**UNITED ST AT**  **ES ENVIRONMENT AL**  **PROTECTION A GENCY**  **WAS HINGT**  **ON, D.C. 20460 OFFICE OF**  **CHEMICA L**  **S AF**  **ETY AND POLLUTION PREVENTION**  **MEMORANDUM** Sept. 30 , 2013 **SUBJECT :**  Quinclorac: Risk Assessment to Support Permanent T olerance for Rapeseed Subgroup 20A

Wi thout U.S. Registration. **PC Code:** 128974, 028974 **DP Bar**  **code:** D406420 **Decision No.:** 464830 **Registration No. :**  NA **Petition No .:**  2E8035 **Regulatory Action:**  To lerance, No Registration **Risk Assessment T** 

**ype :**  Single Chemical/ Aggregate **Case No.:** 7222 **T XR 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., To xicologist Bonnie Cropp
- Kohlligian, Chemistry and Dietary Exposure Assessor Risk Assessment Branch IV , Health Ef

fects Division (7509P) **THROUGH:** Elissa Reaves, Ph.D. , Acting Branch Chief

Risk Assessment Branch IV Health Ef fects Division (7509P) **TO:** Maggie Rudick and Kable Davis, PM25

Herbicide Branch, Registration Division (7505P) This document provides the Health Ef fect Division’ s (HED’ s) risk assessment on quinclorac and quinclorac dimeth ylamine, as proposed b y BASF
. The current request is for a tolerance without U.S. registration. HED notes that r egistration in Canada was proposed for the end use product, ACCORD SL

Herbicide, active ingredient quinclorac dimeth ylamine on rapeseed subgroup 20A. However, PMRA

required that the proposal be changed to the use of AC CORD DF, active ingredient quinclorac (acid)
.

### Contents

**1.0. Executive Summary**  **................................ ................................**  **................................ ...........**  **4 2.0.**  **HED Recommendations ................................**  **................................ ................................**  **.... 8**  2.1. Data Deficiencies
................................ ................................ ................................ ............. 8 2.2. To lerance Considerations
................................ ................................ ................................ . 8 Enforcement Analy

tical Method: Adequate anal ytical methods (GC/ECD) are available for enforcing quinclorac tolerances on plant (BASF Method A8902; MRID# 41063537) and livestock (BASF Method 268/1; MRID# 41 063536) commodities. Both methods have undergone successful agency method validation trials and have been submitted to FDA for publication in P

AM II as the tolerance enforcement methods. The LOQ of both methods is 0.05 ppm for all matrices.
................................ ................................ ................................ ....... 8 Recommended T

olerances
................................ ................................ ................................ ...... 9 Revisions to Petitioned
- For To lerances and Existing T olerances
................................ ......... 10 International Harmonization
................................ ................................ ................................ . 10 2.3. Label Recommendations
................................ ................................ ................................ 10 **3.0. Intr**  **oduction ................................**  **................................ ................................**  **...................... 10**  3.1. Chemical Identity
................................ ................................ ................................ ........... 10 3.2. Phy sical/Chemical Characteristics
................................ ................................ ................. 12 3.3. Pesticide Use Pattern
................................ ................................ ................................ ...... 13 **3.4. Anticipated Exposur**  **e Pathways ................................**  **................................ .....................**  **15** 3.5. Consideration of Environmental Justice
................................ ................................ ........ 15 **4.0. Hazard Characterization and Dose**  **- Response**  **Assessment ................................**  **.......... 16**  4.1. To xicology

Studies Av ailable for Anal ys is
................................ ................................ .... 16 4.3. Dermal Absorption
................................ ................................ ................................ ......... 17 4.5. Safety

Factor for Infants and Children (FQP A Safety Factor)
................................ ....... 18 Completeness of the To xicology Database
................................ ................................ ........... 18 4.6. To xicity

Endpoint and Point of Departure Selections
................................ .................... 19 Dose
- Response Assessment
................................ ................................ ................................ .. 19 Recommendation for Combining Routes of Exposures for Risk Assessment
...................... 20 Cancer Classification and Risk Assessment Recommendation
................................ ............ 20 Summary of Points of Departure and T oxicity Endpoints Used in Human Risk Assessment

................................ ................................ ................................ ................................ ............... 20 **5.0. Dietary Exposur**  **e and Risk Assessment**  **................................ ................................**  **......... 24**  5.1. Metabolite/Degradate Residue Profile
................................ ................................ ........... 24 Summary of Plant and Animal Metabolism Studies
................................ ............................. 24 Summary of Environmental Degradation
................................ ................................ ............. 25 Comparison of Metabolic Pathway s ................................ ................................ ..................... 25 Residues of Concern Summary and Rationale
................................ ................................ ...... 26 5.2. Food Residue Profile
................................ ................................ ................................ ...... 26 5.3. Water Residue Profile
................................ ................................ ................................ ..... 275.4 Dietary Risk Assessment
................................ ................................ ................................ .... 27 **6.0. Residential (Non**  **- Occupational) Exposur**  **e/Risk Characterization .............................**  **31** 6.1. Residential Handler Exposure
................................ ................................ ........................ 31 6.2. Residential Post
- Application Exposure
................................ ................................ .......... 33 6.2.1. Residential (Non
- occupational) post
- application inhalation
................................ ..... 33 6.2.2. Residential (Non
- Occ upational) 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 Exposur e**  **................................ .....**  **35** 6.6. Spray

Drift
................................ ................................ ................................ ...................... 35 **7.0. Aggr**  **egate Exposur e/Risk Characterization**  **................................ ................................**  **.. 36**  **7.1. Acute**  **Aggregate Risk ................................**  **................................ ................................**  **...... 36**  7.2. Short
- Te rm Aggregate Risk
................................ ................................ ............................ 36 7.3. Intermediate
- Te rm Aggregate Risk
................................ ................................ ................ 37 **7.4. Chr**  **onic Aggr**  **egate Risk ................................**  **................................ ................................**  **.. 37**  **7.5. Cancer**  **Aggregate Risk ................................**  **................................ ................................**  **.... 37**  **7.6. Cumulative Exposur**  **e/Risk Characterization ................................**  **............................... 38**  **8.0. Occupational Exposur**  **e/Risk Characterization ................................**  **............................ 38**  **9.0. Refer**  **ences ................................**  **................................ ................................**  **......................... 38**  **Appendix A. T** 

**oxicology Pr ofile and Executive Summaries**  **................................ ...................**  **40** 9.1. A.1 T

oxicology Data Requirements
................................ ................................ ............... 40 9.2. A.2 T

oxicity Profiles
................................ ................................ ................................ ...... 41 9.3. A.3 Hazard Identification and Endpoint Selection
................................ ......................... 45 9.4. A.4 Executive Summaries
................................ ................................ .............................. 49 **Appendix B. Review of Human Resear ch**  **................................ ................................**  **................ 58**  **Appendix C: International Residue Limits ................................**  **................................ ..............**  **59 1.0.**  **Executive Summary**

Q uinclorac is an herbicide for the selective post
- emergent control of various annual grasses and broadleaf weeds. It is adsorbed via the root s ys tem and partiall y through the foliage and acts as an inhibitor of cell wall sy nthesis. Quinclorac is currentl y formulated into a variet y of product formulations including; dry flowable, wettable powder, read y - 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 quin clorac 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 pol es/rights of way ; airports/landing fields; ornamental sod farms; commercial/industrial lawns. Additionally

, quinclorac is registered for use b y commercial applicators and homeowners on lawns, parks, in and around ornamentals, and golf courses. A new ph ys ical form of quinclorac (EP A Reg. No. 7969
- 272) has recentl y been registered in the U. S.: Drive XLR
- 8 (Reg. No 7969
- 272), Paramount L Herbicide (Reg. No. 7969
- 315), and Facet L Herbicide (EP

A Reg. No. 7969
- 316). These products are DMA (dimethylamine) sal t 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. Hazar d Quinclorac toxicity

in experiment al animals is observed mostly at doses above 150 mg/kg/day following subchronic and chronic exposures. Subchronic exposure to quinclorac caused decreased bod y weight gains, increased water intake, increased liver enzymes and focal chronic interstitial nep hritis (rats). Chronic toxic ef fects include body weight decrement, increase in kidney and liver weights, and hydropic degeneration of the kidney s (dogs). At high doses, chronic toxicity

also includes increased incidences of pancreatic acinar cell hy perp lasia and adenomas. Neurotoxic ef fects 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 b y the HED Cancer Peer Review committee (CPRC) as a group D carcinogen
- not classifiable as to human carcinogenicity
- based on recommendation b y the EP A Scientific Advisory Panel. Quantificationof risk using the chronic RfD will adequatel y account for all chronic ef fects, including carcinogenicity

