Clopy

ralid Human Health Risk Assessment DP Nos. D391397, D401055

Page 1 of 51 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460
**OFFICE OF CHEMICA**  **L SA FETY**  **AN D**  **POLLUTION PREVENTION MEMORANDUM**  **Date :**  **6 /**  **6 /201**  **2 SUBJECT:**  **Clopyralid** . Human Health Risk Assessment for New U ses on Apples, Teff,

Brassica Leafy

Greens, and Rapeseed **PC Code:** 117403 (acid)

117401 (alkanolamine salt) **DP Barcode:** D3 91397 , D401055 **Decision No.:** 4 50262 , 463332 **Registration Nos. :**  62719 - 73, 62719 - 80, 62719 - 81, and 62719 - 84 **Petition No.:** 1E7882 , 2E8013 **Regulatory Action:** Section 3 Registration **Risk Assessment Type:** Single Chemical A ggregate **Case No.:** NA **T XR No.:**  NA **CAS No.:** 1702 - 17 - 6 (acid) 57754 - 85 - 5 (monoethanolamine salt) **MRID No.:** NA **40 CFR:** §180. 431 **FROM:** Douglas A. Dotson, Ph.D., Chemist

Linnea Hansen , Ph.D., Toxicologist Suku Oonnithan , Ph.D., Biologist Registration Action Branch II Health Effects Division (7509P) **THROUGH:** Karl yn Middleton , M.S., Toxicologist

Michael A. Doherty, Ph.D. , Chemist Margarita Collantes, M.S., Biolog ist Christina Swartz, Branch Chief Registration Action Branch II Health Effects Division (7509P) **TO:** Laura Nollen/Barbara Madden , RM Team 5

RIMUERB Registration Division (7505P)Clopy

ralid Human Health Risk Assessment DP Nos. D391397, D401055

Page 2 of 51 **1.0 Executive Summary**  ................................ ................................ ................................ .......... 4 **2.0 HED Re**  **commendations** ................................ ................................ ................................ ... 7 **2.1 Data Deficiencies/Conditions of Registration**  ................................ ............................. 7 **2.2 Tolerance Considerations**  ................................ ................................ ............................. 7 **2 .2**  **. 1**  **Enforcement Analytical Method** ................................ ................................ ............. 7 **2.2 .2**  **International Harmonization** ................................ ................................ ................... 7 **2.2 .3**  **Recommended Tolerances** ................................ ................................ ........................ 8 **2.2 .4**  **Re visions to Petitioned**  **- For Tolerances**  ................................ ................................ .. 8 **2.3 Label Recommendations**  ................................ ................................ .............................. 8 **3.0 Introduction**  ................................ ................................ ................................ ....................... 9 **3.1 Chemical Identity**  ................................ ................................ ................................ .......... 9 **3.2 Physical/Chemical Characteristics**  ................................ ................................ .............. 9 **3.3 Pesticide Use Pattern**  ................................ ................................ ................................ .... 9 **3.4 Anticipated Exposure**  **Pathways** ................................ ................................ ................ 10 **3.5 Consideration of Environmental Justice**  ................................ ................................ .. 1 1 **4.0 Hazard Characterization and Dose**  **- Respon**  **se Assessment**  ................................ ......... 17 **4.1 Toxicology Studies Available for Analysis**  ................................ ................................ 1 1 **4. 1**  **.1 Sufficiency of Studies/Data**  ................................ ................................ ..................... 1 1 **4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)**  ............................ 1 2 **4.2.1 Dermal Absorption**  ................................ ................................ ................................ . 1 2 **4.3 Toxicological Effects**  ................................ ................................ ................................ ... 1 2 **4.4 Safety**  **F actor for Infants and Children (FQPA Safety Factor)**  .............................. 1 3 **4.4.1 Completeness of the Toxicology Database**  ................................ ............................ 1 4 **4.4.2 Evidence of Neurotoxicity**  ................................ ................................ ...................... 1 4 **4.4.3 Evidence o**  **f Sensitivity/Susceptibility in the Developing or Young Animal** ...... 1 4 **4.4.4 Residual Uncertainty in the Exposure Database**  ................................ .................. 1 4 **4.5 Toxicity Endpoint and Point of Departure Selections**  ................................ ............. 1 4 **4.5.1 Dose**  **- Response**  **Assessment** ................................ ................................ .................... 1 4 **4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment**  ... 1 6 **4.5.3 Cancer**  **Classification and Risk Assessment Recom**  **mendations** ......................... 1 6 **4.5.4 Summary of**  **Points of Departure and Toxic**  **ity E**  **ndpoints** ................................ 1 6 **5.0 Dietary Exposure and Risk Assessment**  ................................ ................................ ........ 17 **5.1 Metabolite/Degradate Residue Profile**  ................................ ................................ ...... 17 **5.1.1 Summary of Plant and Animal Metabolism Studies**  ................................ ........... 18 **5.1.2 Summary of Environmental Degradation**  ................................ ............................ 1 8 **5.1.3 Comparison of Metabolic Pathways**  ................................ ................................ ...... 1 8 **5.1.4 Residues of Concern Summary and Rationale**  ................................ ..................... 18 **5.2 Food Residue Profile**  ................................ ................................ ................................ ... 19 **5.3 Water Residue Profile**  ................................ ................................ ................................ . 20 **5.4 Dietary Risk Assessment**  ................................ ................................ ............................ 20 **5.4.1 Description of Residue Data Used in Dietary Assessment**  ................................ .. 20 **5.4.2 Percent Crop Treated Used in Dietary Assessment**  ................................ ............. 21 **5.4.3 Acute Dietary Risk Assessment**  ................................ ................................ ............. 21 **5.4.4 Chronic Dietary Risk Assessment**  ................................ ................................ ......... 21 **5.4.5 Cancer Dietary Risk Assessment**  ................................ ................................ ........... 21 **5.4.6 Summary Table**  ................................ ................................ ................................ ....... 21Clopy

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Page 3 of 51 **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  ............................ 2 2 **6.1 Residential Handler Exposure**  **and Risk** ................................ ................................ ... 22 **6.2 Residential**  **Post -**  **application Exposure**  ................................ ................................ ..... 23 **6.3 Combined**  **Residential Risk Estimates** ................................ ................................ ...... 2 4 **6.4 Spray Drift**  ................................ ................................ ................................ ................... 2 4 **7.0 Aggregate Exposure/Risk Characterization**  ................................ ................................ . 24 **7.1 Acute Aggregate Risk**  **Estimates** ................................ ................................ ................ 24 **7.2 Short**  **- Term Aggregate Risk**  **Estimates** ................................ ................................ ..... 25 **7. 3**  **Intermediate -**  **Term Aggregate Risk Estimates**  ................................ ........................ 25 **7.4 Chronic**  **Aggregate Risk Estimates**  ................................ ................................ ............ 2 6 **7.5 C**  **an c**  **er Aggregate Risk**  **Estimates** ................................ ................................ ............. 26 **8.0 Cumulative Exposure/Risk Characterization**  ................................ .............................. 26 **9.0 Occupational Exposure/Risk Characterization**  ................................ ........................... 26 **9.1 Short**  **- /** **Intermediate -**  **Term Handler Risk** ................................ ................................ . 26 **9.2 Occupational/Commercial**  **Post -**  **application Risk**  ................................ .................... 29 **9.2.1 Post**  **- application**  **Inhalation Exposure**  ................................ ................................ ... 29 **10.0 References**  ................................ ................................ ................................ ........................ 30 **Appendix A. T**  **oxicology Profile and Executive Summaries**  ................................ .................. 3 1 **A.1 Toxicology**  **Data Requirements** ................................ ................................ .................. 3 1 **A.2 T**  **oxicity Profiles** ................................ ................................ ................................ .......... 3 2 **A. 3**  **Hazard Identification and Endpoint Selection** ................................ ......................... 3 6 **A.4 Executive**  **Summaries** ................................ ................................ ................................ .. 39 **Appendix B**  **. Clopyralid**  **Physical/Chemical Properties** ................................ ......................... 5 0 **Appendix C**  **. Review of Human Research** ................................ ................................ ................ 51Clopy

ralid Human Health Risk Assessment DP Nos. D391397, D401055

Page 4 of 51 **1.0 Executive Summary**  The Interregional Research Project Number 4 (IR - 4) submitted a tolerance petition proposing the use of the herbicide clopy ralid ( 3,6 - dichloro - 2 - pyridinecarbox yl ic acid) on apples . As part of the same tolerance petition, IR - 4 proposed to amend the Stinger ® Herbicide label to expand the mustard greens use to the entire Brassica leafy greens subgroup (5B), and to expand the use on canola, crambe, and rapeseed to the entire Rapeseed s ubgroup (20A), except gold of pl easure. In addition, IR - 4 submitted a separate tolerance petition for the use of clopy ralid on teff

. Clopy ralid is a p yridine herbicide registered for use on a variety of food and feed crops in the U.S. for the postemergen ce control of broadleaf weed s , particularl y thistles and clover. The end use product that IR - 4 proposed for use on these commodities is Stinger ® Herbicide ( EPA Reg. No. 62719 - 73 ) , which is a 3 lb acid equivalent (ae)/gal emulsifiable concentrate (EC) formulation of the monoethanolamine salt of clopy ralid. The toxicology

database for clopy

ralid is considered to be complete for characterizing hazard and assessing human health risk. Toxicity was observed in the rat and dog after chronic exposure, and the mouse after subchronic and chroni c exposure, but consistent target organs were not identified . In dogs, reductions in red blood cell parameters, increased liver weight , and vacuolated adrenal cortical cells were observed, with skin lesions and clinical chemistry changes at the highest do se. In rats, stomach lesions were observed at the LOAEL , and decreased body weight was observed at the high dose. In m ic e , the only observed effects were decreased body weight and weight gain. No effects were seen in a rabbit 21 - day dermal study . The available studies did not indicate any potential for neurotoxicity , immunotoxicity, or reproductive toxicity , and there is no evidence of increased qualitative or quantitative susceptibility

of fetuses or offspring in developmental and reproduction studies . Additionally , the e xposure estimates are based on conservative, health - protective assumptions. Therefore, HED has reduced the required 10x F ood Q uality P rotection A ct (FQPA) Safety Factor to 1x. Clopy ralid i s classified as “not likely to be carcinogenic to humans,” based on the lack of treatment - related tumors in the rat and mouse carcinogenicity studies and negative results of the genotoxicity

assays. HED selected endpoints for assessment of human health ri sk f o r chronic dietary

exposure, occupational and residential inhalation exposure, and residential incidental oral exposure, based on the proposed and existing use patterns and the submitted toxicology studies. Acute dietary risk was not evaluated because an appropriate endpoint (toxicity from a single dose) was not identified. Chronic dietary risk (food and drinking water) was evaluated based on gastric lesions in the rat chronic toxicity/carcinogenicity study . Short - term incidental oral exposure of young children was evaluated based on decreased maternal body weight gain in the rat developmental toxicity study . Dermal exposure w as not evaluated because of the lack of toxicity via the dermal route. Inhalation exposure was assessed using endpoints and doses obtained from oral studies and route - to - route extrapolation. Short - term inhalation exposure was evaluated based on decreased maternal body weight gain in the rat developmental toxicity study. Intermediate - termClopy

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Page 5 of 51 inhalation exposure was evaluated based on gastric lesions observed b y six months’ exposure in the rat chronic toxicity

/carcinogenicity study , which is considered to be protective for potential portal - of - entry effects to the lungs . The nature of the residue in plants and livestock is adequat el y understood based on acceptable metabolism studies in cabbage, grass, barley , wheat , goat s, and poultry . In plants , the major residue was the parent compound. Inlivestock, the major residues are clopy ralid and its gl ycine conjugate. No changes to the livestock tolerances are being made as a result of th e new uses . In the environment, clopyralid has a low rate of soil sorption, is stable to photoly sis and anaerobic metabolism , and is moderatel y stable to aerobic metabolism. Because of its stability and high mobility , clopy

ralid is likely

to persist in groundwater. Based on the available information, OPP has determined that the residue of concern in drinking water is the parent compound only . The submitted residue data are adequate to support the proposed use s . The data includ e adequate field trial studies , processing studies , and storage stability data . The data support a tolerance at the limit of quantitation (LOQ ) of 0.05 ppm for apple fruit. For the other commodities in the petition, the tol erances are being translated from other commodities with established tolerances. There is no acute dietary

endpoint for clopy

ralid and clopy

ralid is c lassified as “ n ot likely to be carcinogenic to humans . ” As a result, an acute dietary exposure assessment was not conducted for the chemical , and there i s no cancer risk . The chronic dietary exposure assessment is highl y conservative with regard to protecting human health. The assessment is based on toleran ce - level residues for all commodities and the assumption that 100% of all commodities with tolerances will be treated (i.e., 100% crop treated). Modeled estimates of clopy ralid residues in drinking water have been incorporated into the anal ys es. The comb ined dietary risk estimates from exposure to residues of clopy ralid in food and drinking water are not of concern for the U.S. population or any

of the population sub groups. The general U.S. population uses 9.3% of the chronic population - adjusted dose (cP AD). The population subgroup Children 1 - 2 years old is estimated to have the highest dietary exposure to clopy

ralid. This subgroup uses 25% of the cPAD. Because such conservative assumptions were made in the assessment, HED is confident that the chronic dietary

exposure assessment do es not underestimate risk to the general U.S. population or any

population subgroup or life stage . Although no new residential uses are be ing proposed, s everal clop yralid f ormulations are registered for weed control on lawns, turf, and ornamentals in residential and public areas. For the purpose of conducting an aggregate risk assessment, a previous residential exposure assessment was updated to incorporate the revisions to the Standard Operating Procedures for Residential Exposure Assessment (R esidential SOPs , 2012 ). Scenarios assessed include short term inhalation exposure for residential handlers and post - application oral exposure for children playing on treated lawns. All residential handler and post - application scenarios resulted in estimated MOEs ≥100 and are not of concern. The chronic aggregate risk estimate s are equivalent to the corresponding dietary (food plus water) risk estimate s, which are not of concern. Short - term aggregate assessments wereClopy

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Page 6 of 51 performed for adults and children. For the adult short - term aggregate risk assessment, the residential handler inhalation exposure estimate was aggregated with the chronic dietary exposure estimate . For children, the incidental oral exposure estimate was aggregated with the chronic dietary

exposure estimate. The short - term aggregate risk estimates were not of concern (MOEs ≥100) . No specific concerns with respect to environmental justice were identified for clopy ralid. No chemical - specific handler exposure data were submitted in support of this registration. It is HED policy

to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical - specific data, include th e Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the AHETF database, or other registrant submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. Default assumptions established by the HED ExpoSAC were used for parameters such as body weight , acres treated , and amount handled per day . Occupational handler assessments are based onl y on inhalation exposures , becaus e clopy ralid does not cause s ys temi c toxicity via the dermal route . The short - term handler inhalation risk estimate s are not of concern at the baseline level of p ersonal p rotective e quipment (PPE) , which consist s of l ong - sleeved shirt , long pants , socks and shoes . Further, for intermediate - term exposure, MOEs were ≥ 180 ,000 assuming baseline PPE . As stated above, the label amendments that expand the uses of clop yr alid on mustard greens and rapeseed commodities to the entire crop subgroups are being proposed witho ut any change s to the registered use patterns. As a result, a separate occupational exposure assessment is not required to support the proposed label amendment s . Also a separate exposure assessment is not required for the use of Stinger ® Herbicide on tef f because the SLN registration is being proposed without any

change to the use pattern for wheat. Dermal p ost - application exposure is not of concern becau se there is no hazard associated with exposure to clopy

ralid via the dermal route. Although there i s potential for post - application inhalation exposure, a quantitative post - application inhalation exposure assessment was not performed. However, an inhalation exposure assessment was performed for occupational handlers and the risk estimates w ere not of c oncern . This exposure is likely to result in higher risk than post - application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of occupational post - application inhalation exposure scenarios. The submitted parent label for Stinger® Herbicide is for a monoethanolamine salt of clopy ralid acid and has a restricted entry interval (REI) of 12 hours , which is appropriate. This risk assessment is based, in part, o n data from studies in which adult human subjects were intentionally

exposed to a pesticide or other chemical. These studies are compliant with applicable ethics requirements . Additional information concerning human studies is provided in Appendix C.Clopy

