0.013728
                                     0.019
                                   0.032728
                                     2100
Child 1< 2 years old  -  Turf (Liquids) Hand-to-Mouth[2]
                                      70
                                      100
                                     0.70
                                   0.023500
                                     0.021
                                   0.044500
                                     1600
[1] The LOC of 100 includes the standard inter- (10x) and intra- (10x) species uncertainty factors totaling 100, as well as an FQPA SF of 1x.)
[2] Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC
[3] Residential Exposure = [Oral exposure + Inhalation Exposure].  (Source: Table 6.4, Section 6.4).
[4] Total Exposure = Avg Food & Water Exposure + Residential Exposure)
[5] Aggregate MOE = [NOAEL / (Avg Food & Water Exposure + Residential Exposure)]

      6.7.  Intermediate-Term Aggregate Risk

Intermediate-term aggregate exposure takes into account intermediate-term residential exposure plus chronic exposure to food and water (considered to be a background exposure level). An intermediate-term adverse effect was identified, however, quinclorac is not registered for any use patterns that would result in intermediate-term residential exposure; therefore, an intermediate-term aggregate risk assessment was not performed nor required.

      6.8.  Chronic Aggregate Risk

In examining chronic aggregate risk, HED has assumed that the only pathway of exposure relevant to the chronic time frame is dietary exposure. Therefore, the chronic aggregate risk is comprised of exposures to quinclorac residues in food and drinking water and is equivalent to the chronic dietary risk estimates summarized in Table 5.4.6 in Section 5.4.4. The chronic risk estimates are below HED's level of concern for all population subgroups.

      6.9.  Cancer Aggregate Risk

HED has concluded that assessments using a non-linear approach (e.g. a chronic RfD-based approach) will adequately account for all chronic toxicity, including carcinogenicity that could result from exposure to quinclorac. Chronic aggregate risk estimates are below HED's level of concern, therefore, cancer risk is also below HED's level of concern.

      6.10.  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 quinclorac and any other substances and quinclorac 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 quinclorac 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/.

 Occupational Exposure/Risk Characterization

There are registered agricultural uses associated with quinclorac, and the proposed new uses (i.e., rhubarb and low growing berries in subgroup 13-07H, except strawberry) are agricultural uses as well; therefore, there is the potential for occupational handler and post-application exposure. However,  since no dermal endpoints were selected, only inhalation exposure estimated risks were able to be quantified.

      6.11.  Short-/Intermediate-/Long-Term/Cancer (if needed) Handler Risk

Table 8.1.1 presents the short-term inhalation risk estimates for the quinclorac proposed new uses.  Table 8.1.2 presents occupational handler risk estimates associated with already registered uses.  Since the short- and intermediate-term endpoints and PODs are the same for each route of exposure, only short-term exposures were estimated, and are considered protective of intermediate-term exposure and risk.  Occupational handler scenarios resulted in estimated MOEs greater than the levels of concern (inhalation LOC = 100) at baseline.

The Agency has evaluated scenarios that may be limited in nature such as flagging during aerial applications because engineering controls (i.e., Global Positioning Satellite technology) are now predominantly used as indicated by the 1998 National Agricultural Aviation Association (NAAA) survey of their membership.  It appears, however, flaggers are still used in approximately 10 to 15 percent of aerial application operations.  In cases like these, the Agency strongly encourages the use of the engineering control system but will continue to evaluate risks for flaggers and any other population where a clear exposure pathway exists until the potential for exposure is eliminated.  The Agency is aware that NAAA is conducting another survey on exposure issues and will consider those results as are timely and appropriate.

HED has no data to assess exposure for pilots using open cockpits.  The only data available are representing exposure for pilots in enclosed cockpits.  Therefore, pilot exposure and risk estimates are determined assuming use of engineering control (enclosed cockpits) and baseline attire (i.e., long-sleeve shirt, long pants, shoes, and socks); pilots are not required to wear protective gloves.  With this level of protection, there are no risk estimates of concern for aerial applicators.

Table 8.1.1. Quinclorac Occupational Handler Risk Estimates For Proposed New Uses
                                     Site
                               Exposure Scenario
                              Application Rate[1]
                       Amount Handled / Area Treated[2]
                    Inhalation Unit Exposures[3] (ug/lb ai)
                              Inhalation Dose[4]
                                  (mg/kg-day)
                               Inhalation MOE[5]

                                Worker Activity
                                  Formulation
                             Application Equipment
                                     Value
                                     Units
                                     Value
                                     Units
                                      No-R
           Low growing berries, except strawberries, subgroup 13-07H
                                      M/L
                                    DF/WDG
                              Aerial; Chemigation
                                     0.25
                                  lb ai/acre
                                      350
                                     acres
                                     8.96
                                    0.0098
                                     7,100

                                  Groundboom

                                      80

                                    0.0022
                                    31,000

                                  Applicator
                       Spray
(all starting formulations)
                                    Aerial
                                     0.25
                                  lb ai/acre
                                      350
                                     acres
                         0.068
(Engineering Controls)
                        0.000074
(Engineering Controls)
                        940,000
(Engineering Controls)

                                  Groundboom

                                      80

                                     0.34
                                   0.000085
                                    820,000

                                     M/L/A
                                    DF/WDG
                       Mechanically-pressurized Handgun
                                     0.025
                                 lb ai/gallon
                                     1000
                                    gallons
                                      3.9
                                    0.0012
                                    57,000

                                    Flagger
                       Spray
(all starting formulations)
                                    Aerial
                                     0.25
                                  lb ai/acre
                                      350
                                     acres
                                     0.35
                                    0.00038
                                    180,000
                                    Rhubarb
                                      M/L
                                    DF/WDG
                              Aerial; Chemigation
                                     0.37
                                  lb ai/acre
                                      350
                                     acres
                                     8.96
                                     0.015
                                     4,800

                                      M/L

                                  Groundboom

                                      80

                                    0.0033
                                    21,000

                                  Applicator
                       Spray
(all starting formulations)
                                    Aerial
                                     0.37
                                  lb ai/acre
                                      350
                                     acres
                         0.068
(Engineering Controls)
                        0.00011
(Engineering Controls)
                        640,000
(Engineering Controls)

                                  Groundboom

                                      80
                                     acres
                                     0.34
                                    0.00013
                                    560,000

                                     M/L/A
                                    DF/WDG
                       Mechanically-pressurized Handgun
                                     0.037
                                 lb ai/gallon
                                     1000
                                    gallons
                                      3.9
                                    0.0018
                                    39,000

                                    Flagger
                       Spray
(all starting formulations)
                                    Aerial
                                     0.37
                                  lb ai/acre
                                      350
                                     acres
                                     0.35
                                    0.00057
                                    120,000
[1] Based on the proposed crops listed on the registered label (EPA Reg. No. 42750-169);
[2] Exposure Science Advisory Council Policy #9.1 ;
[3] Based on "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (March, 2012);
[4] Inhalation Dose = Dermal Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/A) x Area Treated or Amount Handled (A/day or gal/day)/BW (kg);
[5] Inhalation MOE = Inhalation NOAEL (70 mg/kg/day)/ Inhalation Dose (mg/kg/day); LOC = 100.

              Table 8.1.2. Summary of Quinclorac Registered Uses
                                     Site
                               Exposure Scenario
                              Application Rate[1]
                       Amount Handled / Area Treated[2]
                    Inhalation Unit Exposures[3] (ug/lb ai)
                              Inhalation Dose[4]
                                  (mg/kg-day)
                               Inhalation MOE[5]

                                Worker Activity
                                  Formulation
                             Application Equipment
                                     Value
                                     Units
                                     Value
                                     Units
                                     No-R
                                     Rice
                                      M/L
                                    DF/WDG
                                    Aerial
                                      0.5
                                  lb ai/acre
                                     1200
                                     acres
                                     8.96
                                     0.068
                                     1,000

                                  Groundboom

                                      200

                                     0.011
                                     6,200

                                      WSP
                                    Aerial

                                     1200

                         0.068
(Engineering Controls)
                        0.00051
(Engineering Controls)
                        140,000
(Engineering Controls)

                                  Groundboom

                                      200

                          0.24
(Engineering Controls)
                        0.00030
(Engineering Controls)
                        230,000
(Engineering Controls)

                                    L/SC/EC
                                    Aerial
                                     0.47

                                     1200

                                     0.219
                                    0.0016
                                    45,000

                                  Groundboom

                                      200

                                    0.00026
                                    270,000

                                  Applicator
                       Spray
(all starting formulations)
                                    Aerial
                                      0.5
                                  lb ai/acre
                                     1200
                                     acres
                         0.068
(Engineering Controls)
                        0.00051
(Engineering Controls)
                        140,000
(Engineering Controls)

