CLODINAFOP

- PROPARGYL Human Health Risk Assessment DP No. D400607

Page 3 of 13 Table of Contents 1.0 Executive Summary ................................ ................................ ................................ ........... 4 2.0 HED Recommendations ................................ ................................ ................................ .... 5 2.1 Data D eficiencies ................................ ................................ ................................ ............ 5 2.2 Tolerance Considerations ................................ ................................ .............................. 6 2.2.1 Enforcement Analytical Method ................................ ................................ ............... 6 2.2.2 Recommended Tolerances ................................ ................................ ......................... 6 2.2.3 Revisions to Petitioned - For Tolerances ................................ ................................ .... 7 2.2.4 International Harmonization ................................ ................................ ..................... 7 3.0 Hazard Characterization and Dose - Response Assessment ................................ ............ 7 4.0 Dietary Exposure and Risk Assessment ................................ ................................ ........... 8 Appendix A. International Tolerances ................................ ................................ ..................... 12 Appendix B. Summary of Endpoints, Points of Departure, and Toxicology Data Requirements for Clodinafop - Propargyl ................................ ................................ .................. 13CLODINAFOP

- PROPARGYL Human Health Risk Assessment DP No. D400607

Page 4 of 13 1.0 Executive Summary Syngenta Crop Protection, LLC, joint ly with Syngenta Crop Protection Canada, Inc., has submitted a petition to amend the established tolerance for clodinafop

- propargyl on wheat grain from 0.1 ppm to 0.02 ppm. Syngenta has proposed using Method REM 138.10, which determines the metabolite clodinafop only, as the enforcement method. Method RE M 138.10 is the current US enforcement method for the metabolite clodinafop. Method REM 138.01 is the current enforcement method for the parent. The LOQs in wheat grain are 0.05 ppm for clodinafop

- propargyl and 0.02 ppm for clodinafop (D267870, N. Dodd, 8 /8/00). A tolerance was established (D246730, N. Dodd, 4/7/00; D324689, N. Dodd, 3/30/06) for combined residues of clodinafop

- propargyl and its metabolite clodinafop at 0.1 ppm in wheat grain. Tolerances were also established on wheat forage and wheat ha y at 0.1 ppm and wheat straw at 0.5 ppm (40 CFR 180.559). The tolerance s w ere based on the limits of quantitation (LOQ s ) of the methods since residues in grain were all less than the LOQ s . No tolerances other than those on wheat commodities have been est ablished for clodinafop

- propargyl. The lower tolerance of 0.02 ppm will harmonize with the maximum residue limit proposed for the European Union (EU) by the European Food Safety Authority (EF SA )
. The EFSA has proposed residues of the metabolite clodinafop only as the residue of concern since residues of parent are not expected to occur in wheat grain. No request has been made to change the established tolerances on wheat forage, wheat hay, or wheat straw. T he US registered end

- use products are Discover® Herbicide (EPA Reg. No. 100

- 907) and Discover ® NG Herbicide (EPA Reg. No. 100

- 1173). Discover Herbicide ® contains 2 lb ai/gallon. Discover ® NG Herbicide contains 0.5 lb ai/ gallon. One postemergence broadcast foliar application is made at the r ate of 3.2

- 4 oz Discover ® Herbicide/A (0.05

- 0.06 lb ai/A) or 12.8

- 16 oz Discover ® NG Herbicide/A (0.05

- 0.06 lb ai/A). Preharvest intervals (PHIs) are 30 days for forage and hay, and 60 days for grain and straw. Syngenta Crop Protection, LLC has submitted a new analytical method using high performance liquid chromatography with tandem mass spectrometry detection (LC/MS/MS), Enviro

- Test Laboratories Report No. MS 247, for the determination of residues of clodinafop

- proparg yl (CGA

- 184927) and its metabolite clodinafop ( CGA

- 193469 ) in/on wheat forage, grain, and straw. The method is adequate for determination of residues of clodinafop

- propargyl and its metabolite clodinafop in wheat grain at 0.02 ppm (i.e., 0.01 ppm for each analyte). Also, Syngenta Crop Protection, LLC, has submitted field trial data for clodinafop

