Document ID: EPA-HQ-OPP-2012-0010-0008
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-12-21T05:00Z

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

MEMORANDUM

Date:		November 6, 2012

SUBJECT:	Quinclorac:  Risk Assessment In Support of Registration Review and for New Proposed Use on Rhubarb and Berry, low growing, except Strawberry, Subgroup 13-07H.
 
PC Code:  128974, 028974
DP Barcode:  D404794, D404808
Decision No.:  459055, 468877
Registration No.:  NA
Petition No.:  1E7957
Regulatory Action:  Section 3 Registration and Registration Review
Risk Assessment Type:  Single Chemical/ Aggregate
Case No.:  7222
TXR No.:  NA
CAS No.:  84087-01-4, 84087-48-9
MRID No.:  NA
40 CFR:  180.463

FROM:	Jessica Kidwell, Risk Assessor
		Abdallah Khasawinah, Ph.D., Toxicologist
		Susan Hummel/Gary Otakie, Chemists
		Bonnie Cropp-Kohlligian, Dietary Exposure Assessor
		Ivan Nieves, ORE Assessor
		Risk Assessment Branch IV, Health Effects Division (7509P)

THROUGH:	Elissa Reaves, Ph.D., Branch Chief		
		Risk Assessment Branch IV
		Health Effects Division (7509P)

TO:		Wilhelmena Livingston, RM60
		Risk Management and Implementation Branch 4
      Pesticide Re-Evaluation Division (7508P)
      
		Erik Kraft and Kable Davis, PM25
	        	Herbicide Branch, Registration Division (7505P)

            Barbara Madden, PM5
            RIMUERB, Registration Division (7505P)

		
This document provides the Health Effect Division's (HED's) risk assessment on quinclorac conducted in support of registration review of currently registered uses including the use of quinclorac dimethyl amine, as well as the Albaugh Inc. and the Interregional Research Project No. 4 (IR4) request for proposed uses of the product QUINCLORAC 4L AG Herbicide (EPA Reg. No. 42750-169).  Registration is proposed for QUINCLORAC 4L AG Herbicide with the active ingredient quinclorac on rhubarb and berry, low growing, except strawberry, subgroup 13-07H.

Table of Contents

1.0.	Executive Summary	5
2.0.	HED Recommendations	8
2.1.	Data Deficiencies	9
2.2.	Tolerance Considerations	9
2.2.1.	Enforcement Analytical Method	9
2.2.2.	Recommended Tolerances	9
2.2.3.	Revisions to Petitioned-For Tolerances	12
2.2.4.	International Harmonization	13
2.3.	Label Recommendations	13
2.3.1.	Recommendations from Residue Chemistry Reviews	13
2.3.2.	Recommendations from Occupational Assessment	13
2.3.3.	Recommendations from Residential Assessment	13
3.0.	Introduction	13
3.1.	Chemical Identity	13
3.2.	Physical/Chemical Characteristics	14
3.3.	Pesticide Use Pattern	15
3.4.	Anticipated Exposure Pathways	21
3.5.	Consideration of Environmental Justice	21
4.0.	Hazard Characterization and Dose-Response Assessment	22
4.1.	Toxicology Studies Available for Analysis	22
4.2.1.	Dermal Absorption	23
4.4.	Safety Factor for Infants and Children (FQPA Safety Factor)	24
4.4.1.	Completeness of the Toxicology Database	24
4.5.	Toxicity Endpoint and Point of Departure Selections	25
4.5.1.	Dose-Response Assessment	25
4.5.2.	Recommendation for Combining Routes of Exposures for Risk Assessment	26
4.5.3.	Cancer Classification and Risk Assessment Recommendation	26
4.5.4.	Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment	26
4.6.	Incident Reports	29
5.0.	Dietary Exposure and Risk Assessment	31
5.1.	Metabolite/Degradate Residue Profile	31
5.1.1.	Summary of Plant and Animal Metabolism Studies	31
5.1.2.	Summary of Environmental Degradation	33
5.1.3.	Comparison of Metabolic Pathways	34
5.1.4.	Residues of Concern Summary and Rationale	34
5.2.	Food Residue Profile	34
5.3.	Water Residue Profile	37
5.4.	Dietary Risk Assessment	40
5.4.1.	Description of Residue Data Used in Dietary Assessment	40
5.4.2.	Percent Crop Treated Used in Dietary Assessment	41
5.4.3.	Acute Dietary Risk Assessment	41
5.4.4.	Chronic Dietary Risk Assessment	41
5.4.5.	Cancer Dietary Risk Assessment	42
5.4.6.	Summary Table	42
6.0.	Residential (Non-Occupational) Exposure/Risk Characterization	43
6.1.	Residential Handler Exposure	43
6.2.	Residential Post-Application Exposure	45
6.2.3. Residential (Non-occupational) post-application inhalation	45
6.2.4. Residential (Non-Occupational) Post-Application Dermal and Incidental Oral	45
6.3.	Combined Residential Risk Estimates (Multiple Exposure Scenarios)	46
6.4.	Residential Risk Estimates for Use in Aggregate Assessment	46
6.5.	Residential Bystander Post-application Inhalation Exposure	47
6.6.	Spray Drift	47
7.0.	Aggregate Exposure/Risk Characterization	48
7.1.    Acute Aggregate Risk	48
7.2.    Short-Term Aggregate Risk	48
7.3.    Intermediate-Term Aggregate Risk	49
7.4.    Chronic Aggregate Risk	49
7.5.    Cancer Aggregate Risk	50
7.6.    Cumulative Exposure/Risk Characterization	50
8.0.	Occupational Exposure/Risk Characterization	50
8.1.    Short-/Intermediate-/Long-Term/Cancer (if needed) Handler Risk	50
8.2.   Short-/Intermediate-/Long-Term/Cancer (if needed) Post-Application Risk	57
8.2.1.    Dermal Post-application Risk	57
8.2.2.   Inhalation Post-application Risk	57
9.0.	References	58
Appendix A.  Toxicology Profile and Executive Summaries	60
A.1	Toxicology Data Requirements	60
A.2	Toxicity Profiles	61
A.3	Hazard Identification and Endpoint Selection	65
A.4	Executive Summaries	69
Appendix B.  Review of Human Research	78
Appendix C: International Residue Limits	79

 Executive Summary

Quinclorac is an herbicide for the selective post-emergent control of various annual grasses and broadleaf weeds. It is adsorbed via the root system and partially through the foliage and acts as an inhibitor of cell wall synthesis.  Quinclorac is currently formulated into a variety of product formulations including; dry flowable, wettable powder, ready-to-use, granular, emulsifiable concentrate, flowable concentrate, and liquid formulations. Two new agricultural uses of quinclorac have been proposed for the dry flowable formulation of the end-use product QUINCLORAC 4L AG Herbicide (EPA Reg. No. 42750-169), a 3.8 lb a.i./gallon liquid formulation.  The new uses include the following crops; low growing berries, except strawberries, subgroup 13-07H, and rhubarb.  The maximum single application rates for the proposed uses are 0.25 and 0.37 lb ai/A for low growing berries, except strawberries, subgroup 13-07H, and rhubarb, respectively.  QUINCLORAC 4L AG Herbicide may be applied as a foliar spray using ground equipment only.  

The variety of end-use products containing quinclorac is currently registered on rice, sorghum, and wheat. In addition to agricultural crops, quinclorac is also registered for: agricultural fallow/idleland/conservation reserves; nonagricultural uncultivated areas/soils; grass forage/fodder/hay; grasses grown for seed; pastures and rangelands; agricultural and nonagricultural rights of way/fencerows/hedgerows; agricultural uncultivated areas; utility poles/rights of way; airports/landing fields; ornamental sod farms; commercial/industrial lawns.  Additionally, quinclorac is registered for use by commercial applicators and homeowners on lawns, parks, in and around ornamentals, and golf courses.

A new physical form of quinclorac (EPA Reg. No. 7969-272) has recently been registered: Drive XLR-8 (Reg. No 7969-272), Paramount L Herbicide (Reg. No. 7969-315), Facet L Herbicide (EPA Reg. No. 7969-316), and Quinclorac 1.5 DMA (Reg. No 42750-224).  These products are DMA (dimethylamine) salt forms of quinclorac.  These products were not proposed for the new uses of quinclorac, proposed in the current petition, but are registered for use on rice and ornamental turf.  

Hazard

Quinclorac toxicity in experimental animals is observed mostly at doses above 150 mg/kg/day following subchronic and chronic exposures.  Subchronic exposure to quinclorac caused decreased body weight gains, increased water intake, increased liver enzymes and focal chronic interstitial nephritis (rats).  Chronic toxic effects include body weight decrement, increase in kidney and liver weights, and hydropic degeneration of the kidneys (dogs).  At high doses, chronic toxicity also includes increased incidences of pancreatic acinar cell hyperplasia and adenomas.  Neurotoxic effects were not observed in any of the acute, subchronic and chronic studies with quinclorac.  There was no increased qualitative or quantitative fetal or offspring susceptibility in the prenatal developmental studies in rats or rabbits or postnatal reproduction study in rats.  

There are no mutagenicity concerns.  Quinclorac was classified in 1992 by the HED Cancer Peer Review committee (CPRC) as a group D carcinogen - not classifiable as to human carcinogenicity- based on recommendation by the EPA Scientific Advisory Panel.  Based on the classification, a quantification of cancer risk is not warranted because the chronic RfD will adequately account for all chronic effects, including carcinogenicity, that may result from exposure to quinclorac.

Quinclorac (technical grade material) has a low order of acute toxicity as demonstrated by Toxicity Category III by the oral, dermal, and inhalation routes. The chemical is a mild eye irritant, is not a skin irritant, but was positive for dermal sensitization.

Endpoints and Uncertainty Factors for Risk Assessment

HED reviewed the toxicity database for quinclorac as well as the most recent risk assessment (D359759, Y. Donovan et al, 8/5/2009) and concluded that no changes in the points of departure (PODs) or FQPA SF (1x) are warranted. Since the last risk assessment the immunotoxicity study in mice was submitted and reviewed. The results of this study did not impact the overall risk assessment.  Since the last risk assessment, the HED Hazard and Science Policy Council (HASPOC) waived the requirement for a neurotoxicity battery (acute and subchronic neurotoxicity studies) and a DNT study.

Chemistry

Permanent tolerances have been established for residues of quinclorac per se in/on barley, rice, sorghum and wheat at levels ranging from 0.1 ppm in wheat straw to 1200 ppm in aspirated grain fractions [40 CFR §180.463(a)].  Permanent tolerances have also been established for residues of quinclorac, per se, in/on livestock commodities at levels ranging from 0.05 to 1.5 ppm.  In addition, there is a tolerance for quinclorac residues on cranberry in §180.463(b), as a result of a Section 18 emergency exemption at 15 ppm.

The Inter Regional Project No. 4 (IR-4) has submitted a request for tolerances and registration of quinclorac on low growing berries, except strawberries, subgroup 13-07H, and rhubarb.  Tolerances were proposed for residues of quinclorac in low growing berries, except strawberries, subgroup 13-07H, at 1.1 ppm, and rhubarb at 0.4 ppm.

The qualitative nature of quinclorac residues in plants was considered adequately understood for the currently registered crops, based upon the metabolism studies on rice, sorghum, and wheat.  Further metabolism data may be needed if uses are further expanded.  The qualitative nature of quinclorac residues in livestock is also understood based upon the adequate goat and poultry metabolism studies.  The Agency had concluded that parent is the only residue of concern in both plant and livestock commodities for purposes of the tolerance expression and risk assessment.  

An adequate enforcement method is available for enforcing quinclorac tolerances on plants and livestock, a GC/ECD method that uses methylation with diazomethane.  There is available FDA multi-residue method (MRM) testing data that indicate that quinclorac is completely recovered using Protocol B.  

Adequate cattle and poultry feeding studies are available and support the use of quinclorac.

Adequate rotational crop studies are available and support the use of quinclorac.

Dietary (food+water) Exposure and Risk

The Environmental Fate and Effects Division (EFED) completed a drinking water assessment in support of human health risk assessment. The current assessment is performed according to current EFED guidance and up-to-date models including the Tier II surface water model (PRZM/EXAMS) for all uses of quinclorac, except cranberries and rice. Screening-level Tier I modeling was used to estimate surface water concentrations for use on cranberry (provisional cranberry model) and rice (Tier I rice model) because the current Tier II model is not parameterized for those uses.  The Tier I SCI-GROW model was used to estimate groundwater concentrations for all uses.  Surface water EDWCs (acute = 511 ug/L and chronic = 511 ug/L) resulting from use on rice supersede previously recommended EDWCs.  The recommended groundwater EDWC has not changed (29 ug/L for acute and chronic exposure). 
 