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Page 7 of 51 **2.0 HED**  **Recommendations** HED recommends i n favor of granting the requested registrations and establishing the tolerances listed in Table 2.2.3. **2.1 Data Deficiencies/Conditions of Registration**  None **2.2 Tolerance Considerations**  **2.2.1 Enforcement Analytical Method**  Plant Commodity

Enforcement Method The Pesticide Anal ytical Manual (PAM) Vol. II lists a GC/ECD method for determining clopy ralid residues in/on plant commodities (Method Ior Method ACR 75.6). For this method, residues are extracted with dilute NaOH (0.25% or 0.1%) and filtered. The extract is then acidified and salinized, and residues are partitioned into ethyl ether. Residues are then methylated using diazomethane and cleaned up on an activated alumina column. Residues are then determined b y GC/ECD using external standards. The reported LO Qs are 0.5 ppm for grains and 2.0 ppm for green forage . The data gathering method used in the apple field trials is almost identical to the analy tical enforcement method, the only difference being the typ e of alumina column used for sample clean - up. The method was adequatel y validated in conjunction with analy sis of field trial samples. The method LOQ and LOD are 0.05 ppm and 0.02 ppm, respectivel y. Livestock Commodity

Enforcement Method The Pesticide Anal ytical Manual (PAM) Vol. II list s a GC/ECD method for the determination of clopy ralid residues in animal commodities (Method II or Method ACR 86.1). Method II is essentially

the same as Method I , except that aqueous potassium hydroxide is used for extraction instead of sodium hydroxide. The reported detection limits are 0.1 ppm for milk and eggs, and 0.2 ppm for liver. Multiresidue Methods The FDA Pestrak database (PAM Vol. I, Appendix dated 11/6/90) indicates that the existing FDA multiresidue methods are not likel y to recover clop y ralid. Clopy

ralid does appear to be adequatel y recovered b y the “QuEChERS” multiresidue method (http://www.quechers.com). **2.2.2 International Harmonization**  There are no Codex or Mexican maximum residue limits (MRL s) for residues of clopy ralid in/on the proposed commodities. However, there is a Canadian MRL for residues of clopy ralid in or on flax at 0.2 ppm. This MRLdoes not harmonize with the existing U.S. tolerance of 3.0 ppmClopy

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Page 8 of 51 for flax seed (or the proposed tolerance of 3.0 ppm for the Rapeseed subgr oup). Based on the differing use patterns and the available residue data, the recommended tolerance for the Rape seed subgroup cannot be harmonized with the Canadian MRL on flax. **2.2.3 Recommended Tolerances**  Table 2.2.3 provides a summary of the proposed tolerances, the recommended tolerances, and the correct commodity

definitions . **Table 2.2.3**  **. Tolerance Summary for Clopyralid** Commodity as Proposed by Registrant Proposed Tolerance (ppm) Recom mended Tolerance (ppm) Comments

( **correct commodity definition**  ) **40 CFR §180.431(a)** Apple 0.05 0.05 Adequate field trial data are available. Leafy Brassica greens subgroup 5B 5.0 5.0 B ased on the existing tolerance for mustard greens, the representative commodity of the Leafy Brassica greens subgroup ( **Brassica, leafy greens, subgroup 5B** ) Rapeseed subgroup 20A, except Gold of pleasure, seed 3.0 3.0 B ased on the existing tolerance of 3.0 ppm for rapeseed, canola, and flax seed ( **Rapeseed, subgroup 20A, except gold of pleasure**  ) Rapeseed subgroup 20A, except Gold of pleasure, meal 6.0 6.0 B ased on the existing tolerance of 6.0 ppm for canola meal and flax meal ( **Rapeseed, meal** ) Rapeseed subgroup 20A, except Gold of pleasure, forage 3.0 None Tolerance is n ot needed because rapeseed forage is not a significant livestock feed item. Teff, forage 9.0 9.0 Based on wheat forage (9.0 ppm) Teff, grain 3.0 3.0 Based on wheat and barley grain (3.0 ppm) Teff, hay 9.0 9.0 Based on barley hay (9.0 ppm) Teff, straw 9.0 9.0 Based on wheat and barley straw (9.0 ppm) **2.2.4 Revisions to Petitioned**  **- For Tolerances**  None **2.3 Label Recommendations**  The submitted supplemental labels for apples, teff, Brassica leafy greens, and the Rapeseed subgroup are adequate. HED has no label recommendations.Clopy

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Page 9 of 51 **3.0 In**  **troduction 3.1**  **Chemical Identity Table**  **3. 1.**  **Clopyralid Nomenclature** Compound

Common N ame Clopyralid, monoethanolamine salt Company E xperimental N ame Dowco 290 IUPAC N ame 3,6 - dichloropyridine - 2 - carboxylic acid, monoethanolamine salt CAS N ame 3,6 - dichloro - 2 -pyridinecarboxylic acid, monoethanolamine salt CAS Registry Number 1702 - 17 - 6 (acid) 57754 - 85 - 5 (monoethanolamine salt) End -use P roduct s (EUP) Stinger® H erbicide ( EPA Reg. No. 62719 - 73) , 3 lb ae/gal EC **3.2 Physical/Chemical Characteristics**  Clopy ralid has a relatively low octanol/water partition coefficient. The l og KOW value is - 1.81 at a pH of 5 ( K OW = 0.015 ). Based on th i s value, the chemical would not bioaccumulate to any great extent . Th e relatively low K OW value also de creases clop yr alid’s potential for dermal absorption. Clopy

ralid has a vapor pressure of 1. 0 x 10 - 5 mm Hg at 2 5 oC . As a result, there is the potential for inhalation exposure. See Appendix B for a table of clopy ralid ’s p hy sical and c hemical properties. **3.3 Pesticide Use Pattern**  A 3.0 lb ae/gal EC formulation of clopy ralid is currently

registered to Dow AgroSciences (Stinger ® ; EPA Reg. No. 62719 - 73) for control of postemergence weeds in : (1) mustard greens, (2) c anola (rapeseed) and crambe, and (3) barley , oats, and wheat. IR - 4 submitted supplemental labels for the Brassica leafy greens subgroup and the Rapeseed subgroup. The use directions on those supplemental labels are consistent with the use directions for the commodities from which the tolerances are being extended. IR - 4 also submitted a supplemental label for apples. Finally , IR - 4 submitted a FIFRA 24(c) SLN label for teff. The use directions are based on the use directions on the Stinger ® label for barley , oats, and wheat. The proposed use directions are summarized bel ow in Table 3.3. N Cl Cl O O O H NH 3 +Clopy

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Page 10 of 51 **Table 3. 3.**  **Summary of Directions for Use of Clopyralid** Applic. Timing, Type, and Equip. 1 Formulation [EPA Reg. No.] Applic.

Rate (lb ae/A) Max. No.

Applic. per Season Max.

Seasonal Applic. Rate (lb ae/A) PHI Use Directions and Limitations 2 **Apple** Apply to non -bearing (well established, 1 year or older) and bearing trees. Apply to actively growing weeds. Apply with ground equipment only. Stinger, 3.0 lb ae/gal EC [62719 - 73] 0.094 -

0. 25 1 0. 25 30 days Apply in a minimum of 10 gal/A . Do not use in Florida or in Nassau or Suffolk Counties, New York. Do not apply by aircraft. **Leafy Brassica Greens Subgroup 5**  **B 3**  Apply to actively growing weeds. Apply with ground equipment only. Stinger, 3.0 lb ae/gal EC [62719 - 73] 0.06 - 0.25 2 0.5 30 days Apply in a minimum of 10 gal/A, with a minimum RTI of 14 days. Do not apply by aircraft. **Rapeseed Subgroup 20A, Except Gold of Pleasure** Apply in the 2 - to 6 - leaf stage of crop growth. Apply to actively growing weeds. Apply with ground and aerial equipment only. Stinger, 3.0 lb ae/gal EC [62719 - 73] 0.113 -

0.25 1 0.25 7 days Use in the State of Oregon only. Apply in a minimum of 20 gal/A. Do not use with a surfactant. Apply with ground and aerial equipment only. **Teff** Apply when crop is from 3 - leaf stage up to early boot stage of growth . Stinger, 3.0 lb ae/gal EC [62719 - 73] 0.094 -

0.1 25 1 0. 1 25 Not Speci fied Do not harvest hay from treated grain fields . 4 1 Do not apply through any type of irrigation system. 2 The label for the 3 lb ae/gal EC contains the following rotational crop restrictions: barley, canola, cole crops, flax, gard en beets, grasses, corn (field, pop and sweet), oats, spinach, sugar beets, turnips and wheat may be planted at anytime following a treated crop. Depending on the amount of soil organic matter, rainfall and location (state), the plant -back intervals for all other crops range from 10.5 to 18 months. 3 For use and distribution only in the states of AZ, AR, CA, CO, DE, FL, GA, MD, MI, MO, NJ, NM, NY, NC, OH, OK, PA, SC, TX, VA and WI. Not for sale or distribution in Nassau and Suffolk Counties in New York State. 4 Do not permit lactating dairy animals or meat animals being finished for slaughter to forage or graze treated grain fields within one week after treatment . The PPE for applicators and other handlers on the registered Stinger® Herbicide label is baseline clothing (long - sleeved shirt, long pants, and shoes plus socks), chemical - resistant gloves made of any waterproof material, and protective eyewear.Clopy

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Page 11 of 51 **3.4 Anticipated Exposure Pathways**  The Registration Division requested that HED perform an assessment of human health risk to support the proposed new use s of clop yr alid . Humans could be exposed to clopy ralid residues through dietary

intake of apples, teff, Brassica leafy greens, rapeseed commodities , and drinking water. The proposed use also result s in the potential for occupational (handler/ post - application) exposures. **3.5 Consideration of Environmental Justice**  Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, “ Federal Actions to Address Environmental Justice in Minority Populations and 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 OPP policy , HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey s of Food Intake s by Individuals (CSFII) and are used in pest icide 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 region of the country . Additionally , OPP is able to assess dietary

exposure to sm aller, 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 resources 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**  **4.1 Toxicology Studies Available for Analysis**  **4.1.1 Sufficiency of studies/** **data** The toxicology

database for clopy

ralid is considered to be complete. Studies submitted include a 21 - day dermal toxicity study in the rabbit and the following oral studies: subchronic toxicity in the mou se, chronic toxicity in the dog, chronic toxicity /carcinogenicity in the rat, carcinogenicity in the mouse, prenatal toxicity in the rat and rabbit, reproductive toxicity in the rat, metabolism in the rat , and immunotoxicity in the rat . In addition, there is a complete battery of genotoxicity studies. S ubchronic studies for rat s and dog s are not available; however, requirements for these studies were satisfied b y the chronic studies.Clopy

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Page 12 of 51 Based on the toxicology

data requirements outlined in the recentl y revised 40 CFR Part 158, acute and subchronic neurotoxicity studies in the rat are required for food use chemicals. However, HED’s Hazard and Science Policy Council (HASPOC) concluded that these studies are not required for clop yralid, based on the lack of evidence of neurotoxicity in the available studies conducted with clopy ralid as well as with other structurall y related compounds. HASPOC also determined that a 28 - day inhalation toxicity study

in the rat (§870.3465) is not required, based on the low volatility, low acute inhalation toxicity, and selection of conservative, adequatel y protective points o f departure from oral studies. **4.2 Absorption, Distribution, Metabolism, & Elimination**  **(ADME)** Metabolism of clopy

ralid following oral dosing was evaluated in the rat. Clopy ralid was essentially

completely

absorbed (95 - 115% of administered dose, or AD) at both low (5 mg/kg/day) and high (150 mg/kg/day) doses. There were no significant dif ferences in metabolic disposition between males and females or dose groups. Excretion was primarily via the urine (91 - 113% AD at 72 hrs post - dosing, with 74 - 98% AD excreted within 6 - 12 hrs post - dosing), whether b y oral or intravenous dosing. Less than 4% of the excretion was via feces. Radioactivity

was not retained in tissues (<0.01% AD at 72 hrs post - dosing). Plasma pharmacokinetic parameters were not evaluated. There was no evidence of metabolism; only parent compound was identified in the urine and feces. **4.2.1 Dermal Absorption**  A dermal absorption study was not required or submitted for clopy ralid. However, a

bsorption appear s to be low, based on the lack of toxicity observed at the limit dose in the 21 - day rabbit dermal study . This is consistent with the low Kow identified for clop yr alid. **4.3 Toxicological Effects**  Clopy ralid is an herbicide of the py ridinoxy acid chemical group that is used to control broadleaf weeds. It is structurally

similar to plant auxins and acts as an “auxin imitator,” disrupting plant growth by

binding to auxin receptors. However, the mode of action for mammalian toxicity has not been characterized. Toxicity was observed in the rat and dog following chronic exposure, but consistent target organs were not identified. In a one - ye ar dog study , reductions in red blood cell parameters, incre ased liver weight (males), and vacuolated adrenal cortical cells (females) were reported. Skin lesions and clinical chemistry changes (decreased serum glucose, protein, albumin) were observed at the highest dose. In the rat, epithelial hy perplasia and th ickening of the limiting ridge of the stomach were observed at the LOAEL , and decreased body weight was observed at the highest dose. Only

decreased body weight/weight gain and food efficiency in males were observed in the mouse carcinogenicity study at d oses exceeding the limit dose. Subchronic data were available onl y for the mouse, where decreased body weight was observed in a 90 - day oral study in males and females at dietary levels exceeding the limit dose (1000 mg/kg/day). No sy stemic toxicity

or lo cal dermal irritation was observed in rabbits following dermal exposure toClopy