, that may result from exposure to quinclorac. Quinclorac (technical grade materi al) has a low order of acute toxicity as demonstrated by To xicity Category I II b y 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 c omplete. The HED Hazard and Science Policy Council (HASPOC) waived the requirement for a neurotoxicity battery (acute and subchronic neurotoxicity studies) and a DNTstudy (TXR 0056385 )
. Endpoints and Uncertainty Factors for Risk Assessment To xicity 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 b ased 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 FQP A sa fet y factor) was applied to the dose to obtain an acute reference dose/population adjusted dose (aRfD/aP AD) of 2.0 mg/kg. An appropriate endpoint attributable to a single exposure to assess dietary exposure for the g eneral 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 inters pecies extrapolation and a 1x FQP A factor) was applied to the dose to obtain a chronic reference dose/population adjusted dose (cRfD/cP AD) 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 b y sub chronic 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 FQP A SF
. A dermal endpoint was not selected because no derma l 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
- t erm 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 es tablished 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 submitte d 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 stu dies. Inearlier risk assessments, the risk assessment team had concluded that parent is the onl y 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 plant s and livestock ( BASF Method 268/1 ) , a gas chromatograph y/ 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 recov ered using Protocol B. Updated enforcement analy tical methods were submitted for determining residues of quinclorac, per se, in/on plant parts, an L C/MS/MS method (BASF Method D9708/1). The validated LOQ for quinclorac is 0.05 ppm. Quinclorac meth yle ster can be determined by an L C/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 dry ness, and re - dissolved in NaOH solution. Canola oil extracts are partitioned with acetonitrile/ water:methanol. Both canola seed and oil extracts are cleaned up b y solid phase extraction (SPE), and quantitated by liquid chromatography

(L C) method with tandem mass spectrometry (MS/MS) detection, monitoring 2 ion transitions
. In BA SF Analy

tical 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 b y 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 spectr ometry (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 meth ylester 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 onl y m embers of the rapeseed subgroup 20A which have processed fractions which are livestock feedstuf fs. The addition of these feedstuf fs 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 commodit i esResidue 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, P MRA 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) Exposur e 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, Ve rsion 3.16 which uses food consumption data from th e U.S. Department of Agriculture’ s National Health and Nutrition Examination Survey , What W e 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 ass essment, because there is no new use proposed in the U. S. The drinking water assessment for surface water used the Ti er 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 **51 1 μg/L**  . The recommended groundwater EDWC is **29 μg/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 Ti er I modeling was used to estimate drinking water concentrations. T he acute (food + water) dietary risk estimate at the 95 th percentile of exposure utilized **1.6%** of the acute population adjusted dose (aP AD) for females age 13 to 49
. This is the only population subgroup for which an acute endpoint was selected. The c hronic (food + water) dietary risk estimates are less than or equal to **8.9%** of the chronic population adjusted dose (cP AD) for al l population subgroups. All Infants < 1 year of age is the most highly
- exposed subgroup, utilizing 8.9 % of the cP AD, while the general US population utilizes 3.6 % of the cP

AD. Occupational Exposur

e/Risk No occupational risk assessment is needed for th is risk assessment. No new use is proposed in the U. S. Residential Exposur

e/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 sodfarms 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 previous ly 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. Aggr egate In gene ral, 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 expos ure scenarios would be appropriate to combine with dietary exposure for an aggregate risk assessment. The only applicable exposure pathway s 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 ef fect was identified; however **,** quinclorac is not registered f or an y 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 c PA D 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 fo r crop subgroup 20A. **2.1. 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 anal ys is for quinclorac meth ylester. ORE: None. **2.2. To**  **lerance Considerations Enfor**  **cement Analytical Method**  **:** Adequate analy tical 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 P

AM II as the tolerance enforcement methods. The LOQ of both methods is 0.05 ppm for all matrices.In BASF Method 26 8/1, 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 chromatograph y using a DB
- 5 column and electron capture detection. Methylated standard i s used for quantitation. The LOD was reportedly 0.05 ppm, but this was also the lowest level validated. Updated enforcement analy tical methods were submitted for determining residues of quinclorac, per se, in/on plant parts, an L C/MS/MS method (BASF Meth od D9708/1). The validated LOQ for quinclorac is 0.05 ppm. Quinclorac meth ylester can be determined by an L C/MS/MS method (BASF method D9806 /02 ). In Method D9708/1 , for the determination of quinclorac, per se , the samples are soaked in NaOH, extract ed with acetone (canola oil in hexane), concentrated and acidified, partitioned into dichloromethane, concentrated to dry ness, and re dissolved in NaOH solution. Canola oil extracts are partitioned with acetonitrile/ water:methanol. Both canola seed and oil extracts are cleaned up b y 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 meth yl ester, r esidues 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 clean ed
- up using a C18 solid phase extraction (SPE) column. Quinclorac meth yl ester residues in canola seed and oil were quantitated b y liquid chromatograph y ( LC) with tandem mass spectrometry (MS/MS) detection, monitoring 2 ion transitions
. Quinclorac is detected b y FDA Multiresidue Protocol B, but not the other FDA Multiresidue Method (MRM) Protocols. **Recommended T**

**olerances** The current tolerance expression for quinclorac is: “T olerances 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 b y measuring onl y quinclorac, 3,7
- dichloro
- 8
- quinolinecarboxylic acid, in or on the commodity .” The current tolerance expression is in a ccord 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. r egistration. “T olerances 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 determ ined b y measuring onl y quinclorac, 3,7
- dichloro
- 8
- quinolinecarboxylic acid, and its methyl ester, methyl
- 3,7
- dichloro
- 8
-quinolinecarbox yl ate, calculated as the stoichiometric equivalent of quinclorac, in or on the

commodity

.” Curr ent Petition: To lerance recommendations for the current petition (2E8035) for residues of quinclorac on rapeseed subgroup 20A are in Ta ble 2.2.2. 10. T he tolerance should go into a separate subsection of 180.463, because the residue definition is dif ferent. Additiona lly

, a footnote is needed indicating that there are no U. S. registrations.
**Ta ble 2.2.2**  **To lerance Summary for**  **Quinclorac. § 180.463**  Commodity Current/Proposed To lerance (ppm) Recommended

To lerance (ppm) Comments; Corr ect Commodity Definition Rapeseed subgroup 20A 1.0 1.5 Revised level based on OECD tolerance calculation procedures. **Revisions to Petitioned -**  **Fo r T**  **olerances and Existing To**  **lerances** C urr ent Petition: Revisions are recommended to petitioned
- for tolerances due to the use of the OECD tolerance calculation procedures. The recommended changes are documented in Ta ble 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 an y established maximum residue limits (MRLs) for quinclorac. Canada has established maximum residue limits (MRL s) for quinclorac on selected agricultural commodities but not the commodities in the current petition. The current petition is a workshare with PMRA, and MRL s 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. **2.3. 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. Intr**  **oduction 3.1.**  **Chemical Identity**Quinclorac is a herbicide for the selective post
- emergent control of vari ous annual grasses and

broadleaf weeds. Quinclorac is adsorbed via the root sy stem and partially through the foliage and acts as an inhibitor of cell wall s ynthesis. The nomenclature of quinclorac and quinclorac DMA salt are summarized in Ta ble 3.1.**Ta ble 3.1.**  **Quinclorac and Quinclorac (DMA salt) Nom**  **enclatur e.**  Com pound

N Cl Cl

O O H

Common name Quinclorac, Com pany experimental name BAS 514 34H IUP AC 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® 75 DF Com pound

Common name Quinclorac, DMA salt Com pany experimental name BAS 514 51H IUP AC 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®XLR8 Herbicide, EP A Reg. No. 7969
- 272; Paramount® L Herbicide, EP

A Reg. No. 7969
- GRA; Facet L Herbicide, EP

A Reg. No. 7969
- GRL **3.2. Physical/Chemical Characteristics**  The phy sicochemical properties of the technical grade quinclorac are summarized in Ta ble 3.2.1. Only a few phy sicochemical properties of the DMA salt of quinclorac are available (T able 3.2.2). The phy sical and chemical properties of quinclorac indicate that it is unlikely to volatilize and has low potential to accumulate in fatty tissues. **N Cl** 
**Cl**