- propargyl on wheat
. Twenty field trials were conducted in Canada during the 2001 growing season in the North American Free Trade A greement (NAFTA) Growing Zones 5 (MB; 2 trials), 7 (AB and SK; 7 trials), 7A (AB; 1 trial), and 14 (AB, SK, and MB; 10 trials). Field trial data show <0.02 ppm of residues in wheat grain. Since the last human health risk assessment, three toxicity studies have been submitted and reviewed: acute neurotoxicity ( AC N, MRID 46012922), subchronic neurotoxicity (SCN, MRID 46012921), and developmental neurotoxicity (DNT, MRID 47085301).CLODINAFOP

- PROPARGYL Human Health Risk Assessment DP No. D400607

Page 5 of 13 2.0 HED Recommendations Provided Syngenta proposes use of Method MS 247 as an enforcement method for the combined residues of clodinafop

- propargyl and clodinafop on wheat grain, HED recommends for the reduction of the established clodinafop

- propargyl tolerance on wheat grain from 0.1 ppm to 0.02 ppm . HED will retain both the parent clodinafop

- propargyl and the metabolite clodinafop as residues of concern for the tolerance expression. Syngenta has not proposed Method MS 247 as an enforcement method because the lowest level of method validation (1 .0 ppb for each analyte) may not be reproducible in all lab oratories
. However, EPA has determined that Method MS 247 is adequate as an enforcement method for determination of residues of clodinafop

- propargyl and its metabolite clodinafop in wheat grain at 0.02 ppm (i.e., 0.01 ppm for each analyte). The method is also adequate as a data collection method based on adequate fortified control sample recoveries. According to HED’s Interim Guidance on Tolerance Expressions (5/27/09, S. Knizner), the tolerance expression s for clodinafop

- propargyl in 40 CFR § 1 80. 559 should be revised as follow: Under 40 CFR § 180.5 59(a) : “Tolerances are established for clodinafop

- propargyl, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only clodinafop

- propargyl [(2 R )

- 2

- [4

- [(5

- chloro

- 3

- fluoro

- 2

- pyridinyl)oxy]phenoxy]propanoic acid, 2

- propynyl ester] and its metabolite clodinafop [(2 R )

- 2

- [4

- [(5

- chloro

- 3

- fluoro

- 2

- pyridinyl)oxy]phenoxy]propanoic acid] .” 2.1 Data Deficiencies The following deficiencies relevant to wheat grain remain outstanding as conditions of registration: Toxicology 870.7800 Immunotoxicity An immunotoxicity study is required under 40 CFR §158.500. Residue Chemistry 860.1300 Nature of the Residue

- Livestock The requirement from the 0 4/ 0 7/ 20 00 review for additional information pertaining to the goat metabolism study has not been addressed by the petitioner. The petitioner must submit information pertaining to the time from sampling to final analysis for milk and tissue samples for the rumina nt metabolism study reported in MRIDs 44399204 and 44399205. The petitioner should note that if the time between sampling and final analysis of the samples exceeded six months, evidence should be provided that the identity of residues did not change durin g theCLODINAFOP

- PROPARGYL Human Health Risk Assessment DP No. D400607

Page 6 of 13 period between collection and final analysis. 860.1380 Storage Stability The requirement from the 4/7/00 review for additional information to support the study reported in MRID 44399210 (storage stability of CGA

- 193469 in wheat grain) has not been addressed by the petitioner. The petitioner must submit the following additional data to support the study: (1) raw data, including residues (ppm) found and representative chromatograms (for standards, controls, freshly fortified samples, and stored sam ples); (2) description of storage containers; and (3) submission or identification by number of the method used to analyze the storage stability samples. 2.2 Tolerance Considerations 2.2.1 Enforcement Analytical Method Method MS 247 ( MRID 48693701) is a high performance liquid chromatography method with tandem mass spectrometry detection (LC/MS/MS ) for the determination of residues of clodinafop

- propargyl (CGA

- 184927) and its metabolite clodinafop ( CGA

- 193469 ) in/on wheat forag e, grain, and straw. Since Method MS 247 determines only one ion transition for each analyte, a confirmatory method is needed. T he enforcement methods (REM 1 38. 01 for parent and REM 138
. 10 for the metabolite) can serve as confirmatory methods for Method MS 247 on wheat grain since they use a different detection system [high performance liquid chromatography/ultraviolet detection (HPLC/UV)]
. R ecovery data at the lowest fortification level ( 1 ppb ) was acceptable (i.e., within the range of 70