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Page 13 of 51 the limit dose for 21 day s. A rat immunotoxicity study showed no treatment - related effects on the immune sy stem , and immunotoxicity was also not observed in other studies. There was no indication of increased qualitative or quantitative pre - and/or postnatal susceptibility . No developmental toxicity was observed in the rat at doses that caused maternal mortality and decreased maternal body weight gain. Decreased fetal body weight and hydrocephalus were observed in the rabbit but only at a dose that caused significant maternal toxicity, including mortality , clinical signs of toxicity , decreased body weight gain , and gastric mucosal lesions. Reproductive toxicity was not observed in the rat, but mean pup weights (Day 28) were reduced , and relative liver weights were increased at doses that caused parental toxicity (decreased body weight/weight gain and food consumption; gastric lesions). There were no direct clinical or histopath ological indications of neurotoxicity in the available studies at doses up to or exceeding the limit dose. Hydrocephalus was observed in the young in the rabbit developmental study in the presence of significant maternal toxicity , including a high rate of mortality. However, no indications of neurotoxicity were observed in maternal animals at the same dose, in other species, or in studies on other structurally related chemicals. Therefore, a cute and subchronic neurotoxicity studies in the rat are not required based on lack of evidence o f neurotoxicity

for clopy ralid and related chemicals. Clopy ralid is classified as “not likely to be carcinogenic to humans.” No evidence o f carcinogenicity

was observed in rat and mouse 2 - ye ar bioassay s at doses exceedi ng the limit dose. No positive findings for mutagenicity or clastogenicity were observed in a battery of mutagenicity

studies ( in vitro and in vivo host mediated assay s in Salmonella and Saccharomyces , in vivo chromosomal aberrations, unscheduled DNA sy nthesis, and dominant lethal assay). Clopy ralid is rapidl y absorbed and excreted, predominantly as parent compound, and primaril y in the urine with very

low fecal excretion. It is not retained in tissues (see S ection 4.2, above). The acute toxicity

of clopy ralid is low (Toxicity

Category III or IV) via oral, inhalation and dermal exposure , and it is not a dermal irritant or sensitizer. However , in its acid form, clopy ralid is a severe eye irritant (Category I ) . **4.4 Safety factor for Infants and Children (FQPA Safety Factor)**  HED recommends reduction of the 10 x FQPA safety factor for protection of infants and children to 1 x . This recommendation is based on the following considerations: 1) the toxicity database is complete, with required studies either submitted or waived; 2) there is no evidence of increased qualitative or quantitative pre - and/or postnatal susceptibility in the developmental or 2 - generation reproduction toxicity studies ; 3) there is no evidence of neurotoxicity, and a developmental neurotoxicity study is not required; and 4) the e xposure assessments are based on conservative, health - protective assumptions that will not underestimate exposure and risk.Clopy

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Page 14 of 51 **4.4.1 Completeness**  **o f**  **the Toxico**  **logy Database** The database for clop yral id is considered to be adequate for FQPA assessment. Acceptable developmental toxicity

studies in the rat and rabbit and a two - generation reproduction study in the rat are available for FQPA assessment. As previously discussed (Section 4. 1.1 ), the required acute and subchronic neurotoxicity and 28 - day

inhalation studies in the rat have been waived . Therefore , no additional uncertainty factors are needed to account for missing data . **4.4.2 Evidence of N**  **eur otoxicity**  There are no direct clinical or micropathological indications of neurotoxicity in the available subchronic and chronic studies in multiple species. Hydrocephalus was observed in the young in the rabbit developmental study in the presence of significant maternal toxicity , including mortality . However, no indications of neurotoxicity were observed in maternal animals at the same dose, in other species, or in structurall y related chemicals. Therefore, acute and subchronic neurotoxicity

studies in the rat are not required based on lack of evidence o f neurotoxicity for clopy ralid and related chemicals. **4.4.3 Evidence**  **o f Sensitivity/Su**  **sceptibility in the Developing o r Young Animal**  There was no evidence of increased qualitative or quantitative sens itivity /susceptibility

in the developing or young animal. In the rat developmental toxicity study , no developmental toxicity was observed at a maternally toxic dose. In the rat two - generation reproductive toxicity study , decreased pup weight (postnatal d ay 28) and increased relative liver weights were observed at the parental LOAEL. As noted above, hydrocephalus and decreased mean fetal weight were observed in the rabbit developmental study , but at a dose that also caused significant maternal toxicity, i ncluding mortality : the fetal findings were therefore considered to be comparable to those of adult animals . **4.4.4 Residual**  **Uncertainty in the Exposure Datab ase**  There are no residual uncertainties with regard to dietary and residential exposure. The dietary exposure assessment is based on conservative, health - protective assumptions that ensure that exposures to clopy

ralid are not underestimated. These assumptions include tolerance - level residues and 100% crop treated estimates for all commodities. A ctual exposures and risk estimates from the use of clopy ralid will likely

be lower. Furthermore, conservative, upper bound assumptions were used to determine exposure through drinking water and residential sources, such that these exposures have not been underestimated. **4.5 Toxicity Endpoint and Point of**  **D eparture Selections**  **4.5.1 Dose**  **- Response Assessment**  For acute oral exposure, an endpoint resulting from a single exposure was not identified . As a result, an aRfD was not determined. The finding of hydrocephalus in the young in the rabbit developmental study

was not considered to be an appropriate endpoint because it was observedClopy

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Page 15 of 51 only at the highest dose tested in the presence of severe maternal toxicity, including a high rate of mortality . For chronic dietary

exposure, the NOAEL of 15 mg/kg/day from the rat chronic toxicity /carcino genicity study was selected, based on increased epithelial hy perplasia and thickening of the limiting ridge of the stomach in both sexes at the LOAEL of 15 0 mg/kg/day. The study was selected because it was of the appropriate route and duration. This histological finding was considered to be the result of direct irritation of the stomach by the test material , and it provided the most sensitive NOAEL for thi s risk assessment scenario. For incidental oral short - term exposure, the maternal toxicity NOAE L of 75 mg/kg/day from the rat developmental toxicity study was selected based on mortality , decreased maternal body weight gain , and decreased food consumption at the LOAEL of 250 mg/kg/day . This study was selected because it was of the appropriate duration and route, and it provided the most sensitive NOAEL. For short - and intermediate - term dermal exposure, an appropriate endpoint was not identifie d. No sy stemic toxicity

was observed in a 21 - day rabbit dermal study

which tested up to the limit dose of 1000 mg/kg/day . Developmental toxicity in the rabbit was onl y seen in the presence of significant maternal toxicity (maternal/developmental NOAEL = 250 mg/kg/day) , and in the rat developmental study was not observed up to a maternall y toxic dose (250 mg/kg/day). In the rat reproduction study, fetal body and liver weight effects were seen at doses causing decreased maternal body weight. Therefore, no pre - and/or postnatal toxicity would be expected at dermal doses up to and including the limit dose. A 28 - day inhalation toxicity study is not available or required ; therefore , oral studies were considered for use with route - to - route extrapolation for i nhalation exposure assessment. For short - term inhalation exposure, the maternal toxicity NOAEL of 75 mg/kg/day from the rat developmental toxicity

study was selected based on mortality , decreased maternal body weight gain , and decreased food consumption at the L OAELof 250 mg/kg/day . This study was selected because it was of the appropriate duration and route, and it provided the most sensitive NOAEL. This endpoint is protective of pre - and/or postnatal toxicity because developmental toxicity in the rabb it was onl y seen in the presence of significant maternal toxicity (maternal/developmental NOAEL = 250 mg/kg/day) , and developmental toxicity in the rat was not observed up to a maternall y toxic dose. For intermediate - term inhalation exposure, the NOAEL of 15 mg/kg/day from the rat dietary chronic toxicity

/carcinogenicity

study was selected based on increased epithelial hy perplasia and thickening of the limiting ridge of the stomach in both sexes at the L OAEL of 150 mg/kg/day . Although it is of chronic duration, it was selected to be protective of gastric irritation that m ight result from oral exposure of intermediate duration becau se it was observed at the interim sacrifices (6 and 12 - month) in some animals. As such, it is considered to be a conservative endpoint for this exposure scenario.Clopy

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Page 16 of 51 **4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment**  HED has considered oral, dermal , and inhalation routes of exposure in its assessment of clopy ralid. It is appropriate to combine routes of exposure when such exposures are expected to co - occur and result in the same toxicological effects. For aggregate assessments, adults are onl y exposed via the inhalation and oral (food + water) routes, and these exposures should be combined and compared t o the short - term inhalation endpoint and dose. For children, the onl y relevant exposures consist of postapplication oral exposure to residues on lawns and oral dietary (food + water) exposure . These exposures should be combined and compared to the short - term incidental oral endpoint and dose. F or occupational workers, onl y inhalation exposure and risk are being assessed. **4.5.3 Cancer Classification and Risk Assessment Recommendation**  In accordance with the EPA’s Final Guidelines for Carcinogen Risk Assessment (March, 2005), clopy ralid is classified as “not likely to be carcinogenic to humans.” There was no evidence of treatment - related increases in tumor incidence in the 2 - year rat and mouse dietary studies. Both studies included a high dose that e xceeded the limit dose. Genotoxicity studies were negative. **4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk**  **Assessment Table 4.5.4.1. Toxicological Doses and Endpoints for Clopyralid for Use in Dietary and Residential H**  **uman Health Risk Assessments.**  Exposure/ Scenario Point of

Departure Uncertainty/FQP

A Safety Factors Level of Concern

for Risk Assessment Study and Toxicological Effects Ac ute Dietary (All populations including infants and children) An appropriate endpoint for a single exposure was not identified. Chronic Dietary ( All populations including infants and children) NOAEL= 15 mg/kg/day UF A= 10X

UF H = 10X SF FQPA=1 cRfD=0.15

mg/kg/day cPAD=0.15 mg/kg/day 2 - Year Combined Chronic

Toxicity/Carcinogenicity (oral)

– rat LOAEL = 150 mg/kg/day, based on increased epithelial hyperplasia and thickening of the limiting ridge of the stomach in both sexes. Incidental Oral, Short term (1 - 30 days) NOAEL= 75 mg/kg/day UF A= 10X

UF H = 10X SF FQPA=1 Residential LOC

for MOE= 100 Developmental Toxicity (oral)

– rat

Maternal LOAEL = 250 mg/kg/day, based on decreased body weight gain and food consumption during GD 6 - 9. Dermal, Short - term (1 - 30 days) No dermal or systemic toxicity was observed at the limit dose (1000 mg/kg/day) in a rabbit 21 - day dermal toxicity study and there are no developmental or reproductive concerns. Inhalation, Short - term (1 - 30 days) Oral study NOAEL = 75 mg/kg/day (inhalation toxicity assumed to be equivalent to toxicity via the oral route) UF A= 10X

UF H = 10X SF FQPA=1 Residential LOC

for MOE = 100 Developmental Toxicity (oral)

– rat

Maternal LOAEL = 250 mg/kg/day, based on decreased body weight gain and food consumption during GD 6 - 9.Clopy

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Page 17 of 51 **Table 4.5.4.1. Toxicological Doses and Endpoints for Clopyralid for Use in Dietary and Residential H uman Health**  **Risk Assessments.** Exposure/ Scenario Point of

Departure Uncertainty/FQP

A Safety Factors Level of Concern

for Risk Assessment Study and Toxicological Effects Inhalation Intermediate term (1 - 6 months) Oral study

NOAEL= 15 mg/kg/day (inhalation toxicity assumed to be equivalent to toxicity via the oral route) UF A= 10X

UF H = 10X SF FQPA=1 Residential LOC

for MOE= 100 2 - Year Combined Chronic

Toxicity/Carcinogenicity (oral)

– rat LOAEL 150 mg/kg/day, based on increased epithelial hyperplasia and thickening of the limiting ridge of the stomach in both sexes. Cancer (all routes) “Not likely to be carcinogenic to humans . ” Cancer risk is not of concern. 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). SF FQPA = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. **Table 4.5.4.2. Summ ary of Toxicological Doses and Endpoints for Clopyralid for Use in**  **Occupational Hum an Health**  **Risk Assessments.** Exposure/ Scenario Point of Departure Uncertainty Factors Level of Concern

for Risk Assessment Study and Toxicological Effects Dermal, Short - and Intermediate - term (1 - 30 days and 1 - 6 mo nths, respectively) No dermal or systemic toxicity was observed at the limit dose (1000 mg/kg/day) in a 21 - day dermal toxicity study and there are no developmental or reproductive concerns. Inhalation, Short term (1 - 30 days) NOAEL = 75

mg/kg/day (inhalation toxicity assumed to be equivalent to toxicity via the oral route) UF A= 10X UF H = 10X Occupational

LOC for MOE = 100 Developmental Toxicity (oral)

– rat

Maternal LOAEL = 250 mg/kg/day, based on decreased body weight gain and food consumption during GD 6 - 9. Inhalation, Intermediate - term (1 - 6 months) NOAEL = 15

mg/kg/day (inhalation toxicity assumed to be equivalent to toxicity via the oral route) UF A = 10X UF H = 10X Occupational

LOC for MOE = 100 2 - Year Combined Chronic

Toxicity/Carcinogenicity (oral)

– rat LOAEL = 150 mg/kg/day, based on increased epithelial hyperplasia and thickening of the limiting ridge of the stomach in both sexes. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = e xtrapolati on from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. N/A = not applicable . **5.0 Dietary Exposure and Risk Assessment**  **5.1 Metabolite/Degradate Residue Profile** Clopy

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Page 18 of 51 **5.1.1 Summary of Plant and Animal Metabolism Studies**  The nature of the residue in plants is adequatel y understood based on acceptable cabbage, grass, barley , and wheat metabolism studies. In each of these studies, the major 14 C - residue was determined to be onl y parent compound. HED concludes that the residue of concern in plants for purposes of this petition is clopy ralid. Although the available crop metabo lism data all indicate that the parent compound is the only major residue, the data are from onl y two dissimilar crops (leafy vegetable and cereal grain) . Addi tional metabolism studies m ight be required in the future should the petitioner request the esta blishment of clopy

ralid tolerances for additional crops. The nature of the residue in livestock commodities is adequatel y understood based on acceptable goat and poultry metabolism studies. Inlivestock, the major residues are the parent clopy ralid and it s gl ycine conjugate (3,6 - DCPA - gl yc ine). **5.1.2 Summary of Environmental Degradation**  In the environment, clopyralid has a low rate of soil sorption, is stable to photoly sis and anaerobic metabolism , and is moderatel y stable to aerobic metabolism. Because of its stability and high mobility , clopy

ralid is likely

to persist in groundwater. Based on the available information, OPP has determined that the residue of concern in drinking water is the parent compound only . **5.1.3 Comparison of Metabolic Pathways**  Data depicting the metabolism of clopy ralid in plants and animals have been submitted to the Agency . In rats, there was no evidence of metabolism. Only parent compound was identified in the rat urine and feces. Clopy ralid was essentially

completely

abso rbed at both low and high doses (5 and 150 mg/kg/day , respectivel y). Excretion was primarily via the urine. Less than 4% of the excretion was via feces. Radioactivity was not retained in tissues (<0.01% AD at 72 hrs postdosing). Plant metabolism studies were performed on cabbage, grass, barley , and wheat . In all of these studies, the major residue was determined to be parent compound. Li vestock metabolism studies were performed on goat s and poultry . In livestock, the major resi dues are the parent clop yr alid and its gl ycine conjugate (3,6 - DCPA - gl ycine). Finall y, p arent clop yr alid is also the predominant compound found in drinking water. In effect, p arent clopy ralid is the predominant compound in rats, plants, livestock, and drinking water. In livestock, gl ycine conjugates of clop yr alid are also found. As a result, the primary metabolites and degradates to which humans would be exposed are accounted fo r in the rat metabolism study . **5.1.4 Residues of Concern Summary and Rati**  **onale** As stated above, the nature of the residue in plants is adequatel y understood for purposes of this petition based on acceptable cabbage, grass, barley , and wheat metabolism studies. In each of these studies, the major residue was determined to be o nly parent compound. HED concludes that the residue of concern in plants for purposes of this petition is clopy ralid. Inlivestock, the major residues are the parent clop yralid as well as its glycine conjugate (3,6 - DCPA - gl ycine). In the environment, clo py

ralid has a low rate of soil sorption, is stable to photoly sis and anaerobic metabolism , and is moderatel y stable to aerobic metabolism. Because of its stability and highClopy