                                  Groundboom

                                      200

                                     0.34
                                    0.00043
                                    160,000

                                    Aerial
                                     0.47

                                     1200

                         0.068
(Engineering Controls)
                        0.00048
(Engineering Controls)
                        150,000
(Engineering Controls)

                                  Groundboom

                                      200

                                     0.34
                                    0.0004
                                    180,000

                                    Flagger
                       Spray
(all starting formulations)
                                    Aerial
                                      0.5
                                  lb ai/acre
                                      350
                                     acres
                                     0.35
                                    0.00077
                                    91,000

                                     0.47

                                    0.00072
                                    97,000
                               Sorghum and Wheat
                                      M/L
                                    DF/WDG
                                    Aerial
                                     0.375
                                  lb ai/acre
                                     1200
                                     acres
                                     8.96
                                     0.050
                                     1,400

                                  Groundboom

                                      200

                                     8.96
                                    0.0084
                                     8,300

                                    L/SC/EC
                                    Aerial
                                     0.35

                                     1200

                                     0.219
                                    0.0012
                                    61,000

                                  Groundboom

                                      200

                                     0.219
                                    0.00019
                                    370,000

                                  Applicator
                       Spray
(all starting formulations)
                                    Aerial
                                     0.375
                                  lb ai/acre
                                     1200
                                     acres
                         0.068
(Engineering Controls)
                        0.00038
(Engineering Controls)
                        180,000
(Engineering Controls)

                                  Groundboom

                                      200

                                     0.34
                                    0.00032
                                    220,000

                                    Aerial
                                     0.35

                                     1200

                         0.068
(Engineering Controls)
                        0.00036
(Engineering Controls)
                        200,000
(Engineering Controls)

                                  Groundboom

                                      200

                                     0.34
                                    0.00030
                                    230,000

                                    Flagger
                       Spray
(all starting formulations)
                                    Aerial
                                     0.375
                                  lb ai/acre
                                      350
                                     acres
                                     0.35
                                    0.00057
                                    120,000

                                    Aerial
                                     0.35

                                    0.00054
                                    130,000
Agricultural fallow/idleland/conservation reserves; Nonagricultural uncultivated areas/soils; Grass forage/fodder/hay; Grasses grown for seed; Pastures and Rangelands
                                      M/L
                                    DF/WDG
                                    Aerial
                                     0.75
                                  lb ai/acre
                                     1200
                                     acres
                                     8.96
                                     0.10
                                      690

                                  Chemigation

                                      350

                                     0.029
                                     2,400

                                  Groundboom

                                      200

                                     0.017
                                     4,200

                                    L/SC/EC
                                    Aerial
                                     0.73
                                  lb ai/acre
                                     1200
                                     acres
                                     0.219
                                    0.0024
                                    29,000

                                  Chemigation

                                      350

                                    0.00070
                                    100,000

                                  Groundboom

                                      200

                                    0.00040
                                    180,000

                                  Applicator
                       Spray
(all starting formulations)
                                    Aerial
                                     0.75
                                  lb ai/acre
                                     1200
                                     acres
                         0.068
(Engineering Controls)
                        0.00077
(Engineering Controls)
                         92,000
(Engineering Controls)

                                  Groundboom

                                      200

                                     0.34
                                    0.00064
                                    110,000

                                    Flagger
                       Spray
(all starting formulations)
                                    Aerial
                                     0.75
                                  lb ai/acre
                                      350
                                     acres
                                     0.35
                                    0.0012
                                    61,000
Agricultural and nonagricultural rights of way/fencerows/hedgerows; Agricultural uncultivated areas; Utility poles/rights of way
                                      M/L
                                    DF/WDG
                       Mechanically-pressurized Handgun
                                     0.15
                                 lb ai/gallon
                                     1000
                                    gallons
                                     8.96
                                     0.017
                                     4,200

                                  Applicator
                       Spray
(all starting formulations)
                       Mechanically-pressurized Handgun
                                     0.15
                                 lb ai/gallon
                                     1000
                                    gallons
                                      3.9
                                    0.0073
                                     9,600

                                     0.296

                                     0.014
                                     4,900

                                      L/A
                                       G
                                Rotary spreader
                                     0.68
                                  lb ai/acre
                                       5
                                     acres
                                      10
                                    0.00043
                                    160,000

                                     M/L/A
                                    DF/WDG
                                   Backpack
                                     0.15
                                 lb ai/gallon
                                      40
                                    gallons
                                     2.58
                                    0.00019
                                    360,000

                                    L/SC/EC

                                     0.296

                                    0.00038
                                    180,000
Airports/landing fields
                                     M/L/A
                                DF/WDG; L/SC/EC
                                   Backpack
                                     0.15
                                 lb ai/gallon
                                      40
                                    gallons
                                     2.58
                                    0.00019
                                    360,000

                         Manually-pressurized Handwand

                                      30
                                    0.0023
                                    31,000

                       Mechanically-pressurized Handgun
                                     0.75
                                  lb ai/acre
                                       5
                                     acres
                                      42
                                    0.0020
                                    35,000
Commercial/industrial lawns; Recreation area and residential lawns; Ornamental lawns and turf
                                      L/A
                                       G
                                 Belly grinder
                                     0.68
                                  lb ai/acre
                                       1
                                     acres
                                      62
                                    0.00053
                                    130,000

                                Rotary spreader

                                       5

                                      10
                                    0.00043
                                    160,000

                                  Applicator
                                    RTU (L)
                             Trigger-spray bottle
                                    0.0172
                                 lb ai/bottle
                                       5
                                    bottles
                                     61.2
                                   0.000066
                                   1,100,000

                                     M/L/A
                                    DF/WDG
                                   Backpack
                                     0.28
                                 lb ai/gallon
                                      40
                                    gallons
                                     2.58
                                    0.00036
                                    190,000

                         Manually-pressurized Handwand

                                      30
                                    0.0042
                                    17,000

                                   Backpack
                                     0.15
                                 lb ai/gallon
                                      40
                                    gallons
                                     2.58
                                    0.00019
                                    360,000

                         Manually-pressurized Handwand

                                      30
                                    0.0023
                                    31,000

                       Mechanically-pressurized Handgun
                                      1.4
                                  lb ai/acre
                                       5
                                     acres
                                      42
                                    0.0037
                                    19,000

                       Mechanically-pressurized Handgun
                                     0.75

                                    0.0020
                                    35,000

                                    L/SC/EC
                                   Backpack
                                     0.16
                                 lb ai/gallon
                                      40
                                    gallons
                                     2.58
                                    0.00021
                                    340,000

                         Manually-pressurized Handwand

                                      30
                                    0.0024
                                    29,000

                       Mechanically-pressurized Handgun
                                     0.78
                                  lb ai/acre
                                       5
                                     acres
                                      1.9
                                   0.000093
                                    760,000
Ornamental lawns and turf
                                      M/L
                                    DF/WDG
                              Aerial; Chemigation
                                      1.4
                                  lb ai/acre
                                      350
                                     acres
                                     8.96
                                     0.055
                                     1,300

                                  Groundboom

                                      80

                                     0.013
                                     5,600

                                    L/SC/EC
                              Aerial; Chemigation
                                     0.78

                                      350

                                     0.219
                                    0.00075
                                    94,000

                                  Groundboom

                                      80

                                    0.00017
                                    410,000

                                  Applicator
                       Spray
(all starting formulations)
                                    Aerial
                                      1.4
                                  lb ai/acre
                                      350
                                     acres
                         0.068
(Engineering Controls)
                        0.00042
(Engineering Controls)
                        170,000
(Engineering Controls)

                                  Groundboom

                                      80

                                     0.34
                                    0.00048
                                    150,000

                                    RTU (L)
                             Trigger-spray bottle
                                    0.0172
                                 lb ai/bottle
                                       5
                                    bottles
                                     61.2
                                   0.000066
                                   1,100,000

                                    Flagger
                       Spray
(all starting formulations)
                                    Aerial
                                      1.4
                                  lb ai/acre
                                      350
                                     acres
                                     0.35
                                    0.0022
                                    33,000
Golf course turf
                                      M/L
                                    DF/WDG
                                  Groundboom
                                      1.4
                                  lb ai/acre
                                      40
                                     acres
                                     8.96
                                    0.0063
                                    11,000

                                       G
                            Tractor-drawn Spreader
                                     0.68

                                      1.7
                                    0.00058
                                    120,000

                                    L/SC/EC
                                  Groundboom
                                     0.78

                                     0.219
                                   0.000085
                                    820,000

                                      L/A
                                       G
                                Rotary spreader
                                     0.68
                                  lb ai/acre
                                       5
                                     acres
                                      10
                                    0.00043
                                    160,000

                                  Applicator
                                       G
                            Tractor-drawn Spreader
                                     0.68
                                  lb ai/acre
                                      40
                                     acres
                                      1.2
                                    0.00041
                                    170,000

                       Spray
(all starting formulations)
                                  Groundboom
                                     0.78

                                     0.34
                                    0.00013
                                    530,000

                                     M/L/A
                                    DF/WDG
                       Mechanically-pressurized Handgun
                                      1.4
                                  lb ai/acre
                                       5
                                     acres
                                      42
                                    0.0037
                                    19,000

                                    L/SC/EC

                                     0.78

                                      1.9
                                   0.000093
                                    760,000
[1] Based on latest LUIS report current as of 7/19/2012;
[2] Exposure Science Advisory Council Policy #9.1;
[3] Based on "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (March, 2012);
[4] Inhalation Dose = Dermal Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/A) x Area Treated or Amount Handled (A/day or gal/day)/BW (kg);
[5] Inhalation MOE = Inhalation NOAEL (70 mg/kg/day)/ Inhalation Dose (mg/kg/day); LOC = 100.