**O O**  **N H**  **C H**  **3 C**  **H 3**  **H +** **Ta ble 3.2.1**  **Physico chemical Properties of the T**  **echnical Grade Quinclorac.** Parameter Va lue Reference Melting point/range ~269°C D342446, M. Doherty , 9/1 1/07 pH 3.4
- 3.5 RCB 3283 S. Hummel, 2/26/88 Density ~560 g/L D342446, M. Doherty , 9/1 1/07 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® <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) <1.0×10 - 7 mb ar (<0.75×10 - 7 To rr) Dissociation constant, pK a 4.34 at 20°C 4.35 at 25°C Octanol/water partition coefficient, log P OW (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 **Ta ble 3.2.2**  **Physicochemical Properties of the Quinclorac, DMA Salt.**  Parameter Va lue 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, pK a 4.33 ± 0.15 (Temperature not reported) MRID 48051092 Octanol/water partition coefficient, log P OW (20°C) NA UV/visible absorption spectrum 314 nm, 300 nm, 278 nm (95% ethanol) MRID 48051092 **3.3. Pesticide Use Pattern**  Pr oposed new uses. BASF is proposing use of Accord SL (Registered in Canada to BASF, Reg. No. 251 18 ), containing the dimethylamine salt of quinclorac, 180 g quinclorac ae/L, in connection with the current petition. PMRA has request ed 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
.**Ta ble 3.3.1. Summ**  **ary of Canadian**  **Directions for Proposed Use of Quinclorac on Rapeseed Subgroup 20A** 

**Form ulation**  **Applic.**

**Ti ming, T** 

**ype, 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, L ibert yLink and Roundup ReadyPage **15** of **59**

**3.4. Anticipated Exposur**  **e Pathways** The Registration Division has requested an assessment of human health risk to support the p roposed new uses of quinclorac. The variety of end
- use products containing quinclorac currentl y 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/hedger ows; 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

onl y)
. Humans may

be exposed to quinclorac in food and drinking water, since quinclorac may be ap plied directl y 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 durat ions 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, o nly inhalation exposure was quantified. In cidental oral residential exp osures (short
- term only) are also expected. Risk assessments have been previousl y 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 al so considers the existing uses as well, particularl y for the dietary exposure assessment. **3.5. Consideration of Envir**  **onmental 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 L ow - 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 OPPpolicy , HED estimates risks to population subgroups from pest icide 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 anal yz ed and categorized by subgroups based on age, season of the ye ar, ethnic group, and r egion 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 currentl y in development as OPP has committed resourcesPage **16** of **59**

and expertise to the development of specialized software and models that consider exposure to by standers and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. **4.0. Hazard Characterization and Dose**  **- Response**  **Assessment** H ED 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 , 1 1/6/2012) and concluded that no changes in the points of departure (PODs) or FQP A 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 ri sk assessment. **4.1. To**  **xicology Studies Av**  **ailable for A**  **nalysis** T he 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 DNTstudy based on a weight of the evidence ( WOE ) approach that considered (1) lack of neurotoxic ef fects in the available acute, subchronic, chronic, developmental, and reproduction studies; (2) the selected endpoints are considered to be protective of neurotoxic ef fects; (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 previousl y bas ed on low volatility

, low acute inhalation toxicity and large extrapolated inhalation MOE (D376603, 23 September 2010)
. 4.2. **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 o r after dail y exposures of unlabeled compound at 15 mg/kg for 14 day s followed b y a single 15 mg/kg oral dose of labeled compound. Elimination in the urine 5 day s 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 (1 1.5 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 ra dioactivity in the bile is associated with the glucuronide conjugate of quinclorac. The conjugate is apparentl y h ydrol yz ed in the intestines and reabsorbed. Almost all the radioactivity in the urine is unchanged quinclorac. Radioactive tissue residue level s 5 days after dosing were dose
- dependent. Results from these and whole
- body autoradiograph y and time
- course studies indicate that relativel yPage **17** of **59**

higher radioactivity

levels were detected in the adrenal glands, bone marrow, thy roid, 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 ra pid 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 day s) were noted for 7 to 48 hours post dosing; saturation kinetics were als o noted at these higher doses. **4.3. 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. 4.4. **To xicological 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 enzy mes (SGOT, SGPT) and focal chronic interstitial nephritis (rats). Chronic toxic ef fects include body weight decrement, increase in kidney and liver weights, and hydropic degeneration of the kidney s (dogs). At high doses, chronic toxicity

also includes increased incidence s of pancreatic acinar cell hy perplasia and adenomas (rats). Neurotoxic ef fects were not observed in an y 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 ef fects occurred at mu ch higher doses than the maternal ef fects 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 repr oduction study , parental toxicity

and of fspring 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, development al delay s and possible marginal ef

fect 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 D NA damage in primary

rat hepatocy

tes. There is also no evidence of a genotoxic response in whole animal test sy stems ( in vivo mouse bone marrow micronucleus assay). Quinclorac was negative in a mammalian cell in vitr o cy togenetic chromosomal aberration as say

in Chinese hamster ovary cells (CHO).Page **18** of **59**

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 b y the EP A Scientific Advisory

Pan el (TXR# 0010416). This classification was based on equivocal increase in the incidence of one ty pe of benign tumor (pancreatic acinar cell adenomas) in only one sex and one species of animals (male W istar rats). Based on this classification, a quantific ation of cancer risk is not warranted because the chronic RfD will adequatel y 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 To xicity Category I II b y 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 Appen dix A. **4.5. Safety Factor** 

**for Infants and Childr**  **en (FQP A**  **Safety Factor)** The FQP A Safet y Factor Committee recommended in 1998 that the 10x factor for the protection of infants and children (as required b y FQP A) be removed (TXR 0012902) **.** The removal of the 1 0x 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 uter o 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 sourc e drinking water exposure assessments resulting in conservative upper
- bound concentrations. **Completeness of the T**

**oxicology Database** The toxicology

database for quinclorac is complete and the risk assessment team has concluded that the FQP

A safet y factor can be reduced to 1x. The following acceptable studies are available for FQP A consideration: (1) Developmental toxicity studies in rats and rabbits; and (2) Tw o generation reproduction study in rats. Acute and subchronic neurotoxicity studies have been waived per HASPOC (TXR# 0056385).

**4.5.1. Evidence of Neur**  **otoxicity** There are no acute, subchronic or chronic neurotoxicity studies on quinclorac available from the registrant or from the published literature. Neurotoxic ef fects were not observed in an y of the acute, subchronic and chronic studies with quinclorac. Because of the lack of evidence of neurotoxic ef

fects, HIARC (TXR# 0012717) determined in 1998 that no acute, subchronic, or developmental neurotoxicity studies are required for quinclorac. This w as confirmed b y HASPOC in 2012 (TXR# 0056385)
.

**4.5.2. Evidence of Sensitivity/Susceptibility in the Developing or**  **Y oung**  **Animal**Page **19** of **59**

The toxicology

database for quinclorac is adequate for the FQP A assessment. Developmental toxicity studies in rats and rabbits and the reproduction studies in rats provided no indication of increased qualitative or quantitative susceptibility
. **4.5.3. Residual Uncertainty in the Exposur**  **e 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. **4.6. To**  **xicity Endpoint and Point of Dep arture Selections**  **Dose -**  **Response Assessment**  To xicity 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 prese nted in Appendix A. An appropriate endpoint attributable to a single exposure to assess dietary exposure for the g eneral populations including infants and children was not available from the oral toxicity studies including the rat and rabbit development al 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 numb er 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 FQP A safet y factor) was applied to the dose to obtain an acute reference dose/population adjusted dose (aRfD/aP AD) 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 ef

fects on decreased body

weight at 150 mg/kg/day

. A UF 100x (10x for intraspecies variation, 10x for interspecies extrapolation and a 1x FQP A factor) was applied to the dose to obtain a chronic reference dose/population adjusted dose (cRfD/cP

AD) of 0.38 mg/kg/day

. A POD of 70 mg/kg/day (NOAEL) for assessing incidental oral short
- term (1
- 30 day s) 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 consumpt ion) at 200 mg/kg/day . This is supported b y 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 FQP A SF
.Page **20** of **59**

A de rmal 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 Exposur es for**  **Risk Assessment**  Under FQP

A, when there are potential residential expos ures 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 deter mine 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 th ese 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 recomme ndation by the EP A Scientific Advisory

Panel (TXR# 0010416). This classification was based on equivocal increase in the incidence of one ty pe of benign tumor (pancreatic acinar cell adenomas) in only one sex and one species of animals (male W istar rats). Quantification of risk using the chronic RfD will adequatel y account for all chronic ef fects, including carcinogenicity , that may result from exposure to quinclorac. There was no evidence of carcinogenicity in mice or female rats. **Summary of Points of Dep arture and T**  **oxicity Endpoints Used in Human Risk Assessment**  To xicological doses and endpoints for dietary and non
- occupational human health risk assessments for quinclorac are presented below in T able 4.5.4.1.Page **21** of **59**

**Ta ble 4.5.4.1. Summary of T**  **oxicological Doses and Endpoints for Quinclorac for Use in Dietary and Non**  **** **Occupational Hum an Health Risk**  **Assessments. Exposur**  **e/ Scenario**  **Point of**

**Departure Uncertainty/FQP**  **A Safety Factors**  **RfD, P AD,**  **Level of Concern**  **for Risk**  **Assessment Study and T**  **oxicological Effects**

Ac ute 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).