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Page 19 of 51 mobility, clop yr alid is likely to persist in groundwater. Based on the available information, OPP has determined that the residue of concern in drinking water is the parent compound only . **Table 5.1 .**  **Summ ary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance**  **Expression** Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants Primary Crop Clopyralid Clopyralid

Rotational Crop Clopyralid Clopyralid Livestock Ruminant Clopyralid + Glycine Conjugate Clopyralid

Poultry Clopyralid + Glycine Conjugate Clopyralid Drinking Water Clopyralid Not Applicable **5 .2**  **Food Residue**  **Profile** The only study that IR - 4 submitted in support of the current tolerance petition was a combined field trial/processing study for apples. For the other commodities, IR - 4 is proposing that currentl y established tolerances be extended to the proposed commodities. As a result, no new field trial data were submitted for the Brassica leafy greens subgroup, the R apeseed subgroup, or teff. The submitted apple field trial data are adequate and support the proposed use. IR - 4 performed an adequate number of trials and they were performed in the recommended EPA growing zones. The application rate was 1x the maximum proposed rate, and the samples were collected at the proposed PHI. Residues of clopy ralid in/on each commodity were determined using an adequate GC/ECD method, and the duration and conditions of sample storage are supported b y the available storage stability data. The available field trial data support an LOQ tolerance of 0.05 ppm for apple fruit. Table 5.2 provides a summary of the apple field trial data. **Table 5.2. Summary of Residue Data from Crop Field Trials with Clopyralid**  **Commodity Total Applic.** 

**Rate 2**  **(lb a e** **/A) PHI** 

**(days) Residue Levels (ppm)**  **1**

**n Min.**  **Max. HAFT**  **3 Median**  **Mean Std.**  **Dev.** Apple Fruit 0.244

–0.275 28 - 30 25 <0.05 < 0.05 < 0.05 < 0.05 < 0.05 NA4
1 These values represent residues of clopyralid 2 One foliar application of Stinger Herbicide at approximately 0.25 lb a e /A was made. 3 HAFT = Highest Average Field Trial. 4NA = Not applicable In the apple processing study , no detectable residues were found in the samples of apple fruit, apple juice, or wet apple pomace. Because of phytotoxicity concerns, IR - 4 did not perform an exaggerated rate study. No residues were found in the processed commodities; which indicates that if concentration did occur, it was not to a considerable extent.Clopy

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Page 20 of 51 **5.3 Water Residue Profile**  The estimated drinking water concentrations (EDWCs) used in the dietary risk assessment were provided b y the Environmental Fate and Effects Division (EFED) in the following m emorandum: “ Tier I Drinking Water Assessment for Proposed New Use of Clopyralid on Apple, L eafy

Brassica Greens Subgroup 5B, and Rapeseed Subgroup 20A, except Camelina (Gold of Pleasure) ” (D 391398 , W. Shaughness y, 12/19/2011) and incorporated directl y into the dietary assessment. Water residues were incorporated in the DEEM - FCID into the food categories “water, direct, all sources” and “water, indirect, all sources.” A modeled upper - bound estimate of the clop yr alid concentration in surface water (11.9 ppb) from the FQPA Index Reservoir Screening Tool (FIRST) Model was used for the assessment (Table 5.3). This estimate is greater than that for groundwater from the Screening Concentration in Ground Water (SCIGROW) Model. The same value was used in the p revious dietary exposure assessment. The drinking water models and their descriptions are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/ . **Table 5.3**  . **Maximum Tier 1**  **Estimated Drinking Water Concentrations** Drinking Water Source Model Used and Rate EDWC (ppb) Groundwater NAWQA (Oregon) 0.2588 Surface Water (Acute) FIRST (non - food crop, one application per year @ 0.5 lb ai/A) 45 **Surface Water (Chronic)**  FIRST (non - food crop, one application per year @ 0.5 lb ai/A) **11.9**
**5.4 Dietary Risk Assessment**  **5.4.1 Description of Residue Data Used in Dietary Assessment**  There is no acute dietary

endpoint for clopy

ralid. As a result, an acute dietary exposure assessment was not conducted for the chemical. A chronic dietary (food + drinking water) exposure and risk assessment was conducted for clopy ralid using the Dietary

Exposure Evaluation Model DEEM - FCIDTM, Version 2.03 which uses food consumption data from the U.S. Department of Agriculture’s Continuing Survey s of Food Intakes by Individuals (CSFII) from 1994 - 1996 and 1998. The assessment is highly conservative with regard to protecting human health. The assessment is based on tolerance - level residues for all commodities. DEEM Version 7.81 default proc essing factors were used for all processed commodities for which they were available. Modeled estimates of clop yralid residues in drinking water have been incorporated into the analy ses. Because such conservative assumptions were made in the assessment, the resulting exposure and risk estimates are considered to be conservative as well. HED is confident that the chronic dietary exposure assessment significantly overestimate s risk to the general U.S. population an d its various population subgroup s .Clopy

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Page 21 of 51 Clopy ralid is c lassified as “n ot likely to be carcinogenic to humans . ” As a result, cancer risk is not an issue for this chemi c al . **5.4.2 Percent Crop Treated Used in Dietary Assessment**  The chronic dietary

exposure assessment w as based on the assumption that 100% of all commodities with clopy

ralid tolerances will be treated. **5.4.3 Acute Dietary Risk Assessment**  An acute dietary

endpoint was not selected for clopy ralid. As a result, an acute dietary exposure assessment was not performed. **5.4.4 Chronic Dietary Risk Assessment**  Chronic risk estimates are below HED’s level of concern for the general U.S. population and all population subgroups. The U.S. population uses 9.3% of the cPAD. The population subgroup Children 1 - 2 years old ha s the highest estimated dietary exposure to clopy

ralid. This subgroup uses 25% of the cPAD. Generally , HED is concerned about dietary risk when the exposure esti mate exceeds 100% of the PAD. The combined dietary risk from exposure to residues of clopy ralid in food and drinking water are not of concern for the general U.S. population or any of the population sub groups. The chronic dietary risk estimates are given in Table 5.4.6. **5.4.5 Cancer Dietary Risk Assessment**  Clopy ralid is c lassified as “n ot likely to be carcinogenic to humans . ” As a result, cancer risk is not an issue for clop yr alid . **5.4.6 Summary Table**  Table 5. 4. 6. Summary of the Combined Dietary (Food + Drinking Water) Exposure and Risk Estimates

for Clopyralid Population Subgroup Ac ute Chronic Cancer Dietary Exposure (mg/kg/day) %

aPAD Dietary Exposure

(mg/kg/day) % cPAD Dietary Exposure (mg/kg/day) Risk General U.S. Population NA NA 0.013895 9.3 N/A N/A All Infants (< 1 year old) 0.013726 9.2 **Children 1 -**  **2 years old** ***** **0.03 7039**  **2 5**  Children 3 - 5 years old 0.033869 23 Children 6 - 12 years old 0.022590 15 Youth 13 - 19 years old 0.013383 8.9 Adults 20 - 49 years old 0.010847 7.2 Adults 50+ years old 0.009407 6.3 Females 13 - 49 years old 0.010170 6.8 * The most highly exposed population subgroupClopy

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Page 22 of 51 **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  No new r esidential use s for clopy ralid are being proposed at this time. However, for the purpose of performing an aggregate human health risk assessment, the previous residential exposure and risk estimate s ( D270507 , S. Wang, 9/26/2007) w ere updated in accordance with the Revised Standard Operating Procedures for Residential Exposure (R esidential SOPs , 2012 ). Several clop yr alid formulations are registered for weed control on residential lawns and/or professionall y maintained turf areas. HED previously review ed two clopy ralid formulations for residential exposures: Lawn Fertilizer Plus Confront ® Weed Control (EPA Reg. No. 62719 - 263), a granule plus fertilizer mix containing 0.18 % clopy ralid (0.12 % ae) and Lo ntrel ® Turf and Ornamental (EPA Reg. No. 62719 - 305 ), an EC formulation containing 40.9% clopy ralid (or 3.0 lb ae/gal). The granule has an application rate of 15.55 lbs of product per 4,500 sq. ft. (0.19 lb ae/A) and the EC has a maximum single application rate of 1 

### 1⁄3 pt./A (0.5 lb ae/A) on turf. **6.1 Resi**  **dential Handler Exposure and Risk**  Based on the use pattern on home lawns, homeowners would be exposed via dermal and inhalation routes for a short - term duration onl y. A quantitative short - term dermal residential handler exposure assessment was not conduc ted because of the lack of toxicity via the dermal route. The estimated short - term inhalation handler MOEs ranged from 34 0,000 to 2 4 , 0 00,000 . A ll residential handler scenarios resulted in estimated MOEs greater than 100, with no risks of concern (Table 6 .1 ). **Table 6.1**  **. Summ ary of Residential Handler Exposure and Risk Estimates for Clopyralid**  **1 Exposure**  **Scenario Appl**  **ication**

**R ate**  **2 Area Treated** 

**or Gallons Used/Day)**  **3 Unit Exp.** 

**(m g/lb ae)**  **3 Short**  **- term**  **Inhalation**

**Dose (**  **m g/kg/day)**  **4 MOE**  **5** Granule: Applied with push - type spreader 0.19 lb ae/A 0.5 A 0.0026 3.1 x10 - 6 24 ,000,000 EC: Mixing and applying spray with hose - end sprayer 0.5 lb ae/A 0.5 A 0.022 6.9 x10 - 5 1 , 1 00,000 EC: Mixing and applying spray with back-pack sprayer 0.025 lb ae/gal 5 Gallons 0.14 2.2 x10 - 4 34 0,000 EC: Mixing and applying with manually pressurized handwand sprayer 0.025 lb ae/gal 5 Gallons 0.018 2.8 x10 - 5 2 , 7 00,000 1. The previous estimate (S. Wang, D270507, 9/26/2007) was recalculated using unit exposures and area treated from the revised Residential SOP (2012). 2. Application rate is expressed either in lb ae/A or in lb ae/gal. The EC formulation (Lontrel Turf and Ornamental, (EPA Reg. No. 62719 - 305) recommends a minimum spray volume of 20 gal/A. Therefore, for back-pac k and handwand sprayers, the application rate was calculated in lb ae/gal (0.5 lb ae/A/20 gal=0.025 lb ae/gal). 3. Area treated/A or spray vol. used/day assumptions are from the Lawn and Turf, Residential SOP (2012). 4. Inhalation Dose (mg/kg/day) = [A ppl. Rate (lb a e /A or lb a e /gal) * Area Treated/day (acres or spray v olume * Inhal. Unit Exp. ( mg/lb a e ) * Inhalation Absorption (100%)] / b ody wt (80 kg). 5. Short - term

Inhalation MOE = Short - term NOAEL (75 mg/kg/day) / Inhalation Dose (mg/kg/day).Clopy

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Page 23 of 51 **6.2 Residential**  **Post -**  **application Exposure**  The only short - term residential post - application exposure quantitativel y assessed was for children playing on treated lawns , and in the absence of a dermal endpoint, only incidental oral exposure was included in the assessment. There is a potential for post - application inhalation exposure to both adults and children following applications to lawns. However, b ased on the Agency ’ s current practices, a quantitative residential postapplication inhalation exposure a ssessment was not performed for clop yr alid primarily because it has low inhalation toxicity and is applied as a soil directed spray to control broadleaf weeds. However, volatilization of pesticides may be a potential source of postapplication inhalation e xposure to individuals nearb y to agricultural 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. 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 proce dures to identify the need for and, subsequently , the way to incorporate postapplication 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 postappli cation inhalation exposure assessment for clop yr alid. Provided in Table 6.2 , below , are risk estimates associated with i ncidental oral post - application exposure (i.e., hand to mouth, object to mouth, and soil and granule ingestion) for children following use of clopy

ralid granules and liquids on recreational and home lawns. All MOEs range from 10,000 to 4 , 6 00,000 , and are not of concern. **Table: 6. 2.**  **Summ ary of Children’s**  **Post -**  **application Exposure and Risk Estim**  **ates for Clopyralid. 1**  **Form ulation**  **Type Exposure** 

**Scenario Appl**  **ication R**  **ate lb/A**  **E/A Short**  **- term**  **incidental oral**

**Dose (m**  **g/kg/day) 2**  **MOE 3**  EC Hand - to - mo uth 0.5 0.00745 10,000

Objects - to - mo uth 0.5 0.00023 330,000 Soil ingestion 0.5 0.000016 4,600,000 Granule Hand - to - mo uth 0.19 0.00028 270,000

Objects - to - mo uth 0.19 0.00009 860,000 Granule ingestion (episodic) - - Not applicable **4** 1. Revised estimates based on new Residential SOP for Exposure (2012). Original estimates: D270507, S. Wang, 9/26/2007 2 . Oral doses were calculated based on new Residential SOP for Exposure (2012). 3. Short - term

incidental oral MOE = NOAEL 75 ( mg/kg/day) / oral dose (mg/kg/day). 4. Granule ingestion is viewed as an acute oral exposure. As there is no acute dietary endpoint for clopyralid , exposure from granule ingestion was not assessed .Clopy

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Page 24 of 51 **6.3 Combined Residential Risk Estimates** HED believes that c ombining children’s post - application exposures, such as hand - to - mouth, object - to - mouth, and soil and granule ingestion resulting from EC and granule formulations of clopy ralid on home lawns , would be overl y conservative . Although these exposures m ight occur simultaneously

based on the use p attern of the pesticide and the behavior associated with the exposed population, the inputs used in calculating the risk estimates are conservative, and combining these conservative exposure and risk estimates would result in an unrealistic all y high estimate of exposure and risk. In the case of clopyralid on turf, the scenario with the highest oral exposure for children (hand - to - mouth, MOE=10,000) is considered to be protective of all children’s post - application exposure and risk, and should be used in the aggregate exposure and risk calculations. **6.4 Spray Drift**  Spray drift is alway s a potential source of exposure to residents in close proximity to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for clop yr alid . The Agency

has been working with the Spray Drift Task Force, EPA Regio nal Offices , State Lead Agencies for pesticide regulation , and other parties to develop the best spray drift management practices (see the Agency ’s Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a ch emical 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 submitted by

the Spray

Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy

on how to appropriatel y apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied b y air, orchard airblast , and ground hydraulic methods. After the p olicy

is in place, the Agency

m ay impose further refinements in spray drift management practices to reduce off - target drift with specific products with significant risks associated with drift. **7.0 Aggregate Exposure/Risk Characterization**  In accordance with th e FQPA, HED must consider and aggregate (add) pesticide exposures and risk estimate s from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risk estimate s themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. **7.1 Acute Aggregate Risk**  **Estim ates**  Acute aggregate risk result s from exposure to residues in food and drinking water alone. An acute dietary

endpoint was not selected for clopy ralid. As a result, an acute aggregate risk assessment was not performed.Clopy