Both the acute and chronic dietary assessments are highly conservative, and assume 100% crop treated (%CT), along with tolerance-level residues for all agricultural commodities.  Default processing factors from DEEM 7.81 were used (for dried beef and cranberry juice) in the analyses. The acute (food + water) dietary risk estimate at the 95[th] percentile of exposure is 1.6% of the acute population adjusted dose (aPAD) for females age 13 to 49.  This is the only population subgroup for which an acute endpoint was selected.  The chronic (food + water) dietary risk estimates are less than or equal to 8.9% of the chronic population adjusted dose (cPAD) for all population subgroups.  All Infants < 1 year of age is the most highly-exposed subgroup, utilizing 8.9% of the cPAD, while the general US population utilizes 3.6% of the cPAD.  

Occupational Exposure/Risk

The occupational handler assessment was completed assuming the maximum label application rate from the list of end-use products for each crop.  The labels allow for application via aerial, groundboom, chemigation, backpack, manually-pressurized handwand, mechanically-pressurized handgun, trigger-spray bottle, belly grinder, rotary spreader, and tractor-drawn spreader equipment. Based on the activity use pattern, the duration of exposure is expected to be short- term (ST; 1 to 30 days) and intermediate-term (IT; 1 to 6 months) for occupational scenarios; long-term exposures (greater than 6 months) are not anticipated based on the proposed use pattern.  No dermal endpoint was selected therefore only inhalation exposure was quantified.  For the inhalation route of exposure, the same points of departure were chosen for short- and intermediate-term exposures; therefore, risk estimates are the same for all durations of exposure.  An estimated short- and intermediate-term inhalation NOAEL of 70 mg/kg/day for quinclorac was selected from a developmental rabbit toxicity study.  Therefore, for risk characterization purposes, since no inhalation absorption data are available, toxicity by the inhalation route is considered to be equivalent to the estimated toxicity by the oral route of exposure. The proposed label requires long-sleeved shirt, long pants, shoes plus socks, and chemical-resistant gloves as personal protective equipment (PPE) for all applicators and other handlers.  All risk estimates of the proposed uses for occupational handlers are above the target MOE of 100. Occupational handler risk estimates resulted in inhalation MOEs ranging from 4800-940,000 for proposed new uses and 1000-1,100,000 for registered uses. The occupational handler inhalation risk estimates above 100 do not exceed HED's level of concern.  

Based on the Agency's current practices, a quantitative non-cancer occupational post-application inhalation exposure assessment was not performed for quinclorac at this time; handler inhalation exposure estimates are considered to be protective of occupational post-application inhalation exposure scenarios.  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.

There is potential for dermal exposure during occupational post-application activities, such as crop maintenance activities, scouting, irrigation, and harvesting.  However, since no dermal (short- or intermediate-term) toxicological endpoints were identified, an assessment of post-application exposure and risk cannot be quantified.   

Residential Exposure/Risk

There are no proposed residential uses at this time; however, there are existing uses for quinclorac on residential, non-residential turf (i.e., athletic fields, cemeteries, parks, etc.) and sod farms to control several broadleaf and grass weeds that have been reassessed in this document to reflect updates to HED's 2012 Residential SOPs, along with policy changes for body weight assumptions.  Since individuals can potentially be exposed to treated turf, a residential post-application assessment was previously conducted (T. Moriarty; 08/13/2008; D342993).  The revision of residential exposures will impact the human health aggregate risk assessment for quinclorac.  Post-application exposure and risk estimates resulted in inhalation MOEs ranging from 3600-250,000,000. These MOEs were greater than the LOC of 100, and, therefore, were not of concern. 

Aggregate

In general, aggregate exposures are calculated by summing dietary (food and drinking water) and residential exposures (residential or other non-occupational exposures).  HED reviewed all residential sources of exposure to determine which residential exposure scenarios would be appropriate to combine with dietary exposure for an aggregate risk assessment.  The only applicable exposure pathways are inhalation (for adult handlers) and incidental oral (for post-application exposure to children). The short-term aggregate MOEs for the adult handlers and the children were 2100 and 1600, respectively, which are above the LOC of 100 and, therefore, not of concern. 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. Additionally, aggregate acute and chronic (food and water) exposures were <=100% the cPAD for all population subgroups as a result of all registered/proposed uses.  Thus, acute and chronic aggregate exposure to quinclorac is not of concern.    

 HED Recommendations

HED is recommending in favor of registration of quinclorac on the requested crops and establishment of tolerances as summarized in Table 2.2.3. HED has evaluated current uses of quinclorac and its dimethylamine salt. Tolerance changes are recommended due to recalculation of the dietary burden and for harmonization. 

      0.1.  Data Deficiencies

Toxicology: None

Residue Chemistry: 

::Data on catfish and crayfish are required, or the label must prohibit use of treated water from rice and cranberry fields for aquaculture (See Section 2.3). For registration review, data are required or the PM must ensure that all quinclorac labels with uses on rice and cranberry contain such a restriction.
      
::Further expansion of the use of quinclorac to other commodities grown on larger acreages than rhubarb and cranberry will trigger a requirement of additional metabolism data.
            
::For the current petition, Albaugh must supply the Pesticide Repository with analytical standards for quinclorac and the quinclorac methyl ester which is used in the current enforcement method.

::For registration review, an analytical standard for the quinclorac DMA salt must be submitted to the EPA National Pesticide Standards Repository.

ORE:  None.

      0.2.  Tolerance Considerations

            0.2.1. Enforcement Analytical Method

Adequate analytical methods (GC/ECD) are available for enforcing quinclorac tolerances on plant (BASF Method A8902; MRID# 41063537) and livestock (BASF Method 268/1; MRID# 41063536) commodities.  Both methods have undergone successful agency method validation trials and have been submitted to FDA for publication in PAM II as the tolerance enforcement methods.  The LOQ of both methods is 0.05 ppm for all matrices.  

In BASF Method 268/1, used for both plant and animal matrices, samples are extracted with acetone and dichloromethane and redissolved in acetone/hexane. An aliquot is subjected to GC chromatography using a DB-5 column and electron capture detection.  Methylated standard is used for quantitation.  The LOD was reportedly 0.05 ppm, but this was also the lowest level validated.

Quinclorac is detected by FDA Multiresidue Protocol B, but not the other FDA Multiresidue Method (MRM) Protocols.

            0.2.2. Recommended Tolerances

The current tolerance expression for quinclorac is: 

"Tolerances are established for residues of the herbicide quinclorac, including its metabolites and degradates, in or on the commodities in the table in this paragraph. Compliance with the tolerance levels 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 expression is in accord with our current guidance on tolerance expressions.

Current Petition: Tolerance recommendations for the current petition (IE7957) on low growing berries, except strawberries, subgroup 13-07H, and rhubarb are in the first two lines of Table 2.2.2.  

Tolerance Consideration for Registration Review: Permanent tolerances have been established for residues of quinclorac in/on small cereal grain commodities at levels ranging from 0.1 ppm in wheat straw to 15 ppm in rice bran [40 CFR §180.463(a)], and for grass forage at 150 ppm and grass hay at 130 ppm.  There is also a 1200 ppm tolerance for AGF; however, recently reviewed data indicate that a tolerance on AGF is not necessary (DP# 344496, G. Otakie, 9/25/08).  Permanent tolerances have also been established for residues of quinclorac per se in/on livestock commodities at levels ranging from 0.05 to 1.5 ppm.  

Based on the recalculated dietary burdens for livestock and the data from the available cattle and poultry feeding studies, the current tolerances for livestock commodities are adequate, with the exceptions of the tolerances on poultry meat byproducts and hog fat and meat byproducts.  Based on the recalculated Maximum Dietary Burdens (MDBs) for swine (6.0 ppm) and poultry (5.4 ppm) and the data from the poultry and cattle feeding studies, the existing tolerances for poultry meat byproducts and hog fat and meat byproducts are too high as quinclorac residues in these commodities are expected to be <0.05 ppm at 1x the MDB.  Therefore, the tolerances for these livestock commodities should be lowered to 0.05 ppm.  Lowering the tolerances on these commodities will also harmonize the U.S. tolerances with the existing Canadian MRLs for poultry meat byproducts and hog fat and meat byproducts.

In addition, HED notes that the Agency no longer considers rice straw to be a significant livestock feedstuff (OPPTS 860.1000, Table I, ChemSAC memo 6/30/08).  Therefore, the current tolerance for residues of quinclorac on rice straw may be revoked.

The use of the DMA salt of quinclorac will not affect the established tolerances for quinclorac on rice, grain sorghum, and wheat.

Table 2.2.2 	Tolerance Summary for Quinclorac.  § 180.463
Commodity
                       Current/Proposed Tolerance (ppm)
                          Recommended Tolerance (ppm)
Comments; Correct Commodity Definition
Berry, low growing, except strawberry, subgroup 13-07H
                                      1.1
                                      1.5
Revised level based on OECD tolerance calculation procedures.  At the time of publication of this tolerance, the tolerance for residues quinclorac on cranberry in § 180.463(b) should be revoked.
Rhubarb
                                      0.4
                                      0.5
Revised level based on OECD tolerance calculation procedures. 
     Currently Established Tolerances Reevaluated for Registration Review
Barley, grain
                                      2.0
                                      2.0
The tolerance needs a footnote to indicate that there are no U. S. Registrations.
Cattle, fat
                                      0.7
                                      0.7

Cattle, meat byproducts
                                      1.5
                                      1.5

Cattle, meat
                                     0.05
                                     0.05

Egg
                                     0.05
                                     0.05

Goat, fat
                                      0.7
                                      0.7

Goat, meat byproducts
                                      1.5
                                      1.5

Goat, meat
                                     0.05
                                     0.05

Grain, aspirated fractions
                                     1200
                                    revoke
Data submitted demonstrate that the tolerance is not needed. Current tolerance was based on a theoretical calculation.
Grass, forage
                                      150
                                      150

Grass, hay
                                      130
                                      130

Hog, fat
                                      0.7
                                     0.05
Based on the residue data from the cattle feeding and the calculated MDB of 6.0 ppm for swine, the tolerances can be lowered to the method LOQ (0.05 ppm).  This level is harmonized with Canada. 
Hog, meat byproducts
                                      1.5
                                     0.05
Based on the residue data from the cattle feeding and the calculated MDB of 6.0 ppm for swine, the tolerances can be lowered to the method LOQ (0.05 ppm).  This level is harmonized with Canada. 
Hog, meat
                                     0.05
                                     0.05

Horse, fat
                                      0.7
                                      0.7

Horse, meat byproducts
                                      1.5
                                      1.5

Horse, meat
                                     0.05
                                     0.05

Milk
                                     0.05
                                     0.05

Poultry, fat
                                     0.05
                                     0.05

Poultry, meat byproducts
                                      0.1
                                     0.05
Based on the residue data from the poultry feeding and the calculated MDB of 5.4 ppm for poultry, the tolerance can be lowered to the method LOQ (0.05 ppm).   This level is harmonized with Canada.
Poultry, meat
                                     0.05
                                     0.05

Rice, bran
                                     15.0
                                     15.0

Rice, grain
                                      5.0
                                      5.0

Rice, straw
                                     12.0
                                    Revoke
Rice straw is no longer a regulated livestock feedstuff.
Sheep, fat
                                      0.7
                                      0.7

Sheep, meat byproducts
                                      1.5
                                      1.5

Sheep, meat
                                     0.05
                                     0.05

Sorghum, grain, forage
                                      3.0
                                      3.0

Sorghum, grain, grain
                                      6.0
                                      6.0

Sorghum, grain, stover
                                      1.0
                                      1.0

Wheat, forage
                                      1.0
                                      1.0

Wheat, germ
                                     0.75
                                     0.75

Wheat, grain
                                      0.5
                                      0.5

Wheat, hay
                                      0.5
                                      0.5

Wheat, straw
                                      0.1
                                      0.1

            0.2.3. Revisions to Petitioned-For Tolerances and Existing Tolerances

Current Petition: Revisions are recommended to petitioned-for tolerances due to the use of the OECD tolerance calculation procedures.  The recommended changes are documented in Table 2.2.2.

Tolerance Revisions for Registration Review: Revisions to current tolerances for registration review are documented in Table 2.2.2.  Some tolerances are being removed because the commodity is no longer regulated.  The tolerance for Grain, Aspirated Fractions is being removed because it it not necessary.  Tolerances on meat, poultry, milk, and eggs are being revised based on a recalculation of the dietary burden, and to harmonize internationally.

