Document ID: EPA-HQ-OPP-2012-0429-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2013-11-29T05:00Z

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

Sept. 30, 2013  

SUBJECT:	Quinclorac:  Risk Assessment to Support Permanent Tolerance for Rapeseed Subgroup 20A Without U.S. Registration.  
 
PC Code:  128974, 028974
DP Barcode:  D406420
Decision No.:  464830
Registration No.:  NA
Petition No.:  2E8035
Regulatory Action:  Tolerance, No Registration
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:	Susan V. Hummel, Risk Assessor
		Abdallah Khasawinah, Ph.D., Toxicologist
		Bonnie Cropp-Kohlligian, Chemistry and Dietary Exposure Assessor
		Risk Assessment Branch IV, Health Effects Division (7509P)

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

TO:		Maggie Rudick and Kable Davis, PM25
	        	Herbicide Branch, Registration Division (7505P)

	
This document provides the Health Effect Division's (HED's) risk assessment on quinclorac and quinclorac dimethyl amine, as proposed by BASF.  The current request is for a tolerance without U.S. registration.  HED notes that registration in Canada was proposed for the end use product, ACCORD SL Herbicide, active ingredient quinclorac dimethyl amine on rapeseed subgroup 20A.  However, PMRA required that the proposal be changed to the use of ACCORD DF, active ingredient quinclorac (acid).

Contents
1.0.	Executive Summary	4
2.0.	HED Recommendations	8
2.1.	Data Deficiencies	8
2.2.	Tolerance Considerations	8
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.	8
Recommended Tolerances	9
Revisions to Petitioned-For Tolerances and Existing Tolerances	10
International Harmonization	10
2.3.	Label Recommendations	10
3.0.	Introduction	10
3.1.	Chemical Identity	10
3.2.	Physical/Chemical Characteristics	11
3.3.	Pesticide Use Pattern	12
3.4.	Anticipated Exposure Pathways	14
3.5.	Consideration of Environmental Justice	14
4.0.	Hazard Characterization and Dose-Response Assessment	15
4.1.	Toxicology Studies Available for Analysis	15
4.3.	Dermal Absorption	16
4.5.	Safety Factor for Infants and Children (FQPA Safety Factor)	17
Completeness of the Toxicology Database	17
4.6.	Toxicity Endpoint and Point of Departure Selections	18
Dose-Response Assessment	18
Recommendation for Combining Routes of Exposures for Risk Assessment	19
Cancer Classification and Risk Assessment Recommendation	19
Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment	19
5.0.	Dietary Exposure and Risk Assessment	23
5.1.	Metabolite/Degradate Residue Profile	23
Summary of Plant and Animal Metabolism Studies	23
Summary of Environmental Degradation	24
Comparison of Metabolic Pathways	24
Residues of Concern Summary and Rationale	25
5.2.	Food Residue Profile	25
5.3.	Water Residue Profile	26
5.4  Dietary Risk Assessment	26
6.0.	Residential (Non-Occupational) Exposure/Risk Characterization	30
6.1.	Residential Handler Exposure	30
6.2.	Residential Post-Application Exposure	33
6.2.1.  Residential (Non-occupational) post-application inhalation	33
6.2.2.  Residential (Non-Occupational) Post-Application Dermal and Incidental Oral	33
6.3.	Combined Residential Risk Estimates (Multiple Exposure Scenarios)	34
6.4.	Residential Risk Estimates for Use in Aggregate Assessment	34
6.5.	Residential Bystander Post-application Inhalation Exposure	35
6.6.	Spray Drift	35
7.0.	Aggregate Exposure/Risk Characterization	36
7.1.	Acute Aggregate Risk	36
7.2.	Short-Term Aggregate Risk	36
7.3.	Intermediate-Term Aggregate Risk	37
7.4.	Chronic Aggregate Risk	37
7.5.	Cancer Aggregate Risk	37
7.6.	Cumulative Exposure/Risk Characterization	38
8.0.	Occupational Exposure/Risk Characterization	38
9.0.	References	38
Appendix A.  Toxicology Profile and Executive Summaries	40
9.1.	A.1 Toxicology Data Requirements	40
9.2.	A.2 Toxicity Profiles	41
9.3.	A.3 Hazard Identification and Endpoint Selection	45
9.4.	A.4 Executive Summaries	49
Appendix B.  Review of Human Research	58
Appendix C: International Residue Limits	59