      6.12.  Short-/Intermediate-/Long-Term/Cancer (if needed) Post-Application Risk

HED uses the term post-application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re-entry exposure).  Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting.  Post-application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical's degradation properties.  In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post-application exposure.

            6.12.1. Dermal Post-application Risk

Quinclorac proposed new uses, as well as already registered, include agricultural sites including rice, sorghum, wheat, rhubarb and low growing berries (subgroup 13-07H), except strawberries.  Since no toxicological dermal endpoint was selected; no dermal occupational risk estimate was quantified, and therefore no risks of concerns were identified.

It is the policy of HED to use the best available data to assess post-application exposure.  Sources of generic post-application data, used as surrogate data in the absence of chemical-specific data, are derived from Agricultural Reentry Task Force (ARTF) exposure monitoring studies, and, as proprietary data, are subject to the data protection provisions of FIFRA.  The standard values recommended for use in predicting post-application exposure that are used in this assessment, known as "transfer coefficients",  are presented in the "Science Advisory Council for Exposure (ExpoSAC) Policy 3" http://www.epa.gov/pesticides/science/exposac_policy3.pdf)), which, along with additional information about the ARTF data, can be found at http://www.epa.gov/pesticides/science/post-app-exposure-data.html.

            6.12.2. Inhalation Post-application Risk

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for quinclorac at this time primarily because of its vapor pressure (2.7 x 10-7 mm Hg @ 25.0°C), and the proposed use rates.  However, there are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated areas.  These potential sources include volatilization of pesticides and re-suspension 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 quinclorac.

Although a quantitative post-application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational handlers.  Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post-application exposure.  Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post-application inhalation exposure scenarios.

 References

Cropp-Kholligian, B. 9/24/2012. Quinclorac and the Dimethylamine (DMA) Salt of Quinclorac.  Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 Registration Action on Rhubarb and Low Growing Berry except Strawberry, Subgroup 13-07H and the Registration Review Action.  D404795 and D404914

Y. Donovan et al, 8/5/2009. PP# 8F7442. Human Health Risk Assessment for Quinclorac New Use on Pasture/Rangeland.  D359759.

Drew, W. and Dow, M. 6/2/2009. Quinclorac. Human Health Risk Assessment for the Proposed Food/Feed Use of the Herbicide (Associated with Section 18 Registration) on Cranberries in Massachusetts.

Greear, W. and Rinde, E. 8/26/1992. Second Carcinogenicity Peer Review of Quinclorac. TXR No. 0010416.

Hummel, S. and Otakie, G. 9/6/2012. Draft. Quinclorac on Rhubarb and Low Growing Berries (except Strawberry).   Summary of Analytical Chemistry and Residue Data.  Residue Chemistry Considerations for Registration Review. D397719, 404569, 404912

Lowit, M. and Andrews, M. 8/9/2012. Quinclorac: Drinking Water Assessment to Support Proposed New Use on Rhubarb and Low Growing Berries Except Strawberry (subgroup 13-07H). D397720.

Lowit, M. and Andrews, M. 9/14/2012. Quinclorac: Registration Review Drinking Water Assessment. D405093.

Nieves, I. 9/18/2012. Quinclorac: Occupational and Residential Exposure/Risk Assessment for Registration Review and for Proposed Uses on Rhubarb and Cranberry (and other Low Growing Berries in Subgroup 13-07H, except strawberry). D404915, D404797

O'Rourke, K. 9/23/2010. Quinclorac. Response to BASF Corporation's Request to Waive the Requirement of a 28-Day Inhalation Toxicity Study for Quinclorac. D376603. TXR No. 0055511.

Recore, S. 9/25/12. Quinclorac: Updated Tier 1 Review of Human Incidents. D405512.

Shah, PV and Rowland, J. 8/4/1998. Quinclorac  -  Report of the Hazard Identification Assessment Review Committee. HED Doc. No. 012717.
Tarplee, B. 10/14/1998. Quinclorac  -  Report of the FQPA Safety Factor Committee. TXR No. 0012902.

Van Alstine, J. 9/2012. Quinclorac: Summary of Hazard and Science Policy Council (HASPOC) Meeting of June 21, 2012:  Recommendations on the need for a neurotoxicity Battery Study and a DNT study. TXR #:  0056385

 Appendix A.  Toxicology Profile and Executive Summaries

A.1	Toxicology Data Requirements
The requirements (40 CFR 158.340) for [Type of Use (e.g., food vs. non food)] for [CHEMICAL NAME] are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.
                                     Test

                                   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    21-/90-Day Inhalation
                                      yes
                                      yes
                                      yes
                                      no
                                     no[2]
                                      yes
                                    yes[1]
                                      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
870.5900    Mutagenicity -- Other Genotoxic Effects
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.6100a  Acute Delayed Neurotox. (hen)
870.6100b  90-Day Neurotoxicity (hen)
870.6200a  Acute Neurotox. Screening Battery (rat)
870.6200b  90-Day Neuro. Screening Battery (rat)
870.6300    Develop. Neuro
                                      no
                                      no
                                     no[3]
                                     no[3]
                                     no[3]
                                       -
                                       -
                                       -
                                       -
                                       -
870.7485    General Metabolism
870.7600    Dermal Penetration
870.7800    Immunotoxicity
                                      yes
                                       -
                                      yes
                                      yes
                                       -
                                      yes
[1] The data requirement for a dog 90-day subchronic oral toxicity is satisfied by the dog 1-year chronic oral study.
2 waived (D376603, TXR 0055511)
3 waived (HASPOC, TXR 0056385)

A.2	Toxicity Profiles

Table A.2.1	Acute Toxicity Profile  -  Quinclorac
Guideline No.
Study Type
MRID(s)
                                    Results
                               Toxicity Category
870.1100
Acute oral - rat
                                   41063505
                                    (1989)

LD50 >2610 mg/kg

                                     III
870.1100
Acute oral - rat
                                   41063506
                                    (1983)
LD50 (male) = 3060 mg/kg
LD50 (female) = 2190 mg/kg
LD50 (combined) = 2680 mg/kg
                                      III
870.1100
Acute oral - mouse
                                   41063507
                                    (1986)
LD50 >5000 mg/kg

                                      IV
870.1200
Acute dermal - rat
                                   41063509
                                    (1983)
LD50 > 2000 mg/kg
                                      III
870.1300
Acute inhalation - rat
                                   41063510
                                    (1985)
LC50 > 5.2 mg/L
(4 hr exposure)
                                      III
870.2400
Acute eye irritation  -  rabbit
                                   41063511
                                    (1983)
Mild irritant reversible by day 8
                                      III
870.2500
Acute dermal irritation  -  rabbit
                                   41063512
                                    (1983)
Not an irritant
                                      III
870.2600
Skin sensitization  -  guinea pig
                                   40573301
                                    (1986)
Dermal sensitizer
                                      n/a

Table A.2.2	Subchronic, Chronic and Other Toxicity Profile  -  Quinclorac
                                Guideline No.
                                  Study Type
                    MRID No. (year)/ Classification /Doses
                                    Results
870.3100

90-Day oral toxicity (Wistar rat)
41063516 (1986)

Unacceptable/non-guideline based on lack of analyses of diet concentration, homogeneity, stability.