- 120%). The limit of detection (LOD) was set at 0.5 pp b for each analyte in wheat grain, forage, and straw, based on a signal to noise ratio ( S/N ratio) of >3:1. The method is adequate as an enforcement method for determination of residues of clodinafop

- propargyl and its metabolite clodinafop in wheat grain at 0.02 ppm (i.e., 0.01 ppm for each analyte)
. 2.2. 2 Recommended Tolerances According to HED’s Interim Guidance on Tolerance Expressions (5/27/09, S. Knizner), the tolerance expression for clodinafop

- propargyl in 40 CFR § 1 80. 559 should be revised as follow: Under 40 CFR § 180.5 59(a) : “Tolerances are established for clodinafop

- propargyl, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels s pecified below is to be determined by measuring only clodinafop

- propargyl [(2 R )

- 2

- [4

- [(5

- chloro

- 3

- fluoro

- 2

- pyridinyl)oxy]phenoxy]propanoic acid, 2

- propynyl ester] and its metabolite clodinafop [(2 R )

- 2

- [4

- [(5

- chloro

- 3

- fluoro

- 2

- pyridinyl)oxy]phenoxy]propanoi c acid] , expressed as the stoichiometric equivalent of clodinafop

- propargyl .” Table 2.2.2 . Tolerance Summary for Clodinafop - propargyl Commodity Established/Proposed

Tolerance (ppm) Recommended

Tolerance (ppm) Comments

Correct Commodity Definition Wheat, grain 0.10 0.02CLODINAFOP

- PROPARGYL Human Health Risk Assessment DP No. D400607

Page 7 of 13 2.2. 3 Revisions to Petitioned - For Tolerances The US tolerance expression will continue to contain both parent clodinafop

- propargyl and the metabolite clodinafop as residues of concern. 2.2. 4 International Harmonization A Codex Sheet is attached. A tolerance is established in Canada for residues of parent and the metabolite clodinafop on wheat at 0.1 ppm. No Codex MRLs are established for clodinafop

propargyl
. The E uropean Union h as proposed a tolerance of 0.02 ppm on wheat g rain, to be determined as clodinafop. 3.0 Hazard Characterization and Dose - Response Assessment Clodinafop

- propargyl exhibits low acute mammalian toxicity via oral (Toxicity Category III), dermal (Toxicity Category III), and inhalation (Toxicity Category IV) routes of exposure. Clodinafop is not an eye or skin irritant but is a dermal sensitizer. The primary target organ of toxicity is the liver in dogs, mice, and rats in subchronic and chronic studies. Skin lesions were observed in dogs during subchron ic and chronic exposure. The most recent human health risk assessment of clodinafop

- propargyl (D264702, A. Lowit, 05/15/00) considered the entire toxicology database and retained the FQPA safety factor, in part, for neurotoxicity data deficiencies. Since then, a neurotoxicity screening battery and a developmental neurotoxicity study have been submitted. The acceptable/guideline neurotoxicity studies have been reviewed but not incorporated into the endpoint selection for risk assessment for this action. A brief summary of clodinafop

- propargyl neurotoxicity studies follows: Acute neurotoxicity (ACN), MRID 46012922: There was evidence of acute neurotoxicity in the form of demyelination of the tibial (distal and proximal) and sciatic (proximal) nerves in rats administered a single bolus dose of 300 mg/kg [ACN lowest observed adverse effect level (LOAEL)] and higher. NOAEL = 100 mg/kg; Subchronic neurotoxicity (SCN), MRID 46012921: When rats were administered 83.6 mg/kg/day (highest dose tested) in the diet for 90 days, no treatment

- related effects on brain weight or morphometrics, nervous tissue histopathology or neurobehavior were observed. The SCN LOAEL in male rats is 78.7 mg/kg/day and is based on an 11

- 13% decrease in body weight and decreased fo od consumption and utilization. The SCN LOAEL in females is greater than 83.6 mg/kg/day. NOAEL = 9.3 mg/kg/day in males and 86.3 mg /kg / day in females; Developmental neurotoxicity (DNT), MRID47085301: No maternal toxicity was observed in the DNT but an of fspring LOAEL was established at 44 mg/kg/day based on decreased body weight gain, increased liver weight, and decreased auditory response on PND 23 and increased thickness of the corpus callosum in females in PND 63. NOAEL = 9.0 mg/kg/day. HED has deter mined that the results of the neurotoxicity studies adequately elucidate the hazard and will not increase the risk associated with clodinafop