Ac ute Dietary (Females 13
- 49 years of age) NOAEL

(developmental ) = 200 mg/kg/day UF A= 10x

UF H =10x FQP A SF= 1x aRfD = 2.0

mg/kg/day aP AD = 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 fe tal body weight. These fetal effects are presumed to occur after a single dose. Chronic Dietary (All Populations) NOAEL= 37.5

mg/kg/day UF A= 10x

UF H =10x FQP A SF= 1x cRfD = 0.38

mg/kg/day cP AD = 0.38 mg/kg/day Carcinogenicity study in mice

(MRID # 41063523) LOAEL = 150 mg/kg/day based on decreased body weight. Incidental Oral Short
Te rm (1
- 30 days) NOAEL= 70

mg/kg/day UF A= 10x

UF H =10x FQP A 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
- Te rm (1
- 30 days) and Intermediate
Te rm (1
- 6 mo nths) NOAEL= 70

mg/kg/day [Inhalation absorption rate = 100% relative to oral absorption] UF A= 10x

UF H = 10x FQP A 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 i ncreased water consumption. Inhalation Long
- Te rm (>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 Revie w committee (CPRC) as a group

D carcinogen
- not classifiable as to human carcinogenicity
- based on recommendation by the EP A Scientific Advisory Panel (TXR# 0010416). This classification was b ased 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 e ffects, including carcinogenicity , that may result from exposure to quinclorac. There was no evidence of carcinogenicity in mice or female rats.Page **22** of **59**

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose
- response dat a and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL

= no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short
- term study for long
- term

risk assessment. UF DB = to account for the absence of key date (i.e., lack of a critical study). FQP A SF = FQP

A Safety Factor. P

AD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.Page **23** of **59**

**Ta ble 4.5.4.2 Summ**  **ary of To**  **xicological Doses and Endpoints for Quinclorac for Use in Occupational Hum an**  **Health Risk Assessments**  **Exposur e/**  **Scenario Point of** 

**Departure Uncertainty** 

**Factors Level of Concern** 

**for Risk**  **Assessment Study and**  **To xicological 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
- Te rm

(1
- 30 days) and Intermediate
Te rm (1
- 6 mo nths) NOAEL=70

mg/kg/day [Inhalation absorption rate = 100% relative to oral absorption] UF A= 10x

UF H = 10x FQP A 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 Revie w committee (CPRC) as a group

D carcinogen
- not classifiable as to human carcinogenicity
- based on recommendation by the EP A Scientific Advisory Panel (TXR# 0010416). This classification was b ased 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 e ffects, 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 dat a and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL

= no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short
- term study for long
- term

risk assessme nt. UF DB = 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.Page **24** of **59**

**5.0. Dietary Exposur**  **e and Risk Assessment**  **5.1. Metabolite/Degradate Residue Pr**  **ofile 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 stud ies, 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 h ydrox yl ation of the quinoline ring of the parent, followed b y 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 onl y re sidue 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 EP A/PMRA risk assessment team concluded that the quinclorac meth ylester should be included in the residue of concern for both risk assessment and enforcement. **Metabolism in Canola:** The majorit y (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% o f T RRs) 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 i ndication 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 b y the enforcement method, which includes a methylation step to measure all residues as quinclorac methyl ester. Quinclorac meth ylester 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 carbox yl ic 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 Natur e of the Residue**  **- Livestock**  D241204, J. Stokes, 1 1/6/1998 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, respectivel y). In both studies, quinclorac was the principal residue identified in each comm odity . HED concluded that parent is the onl y residue of concern for risk assessment and tolerance expression for livestock.Page **25** of **59**

However, the enforcement method includes a methylation step and determines the methyl ester of quinclorac. In a rat metabolism s tudy (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 Envir onmental Degradation**  M. Lowit, N. Andrews, D397720, 8/9/12; M. Lowit, N. Andrews, D405093, 9/14/12 Va por 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 lo w possibility of volatilization from soil and water. Laboratory data indicate that quinclorac is stable to hydrol ys is, photoly sis in sterile water, aerobic soil metabolism, and aquatic metabolism (aerobic and anaerobic). Conversely , quinclorac undergoes rapid photoly sis in non
- sterile rice paddy , natural river waters, and solutions containing activated sewage sludge (half

- lives of 5
- 10 day s). Photoly sis on soil surface is also a route of dissipation with a mean half life of 141 day s. 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 coef ficients 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 coef ficient (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 chem ical risk assessment (DP250179 ). **Comparison of Metabolic Pathways** Quinclorac was the predominant metabolite in all 3 plant metabol ism 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 w ere reported. Quinclorac meth yl ester is a major metab olite in canola (present at >10%). The primary

path b y which plants metabolize quinclorac is through the h ydrox yl ation of the quinoline ring of the parent, followed by the conjugation of glucose and other biologically available compounds at the hydroxylat ed 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 hydrox yl ated 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 w as not reported as a livestock metabolite.Page **26** of **59**

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%) eliminat ed 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 b y ROCKs or its predecessor s . Previous risk assessment teams determined that quinclorac was the residue of concern since it was the predominant residue, and there were no other primary metabolite s . In the case of canola, quinclorac methyl ester was a prim ary metabolite, comprising a s ignificant portion of the residue
. The current joint EP A/PMRA risk assessment team determined that the residue of concern in canola was quinclorac plus its methyl ester for both risk assessment and enforcement. **Ta ble 5.1.4 Summary of Metabolites and**  **Degradates to be included in the Risk Assessment and T** 

**olerance Expr ession**  Matrix Residues included in Risk Assessment Residues included in To lerance 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 W

ater Quinclorac Not Applicable **5.2. Food Residue**  **Profile** D397719, D404569, D404912, S. Hummel, G. Otakie, 9/6/12 D402192, S. Hummel, 5/1/13 Residue Field T

rials
. 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 c attle and poultry feeding studies are available. The uses proposed in this petition will not af fect the existing tolerances on meat, milk, poultry and eggs. Cr op Field T

rials: 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/sea son. Mature canola seed were harvested atPage **27** of **59**

preharvest intervals (PHIs) of 60 day s. In two trials, samples were collected at dif ferent time intervals (PHIs of 53, 60, 67, 74 day s) to monitor residue decline. Maximum residues in canola seed were 0.85 ppm for quinclorac, 0.23 ppm for the metabolite quinclorac meth yl 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 day s. Due to very low le vels of observed residues, no decline trend could be determined in canola seed. Pr ocessed Food and Feed P rocessing 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 meth ylester) concentrated 1.5 x in oil but were slightly reduced in canola meal (0.92x). Quinclorac acid di d not concentrate in canola commodities. No tolerance is necessary

for canola oil, since the HAFTfrom 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 Cr ops 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 day s after a quinclorac application to rice. (The anal yt ical 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 expecte d at rotational crop intervals of 120 days or longer
. **5.3. Wa**  **ter**

**Residue Pr ofile**  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 f

or U. S. registration. T he most recent assessment is performed according to current EFED guidance
. Screening
- level Ti er I modeling was used to estimate surface water concentrations for use on cranberry (provisional cranberry

mode l) 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 51 1 μg/L , from the Tier I rice model. The recommended groundwater EDWC s are 29 μg/L for both acute and chronic expo sure . **5.4 Dietary Risk**  **Assessment** D406419 , B. Cropp
- Kohlligian, 8/1 /2013 **Description of Residue Data Used in Dietary Assessment** Page **28** of **59**

Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model DEEM
- FCID, Ve rsion 3.16 which uses food consumption data from the U.S. Department of Agriculture’ s Nation al Health and Nutrition Examination Survey , What W e Eat in America, (NHANES/WWEIA). This dietary survey was conducted from 2003 to 2008. These anal ys es 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. To lerances 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 af

fect the estab lished tolerances for quinclorac on rice, grain sor ghum, 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 b y EFED ( DP# 397720, M. Lowit/N. Andrews, 8/9/12 and DP# 405093, M. Lowit/N.Andrews, 9/14/12 ), and incorporat ed 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 0.51 1 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 Ti er I Rice Model , Ve rsion 1.0 (May 8, 2007). T

urf grass was identified as the use resu lting in the highest EDWCs for ground water. The EDWC in ground water was assessed using the Tier I Screening Concentration in Ground W ater (SCI
- GROW

, V ersion 2.3) model. These models, and their descriptions, are available at the EP A internet website via the web link, http://www.epa.gov/oppefed1/models/water/ . No surface or ground water monitoring data were available for quinclorac. **Per cent Cr**  **op Tr**  **eated 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
- le vel residues for all agricultural commodities. Itused DEEM default processing factors and an empirical processing factor for oil commodities of Rapeseed SubgroupPage **29** of **59**

20A. In addition, Tier I drinking water estimates were used. Ti er I modeling was used to e stimate 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 (aP AD) for females age 13 to 49. This is the only population subgroup for which an acut e endpoint was selected. Generally , the Agency

is concerned when risk estimates exceed 100% of the P AD. The acute dietary risk estimate for quinclorac is below HED’ s level of concern. **Chr onic 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 analy ses. Tier I modeling w as 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 (cP AD) for all population subgroups. All Infants < 1 year of age is the most highly
- exposed subgroup, utilizing 8.9% of the cP AD, while the general US population utilizes 3.6% of the cP

AD. Generally , the Agency

is concerned when risk estimates exceed 100% of the P AD. 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 recommend ation by the EP A Scientific Advisory

Panel (TXR# 0010416). This classification was based on equivocal increase in the incidence of one ty pe of benign tumor (pancreatic acinar cell adenomas) in only one sex and one species of animals (male W istar rats). Quantification of risk using the chronic RfD will adequatel y account for all chronic ef fects, including carcinogenicity , that may result from exposure to quinclorac.Page **30** of **59**

**Ta ble 5.4.6. Summary of Dietary**  **(Food and Drinking W ater)**  **Exposure and Risk for Quinclorac** 
**Population Subgroup Acute Dietary**  **(95th Per centile)**  **Chronic Dietary Cancer**  **Dietary Exposur**  **e (m**  **g/kg/day) % aP** 

**AD*** **Dietary Exposur**  **e (m**  **g/kg/day) % cP** 

**AD*** **Dietary Exposur**  **e (m**  **g/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 y ears old 0.023500 6.2 Children 3
- 5 y ears old 0.019280 5.1 Children 6
- 12 y ears old 0.013431 3.5 Yo uth 13
- 19 y ears old 0.010195 2.7 Adults 20
- 49 y ears old 0.013614 3.6 Adults 50+ years old 0.012525 3.3 **Fem ales 13**  **- 49 years old**  **0.032 207**  **1.6** 0.012893 3.4Page **31** of **59**

**6.0. Residential (Non**  **- Occupational) Exposur**  **e/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 specificall y marketed towards residential handler use (i.e., homeowners); a residential handler assessment was performed to be protective of an y such use. Quinclorac is currentl y 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 quinc lorac products used in residential settings can be formulated as granular, liquid, and dry

flowable formulations. **6.1. Residential Handler**  **Exposur e**  Based on the anticipated use patterns and current labeling, typ es 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 residentia l 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 gran

ules 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 spray er. For residential handlers, HED presents exposure estimates for individuals wearing shorts, short
sleeved shirts, shoes plus socks. Pesticide application area assumed to be performed b y adults only , however the assessment does group 16 y ear olds with a dults. Ta ble 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).Page 32 of 59 **Ta ble 6.1. Quinclorac Residential (Non**  **- Occupational) Handler Estim**  **ated Risks Form**  **ulation Application** 

**Equipment/Method Application Rate**  **1 Units**  **Area Tr**  **eated or Am**  **ount Handled**  **Daily Units (per** 

**day) Inhalation** 

**Unit Exposur**  **e (m**  **g/lb ai) 2**  **Inhalation**

**Exposur e**  **(m g/day)**  **Inhalation**

**Absorbed Dose**  **3 (m**  **g/kg/day) Inhalation** 

**MOE 4** 

Granule Push
- ty

pe spreader 0.68 lb ai/acre 0.5 acres 0.0026 0.00088 0.00001 1 6,300,000 Belly grinder 0.0000172 lb ai/ft2 1200 ft2 0.039 0.0008 0.00001 7,000,000 Spoon 100 ft2 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 0.0001 1 650,000

Manually
- pressurized handwand 0.16 lb ai/gallon 5 gallons 0.018 0.014 0.00018 390,000 Backpack 0.14 0.1 1 0.0014 50,000 Sprinkler can 0.0000172 lb ai/ft2 1000 ft2 0.022 0.00038 0.0000047 15,000,000 Tr igger
- 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 Waterdispersible 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/ft2 1000 ft2 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/EP A
- 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.Page 33 of 59

**6.2. Residential Post**  **- Application Exposur**  **e** 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 R egistration 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 y ear old c hildren 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).Page 34 of 59

**Ta ble 6.2.**  **Short -**  **Te rm** **Oral Non -**  **dietary Ingestion Residential Post -**  **application Exposure and Risk Estim ates**  **for Quinclorac Resulting from**  **Application to T urf**  **Lifestage Post**  **- application Exposure**  **Scenario Application**  **Rate a**  **(lb ai/A) TTR**  **b**

**(ug/cm 2**  **) Oral Dose**  **c, d, e**

**(m g/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 11 0,000 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 T

ransferable Residue (TTR) (Not Chemical Specific) = AR *F AR ((1
- F D ) t )* 4.5x10 8 [ug/lb]* 2.5 - 8 [acre/cm2 ] c. Hand
- to - Mouth Dose (mg/kg/day) = E = [HR * ( F M * SAH ) * (ET * N_Replen) * (1
- (1
- SE ) (Freq_Replen/N
- Replens) )] d. Object
- to - Mouth Dose (mg/kg/day) = E = [OR* CF1 * SAM O * (ET* N_Replen) * (1
- (1
- SE O ) (Freq_Replen/N_Replen) )] e. Soil Ing estion Dose (mg/kg/day) = E = SRt * SIgR * CF1 f. Oral MOE = NOAEL (70 mg/kg/day) / Oral Dose (mg/kg/day) **6.3. Combined Residential Risk Estimates (Multiple Exposur**  **e Scenarios)** HED combines risk values resulting from separate exposure pathway s when it is likely they can occur simultaneousl y 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 onl y applicable exposure pathway s 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 overl y conse rvative because of the conservative nature of each individual assessment. **6.4. Residential Risk Estimates for**  **Use in Aggr**  **egate Assessment**  Ta ble 6.4 reflects the residential risk estimates that are recommended for use in the aggregate assessment for quincl orac.  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.Page 35 of 59

**Ta ble 6.4. Residential Risk Estimates for Use in the**  **Quinclorac Aggr**  **egate Assessment**  **Lifestage / Exposure Scenario Dose**  **MOE** Adults

– Residential Handler M/L/A, W ater - dispersible Granule/Dry Flow able, Manually
Pressurized Handwand and/or Backpack 0.019 3,600 Children 1 < 2 Ye ars Old
- Turf (Liquids), Hand
- to - Mouth 0.021 3,300 **6.5.** Residential By stander Post
- application **Inhalation Exposur e**  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

(T oxicity 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 ind ividuals nearb y 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 1 . 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. I f new policies or procedures are developed, the Agency may revisit the need for a quantitative post
- application inhalation exposure assessment for quinclorac. **6.6. Spray Drift**  Spray drift is alway s a potential source of exposure to residents nearby to spraying operations. This is particularly

the case with aerial application (a method proposed to be employed for quinclorac), but, to a lesser extent, could also be a potential so urce of exposure from the ground application method also employ ed for quinclorac. The Agency has been working with the Spray Drift T ask Force, EP