0, 1000, 4000 or 12,000 ppm in diet
M: 0, 76.8, 302, 930 mg/kg/day
F: 0, 86.7, 358, 1035 mg/kg/day
NOAEL = 302 mg/kg/day (males) and 358 mg/kg/day (females)
LOAEL = 930 mg/kg/day (males) and 1035 mg/kg/day (females) based on decreased body weight gain, food consumption and increased water intake in males and females; increased SGOT, SGPT and focal chronic interstitial nephritis in males.
870.3100

90-Day oral toxicity (B6C3F1/Crl Br  mouse)
41063519 (1988)
Acceptable/guideline when considered together with 41063519
0 or 500 ppm in diet
0 or 75 mg/kg/day
NOAEL = 75 mg/kg/day (HDT)
LOAEL was not established in this study (> 75 mg/kg/day)
870.3100

90-Day oral toxicity (B6C3F1/Crl Br  mouse)
41063518 (1986)
Acceptable/guideline when considered together with 41063518
0, 4000, 8000 or 16,000 ppm in diet
M: 0, 1000, 2202 or 4555 mg/kg/day
F: 0, 1467, 2735 or 5953 mg/kg/day
NOAEL not established in this study (<1000 mg/kg/day)
LOAEL = 1000 mg/kg/day (males) and 1467 mg/kg/day (females), based on decreased body weight gains.
870.3200

21-Day dermal toxicity (New Zealand White rabbit)
44342905 (1990)
Acceptable/guideline
0, 200 or 1000 mg/kg/day applied to skin daily for 21 days.
NOAEL = 1000 mg/kg/day (limit dose)
LOAEL not established in this study (> 1000 mg/kg/day).
870.3700a

Prenatal developmental in (Wistar rat)
41063524 (1987)
Acceptable/guideline
0, 24.4, 146 or 438 mg/kg/day (gavage)

Maternal NOAEL = 146 mg/kg/day
LOAEL = 438 mg/kg/day based on increased mortality, decreased food consumption and increased water consumption.
Developmental NOAEL >=438 mg/kg/day
LOAEL not established in this study (> 438 mg/kg/day).
870.3700b

Prenatal developmental in (Himalayan rabbit)
41063525 (1986), 41680501 (1990)
Acceptable/guideline
0, 70, 200 or 600 mg/kg/day (gavage)

Maternal NOAEL = 70 mg/kg/day
LOAEL = 200 mg/kg/day based on decreased body weight gain and food consumption (and increased water consumption).
Developmental NOAEL = 200 mg/kg/day
LOAEL = 600 mg/kg/day based on increased resorption rate, postimplantation loss, decreased live fetuses and reduced fetal body weight.
870.3800

Reproduction and fertility effects
(Wistar rat)
41063526 (1988); 41874201, -02 (1991, 1988); 41910001 (1991)
Acceptable/guideline
0, 1000, 4000 or 12,000 ppm in diet
0, 40, 160 or 480 mg/kg/day
Parental/Systemic NOAEL = 160 mg/kg/day
LOAEL = 480 mg/kg/day based on reduced body weight in both sexes during premating and lactation periods.
Reproductive NOAEL = 480 mg/kg/day
LOAEL not established in this study (> 480 mg/kg/day).
Offspring NOAEL = 160 mg/kg/day
LOAEL = 480 mg/kg/day based on decreased pup weight, developmental delays and possible marginal effect on pup viability.
870.4300

Combined chronic toxicity/ carcinogenicity
(Wistar rat)
41063522 (1988); 42012901, -02 (1991)
Acceptable/guideline
0, 1000, 4000, 8000 or 12,000 ppm in diet
M:  0, 56, 186, 385 or 487 mg/kg/day
F: 0, 235, 478 or 757 mg/kg/day
NOAEL = 385 mg/kg/day (males and 478 mg/kg/day (females)
LOAEL = 487 mg/kg/day (males) based on increased incidence of pancreatic acinar cell hyperplasia and 757 (females) based on decreased body weight.

Equivocal increase in pancreatic acinar cell adenomas in males.
870.4100b

Chronic toxicity
 (Beagle dog)
41123201 (1987)
Acceptable/guideline
0, 1000, 4000 or 12,000 in diet
M:  0, 34, 142 or 513 mg/kg/day
F: 0, 35, 140 or 469 mg/kg/day
NOAEL = 142 mg/kg/day (males) and 140 mg/kg/day (females)
LOAEL = 513 mg/kg/day (males) and 469 mg/kg/day (females) based on decreased body weight gain and food efficiency, increased liver and kidney weights, decreased HgB, RBC, MCH and MCV and kidney degeneration.
870.4200

Carcinogenicity
(B6C3F1/Crl Br  mouse)
41063523 (1988)
Acceptable/guideline
0, 250, 1000, 4000 or 8000 ppm in diet
M: 0, 37.5, 150, 600 or 1200 mg/kg/day
NOAEL = 37.5 mg/kg/day
LOAEL = 150 mg/kg/day based on decreased body weight in males and females.

No evidence of carcinogenicity.
870. 5100
Bacterial reverse gene mutation
Ames assay S. typhimurium
41063527 (1984)
Acceptable/guideline
Dose range 0 to 5000 ug/plate with and without S9
Negative up to the limit dose (5000 ug/plate) with or without S9 in S. typhimurium strains TA98, TA100, TA1535, TA1537
870.5100

Bacterial reverse gene mutation
S. typhimurium/E.coli
41063528 (1988) Acceptable/guideline
Dose range 0 to 5000 ug/plate with and without S9
Negative up to the limit dose (5000 ug/plate) with or without S9 in S. typhimurium  strains TA98, TA100, TA1535, TA1537 and E. coli strain WP2 uvrA
870.5300
In vitro mammalian forward gene mutation, CHO cells/HGPRT locus
41680503 (1989)
Acceptable/guideline
Dose range 0 to 2150 ug/mL with or without S9
Negative for gene mutations up to cytotoxic doses (2000 ug/mL) with or without S9.
870.5375
In vitro mammalian chromosome aberration assay, human lymphocytes
41076103 (1986)
Acceptable/guideline
Dose range 125 to 1500 ug/mL without S9 and 250 to 2500 ug/mL with S9
Positive for chromosomal aberrations but only at cytotoxic concentrations (2000 ug/mL with S9 and 1000 ug/mL without S9).
870.5385

Cytogenetics  -  in vivo mouse micronucleus assay

41063530 (1989)
Acceptable/guideline
Single gavage doses up to 1000 mg/kg
Negative in male and female NMRI mice at all doses up to limit dose (1000 mg/kg).  Mid and high dose groups showed clinical signs of toxicity (irregular breathing, apathy, piloerection) but no toxicity to target cell was observed.
870.5550

Unscheduled DNA synthesis in primary rat hepatocytes
41063531 (1986)
Acceptable/guideline
Dose range 0 to 1520 ug/mL
Negative up to cytotoxic dose (1520 ug/mL).
870.7485

Metabolism and pharmacokinetics
(rat) - biodisposition
41063533 (1987)
Acceptable/guideline
Single gavage doses of 15 or 600 mg/kg of [14]C-quinclorac; 14 daily gavage doses of unlabeled quinclorac following by a single dose of [14]C-quinclorac
Quinclorac was rapidly absorbed and eliminated primarily in the urine (91-98% of dose) with small amounts (1-4%) eliminated in the feces by day 5 after dosing.  No radioactivity was detected in exhaled air.
870.7485
Metabolism and pharmacokinetics
(rat)  -  Biliary excretion studies
41063533 (1987)
Acceptable/guideline
Single gavage doses of 15 or 600 mg/kg [14]C-quinclorac
Biliary excretion was significant (11.5 to 14.5% of dose) at 600 mg/kg but was reabsorbed from the intestine and eliminated in the urine.
870.7485
Metabolism and pharmacokinetics
(rat)  -  Plasma level studies
41063533 (1987)
Acceptable/guideline
Single gavage doses of 15, 100, 600 or 1200 mg/kg
Multiple gavage doses of 15 or 600 mg/kg/day [14]C-quinclorac for 7 days.
Mean residues were detected in plasma 30 minutes postdosing following all dose regimens.  Quinclorac is poorly metabolized:  most of radioactivity was the parent compound.  Peak plasma levels of radioactivity after 7 days of dosing at 600 or 1200 mg/kg/day were observed between 7 to 48 hrs postdosing.
870.7485
Metabolism and pharmacokinetics
(rat)  -  Tissue level studies
41063533 (1987)
Acceptable/guideline
Multiple gavage doses of [14]C-quinclorac 15 or 1200 for 7 days.
The highest concentrations of radioactivity in tissues were found at 30 minutes after the final dose for low and high doses.  Significant tissue levels were not observed (<=0.45% of dose), with highest levels observed in the thyroid, bone marrow and adrenal.  Tissue levels were slightly greater in females.
870.7800
Immunotoxicity
female C57BL/6 J Rj mice (8/group)

48346101 (2010)
Acceptable/guideline
0 (control), 500, 1500, or 5000 ppm (equivalent to 0, 176, 439, or 1760 mg/kg bw/day, for 28  days
Immunotoxicity NOAEL is 5000 ppm (equivalent to 1760 mg/kg/day, the highest dose tested and above the limit dose);
LOAEL was not established.