- propargyl exposure. The current pointsCLODINAFOP

- PROPARGYL Human Health Risk Assessment DP No. D400607

Page 8 of 13 of departure (PoD) for clodina fop

- propargyl risk assessment are protective of all effects, including neurotoxicity, observed in the ACN, SCN and DNT submitted since the last risk assessment (D264702, A. Lowit, 05/15/00). The ACN no observed adverse effect level (NOAEL), 100 mg/kg, is 4 times greater than the current dose and en dpoint selected for an aRfD (based currently on mortality and clinical signs of toxicity in the rabbit developmental study). The current acute dietary PoD for females 13

- 49 years is 5 mg/kg and nearly ten times less than the dose eliciting any effect in p ups exposed perinatally to clodinafop

- propargyl (DNT LOAEL = 44 mg/kg/day). The SCN and DNT NOAELs, both approximately 9 mg/kg/day, are two

- and ten
- fold greater than the current dose and endpoint selected for the short

- and intermediate

- term inhalation e xposure scenarios, respectively. Developmental toxicity was observed in rats following in utero exposures but not in the rabbits administered clodinafop

- propargyl. There was no evidence of reproductive toxicity. Toxicity to the offspring was seen in the DNT. There is also evidence of neurotoxicity in the recently submitted ACN and DNT studies. Clodinafop

- propargyl is classified “Suggestive Evidence of Carcinogenic Potential” but quantification of carcinogenic potential is not required based on adequate data on the mode of action for hepatocarcinogenesis in mice . Clodinafop

- propargyl is negative for mutagenicity in a battery of genotoxicity studies. Absent a functional immunotoxicity study, there is evidence in the database that clodinafop

propargyl ma y perturb immune function. In a subchronic oral toxicity study in rats, a treatment

related 37% decrease in thymus weight was observed and accompanied by an increased incidence of thymic atrophy. Thymus effects were observed only in males, only at the hi ghest dose tested (71 mg/kg/day) and fully reversed after a 4 week recovery period. No thymus effects were noted in the chronic toxicity/carcinogenicity study in rats. And no other indicators of structural immunotoxicity were observed elsewhere in the to xicology database. While an immunotoxicity study is required to complete the clodinafop

- propargyl database in accordance with the 2007 revised 40 CFR §158 toxicology data requirements, this data gap will not increase the risk associated with clodinafop

- pr opargyl exposure. 4 .0 Dietary Exposure and Risk Assessment A dietary risk assessment was not conducted, as there have been no changes in the dietary intake values since the last assessment. The present action lowers the tolerance for wheat grain from 0 .1 to 0.02 ppm, and this change would have no significant effect on the dietary exposure. An analytical method (MS 247) and field trials on wheat were submitted to support the proposed reduction in tolerance level for wheat grain from 0.1 ppm to 0.02 ppm
. Syngenta has not proposed Method MS 247 as an enforcement method because the lowest level of method validation (1.0 ppb for each analyte) may not be reproducible in all laboratories. 860.1340 Residue Analytical Method (MRID 48693701) Syngenta Crop P rotection, LLC has submitted an analytical method description and validation data for a high performance liquid chromatography method with tandem mass spectrometry detection (LC/MS/MS), Enviro

- Test Laboratories Report No. MS 247, for the determination ofCLODINAFOP

- PROPARGYL Human Health Risk Assessment DP No. D400607

Page 9 of 13 residues of clodinafop

- propargyl (CGA

- 184927) with its metabolite CGA

- 193469 and cloquintocet

- mexyl (CGA

- 185072) with its metabolite CGA

- 153433 in/on wheat forage, grain, and straw. The method was used for data collection in the wheat crop field trials reviewed under DP # D 399618 (MRID 48693702)
. Briefly , homogenized samples of wheat forage, grain, and straw are extracted twice with 80% acetone/water, buffered to a pH of 3 using citric acid. After centrifuging and bringing to volume, one aliquot is taken for the analysis of clodinafop