1.0.   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. Quinclorac is also available as the dimethyl amine salt. The current proposal is for a tolerance for crop group 20A without U.S. registration.  Use of the dry flowable formulation of the end-use product ACCORD DF Herbicide is proposed in Canada, a 75% dry flowable formulation.  The maximum single application rates for the proposed uses are 100 g ae/A for rapeseed subgroup 20A.  Accord DF Herbicide may be applied as a foliar spray using ground equipment only.  MERGE adjuvant may be added to the spray formulation.

A variety of end-use products containing quinclorac and quinclorac dimethyl amine are currently registered in the U. S. on rice, sorghum, and wheat, low growing berries, except strawberries, subgroup 13-07H, and rhubarb. In addition to agricultural crops, quinclorac is also registered for: agricultural fallow/idle land/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 in the U. S.: Drive XLR-8 (Reg. No 7969-272), Paramount L Herbicide (Reg. No. 7969-315), and Facet L Herbicide (EPA Reg. No. 7969-316).  These products are DMA (dimethylamine) salt forms of quinclorac.  A similar product, Accord SL, was originally proposed for the use of quinclorac in Canada, but was not supported by adequate residue data, So, the use of ACCORD DF is now proposed instead. 

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.  Quantification of risk using 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.

The toxicology database is complete.  The HED Hazard and Science Policy Council (HASPOC) waived the requirement for a neurotoxicity battery (acute and subchronic neurotoxicity studies) and a DNT study (TXR 0056385).

Endpoints and Uncertainty Factors for Risk Assessment

Toxicity endpoints and points of departure (PODs) were selected for dietary and occupational exposure scenarios.  For the acute dietary endpoint for the sub-population females 13-49 years, a POD of 200 mg/kg 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.   An appropriate endpoint attributable to a single exposure to assess dietary exposure for the general populations including infants and children was not available.

A chronic dietary POD of 37.5 mg/kg/day was selected for the general population from a carcinogenicity study in mice based on decreased body weight at 150 mg/kg/day.  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  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 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.

Chemistry

Permanent tolerances have been established for residues of quinclorac per se in/on barley, rice, sorghum, wheat, low growing berries, except strawberries, subgroup 13-07H, and rhubarb 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.  

BASF has submitted a request for tolerances with no U. S. registration for quinclorac on rapeseed subgroup 20A at 1.5 ppm.  Registration is proposed in Canada. 

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.  Additional metabolism data were submitted for quinclorac on canola to support use on rapeseed.  This study showed a significant level of quinclorac methyl ester.  The qualitative nature of quinclorac residues in livestock is also understood based upon the adequate goat and poultry metabolism studies.  In earlier risk assessments, the risk assessment team 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.  For the current action, because of the significant level of quinclorac methyl ester found, the risk assessment team concluded that the residue of concern on canola is quinclorac and its methyl ester.  

An adequate enforcement method is available for enforcing quinclorac tolerances on plants and livestock (BASF Method 268/1), a gas chromatography/electron capture detection (GC/ECD) method that uses methylation with diazomethane.  There are available FDA multi-residue method (MRM) testing data that indicate that quinclorac is completely recovered using Protocol B.  

Updated enforcement analytical methods were submitted for determining residues of quinclorac, per se, in/on plant parts, an LC/MS/MS method (BASF Method D9708/1).  The validated LOQ for quinclorac is 0.05 ppm.  Quinclorac methyl ester can be determined by an LC/MS/MS method (BASF method D9806/02).  

In Method D9708/1, the samples are soaked in NaOH, extracted with acetone (canola oil in hexane), concentrated and acidified, partitioned into dichloromethane, concentrated to dryness, and re-dissolved in NaOH solution.  Canola oil extracts are partitioned with acetonitrile/ water:methanol.  Both canola seed and oil extracts are cleaned up by solid phase extraction (SPE), and quantitated by liquid chromatography (LC) method with tandem mass spectrometry (MS/MS) detection, monitoring 2 ion transitions.