A.3	Hazard Identification and Endpoint Selection

A.3.1	Acute Reference Dose (aRfD) - Females age 13-49

Study Selected: Developmental toxicity study in rabbits

MRID No.:  41063525; 41680501

Executive Summary: In a developmental toxicity study (MRID# 41063525), quinclorac (98.3% a.i.) was administered to fifteen female Himalayan Rabbits by gavage at dose levels of 0, 70, 200, or 600 mg/kg/day from gestational days 7 - 19, inclusive.

Maternal toxicity, observed at 200 mg/kg/day, was manifested as decreased body weight gain (36%) and food consumption (13%) during the dosing period.  Additional findings noted at 600 mg/kg/day, included increased water consumption (7% over entire gestation), increased incidence of clinical signs (reduced/no defecation, diarrhea, apathy and poor general state) and mortality and discoloration of the kidney. The maternal LOAEL is 200 mg/kg/day, based on decreased body weight gains and food consumption. The maternal NOAEL is 70 mg/kg/day.

Developmental toxicity, observed at 600 mg/kg/day consisted of increased rate of resorption and post-implantation loss, a decrease in the number of live fetuses, and reduced fetal body weight.  The NOAEL for developmental toxicity is 200 mg/kg/day.

Dose and Endpoint for Risk Assessment: Developmental NOAEL= 200 mg/kg/day based on increased rate of resorption and post-implantation loss, a decrease in the number of live fetuses, and reduced fetal body weight at 600 mg/kg/day  (LOAEL).

Comments about Study/Endpoint: The developmental effects are presumed to occur after a single exposure (dose) and thus were considered to be appropriate for this (acute) risk assessment.  This dose/endpoint is applicable only to Female 13 to 49 years old.

Uncertainty Factor (UF): 100 (10 x for inter-species extrapolation and 10x for intra-species variability, FQPA SF = 1x).

      aRfD=200 mg/kg/day (NOAEL)100 UF=2.0 mg/kg

      aPAD=2 mg/kg/day (aRfD)1 FQPA SF=2.0 mg/kg

A.3.2	Acute Reference Dose (aRfD) - General Population

An endpoint for acute dietary exposure to the general population was not selected because there was no single dose endpoint available in the database that was appropriate for this scenario

A.3.3	Chronic Reference Dose (cRfD) `

 Study Selected: Oncogenicity Feeding Study in Mice

MRID No.: 41063523

Executive Summary: In a carcinogenicity study (MRID# 41063523), B6C3F1/Crl Br mice (60 sex/dose) were administered via diets with Quinclorac (97.4 or 98.3% a.i) at dose levels of 0, 250, 1000, 4000, or 8000 ppm (equivalent to 0, 37.5, 150, 600 or 1200 mg/kg/day) for 6 months or 78 weeks.  Ten mice were terminated at 6 months.  The remainders were continued on the test material for 18 months.

At the end of 13 weeks, body weights in males and females receiving 8000 ppm were significantly lower than controls by 9.6% and 7.4%, respectively.  Body weights in males and females receiving 1000, 4000, and 8000 ppm for 78 weeks were significantly lower than controls (7.9 to 15.9% for males; 14.3 to 17.9 for females.  Treatment-related body weight reductions compared to controls were also noted in satellite males and females receiving 4000 and 8000 ppm for 6 months.  Absolute liver weights were significantly reduced in male and female mice receiving 8000 ppm for 78 weeks, but there was no effect on liver-to-body weight ratio.  Absolute kidney weights were decreased in males receiving 1000, 4000, and 8000 ppm and in females receiving 4000 and 8000 ppm for 78 weeks.  Relative kidney weights were decreased in males receiving 1000, 4000, and 8000 ppm for 78 weeks.  Dose-related increases in relative brain weights seen in males and females receiving 1000, 4000, and 8000 ppm.  Absolute liver weights were also reduced in males receiving 4000 and 8000 ppm for 6 months, while absolute kidney weights were reduced in all treated males.  A slight decrease in hematocrit values was noted in males and females receiving 8000 ppm for 6 months, but not 78 weeks.  Effects on other hematological parameters were not of biological significance.  There was no effect of dosing on mortality, food consumption, or clinical signs.  The LOAEL is 1000 ppm (150 mg/kg/day) based on effects on body weight.  The NOAEL is 250 ppm (37.5 mg/kg/day).  A maximum tolerated dose (MTD) was approached based on decreased body weights in males and females receiving 8000 ppm.

No evidence of histopathological or neoplastic lesions attributable to administration of any dose of Quinclorac was found in any tissue of any mouse.

Dose and Endpoint for Establishing RfD:  NOAEL = 37.5 mg/kg/day based on decreased body weights seen at 150 mg/kg/day (LOAEL).

Comments about Study/ Endpoint:  The endpoint selected from the mouse carcinogenicity study is appropriate for both the population and the duration of exposure. The NOAEL from this study is the lowest NOAEL in the database and therefore protective of all other effects.

Uncertainty Factor(s): 100 (10 x for inter-species extrapolation and 10x for intra-species variability; FQPA SF = 1X).

      cRfD=37.5 mg/kg/day (NOAEL)100 UF=0.38 mg/kg/day

cPAD=0.375 mg/kg/day (cRfD)1 FQPA SF=0.38 mg/kg/day

A.3.4	Incidental Oral Exposure (Short- and Intermediate-Term)

Study Selected: Developmental toxicity study in rabbits.

MRID Nos.: 41063525; 41680501

Executive Summary: See Appendix A, §870.3700b
Dose and Endpoint for Risk Assessment: Maternal NOAEL= 70 mg/kg/day based on decreased body weight gains and food consumption accompanied with increased water consumption at 200 mg/kg/day (LOAEL).

Comments about Study/Endpoint: This endpoint of toxicity occurred after short exposures to quinclorac and is suitable for this exposure scenario.

A margin of exposure (MOE) of 100 is applied to account for inter-species extrapolation (10x) and for intra-species variability (10x).

A.3.5	Dermal Exposure (Short-, Intermediate- and Long-Term)

A dermal endpoint was not selected because an appropriate endpoint was not available (no dermal toxicity was seen at the limit dose of 1000 mg/kg/day in a 21-day dermal toxicity study). Also, there are no susceptibility concerns.

A.3.6	Inhalation Exposure (Short-, Intermediate- and Long-Term)

A.3.7 	Inhalation Exposure (Short and Intermediate-Term)

Selected Study: Developmental toxicity study in rabbits.

MRID Nos.: 41063525; 41680501

Executive Summary: See Appendix A, §870.3700b

Dose and Endpoint for Risk Assessment: Maternal NOAEL= 70 mg/kg/day based on decreased body weight gains and food consumption accompanied with increased water consumption at 200 mg/kg/day (LOAEL).

Comments about Study/Endpoint: This endpoint of toxicity occurred after short exposures to quinclorac and is suitable for this exposure scenario.

A margin of exposure (MOE) of 100 is applied to account for inter-species extrapolation (10x) and for intra-species variability (10x).

A.3.7 	Inhalation Exposure (Long-Term)

Not applicable.  Long-term inhalation exposure is not anticipated under current use scenarios.

A.4	Executive Summaries

A.4.1	Subchronic Toxicity

	870.3100	90-Day Oral Toxicity - Rat

In a subchronic toxicity study (MRID 41063516), Quinclorac (96.5% a.i.) was administered to 10 Wistar Chhb-THOM (SPF) rats/sex/dose in diet, at dose levels of 0, 1000, 4000, or 12000 ppm (0, 76.8, 302.3 or 929.9 mg/kg/day for males and 0, 86.7, 358.0 or 1035.4 mg/kg/day for females).  There were no deaths occurred. No compound related clinical signs of toxicity were observed. The LOAEL is 12,000 ppm (males 929.9 and females 1035.4 mg/kg/day), based on decreases in body weight gain, food consumption and an increase in water intake in males and females, and decrease in monocytes in female, increases in SGOT and SGPT in males, and pathological changes in kidneys of males (slight to minimal focal chronic interstitial nephritis. The NOAEL is 4000 ppm (males 302.3 and females 358.0 mg/kg/day).

This subchronic toxicity study is classified unacceptable/non-guideline due to lack of information on the purity of the test material and information on stability and homogeneity of the test substance in the diet.