            0.2.4. International Harmonization

CODEX has not established any established maximum residue limits (MRLs) for quinclorac.  Canada has established maximum residue limits (MRLs) for quinclorac on selected agricultural commodities but not the commodities in the current petition. Recommendations for harmonization are in Table 2.2.2 for Registration Review.

      0.3. Label Recommendations

            0.3.1. Recommendations from Residue Chemistry Reviews

      ::Cranberry is an aquatic crop, and as such, a label restriction is needed regarding the use of treated rice and cranberry fields for aquaculture.  Alternatively, the petitioner may determine residues in catfish and crayfish raised in treated fields and propose tolerances for these commodities, if necessary.  The label provided for Quinclorac/QuinStar 4-L does not contain any restriction against aquaculture.
      
      ::For Registration Review, the PM must ensure that all labels for quinclorac on rice and cranberry contain a label restriction restricting the use of treated rice and cranberry fields for aquaculture.
     
            0.3.2. Recommendations from Occupational Assessment

The proposed label requires long-sleeved shirt, long pants, shoes plus socks, and chemical-resistant gloves as personal protective equipment (PPE) for all applicators and other handlers. The 12 hour REI which is currently on the label is adequate for the new crop uses with the product QUINCLORAC 4L AG Herbicide.

            0.3.3. Recommendations from Residential Assessment
None.

 Introduction

      0.4.  Chemical Identity

Quinclorac is a herbicide for the selective post-emergent control of various annual grasses and broadleaf weeds.  Quinclorac is adsorbed via the root system and partially through the foliage and acts as an inhibitor of cell wall synthesis.  The nomenclature of quinclorac and quinclorac DMA salt are summarized in Table 3.1.  

Table 3.1.	Quinclorac and Quinclorac (DMA salt)  Nomenclature.	
Compound
                                       
Common name
Quinclorac,
Company experimental name
BAS 514 34H  
IUPAC name
3,7-dichloroquinoline-8-carboxylic acid
CAS name
3,7-dichloro-8-quinolinecarboxylic acid
CAS registry number
84087-01-4
Molecular weight
242.1
End-use product (EP)
Drive(R) 75 DF  
                                       
Compound

                                       
Common name
Quinclorac, DMA salt
Company experimental name
BAS 514 51H  
IUPAC name
3,7-dichloroquinoline-8-carboxylic acid, DMA salt
CAS name
3,7-dichloro-8-quinolinecarboxylic acid, DMA salt
CAS registry number
84087-48-9
Molecular weight
287.2
End-use product (EP)
Drive(R)XLR8 Herbicide, EPA Reg. No. 7969-272; Paramount(R) L Herbicide, EPA Reg. No. 7969-GRA; Facet L Herbicide, EPA Reg. No. 7969-GRL

      0.5.  Physical/Chemical Characteristics

The physicochemical properties of the technical grade quinclorac are summarized in Table 3.2.1.  
Only several physicochemical properties of the DMA salt of quinclorac are available (Table 3.2.2). The physical and chemical properties of quinclorac indicate that it is unlikely to volatilize and has low potential to accumulate in fatty tissues.

In addition, the registrant has submitted a comparative study of the dissociation behavior of quinclorac and its dimethylamine salt (MRID 48051902, "Comparative study of the Dissociation Behavior of Quinclorac Acid and its Dimethylamine Salt").  The UV/Vis spectra of quinclorac TGAI and the UV/Vis spectra and dissociation constant of quinclorac DMA were presented.  The results of the study show that in aqueous solutions, the chemical form of the quinclorac dimethylamine salt is the same as that of the quinclorac acid form.  

Table 3.2.1		Physicochemical Properties of the Technical Grade Quinclorac.
Parameter
Value
Reference
Melting point/range
~269°C
D342446, M. Doherty, 9/11/07
pH
3.4-3.5
RCB 3283 S. Hummel, 2/26/88
Density
~560 g/L
D342446, M. Doherty, 9/11/07
Water solubility (20°C)
0.0064 g/100 mL

Solvent solubility (g/100 mL at 20°C to 25°C)
ethanol	0.2 	toluene	<0.1
Lutrol(R)	<0.1	acetone	0.2
olive oil	<0.1	n-octanol	<0.1
acetonitrile	<0.1	1,2-propandiol	<0.1
ethyl acetate	0.1	dichloromethane	<0.1
ethyl ether	0.1	n-hexane	<0.1

Vapor pressure (20°C)
<1.0x10-7 mbar (<0.75x10-7 Torr)

Dissociation constant, pKa
4.34 at 20°C
4.35 at 25°C

Octanol/water partition coefficient, log POW (20°C)
1.76 at pH 4
-0.74 at pH 7
 3.74 at pH 10

UV/visible absorption spectrum
314 nm, 300 nm, 278 nm (95% ethanol)
MRID 48051092

Table 3.2.2		Physicochemical Properties of the Quinclorac, DMA Salt.
Parameter
Value
Reference
Melting point/range
NA

pH
NA

Density
NA

Water solubility (20°C)
NA

Solvent solubility (g/100 mL at 20°C to 25°C)
NA

Vapor pressure (20°C)
NA

Dissociation constant, pKa
4.33 +- 0.15  (Temperature not reported)
MRID 48051092
Octanol/water partition coefficient, log POW (20°C)
NA

UV/visible absorption spectrum
314 nm, 300 nm, 278 nm (95% ethanol)
MRID 48051092

      0.6.  Pesticide Use Pattern

Proposed new uses.  IR-4 is proposing use of the Quinclorac 4-L AG (Reg. No. 42750-169), registered to Albaugh, Inc., containing 3.8 lb quinclorac/gallon, in connection with the current petition.  

Table 3.3.1.  Summary of Directions for Proposed Use of Quinclorac on Low Growing Berries (Crop Sub- Group 13-07H), Except Strawberries, and Rhubarb.
                       Applic. Timing, Type, and Equip.
                     Formulation [EPA Reg. No. 42750-169]
                         Max. Single Application Rate 
                                   (lb ai/A)
                          Max. No. Applic. per Season
                   Max. Seasonal Application Rate (lb ai/A)
                                  PHI (days)
                        Use Directions and Limitations
Low Growing Berries (Crop Sub- Group 13-07H), Except Strawberries
Foliar; Ground.
QUINCLORAC 4L AG Herbicide 40% ai, Dry Flowable
(3.8 lb ai/gal)
                          0.25 lb ai/A (8.4 fl oz/A)
                                       2
                                 0.50 lb ai/A 
                                (16.8 fl oz/A)
                                      60
Re-treatment Interval = 30 days. 
Ground application (foliar) only.
Do not apply by air.
Do not apply to irrigation ditches.
Crop oil concentrate permitted.
Rhubarb
Foliar; Ground.
QUINCLORAC 4L AG Herbicide 40% ai, Dry Flowable
(3.8 lb ai/gal)
                          0.37 lb ai/A (12.6 fl oz/A)
                                       2
                                 0.74 lb ai/A 
                                (25.2 fl oz/A)
                                      30
Re-treatment Interval = 30 days. 
Ground application (foliar) only.
Do not apply by air.
Do not apply to irrigation ditches.
Crop oil concentrate permitted.
Maximum Single Application Rate for Low Growing Berries (Crop Sub- Group 13-07H), Except Strawberries (lb ai/A) = (8.4 fl oz/A) (3.8 lb ai/gal)(1 gal/128 fl oz) = 0.25 lb ai/A.  Maximum Single Application Rate for Rhubarb (lb ai/A) = (12.6 fl.oz/A)(1 gal/1 128 fl.oz) (3.8 lb ai/gal) = 0.37 lb ai/A.    

Existing Uses.  Existing uses of quinclorac include use on rice, grain sorghum, wheat, pasture and rangeland grasses, and use on barley in Canada for import into the US.  The dimethylamine salt of quinclorac has recently been registered for use on rice, grain sorghum, and wheat.

Table 3.3.3 provides use sites and maximum application rates for the existing uses for quinclorac.  Please refer to Section 2.3 for recommended modifications to the proposed label.
Table 3.3.2. Summary of Quinclorac Registered Uses Assessed Under Registration Review
                                   Commodity
                                 Form-ulation
                                 Product Name 
                                (EPA Reg. No.)
                             Application Equipment
                             Max. Single App Rate
                                   (lb ai/A)
                                      PHI
                                    (days)
                                     Rice
                                      DF
279-3366; 34704-920; 42750-88; 66222-160; 7969-222; 7969-313; 80289-14
Aerial; Groundboom
                                     0.503
                                      309
                                       
                                       L
42750-169; 71085-26; AR080007; AR120003

                                     0.47
                                       
                                       
                                      WSP
7969-93

                                      0.5
                                       
                               Sorghum and Wheat
                                      DF
7969-152; 7969-113; 66222-160; 42750-131

                                     0.375
                                       
                                       
                                       L
42750-169; 42750-171

                                     0.35
                                       
Agricultural fallow/idleland/conservation reserves; Nonagricultural uncultivated areas/soils; Grass forage/fodder/hay; Grasses grown for seed; Pastures and Rangelands
                                      DF
7969-113; 42750-131; 7969-152
Aerial; Groundboom
                                     0.75
                                      40

                                       L
42750-169; 42750-171

                                     0.75
                                       
Agricultural and nonagricultural rights of way/fencerows/hedgerows; Agricultural uncultivated areas; Utility poles/rights of way 
                                      DF
42750-131; 83070-9; 7969-130; 7969-113; 66222-160; 42750-131; 228-592
Backpack; Mechanically-pressurized Handgun
                                     0.75
                              (0.15 lb ai/gal)[*]
                                     7-309

                                       L
7969-267; 70506-282; 42750-220; 42750-172; 42750-171; 42750-169; 228-705; 228-595; 228-531; 228-423; 2217-946; 2217-919; 2217-901; 2217-888; 2217-886; 42750-169; 42750-171 

                                     1.48
                              (0.296 lb ai/gal) *
                                       

                                       G
2217-927; 2217-964
Rotary Spreader
                                     0.68
                                       
Airports/landing fields
                                      DF
228-592; 7969-130
Backpack; Manually-pressurized Handwand; Mechanically-pressurized Handgun
                                     0.75
                              (0.15 lb ai/gal)[*]
                                     NS[3]

                                       L
228-531; 228-705; 42750-172; 42750-220; 70506-282; 7969-267

                                     0.75
                              (0.15 lb ai/gal)[*]
                                       
Commercial/industrial lawns
                                      DF
228-592; 279-3355; 66222-160; 7969-130; 83070-9
Backpack; Manually-pressurized Handwand; Mechanically-pressurized Handgun
                                      1.4
                              (0.28 lb ai/gal)[*]
                                      NS

                                       L
7969-267; 70506-282; 42750-220; 42750-172; 228-705; 228-595; 228-531; 228-423; 2217-946; 2217-919; 2217-901; 2217-888; 2217-886

                                     0.78
                             (0.156 lb ai/gal)[*]
                                       

                                       G
2217-927; 2217-964
Belly grinder; Rotary spreader
                                     0.68
                                       

                                      RTU
228-594
Trigger-spray bottle
                                     0.76
                           (0.0172 lb ai/bottle)[*]
                                       
Ornamental lawns and turf
                                      DF
83070-9; 7969-130; 66222-160; 42750-90; 228-592
Backpack; Manually-pressurized Handwand; Mechanically-pressurized Handgun
                                     0.75
                              (0.15 lb ai/gal)[*]
                                      NS

                                       L
7969-267; 70506-282; 42750-172; 239-2713; 228-705; 228-704; 228-595; 228-423; 2217-946; 2217-919; 2217-901; 2217-888; 2217-886

                                     0.78
                             (0.156 lb ai/gal)[*]
                                       

                                       G
2217-927; 2217-964; 538-296
Hand dispersal; Belly grinder; Cup; Rotary spreader; Spoon
                                     0.68
                                       

                                      RTU
228-594; 228-703
Trigger-spray bottle
                                     0.76
                           (0.0172 lb ai/bottle)[*]
                                       
Recreation area and residential lawns
                                      DF
83070-9; 7969-130; 66222-160; 279-3355; 228-592
Backpack; Manually-pressurized Handwand; Mechanically-pressurized Handgun
                                      1.4
                              (0.28 lb ai/gal)[*]
                                      NS

                                       L
7969-267; 72155-86; 70506-282; 42750-220; 42750-172; 228-705; 228-704; 228-595; 228-531; 228-423; 2217-954; 2217-946; 2217-945; 2217-939; 2217-938; 2217-919; 2217-901; 2217-896; 2217-894; 2217-888; 2217-886; 2217-885; 

                                     0.78
                             (0.156 lb ai/gal)[*]
                                       

                                       G
2217-927; 2217-963; 2217-964
Belly grinder; Rotary spreader
                                     0.68
                                       

