UNITED STATES ENVIRONMENTA L PROTECTION A GENCY WASHINGTON, D.C. 20460 OFFICE OF PREVENTION, PESTICIDE

AND TOXIC SUBSTANCES
MEMORANDUM Date: 3 December 2009 SUBJECT: Clopy

ralid

– Human Health Risk Assessment to Evaluat e New Uses on Swiss Chard, Bushberry

Subgroup (13 - 07B), and Strawberry (Regional Restriction). PC Code: 117401 ( alkanolamine salt s ), 117403 ( acid) DP Barcode: D361316 Decision No.: 403248 Registration Nos. : 62719 - 80, 62719 - 81, and 62719 - 84 Petition No.: 8E7481 Regulatory Action: Section 3 and 24(c) Registrations Risk Assessment Type: NA Case No.: NA T XR No.: NA CAS Nos.: 1702 - 17 - 6 (acid) 577 5 4 - 85 - 5 (monoethanolamine salt) MRID No s .: 47604401, 47604402, 47604403 40 CFR: 180.431 FROM: Mi chael A. Doherty, Ph.D., Senior Chemist Linnea Hansen, Ph.D., Toxicologist S uku Oonnithan, Biologist Risk Assessment Branch II Health Effects Division (7509P) THROUGH: Edward Scollon, Ph.D., Toxicologist

Zaida Figueroa , In dustrial Hygenist William Drew, Environmental Scientist Richard A. Loranger, Ph.D., Senior Scientist Christina Swartz, Branch Chief Risk Assessment Branch II Health Effects Division (7509P) TO: Barbara Madden, RM 05 Risk Integration, Minor Us e, and Emergency Response Branch Registration Division (7505P)Page 2 of 33 Table of Contents 1.0 Executive Summary ................................ ................................ ................................ ............. 4 2.0 Ingredient Profile ................................ ................................ ................................ ................. 5 2.1 Summary

of Proposed Uses ................................ ................................ .......................... 5 2.2 Structure and Nomenclature ................................ ................................ ......................... 6 2.3 Phy sical and Chemical Properties ................................ ................................ ................. 7 3.0 Hazard Characterization/Assessment ................................ ................................ ................ 7 3 .1 Hazard and Dose - Response Characterization ................................ ............................... 7 3.1.1 Database Summary ................................ ................................ ............................ 7 3.1.1.1 Studies available and considered (animal, human, general literature) 7 3.1.1.2 Mode of action, metabolism, toxicokinetic data ................................ 7 3.1.1.3 Sufficiency

of studies/data ................................ ................................ . 8 3.1.2 Toxicological Effects ................................ ................................ ......................... 8 3.1.3 Dose - response ................................ ................................ ................................ .... 9 3.1. 4 FQPA ................................ ................................ ................................ ............... 10 3.2 Absorption, Distribution, Metabolism, Excretion (ADME) ................................ ....... 10 3.3 FQPA Considerations ................................ ................................ ................................ . 10 3.3.1 Adequacy

of the Toxicity

Database ................................ ................................ . 10 3.3.2 Evidence of Neurotoxicity ................................ ................................ ............... 10 3.3.3 Developmental Toxicity and Developmental Neurotoxicity Studies .............. 11 3.3.4 Reproductive Toxicity Study ................................ ................................ ........... 11 3.3.5 Additional In formation from L iterature Sources ................................ ............. 11 3.3.6 Pre - and/or Postnatal Toxicity ................................ ................................ .......... 11 3.3.6.1 Determination of Susceptibility ................................ ....................... 12 3.3.6.2 Degree of Concern Analysis and Resid ual Uncertainties for Pre and/or Postnatal Susceptibility ................................ ................................ ........ 12 3.3.7 Recommendation Regarding a Developmental Neurotoxicity Study .............. 12 3.4 Safety