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Page 25 of 51 **7.2 Short**  **- Term Aggregate Risk**  **Estimates** For a short - term aggregate risk assessment, exposures from the oral, dermal, and inhalation routes need to be added. A dermal endpoint was not selected for clop yralid; as a result, only exposures from the oral and inhalation routes need to be aggregated. The incidental oral and inhalation endpoints were selected from the same study : the rat developmental toxicity study . The toxicological effects were decreased body weight gain and food consumption during gestation day s 6 through 9. The LOC for short - term aggregate risk is an MOE of 100. A dults are exposed to clopy ralid through the residential handler inhalation route of exposure; however, they are not exposed through the incidental oral route. As a result, the residential handler inhalation exposure estimate onl y needs to be aggregated with the chronic dietary exposure estimate, which serves as a background exposure level. As the oral and inhalation endpoints are the same, the additive dose approach can be used for aggregating adult short - term exposures. The adult population subgroup with the highest exposure estimate is Adults 20 - 49 ; h owever, the general U.S. population has a higher dietary e xposure estimate. As a result, the dietary exposure estimate for the general U.S. population was used to determine aggregate risk . The residential exposure estimate that resulted in the lowest MOE was that for mixing/loading/ appl yi ng spray s with a backpa ck sprayer , so exposure from this scenario was combined with exposure from food and water. The resulting aggregate exposure estimate yi elds an MOE of 5 , 3 00 , which exceeds the LOC of 100 and is not of concern. Children are exposed to clopy ralid through the incidental oral route of exposure . The incidental oral exposure estimate was aggregated with the chronic dietary exposure estimate, which serves as a background exposure level. As the oral route is the only route of exposure , the additive dose approa ch can be used for aggregating children’s short - term exposures. The population subgroup with the highest exposure estimate is Children 1 - 2 , so this exposure was combined with the oral hand - to - mouth exposure estimate . The resulting aggregate risk estimate is an MOE of 1 , 7 00 , which exceeds the LOC of 100 and is not of concern. The aggregate risk estimates for adults and children are given in Table 7.2. As stated in the two preceding paragraphs, the MOEs given in the table are worst - case scenarios because the short term MOEs for any other population subgroups would be higher than those given in Table 7.2. In effect, short - term aggregate risk estimates are not of concern for any population subgroup. **Table 7.2. Residential**  **Short -**  **Term Aggregate Risk Calculations**  Population Short - Term Scenario

NOAEL mg/kg/day LOC 1 Average Food and

Water Exposure mg/kg/day Residential

Inhalation Exposure mg/kg/day Hand - to Mouth Exposure mg/kg/day Total

Exposure 2 mg/kg/day Aggregate

MOE (food, water, and residential) 3 Children 1 - 2 75 100 0.0 37039 NA 0.00745 0.0 44489 1,700 U.S. Population 75 100 0.0 1 3895 0.000 218 NA 0.0 10916 5,3 00

1. An UF of 100x was applied to account for interspecies extrapolation (10x) and intraspecies variation (10x). No additional uncertainty factors/safety factors are required. 2 . Total Exposure = Avg Food & Water Exposure + Residential Exposure 3 . Aggregate MOE = [NOAEL ( 75 mg/kg/day) / ( Avg Food & Water Exposure + Residential Exposure ) ]Clopy

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Page 26 of 51 **7.3 Intermediate**  **- Term Aggregate Risk Estimates**  There are no residential uses for clop yr alid that result in intermediate - term exposures. As a result, no intermediate - term aggre gate risk assessments were performed. **7. 4**  **Chronic Aggregate Risk Estimates**  There are no residential scenarios that result in long - term exposure. As a result, the chronic aggregate risk assessment includes l ong - term exposure to residues in food and drinking water only . The chronic dietary exposure anal ys is included both food and drinking water and, therefore, the chronic aggregate risk assessment is equivalent to the chronic dietary risk assessment discussed in Section 5.4.4, above. All risk estim ates are not of concern. **7. 5**  **Cancer Aggregate Risk Estimates**  Clopy ralid is c lassified as “n ot likely to be carcinogenic to humans . ” As a result, cancer risk is not an issue for the chemical . **8.0 Cumulative Exposure/Risk Characterization**  Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to c lopy ralid and any other substances , and c lopy ralid does not appear to produce a toxic metabolite produced b y other substances. For the purposes of this risk assessment , therefore, EPA has not assumed that c lopy ralid has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by

EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating e ffects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/ . **9.0 Occupational Exposure/Risk Characterization**  **9.1 Short**  **- /Intermediate**  **- Term**  **Handle r Risk**  **Occupational Handlers** The proposed use pattern for apples is expected to result in short - term (1 - 30 day s) exposure for most handlers. However, a s commercial applicators m ight appl y Stinger® Herbicide at several locations during the crop season, intermediate - term (1 - 6 months) handler exposure could occur , and therefore an intermediate - term assessment was also conducted. The label amendment to expand uses on individual crops to entire crop subgroups are b ased on registered use patterns. The proposed use pattern for the Brassica leafy greens subgroup is theClopy

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Page 27 of 51 same as the registered use pattern on mustard greens, and the proposed use pattern for the Rapeseed subgroup is the same as the registered use pattern for canola, crambe, and rapeseed. Similarly the request to register the use of clopy ralid on teff is based on the registered use pattern for wheat. Because these actions are being proposed without changes to the registered use patterns, separate occupati onal exposure assessments are not required. Potential Exposure Scenarios : E xposure scenarios describe the handler activities (mixer, loader and applicator) and ty

pe of application equipment. Based on the proposed use pattern , the following exposure scenarios were identified :

• mixing of EC formulation and loading diluted spray in groundboom sprayer • applying the spray using groundboom equipment • mixing, loading and applyingthe EC formulation using a back - pack sprayer for spot treatment. The regi strant has not submitted a chemical - specific exposure study to select unit exposures required for estimating handler exposure. HED ’s policy is to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate d ata in the absence of chemical - specific data, include the PHED Version 1.1, AHETF , Outdoor Residential Exposure Task Force (ORETF) database s , or other registrant - submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and are subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting handler exposure that are used in this assessment, known as “unit exposures , ” are outlined in the “Occupational Pesticide Handler Unit Exp osure Surrogate Reference Table” (http://www.epa.gov/opp00001/science/handler- exposure - table.pdf), which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at http://www.ep a.gov/pesticides/science/handler - exposure data.html. O ther inputs from ExpoSAC’s Policy No. 9.1 (Standard Values of Dail y Acres Treated) were use d to estimate handler exposure . Regardless of what the proposed label stipulates for PPE, HED ty pically conducts an initial assessment at the baseline level of personal protection consisting of a long - sleeve shirt, long pants, shoes and socks (no gloves and no respirator) . Additional PPE and mitigation measures, such as gloves, respirators, engineering, and administrative controls are added , if required, to obtain a risk level that does not exceed HED ’ s LOC. Table 9.1 summarizes the short - and inter mediate - term inhalation risk estimates for handlers resulting from the proposed use of Stinger® EC Herbicide on apples applied as broadcast and spot treatments. No dermal endpoint and dose w ere selected for clopy ralid because of the lack of dermal toxicity and , therefore , there i s no risk associated with exposure via the dermal route . At baseline PPE, the short - term (MOE ≥ 880 ,000 ) and intermediate - term (MOE ≥ 180 ,000) inhalation risk estimate s are significantl y above HED’s LOC of an MOE of 100, and are not of concern.Clopy

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Page 28 of 51 **Table 9.1**  **. Occupational Handler Inhalation**  **Exposure and Risk Estimates from Applying Clopyralid in Apple Orchards.**  **Handler S**  **cenario Used**  **for Apple 1**  **Application Rate**  **2 Area**  **Treated**

**or Gallons Used** **/day 3**  **Risk**

**Mitigation Level**  **4 Inhalation** 

**Unit Exp. (μg/lb a**  **e )**  **5 Inhalation**  **Dose**

**(m g/kg/day)**  **6 Short**  **- term** 

**Inhalation MOE**  **7 Interm.**  **- term** 

**Inhalation MOE**  **8** Mixing/Loading Liquids for Groundboom (AHETF) 0.25 lb ae/A 80 acres Baseline 0.219 5.5E - 5 1,400,000 270,000 Applying by Groundboom (AHETF) 0.25 lb ae/A 80 acres Baseline 0.34 8.5E - 5 880,000 180,000 Mixing/Loading/Applying by backpack Sprayer (MRID 44339801) (ground - directed - orchards) 0.025 lb ae/gal) 40 gals Baseline 2.58 3.2E - 5 2,300,000 470,000 1 . Occupational Pesticide Handler Unit Exposure Surrogate Reference Table used for each scenario is indicated in parenthesis. 2. The parent label (62719 - 73 recommends a minimum spray volume of 10 gal/A for ground application and therefore, for back-pack sprayer, application rate wa s calculated as 0.25 lb ae/A/10 gal/A = 0.025 lb ae/gal. 3. Area treated per day assumptions are from ExpoSAC (SOP No. 9.1). 4. Baseline PPE includes long - sleeved shirt, long pants, shoes and socks, and no respirator. 5 . From http://www.epa.gov/pesticides/science/h andler - exposure - data.html 6. Inhalation Dose (mg/kg/day) = [Appl. Rate (lb ae/A or lb ae/gal) * Area Treated/day (acres or spray volume) * Inhal. Unit Exp. (μg/lb ae/1000) * Inhalation Absorption (100%)] / Body Wt (80 kg). 7. Short - term

Inhalation MOE = Short - term NOAEL (75 mg/kg/day) / Inhalation Dose (mg/kg/day). 8. Intermediate - term Inhalation MOE = intermediate - term NOAEL (15 mg/kg/day) / Inhalation Dose (mg/kg/day).Clopy

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Page 29 of 51 **9 .2**  **Occupational/Commercial Post**  **- application**  **Risk** Post - application workers can be exposed to residues of clop yralid through dermal and inhalation routes when they

enter treated areas to perform post - application activities, such as thinning, irrigation, scouting, etc. As there is no s ys temic toxicity asso ciated with dermal exposure to clopy ralid , a dermal post - application exposure assessment was not conducted , and there i s no risk associated with post - application exposure via the dermal route . **9 .2.1**  **Post -**  **application Inhalation Exposure**  Based on the Agen cy ’ s current practices, a quantitative post - application inhalation exposure assessment i s not being performed for clop yr alid at this time primarily because of the low acute inhalation toxicity

(Toxicity Category IV ) of the end - use product formulation (M. H ashim, D291712, 10/16/2003) , low vapor pressure , and the low proposed use rate (0.25 lb ae/A). However, there are multiple potential sources of post - application inhalation exposure to individuals performing post - application activities in previously treated fields. These potential sources include volatilization of pesticides and re - suspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization o f pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available post - application inhalation exposure data generated b y the Agricultural Reentry Task Force and may , as appropriate, develop policies and procedures, to identify the need for and, subsequently , the way to incorporate occupational post - application inhalation exposure into the Agency ’ s risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post - application inhalation exposure assessment for clopy ralid. Although a quantitative occupational post - application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides to crops is likely to result in higher exposure than exposure to workers if they enter treated fields . Therefore, it is expected that the handler inhalation exposure estimates are protective of most occupational post application inhalation exposure scenarios. The registrant has provided s upplemental labels for Stinger ® Herbicide (EPA Reg. No. 62719 - 73) with this submission. The active ingredient in Stinger® is the monoethanolamine salt of clopy ralid acid and has a 12 - hour REI , which is appropriate.Clopy

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Page 30 of 51 **10.0 References**  D361316 , M. Doherty , et al . , 12 / 3 /20 09 , Clopy ralid

– Human Health Risk Assessment to Evaluate New Uses on Swiss Chard, Bushberry Subgroup (13 - 07B), and Strawberry (Regional Restriction) D391747, D. Dotson, 6/6/2012, Cl opy rali d. Petition for the Section 3 Registration and the Establishment of Tolerances on Apples, Brassica Leafy Greens (Subgroup 5 - B), Teff, and Rapeseed (Subgroup 20 - A) Except Gold of Pleasure . Summary of Analy tical Chemistry

and Residue Dat a D399390 , D. Dotson, 6 / 6 /201 2 , Clopy ralid Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section 3 Registration Action on Apples, Teff, the Leafy Brassica Greens Subgroup (5 - B), and the Rapeseed Subgroup (20 - A) D391398, W. Shaughnessy , 12/19/2011, Tier I Drinking Water Assessment for Proposed New Use of Clopy

ralid on Apple, Leafy

Brassica Greens Subgroup 5B, and Rapeseed Subgroup 20A, E xcept Camelina (Gold of Pleasure) D3 91748 , S. Oonnithan, 4 /30/2012 , Clopy ral id: Occupational Exposure Assessment for a New Use on Apples; Expansion of Crop Group 5B; and Revised Residential Exposure Assessment for use on Turf.

**List of Appendices** Appendix A . Clopy

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Profile and Executive Summaries Appendix B. Clopy

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Page 31 of 51 **Appendix A: Toxicology Profile and**  **Executive Summaries Appendix A.1. Toxicology Data Requirements**  The requirements (40 CFR 158.340) for food use for clopyralid are in the t able below . Use of the ne w guideline numbers does not imply that the new (1998) guideline protocols were used. **Study Technical**  **Required Satisfied**  870.1100 Acute Oral Toxicity ................................ ....................... 870.1200 Acute Dermal Toxicity ................................ .................. 870.1300 Acute Inhalation Toxicity ................................ .............. 870.2400 Primary Eye Irritation ................................ .................... 870.2500 Primary Dermal Irritation ................................ .............. 870.2600 Dermal Sensitization ................................ ...................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 Oral Subchronic (rodent) ................................ ............... 870.3150 Oral Subchronic (nonrodent) ................................ ......... 870.3200 21 - Day

Dermal ................................ .............................. 870.3250 90 - Day

Dermal ................................ .............................. 870.3465 28 - Day

Inhalation ................................ .......................... yes yes yes no no 4 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 2

yes yes 2 yes yes 870.5100 Mutagenicity

—Gene Mutation - bacterial ..................... 870.5300 Mutagenicity

—Gene Mutation - mammalian ................ 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations ... 870.5xxx Mutagenicity

—Other Genotoxic Effects ....................... yes yes yes yes yes 3

yes yes yes 870.6100a Acute Delayed Neurotoxicity (hen) ............................... 870.6100b 90 - Day

Neurotoxicity (hen) ................................ ........... 870.6200a Acute Neurotoxicity Screening Battery (rat) ................. 870.6200b 90 - Day

Neurotoxicity Screening Battery (rat) ............... 870.6300 Develop. Neurotoxicity ................................ ................. no no no 4 no 4 no -

-

-

-

- 870.7485 General Metabolism ................................ ...................... 870.7600 Dermal Penetration ................................ ........................ 870.7800 Immunotoxicity ................................ ............................. yes no yes yes

- yes Special Studies for Ocular Effects

Ac ute Oral (rat) ................................ ........................... Subchronic Oral (rat) ................................ .................. Six - mo nth Oral (dog) ................................ .................. no no no -

-

- 1 Satisfied by 870.4100b, chronic dog 2 Satisfied by 870.4300, rat combined chronic toxicity/carcinogenicity 3 Satisfied by overall negative genotoxicity database including host - mediated assay of S. typhimurium and S. cerevisia 4 Requirement waived by HED HASPOC based on a weight of evidence consideration of hazard, exposure, physicochemical properties , and structurally - related chemicals.Clopy

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Page 32 of 51 **Appendix A.2. Toxicity Profiles Table A**  **. 2.1**  **. Acute Toxicity Profile for Clopyralid**  **Guideline Number**  **Study Type**

**Classification MRID**  **Number Results**  **Toxicity Category**  870.1100 Ac ute - oral - rat 41641301 LD 50 (M/F) > 5,000 mg/kg IV 870.1200 Ac ute - dermal - rat 41641302 LD 50 (M/F) > 5000 mg/kg IV 870.1300 Ac ute - inhalation - rat 41848301 LC 50 (M/F) > 1 mg/L I II 870.2400 Ac ute - eye irritation rabbit 41641304 Severe irritation at 7 days (corrosive) I 870.2500 Ac ute - dermal

irritation - rabbit 41641305 Not an irritant I V 870.2600 Skin sensitization -

guinea pig 41641306 Not a sensitizer -

**Table A.2.2 Subchronic, Chronic and Other Toxicity Profile**  **for Clopyralid Guideline**  **No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** 870.3100 90 - Day

oral toxicity (rat) An acceptable study is not available. Requirement satisfied by combined

chronic oral toxicity/carcinogenicity study in the rat (870.4300). 870.3100 90 - Day

oral toxicity (mouse) 00127276 (2003)