                                      RTU
2217-887; 2217-917; 2217-918; 2217-953; 228-594; 228-703; 239-2689
Trigger-spray bottle
                                     0.76
                           (0.0172 lb ai/bottle)[*]
                                       
Ornamental sod farms (turf)
                                      DF
83070-9; 7969-130; 66222-160; 42750-90; 279-3355; 228-592
Aerial; Groundboom; Chemigation
                                      1.4
                                      90

                                       L
70506-282; 42750-220; 42750-172; 228-705; 228-595; 228-531; 228-423; 2217-946; 2217-919; 2217-901; 2217-888; 2217-886

                                     0.78
                                       

                                      RTU
228-594
Trigger-spray bottle
                                     0.76
                                       
Golf course turf
                                      DF
42750-90; 228-592; 279-3355; 83070-9; 7969-130; 66222-160;
Groundboom; Mechanically-pressurized Handgun
                                      1.4
                                      NS

                                       L
2217-886; 2217-888; 2217-901; 2217-919; 2217-946; 228-423; 228-531; 228-595; 228-705; 42750-172; 42750-220; 70506-282; 7969-267

                                     0.78
                                       

                                       G
2217-964; 2217-927
Tractor-drawn Spreader; Rotary spreader
                                     0.68
                                       

                                      RTU
228-594
Trigger-spray bottle
                                     0.76
                                       

 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed new uses of quinclorac. The Pesticide Re-Evaluation Division also has requested an assessment for registration review.  The variety of end-use products containing quinclorac currently registered is as follows; rice, sorghum, and wheat.  In addition to agricultural crops, quinclorac is also registered for: agricultural fallow/idleland/conservation reserves; nonagricultural uncultivated areas/soils; grass forage/fodder/hay; grasses grown for seed; pastures and rangelands; agricultural and nonagricultural rights of way/fencerows/hedgerows; agricultural uncultivated areas; utility poles/rights of way; airports/landing fields; ornamental sod farms; commercial/industrial lawns.  Additionally, quinclorac is registered for use by commercial applicators and homeowners on lawns, parks, in and around ornamentals, and golf courses. The new uses include the following crops; low growing berries, except strawberries, subgroup 13-07H, and rhubarb.   

Humans may be exposed to quinclorac in food and drinking water, since quinclorac may be applied directly to growing crops and application may result in quinclorac reaching surface and ground water sources of drinking water.  In the occupational and residential settings, inhalation exposure is expected to be of short- and intermediate term durations based on the activity use pattern. Long-term exposures (greater than 6 months) are not anticipated based on the proposed use pattern. No dermal endpoint was selected, therefore, only inhalation exposure was quantified.  Incidental oral residential exposures (short-term only) are also expected.

Risk assessments have been previously prepared for the existing uses of quinclorac. This risk assessment considers all of the aforementioned exposure pathways based on the proposed new uses of quinclorac, but also considers the existing uses as well, particularly for the dietary exposure assessment.  

      0.7.  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 post-application 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.

 Hazard Characterization and Dose-Response Assessment

HED reviewed the toxicity database for quinclorac as well as the most recent risk assessment which was conducted in association with the new use on pasture/rangeland (D359759, Y. Donovan et al, 8/5/2009) and concluded that no changes in the points of departure (PODs) or FQPA SF (1x) are warranted. Since the last risk assessment the immunotoxicity study in mice was submitted and reviewed (TXR 0052889). The results of this study did not impact the overall risk assessment.  

      0.8.  Toxicology Studies Available for Analysis

The toxicology database for quinclorac is adequate for evaluating and characterizing its toxicity and selecting endpoints for purposes of risk assessment. Studies considered for this assessment include acute lethality (oral, dermal and inhalation routes), primary eye and dermal irritation, dermal sensitization, subchronic oral toxicity (rat and mouse), rat 21-day dermal toxicity, dog chronic toxicity, rat combined chronic toxicity/carcinogenicity, mouse carcinogenicity, developmental toxicity (rat and rabbit), rat two-generation reproductive toxicity, genotoxicity, rat metabolism, and mouse immunotoxicity.  Since the last risk assessment, the HED HASPOC 
waived the requirement for a neurotoxicity battery (acute and subchronic) and a DNT study based on a WOE approach that considered (1) lack of neurotoxic effects in the available acute, subchronic, chronic, developmental, and reproduction studies; (2) the selected endpoints are considered to be protective of neurotoxic effects; (3) dietary exposure to quinclorac is low; and (4) residential and occupational MOEs are high (HASPOC TXR 0056385).  The requirement of a 28-day inhalation toxicity study was also waived previously based on low volatility, low acute inhalation toxicity and large extrapolated inhalation MOE (D376603, 23 September 2010).  

      0.9.  Absorption, Distribution, Metabolism, & Elimination (ADME)

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. 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 or after daily exposures of unlabeled compound at 15 mg/kg for 14 days followed by a single 15 mg/kg oral dose of labeled compound. 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 whole-body autoradiography and time-course studies indicate that relatively higher radioactivity levels were detected in the adrenal glands, bone marrow, thyroid, squamous epithelium of the non-fundic stomach, and ovaries compared to the other body organs/tissues. 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 post dosing; saturation kinetics were also noted at these higher doses.

            0.9.1. Dermal Absorption

Dermal penetration studies on quinclorac are not available. There was no dermal toxicity seen at the limit dose of 1000 mg/kg/day in a 21-day dermal toxicity study in rabbits.

      0.10. Toxicological Effects

Quinclorac toxicity in experimental animals is observed mostly at doses above 150 mg/kg/day following subchronic and chronic exposures.  Subchronic toxicity includes decreased body weight gains, increased water intake, increased liver enzymes (SGOT, SGPT) and focal chronic interstitial nephritis (rats).  Chronic toxic effects include body weight decrement, increase in kidney and liver weights, and hydropic degeneration of the kidneys (dogs).  At high doses, chronic toxicity also includes increased incidences of pancreatic acinar cell hyperplasia and adenomas (rats).  Neurotoxic effects were not observed in any of the acute, subchronic and chronic studies with quinclorac.  

There was no increased qualitative or quantitative fetal or offspring susceptibility in the prenatal developmental or postnatal reproduction studies.  Developmental toxicity in the rabbit consisted of increased resorptions, post-implantation loss, decreased number of live fetuses, and reduced fetal body weight. These effects occurred at much higher doses than the maternal effects of decreased food consumption and increased water consumption and decreased body weight gain.  In the rat no developmental toxicity was observed at the highest dose tested (438 mg/kg/day).  In the 2-generation reproduction study, parental toxicity and offspring toxicity occurred at the same dose.  Parental toxicity consisted of reduced body weight in both sexes during premating and lactation periods.  Offspring toxicity consisted of decreased pup weight, developmental delays and possible marginal effect on pup viability.  No reproductive toxicity occurred at the highest dose tested (480 mg/kg/day).  

There are no mutagenicity concerns.  Quinclorac is not mutagenic in bacterial assays and does not cause unscheduled DNA damage in primary rat hepatocytes.  There is also no evidence of a genotoxic response in whole animal test systems (in vivo mouse bone marrow micronucleus assay). Quinclorac was negative in a mammalian cell in vitro cytogenetic chromosomal aberration assay in Chinese hamster ovary cells (CHO).  

Quinclorac was classified in 1992 by the HED Cancer Peer Review committee (CPRC) as a group D carcinogen - not classifiable as to human carcinogenicity- based on recommendation by the EPA Scientific Advisory Panel (TXR# 0010416).  This classification was based on equivocal increase in the incidence of one type of benign tumor (pancreatic acinar cell adenomas) in only one sex and one species of animals (male Wistar rats).  Based on this classification, a quantification of cancer risk is not warranted because the chronic RfD will adequately account for all chronic effects, including carcinogenicity, likely to result from exposure to quinclorac.

Quinclorac (technical grade material) has a low order of acute toxicity as demonstrated by Toxicity Category III by the oral, dermal, and inhalation routes. The chemical is a mild eye irritant, is not a skin irritant, but was positive for dermal sensitization.

The complete toxicity profile for quinclorac is provided in Appendix A. 

      0.11.  Safety Factor for Infants and Children (FQPA Safety Factor)

The FQPA Safety Factor Committee recommended in 1998 that the 10x factor for the protection of infants and children (as required by FQPA) be removed (TXR 0012902).  The removal of the 10x factor is based on 1) completeness of the data base; 2) there is no indication of increased susceptibility of rats or rabbit fetuses to in utero and/or postnatal exposure in the developmental and reproductive toxicity data; 3) unrefined (Tier 1) dietary exposure estimates are protective since they exaggerate the dietary exposure estimates; and 4) modeling data are used for ground and surface source drinking water exposure assessments resulting in conservative upper-bound concentrations.

            0.11.1. Completeness of the Toxicology Database

The toxicology database for quinclorac is complete and the risk assessment team has concluded that the FQPA safety factor can be reduced to 1x.  The following acceptable studies are available for FQPA consideration:  (1) Developmental toxicity studies in rats and rabbits; and (2) Two-generation reproduction study in rats.  Acute and subchronic neurotoxicity studies have been waived per HASPOC (TXR# 0056385).
  
            0.11.2. Evidence of Neurotoxicity

There are no acute, subchronic or chronic neurotoxicity studies on quinclorac available from the registrant or from the published literature.  Neurotoxic effects were not observed in any of the acute, subchronic and chronic studies with quinclorac.  Because of the lack of evidence of neurotoxic effects, HIARC (TXR# 0012717) determined in 1998 that no acute, subchronic, or developmental neurotoxicity studies are required for quinclorac. This was confirmed by HASPOC in 2012 (TXR# 0056385).  

            0.11.3. Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

The toxicology database for quinclorac is adequate for the FQPA assessment.  Developmental toxicity studies in rats and rabbits and the reproduction studies in rats provided no indication of increased qualitative or quantitative susceptibility.

            0.11.4. Residual Uncertainty in the Exposure Database

There are no residual uncertainties with regard to dietary and residential/occupational exposure.  
The dietary exposure assessments are based on tolerance level residues and 100% crop treated information. Modeled values were used for drinking water estimates. Occupational and residential exposure assessments are based on reasonable worst-case assumptions and will not likely underestimate potential exposure or risk. Based on these data, the quinclorac risk assessment team concluded that no additional safety factor is needed to account for exposure considerations.

      0.12.  Toxicity Endpoint and Point of Departure Selections

            0.12.1. Dose-Response Assessment

Toxicity endpoints and points of departure (PODs) for dietary and occupational exposure scenarios are summarized below.  A detailed description of the studies used as a basis for the selected endpoints are presented in Appendix A.  

An appropriate endpoint attributable to a single exposure to assess dietary exposure for the general populations including infants and children was not available from the oral toxicity studies including the rat and rabbit developmental toxicity studies.

An acute dietary POD of 200 mg/kg (NOAEL) for the sub-population females 13-49 years old was selected from a rabbit developmental toxicity study based on increased rate of resorptions and post-implantation loss, a decrease in the number of live fetuses, and reduced fetal body weight seen at 600 mg/kg/day.  A UF 100x (10x for intraspecies variation, 10x for interspecies extrapolation and a 1x FQPA safety factor) was applied to the dose to obtain an acute reference dose/population adjusted dose (aRfD/aPAD) of 2.0 mg/kg.

A chronic dietary POD of 37.5 mg/kg/day (NOAEL) was selected for the general population from a carcinogenicity study in mice based on effects on body weight.  A UF 100x (10x for intraspecies variation, 10x for interspecies extrapolation and a 1x FQPA factor) was applied to the dose to obtain a chronic reference dose/population adjusted dose (cRfD/cPAD) of 0.38 mg/kg/day.

A POD of 70 mg/kg/day (NOAEL) for assessing incidental oral short-term (1-30 days) as well as short- and intermediate term inhalation exposure scenarios was selected from the developmental toxicity study in rabbits based on decreased maternal body weight gain and food consumption (and increased water consumption) at 200 mg/kg/day. This is supported by subchronic and chronic dietary data on mice.  The LOC for MOE of 100 is applied for this exposure scenario. This includes 10X for interspecies extrapolation, 10X for intraspecies variation and a 1x FQPA SF.

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

Long-term inhalation exposure is not anticipated based on the current use pattern for quinclorac. Therefore, long-term PODs have not been established.

            0.12.2. Recommendation for Combining Routes of Exposures for Risk Assessment

Under FQPA, when there are potential residential exposures to the pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal and inhalation exposures.  These combined residential exposures must then be aggregated with dietary exposure (food and drinking water) to determine aggregate risk. Dermal exposures were not quantified due to a lack of a dermal toxicological endpoint. Because the inhalation and incidental oral endpoints are based on the same endpoint from the same study, the developmental rabbit, exposures from these routes may be combined.