Factor for Infants and Children ................................ ................................ ........ 13 3.5 Hazard Identification and Toxicity Endpoint Selection ................................ .............. 13 3.5.1 Acute Reference Dose (aRfD) ................................ ................................ ......... 13 3.5.3 Chronic Reference Dose (cRfD) ................................ ................................ ...... 13 3.5.3 In cidental Oral Exposure (Short - Term) ................................ ........................... 14 3.5.4 In cidental Oral Exposure (Intermediate - Term) ................................ ............... 14 3.5.5 Dermal Absorption ................................ ................................ ........................... 14 3.5.6 Dermal Exposure (Short - , Intermediate - and Long - T erm) .............................. 14 3.5.7 Inhalation Exposure (Short - Term) ................................ ................................ ... 15 3.5.8 Inhalation Exposure (Intermediate - Term) ................................ ....................... 15 3.5.9 Level of Concern for Margin of Exposure ................................ ....................... 15 3.5.10 Recommendation for Aggregate Exposure Risk Assessments ........................ 16 3.5.11 Classification of Carcinogenic Potential ................................ .......................... 16 3.5.12 Summary

of Toxicological Doses and Endpoints for Use in Human Risk Assessments ................................ ................................ ................................ ................. 16 3.6 Endocrine disruption ................................ ................................ ................................ ... 18 4.0 Public Health and Pesticide Epidemiology Data ................................ ............................. 18 5.0 Dietary Exposure/Risk Characterization ................................ ................................ ........ 18 5.1 Pesticide Metabolism and Environmental Degradation ................................ .............. 18Page 3 of 33

5.2 Analy

tical Methodology ................................ ................................ ............................. 19 5.3 Food Residue Profile ................................ ................................ ................................ ... 19 5.3.1 Anticipated Residue and Percent Crop Treated (%CT) Information .................. 20 5.3.2 International Residue Limits ................................ ................................ ............ 20 5.4 Drinking Water Residue Profile ................................ ................................ .................. 20 5.5 Dietary

Exposure and Risk ................................ ................................ ......................... 20 6.0 Residential (Non - Occupational) Exposure/Risk Characterization ............................... 21 6.1 Residential Handler Exposure ................................ ................................ ..................... 21 6.2. Residential Postapplication Exposure ................................ ................................ ......... 21 6.3 Other (Spray

Drift, etc .) ................................ ................................ .............................. 22 7.0 Aggregate Risk Assessments and Risk Characterization ................................ ............... 22 7.1 Acute Aggregate Risk ................................ ................................ ................................ . 22 7.2 Short - and Intermediate - Term Aggregate Risk ................................ ........................... 22 7.3 Long - Term Aggregate Risk ................................ ................................ ........................ 23 7.4 Cancer Risk ................................ ................................ ................................ ................. 23 8.0 Cumulative Risk Characterization/Assessment ................................ .............................. 23 9.0 Occupational Exposure/Risk Pathway ................................ ................................ ............. 23 10.0 Data Needs and Label/Regulatory Recommendations ................................ ................... 23 10.1 Toxicology ................................ ................................ ................................ .................. 23 10.2 Residue Chemistry ................................ ................................ ................................ ...... 24 10.3 Occupational and Resident ial Exposure ................................ ................................ ..... 24 References: ................................ ................................ ................................ ................................ ... 24 Appendix A: Toxicology Assessment ................................ ................................ ....................... 26 A.1 Toxicology

Data Requirements ................................ ................................ .................. 26 A.2 Toxicity

Profiles ................................ ................................ ................................ .......... 26 A.3 Rationale for Toxicology Data Requirements ................................ ............................ 31Page 4 of 33