- propargyl, cloquintocet

- mexyl , and CGA

193469. The aliquot is purified by two solid phase extraction (SPE) clean

- up steps in a series (C18 SPE and Envi

- Carb SPE), concentrated using nitrogen, reconstitut ed in 20% acetonitrile/ 0.1 % formic acid/w ater, and analyzed by liquid chromatograph y with tandem mass spectrometry (LC/MS/MS). A second aliquot is taken for analysis of CGA

- 153433 only. The aliquot is purified by selective liquid/liquid partitions with 8:2 hexane/ether and ethyl acetate, concentrated using nitrogen, reconstituted in phosphate/water (pH 7), and cleaned

- up by C18 SPE. Samples are then evaporated to dryness, reconstituted in 20% acetonitrile/0.1% formic acid/water, and analyzed by LC/MS/M S. The method monitors one ion transition for each analyte: m/z 350→266 for clodinafop

propargyl, m/z 312→266 for CGA

- 193469, m/z 336→238 for cloquintocet

- mexyl, and m/z 238 →192 for CGA

- 153433. Since only one ion transition was monitored for each analyte, a confirmatory method is needed for the method to be an enforcement method . The current HPLC/UV enforcement methods (REM 1 38 .01 for parents and REM 138
. 10 for metabolites) can serve as confirmatory m ethods for wheat grain. R ecovery data at the lowest fortification level ( 1 ppb ) was acceptable (i.e., within the range of 70

- 120%). The limit of detection (LOD) was set at 0.5 pp b for each analyte in wheat grain, forage, and straw, based on a signal to noise ratio ( S/N ratio) of >3:1. The method was adequately validated by Enviro

- Test Laboratories using samples of wheat grain, forage, and straw fortified with each analyte at 1.0 , 5.0 , and 10.0 pp b (1x to 10x the LOQs). O verall average recoveries were 8 0

- 115% (standard deviation of 5.4

- 6.8%) for c lodinafop

propargy l, 75

- 78% (standard deviation of 5.1

- 9.7%) for CGA

- 193469 , 73

- 111% (standard deviation of 5.9

- 11.1%) for cloquintocet

- mexyl, and 87

- 111% (standard deviation of 4.5

- 12.3%) for CGA

- 153433
. Radiovalidation data were not submitted as part of the study; however, radiovalidation data have been conducted for Methods REM 138.01, REM 138.06, REM 138.10, and REM 138.12 (D324689, N. Dodd, 3/30/06). Methods 138.01 and 138.12 use acetonitrile to extr act parent residues of clodinafop

- propargyl and cloquintocet

- mexyl ( acetonitrile was also used in the metabolism studies) . Method REM 138.06 uses an acetone buffer at pH 3 to determine the metabolites CGA

- 193469 and CGA

- 153433. Method REM 138.10 uses an acetone:citrate buffer (8:2, v:v) to extract CGA

- 193469 and CGA

- 153433. Method MS 247 uses 80% acetone/water, buffered to a pH of 3 using citric acid, to extract parents and metabolites. While acetonitrile was used to extract clodinafop

- propargyl and clo quintocet

- mexyl , acetone and acetonitrile are both aprotic polar solvents of similar polarity and are expected to show similar extraction efficiencies.CLODINAFOP

- PROPARGYL Human Health Risk Assessment DP No. D400607

Page 10 of 13 Therefore, the previously submitted radiovalidation data are adequate to support MS 247 for both the pa rents and the metabolites. Adequate method validation data have been submitted by Enviro

- Test Laboratories in MRID 48693701 and by Syngenta as concurrent recovery data in MRID 48693702. No additional method validation data are required. Conclusions: Th e analytical method test data for Method MS 247 are classified as scientifically acceptable . The method is adequate as a data collection method based on adequate fortified control sample recoveries. The method is also adequate , when used in combination with the HPLC/UV method s as confirmatory methods , as an enforcement method for determination of residues of clodinafop

- propargyl and its metabolite clodinafop in wheat grain at 0.02 ppm (i.e., 0.01 ppm for each analyte)
. 860.1500 Crop Field Trial Data on Wheat (MRID 48693702) Syngenta Crop Protection, LLC, has submitted field trial data for clodinafop

- propargyl on wheat
. Twenty field trials were conducted in Canada during the 2001 growing season in the North American Free Trade A greement (NAFTA) Grow ing Zones 5 (MB; 2 trials), 7 (AB and SK; 7 trials), 7A (AB; 1 trial), and 14 (AB, SK, and MB; 10 trials). The submission also includes data for cloquintocet