            0.12.3. Cancer Classification and Risk Assessment Recommendation

Quinclorac was classified in 1992 by the HED Cancer Peer Review committee (CPRC) as a group D carcinogen - not classifiable as to human carcinogenicity- based on recommendation by the EPA Scientific Advisory Panel (TXR# 0010416).  This classification was based on equivocal increase in the incidence of one type of benign tumor (pancreatic acinar cell adenomas) in only one sex and one species of animals (male Wistar rats).  Based on this classification, a quantification of cancer risk is not warranted because the chronic RfD will adequately account for all chronic effects, including carcinogenicity, that may  result from exposure to quinclorac. There was no evidence of carcinogenicity in mice or female rats.

            0.12.4. Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment

Toxicological doses and endpoints for dietary and non-occupational human health risk assessments for quinclorac are presented below in Table 4.5.4.1.

Table 4.5.4.1.  Summary of Toxicological Doses and Endpoints for Quinclorac 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 (General Population, including Infants and Children)
Not applicable.  An endpoint for acute dietary exposure to the general population was not selected because there was no available endpoint attributable to a single dose that was appropriate for this scenario (effects observed in the available studies are presumed to require more than one exposure).

Acute Dietary
(Females 13-49 years of age)
NOAEL (developmental) = 200 mg/kg/day
UFA= 10x
UFH=10x
FQPA SF= 1x

aRfD =  2.0 mg/kg/day

aPAD = 2.0 mg/kg/day
Developmental toxicity study in rabbits (MRID# 41063525 and 41680501) Developmental toxicity LOAEL =  600 mg/kg/day based on increased early resorptions and postimplantation loss, decreased live fetuses, decreased fetal body weight.  These fetal effects are presumed to occur after a single dose.
Chronic Dietary (All Populations)
NOAEL= 37.5 mg/kg/day
UFA= 10x
UFH=10x
FQPA SF= 1x

cRfD = 0.38
mg/kg/day

cPAD = 0.38 mg/kg/day
Carcinogenicity study in mice 
(MRID # 41063523)
LOAEL = 150 mg/kg/day based on decreased body weight.
Incidental Oral Short-Term (1-30 days) 
NOAEL= 70 mg/kg/day
UFA= 10x
UFH=10x
FQPA SF= 1x
Residential LOC for MOE = 100
Developmental toxicity study in rabbits. (MRID# 41063525 and 41680501)
Maternal toxicity LOAEL = 200 mg/kg/day based on decreased maternal body weight gain and food consumption, and increased water consumption.
Dermal (all durations)
Not applicable.  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).
Inhalation Short-Term (1-30 days) and Intermediate-Term (1-6 months)
NOAEL= 70 mg/kg/day
[Inhalation absorption rate = 100% relative to oral absorption]
UFA= 10x 
UFH= 10x
FQPA SF= 1x
Residential LOC for MOE = 100
Developmental toxicity study in rabbits. (MRID# 41063525 and 41680501)
Maternal toxicity LOAEL = 200 mg/kg/day based on decreased maternal body weight gain and food consumption, and increased water consumption.

Inhalation Long-Term (>6 months)
Not applicable.  Long-term inhalation exposure is not anticipated under current use scenarios.
Cancer (oral, dermal, inhalation)
Quinclorac was classified in 1992 by the HED Cancer Peer Review committee (CPRC) as a group D carcinogen - not classifiable as to human carcinogenicity- based on recommendation by the EPA Scientific Advisory Panel (TXR# 0010416).  This classification was based on equivocal increase in the incidence of one type of benign tumor (pancreatic acinar cell adenomas) in only one sex and one species of animals (male Wistar rats).  A quantification of cancer risk is not warranted because the chronic RfD will adequately account for all chronic effects, including carcinogenicity, that may  result from exposure to quinclorac. There was no evidence of carcinogenicity in mice or female rats. 
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).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use of a short-term study for long-term risk assessment.  UFDB = to account for the absence of key date (i.e., lack of a critical study).  FQPA SF = FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c = chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level of concern.  N/A = not applicable.

Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Quinclorac for Use in Occupational Human Health Risk Assessments
                              Exposure/ Scenario
                              Point of Departure
                              Uncertainty Factors
                     Level of Concern for Risk Assessment
                        Study and Toxicological Effects
Dermal (all durations)
Not applicable.  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).
Inhalation Short-Term (1-30 days) and Intermediate-Term (1-6 months)
NOAEL=70 mg/kg/day
[Inhalation absorption rate = 100% relative to oral absorption]
UFA= 10x 
UFH= 10x
FQPA SF= 1x
Residential LOC for MOE = 100
Developmental toxicity study in rabbits. (MRID# 41063525 and 41680501)
Maternal toxicity LOAEL = 200 mg/kg/day based on decreased maternal body weight gain and food consumption, and increased water consumption.
Cancer (oral, dermal, inhalation)
Quinclorac was classified in 1992 by the HED Cancer Peer Review committee (CPRC) as a group D carcinogen - not classifiable as to human carcinogenicity- based on recommendation by the EPA Scientific Advisory Panel (TXR# 0010416).  This classification was based on equivocal increase in the incidence of one type of benign tumor (pancreatic acinar cell adenomas) in only one sex and one species of animals (male Wistar rats).  A quantification of cancer risk is not warranted because the chronic RfD will adequately account for all chronic effects, including carcinogenicity, that may result from exposure to quinclorac. There was no evidence of carcinogenicity in mice or female rats.
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).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use of a short-term study for long-term risk assessment.  UFDB = to account for the absence of key data (i.e., lack of a critical study).  MOE = margin of exposure.  LOC = level of concern.  N/A = not applicable.

      0.13.  Incident Reports

Quinclorac incidents were previously analyzed in 2007 (M. Hawkins, 08/30/2007, D343370).  In the previous review, two incidents were identified in IDS from 1999 to 2007; a total of five quinclorac cases were identified in the PCC data base 1993 to 2005; and there were no incidents identified in National Institute of Occupational Safety and Health Sentinel Event Notification System for Occupational Risks (NIOSH SENSOR) data from 1998 to 2003.  The document concluded that "No mitigation actions are necessary for quinclorac at this time."  Updated incident analysis of the Main and Aggregate Incident Data System (IDS) from January 1, 2007, to August 14, 2012, shows an increase in the number of incidents since the previous incident review performed in 2007.  This is most likely due to the fact that, prior to 2007, all quinclorac products used to treat residential turf could be applied only by a certified applicator. This was a self-imposed restriction by the registrant.  In 2007, the registrant requested this restriction be removed. Since the restriction was removed in 2007, there have been approximately 19 quinclorac products intended for use on residential turf registered that may be applied by the homeowner.  Obtaining additional information on current usage data for quinclorac would improve future assessments.  The updated analysis of NIOSH SENSOR from 1998 to 2008, is not current enough to represent the more recent residential registrations but is consistent with the previous 2007 review.  It should be noted the SENSOR dataset through 2009 is forthcoming (NIOSH plans to provide the updated dataset within the 2012 calendar year) and will be analyzed for additional quinclorac cases.  

Overall, only a moderate number of incidents have been reported involving quinclorac.  The vast majority of these incidents were of low severity, although, there were a few high severity outcomes reported in the IDS database.  While incident information can be an important source of feedback to the Agency, reports of adverse health effects allegedly due to a specific pesticide exposure (i.e., an "incident") are largely self-reported and therefore, generally speaking, neither exposure to a pesticide or reported symptom (or the connection between the two) is validated or otherwise confirmed.  Typically, causation cannot be determined based on incident data.  The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be performed (Memo, S. Recore, 9/25/2012, D405512).

 Dietary Exposure and Risk Assessment 

      0.14.  Metabolite/Degradate Residue Profile

            0.14.1. Summary of Plant and Animal Metabolism Studies

The qualitative nature of quinclorac residues in plants was considered adequately understood for the currently registered uses, based upon the metabolism studies on rice, grain sorghum, and wheat.  In each of these studies, the major [14]C-residue in/on various matrices was identified as parent compound.  Based on the metabolite profiles observed in these studies, quinclorac undergoes hydroxylation of the quinoline ring of the parent, followed by conjugation with glucose and other biologically available compounds at the hydroxylated site.   Some radioactive residues are incorporated into the high molecular weight natural products.  Based on the above studies, HED concluded that parent is the only residue of concern in plant commodities for purposes of the tolerance expression and risk assessment.  However, all three metabolism studies are on grain commodities.  A 4[th] metabolism study, on canola, is available but has not been reviewed.

Metabolism in Rice:  (MRID 41063534).  The metabolism of 14C-ring labeled quinclorac in rice plants was studied under growth chamber and field conditions.  Growth chamber plants were treated at 1.4 lb.ai/A 14C-BAS 514H, an exaggerated dosage rate, at the four leaf stage of plant development. Growth-chamber rice plant samples were harvested for analysis at PHI=97 days. Field plants were treated at 0.75 lb/A 14C-BAS 514H, at the 3-5 leaf stage. The treatment level of field plants simulates the expected herbicide use rate. Field rice plants were harvested at PHI= 28 and 118 days.  Greater than 84% of the TRR in rice grain or straw was identified as the parent compound, quinclorac. 

Metabolism in Sorghum:  (MRID #44322211).  Preemergence and post emergence applications of radiolabeled quinclorac were made to a confined sorghum plot.  The soil was a loamy sand soil with low organic matter.  Treatment levels were 0.47 lb ai/A preemergence (0 DAT) and 0.45 lb a.i./A postemergence (25 DAT) for a total of 0.92 lb ai/A.  Crop samples were collected and analyzed at various stages of maturity, including forage samples collected at twenty-five days after the postemergence treatment, and mature stover and grain collected at the final harvest (120 DAT).  

Table 5.1.  Distribution and Identification of Residues from Sorghum RACs Treated at 0.92 lb a.i./A. 

RAC
Radioactive Residues

Identified 
Unidentified
Residuum

quinclorac
quinclorac methyl ester
Soluble polars
Organosoluble

ppm
%TRR
ppm
%TRR
ppm
%TRR
ppm
%TTR
ppm
%TRR
ppm
forage
4.01
73.4
2.94
3.6
0.145
18.7
0.750
4.7
0.188
<1
<0.01
fodder
0.87
21.5
0.186
5.9
0.051
52.4
0.455
19.4
0.169
<1
<0.01
grain
0.83
73.5
0.610
1.7
0.014
5.5
0.044
6.6
0.055
<1
<0.01

The radioactive residues of quinclorac found in sorghum following typical agricultural practices consist predominantly of parent compound.  A minor metabolite, the methyl ester of quinclorac, is found in all tissues, but always at less than 10% TRR.   A lower percentage of the residue in sorghum fodder was found to be quinclorac, but the majority of the residue was soluble polar compounds.  The current analytical methodology (BASF Method No. A8902) employs a similar acetone extraction step as used in the above extractions.  Therefore, the accountability of the residues is high.   
 
Metabolism in Wheat:   (MRID #44322207).   The test substance used in this study was quinclorac (labeled at the 3 position) at two application rates (0.112 lb ai/A (0.45X the proposed  rate) and 0.446 lb ai/A (1.8X the proposed rate)).  Only the higher application rate is presented in the table below.  Plants were grown in greenhouse conditions and sprayed 22 days after planting, when they were in the 3 to 5 leaf stage.  Forage samples were collected at a 37-day PHI, straw and grain at a PHI of 92 days.    

Table 5.2.  Distribution and Identification of Residues from Wheat RACs Treated at 0.446 lb ai/A Quinclorac. 

RAC
Radioactive Residues

ppm
Identified
Unidentified
Unextracted Marc

quinclorac
quinclorac methyl ester
aqueous acetone soluble
hydrolyzable
non-hydrolyzable

%TRR
ppm
%TRR
ppm
%TRR
ppm
%TRR
ppm
%TRR
ppm
forage
13.1
45.1
5.9
6.4
0.84
38.4
5.1
10.3
0.34
1.9
0.06
straw
8.2
22.4
1.8
12.6
1.0
45.1
3.7
12.4
0.23
3.3
0.06
grain
3.9
68
2.7
3.7
0.15
17.2
0.68
3.3
0.04
0.3
<0.01

The primary path by which plants metabolize quinclorac is through the hydroxylation of the quinoline ring of the parent, followed by the conjugation of glucose and other biologically available compounds at the hydroxylated site.  Ultimately, some radioactive residues are incorporated into the high molecular weight natural products. 

The petitioner, IR-4, requests a waiver from the requirement of another metabolism study based on the following.  In the studies to date it has been shown that in plants the primary path by which quinclorac is metabolized is through hydroxylation of the quinolone ring of the parent, followed by the conjugation of glucose and other biologically available compounds at the hydroxylated site.    These results were similar for all quinclorac metabolism studies submitted to date.