A Regional Of

fices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices. On a chemical b y 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 sub mitted by

the Spray

Drift T ask Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately

appl y the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and g round h ydraulic methods. After the policy is in place, the Agency

may impose further refinements in spray drift management practices to reduce of f
- target drift with specific products with significant risks associated with drift. Although a quantitative r esidential 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 representativ e of a 1 Av ailable: http://www.epa.gov/scipol y/ SAP/meetings/2009/120109meeting.htmlPage 36 of 59

worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post
- application inhalation exposure scenarios. **7.0. Aggregate Exposur**  **e/Risk Characterization** In accordance with the FQP A, 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 P AD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. **7.1. Acute**  **Aggr egate 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 esti mates summarized in Ta ble 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. **7.2. Short**  **- Te**  **rm 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
- a pplication 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. Comb ining these scenarios together would be overl y - 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 han dlers mixing/loading/appl yi ng 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.Page 37 of 59

The Aggregate MOEs are above the LOC of 100 and are not of concern (T able 7.2). **Ta ble 7.2 Short**  **- Te**  **rm Aggregate Risk Calculations**  **Population Short**  **- Te**  **rm Scenario**

**NOAEL mg/kg/day**  **LOC 1**  **Max**

**Allowable Exposur**  **e 2**  **mg/kg/day Av**  **erage**

**Food and Wa**  **ter Exposur**  **e mg/kg/day**  **Residential**

**Exposur e**  **mg/kg/day 3**  **To tal** 

**Exposur e**  **mg/kg/day 4**  **Aggr egate** 

**MOE (food, water**  **, and residential)**  **5** Adult ma les 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 Mouth2 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 FQP

A 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 To tal Exposure = Av g Food & W ater Exposure + Residential Exposure) 5 Aggregate MOE = [NOAEL / ( A v g F o o d & W

at e r E xp o s ur e + R e s i d e nt i a l E xp o s ur e ) ] **7.3. Intermediate**  **- Te**  **rm Aggr**  **egate Risk** Intermediate
- term aggregate expo sure 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. **7.4. Chr**  **onic Aggr**  **egate Risk** In examining chronic aggregate risk, H ED 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 diet ary

risk estimates summarized in Ta ble 5.4.6 in Section 5.4.4. The chronic risk estimates are below HED’ s level of concern for all population subgroups. **7.5. Cancer**  **Aggr egate Risk**  HED has concluded that assessments using a non
- linear approach (e.g. a chroni c RfD
- based approach) will adequately account for all chronic toxicity , including carcinogenicity that couldPage 38 of 59

result from exposure to quinclorac. Chronic aggregate risk estimates are below HED’ s level of concern, therefore, cancer risk is also below HED’ s l evel of concern. **7.6. Cumulative Exposur**  **e/Risk Characterization** Unlike other pesticides for which EP A has followed a cumulative risk approach based on a common mechanism of toxicity , EP A 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 b y other substances. For the purposes of this tolerance action, therefore, EP A has not assumed that quinclorac has a common mechanism of toxicity with other subst ances. For information regarding EP A’ s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative ef fects of such chemicals, see the policy statements released by

EP A’ s Of fice of Pesticide Programs concerning co mmon mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EP A’ s website at http://www.epa.gov/pesticides/cumulative/. **8.0. Occupational Exposur**  **e/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. **9.0. Refer**  **ences** Cropp
- Kohlligian, B. 8/1 /2013 Quinclorac and the Dimethylamine (DMA) Salt of Quinclorac. Acute and Chronic Aggregate Dietary (Food and Drinking W ater) 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 W ater 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 Analy tical 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. 9/18/20 12
. 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 Re view Committee. HED Doc. No. 012717.Page 39 of 59

Tarplee, B. 10/14/1998. Quinclorac

– Report of the FQP A Safet y Factor Committee. TXR No. 0012902. Van Alstine, J. 9/2012. Quinclorac: Summary of Hazard and Science Policy Council (HASPOC) Meeting of June 21, 2012: R ecommendations on the need for a neurotoxicity Battery Study and a DNT study

. TXR #: 0056385Page 40 of 59

**Appendix A. T** 

**oxicology Pr ofile and Executive Summaries**  **9.1. A.1**  **To xicology Data Requir**  **ements** The requirements (40 CFR 158.340) for [T ype 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 w ere used. **Te st**  **Te chnical**  **Requir ed**  **Satisfied** 870.1 100 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
- ma mmalian
................ 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 wa ived (D376603, TXR 005551 1 ) 3 wa ived (HASPOC, TXR 0056385 )Page 41 of 59

**9.2. A.2**  **To xicity Pr**  **ofiles**
**Ta ble**  **A.2.1 Acute T**  **oxicity Profile**

**– Quinclorac**  Guideline No. Study T

ype MRID(s) Results To xicity Category 870.1 100 Ac ute oral
- rat 41063505 (1989) LD 50 >2610 mg/kg III

870.1 100 Ac ute oral
- rat 41063506 (1983) LD 50 (male) = 3060 mg/kg

LD 50 (female) = 2190 mg/kg LD 50 (com

bined) = 2680 mg/kg III

870.1 100 Ac ute oral
- mo use 41063507 (1986) LD 50 >5000 mg/kg IV 870.1200 Ac ute dermal
- rat 41063509 (1983) LD 50 > 2000 mg/kg III 870.1300 Ac ute inhalation
- rat 41063510 (1985) LC 50 > 5.2 mg/L

(4 hr exposure) III 870.2400 Ac ute eye irritation

–

rabbit 4106351 1 (1983) Mild irritant reversible by

day 8 III 870.2500 Ac ute dermal irritation

–

rabbit 41063512 (1983) Not an irritant III 870.2600 Skin sensitization

–

guinea pig 40573301 (1986) Dermal sensitizer n/aPage 42 of 59

**Ta ble**  **A.2.2 Subchronic, Chronic and Other T**  **oxicity Pr ofile** 

**– Quinclorac**  **Guideline No.**  **Study T**

**ype 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 mo use) 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 w as not established in this study (> 75 mg/kg/day)

870.3100 90
- Day

oral toxicity (B6C3F1/Crl Br mo use) 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 (Ne w 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 mo rtality , decreased food consumption and increased water consumption. **Developm ental**  NOAEL ≥438 mg/kg/day LOAEL not established in this study (> 438 mg/kg/day).Page 43 of 59

**Ta ble**  **A.2.2 Subchronic, Chronic and Other T**  **oxicity Pr ofile** 

**– Quinclorac**  **Guideline No.**  **Study T**

**ype MRID No. (year)/** 

**Classification /Doses Results**  870.3700b Prenatal

developmental in (Himalayan rabbit) 41063525 (1986),

41680501 (1990) Acceptable/guideline 0, 70, 200 or 600 mg/kg/day (gavage) **Materna** l NOAEL = 70 mg/kg/day LOAEL = 200 mg/kg/day based on decreased body weight gain and food consumption (and increased water consumption). **Developm enta**  l 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 **Par ental/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 margina l ef

fect on pup viability

. 870.4300 Com

bined 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 c ell**  **adenom as in males.**  870.4100b Chronic toxicity

(Beagle dog) 41 123201 (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 mo use) 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 car**  **cinogenicity .** Page 44 of 59

**Ta ble**  **A.2.2 Subchronic, Chronic and Other T**  **oxicity Pr ofile** 

**– Quinclorac**  **Guideline No.**  **Study T**

**ype MRID No. (year)/** 

**Classification /Doses Results**  870. 5100 Bacterial reverse

gene mutation Ames assay S. typhimurium 41063527 (1984)

Acceptable/guideline Dose range 0 to 5000 μg/plate with and without S9 Negative up to the limit dose (5000 μg/plate) with or without S9 in S. typhimurium strains TA 98, TA 100, TA 1535, T A1537

870.5100 Bacterial reverse

gene mutation S. typhimurium/E.coli 41063528 (1988)

Acceptable/guideline Dose range 0 to 5000 μg/plate with and without S9 Negative up to the limit dose (5000 μg/plate) with or without S9 in S. typhimurium strains TA 98, TA 100, TA 1535, T A1537 and E. coli strain WP2 uvrA 870.5300 In vitr

o ma mmalian forward gene mutation, CHO cells/HGPR

T locus 41680503 (1989)

Acceptable/guideline Dose range 0 to 2150 μg/mL w ith or without S9 Negative for gene mutations up to cytotoxic

doses (2000 μg/mL) with or without S9.