	870.3100	90-Day Oral Toxicity - Mouse

In a subchronic toxicity study (MRID 41063518), Quinclorac (98.29% a.i.) was administered to 10 B6C3F1/Crl BR mice/sex/dose in diet, at dose levels of 0, 4000, 8000, or 16000 ppm (0, 1000, 2202 or 4555 mg/kg/day for males and 0, 1467, 2735 or 5953 mg/kg/day for females). No deaths occurred. No compound related clinical signs of toxicity were observed. At 8000 and 16000 ppm there was an increase in water intake in males and females and BUN in males. There was decreased kidney weight in males and females and relative kidney weight in males in the 16,000 ppm group. At 4000 ppm there was decreased body weight gain in males and females. The LOAEL is 4,000 ppm (males 1,000 and females 1467 mg/kg/day), based on decreases in body weight. The NOAEL was not established.

This subchronic toxicity study is classified Acceptable/non- guideline requirement for a subchronic oral study (82-1) in mice. However taken with MRID 41063519, it is acceptable/ guideline.

In another subchronic toxicity study (MRID 41063519), Quinclorac (98.29% a.i.) was administered to 10 B6C3F1/Crl BR mice/sex/dose in diet, at dose levels of 0 or 500 ppm (75 mg/kg/day, HDT).  No deaths occurred. No compound related clinical signs of toxicity were observed. Females in the 500 ppm group had slightly (although statistically significant) reduced body weights when compared to controls on day 98. This decrease was minimal and is not believed to be compound related since body weights were not significantly different at any other time intervals. The NOAEL is 500 ppm (75 mg/kg/day).

This subchronic toxicity study is classified Unacceptable because only one dose level was tested.  However taken with MRID 41063518, it is acceptable /guideline.
	870.3150	90-Day Oral Toxicity - Dog

The data requirement for a dog 90-day subchronic oral toxicity is satisfied by the 1-year dog chronic oral study.

	870.3200	21/28-Day Dermal Toxicity  -  Rabbit

In a twenty-one day dermal toxicity study (MRID 44342905), Quinclorac (98.29% a. I.) in 0.5% carboxymethyl cellulose was applied dermally to 5 New Zealand White (KFM) albino rabbits/sex/dose at dose levels of 0, 40, 200 and 1000 mg/kg/day for 7 days a week for 3 weeks. The hair was clipped from the dorsal surface prior to treatment and once a week during the study. Test material was applied daily for 3 weeks to an area of skin approximately 10% of the total body surface area on the back of each rabbit and covered with a semi-occlusive gauze. After 6 hour exposure, the excess test material was removed from the treated area with a luke-warm water and kept open until next application. Vehicle control group received 2 ml/kg b.w of 0.5% carboxymethyl cellulose in water, while test groups received suspension of test material in aqueous 0.5% carboxymethyl cellulose (2 ml/kg/b.w).  There was no treatment-related clinical observations, changes in body weight gain, food consumption, histopathologic findings or hematologic or blood chemistry parameters after a 21 day (7 days/week) repeated application of Quinclorac at a nominal concentrations of 0, 40, 200 or 1000 mg/kg/day in 0.5% carboxymethyl cellulose. The limit dose is 1000 mg/kg/day. No mortality occurred at any dose level tested. No local skin irritation was reported during the study. The NOAEL >=1000 mg/kg/day, Limit Dose, (HDT; males and females). The LOAEL >1000 mg/kg/day (HDT; males and females).

This study is classified as Acceptable/Guideline and does satisfy the guideline requirements for a 21-day repeated dermal toxicity study in rabbits (82-2).

	870.3465	90-Day Inhalation  -  Rat

The requirement of a 28-day inhalation toxicity study was waived based on low volatility, low acute inhalation toxicity and large extrapolated inhalation MOE (D376603, 23 September 2010).

A.4.2	Prenatal Developmental Toxicity

	870.3700a Prenatal Developmental Toxicity Study - Rat

In a developmental toxicity study (MRID # 41063524), Quinclorac (96.5% a.i.) was administered to twenty-five female Wistar rats by gavage at dose levels of 0, 24.4, 146, and 438 mg/kg/day from gestational days 6-15, inclusive.  Maternal toxicity, observed at 438 mg/kg/day, was manifested as decreased food consumption (10-15%) and increased water consumption (31-54%) during the dosing and/or gestation period as well as mortality.  The maternal LOAEL is 438 mg/kg/day, based on decreased food consumption, increased water consumption and mortality.  The maternal NOAEL is 146 mg/kg/day.  No developmental toxicity was observed. The LOAEL for developmental toxicity is >436 mg/kg/day.  The developmental NOAEL is >=436 mg/kg/day.

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a developmental toxicity study in rats.

	870.3700b Prenatal Developmental Toxicity Study - Rabbit

In a developmental toxicity study (MRID# 41063525), Quinclorac (98.3% a.i.) was administered to fifteen female Himalayan Rabbits by gavage at dose levels of 0, 70, 200, or 600 mg/kg/day from gestational days 7 - 19, inclusive.  Maternal toxicity, observed at 200 mg/kg/day, was manifested as decreased body weight gain (36%) and food consumption (13%) during the dosing period.  Additional findings noted at 600 mg/kg/day, included increased water consumption (7% over entire gestation), increased incidence of clinical signs (reduced/no defecation, diarrhea, apathy and poor general state) and mortality and discoloration of the kidney. The maternal LOAEL is 200 mg/kg/day, based on decreased body weight gains and food consumption. The maternal NOEL is 70 mg/kg/day. Developmental toxicity, observed at 600 mg/kg/day consisted of increased rate of resorption and post-implantation loss, a decrease in the number of live fetuses, and reduced fetal body weight.  The NOAEL for developmental toxicity is 200 mg/kg/day. This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a developmental toxicity study (83-3b) in rabbits.

A.4.3	Reproductive Toxicity

	870.3800 Reproduction and Fertility Effects - Rat

In a 2-generation reproduction study (MRID # 41063526), Quinclorac (>=97.3% a.i.) was administered to Wistar rats (24/sex/group) at dietary levels of 0, 1,000, 4,000 or 12,000 ppm (0, 40, 160 or 480 mg/kg/day, respectively).

Parental toxicity: Evidence of toxicity was observed in the parental rats at 12,000 ppm (480 mg/kg/day). Fl males showed reduced mean body weight during premating, which largely reflected their decreased weights as pups at weaning (at week 0, -24%, p<0.0l, becoming less pronounced at week 18, -6% below controls, p<0.05). F0 males showed no effects. F0 females showed a small but statistically significant decrease in mean body weight at Week 24 of premating (-4%, p<0.05) but not at earlier times. F1 females had decreased body weights during premating (at Week 18, -12%; p<0.01): as with males, part of the decrease reflected smaller weights at weaning. During gestation, decreases of about -6% in mean body weight at Day 20 were observed for the F0 females in the second mating (p<0.01) and the Fl females in their only mating (p<0.05). However, in the second mating of F0 females, there was no significant effect. The F0 (first mating only) and Fl females showed reduced body weights during part or all of lactation (up to -10% below controls). In addition to body weight changes, an increased incidence of interstitial nephritis was observed in F0 and Fl females. The parental systemic toxicity LOAEL is 12,000 ppm (480 mg/kg/day), based on decreased body weight during premating and lactation. The NOAEL is 4000 ppm (160 mg/kg/day).

Reproductive toxicity: No effects on reproductive parameters were observed. The reproductive toxicity NOAEL is 12,000 ppm (480 mg/kg/day). A reproductive toxicity LOAEL was not established (>480 mg/kg/day).

Offspring toxicity: At 12,000 ppm (480 mg/kg/day), the major effect on pup growth and development was observed during lactation. Decreased pup weights were observed in male and female Fl and F2 pups during lactation (at Day 21 of lactation, 15-26% below controls; all generations p<0.0 1) and delayed physical development (delayed pinna unfolding and eye opening) was also observed. Decreased pup weight at Lactation Day 0 was seen only in the F2 male and female pups (approximately 7% below controls), a dose also associated with a slight decrease in maternal weight during gestation. Slightly decreased pup viability and survival were reported; however, these effects were marginal (<6%), not seen in all offspring generations and did not achieve statistical significance. The relationship to treatment of this finding is considered equivocal. The offspring LOAEL is 12,000 ppm (480 mg/kg/day), based on effects on pup growth with a possible marginal effect on pup viability. The offspring NOAEL is 4000 ppm (160 mg/kg/day).

This study is classified as Acceptable/guideline and satisfies the guideline requirement for a multigeneration reproductive toxicity study in the rodent (870.3800).

A.4.4	Chronic Toxicity

	870.4100a (870.4300) Chronic Toxicity  -  Rat

The combined chronic/carcinogenicity study satisfies this requirement.