In BASF Analytical Method D9806/02, quinclorac methyl ester residues in canola seed are extracted with acetone (canola oil in hexane), concentrated, then partitioned twice with acetonitrile:water : 5% MeOH. The sample was purified by column clean-up using a C18 solid phase extraction (SPE) column.  Quinclorac methyl ester residues in canola seed and oil were quantitated by liquid chromatography (LC) method with tandem mass spectrometry (MS/MS) detection.  The ion transitions monitored were 255 --> 224 and 256 --> 161.  The limit of quantitation of the method was reported as 0.05 ppm for the metabolite quinclorac methyl ester in each matrix.

Adequate cattle and poultry feeding studies are available and support the current and proposed uses of quinclorac.  Canola and flax are the only members of the rapeseed subgroup 20A which have processed fractions which are livestock feedstuffs.  The addition of these feedstuffs does not change the dietary burden for livestock; therefore no revision to the current livestock tolerances are required to support the use on imported crop group 20A commodities

Residue field trial data are not adequate to support use of quinclorac dimethylamine salt on rapeseed subgroup 20A, but are adequate to support the use of quinclorac acid on this crop subgroup, when a single application is made at 100 g ai/ha. Therefore, PMRA has requested the end-use product be limited to the product containing the quinclorac acid. 

Adequate processing data have been submitted to support the use of quinclorac on rapeseed subgroup 20A.  No tolerances for processed commodities are needed.
 
Dietary (food+water) Exposure and Risk

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.  

The drinking water assessment did not need to be updated for this risk assessment, because there is no new use proposed in the U. S.  The drinking water assessment for surface water used the Tier I rice model.   The Tier I SCI-GROW model was used to estimate groundwater concentrations for all uses.  Surface water EDWCs for acute and chronic dietary exposure are both 511 ug/L.  The recommended groundwater EDWC is 29 ug/L, for acute and chronic exposure. 

Both the acute and chronic dietary exposure assessments are highly conservative and incorporate tolerance/maximum residue level estimates based on field trial data for the residues of concern and assume 100% crop treated.  Default processing factors were used and, based on empirical data, a processing factor of 1.5x was used for oil commodities of the Rapeseed Subgroup 20A.  Screening-level Tier I modeling was used to estimate drinking water concentrations.

The acute (food + water) dietary risk estimate at the 95[th] percentile of exposure utilized 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

No occupational risk assessment is needed for this risk assessment.  No new use is proposed in the U. S.  

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).  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 chronic 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 residential 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.    

2.0.  HED Recommendations

There are no risk concerns that would preclude establishing a tolerance for crop subgroup 20A.  

 Data Deficiencies

Toxicology: None

Residue Chemistry: None for this use.  

Additional metabolism data are needed if use on dissimilar commodities is proposed.
Future field trials must include analysis for quinclorac methyl ester.

ORE:  None.

 Tolerance Considerations

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 re dissolved 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.

Updated enforcement analytical methods were submitted for determining residues of quinclorac, per se, in/on plant parts, an LC/MS/MS method (BASF Method D9708/1).  The validated LOQ for quinclorac is 0.05 ppm.  Quinclorac methyl ester can be determined by an LC/MS/MS method (BASF method D9806/02).   

In Method D9708/1, for the determination of quinclorac, per se, the samples are soaked in NaOH, extracted with acetone (canola oil in hexane), concentrated and acidified, partitioned into dichloromethane, concentrated to dryness, and re dissolved in NaOH solution.  Canola oil extracts are partitioned with acetonitrile/ water:methanol.  Both canola seed and oil extracts are cleaned up by solid phase extraction (SPE), and quantitated by liquid chromatography (LC) method with tandem mass spectrometry (MS/MS) detection, monitoring 2 ion transitions.

In Method D9806/02, for the determination of quinclorac methyl ester, residues in canola seed were extracted with acetone, mixed with hexane (canola oil extracted with hexane), then partitioned with 95% 2:1 acetonitrile:water (v/v), 5% MeOH. The sample was cleaned-up using a C18 solid phase extraction (SPE) column.  Quinclorac methyl ester residues in canola seed and oil were quantitated by liquid chromatography (LC) with tandem mass spectrometry (MS/MS) detection, monitoring 2 ion transitions.