Acceptable/guideline 0, 200, 750, 2000 or 5000 mg/kg/day NOAEL = 2000 mg/kg/day LOAEL = 5000 mg/kg/day based on decreased body weight gain. 870.3150 90 - Day

oral toxicity (dog) An acceptable study is not available. Requirement satisfied by chronic oral

study in the dog (870.4100). 870.3200 21 - Day

dermal toxicity (rabbit) 41790701 (1990)

Acceptable/guideline 0, 100, 500 or 1000 mg/kg/day **Systemic** NOAEL = 1000 mg/kg/day (limit dose) **Systemic** LOAEL = not established (>1000 mg/kg/day). **Local derm al**  NOAEL < 100 mg/kg/day (LDT) **Local derm al LOAEL**  = 100 mg/kg/day, based on epithelial hyperplasia at application site 870.3250 90 - Day

dermal toxicity Study not required, 870.3465 28 - Day

inhalation toxicity (rat) Study not required.Clopy

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Page 33 of 51 **Table A.2.2 Subchronic, Chronic and Other Toxicity Profile**  **for Clopyralid Guideline**  **No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** 870.3700a Prenatal

developmental in (rat) 00127279 (1981)

Acceptable/guideline 0, 15, 75 or 250 mg/kg/day **Maternal** NOAEL = 75 mg/kg/day LOAEL = 250 mg/kg/day based on mortality, decreased body weight gains and reduced food consumption. **Developm ental**  NOAEL = 250 mg/kg/day (HDT) LOAEL = not established (>250 mg/kg/day). 870.3700b Prenatal

developmental in (rabbit) 41649801, - 02 (1990)

Acceptable/guideline 0, 5 0 , 110 or 250 mg/kg/day by gavage **Materna** l NOAEL = 110 mg/kg/day LOAEL = 250 mg/kg/day based on mortality, decreased body weight gains, reduced food consumption and lesions in the gastric mucosa. **Developm enta**  l NOAEL = 110 mg/kg/day LOAEL = 250 mg/kg/day based on decreased fetal body weight and hydrocephalus. 870.3800 Reproduction and

fertility effects (rat) 00138155 (1983)

Acceptable/guideline 0, 150, 500 or 1500 mg/kg/day in diet **Parental** N OAEL = 500 mg/kg/day ( M/F ) LOAEL = 1500 mg/kg/day (M/F) , based on decreased body weights and body weight gain in F 0 and F 1 males ; body weights in F 1 and F 2 females **Reproductive** NOAEL ≥1500 mg/kg/day LOAEL = n ot attained based on lack of effects on reproductive parameters ( >1500 mg/kg/day) **Offspring** NOAEL = 500 mg/kg/day (M/F ) LOAEL = 1500 mg/kg/day (M/F ), based on decreased Day 28 body weights in F 1 male pups and increased relative liver weights of F 1a male and female pups and F 1b male pups . 870.4100a Chronic toxicity

(rat) Requirement satisfied by 870.4300. 870.4100b Chronic toxicity

(dog) 00158256 (1984)

Acceptable/guideline 0, 100, 320 or 1000 mg/kg/day by capsule NOAEL = 100 mg/kg/day LOAEL = 320 mg/kg/day based on decreases in RBC parameters, increased liver weight (males) and vacuolated adrenal cortical cells (females). Clinical chemistry changes (decreased serum albumin, globulin, protein) and skin lesions were observed at high dose. 870.4200a Carcinogenicity

(rat) Requirement satisfied by 870.4300.Clopy

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Page 34 of 51 **Table A.2.2 Subchronic, Chronic and Other Toxicity Profile**  **for Clopyralid Guideline**  **No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** 870.4200b 24 - mo nth

Carcinogenicity (mouse) 00162393, 00162434

(1984) Acceptable/guideline 0, 100, 500 or 2000 mg/kg/day in the diet (24 mo nths) NOAEL = 500 mg/kg/day LOAEL = 150 mg/kg/day based on decreased body weight/weight gain and reduced food efficiency. **(no) evidence of carcinogenicity** 870.4300 Chronic

toxicity/carcinoge nicity (rat) 00162393, 00162434

(1986) Acceptable/guideline 0, 15, 150 or 1500 mg/kg/day in the diet (104 weeks) NOAEL = 15 mg/kg/day LOAEL = 150 mg/kg/day based on gastric lesions (epithelial hyperplasia and thickening of the limiting ridge). At 1500 mg/kg/day, decreased body weight gains and food consumption were also observed. **(no) evidence of carcinogenicity** Gene Mutation 870.5100 Study not submitted. Not required due to lack of tumorigenicity in rat and mouse bioassays and

negative findings in all other genotoxicity assays, including host - mediated assays in Salmonella and Saccharomyces. Gene Mutation 870.5300 In Vitro and In

Vivo Host Mediated Assay ( Salmonella strains TA 1530, G - 46 and Saccharomyces strain D - 3) (1973) In vivo assays were conducted using mice 00057086 (1973)

Acceptable/guideline In vitro testing: without S9 activation at 5% w/v solution In vivo testing: 0, 4, 40 or 400 mg/kg by gavage to 10 mice Negative

– no evidence of induced mutant colonies over background levels in Salmonella or Saccharomyces strains tested in either the in vitro or the in vivo assays.

Cy togenetics 870. 5385 In V

iv o M icronucleus assay, Rat 00073638 (1973)

Acceptable/guideline 0, 4, 40 or 400 mg/kg for one day or for 5 days to male rats; sacrifice at 6, 24 or 48 hrs postdosing for all groups. Negative

– no evidence of an increase in the formation of chromosomal aberrations in bone marrow at any dose tested.

Other Effects 870.5450 Dominant Lethal

Assay in Rats 00059053, 00099100

(1973) Acceptable/guideline 4, 40 or 400 mg/kg/day for 5 days to male rats prior to mating Negative

– no evidence of treatment - related resorptions.Clopy

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Page 35 of 51 **Table A.2.2 Subchronic, Chronic and Other Toxicity Profile**  **for Clopyralid Guideline**  **No. Study Type**  **MRID No. (year)/ Classification /Doses**  **Results** Other Effects 870.5550 Unscheduled

DNA Synthesis, Rat Hepatocytes 00156387 (1985),

41790702 (1990) Acceptable/guideline 5 x 10 - 5 , 1.56 x 10 - 4 , 5 x 10 - 4 , 1.56 x 10 - 3 , 5 x 10 - 3 , 1.56 x 10 - 2 , 5 x 10 - 2 M, incubated for 18 - 20 hrs Negative

– no evidence of increased unscheduled DNA synthesis in the initial or supplementary assays testing up to insoluble/toxic concentrations.

870.6200a Ac ute

neurotoxicity screening battery (rat) Study not required.

870.6200b Subchronic

neurotoxicity screening battery (rat) Study not required.

870.6300 Developmental

neurotoxicity Study not required. 870.7485 Metabolism and

pharmacokinetics (rat) 41790703 (1991)

Acceptable/guideline 5.0 and 50 mg/kg, single oral dose; 5.0 mg/kg, single IV dose and 5.0 mg/kg/day, repeated daily dose for 14 days Clopyralid was rapidly and completely absorbed and eliminated with 95 to 115% of the administered dose recovered by 72 hr, most within 6 - 12 hrs postdosing. Almost all radio activity was eliminated via the urine irrespective of dose or route of administration (91 to 113% of AD), with <4% excreted in the feces. Tissue retention was negligible (<0.01% AD). There was essentially no metabolism of clopyralid: only parent compoun d was identified. No significant gender, dose or exposure route differences were identified. 870.7600 Dermal

penetration Study not available. 870.7800 Immunotoxicity

(rat) 48300001 (2011)

Acceptable/guideline 0, 158, 530 , or 1062 mg/kg/day Sy stemic NOAEL = 1062 mg/kg/day (limit dose) Sy stemic LOAEL = not established (>1062 mg/kg/day) Immunotoxicity NOAEL = 1062 mg/kg/day Immunotoxicity LOAEL = not established (>1062 mg/kg/day)Clopy

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Page 36 of 51 **Appendix A.3. Hazard Identification and Endpoint Selection A.3.1**  **Acute Reference Dose (aRfD)**
**– All Populations (Including Females Age 13**  **- 49 and**  **Infants and Children)** This risk assessment was not performed. An appropriate endpoint for acute oral exposure was not identified. Although hydrocephalus was observed, it occ urred onl y in the presence of severe mat ernal toxicity, including a high rate of mortality (considered treatment - related in 8/29 females), and was therefore not selected for this exposure scenario . **A.3.2 Chronic Reference Dose (cRfD)** 
**– All Populations**  **(Including Females Age 13 -**  **49 and Infants and Children)**  **Study Selected :**  Combined Chronic/Carcinogenicity - rat (OPPTS 870.4300) **MRID Nos .:**  00162393, 00162434 **Dose and Endpoint for Risk Assessment :**  NOAEL= 15 mg/kg/day , based on histopathology in the sto mach (epithelial hyperplasia and thickening of the limiting ridge) at the L OAEL of 150 mg/kg/day : **Comments on Study/Endpoint/Uncertainty Factors :**  The 2 - year rat chronic toxicity /carcinogenicity s tudy

with a NOAEL of 15 mg/kg/day is via an appropriate route of administration (diet) and is the lowest NOAEL for all chronic studies in the dog, rat , and mouse. The limiting ridge is the structure between the forestomach (nonglandular) and glandular portions of the rodent stomach. Although the limiting ridge i s absent in dogs and primates, the histological effects are believed to be due to the irritating properties of the chemical and, therefore, may

be of potential toxicity

in humans. The finding was observed in some interim sacrifice animals at 6 and 12 months, as well as at terminal (24 - month) sacrifice. The endpoint is considered conservative because onl y 1 - 2 animals/sex were affected at 6 months. Stomach lesions were also observed in the developmental rabbit study and rat reproduction study . The NOAEL i s lower than all endpoints for developmental and reproductive effects and therefore protective of potential pre - and/or postnatal toxicity . An UF of 100 was applied to account for inter - species extrapolation (10X) and intra - species variation (10X). Chronic RfD = 15 mg/kg/day (NOAEL) = 0.15 mg/kg/day 100 (UF) **A.3.3 Incidental Oral Exposure (Short** **- Term)**  **Study Selected:** Developmental Toxicity Study

– rat (OPPTS 870.3700a) **MRID No .:**  00127279 **Dose and Endpoint for Risk Assessment :**  NOAEL= 75 mg/kg/day , based on maternal mortality and decreased body

weight gain and food consumption during day s 6 - 9 of gestation at the L OAEL of 250 mg/kg/day . **Comments on Study/Endpoint :**  This endpoint is based on a study of an appropriate duration and route. The selected dose is protective of potential prenatal toxicity because fetal effects were seen only at the maternal L OAEL, and of potential postnatal toxicity based on the offspringClopy

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Page 37 of 51 NOAEL of 500 mg/kg/day in the rat reproduction study . An UF of 100 was applied to account for inter - species extrapolation (10X) and intra - species variation (10X). **A.3.4 Incidental Oral Exposure (Intermediate**  **- Term)**  **Study Selected :**  Combined Chronic/Carcinogenicity - rat (OPPTS 870.4300) **MRID Nos .:**  00162393, 00162434 **Dose and Endpoint for Risk Assessment**  **:** NOAEL= 15 mg/kg/day , based on histopathology in the stomach (epithelial hy perplasia, thickening of the limiting ridge) at the LOAEL of 150 mg/kg/day : **Comments on Study/Endpoint/Uncertainty Factors :**  This study was of an appropriate route and effects were observed by six months’ exposure duration. An UF of 100 was applied to account for inter- species extrapolation (10X) and intra - species variation (10X). **A.3.5 Dermal Absorption**  Dermal absorption data are not available for clop yralid; however, a 21 - day dermal toxicity study was available and showed no sy stemic toxicity up to the limit dose of 1000 mg/kg/day (see below). **A.3.6 Dermal Exposure (Short**  **- and Intermediate**  **- Term**  **)** This risk assessment was not performed. No sy stemic toxicity was observed in a rabbit 21 - day dermal study

up to the limit dose of 1000 mg/kg/day (MRID 41790701). In the rabbit, the more sensitive species for developmental effects, fetal toxicity was observed onl y in the presence of severe maternal toxicity

(decreased maternal body weight, clinical signs of toxicity and mortality). Therefore, these findings were not observed following dermal exposure in the same species, developmental effects would not be expected at the limit dose. The 21 - day study indicates that dermal absorption is low . B ased on comparison of the two studies, risk from exposure via the dermal route is not a concern. **A.3.7 Inhalation Exposure (Short** **- Term)**  **Study Selected :**  Developmental toxicity in rat **MRID No .:**  00127276 **Dose and Endpoint for Risk Assessment :**  Maternal NOAEL = 75 mg/kg/day based on mortality , decreased body weight gain and food consumption at the L OAEL of 250 mg/kg/day . **Comments about the Study/Endpoint :**  This endpoint is based on an oral study because no inhalation studies are available. Therefore, an oral study is selected to estimate risk using a route - to - route extrapolation. The rat d evelopmental study and endpoint were selected because they are protective of pre - and/or postnatal effects, including hydrocephalus as observed in the rabbit developmental study at 250 mg/kg/day

(maternal and developmental NOAEL = 110 mg/kg/day). The observed effects are a result of short - term exposure. Absorption via inhalation is assumed to be equivalent to absorption via the oral route, i.e., 100% inhalation absorption is assumed in risk assessment. An UF of 100 was applied to account for inter- specie s extrapolation (10X) and intra - species variation (10X). An additional 10x UF DB was not applied for lack of theClopy

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Page 38 of 51 inhalation study

because an inhalation study is not required , and the oral study is considered protective based on low vapor pressure and high inhalation MOEs estimated using the oral endpoint. **A.3.8 Inhalation Exposure (Intermediate**  **- Term)**  **Study Selected :**  Chronic toxicity /carcinogenicity in rats **MRID No .:**  00162393, 00162434 **Dose and Endpoint for Risk Assessment :**  The NOAEL = 15 mg/kg/day , based on epithelial hy perplasia and thickening of the limiting ridge of the stomach in both sexes. **Comments about the Stu dy/Endpoint**  **:** No inhalation studies are available. Therefore, an oral study was selected to estimate risk using route - to - route extrapolation. The study and endpoint were selected because they were observed by

six months’ exposure and are protective of ef fects observed in all available studies, including maternal and developmental effects in the rabbit. Absorption via inhalation is assumed to be equivalent to absorption via the oral route, i.e., 100% inhalation absorption is assumed in risk assessment. An UF of 100 was applied to account for inter - species extrapolation (10X) and intra - species variation (10X). An additional 10x UF DB was not applied for lack of the inhalation study because an inhalation study is not required and the oral study is considere d to be protective based on low vapor pressure and high inhalation MOEs estimated using the oral endpoint.Clopy

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Page 39 of 51 **Appendix A.4. Executive Summaries A.4.1**  **Subchronic Toxicity 870.3100**  **90 -**  **Day Oral Toxicity -**  **Rat** Satisfied by