1.0 Executive Summary The Interregional Research Project No.4 (IR - 4) has petitioned the Agency to register clopy

ralid , a py ridinoxy acid herbicide, for use on Swiss chard and the bushberry crop subgroup (Subgroup 13 - 07B), and to grant a regional registration (Florida and North Carolina) for use on strawberry in an annual crop production sy stem. A use on strawberry grown as a perennial crop has already been established. HED has reviewed the available toxicological and residue chemistry studies for clop yralid and is recommending that the requested uses be conditionally registered and that permanent tolerances be establish ed. No mammalian target organ was identified i n the clopy ralid toxicological studies submitted to the Agency . Effects were noted in various organs and sy stems, including increases in liver weight, changes in clinical chemistry and blood cell parameters, skin lesions , and decreases in body weight gain. There is no evidence of increased pre - or post - natal sensitivity to clopy ralid as effects in offspring were only observed at doses that caused severe toxicity in the maternal animals. There are no indicati ons of neurotoxic or immunotoxic activity and clopy

ralid has been classified as not likel y to be carcinogenic to humans. No adverse dermal effects were noted, even at the highest dose tested. Studies with rats, goats, hens, various crops, and environment al conditions show clopy r alid to be relativel y stable. In animals, the compound is rapidly absorbed and essentially completel y excreted as the parent compound, al though some conjugation to gl ycine was observed in the livestock studies. Field trials with Swiss chard, blueberry , and strawberry resulted in quantifiable residues in all three crops. The residue data are adequate to support the establishment of tolerances at 3.0 ppm on Swiss chard, 4.0 ppm on strawberry , and 0.5 ppm on bushberry (Subgroup 13 - 0 7B) . HED has used conservative assumptions to assess the risk from exposure to clopyralid from dietary and non - dietary

sources. Risk estimates are below our level of concern for all population subgroups for all exposure durations. Based on the previous assessment from 2002 , occupational exposures to clopy

ralid , assuming baseline personal protective equipment, are also below HED’s level of concern for all scenarios. A new occupational risk assessment is being developed. Provided the label is modified to prohibit application to low - bush varieties of bushberry , HED recommends that the requested uses be conditionally granted and that permanent tolerances, as listed above, be established. Submission of acceptable toxicity studies ( 870.3465

– 28 - or 90 - Day Inhalation Toxicity ; 870.6200

– Acute and Subchronic Neurotoxicity ; and 870.7800

– Immunotoxicity) should be made a condition of registration. 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 ris k 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 an d water consumption,Page 5 of 33

and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intakes by

Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized by subgroups based on age, season of the ye ar, ethnic group, and region of the country . Whenever appropriate, non dietary exposures b ased on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currentl y in development as OPP has commi tted resources and expertise to the development of specialized software and models that consider exposure to b ys tanders and farm workers as well as lifestyl e and traditional dietary patterns among specific subgroups. 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 studies, which comprise the Pesticide Handlers Exposure Database (PHED), have been determined to require a review of their ethical conduct, and have received that review. The studies in PHED are considered appropriate (ethicall y conducted) for use in risk assessments. 2.0 Ingredient Profile Clopy ralid [3,6 - dichloro - 2 - py

ridinecarboxylic acid] is a py ridine 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. Permanent tolerances are established for residues of clopy ralid in/on a wide variety of plant commodities at levels ranging from 0.5 ppm in/on stone fruits to 500 ppm in/on grass forage and hay [40 CFR §180.431(a)], including a tolerance of 1.0 ppm on strawberry . Permanent tolerances are also established for residues of clopy ralid in livestock commodities at levels ranging from 0.1 ppm in eggs to 36 ppm in meat b yp roducts, except liver, of cattle, goats, horses and sheep . There are currently no tolerances for inadvertent or indirect residues of clop yr alid. 2.1 Summary of Proposed Uses In the current petition (PP#8E7481), IR - 4 is proposing to expand the use of clopy ralid to i nclude applications to Swiss chard and bushberries for the postemergence control of various weeds. In addition, IR - 4 is proposing a reg ionall y restricted use on strawberries grown only in FL and NC under an annual - ty

pe production sy stem . There is currentl y a use on strawberries grown as a perennial crop (DP# 270507, 8/6/2002, D. Dotson). The proposed end - use product is an emulsifiable c oncentrate containing 3 pounds acid equivalent (ae) clopy ralid per gallon.Page 6 of 33