	870.4100b Chronic Toxicity - Dog

In a 1-year feeding study in dogs (MRID 41123201), Quinclorac (97.4% a.i.) was administered to groups of 6 male and 6 female beagle dogs at dietary levels of 0, 1000, 4000 or 12000 ppm (equivalent to 0, 34, 142, or 513 mg/kg/day for males and 0, 35, 140, or 469 mg/kg/day for females) for 12 months. No effect on mortality was observed. Administration of 12000 ppm resulted in lower mean body weight, compared with control, reduced body weight gain and an adverse effect on food efficiency. There was a marginal reduction of body weight gain and food efficiency in male dogs fed 4000 ppm of test substance. In male dogs fed 12000 ppm of test substance, there were significant (<0.01) treatment-related reductions in hemoglobin concentration, erythrocyte count, and hematocrit, mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) values. In females fed 12000 ppm of test substance, significant reductions (p <0.05 or p <0.01) were seen in hemoglobin concentration, MCH, and MCV at all study intervals (weeks 13, 26, and 52), hematocrit at weeks 26 and 52 and erythrocyte count at week 26. In females fed 4000 ppm test substance, significant reductions (p <0.05) were seen at week 26 in hemoglobin concentration, erythrocyte count, and hematocrit. Administration of 12000 ppm of test substance resulted in decreases in a number of clinical chemistry parameters; however, significant (p <0.01) changes were noted only for creatinine, calcium, and albumin. However, it should be noted that, in most cases, clinical adverse effects are only associated with increased values for these parameters. At the 12000 ppm dose level, increase in absolute (p <0.01 for males) and relative liver weights (p <0.01 for both males and females) were observed for both sexes. Relative liver weights also were significantly increased (p <0.05) in females of the 4000 and 1000 ppm groups. Relative kidney weights were significantly increased (p <0.01) in both males and females of the 12000 ppm group and in males of the 4000 ppm group. There were no histopathologic correlates to account for the increased organ weights. Histopathologic findings in the liver were limited to an increase in focal mononuclear infiltration and to single cell necrosis in two dogs in the 12000 ppm group. Hydropic degeneration of the kidney was seen in two males and two females of the 12000 ppm group.

The LOAEL is 12000 ppm (513 mg/kg/day-males, 469 mg/kg/day- females) based on the reduced body weight gain, adverse effect on food efficiency, hematological and clinical chemistry values, increased liver and kidney weights, and microscopic findings. The NOAEL is 4000 ppm (142 mg/kg/day for males and 140 mg/kg/day for females).
This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a feeding study (83-1) in dogs.

A.4.5	Carcinogenicity

	870.4200a Carcinogenicity Study - rat

In a combined chronic toxicity/carcinogenicity study (MRID# 41063522), Wistar (chbb-THOM) rats (80/sex/group) were administered via diets with Quinclorac (97.4% a.i.) at dose levels of 0, 1000, 4000, 8000, or 12000 ppm (equivalent to 0, 56, 186, 385, or 487 mg/kg/day for males and 0, 60, 235, 478, or 757 mg/kg/day for females, respectively). Ten rats/sex/group were terminated at 12 months. The remainders were continued on the test material for 24 months. Body weights were slightly reduced in females received 12000 ppm when compared to the control. No effects were seen on survival, food consumption, clinical signs of toxicity, clinical laboratory findings, organ weight, or gross or histologic findings. For females, the LOEL was 12000 ppm based on slight decreases in mean body weight and the NOEL was 8000 ppm. For males, the LOEL was not established and the NOEL was 12000 ppm (the highest dose tested).  This study was originally classified as supplementary (upgradeable) because a maximum tolerated dose (MTD) was not established for the carcinogenicity part of the study; in addition, there was a probability of misdiagnosis of microscopic findings caused by tabulation of NAD (no abnormalities detected) for tissues in several animals with severe postmortem autolysis.

Additional data (MRID# 42012901, 42012902) were submitted to the Agency in which adequately addressed the deficiencies described above. For chronic toxicity, the LOEL was estimated to be 12000 ppm (487 mg/kg/day for males and 757 mg/kg/day for females) based on slight decrease in body weight in females and an increase in acinar cell hyperplasia of the pancreas in males. The NOEL was 8000 ppm (385 mg/kg/day for males and 478 mg/kg/day for females). For carcinogenicity, the data indicate an increase in acinar cell hyperplasia of the pancreas in males at 12000 ppm (35%) when compared to controls (5.7%). In addition, there was an increase in the incidence of acinar cell adenoma of the pancreas in males in the 12000 ppm group (20%) when compared to the control (1.4%).

The study was upgraded to acceptable and satisfies guideline requirement for a combined chronic toxicity/carcinogenicity study in rats (83-5).

	870.4200b Carcinogenicity (feeding) - Mouse
In a carcinogenicity study (MRID# 41063523), B6C3F1/Crl Br mice (60 sex/dose) were administered via diets with Quinclorac (97.4 or 98.3% a.i) at dose levels of 0, 250, 1000, 4000, or 8000 ppm (equivalent to 0, 37.5, 150, 600 or 1200 mg/kg/day) for 6 months or 78 weeks.  Ten mice were terminated at 6 months.  The remainders were continued on the test material for 18 months. At the end of 13 weeks, body weights in males and females receiving 8000 ppm were significantly lower than controls by 9.6% and 7.4%, respectively.  Body weights in males and females receiving 1000, 4000, and 8000 ppm for 78 weeks were significantly lower than controls (7.9 to 15.9% for males; 14.3 to 17.9 for females.  Treatment-related body weight reductions compared to controls were also noted in satellite males and females receiving 4000 and 8000 ppm for 6 months.  Absolute liver weights were significantly reduced in male and female mice receiving 8000 ppm for 78 weeks, but there was no effect on liver-to-body weight ratio.  Absolute kidney weights were decreased in males receiving 1000, 4000, and 8000 ppm and in females receiving 4000 and 8000 ppm for 78 weeks.  Relative kidney weights were decreased in males receiving 1000, 4000, and 8000 ppm for 78 weeks.  Dose-related increases in relative brain weights seen in males and females receiving 1000, 4000, and 8000 ppm.  Absolute liver weights were also reduced in males receiving 4000 and 8000 ppm for 6 months, while absolute kidney weights were reduced in all treated males.  A slight decrease in hematocrit values was noted in males and females receiving 8000 ppm for 6 months, but not 78 weeks.  Effects on other hematological parameters were not of biological significance.  There was no effect of dosing on mortality, food consumption, or clinical signs.  The LOEL is 1000 ppm (150 mg/kg/day) based on effects on body weight.  The NOEL is 250 ppm (37.5 mg/kg/day).  A maximum tolerated dose (MTD) was approached based on decreased body weights in males and females receiving 8000 ppm.

No evidence of histopathological or neoplastic lesions attributable to administration of any dose of Quinclorac was found in any tissue of any mouse.

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a carcinogenicity study   (83-2) in mice.

A.4.6	Mutagenicity

	Gene Mutation
870. 5100
Bacterial reverse gene mutation
41063527
Acceptable/Guideline
Negative up to the limit dose (5000 ug/plate) with or without S9 in S. typhimurium strains TA98, TA100, TA1535, TA1537

870. 5100
Bacterial reverse gene mutation
41063528
Acceptable/Guideline
Negative up to the limit dose (5000 ug/plate) with or without S9 in S. typhimurium strains TA98, TA100, TA1535, TA1537 and E. coli strain WP2uvrA

	Cytogenetics
OPPTS 870.5385
In vivo bone marrow cytogenic assay
MRID 41063530.
Acceptable/Guideline
Quinclorac was not clastogenic in this in vivo test. Negative in male and female NMRI mice at all doses up to limit dose (1000 mg/kg).  Mid and high dose groups showed clinical signs of toxicity (irregular breathing, apathy, piloerection) but no toxicity to target cell was observed.

OPPTS 870.5395
In vivo micronucleus assay in mice.  MRID 41063529.
Acceptable/Guideline
Quinclorac did not induce clastogenic or aneugenic at any dose (500, 1000 or 2000 mg/kg) or sacrifice time. Toxic signs of irregular breathing, apathy, and piloerection were noted in the mid- and high-dose groups.

	Other Genotoxicity
870.5300, In vitro mammalian forward gene mutation, CHO cells/HGPRT locus
MRID 41680503
Acceptable/guideline
Negative for gene mutations up to cytotoxic doses (2000 ug/mL) with or without S9.

870.5300, In vitro mammalian chromosome aberration assay, human lymphocytes
MRID 41076103
Acceptable/guideline
Positive for chromosomal aberrations but only at cytotoxic concentrations (2000 ug/mL with S9 and 1000 ug/mL without S9).