870.4300 (Chronic Oral Toxicity /Carcinogenicity

– Rat) **870.3100 90**  **- Day Oral Toxicity**  **- Mouse**  In a subchronic toxicity

study (MRID #00127276) 3,6 - dichloropicolinic acid (technical, 97% purity) was administered to groups of 10/sex/dose BSC3F1 mice at dietary levels of 0, 200, 750, 2000, or 5000 mg/kg body weight/day

for approximately

13 weeks. There was a statisticall y significant decrease in body weight in both sexes at 5000 mg/kg/day . Relative (to body) liver weight was significantl y increased in both sexes at 5000 m g/kg/day . Males and females at 5000 mg/kg/day and females at 2000 mg/kg/day had centrilobular hepatocellular h yp ertrophy with altered tinctorial properties. The increased liver weight and hepatocellular histopathology were considered reversible, adaptive effects resulting from the increased metabolic activity due to dietary

intake of clopy

ralid. **The LOAEL is 5000 mg/kg/day, based on decreased body weight in both sexes. The NOAEL is 2000 mg/kg/day.**  This subchronic toxicity

study is classified Acceptable/guideli ne and does satisfy the guideline requirement for a subchronic oral study (§870.3100) in the rodent (mouse). **870.3150 90**  **- Day Oral Toxicity**  **- Dog**  Satisfied by

870.4100b (Chronic Oral Toxicity

– Dog) **870.3200 21**  **- Day Dermal Toxicity** 
**– Rat**  In a 21 - day repeated dose dermal toxicity study (MRID 41790701), groups of 5 male and 5 female New Zealand white rabbits were treated with Clopy ralid (technical, 95.78%, L ot No. not given) at doses of 0, 100, 500, or 1000 mg/kg/day as a powder under moistened gauze. Animals were treated b y dermal occlusion for 6 hours/day, 5 days/week for 3 weeks. There were no treatment - related deaths or signs of sy stemic toxicity and no treatment - related effects on body weight, hematology, clinical chemistry, or organ weight. No evi dence of skin irritation was observed in control rabbits; however, very slight ery thema was observed on 1 mid and 1 high - dose male and 1 mid - dose female at the end of the study. Treatment - related diffuse epidermal h yperplasia was observed on 1/5, 3/5, and 5/5 low - , mid - and high - dose males and 2/5, 1/5, and 5/5 low - , mid - , and high - dose females, respectivel y, at the end of the study. The effect was not observed in any control animals.Clopy

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Page 40 of 51 **The local**  **dermal LOAEL was 100 mg/kg/day (LDT)**  **based on diffuse epide rmal**  **hyperplasia on the skin of both males and females. A dermal NOAEL was not identified**  **(<100 mg/kg/day) .**  **The systemic NOAEL is 1000 mg/kg/day based on a lack of biologically significant systemic toxicity. A systemic LOAEL was not identified**  **(>1000 mg/ kg/day)**  **.** This study

is classified as Acc eptable/Guidelin e and does satisfy the guideline requirements for a repeated - dose dermal study ( §870.3200 ) in rabbits . Although a dermal NOAELwas not identified based on epithelial hy perplasia (1 - 5 animals affected) at all dose levels, no sy stemic toxicity was reported at any

dose level. **870.3465 28**  **- Day Inhalation** 
**– Rat**  Not required. **A.4.2 Prenatal Developmental Toxicity**  **870.3700a Prenatal Developmental Toxicity Study -**  **Rat** In a developmental toxicity study (MRID 00127279), 29 - 30 presumed pregnant Fischer 344 rats per group were administered Clopy ralid (technical, 97.0%; L ot/Batch No. not provided) by gavage in cottonseed oil at doses of 0, 15, 75, and 250 mg/kg/day on gestation day s (GD) 6 - 15, inclusive (Pha se I). When a low number of malformations were observed at the highest dose tested in Phase I, additional control and high - dose groups (of 25 animals apiece) were evaluated later in Phase II. Controls were treated with cottonseed oil (vehicle). On GD 21, dams were sacrificed, maternal liver, kidney , and thy mus weights were recorded, and all fetuses examined externally . Approximately one - half of each litter was processed for visceral examination, and all carcasses and the heads of the remaining one - half were processed for skeletal examination. During Phase I, one rat in the 250 mg/kg/day group died on GD 11. Moistening of the hair of the perineal region, a th ymus slightly decreased in size, and a gastrointestinal tract devoid of feed or fecal material were o bserved in this animal. During Phase II, two rats in the 250 mg/kg/day group died on GD 10. Both animals exhibited substantial weight loss and exudative material from the nares. Definitive diagnoses as to cause of death could not be made for any of these animals. No other treatment - related clinical signs of toxicity were observed in any

other animals. Maternal necrops y was unremarkable. In Phase I, absolute body weights of the high - dose dams were slightly

decreased to 95 - 97% of I controls on GD 10, 16, and 21, and these differences were statistically

significant (p ≤ 0.05) on GD 10 and 16. Weight gain b y the Phase I high - dose dams was significantly

decreased (p ≤ 0.05) to 25 - 75% of the control group level during the treatment period. In Phase II, absolute bo dy weights of the high - dose dams were statistically significantl y decreased (p ≤ 0.05) to 94 - 97% of controls on GD 10, 16, and 21. Weight gain b y the Phase II high - dose dams was significantly decreased (p ≤ 0.05) to 42 - 74% of the control group level during the treatment period. Inboth Phase I and II, animals of the 250 mg/kg/day group had significantl y (p ≤ 0.05) lower food consumption as compared with the controls during theClopy

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Page 41 of 51 treatment interval. No treatment - related differences in water consumption were observed between the treated and control groups. **The maternal toxicity LOAEL is 250 mg/kg/day, based on death, reduced body weight gains, and reduced food consumption, and the maternal toxicity NOAEL is 75**  **mg/kg/day.** There were no differences between the control group and the 15, 75, or 250 mg/kg/day groups during Phase I or Phase II for number of corpora lutea, number of implantation sites, live fetuses/dam, pre - and post - implantation losses, or fetal sex ratios. During Phase I, the mean fetal body weight in the 75 mg/kg/day group was slightly , but statistically significantly

(p ≤ 0.05), increased to 104% of control group level. No other statistically or biologically

differences between treated and control animals were noted. In Phase I, the overall incidence rates for liners containing fetuses with major external, visceral, and/or skeletal malformations in the 0, 15, 75, and 250 mg/kg/day

groups were 0/29, 0/22, 0i25, and 2/26, respectively . In Phase II, th e overall incidence rates for liners containing fetuses with major external, visceral, and/or skeletal malformations in the 0 and 250 mg/kg/day groups were 1/20 and 0/21. No single malformation occurred at a statisticall y or biologicall y significant great er incidence in the treated groups, and the incidence of total major malformations was also not significantl y increased for any of the treated groups as compared to controls. **The developmental toxicity NOAEL is 250 mg/kg/day. A developmental toxicity LOA EL**  **was not determined (>250 mg/kg/day).** This study

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

study ( **§** 83 - 3a) in rats. Despite numerous deficiencies in the conduct o f this study, an assessment of the d evelopmental toxicity potential of the test article was possible. **870.3700b Prenatal Developmental Toxicity Study -**  **Rabbit** In a developmental toxicity study (MRID 41649801, 41649802), 26 - 34 presumed pregnant New Zealand White rabbits per group were administered Clopy ralid (technical, 96.1 - 96.4% a.i., Lot No. AGR 233257) b y gavage at doses of 0, 50, 110, and 250 mg/kg/day on gestation day s (GD) 7 - 19, inclusive. The controls were given vehicle (corn oil) only for the same dosing period. On GD 28, all d oes were sacrificed, necropsied to assess gross pathology , and uteri and ovaries were removed. All fetuses were sexed, weighed, and examined for external malformations/variations prior to sacrifice. All of the fetuses were opened and checked viscerally the n processed for skeletal examination. Clinical signs of toxicity

consisting of labored breathing, rales, shallow respiration, and/or coughing were observed in 11/29 does at 250 mg/kg/day . Eight of 13 deaths occurring at 250 mg/kg/day

were considered treatment - related. Mean body weight gain was statistically significantl y (p 0.05) decreased during the treatment period (GD 7 - 20) which correlates with a significant reduction in absolute body weight at GD 20 for 250 mg/kg/day animals. Histopathologic lesions of the gastric mucosa were observed in does (8/33) of the 250 m g/k g/day treatment group.Clopy

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Page 42 of 51 **The maternal toxicity LOAEL is 250 mg/kg/day, based on clinical signs of toxicity, mo**  **rtality, reduction in mean body weight, and lesions of the gastric mucosa during the**  **treatment period. The maternal toxicity NOAEL is 110 mg/kg/day.** A statistically

significant (p ≤ 0.05) reduction in fetal body weight (13.2%), observed at 250 mg/kg/day

of Clopy ralid, was considered treatment - related. Also at 250 mg/kg/day , 3/15 litter s contained fetuses (total of eight) with hydrocephaly compared with 0/19 controls (n.s.). **The developmental toxicity LOAEL is 250 mg/kg/day, based on decreased fetal body weight and malformations. The developmental NOAEL is 110 mg/kg/day.**  This study

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

study in rabbi ts ( § 83 - 3b). No deficiencies were noted which would adversel y affect the interpretation of this study . **A.4.3 Reproductive Toxicity**  **870.3800 Reproduction and Fertility Effects -**  **Rat** In a multigeneration reproduction study (M RID 00138155), DOWCO ® 290 (96.7% a.i.; Id entification No. ARG - l92532) was administered to groups of 30 Fischer - 344 rats/sex/dose at dietary concentrations of 0, 15 0, 500, or 1500 mg/kg/day for two generations . Two litters were produced in both generations. F1 adults were chosen from the F 1 b pups and weaned onto the same diet as their parents. Test or control diets were administered to the F0 parental animals for up to 14 weeks and to the F1 parental animals for up to 17 weeks before the animals were mated within the same dose group. All animals were continuously exposed to test material either in the diet or via lactation until sacrifice. D eath of two F0 females and two F1 females was considered incidental to treatment; all other F0 and F1 males and females survived to terminal sacrifice. No treatment - related clinical signs of toxicity were observed in males or females of either generation at any time during the study. Gross necrops y and histological examination of the parental animals revealed a treatment - related effect in the gastric squamous mucosa in high dose males of both generations. Histopathology revealed slight focal h yp erkeratotic changes in the gastric squamous mucosa of 1 of 30 F0 males and 2 of 30 F1 males of the high dose. Body weights, body weight gains, and food consumption of the low - and mid - dose F0 and F1 males and females were not affected in a biologically relevant manner . Absolute body

weights of the high - dose F0 males were significantly (p ≤ 0.05) decreased (96 - 97% of controls) during the premating interval. Overall weight gain b y the high - dose males was 95 % (p ≤ 0.05) of the control group mean. Food consumption by the h igh - dose male group was significantl y (p ≤ 0.05) less than the controls for much of the premating interval. High - dose F0 females had significantly (p ≤ 0.05) lower absolute body weights (96 - 97% of the control levels). Overall mean body weight gain b y the h igh - dose females was slightl y reduced (88% of controls) during the premating interval. Food consumption by the high - dose female group was significantl y (p ≤ 0.05) less than the controls for a only few weeks of the premating interval.Clopy

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Page 43 of 51 Mean body weight among high - dose F0 females was also decreased during the lactation intervals of both litters (93 - 97% of control). Mean body weight among F1 males fed 1500 mg/kg/day was significantl y (p ≤ 0.05) decreased (93 - 94 % of control values) beginning with day 27 and c ontinuing throughout the study ; mean overall body weight gain was 96 % (n.s.) of the control. Mean food consumption was significantl y (p ≤ 0.05) decreased among males receiving 1500 mg/k g/day during a few weeks of the premating interval, values for this group were 92 - 95% of control. Mean body weight among females fed 1500 mg/kg/day was significantl y (p ≤ 0.05) decreased beginning with day 55 of the premating exposure period; mean body weight for this group was consistently 96 % of the control means. Mean food consumption among F1 females fed 1500 mg/kg/day was not effected during the premating interval. Lactational body weight of dams was only sporadicall y affected during the nursing of either the F2a, or F 2 b litters . **The LOAEL for parental systemic tox icity is 1500 mg/kg/day based on decreased body**  **weights, body weight gains, and food consumption in the F0 and F1 males and females and slight focal hyperkeratotic changes in the gastric squamous mucosa of 1 of 30 F0 males and**  **2 of 30 F1 males. The parenta l systemic toxicity NOAEL is 500 mg/kg/day.**  Mating, fertility , gestation, and parturition indices, and mean gestation length were similar between the treated and control female groups of both generations. **The NOAEL for reproductive toxicity is 1500 mg/kg/day (HDT). A LOAEL for**  **reproductive toxicity was not determined (>1500 mg/kg/day).** Mean litter size, live births, and pup survival were also similar between the treated and control groups for both generations. No treatment - related clinical signs of toxicity were observed in the F1 a , F 1 b, F2 a, or F2b pups during lactation. Body weight was significantl y decreased b y 8 - 10% in Day 28 male pups of the high dose of the F1 a and F 1 b litters of the F1 generation , but not the F2 generation in comparison to th e controls. Relative liver weight was significantly increased in F1a pups (both sexes) and F1 b males at the high dose in comparison to controls. No treatment related effects were observed among treated pups compared to the controls upon histopathological e xamination. **The LOAEL for offspring toxicity is 1500 mg/kg/day based on the decreased Day 28 body weight of male pups of both litters of the F1 generation and the increased relative liver**  **weight of F1a pups (both sexes) and F1b males of the F1 generation. The offspring toxicity**  **NOAEL is 500 mg/kg/day.** This study

is classified as Acceptable/Guideline and satisfies the requirements for a reproduction study ( § 8 70.3800 ) in rats.Clopy

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Page 44 of 51 **A.4.4 Chronic Toxicity**  **870.4100a (870.4300) Chronic Toxicity**
**– Rat**  In a chronic toxicity