Table 2.1. Summ ary 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 . Sea sonal

Applic. Rate (lb ae/A) PHI

(days) Use Directions and

Limitations 2 Swiss Chard Broadcast foliar application when crop is at the cotyledon to 8 - leaf stage of growth; ground equipment. 3.0 lb ae/gal EC [62719 - 73] 0.094 - 0.187 1 0.187 30 Apply in a min imum of 10 gal/A . Bushberry subgroup 13 - 07B Directed applications to row middles beginning 1 week after bloom; ground equipment 3.0 lb ae/gal EC [62719 - 73] 0.06 - 0.25 2 0.5 30 Apply in a minimum of 1 0 gal/A, with a minimum RTI of 14 days. Do not apply b y aircraft. Strawberry ( annual fields only in FL and NC ) Broadcast foliar application to well - established plantings; ground equipment 3.0 lb ae/gal EC [62719 - 73] 0. 113 - 0.25 1 0.25 7 Apply in a minimum of 20 gal/A. Do not use with a surfactant. Do not apply by aircraft 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 , garden beets, grasses, corn (field, pop and sweet), oats, spin ach, 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. 2.2 Structur e and Nomenclature T able 2.2 . Clopyralid Nom enclature. Compound
N Cl Cl O O O H NH 3 + Common name Clopyralid , monoethanolamine salt Company experimental name Dowco 290 IUPAC name 3,6 - dichloropyridine - 2 - carboxylic acid, monoethano lamine salt CAS name 3,6 - dichloro - 2 - pyridinecarboxylic acid, monoethanolamine salt CAS registry number 1702 - 17 - 6 (acid) 577 5 4 - 85 - 5 (monoethanolamine salt) End -use product (EP) 3 lb ae/gal EC (Stinger TM herbicide ; EPA Reg. No. 62719 - 73)Page 7 of 33

2.3 Physical and Chemical Properties T able 2 .3 . Physicochemical Properties of Technical Grade Clopyralid Acid. Parameter Value Reference Melting point/range 149.6 D ata were obtained from the FOOTPRINT Pesticide Properties DataBase, (http://www.eu footprint.org/ppdb.html ) . pH Not available Density (specific gravity) 1.76 g/mL Water solubility (g/L) at 20°C 1 43 Solvent solubility (g/L) at 20°C Acetone

– 250 Ethyl ac e tate

– 102 Xylene

– 4.6 Hexane

– 6.0 Vapor pressure at 25°C, mPa 1.36 Dissociation constant, pKa , at 25°C 2.01 Octanol/water partition coefficient, Log(KOW) , at 20°C - 2.63 UV/visible abso rption spectrum Not available 3.0 Hazard Characterization/Assessment This hazard characterization updates the previously prepared assessment of September 26, 2002 (D270885). No additional toxicology stu dies have been received since that time. Additional data requirements in this assessment reflect the recently revised 40 CFR Part 158 guidelines. 3.1 Hazard and Dose - Response Characterization 3.1.1 Database Summary 3.1.1.1 Studies available and considered (animal, human, general literature) The following studies have been conside red for this hazard characterization: subchronic toxicity in mice; chronic toxicity

/carcinogenicity

in rats; carcinogenicity in mice; chronic toxicity in dogs; developmental toxicity in rats and rabbits; two - generation reproduction toxicity in rats; mutagenicity

battery ; metabolism (rats) and 21 - day rabbit dermal toxicity . 3.1.1.2 Mode of action, metabolism, toxicokinetic data Clopy ralid is an herbicide of the p yridinox y 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. The mode of action for mammalian toxicity has not been characterized. The rat met abolism study indicates rapid and essentially complete absorption and excretion, but essentially no metabolism; only

the unchanged parent compound was recovered.Page 8 of 33

3.1.1.3 Sufficiency of studies/data The to xicology

database for clopy

ralid is incomplete at this time. Based on the toxicology data requirements outlined in the recently revised 40 CFR Part 158, there are additional requirements for acute and subchronic neurotoxicity studies in the rat (§870.6200 a and b), and an immunotoxicity

study (§870.7800). In addition, a 28 - day inhalation toxicity

study in the rat (§870.3465) is required. The rationales for requiring these studies are provided in the attached DCITables (see Appendix A.3). 3.1.2 Toxicol ogical Effects The acute toxicity

of clopy ralid is low (Toxicity

Category IV) via oral, inhalation and dermal exposure and i t is not a dermal irritant or sensitizer . In its acid form , clop yralid is a severe eye irrit ant (Category