Rhubarb and cranberry are very low acreage crops.  Cranberry is commercially grown on just over 40,000 acres, and Rhubarb is commercially grown on approximately 2,000 acres in the US (based on 2002 census of Agriculture).

In addition, other related quinoline compounds, such as quinoxyfen have shown similar metabolism results in that the parent is the primary residue component (D276835, 3/26/2003, G. Kramer) when conducted on a wide variety of plant matrices (cucumber, grape, sugarbeet, and tomato).  In these studies, quinoxyfen was the primary residue component and other remaining compounds were incorporated into natural plant constituents.  In cucumber and tomato, unchanged quinoxyfen remained largely on the surface of treated plants.  The presence of multiple unidentified polar residues suggests that metabolism of quinoxyfen does occur to some extent to form more polar soluble components with the incorporation into insoluble material.  

Conclusions.  While the metabolism of quinclorac is adequately understood with regard to the currently registered uses, there are no plant metabolism data for quinclorac on commodities similar to cranberry.  These data are not being required at this time.  However, any further expansion of the use of quinclorac to other commodities grown on larger acreages than rhubarb and cranberry, will trigger a requirement of additional metabolism data.

The methyl ester of quinclorac was reported in some grain commodities at <15% of the TRR.  The methyl ester is measured by the enforcement method, which includes a methylation step.

 860.1300 Nature of the Residue - Livestock
D241204, J. Stokes, 11/6/1998
D325790, M. Doherty, 9/13/2007

The qualitative nature of quinclorac residues in livestock is understood based upon the adequate goat and poultry metabolism studies (MRIDs 41076104 and 41063535, respectively).  In both studies, quinclorac was the principal residue identified in each commodity.  HED concluded that parent is the only residue of concern for risk assessment and tolerance expression for livestock.  However, the enforcement method includes a methylation step and determines the methyl ester of quinclorac. 

In a rat metabolism study (MRID 41063533), quinclorac was the primary metabolite reported.  Elimination was primarily in the urine (91-98%) with small amounts in the feces (1-4%) eliminated by day 5 after dosing.

Conclusions.  No further livestock metabolism data are required at the present time.

            0.14.2. Summary of Environmental Degradation

M. Lowit, N. Andrews, D397720, 8/9/12; M. Lowit, N. Andrews, D405093, 9/14/12

Vapor pressure (7.5 x 10[-8] mm Hg at 20[o] C) and Henry's Law Constant (1.22 to 24.3 x 10[-15] atm.m[3] mol[-1]) indicate a low possibility of volatilization from soil and water.  Laboratory data indicate that quinclorac is stable to hydrolysis, photolysis in sterile water, aerobic soil metabolism, and aquatic metabolism (aerobic and anaerobic).  Conversely, quinclorac undergoes rapid photolysis in non-sterile rice paddy, natural river waters, and solutions containing activated sewage sludge (half-lives of 5-10 days).  Photolysis on soil surface is also a route of dissipation with a mean half life of 141 days.  Based on available laboratory studies, two major (BH 514-1 and BH 514 2-OH; >10% applied) and one minor (BH 514-HMe-ester; <10% applied) metabolites of quinclorac were identified.  The adsorption coefficients for quinclorac and its degradation products suggest that leaching could be a route of dissipation.  Field studies indicate that quinclorac is moderately persistent to persistent (18-176 day half-lives) in terrestrial environments. The octanol/water partition coefficient (KOW) of 0.266 also suggests that quinclorac has a low potential to bioaccumulate.  A detailed assessment of the environmental fate of quinclorac can be found in the new chemical risk assessment (DP 250179+).
      
            0.14.3. Comparison of Metabolic Pathways

Quinclorac was the predominant metabolite in all 3 plant metabolism studies (all in grains), and in the livestock metabolism study and the rat metabolism study.  Small amounts of a methyl ester in plants was reported.

The primary path by which plants metabolize quinclorac is through the hydroxylation of the quinoline ring of the parent, followed by the conjugation of glucose and other biologically available compounds at the hydroxylated site.  Ultimately, some radioactive residues are incorporated into the high molecular weight natural products. The forage, fodder, and straw reported a number of aqueous metabolites, which would be polar metabolites, such as hydroxylated metabolites or conjugates.

The qualitative nature of quinclorac residues in livestock is understood based upon adequate goat and poultry metabolism studies (MRIDs 41076104 and 41063535, respectively).  Quinclorac was the principal residue identified in each commodity.  

In a rat metabolism study (MRID 41063533), quinclorac was the primary metabolite reported.  Elimination was primarily in the urine (91-98%) with small amounts in the feces (1-4%) eliminated by day 5 after dosing.

            0.14.4. Residues of Concern Summary and Rationale

Quinclorac was not reviewed by ROCKs or its predecessor. Previous risk assessment teams determined that quinclorac was the residue of concern since it was the predominant metabolite. 

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
Quinclorac
Quinclorac

Rotational Crop
Quinclorac
Quinclorac
Livestock
Ruminant
Quinclorac
Quinclorac

Poultry
Quinclorac
Quinclorac
Drinking Water
Quinclorac
Not Applicable

      0.15.  Food Residue Profile

D397719, D404569, D404912, S. Hummel, G. Otakie, 9/6/12

Residue Analytical Methods: An adequate GC/ECD method is available for enforcing the proposed tolerances, and the field trial data were collected using an LC/MS/MS method adequate for determining quinclorac, per se.  If LC/MS/MS is to be used, a method is needed for the methyl ester of quinclorac and any other metabolites found in the required metabolism study.

Multiresidue Methods: Adequate data are available evaluating quinclorac through the FDA Multi-Residue Methods Test guidelines, and quinclorac is detected by Protocol B.  Quinclorac is not detected by the other FDA MRM protocols.

Storage Stability: The available storage stability data are adequate and support the storage conditions and durations incurred in the existing field trials, for currently registered uses.  The IR-4 concurrent storage stability data for rhubarb and cranberry are adequate for residues of quinclorac, demonstrating stability for the time and conditions the samples were stored.  Storage stabilty data are needed for residues of the methyl ester of quinclorac and other residues of concern found in the required metabolism study.

Water, Fish, and Irrigated Crops: For existing use on rice and the proposed use on cranberry, a label restriction is needed regarding the use of treated rice and cranberry fields for aquaculture.  Alternatively, the petitioner can determine residues in catfish and crayfish raised in treated fields and propose tolerances for these commodities if necessary.  The label provided for Quinclorac/QuinStar 4-L does not contain any restriction against aquaculture.

Conclusions.  Data on catfish and crayfish are required, or the label must prohibit use of treated water from rice and cranberry fields for aquaculture. For registration review, the PM must ensure that all quinclorac labels with uses on rice and cranberry contain such a restriction.

Meat, Milk, Poultry, and Eggs: Adequate cattle and poultry feeding studies are available. The uses proposed in this petition do not involve livestock feeds, and will not affect the existing tolerances on meat, milk, poultry and eggs. 

For registration review, we are recommending that the tolerance on Grain, aspirated fractions be revoked, since data have been received demonstrating that the tolerance is not needed, as residues on aspirated grain fractions (AGF) are no higher than the tolerances on the grains. AGF were the highest contributor to the livestock dietary burden, but tolerances have since been established for grass commodities, which is now the highest contributor to the livestock dietary burden.

Conclusions. Tolerances in livestock commodities will be changed in connection with Registration Review.  Residues are expected to be found in meat byproducts and fat but not in milk and eggs.  The dietary burden for hogs and poultry is low enough that no quantifiable residues are expected in hog and poultry commodities.

Crop Field Trials:

Cranberry (for Low Growing Berries except strawberry, subgroup 13-07.  Five cranberry field trials were conducted in the United States during the 2009 growing season, in North American Free Trade Agreement (NAFTA) Growing Zones 1 (MA; 2 trials), 5 (WI; 2 trial), and 12 (OR; 1 trial).  The two MA trials (MA01 and MA03) and the two WI trials (WI01 and WI02) were each conducted using the same Field Research Director (FRD).   Careful examination of the field trial records indicates that the only difference between each pair of trials was the use of different varieties of cranberry, and distance between MA trials of > 20 miles, and different soil characteristics for the MA trials.  HED has concluded that there are insufficient distinguishing characteristics to classify the WI pair as separate trials; however, the trials were conducted prior to development of the guidance on field trial differentiation.

Following two foliar broadcast applications of the 3.8 lb ai/gal SC formulation of quinclorac at 0.484-0.528 lb ai/A, residues of quinclorac (and per trial averages) in/on cranberry harvested at a 57- to 62-day PHI were 0.15-0.68 (0.16-0.67) ppm.  Applications were made at a 28- to 32-day retreatment interval (RTI) using ground equipment in spray volumes of 29.7-35.3 gal/A.  A crop oil concentrate (COC) was added to the spray mixture for each of the applications at 2 pints/A.  

Rhubarb.  Four field trials were conducted in the United States during the 2009 growing season in the North American Free Trade Agreement (NAFTA) Growing Zones 5 (MI; 1 trial) and 12 (OR; 3 trials).  The two rhubarb trials in Canby, OR (OR11 and OR12) and the trial in Hillsboro, OR (OR10) were conducted by the same Field Research Director (FRD).  Careful examination of the field trial records indicates there are sufficient distinguishing characteristics to classify the Hillsboro, OR trial as a separate trial from the Canby, OR trials, based on location (>20 miles apart) and spray volume (>25% higher at the Hillsboro site).  There are insufficient distinguishing characteristics to classify the two Canby, OR trials as separate trials; therefore, the Canby, OR trials constitute a single trial with replicate samples for purposes of 860.1500 data requirements.  The adjustment in trial numbers results in a total of three field trials, with one trial in Zone 5 and two trials in Zone 12.

Following two foliar broadcast applications of the 3.8 lb ai/gal SC formulation of quinclorac at 0.736-0.798 lb ai/A, residues (and per trial averages) of quinclorac in/on rhubarb harvested at a 29- to 33-day PHI were 0.05-0.231 (0.082-0.205) ppm.  The method LOQ was 0.05 ppm.  Applications were made at a 28- to 31-day retreatment interval (RTI) using ground equipment in spray volumes of 19.9-36.7 gal/A.  A crop oil concentrate (COC) was added to the spray mixture for each of the applications at a rate of 1-2 pints/A.  

Conclusions.  Field trial data are adequate to determine residues of quinclorac, per se.  Samples must be reanalyzed for the methyl ester of quinclorac and any other residue of concern found in the metabolism study. 

IR-4 should note the current guidance for differentiating field trial sites.

Existing Uses of Remaining Crops: 

Existing uses of Quinclorac include use on rice, wheat, soybeans, barley (import), grass forage and hay.  Field trial data are adequate to support the existing uses of quinclorac on rice, grain sorghum, barley (imported), and pasture and range grasses. In decline studies, residues generally degraded substantially within 14 days.

The established tolerance on aspirated grain fractions should be revoked as it is not needed.  The tolerance on rice straw may be revoked, as rice straw is no longer considered a livestock feedstuff.

Processed Food and Feed

There are no processed commodities in connection with the current petition.

For registration review, processing studies submitted to support existing tolerances are adequate.   Processing studies were submitted for Rice (MRID 41063543), Sorghum (MRID#44322213), and Wheat (MRID#44322209).  Residues of quinclorac concentrate in hulls and in some grain milled products. Available processing data are adequate to support the currently registered uses of quinclorac.

Confined and Field Accumulation in Rotational Crops

Adequate rotational crop studies are available to support the use of quinclorac.  No residues greater than the limit of detection of 0.05 ppm quinclorac were found in mustard leaves and turnip leaves and roots when planted 120 and/or 270 days after a quinclorac application to rice.  (The analytical method was validated down to 0.05 ppm, so 0.05 ppm may be called the limit of quantitation (LOQ) or the lower limit of method validation (LLMV). Quantifiable residues of concern are not expected at rotational crop intervals of 120 days or longer.

      0.16.  Water Residue Profile

M. Lowit, N. Andrews, D397720, 8/9/12; M. Lowit, N. Andrews, D405093, 9/14/12

The current assessment is performed according to current EFED guidance and up-to-date models including the Tier II surface water model (PRZM/EXAMS) for all uses of quinclorac except cranberries and rice. Screening-level Tier I modeling was used to estimate surface water concentrations for use on cranberry (provisional cranberry model) and rice (Tier I rice model) because the current Tier II model is not parameterized for those uses.  The Tier I SCI-GROW model was used to estimate groundwater concentrations for all uses.
  