/carcinogenicity study (MRID 00162393 and 00162434), DOWCO® 290 (Clopy ralid technical, 96.7% a.i.; lot number not reported) was administered in the diet to groups of 70 male and 70 female Fischer - 344 rats at concentrations delivering doses of 0, 15, 150, or 1500 mg/kg/day . Groups of 10 rats per sex per dose were killed at 6 and 12 months for interim evaluations; the remaining 50 rats per sex per dose were maintained on treated or control diets for up to 24 months. No treatment - related effects were observed on mortality or clinical signs of toxicity at any dose. Mean body weights we re significantl y decreased by 2 - 5% (p ≤0.05) in male rats fed 1500 mg/kg/day

and b y 2 - 9% (p ≤0.05) (except for an 11% decre ase at last time point) in 1500 mg/kg/day

group females compared with the weights of controls. Males in the 1500 mg/kg/day group gained 5% less weight than controls during the first year of the study and 7% less weight overall, whereas 1 500 - mg/kg/day group females gained 11% less during the first year and 1:6% less weight overall. Food consumption by 1500 mg/kg/day

group male and female rats was significantl y decreased by as much as 8% and 7%, respectivel y, at sporadic time points during the study . No treatment - related effects were observed o n body weights or food consumption in the 15 or 150 mg/kg/day

groups. Statistically

significant changes were observed for hematologic parameters, serum chemistry parameters, and relative organ weights, but none were considered treatment related. The chang es showed no dose - related trend, were transient in duration, or the magnitude of the change was not considered biologicall y s ignificant. The primary target for DOWCO® 290 was the limiting ridge of the stomach. No gross or microscopic lesions affecting the limiting ridge were observed in 15 mg/kg/day

groups. Gross examination showed that the limiting ridge was increased in size in almost all male and female rats receiving 1500 mg/kg/day for 12 or 24 months. Microscopic examination showed epithelial hy perpla sia of the limiting ridge in almost all 1500 mg/kg/day group male and female rats at 6, 12, and 24 months. The same lesion was observed in one or two male or female rats receiving 150 mg/kg/day for 6 and 12 months and in 52% of males and 42% of females at 24 months. The limiting ridge was thickened in two to seven male and female rats receiving 1500 mg/kg/day for 6 and 12 months and in 80% of males and 58% of females at 24 months. The limiting ridge was also thickened in one or two males or females receivin g the 150 mg/kg/day

dose for up to 24 months. Other treatment - related stomach lesions observed at 1500 mg/kg/day

included chronic active inflammation in 6/10 males at 12 months compared with 0/10 in the control group, and mononuclear cell aggregates in the stomach mucosa in 23/50 (p>0.05) males and 25/50 (p ≤0 . 05 ) females compared with 12/50 controls of each sex. In addition, a statistically

significant increase in the incidence of mononuclear cell aggregates in the lacrimal/Harderian gland was observed in m ales receiving 1500 mg/kg/day (21/50 vs 9/50 for controls, p ≤0 .0 5 ). **The LOAEL is 150 mg/kg/day for male and female rats based on histopathologic findings in the stomach (epithelial hyperplasia and thickening of the limiting ridge). The**  **corresponding NOAEL is 15 mg/kg/day.** Clopy

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Page 45 of 51 There was no evidence of potential carcinogenicity of the test material at the doses given in this study . No neoplastic lesions occurred in treated groups at incidences significantly higher than the incidences in control animals. The dose s administered were adequate for testing carcinogenicity as evidenced b y histopathologic lesions in the stomach at the 150 and 1500 mg/kg/day doses. In addition, the high dose of 1500 mg/kg/day exceeded EPA’s limit dose of 1000 mg/kg/day . This chronic to xicity

/carcinogenicity

study in the rat is Acceptable/Guideline and it satisfies the guideline requirement for a chronic toxicity /carcinogenicity

oral study

[OPPTS §870.4300] in rats. Deficiencies were noted, but none affected the interpretation of the res ults. **870.4100b Chronic Toxicity -**  **Dog** In a chronic oral feeding toxicity study (MRID 00158256), Clopy ralid (Batch No. AGR 192532, 95.8% purity) was administered to groups of six male and six female beagle dogs for 52 weeks at doses of 0, 100, 320, or 1 000 mg/kg/day in the diet. No animals died as a result of treatment, and no treatment - related clinical signs of toxicity were observed. There were no treatment - related effects on mean body weight, body

weight gain, or food consumption. Red blood cell count and its associated parameters showed a dose - related, statistically

significant reduction in both sexes of mid - and high - dose dogs. These changes are judged to be adverse and toxicologically significant, based on their magnitude (10 - 28% reduction in RBCs) . Clinical chemistry changes (decreased albumin, globulin, or serum protein at one or more sampling times) at the high dose in both sexes were highly statistically

significant and considered treatment related. Highl y significant increased absolute and relative liver weight in both sexes of high dose dogs and absolute liver weight in mid dose males was considered toxicologically

significant although in the absence of associated findings. Gross and histological changes seen in the lungs of treated dogs were evidently an inflammatory

response to inhaled food particles, caused b y the dogs “mouthing” their food, and not the result of sy stemic toxicity . Microscopicall y observed skin findings were increased in incidence and severity at the high dose in both sexes and included acanthosis (m,f ), h yp erkeratosis (m), and acute ulcerative dermatitis (f) and were considered treatment related. A dose - related increase in both incidence and severity of slight to mild focal vacuolation of adrenal cortical cells at the mid do se of females and high dose of both sexes was considered a significant toxicological effect. **The chronic oral toxicity LOAEL for dogs is 320 mg/kg/day for both sexes, based on a reduction in the hematological parameters, increased absolute liver weight in**  **males, and vacuolated adrenal cortical cells in females. The NOAEL is 100 mg/kg/day.**  This chronic oral toxicity study is classified as Acceptable/Guideline and satisfies the guideline requirement for a chronic oral toxicity study ( **§** 870.4100 b) in dogs. **A.4.5 Carcinogenicity**  **870.4200a Carcinogenicity Study -**  **rat** See 870.4100a (870.4300)(Chronic oral toxicity /carcinogenicity – rat)Clopy

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Page 46 of 51 **870.4200b Carcinogenicity (feeding) -**  **Mouse** In an oncogenicity

study (MRID 00157783), DOWCO ® 290 (technical, 96.7% a.i., batch/lot no. not supplied) was administered to groups of 70 male and 70 female B6C3F1 mice in the diet at concentrations providing 0, 100, 500, or 2000 mg/kg/day for up to 24 months. The dietary concentrations were adjusted weekl y or monthl y to maintain the target dose level using the food intake and body weights. Ten animals per sex per group were utilized for 6 month and for 12 month interim studies. Treatment w ith DOWCO ® 290 did not result in a significant decrease in survival or increases in clinical signs in treated groups compared with the control groups. Group mean body weights of males at 2000 mg/kg/day were decreased b y 5% to 13% (p ≤ 0.05) from treatment days 91 to 708 compared to the controls. The mean overall body weight gain in males was decrea sed b y about 15% at 2000 mg/kg/day

and by 8% at 100 and 500 mg/kg/day compared to the control group. The overall food efficiency in males was also 18% lower at 2000 mg/kg/day than that of the control group. The body weight and weight gain in females were n ot affected by treatment with DOWCO ® 290 and the food efficiency in females was higher in the treated groups than in the control. No treatment - related changes were seen in hematology parameters. Group mean blood glucose levels were increased in males by 2 0% and 27% (p ≤ 0.05) at 500 and 2000 mg/kg/day , respectivel y, after 6 months of treatment, and b y 42% and 36% (p ≤ 0.05) after 24 months. Blood glucose levels were also increased in females b y 28%, 9%, (NS) and 34% (p ≤ 0. 05) at 100, 500, and 2000 mg/kg/ day , respectivel y, after 6 months, but were not significantly increased at 12 or 24 months. The toxicological significance of the changes in blood glucose levels in treated animals is compromised by the use of non - fasted animals, the lack of a clear dose effe ct in females at 6 months and males at 24 months, and the lack of significant changes at 12 months in both sexes and at 24 months in females. A decrease in alkaline phosphatase activity of 51% was seen in females at 2000 mg/kg/day compared to the control a fter 24 months of treatment. The decreased activity

appears to be associated, at least in part, with a decrease in the incidence of bone fibrous osteodys trophy in high - dose females (control, 35/50; 2000 mg/kg/day , 26/50, NS). A slight decrease in the incid ence of sciatic nerve axon degeneration was seen in high - dose males at 24 months (control, 16/50; 2000 mg/kg/day , 8/50, p ≤ 0.05). No treatment - related adverse effects were seen during the histopathologic examinations. **The LOAEL is 2000 mg/kg/day based on decreased body weight, body weight gain, and**  **food efficiency for males. The LOAEL was not identified for females (>2000 mg/kg/day)**  **. The NOAEL was 500 mg/kg/day for males; 2000 mg/kg/day for females.**  There was no evidence of oncogenic potential under the conditions of this study . Major organs examined included liver, kidney , testes, lung, ovary , bladder, brain, and thyroid. The dosing based on toxic response was marginal in males and inadequate in females. The high dose of 2000 mg/kg/day

was above the limi t dose for non - toxic agents and, therefore, was considered adequate for the oncogenicity

study . This study

is classified as A cceptable/ guideline and does satisfy the guideline requirement for an oncogenicity study ( **§** 8 70.4200b ) in mice.Clopy

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Page 47 of 51 **A.4.6 Mutagenicity**  **Gene Mutation** 870.5300, in vitro (Salmonella and Saccharomyces) and in vivo (mouse) host - mediated gene mutation assay MRID 00057086 Acceptable/Guideline Negative for evidence of induction of mutant colonies over background levels in Salmonella or Saccharomyces strain D - 3 at doses in the presence or absence of S9. Mice exposed to 4, 40 or 400 mg/kg by gavage. **Cytogenetics** 870.5385, in vivo micronucleus assay in the rat MRID 00073638 Acceptable/guideline Negative for evidence of increased incidence of treatment - related bone marrow chromosomal aberrations at 4, 40 or 400 mg/kg/day . **Other Genotoxicity** 870.5450, dominant lethal assay in the rat MRID 00059053, 00099100 Acceptable/guideline Negative for evidence of increased incidence of treatment - related resorptions at 4, 40 or 400 mg/kg/day for 5 days prior to mating . 870.5550, unscheduled DNA synthesis in the rat MRID 00156387, 41790702 Acceptable/guideline Negative for evidence of increased unscheduled DNA sy nthesis up to insoluble concentrations when tested at concentrations between 9.6 to 9600 μg/mL for 18 to 20 hrs.

**A.4.7 Neurotoxicity**  **870.6200 Subchronic Neurotoxicity Screening Battery (Acute and Subchronic)** Not required. **A.4.8 Metabolism**  **870.7485 Metabolism**  **- Rat**  In a metabolism study

(MRID 41790703), groups of five male and five female rats were given a single oral dose of [ 14 4C] - Clopy ralid (5 or 150 mg/kg; Lot no. 805 [ref. no. GHD - 2775 - l 0 a, purity >96%), a single intravenous dose (5 mg/kg) of radiolabeled test article, or 14 - day repeated 5 mg/kg/day

oral doses of non - radiolabeled Clopyralid (Lot no. AGR 233257; radiochemical purity >99%) followed by

a single 5 mg/kg oral dose of radiolabeled test article. Additionally , a pretest experiment to assess pulmon ary excretion was performed in which two male and two female rats were given a single oral dose (5 mg/kg). An untreated control group consisted of one male and one female rat. There were no deaths or overt signs of toxicity reported. Radioactivity

invento ry

indicated an acceptable recovery

(95 - 115%) of the administered dose among the experimental groups in theClopy

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Page 48 of 51 definitive phase of the study . Clopy ralid was nearly

completely

absorbed at the doses tested. Under the conditions of this study , tissue and carcas s burdens were negligible for all groups, suggesting little potential for accumulation. Minimal radioactivity ( ≤ 0.0 1% at 72 hours) was found in the gastrointestinal tract and organs associated with excretion (e.g., liver, kidneys). Urinary excretion accounted for most (91 - 113% at 72 hours postdose) of the administered test material regardless of the administration route or dose. There did not appear to be any biologicall y relevant gender - dependent differences in total urinary excretion or excretion rates. Most urinary

excretion (74 - 98% of administered dose) occurred within 6 hours after administration for all low dose groups and within 12 hours for the repeated - dose group. Fecal excretion was negligible and, at 72 hours, accounted for < 4% of the administered dose in all treatment groups. HPL C and TL C anal ys is of urine and fecal samples indicated that the radioactivity

inventory

represented onl y parent compound. There was no evidence of metabolites. This metabolism study

in rats is classified as Acceptable/Guideline and satisfies the guideline requirement for a Metabolism and Phar macokinetics study in the rat ( §870.7485 ). **A.4.9 Immunotoxicity**  **870.7800 Immunotoxicity**  In an immunotoxicity

study (MRID 483000001 ) Clopy ralid (95.9% a.i., Lot No. 910905 5P ) w as administered to male F344/DuCrl rats in the diet designed to give nominal dose levels of 0 (vehicle control and positive control), 150, 500, or 1000 mg/kg bw/day (actual dose levels of 0, 158, 530, and 1062 mg/kg bw/day , respectivel y) (10 animals/dose) for 29 day s (Day 1 - 29). On Day 25, animals in all groups were immunized with a suspension of sheep red blood cells (SRBC) by

intravenous injection (2x10 8 SRBC/animal, 0.5 mL/animal dose volume). Animals in the positive control group received an intraperi toneal injection of cyclophosphamide on Day s 24 - 28 at a dose of 20 mg/kg bw (1 mL/kg bw dose volume). All animals were evaluated for mortality , clinical signs, body w eight changes, and gross pathology . The vehicle control and test substance treatment gro ups also were evaluated for food consumption, hematologic parameters, and histopathology . Immunotoxicity was assessed for all animals by ELISA assay ; spleen and thy mus weights were determined at necrops y. There were no test substance - related effects o n mortality , clinical signs, body weight changes, food consumption, hematologic parameters, histopathology or gross pathology . **A LOAEL for systemic toxicity could not be determined for Clopyralid in male rats (i.e., greater than the**  **nominal dose of 1000 mg /kg bw/day, actual dose of 1062 mg/kg bw/day, highest dose tested)**  **based on the evaluated parameters. The NOAEL for systemic toxicity is 1000 mg/kg bw/day (actual dose of 1062 mg/kg bw/day), highest dose tested and the limit dose.**  There were no test substance - related effects on serum anti - SRBC IgM antibody levels as measured b y ELISA assay, on th ymus and spleen weights, or on hematologic parameters. **A LOAEL for immunotoxicity could not be determined for Clopyralid in male rats (i.e**  **., greater than the nominal dose of 1000 mg/kg bw/day, actual dose of 1062 mg/kg bw/day,**  **highest dose tested) based on the evaluated parameters. The NOAEL for immunotoxicity is**Clopy

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Page 49 of 51 **1000 mg/kg bw/day (act ual dose of 1062 mg/kg bw/day),**  **highest dose tested and the limit**  **dose.** This immunotoxicity

study is classified as acceptable/guideline and satisfies the guideline requirement for an immunotoxicity study (OPPTS 870.7800) in the rat. Information regarding the stability

of the test substance, storage conditions of the test substance and dietary formulations, and references for the historical control thy mus weight data should be submitted.Clopy

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Page 50 of 51 **Appendix B**  **. Clopyralid**  **Physical/Chemical Properties Physicochemical Properties of the Technical Grade**  **Clopyralid** Parameter Value References Physical State Solid A world Compendium, The Pesticide Manual, 14 th Edition. C.D. S Tomlin (Editor) , 2006. Color Colorless Melting P oint/Range 151 - 152°C Dissociation Constant (pKa) 2 Density at 20°C 1.57 g/cm3 Vapor P ressure at 25°C 1.0 x 10 - 5 mm Hg ( 1.33 mPa) Water S olubility at 20°C 7.85 g/L Solvent solubility (g/L) at 20°C Acetone : 250 Ethyl acetate : 102 Xylene : 4.6 Hexane : 6.0 Octanol/water partition coefficient, Log (K OW) - 1.81 (pH 5)

- 2.63 (pH 7)

- 2.55 (pH 9)Clopy

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Page 51 of 51 **Appendix C**  **. Review of Human Research**  This risk assessment relies in part on data from studies in which adult human subjects were intentionally

exposed to a pesticide or other chemical. These data, which include studies from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database; and other registrant - submitted exposure monitoring studies ( MRID 44339801 ) , are subject to ethics review pursuant t o 40 CFR 26, have received that review, and are compliant with applicable ethics requirements. For certain studies , that review may

have included review b y the Human Studies Review Board. Descriptions of data sources as well as guidance on their use can be found at : http://www.epa.gov/pesticides/ science/handler - exposure - data.html and http://www.epa.gov/pesticides/science/post - app exposure - data.html.