870.5550, Unscheduled DNA synthesis in primary rat hepatocytes MRID 41063531
Acceptable/guideline
Negative up to cytotoxic dose (1520 ug/mL).

A.4.7	Neurotoxicity

	870.6100 Delayed Neurotoxicity Study  -  Hen

Not required.

	870.6200 Acute Neurotoxicity Screening Battery -

Waived (HASPOC TXR 0056385)

	870.6200 Subchronic Neurotoxicity Screening Battery

Waived (HASPOC TXR 0056385)

	870.6300 Developmental Neurotoxicity Study

HED HIARC did not recommend a DNT study. (TXR 0012902)

A.4.8	Metabolism

	870.7485	Metabolism - Rat

The metabolism of quinclorac ([2,3,4-[14]C)3,7 -- dichloro-8- quinolinecarboxylic acid) following oral administration was studied extensively in male and female CD rats (MRID 41063533). The compound was rapidly absorbed and eliminated in the urine following administration of single oral doses of [[14]C] quinclorac at 15 or 600 mg/kg and at 15 mg/kg after the animals were dosed with unlabeled quinclorac at 15 mg/kg/day for 14 days. Elimination in the urine 5 days after dosing accounted for 91 to 98% of the dose with only 1 to 4% eliminated in the feces. No radioactivity was detected in expired air. Biliary excretion was significant (11.5 to 14.5% of the dose) in animals receiving 600 mg/kg. However, most of this radioactivity was reabsorbed from the intestines and eliminated in the urine. Most of the radioactivity in the bile is associated with the glucuronide conjugate of quinclorac. The conjugate is apparently hydrolyzed in the intestines and reabsorbed. Almost all the radioactivity in the urine is unchanged quinclorac. Radioactive tissue residue levels 5 days after dosing were dose-dependent. Results from these and other (whole-body autoradiography and time-course) studies indicate that quinclorac may accumulate in the adrenal glands, bone marrow, thyroid, squamous epithelium of the non-fundic stomach, and ovaries. In 7-day time-course studies (oral gavage at 15 mg/kg/day or dietary at about 1,000 mg/kg/day) maximum [14]C residue levels were detected 30 minutes after the final dose; thereafter, residue levels decreased with time.  Mean [14]C residues in plasma were also detected at 30 minutes in animals receiving single oral doses of 15, 100, or 600 mg/kg or 15 mg/kg/day for 7 days. Elimination was biphasic with half-lives of 3 to 4 hours for the rapid phase at the low doses and a half-life of about 13 hours at 600 mg/kg. Peak plasma levels of radioactivity in animals receiving higher doses (1200 mg/kg or 600 mg/kg/day for 7 days) were noted for 7 to 48 hours postdosing: saturation kinetics were also noted at these higher doses. These studies are acceptable and fulfill EPA's guidelines series 85-1.

	870.7600	Dermal Absorption - Rat

Dermal absorption studies are not available.

A.4.9	Immunotoxicity

	870.7800	Immunotoxicity

In an immunotoxicity study (MRID 48346101), Quinclorac (BAS 514 H, 99.9% a.i., Batch# 479-480) was administered to female C57BL/6 J Rj mice (8/group) in the diet at dose levels of 0 (control), 500, 1500, or 5000 ppm (equivalent to 0, 176, 439, or 1760 mg/kg bw/day, respectively) for 28 consecutive days. Animals in the positive control group (8/group) received cyclophosphamide by gavage at a dose of 10 mg/kg/day throughout the study. Six days before necropsy, animals in all groups were immunized with a suspension of sheep red blood cells (4x108 SRBC/mL) by intravenous injection (0.5 mL/animal dose volume). All animals were evaluated for mortality, clinical signs, body weight changes, food consumption, and gross pathology. Immunotoxicity was assessed using an Enzyme-Linked Immunosorbent Assay (ELISA) approach that measured the concentration of serum anti-SRBC immunoglobulin M (IgM). The absolute and relative (to terminal body weight) organ weights of the spleen and thymus were determined at necropsy.

There were no treatment related effects on mortality, clinical signs, body weight changes, food consumption, organ weights, or gross pathology at any dose concentration that were considered treatment related.

The systemic toxicity NOAEL is 5000 ppm (equivalent to 1760 mg/kg bw/day); the LOAEL was not established, tested above the limit dose.

For immunotoxicity, there were no treatment-related effects on serum anti-SRBC IgM antibody levels as measured by an ELISA, or thymus and spleen weights at any diet concentration. High inter-individual variability was seen in the treatment and vehicle control groups. Examination of individual animal data did not show any trend or distribution that would demonstrate significant suppression of the anti-SRBC IgM response. The mean IgM result from positive control group was 79.6% lower than the vehicle control group, showing it was valid for evaluating immuno-suppression. The positive control group confirmed the ability of the test system to detect immuno-suppressive effects and confirmed the validity of the study design.

A Natural Killer (NK) cell activity assay was not performed in this study. The toxicology database for quinclorac does not reveal any evidence of treatment-related effects on the immune system. The overall weight of evidence suggests that this chemical does not directly target the immune system. Under HED guidance, a NK cell activity assay is not required at this time.

Under conditions of this study, the immunotoxicity NOAEL is 5000 ppm (equivalent to 1760 mg/kg/day, the highest dose tested and above the limit dose); the LOAEL was not established.

This immunotoxicity study is classified as acceptable/guideline and satisfies the guideline requirement for an immunotoxicity study (OPPTS 870. 7800) in rodents.

A.4.9	Special/Other Studies (optional section)

None.

 Appendix B.  Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These data, which include studies from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database; the Outdoor Residential Exposure Task Force (ORETF) database; and the Agricultural Re-entry Task Force (ARTF) database are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements.  For certain studies that review may have included review by the Human Studies Review Board.  Descriptions of data sources as well as guidance on their use can be found at http://www.epa.gov/pesticides/science/handler-exposure-data.html and http://www.epa.gov/pesticides/science/post-app-exposure-data.html.

 Appendix C: International Residue Limits

             Quinclorac (PC Code 128974; Date of Request 7/26/12)
Summary of US and International Tolerances and Maximum Residue Limits
Residue Definition:
US
Canada
Mexico[1]
Codex
40 CFR 180.463
Plant/Livestock: quinclorac, 3,7-dichloro-8-quinolinecarboxylic acid
3,7-dichloro-8-quinolinecarboxylic acid

None
Commodity
Tolerance (ppm) /Maximum Residue Limit (mg/kg)

                                      US
Canada
Mexico[1]
Codex
Barley, grain
2.0
2.0

Cattle, fat
0.7
0.05

Cattle, meat byproducts
1.5
0.05

Cattle, meat
0.05
0.05

Egg
0.05
0.05

Goat, fat
0.7
0.05

Goat, meat byproducts
1.5
0.05

Goat, meat
0.05
0.05

Grass, forage
150

Grass, hay
130

Hog, fat
0.7
0.05

Hog, meat byproducts
0.05
0.05

Hog, meat
0.05
0.05

Horse, fat
0.05
0.05

Horse, meat byproducts
1.5
0.05

Horse, meat
0.05
0.05

Milk
0.05
0.05

Poultry, fat
0.05
0.05

Poultry, meat byproducts
0.05
0.05

Poultry, meat
0.05
0.05

Rice, bran
15.0

Rice, grain
5.0
5.0

Sheep, fat
0.7
0.05

Sheep, meat byproducts
1.5
0.05

Sheep, meat
0.05
0.05

Sorghum, grain, forage
3.0

Sorghum, grain, grain
6.0

Sorghum, grain, stover
1.0

Wheat, forage
1.0

Wheat, germ
0.75

Wheat, grain
0.5
0.5

Wheat, hay
0.5

Wheat, straw
0.1

Proposed MRLs
Low growing berries, except strawberries, subgroup 13-07H
1.5

Rhubarb
0.5

MRLs With No US Equivalent
Barley, bran

3.5

Completed by: M. Negussie; 07/31/2012
[1] Mexico adopts US tolerances and/or Codex MRLs for its export purposes.
(b) Section 18 emergency exemptions . Time-limited tolerances are established for residues of the herbicide quinclorac, including its metabolites and degradates, in or on the commodity in the table in this paragraph. Compliance with the tolerance level specified in this paragraph is to be determined by measuring only quinclorac, 3,7-dichloro-8-quinolinecarboxylic acid, in or on the commodity. The tolerance expires and is revoked on the date specified in the table in this paragraph.
                                   Commodity
                               Parts per million
                          Expiration/revocation date
Cranberry
                                     15.0
                                   12/31/12