- mexyl. Refer to 48693702.de2 for data pertaining to cloquintocet

- mexyl. A number of trials in e ach Zone were conducted by the same Principal Field Investigator (PFI). Based on examination of the field trial records, HED concludes that each of the following trial groups constitutes a single trial with replicate samples for purposes of OCSPP 860.1500 data requirements: MB trials T119 and T120; only difference = variety. AB trials T129 and T130; no differences. SK trials T124 and T125; only difference = variety. AB trials T134, T135, T136 ; no differences. With the classification of these trials as replicates, the number of separate trials for purposes of OCSPP 860.1500 data requirements is adjusted to 15, with 1 trial conducted in Zone 5, 6 trials conducted in Zone 7, and 7 trials conducted in Zone 14
. Each trial consisted of on e untreated plot and one or two treated plots; separate plots were established for the harvest of forage (5 trials) and for the harvest of grain and straw (all trials). At each trial location, the treated plots received one foliar broadcast application of an emulsifiable concentrate (EC) formulation containing clodinafop

- propargyl at 2 lb ai/gal (240 g ai/L) and the safener cloquintocet

- mexyl at 0.5 lb/gal (Horizon 240 EC). Only data pertaining to clodinafop

- propargyl are reviewed herein; therefore, the p roduct will be referred to herein as the 2 lb ai/gal EC formulation. Each treated plot received one application of clodinafop

- propargyl at 0.062 lb ai/A (70 g ai/ha). Applications were targeted at the 3

- 6 leaf growth stage. Applications were made using ground equipment; spray volumes were not reported. A crop oil concentrate/nonionic surfactant (COC/NIS) blend (Score) was added to the spray mixtures for all applications. Samples of forage were harvested from five trials (T119, T124, T127, T137, andCLODINAFOP

- PROPARGYL Human Health Risk Assessment DP No. D400607

Page 11 of 13 T13 8) at preharvest intervals (PHIs) of 5

- 13 days; grain and straw were harvested at maturity (PHIs of 62

- 110 days). Additional forage samples were harvested at PHIs of 3, 7, and 16 days from one trial ( in MB) to assess residue decline. Samples were analyzed for residues of clodinafop

- propargyl and its acid metabolite (CGA

193469) using a liquid chromatography method with tandem mass spectrometry detection ( LC/MS/MS ), Method MS 247. The limit of quantitation (LOQ; determined as the lowest level of m ethod validation, LLMV) was 1 ppb for each analyte. The method was adequate for data collection based on acceptable concurrent recovery data. The fortification levels used in concurrent method recovery were adequate to bracket expected residue levels. C oncurrent recoveries and treated samples were not corrected for residues in controls. HED notes that the analytical method does not specify conversion of metabolite residues to parent equivalents; therefore, quantifiable residues of CGA

- 193469 were conver ted to parent equivalents by the study reviewer using a molecular weight conversion factor of 1.12 (MW of clodinafop

- propargyl 349.74 ÷ MW of CGA

- 193469 311.69). Samples were stored frozen (~

- 25 °C at the analytical laboratory) from collection to analysi s for 187

- 240 days (6.1

- 7.9 months) for forage, 70

- 114 days (2.3

- 3.7 months) for grain, and 103

- 192 days (3.4

- 6.3 months) for straw. All samples were analyzed within 15

- 90 day s of extraction. The available storage stability data support the storage condi tions and intervals of samples from the submitted wheat field trials. Although previously submitted storage stability data indicate the potential for some decline of clodinafop

- propargyl residues in wheat grain and straw samples over the storage intervals used in this study, no correction will be applied because the expected decline would be small, and residues of clodinafop

- propargyl were below the LOQ in all grain and straw samples. Following one foliar broadcast application of the 2.0 lb ai/gal EC for mulation of clodinafop

propargyl at 0.062 lb ai/A (70 g ai/ha), residues of clodinafop

- propargyl, CGA

- 193469, and combined residues, respectively, in/on forage were: <1.0

- 2.5 (<1.0

- <1.8), <1.0

- 8.8 (<1.0

- 8.5), and <2.0

- <10 (<2.0

- <9.5) ppb at the 5

- 13

- day PH I. Corresponding residues in/on grain and straw harvested at PHIs of 62

- 110 days following one application at 0.062 lb ai/A (70 g ai/ha) were all <LOQ. The residue decline results indicate that combined residues of clodinafop

