver 7.78) default 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 MI dry pea application scenario.   Table 5.4.6 summarizes the dietary exposures and the corresponding %cPADs for the population subgroups (D395387, S. Tadayon, 10/25/2011).

5.4.2	Percent Crop Treated Used in Dietary Assessment

The chronic analysis 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 analysis 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-ethyl in support of field corn and sorghum.   Since the drinking water estimate was 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 highly 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 likely" 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 highly 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 population

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 always a potential source of exposure to residents nearby to spraying operations.  This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for 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/labeling.  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 appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods.  After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift with specific products with significant risks associated with drift.


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 analysis incorporating exposures 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 mechanism 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 by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that quizalofop-P-ethyl has a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.


9.0 Occupational Exposure/Risk Characterization

 A separate memorandum summarizes HED's assessment of the occupational exposure and risks of use of quizalofop ethyl 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 pressure (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 potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010 (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 by 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-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for quizalofop-P-ethyl.
















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, D384661, 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 Residue Data., D395630, 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.Appendix 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-ethyl are 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 - mammalian	
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
                                       
                                      yes
                                      yes
                                       
870.6100a  Acute Delayed Neurotoxicity (hen)	
870.6100b  90-Day Neurotoxicity (hen)	
870.6200a  Acute Neurotoxicity Screening Battery (rat)	
870.6200b  90-Day Neurotoxicity Screening Battery (rat)	
870.6300    Develop. Neurotoxicity	
                                      no
                                      no
                                      no
                                      no
                                      no
                                       -
                                       -
                                       -
                                       -
                                       -
                                       
870.7485    General Metabolism	
870.7600    Dermal Penetration	
870.7800    Immunotoxicity	
                                      yes
                                      no
                                 Conditionally
                                      yes
                                      no
                                      yes
                                       


A.2	Toxicity Profiles
 
 Table A.2.1 Acute Toxicity Profile of Quizalofop ethyl.
 
 
                                OPPTS Guideline
 
                                   Study Type
 
                                      MRID
 
                                    Results
 
                               Toxicity Category
 870.1100
 Acute oral toxicity / rat
 00146669
 LD50 = 1670 mg/kg (M)
              1480 mg/kg (F)
                                      III
 870.1200
 Acute dermal toxicity / rat
 00146670
 LD50 => 5000 mg/kg
                                       IV
 870.1300
 Acute inhalation toxicity / rat
 00146674
 LC50 = 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 Type/
 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.
 Reproductive:
 NOAEL=5 mg/kg/day; LOAEL= 20 mg/kg/day based on decreased percentage of pup born alive.
 Offspring:
 NOAEL=5 mg/kg/day; LOAEL= 20 mg/kg/day based on decreased pup weights.
 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 only.
 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 
 - mouse
 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.
 Cancer 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
 