870.5375 In vitr

o ma mmalian chromosome aberration assay

, human lymphocytes 41076103 (1986)

Acceptable/guideline Dose range 125 to 1500 μg/mL w ithout S9 and 250 to 2500 μg/mL

w ith S9 Positive for chromosomal aberrations but only at cytotoxic concentrations (2000 μg/mL w ith S9 and 1000 μg/mL

w ithout S9).

870.5385 Cy

togenetics

– in vivo mo use 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 br eathing, 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 μg/mL Negative up to cytotoxic dose (1520 μg/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
.Page 45 of 59

**Ta ble**  **A.2.2 Subchronic, Chronic and Other T**  **oxicity Pr ofile** 

**– Quinclorac**  **Guideline No.**  **Study T**

**ype MRID No. (year)/** 

**Classification /Doses Results**  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 (1 1.5 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: mo st 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 w as not established.

**A.3 .**  **Hazard Identification and Endpoint Selection A.3.1**  **Acute Refer ence Dose (aRfD)**  **- Females age 13**  **- 49**  **Study Selected:** Developmental toxicity study in rabbits **MRID No.:** 41063525; 41680501 **Executive Summary:** Ina developmental toxicity study (MRID# 41063525), quinclorac (98.3% a.i.) was administered to fifteen female Himalayan Rabbits by gavage at dose l evels of 0, 70, 200, or 600 mg/kg/day

from gestational day s 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), increasedPage 46 of 59

incidence of clinical signs (reduced/no defecation, diarrhea, apath y and poor general state) and mortality and discoloration of the kidney
. **The maternal LOAEL**

**is 20 0 mg/kg/day** 

**, based on decr**  **eased 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 ef fects are presumed to occur after a single exposure (dose) and thus were considered to be appropriate for this (acut e) risk assessment. This dose/endpoint is applicable only to Female 13 to 49 ye ars old. **Uncertainty Factor**

**(UF) :**  100 (10 x for inter
- species extrapolation and 10x for intra
- species variability

, FQP A SF = 1x). aRf D = 200 mg / kg / day ( NOAEL )

100 

### ( UF 

### ) = 2.0 mg / kg
aPA D = 2 mg / kg / day ( aRf

D ) 1 

### ( FQPA SF 

### ) = 2.0 mg / kg **A.3.2 Acute Refer**  **ence 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**  **Chr onic Refer**  **ence Dose (cRfD) ` Study Selected:**  Oncogenicity Feeding Study

in Mice **MRID No.:** 41063523 **Executive Summary:** Ina carcinogenicit y stud y (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. T

en mice were terminated at 6 months. The remainders were continued on the test material for 18 months. At th e end of 13 weeks, body weights in males and females receiving 8000 ppm were significantl y 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 controlsPage 47 of 59

(7.9 to 15.9% for males; 14.3 to 17.9 for females. T reatment - 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 r educed in male and female mice receiving 8000 ppm for 78 weeks, but there was no ef fect 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 wee ks. 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 ef fect of dosing on mortality , food consumption, or clinical signs. The LOAEL is 1000 ppm (150 mg/kg/day) based on ef fects on body

weight. The NOAE L 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 carcinogenicit y study is appropriate for b oth 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. Uncertaint y Factor(s): 100 (10 x for inter
- species extrapolation and 10x for intra
- species variab ility ; FQP

A SF = 1X). cR fD = 37.5 mg / kg / day ( NOAEL )

100 

### ( UF 

### ) = 0.38 mg / kg / day
cPAD = 0.375 mg / kg / day ( cRfD )

1 

### ( FQPA SF 

### ) = 0.38 mg / kg / day

**A.3.4 Incidental Oral Exposur**  **e (Short -**  **and Intermediate -**  **Te rm)**  **Study Selected:** Developmental toxicity study in rabbits. **MRID Nos.:** 41063525; 41680501 **Executive Summary:** See Appendix A, §870.3700bPage 48 of 59

**Dose and Endpoint for**

**Risk Assessment:**  Maternal NOAEL= 70 mg/kg/day based on decreased bod y weight gains and food consumption accompanied with increased water consumption at 200 mg/kg/day (LOAEL). **Comments about Study/Endpoin t:**  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 Exposur**  **e (Short -**  **, Intermediate -**  **and Long -**  **Te rm)**  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 Exposur**  **e (Short -**  **, Intermediate -**  **and Long -**  **Te rm)**  **A.3.7 Inhalation Exposur**  **e (Short and Intermediate -**  **Te rm)**  **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 bod y 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 Exposur**  **e (Long -**  **Te rm)**  Not applicable. Long
- term inhalation exposure is not anticipated under current use scenarios.Page 49 of 59

**9.3. A.4**  **Executive Summaries A.4.1**  **Subchr onic**  **To xicity**  **870.3100 90**  **- Day Oral T**  **oxicity -**  **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 10 35.4 mg/kg/day for females). There were no deaths occurred. No compound related clinical signs of toxicity were observed. The LOAE L 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 i ncrease in water intake in males and females, and decrease in monocy tes in female, increases in SGOTand SGPTin males, and pathological changes in kidney s of males (slight to minimal focal chronic interstitial nephritis. The NOAE L 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. **870.310 0**  **90 -**  **Day Oral T oxicity**  **- 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 decre ase was minimal and is not believed to be compound related since body weights were not significantl y dif ferent at an y other time intervals. The NOAEL is 500 ppm (75 mg/kg/day). This subchronic toxicity

study is classified Unacceptable because onl y one do se level was tested. However taken with MRID 41063518, it is acceptable /guideline.Page 50 of 59

**870.3150 90**  **- Day Oral T**  **oxicity -**  **Dog** The data requirement for a dog 90
- day subchronic oral toxicity

is satisfied by

the 1
- ye ar dog chronic oral study

. **870.3200 21/28**  **- Da**  **y Dermal T oxicity** 

**– Rabbit**  In a twent y - one day

dermal toxicity

study (MRID 44342905), Quinclorac (98.29% a. I.) in 0.5% carbox ym eth ylcellulose 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. Te st 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. V ehicle control group received 2 ml/kg b.w of 0.5 % carbox ym eth ylcellulose in water, while test groups received suspension of test material in aqueous 0.5% carbox ym ethyl 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 day s/week) repeated application of Quinclorac at a nominal concentrations of 0, 40, 200 or 1000 mg/kg/day in 0.5% carbox ym ethyl cellulose. The limit dose is 1000 mg/kg/day . No mortality

occurred at an y dose level tested. No local skin irritation was reported during the study . The NOAE L ≥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 Acceptabl e/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 i nhalation toxicity

and large extrapolated inhalation MOE (D376603, 23 September 2010)
. **A.4.2 Pr**  **enatal Developmental To**  **xicity 870.3700a Pr**  **enatal Developmental T oxicity Study**  **- Rat**  In a developmental toxicity study (MRID # 41063524), Quinclorac (96.5% a.i.) was administered to twent y - five female Wi star rats b y gavage at dose levels of 0, 24.4, 146, and 438 mg/kg/day

from gestational day s 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

.Page 51 of 59

This study

is classified as Acceptable/Guideline and satisfies the guideline requirement for a developmental toxicity

study in rats. **870.3700b Prenatal Developmental T oxicity Study**  **- Rabbit**  In a developmental toxicity study (MRID# 41063525), Quinclorac (98.3% a.i .) was administered to fifteen female Himalayan Rabbits b y gavage at dose levels of 0, 70, 200, or 600 mg/kg/day from gestational day s 7

– 19, inclusive. Maternal toxicity , observed at 200 mg/kg/day , was manifested as decreased body weight gain (36%) and fo od 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, apath y and poor general state) and mortalit y and discoloration of the kidney
. The maternal LOAEL is 200 mg/kg/day

, based on decreased body weight gains and food consumption. The maternal NOE L is 70 mg/kg/day
. Developmental toxicity