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

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 current tolerance expression is in accord with our current guidance on tolerance expressions. (S. Knizner, 5/10/2009) However, in addition to parent quinclorac, quinclorac methyl is also a residue of concern in rapeseed, subgroup 20A.  The tolerance expression for rapeseed should be as follows, in a separate subsection of 40 CFR §180.463.  The rapeseed subgroup 20A tolerance should have a footnote indicating that there is no U. S. registration.

"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, and its methyl ester, methyl-3,7-dichloro-8-quinolinecarboxylate, calculated as the stoichiometric equivalent of quinclorac, in or on the commodity."

Current Petition: Tolerance recommendations for the current petition (2E8035) for residues of quinclorac on rapeseed subgroup 20A are in Table 2.2.2.  10.  The tolerance should go into a separate subsection of 180.463, because the residue definition is different.  Additionally, a footnote is needed indicating that there are no U. S. registrations.

Table 2.2.2 	Tolerance Summary for Quinclorac.  § 180.463
Commodity
                       Current/Proposed Tolerance (ppm)
                          Recommended Tolerance (ppm)
Comments; Correct Commodity Definition
Rapeseed subgroup 20A
                                      1.0
                                      1.5
Revised level based on OECD tolerance calculation procedures.

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.

Registration Review Recommendations:  HED continues to recommend for the revocation of the tolerance on grain, aspirated fractions as it is not needed, and for the resulting lowering of tolerances in livestock commodities, as documented in D397719, 404569, 404912 (S. Hummel, 9/12/2012).

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.  The current petition is a workshare with PMRA, and MRLs for quinclorac on rapeseed subgroup 20A will be established concurrently.  Therefore there are no issues with respect to international harmonization associated with this tolerance petition.

Label Recommendations

This action is limited to a request for a tolerance without U.S. registration; therefore a discussion of label recommendations is not pertinent.

3.0.  Introduction

 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

 Physical/Chemical Characteristics

The physicochemical properties of the technical grade quinclorac are summarized in Table 3.2.1.  
Only a few 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. 

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

 Pesticide Use Pattern

Proposed new uses.  BASF is proposing use of Accord SL (Registered in Canada to BASF, Reg. No. 25118), containing the dimethylamine salt of quinclorac, 180 g quinclorac ae/L, in connection with the current petition.  PMRA has requested that use of Accord SL be withdrawn and use of Accord DF, containing 75% quinclorac be used instead.  A summary of the proposed Canadian use patterns for the two formulations is shown below.

Table 3.3.1.  Summary of Canadian Directions for Proposed Use of Quinclorac on Rapeseed Subgroup 20A
                                 Formulation 
                       Applic. Timing, Type, and Equip.
                         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
Canola*, Clearfield canola quality Brassica juncea, and tame mustard (brown and oriental)

ACCORD SL 180 g/L ae quinclorac
Foliar ground boom application 
                                      100
                                      NS
                                      100
                                      60

Apply in 100 L water, when weeds are small and not actively growing. Use MERGE adjuvant at 0.5-1.0 L/100 L  Do not apply by air.
                                       
ACCORD DF 75% quinclorac
Foliar ground boom application
                                     100 
                                      NS
                                      100
                                      60
Apply in 100 L water, when weeds are small and not actively growing. Use MERGE adjuvant at 0.5-1.0 L/100 L  Do not apply by air.
 Canola includes Brassica napus  -  all varieties, including conventional, Clearfield, LibertyLink and Roundup Ready

      .1.   Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed new uses of quinclorac.  The variety of end-use products containing quinclorac currently registered in the U. S. as follows; rice, sorghum, wheat, rhubarb, and low growing berries (except strawberry).  In addition to agricultural crops, quinclorac is also registered for: agricultural fallow/idle land/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: rapeseed subgroup 20A to be imported into the US (dietary exposure pathway only).   

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.  

 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.

1.0.  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 rhubarb and low growing berries (except strawberry)  (D404794, J. Kidwell. et al, 11/6/2012) 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.  

 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 weight of the evidence (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).  

      1.1.  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.

 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.

      1.2. 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. 

 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.

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).
  
              1.2.1. 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).  

              1.2.2. 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.

              1.2.3. 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.