 As in past assessments, this assessment does not consider quinclorac major degradation products BH 514-1 and BH 514 2-OH. Although these degradates were detected in the laboratory studies, they seem to be intermediate degradates (DP 344485), and were not found in field dissipation studies at any significant levels. Furthermore, since quinclorac is persistent and mobile, it is expected to be the predominant residue in ground and surface waters.
 
Surface water EDWCs (acute = 511 ug/L and chronic = 511 ug/L) resulting from use on rice supersede previously recommended EDWCs.  The recommended groundwater EDWC has not changed (29 ug/L for acute and chronic exposure). 
 
Table 5.3a.  Estimated Drinking Water Concentrations (EDWCs) of Quinclorac in Surface Water Sources.

                                      Use
                                   Scenario
Estimated Drinking Water Concentrations from Surface Water Sources (ug/L)[1,2,3]
                                       
                                       
                              1-in-10 year acute
                             1-in-10 year chronic
                                 30-year mean
Turf grasses
(1.4 lb ai/A x 1)

(0.76 lb ai/A x 2)

FL turf [4]
41.3
28.5
16.8

PA turf [4,5]
58.3
37.8
20.0

FL turf [4]
43.1
32.8
16.3

PA turf [4,5]
74.1
62.0
23.7
Sorghum
(0.375 lb ai/A x 2)

(0.245 lb ai/A x 3)

KS sorghum (postplant)[6]
26.3
10.5
6.9

KS sorghum (postplant/fall)[7]
20.5
10.2
6.3

KS sorghum (preplant)
23.6
9.5
6.4
Wheat
ND wheat (preplant spring)
38.7
26.9
16.5

ND wheat (preplant winter)
46.6
28.6
19.3
Rangeland / Pasture
FL turf[4]
29.3
21.2
14.6

PA turf[4,5]
36.6
25.3
16.0

CArangelandhayRLF_v2[4]
54.0
36.9
20.5
Rights of way /Fencerow /Hedgerows
1.5 lb ai/A x 1
0.76 lb ai/A x 2
CArightofwayRLF_v2[4]
24.7
14.9
8.2

CArightofwayRLF_v2[4]
27.7
14.3
8.4
Grass grown for seed[4,5]
ORgrassseed[4,5]
25.4
15.8
11.0
Fallow land
FL turf[4]
27.1
19.6
13.7

PA turf[4,5]
31.5
21.1
13.6

CArangelandhayRLF_v2[4]
39.3
27.2
16.4
Grass forage /Fodder /Hay
FL turf[4]
26.4
18.5
14.4

PA turf[4,5]
27.1
21.4
14.9

CArangelandhayRLF_v2[4]
46.8
31.7
20.6
Low growing berry (except cranberry and strawberry)
ORberriesOP
3.4
2.0
1.3
Rhubarb
CA cole crop RLF_v2
33.8
18.0
11.4

CA lettuce
27.9
18.8
12.9
Cranberry

Provisional Cranberry Model[8]
161.9
147.2
--
Rice
Tier I Rice Model[9]
511.1
511.1
--
Aquatic Weeds[10]
Labeled concentration
500.0
500.0
--
1 PCA = 1  (www.epa.gov/oppefed1/models/water ) because this is a national drinking water assessment and quinclorac is registered for non-agricultural, non-turf uses.
[2] BOLD indicates highest EDWC
[3] EDWCs based on aerial applications are presented for uses that permit aerial and ground applications at the same application rate.
[4] Highest value of twelve estimates (first application on the first day of each month) because there are no restrictions on when pesticide may be applied.
[5] Although permitted, it was assumed that winter applications would be unlikely (December, January, February).
[6] Two applications between preemergence and postemergence (up to 12 inches)
[7] One application between preemergence and postemergence (up to 12 inches) and one application in the fall prior to the first killing frost
[8]Based on a one-year simulation; 1 in 10 year calculation is not applicable.
[9] Based on a single, screening level concentration; 1 in10 year calculation is not applicable.
[10] Registered as an experimental use permit.

Table 5.3b.  Estimated Drinking Water Concentrations (EDWCs) of Quinclorac in Ground Water Sources 

                                      Use
                               Application Rate
 Estimated Drinking Water Concentrations from Ground Water Sources (ug/L)[1]
                                       
                                       
                                     Acute
                                    Chronic
Turf grasses
1.4 lb ai/A x 1
                                      27
                                      27

0.76 lb ai/A x 2
                                      29
                                      29
Sorghum
0.375 lb ai/A x 2 and 0.245 lb ai/A x 3
                                      14
                                      14
Wheat
0.245 lb ai/A x 3
                                      14
                                      14
Rangeland / Pasture
0.75 lb ai/A x 1
                                      14
                                      14
Rights of way/Fencerow/Hedgerows
1.5 lb ai/A x 1
                                      29
                                      29

0.76 lb ai/A x 2
                                      29
                                      29
Grass grown for seed
0.375 lb ai/A x 2
                                      14
                                      14
Fallow land
0.75 lb ai/A x 1
                                      14
                                      14
Grass forage /Fodder /Hay
0.375 lb ai/A x 2
                                      14
                                      14
Low growing berry (except cranberry and strawberry)
0.25 lb ai/A x 2
                                      10
                                      10
Rhubarb
0.375 lb ai/A x 2
                                      14
                                      14
Rice[2]
--
                                      --
                                      --
Cranberry[2]
--
                                      --
                                      --
Aquatic Weeds[2]
--
                                      --
                                      --
1 BOLD indicates highest EDWC
[2] Groundwater concentrations are not estimated for aquatic uses.

      2.1.  Dietary Risk Assessment

            2.1.1. Description of Residue Data Used in Dietary Assessment

Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model DEEM-FCID, Version 3.16 which uses food consumption data from the U.S. Department of Agriculture's National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA).  This dietary survey was conducted from 2003 to 2008.  These analyses were performed to support the Section 3 request for quinclorac uses on rhubarb and low growing berry, except strawberry, subgroup 13-07H and to support Registration Review for quinclorac and the dimethylamine (DMA) salt of quinclorac.  All registered, pending and proposed uses of quinclorac and the DMA salt of quinclorac, as of the date of this memorandum, are included in these assessments.  
	
Tolerances have been established for quinclorac (40CFR §180.463[a]) in livestock and cereal grain commodities.  HED has determined that the use of the DMA salt of quinclorac on cereal grains will not affect the established tolerances for quinclorac on rice, grain sorghum, and wheat.
The residue of concern (ROC), for both tolerance enforcement and risk assessment, is the parent compound, quinclorac.  

The quinclorac drinking water estimates used in these dietary risk assessments were provided by EFED (DP# 397720, M. Lowit/N. Andrews, 8/9/12 and DP# 405093, M. Lowit/N.Andrews, 9/14/12), and incorporated directly into the dietary assessments.  Water residues were incorporated in DEEM-FCID via entry into the food categories "water, direct, all sources" and "water, indirect, all sources."  The estimated drinking water concentrations (EDWCs) from existing and proposed uses of quinclorac for both acute and chronic scenarios in ground and surface water are 0.029 ppm and 0.511 ppm, respectively.  
	
Rice (labeled for a single application of 0.5 lb ai/A) was identified as the use resulting in the highest EDWCs for surface water.  Because the use on rice involves flooding (for which the current Tier II model is not parameterized), the surface water EDWCs were assessed using a Tier I Rice Model, Version 1.0 (May 8, 2007).  Turf grass was identified as the use resulting in the highest EDWCs for ground water.  The EDWC in ground water was assessed using the Tier I Screening Concentration in Ground Water (SCI-GROW, Version 2.3) model.  These models, and their descriptions, are available at the EPA internet website via the web link, http://www.epa.gov/oppefed1/models/water/.  No surface or ground water monitoring data were available for quinclorac.  

            2.1.2. Percent Crop Treated Used in Dietary Assessment

The acute and chronic assessments are based on the assumption that 100% of all commodities with tolerances will be treated.

            2.1.3. Acute Dietary Risk Assessment

The acute dietary assessment is highly conservative, and assumes 100% crop treated (%CT), along with tolerance-level residues for all agricultural commodities.  Default processing factors from DEEM 7.81 were used (for dried beef and cranberry juice) in the analyses.  Tier I modeling was used to estimate drinking water concentrations.

The acute (food + water) dietary risk estimate at the 95[th] percentile of exposure is 1.6% of the acute population adjusted dose (aPAD) for females age 13 to 49.  This is the only population subgroup for which an acute endpoint was selected.  
	
Generally, the Agency is concerned when risk estimates exceed 100% of the PAD.  The acute dietary risk estimate for quinclorac is below HED's level of concern.  

            2.1.4. Chronic Dietary Risk Assessment

The chronic dietary assessment is highly conservative, and assumes 100% crop treated (%CT), along with tolerance-level residues for all agricultural commodities.  Default processing factors from DEEM 7.81 were used (for dried beef and cranberry juice) in the analyses.  Tier I modeling was used to estimate drinking water concentrations.

The chronic (food + water) dietary risk estimates are less than or equal to 8.9% of the chronic population adjusted dose (cPAD) for all population subgroups.  All Infants < 1 year of age is the most highly-exposed subgroup, utilizing 8.9% of the cPAD, while the general US population utilizes 3.6% of the cPAD.  

Generally, the Agency is concerned when risk estimates exceed 100% of the PAD.  All chronic dietary risk estimates for quinclorac are below HED's level of concern.  

            2.1.5. Cancer Dietary Risk Assessment

Quinclorac was classified in 1992 by the HED Cancer Peer Review committee (CPRC) as a group D carcinogen - not classifiable as to human carcinogenicity- based on recommendation by the EPA Scientific Advisory Panel (TXR# 0010416).  This classification was based on equivocal increase in the incidence of one type of benign tumor (pancreatic acinar cell adenomas) in only one sex and one species of animals (male Wistar rats).   Based on this quantification, a quantification of cancer risk is not warranted because the chronic RfD will adequately account for all chronic effects, including carcinogenicity, that may result from exposure to quinclorac.  

            2.1.6. Summary Table

 Table 5.4.6.  Summary of Dietary (Food and Drinking Water) Exposure and Risk for Quinclorac
                              Population Subgroup
                                 Acute Dietary
                               (95th Percentile)
                                Chronic Dietary
                                     Cancer
                                        
                          Dietary Exposure (mg/kg/day)
                                    % aPAD*
                                Dietary Exposure
                                  (mg/kg/day)
                                    % cPAD*
                                Dietary Exposure
                                  (mg/kg/day)
                                      Risk
 General U.S. Population
                                      N/A
                                      N/A
                                   0.013728
                                      3.6
                                      N/A
                                      N/A
 All Infants (< 1 year old)
 
 
                                   0.033999
                                      8.9
 
 
 Children 1-2 years old
 
 
                                   0.023500
                                      6.2
 
 
 Children 3-5 years old
 
 
                                   0.019280
                                      5.1
 
 
 Children 6-12 years old
 
 
                                   0.013431
                                      3.5
 
 
 Youth 13-19 years old
 
 
                                   0.010195
                                      2.7
 
 
 Adults 20-49 years old
 
 
                                   0.013614
                                      3.6
 
 
 Adults 50+ years old
 
 
                                   0.012525
                                      3.3
 
 
 Females 13-49 years old
                                   0.032108
                                      1.6
                                   0.012893
                                      3.4
 
 

 Residential (Non-Occupational) Exposure/Risk Characterization

Ivan Nieves, D404915, D404797, 9/18/12 

Although this document addresses proposed new agricultural uses which do not involve applications by homeowners or commercial applicators in residential settings, HED has recently updated the residential exposure standard operating procedures (SOPs) and body weights to be used in all human health assessments as well as the incorporation of new chemical specific toxicological information.  As a result of the updated policies and parameters, all of the existing residential (non-occupational) use patterns have been reassessed in this document because these scenarios will impact the quinclorac aggregate assessment.

Although, quinclorac products do not appear to be specifically marketed towards residential handler use (i.e., homeowners); a residential handler assessment was performed to be protective of any such use.  Quinclorac is currently registered for use on turfgrass (lawns, sod, turf areas) including but not limited to grounds or lawns around residential and commercial establishments, multifamily dwellings, military and other institutions, parks, airports, roadsides, schools, picnic grounds, athletic fields, houses of worship, cemeteries, golf courses, prairie grass areas, and sod farms.  Quinclorac may also be used in and around established landscape ornamentals and ornamental gardens.  The quinclorac products used in residential settings can be formulated as granular, liquid, and dry flowable formulations.  