- propargyl and CGA

193469 in /on wheat forage decreased with increasing PHI. Conclusion : The submitted field trial data are adequate to support the request for reduction of the tolerance for clodinafop

- propargyl on wheat grain from 0.1 ppm to 0.02 ppm.
Attachments: Appendix A. International Tolerances Appendix B. Summary of Endpoints, Points of Departure, and Toxicology Data RequirementsCLODINAFOP

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Page 12 of 13 A ppendix A . International Tolerances



### Clodinafop

- propargyl ( 125203 ; 0 9/21/ 20 12 ) Summary of US and International Tolerances and Maximum Resid ue Limits Residue Definition : US Canada Mexico 2 Codex 40 CFR §180.559: clodinafop

propargyl (propanoic acid, 2

- [4

- (5

- chloro

- 3

- fluoro

- 2

- pyridinyl)oxy]phenoxy]

- , 2

- propynyl ester, (2R)

- ) and its acid metabolite (propanoic acid, 2

- [4

- [(5

- chloro

- 3

- fluoro

- 2

- pyridinyl)oxy]phenoxy]

- , (2R)

- ) 2

- propynyl (2R)

- 2

- [4

- [(5

- chloro

- 3

- fluoro

- 2

- pyridinyl) oxy]phenoxy]propanoate, including the metabolite (2R)

- 2

- [4

- [(5

- chloro

- 3

- fluoro

- 2

- pyridinyl)oxy]phenoxy]pr opanoic acid None

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 Codex Wheat, grain 0.02 0.1 wheat Completed: M. Negussie; 09/21/2012

1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant.
2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.CLODINAFOP

- PROPARGYL Human Health Risk Assessment DP No. D400607

Page 13 of 13 Appendix B. Summary of Endpoints, Points of Departure, and Toxicology Data Requirements for Clodinafop - Propargyl Table 4. Summary of Toxicological Doses and Endpoints for Clodinafop - propargyl for Use in Dietary and Non Occupational Human Health Risk Assessments (A. Lowit, D264702, 05/15/2000) Exposure/ Scenario Point of Departure Uncertainty/FQP

A Safety Factors PAD, Level of

Concern for Risk Assessment Study and Toxicological Effects
Acute Dietary ( Females 13

- 49 years of age) NOAEL = 5

mg/kg
. UF A = 10x

UF H = 10x FQPA SF = 10x aPAD = 0.005

mg/kg/day Developmental Toxicity Study in Rats.

Increased incidence of bilateral distension and torsion of ureters, unilateral 14 th ribs and incomplete ossification of metacarpals and cranial bones at 40 mg/kg. Acute Dietary ( General Population ) NOAEL= 25

mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1 x aPAD = 0.25

mg/kg/day Developmental Toxicity Study in

Rabbits. Mortality and clinical signs of toxicity were seen on Day 2 of dosing. Chronic Dietary (All Populations) NOAEL= 0.03

mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1 0 x cPAD = 0.00003

mg/kg/day Chronic Toxicity/Carcinogenicity

Study in Rats. Hepatocytic hypertrophy, chronic progressive nephropathy and tubular pigmentation at 0.3 mg/kg/day. Incidental Oral This risk assessment is not required. There are no residential uses of clodinafop

- propargyl Dermal ( Short

- and Intermediate

- Term ) NOAEL = 50

mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x MOE = 100 Dermal Toxicity in Rats. Increased liver weight and clinical signs including piloerection and hunched posture at 200 mg/kg/day. Inhalation ( Short

Term ) NOAEL = 5

mg/kg/day
. UF A = 10x

UF H = 10x FQPA SF= 1x MOE = 100 Developmental Toxicity Study in Rats. Increased incidence of bilateral distension and torsion of ureters, unilateral 14 th ribs and incomplete ossification of metacarpals and cranial bones at 40 mg/kg/day. Inhalation ( Intermediate

- Term ) NOAEL = 0.9

mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x MOE = 100 Subchronic Toxicity Study in Rats. Increased liver weight and enzyme activity at 8.2 mg/kg/day. Cancer (oral, dermal, inhalation) Classification: "Suggestive Evidence of Carcinogenic Potential". The quantification of

carcinogenic potential is not required. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no ob served 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). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose. N/A = not applicable.