 Toxicity Endpoint and Point of Departure Selections

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 decreased  body weight at 150 mg/kg/day.  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.

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.

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). Quantification of risk using 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.

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).  Quantification of risk using 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
Occupational 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).  Quantification of risk using 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.

2.0.  Dietary Exposure and Risk Assessment 

 Metabolite/Degradate Residue Profile

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, The HED risk assessment team concluded that parent is the only residue of concern in plant commodities for purposes of the tolerance expression and risk assessment, although the methyl ester of quinclorac was present as a minor metabolite.  All three metabolism studies are on grain commodities.  A 4[th] metabolism study, on canola, was reviewed in connection with this petition.  Based on the quinclorac metabolism in canola, the joint EPA/PMRA risk assessment team concluded that the quinclorac methyl ester should be included in the residue of concern for both risk assessment and enforcement.

Metabolism in Canola:  The majority (84%) of the TRRs in canola seed was extractable and a total of 91% was either identified (74.1%) or characterized (17.4%). Identification of the TRRs resulted in the identification of parent (37.1% of TRRs) and quinclorac methyl ester (37.1% of TRRs).   The results indicated that a significant portion of the residue was present in the harvested seed. As quinclorac was applied prior to seed pod formation, the presence of TRRs in the mature seed is an indication of the translocation of the TRRs. 

The methyl ester of quinclorac was reported in some grain commodities at <15% of the TRR.  The methyl ester is expected to be measured by the enforcement method, which includes a methylation step to measure all residues as quinclorac methyl ester.   Quinclorac methyl ester was also observed as a minor metabolite (< 10% of the residue) in rotational crops. This metabolite was not observed in livestock studies and was not seen in the rat metabolism study (a gluco conjugate through the carboxylic acid functional group was postulated to be present in rat urine at ≈1% of the dose).

Additional metabolism data will be needed if use on dissimilar commodities is proposed.

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.

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).
      
Comparison of Metabolic Pathways

Quinclorac was the predominant metabolite in all 3 plant metabolism studies (all in grains), the new quinclorac metabolism study in canola, and in the livestock metabolism study and the rat metabolism study.  Small amounts of the quinclorac methyl ester in plants were reported.  Quinclorac methyl ester is a major metabolite in canola (present at >10%).

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.  Quinclorac methyl ester was not reported as a livestock metabolite.

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.  Quinclorac methyl ester was not reported as a rat metabolite.

Residues of Concern Summary and Rationale

Quinclorac was not reviewed by ROCKs or its predecessors.  Previous risk assessment teams determined that quinclorac was the residue of concern since it was the predominant residue, and there were no other primary metabolites.  In the case of canola, quinclorac methyl ester was a primary metabolite, comprising a significant portion of the residue. The current joint EPA/PMRA risk assessment team determined that the residue of concern in canola was quinclorac plus its methyl ester for both risk assessment and enforcement.

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
Rapeseed, subgroup 20A
Quinclorac + its methyl ester
Quinclorac + its methyl ester

Other Primary Crops
Quinclorac + its methyl ester
Quinclorac 

Rotational Crop
Quinclorac+ its methyl ester
Quinclorac
Livestock
Ruminant
Quinclorac
Quinclorac

Poultry
Quinclorac
Quinclorac
Drinking Water
Quinclorac
Not Applicable

 Food Residue Profile

D397719, D404569, D404912, S. Hummel, G. Otakie, 9/6/12
D402192, S. Hummel, 5/1/13

Residue Field Trials.   The available field trial data on canola are adequate to support use of the quinclorac (acid) DF formulation.  Additional data may be needed before the use of a quinclorac dimethyl amine formulation is supported.

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

Crop Field Trials:

Seventeen field trials for quinclorac DF on canola were conducted in Canada (16 trials) and the United States (1 trial), encompassing Zone 5 (MB; 1 trial), 7 (ND, US; one trial) and 14 (AB; 5 trials, SK; 7 trials; MB; 4 trials) during the 1997 growing season.  A single broadcast spray application at a target rate of 100 g ae/ha/season.  Mature canola seed were harvested at preharvest intervals (PHIs) of 60 days. In two trials, samples were collected at different time intervals (PHIs of 53, 60, 67, 74 days) to monitor residue decline.