      60.1.  Residential Handler Exposure

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, residential handler exposure is expected from the existing uses.  The quantitative exposure/risk assessment developed for residential handlers is based on the following scenarios: 

   1. Loading/Applying granules for belly grinder,
   2. Loading/Applying granules for push type rotary spreader,
   3. Loading/Applying granules for a spoon;
   4. Loading/Applying granules for a cup and shaker can;
   5. Applying granules by hand;
   6. Mixing/loading/applying liquid and dry flowable formulations via manually-pressurized handwand, a hose-end sprayer, a backpack, and a sprinkler can; 
   7. Mixing/loading/applying ready-to-use formulation via a trigger sprayer, and a hose-end sprayer.

For residential handlers, HED presents exposure estimates for individuals wearing shorts, short-sleeved shirts, shoes plus socks.  Pesticide application area assumed to be performed by adults only, however the assessment does group 16 year olds with adults. 

Table 6.1 lists the exposures and risk estimates for the residential handler scenarios. The updated exposure scenarios result in risk estimates that do not exceed HED's level of concern (MOEs >= 100).

Table 6.1. Quinclorac Residential (Non-Occupational) Handler Estimated Risks
                                  Formulation
                         Application Equipment/Method
                              Application Rate[1]
                                     Units
                     Area Treated or Amount Handled Daily
                                Units (per day)
                    Inhalation Unit Exposure (mg/lb ai)[2]
                          Inhalation Exposure (mg/day)
                    Inhalation Absorbed Dose[3] (mg/kg/day)
                               Inhalation MOE[4] 
                                    Granule
Push-type spreader
                                     0.68
                                  lb ai/acre
                                      0.5
                                     acres
                                    0.0026
                                    0.00088
                                   0.000011
                                   6,300,000

Belly grinder
                                   0.0000172
                                  lb ai/ft[2]
                                     1200
                                     ft[2]
                                     0.039
                                    0.0008
                                    0.00001
                                   7,000,000

Spoon

                                      100
                                     ft[2]
                                     0.087
                                    0.00015
                                   0.0000019
                                  37,000,000

Cup; Shaker can

                                     0.013
                                   0.000022
                                  0.00000028
                                  250,000,000

Hand dispersal

                                     0.38
                                    0.00065
                                   0.0000082
                                   8,600,000
                              Liquid concentrate
Hose-end Sprayer
                                     0.78
                                  lb ai/acre
                                      0.5
                                     acres
                                     0.022
                                    0.0086
                                    0.00011
                                    650,000

Manually-pressurized handwand  
                                     0.16
                                 lb ai/gallon
                                       5
                                    gallons
                                     0.018
                                     0.014
                                    0.00018
                                    390,000

Backpack

                                     0.14
                                     0.11
                                    0.0014
                                    50,000

Sprinkler can
                                   0.0000172
                                  lb ai/ft[2]
                                     1000
                                     ft[2]
                                     0.022
                                    0.00038
                                   0.0000047
                                  15,000,000

Trigger-sprayer
(Ready-to-Use)
                                    0.0172
                                 lb ai/bottle
                                       1
                                    bottle
                                     0.061
                                     0.001
                                   0.000013
                                   5,300,000

Hose-end Sprayer
(Ready-to-Use)
                                     0.76
                                  lb ai/acre
                                      0.5
                                     acres
                                     0.034
                                     0.013
                                    0.00016
                                    430,000
                   Water-dispersible Granule / Dry Flowable
Manually-pressurized handwand
                                     0.28
                                 lb ai/gallon
                                       5
                                    gallons
                                      1.1
                                      1.5
                                     0.019
                                     3,600

Hose-end Sprayer
                                      1.4
                                  lb ai/acre
                                      0.5
                                     acres
                                     0.022
                                     0.015
                                    0.00019
                                    360,000

Backpack
                                     0.28
                                 lb ai/gallon
                                       5
                                    gallons
                                      1.1
                                      1.5
                                     0.019
                                     3,600

Sprinkler can
                                   0.0000172
                                  lb ai/ft[2]
                                     1000
                                     ft[2]
                                     0.022
                                    0.00038
                                   0.0000047
                                  15,000,000
   1. Max application rate based on various labels containing non-occupational use sites registered for quinclorac
   2. Based on Standard Operating Procedures for Residential Pesticide Exposure Assessment http://www.epa.gov/pesticides/science/EPA-OPP-HED_Residential%20SOPS_Feb2012.pdf :  
   3. Inhalation Dose (mg/kg/day) = daily unit exposure (mg/ - lb ai) * application rate (lb ai/acre) * amount handled (acres) * inhalation absorption (100%) /  - body weight (79.5 kg);  
   4. Inhalation MOE = PoD (NOAEL of 70 mg/kg/day) / Daily inhalation dose (mg/kg/day). Level of concern = 100. 

      4.1.  Residential Post-Application Exposure

There are no proposed residential uses at this time; however, there are existing registered residential uses on lawns and turf for liquid and granular formulations that have been reassessed as part of Registration Review.  A summary of the exposure and risk is provided below for use in performing an aggregate exposure assessment.
      
            4.1.1. Residential (Non-occupational) post-application inhalation

Based on the Agency's current practices, a quantitative residential post-application inhalation exposure assessment was not performed for quinclorac at this time primarily because quinclorac's vapor pressure (2.7 x 10-7 mm Hg @ 25.0°C) and Henry's Law Constant (3.72 X 10[-2] Pa m[3]/mol-1) indicate that the compound is relatively non-volatile under field conditions.    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.  The Agency 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 and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate 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 post-application inhalation exposure assessment for quinclorac.

            4.1.2. Residential (Non-Occupational) Post-Application Dermal and Incidental Oral

Post-application short-term dermal and incidental oral exposure is expected from quinclorac treated turf in residential settings (i.e., lawns).  Dermal exposures were not quantified due to a lack of a dermal toxicological endpoint.  Incidental oral exposure risk estimates were calculated for hand-to-mouth, object-to-mouth, and soil ingestion exposures for 1 to <2 year old children playing in the treated turf.  Even though there is a granular product, an assessment for episodic granular ingestion was not done since there is no applicable endpoint (i.e., no acute dietary point of departure for children).

Table 6.2.  Short-Term Oral Non-dietary Ingestion Residential Post-application Exposure and Risk Estimates for Quinclorac Resulting from Application to Turf
                                   Lifestage
                      Post-application Exposure Scenario
                             Application Rate [a]
                                   (lb ai/A)
                                    TTR[b] 
                                  (ug/cm[2])
                       Oral Dose [c, d], [e] (mg/kg/day)
                                 Oral MOEs[f]
                                    Liquids
                            Child 1 < 2 year old
                                     Oral 
                                 Hand-to-Mouth
                                      1.4
                                     0.16
                                     0.021
                                     3,300
                                       
                                       
                                Object-to-Mouth
                                       
                                       
                                    0.00065
                                    110,000
                                       
                                       
                                Soil Ingestion
                                       
                                       
                                    4.7E-05
                                   1,500,000
                                   Granular
                            Child 1 < 2 year old
                                    Oral  
                                 Hand-to-Mouth
                                     0.68
                                     0.015
                                    0.0010
                                    68,000
                                       
                                       
                                Object-to-Mouth
                                       
                                       
                                   0.000063
                                   1,100,000
                                       
                                       
                                Soil Ingestion
                                       
                                       
                                    2.3E-05
                                   3,000,000
   a.    Application rates = maximum application rates from latest LUIS report current as of 7/19/2012.
   b.    Turf Transferable Residue (TTR) (Not Chemical Specific) = AR*FAR ((1-FD)[t])* 4.5x108 [ug/lb]*2.5[-8] [acre/cm[2]]
   c.    Hand-to-Mouth Dose (mg/kg/day) = E = [HR * (FM * SAH) * (ET * N_Replen) * (1- (1- SE)[(][Freq_Replen][/N-Replens)])]
   d.    Object-to-Mouth Dose (mg/kg/day) = E = [OR* CF1 * SAMO * (ET * N_Replen) * (1- (1- SEO)[(][Freq_Replen][/][N_Replen][)])]
   e.    Soil Ingestion Dose (mg/kg/day) = E = SRt * SIgR * CF1
   f.    Oral MOE = NOAEL (70 mg/kg/day) / Oral Dose (mg/kg/day)

      6.1.  Combined Residential Risk Estimates (Multiple Exposure Scenarios)

HED combines risk values resulting from separate exposure pathways when it is likely they can occur simultaneously based on the use pattern, the behavior associated with the exposed population, and the hazard associated with the points of departure.  HED reviewed all residential sources of exposure to determine which residential exposure scenarios would be appropriate to combine with dietary exposure for an aggregate risk assessment.  The only applicable exposure pathways are inhalation (for adult handlers) and incidental oral (for post-application exposure to children).  For children, the incidental oral scenarios (i.e., hand-to-mouth, object-to-mouth, and soil ingestion) should be considered inter-related and it is likely that they occur interspersed amongst each other across time.  Combining these scenarios together would be overly-conservative because of the conservative nature of each individual assessment.   

      6.2.  Residential Risk Estimates for Use in Aggregate Assessment

Table 6.4 reflects the residential risk estimates that are recommended for use in the aggregate assessment for quinclorac.
   * The recommended residential exposure for use in the adult aggregate assessment reflects inhalation exposure from residential handlers mixing/loading/applying water-dispersable granule/dry flowable formulations with a manually-pressurized handwand and/or backpack equipment.
   * The recommended residential exposure for use in the children 1<2 years old aggregate assessment reflects hand-to-mouth exposures from post-application exposure to treated turf.

Table 6.4.  Residential Risk Estimates for Use in the Quinclorac Aggregate Assessment
                         Lifestage / Exposure Scenario
                                     Dose
                                      MOE
Adults  -  Residential Handler M/L/A, Water-dispersible Granule/Dry Flowable, Manually-Pressurized Handwand and/or Backpack
                                     0.019
                                     3,600
Children 1 < 2 Years Old - Turf (Liquids), Hand-to-Mouth
                                     0.021
                                     3,300

      6.3.  Residential Bystander Post-application Inhalation Exposure

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 the low acute inhalation toxicity (Toxicity Category III and IV), low vapor pressure 2.7 x 10-7 mm Hg @ 25.0°C, and the low proposed use rates.  However, volatilization of pesticides may be a source of post-application inhalation exposure to individuals nearby pesticide applications.  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.  The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are developed, the Agency may revisit the need for a quantitative post-application inhalation exposure assessment for quinclorac.

      6.4.  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 (a method proposed to be employed for quinclorac), but, to a lesser extent, could also be a potential source of exposure from the ground application method also employed for quinclorac.  The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices.  On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling.  The Agency has completed its evaluation of the new 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.

Although a quantitative residential post-application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers.  This exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post-application inhalation exposure scenarios.   

 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures.  In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated.  When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

      6.5.  Acute Aggregate Risk

In examining acute aggregate risk, HED has assumed that the only pathway of exposure relevant to the acute time frame is dietary exposure. Therefore, the acute aggregate risk is comprised on exposures to quinclorac residues in food and drinking water and is equivalent to the acute dietary risk estimates summarized in Table 5.4.6 in Section 5.4.3. The acute dietary risk estimates are well below HED's level of concern for Females 13-49 years old.

      6.6.  Short-Term Aggregate Risk

In examining short-term aggregate risk, HED reviewed all residential sources of exposure to determine which residential exposure scenarios would be appropriate to combine with dietary exposure for an aggregate risk assessment.  The only applicable exposure pathways are inhalation (for adult handlers) and incidental oral (for post-application exposure to children).  For children, the incidental oral scenarios (i.e., hand-to-mouth, object-to-mouth, and soil ingestion) should be considered inter-related and it is likely that they occur interspersed amongst each other across time.  Combining these scenarios together would be overly-conservative because of the conservative nature of each individual assessment.   The recommended residential exposure for use in the adult aggregate assessment reflects inhalation exposure from residential handlers mixing/loading/applying water-dispersable granule/dry flowable formulations with a manually-pressurized handwand and/or backpack equipment. The recommended residential exposure for use in the children 1<2 years old aggregate assessment reflects hand-to-mouth exposures from post-application exposure to treated turf.

The Aggregate MOEs are above the LOC of 100 and are not of concern (Table 7.2).

Table 7.2  Short-Term Aggregate Risk Calculations
                                  Population
                              Short-Term Scenario
                                       
                                NOAEL mg/kg/day
                                    LOC[1]
                      Max Allowable Exposure[2] mg/kg/day
                   Average Food and Water Exposure mg/kg/day
                       Residential Exposure mg/kg/day[3]
                          Total Exposure mg/kg/day[4]
                Aggregate MOE (food, water, and residential)[5]
Adults  -  Residential Handler M/L/A, Water-dispersible Granule/Dry Flowable, Manually-Pressurized Handwand and/or Backpack[1]
                                      70
                                      100
                                     0.70
                                   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