, observed at 600 mg/kg/day consisted of increased r ate 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 requ irement for a developmental toxicity study (83
- 3b) in rabbits. **A.4.3 Repr**  **oductive T oxicity**  **870.3800 Repr oduction and Fertility Effects**  **- Rat**  In a 2
- generation reproduction study (MRID # 41063526), Quinclorac ( ≥97.3% a.i.) was administered to Wistar rat s (24/sex/group) at dietary levels of 0, 1,000, 4,000 or 12,000 ppm (0, 40, 160 or 480 mg/kg/day , respectivel y). Parental toxicity : Evidence of toxicity was observed in the parental rats at 12,000 ppm (480 mg/kg/day). F l males showed reduced mean body weight during premating, which largel y 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). F 0 males showed no ef fects. F 0 females s howed a small but statistically significant decrease in mean body weight at We ek 24 of premating (
- 4%, p<0.05) but not at earlier times. F 1 females had decreased body weights during premating (at W

eek 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 F 0 females in the second mating (p<0.01) and the F l females in their onl y mating (p<0.05). However, in the second mating of F 0 females, there was no significant ef fect. The F 0 (first mating only) and F l 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 nephri tis was observed in F 0 and F l females. The parental s ys temic toxicity L OAE L is 12,000 ppm (480 mg/kg/day), based on decreased body weight during premating and lactation. The NOAE L is 4000 ppm (160 mg/kg/day). Reproductive toxicity : No ef fects on reproduct ive parameters were observed. The reproductive toxicity NOAE L is 12,000 ppm (480 mg/kg/day). A reproductive toxicity LOAEL was not established (>480 mg/kg/day).Page 5 2 of 59

Of fspring toxicity : At 12,000 ppm (480 mg/kg/day), the major ef fect on pup growth and developm ent was observed during lactation. Decreased pup weights were observed in male and female F l and F 2 pups during lactation (at Day 21 of lactation, 15
- 26% below controls; all generations p<0.0 1) and delay ed ph ys ical development (delayed pinna unfolding and eye opening) was also observed. Decreased pup weight at L actation Day 0 was seen only

in the F 2 male and female pups (approximately 7% below controls), a dose also associated with a slight decrease in maternal weight during gestation. Slightly decreased p up viability

and survival were reported; however, these ef fects 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 of

fspring LO AEL

is 12,000 ppm (480 mg/kg/day), based on ef fects on pup growth with a possible marginal ef fect on pup viability

. The of fspring NOAEL

is 4000 ppm (160 mg/kg/day). This study

is classified as Acceptable/guideline and satisfies the guideline requirement f or a multigeneration reproductive toxicity study in the rodent (870.3800). **A.4.4 Chr**  **onic To**  **xicity 870.4100a (870.4300) Chr**  **onic To**  **xicity**

**– Rat**  The combined chronic/carcinogenicity study satisfies this requirement. **870.4100b Chr onic**  **To xicity**  **- Dog**  In a 1
- ye ar feeding stud y in dogs (MRID 41 123201), 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, o r 469 mg/kg/day for females) for 12 months. No ef fect on mortalit y 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, ery

throcy te count, and hem atocrit, 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 1 3, 26, and 52), hematocrit at weeks 26 and 52 and ery throcy te count at week 26. In females fed 4000 ppm test substance, significant reductions (p <0.05) were seen at week 26 in hemoglobin concentration, ery throcy te 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 e ffects 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 weight s also were significantly increased (p <0.05) in females of the 4000 and 1000 ppm groups. Relative kidney weights were significantl y increased (p <0.01) inPage 53 of 59

both males and females of the 12000 ppm group and in males of the 4000 ppm group. There were no hist opathologic 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 bod y weight gain, adverse effect on food ef ficiency , hematological and clinical chemistry va lues, 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 stud y (83
- 1) in dogs. **A.4.5 Car**  **cinogenicity 870.4200a Car**  **cinogenicity Study -**  **rat** In a combined chronic toxicity /carcinogenicit y 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, respectivel y). Ten rats/sex/group were terminated at 12 months. The remainders were continu ed on the test material for 24 months. Body weights were slightly

reduced in females received 12000 ppm when compared to the control. No ef fects 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 originall y 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 autoly sis. Additional data (MRID# 42012901, 42012902) were submitted to the Agency in which adequatel y 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 m ales 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 c ell 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). **870.4 200b Car**  **cinogenicity (feeding) -**  **Mouse**Page 54 of 59

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, 1 50, 600 or 1200 mg/kg/day) for 6 months or 78 weeks. T en 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 significantl y l ower 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. T reatment - related body

weight r eductions 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 ef fect on l iver
- 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 reduce d 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 ef fect of dosing on mortality , food consumption, or clinical signs. The LOEL is 1000 ppm (150 mg/kg/day) based on ef fects 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 fe males 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 μg/plate) with or without S9 in S. typhimurium strains TA 98, T A100, T A1535, TA 1537

870. 5100 Bacterial reverse gene mutation 41063528 Acceptable/Guideline Negative up to the limit dose (5000 μg/plate) with or without S9 in S. typhimurium strains TA 98, T A100, T A1535, TA 1537 and E. coli strain WP2uvrAPage 55 of 59

**Cytogenetics** OPPTS 870.5385 In vivo bone marrow cy

togenic 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. T oxic signs of irregular breathing, apathy , and piloerection were noted in the mid
- and high
- dose groups. **Other Genotoxicity**  870.5300, In vitr

o mammalian forward gene mutation, CHO cells/HGPR

T locus MRID 41680503 Acceptable/guideline Negative for gene mutations up to cy totoxic doses (2000 μg/mL) with or without S9.

870.5300, In vitr

o mammalian chromosome aberration assay , human ly mphocy tes MRID 41076103 Acceptable/guideline Positive for chromosomal aberrations but only at cy totoxic concentrations (2000 μg/mL with S9 and 1000 μg/mL without S9).

870.5550, Unscheduled DNA sy nthesis in primary

rat hepatocy tes MRID 41063531 Acceptable/guideline Negative up to cy totoxic dose (1520 μg/mL).

**A.4.7 Neur**  **otoxicity 870.6100 Delayed Neurotoxicity Study** 

**– Hen**  Not required. **870.6200 Acute Neur**  **otoxicity Scr eening Battery**  **-** Wa ived ( HASPOC TXR 0056385)Page 56 of 59

**870.6200 Subchr onic Neur**  **otoxicity Scr eening Battery**  Wa ived ( HASPOC TXR 0056385) **870.6300 Developmental Neur otoxicity Study**  HED HIARC did not recommend a DNTstudy . (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 rapidl y absorbed and eliminated in the urine follow ing 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 day s. Elimination in the urine 5 day s after dosing accounted for 91 to 98% of the d ose with only 1 to 4% eliminated in the feces. No radioactivity

was detected in expired air. Biliary excretion was significant (1 1.5 to 14.5% of the dose) in animals receiving 600 mg/kg. However, most of this radioactivity was reabsorbed from the intestine s and eliminated in the urine. Most of the radioactivity in the bile is associated with the glucuronide conjugate of quinclorac. The conjugate is apparently hydroly zed 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 , thy roid, s quamous 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 d ecreased 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 day s. Elimination was biphasic with half
- lives of 3 to 4 hours for the rapid phase at th e 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 day s) were noted for 7 to 48 hours postdosing: saturation kinetics were also noted at these higher doses. These studies are acceptable and fulfill EP

A’ 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 4834610 1 ), 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 0Page 57 of 59

(control), 500, 1500, or 5000 ppm (equivalent to 0, 176, 439, or 1760 mg/kg bw/day , respectivel y) for 28 consecuti ve day s. Animals in the positive control group (8/group) received cyclophosphamide by

gavage at a dose of 10 mg/kg/day throughout the study

. Six day s before necrops y, animals in all groups were immunized with a suspension of sheep red blood cells (4x10 8 SRBC/mL) b y 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 Enzy me - Linked Immunosorbent Assay (ELI SA ) 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 thy mus were determined at necrops y. There were no treatment related ef fects on mortality

, clinical signs, body

weight changes, food consumption, organ weights, or gross pathology at any dose concentration that were considered treatment related. The sy stemic toxicity

NOAEL is 5000 ppm (equi valent 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 antibod y levels as measured b y an ELISA, or thymus and spleen weights at an y 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 s ys tem to detect immuno
- suppressive effec ts 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 an y evidence of treatment
- related effects on the immune sy stem. The overal l weight of evidence suggests that this chemical does not directly target the immune sy stem. 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 176 0 mg/kg/day

, the highest dose tested and above the limit dose); the L OAE L 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.Page 58 of 59

**Appendix B. Review of Human Resear ch**  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 V ersion 1.1 (PHED 1.1); the Agricultural Handler Exposure Ta sk Force (AHETF) database; the Outdoor Residential Exposure Ta sk Force (ORETF) database; and the Agricultural Re
- entry T as k Force (AR

TF) 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. Desc riptions 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
.Page 59 of 59

**Appendix C: International Residue Limits** 



### Quinclorac (PC Code 128974; Date of Request 3/14/2013) **Summary of US and International T olerances 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 To lerance (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