Maximum residues in canola seed were 0.85 ppm for quinclorac, 0.23 ppm for the metabolite quinclorac methyl ester and 1.00 ppm for the combined quinclorac residues, when treated at ~100 g a.e./ha/season and harvested at a PHI of 60 days. Due to very low levels of observed residues, no decline trend could be determined in canola seed.

Processed Food and Feed

Processing studies were submitted to support use on canola, conducted at a 1x and 5x exaggerated rate.   The processing data are adequate to support the use of quinclorac on canola.  Quinclorac residues (including the methyl ester) concentrated 1.5 x in oil but were slightly reduced in canola meal (0.92x).  Quinclorac acid did not concentrate in canola commodities.  No tolerance is necessary for canola oil, since the HAFT from the field trials (0.9 ppm) when multiplied by the concentration factor (1.5x), does not exceed the recommended tolerance for residues of quinclorac and its methyl ester on canola seed.

Confined and Field Accumulation in Rotational Crops

Adequate rotational crop studies are available to support the use of quinclorac in the U S.  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.

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

A new water assessment was not needed to support tolerances on canola, since there is no proposal for U. S. registration.  The most recent assessment is performed according to current EFED guidance.  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).  The Tier I SCI-GROW model was used to estimate groundwater concentrations for all uses. 

 Surface water EDWCs recommended for both acute and chronic dietary exposure are 511 ug/L, from the Tier I rice model.  The recommended groundwater EDWCs are 29 ug/L for both acute and chronic exposure. 
 
       5.4  Dietary Risk Assessment
       D406419, B. Cropp-Kohlligian, 8/1/2013

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 for the commodities registered n the U. S.  However, quinclorac and its methyl ester are the residues of concern in canola.

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.  

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.

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.  It used DEEM default processing factors and an empirical processing factor for oil commodities of Rapeseed Subgroup 20A.  In addition, Tier I drinking water estimates were used.  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.  

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.  

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).   Quantification of risk using the chronic RfD will adequately account for all chronic effects, including carcinogenicity, that may result from exposure to quinclorac.

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
                                   0.032207
                                      1.6
                                   0.012893
                                      3.4

1.0.  Residential (Non-Occupational) Exposure/Risk Characterization
Ivan Nieves, D404915, D404797, 9/18/12 

Although this document addresses proposed new agricultural uses outside of the U. S., 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 turf grass (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.  

 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
   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. 

 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.

		6.2.1.  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.

      6.2.2.  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)

 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.   

 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-dispersible 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

      6.1.  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.

 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.   

2.0.  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.

      2.1.  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.

 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-dispersible 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]
Adult males and female  -  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)]   

 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.  

      2.2.  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. 

      2.3.  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. 

      2.4.  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/.

3.0.  Occupational Exposure/Risk Characterization

There are no U. S. registered agricultural uses associated with the proposed new use on rapeseed subgroup 20A.   This section is not applicable.

4.0.  References

Cropp-Kohlligian, B. 8/1/2013  Quinclorac and the Dimethylamine (DMA) Salt of Quinclorac.   Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the proposed use on Rapeseed subgroup 20A.  D406419 

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

Hummel, S. 9/30/2013.  Quinclorac on Rapeseed Subgroup 20A, PP# 1E7957.   Summary of Analytical Chemistry and Residue Data.  D402192, D412463.

Kidwell, J.  11/6/2012. PP# 8F7442. Human Health Risk Assessment for Quinclorac New Use on Pasture/Rangeland.  D359759.

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. 

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).
        
      
      
      

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).

      
      

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 3/14/2013)
Summary of US and International Tolerances and Maximum Residue Limits 
Residue Definition:
US
Canada-proposed*
Mexico[1]
Codex 
40 CFR 180.463 - proposed
Plant/Livestock: quinclorac, 3,7-dichloro-8-quinolinecarboxylic acid + methyl ester
3,7-dichloro-8-quinolinecarboxylic acid + methyl ester

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

                                      US
Canada
Mexico[1]
Codex 
Rapeseed subgroup 20A
1.5
1.5

Completed by: M. Negussie; 3/14/2013
1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.
* Canadian MRLs are being established concurrently