I ). Subchronic data were available only 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 s ys temic toxicity or local dermal ir

ritation was observed in rabbits following dermal exposure to the limit dose for 21 day s. Subchronic inhalation data are not available. Toxicity was observed in the rat and dog following chronic exposure, but consistent target organs were not identified. Ina one year dog study , reductions in red blood cell parameters, increased 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 thickening of the limiting ridge of the stomach were observed at the LOAEL and decreased body weight at the highest dose. Only

decreased body

weight/weight gain and food efficiency in males were observed in the mouse carcinogenicity study above the limit dose. There was no indication of increased pre - and/or postnatal susceptibility . No developmental toxicity was observed in the rat at doses that caused maternal mortality and decrease d maternal body weight gain. Decreased fetal body weight and hydrocephalus were observed in the rabbit but at a dose that caused severe maternal toxicity , including mortality , clinical signs of toxicity , decreased body weight gain and gastric mucosal lesi ons. Reproductive toxicity was not observed in the rat, but mean pup weights (Day 28) were reduced and relative liver weights increased at doses that caused parental toxicity (decreased body

weight/weight gain and food consumption; gastric lesions). Acut e and subchronic neurotoxicity studies and an immunotoxicity study have not been submitted. However, there were no clinical or histopathological indications of neurotoxicity , nor indications of immunotoxicity, in the subchronic or chronic toxicity studies at doses up to or beyond the limit dose. No evidence for carcinogenicity was observed in rat and mouse 2 - ye ar bioassay s at doses exceeding the limit dose. No positive findings for mutagenicity or clastogenicity

were observed in a battery

of mutagenici ty

studies (bacterial reverse gene mutation, in vitro and in vivo hostPage 9 of 33

mediated assay s in Salmonella and Saccharomyces , in vivo chromosomal aberrations, unscheduled DNA sy

nthesis, dominant lethal activity). Clopy ralid is therefore classified as “not likel y to be carcinogenic to humans.” Clopy ralid is rapidl y absorbed and excreted , predominantly as parent compound , primarily in the urine with very

low fecal excretion . It is not retained in tissues. 3.1.3 Dose - response The e ndpoints selected for this human health risk assessment of clopy ralid are presented and discussed in greater detail in Section 3.5 of this document. An acute dietary

exposure endpoint was selected based on decreased maternal body weight gain/food consumption in the rat developmental study during the first three day s of dosing (gestation day s 6 - 9). This endpoint was selected because the maternal body weight gain changes could have resulted from a single exposure, but only the day 6 - 9 interval data were available. There were no other endpoints of an appropriate duration for this risk assessment. For chronic dietary

exposure, the lowest NOAEL identified in the database was 15 mg/kg/day , based on stomach histopathology in the rat at 150 mg/kg/day in the chro nic toxicity /carcinogenicity feeding study. Although the effects were observed in the limiting ridge of the rat stomach, they

were considered relevant to human risk assessment because they were most likely

the result of irritation. Body weight effects we re observed at the highest dose tested (1500 mg/kg/day), a dose that exceeded the limit dose. For short - term incidental oral exposure to young children, assessment was based on the developmental toxicity

NOAEL of 75 mg/kg/day from the rat developmental study , in which decreased maternal body weight gain and food consumption were observed at the LOAEL of 250 mg/kg/day . This was the lowest available NOAEL for exposure of this duration: the rabbit developmental NOAEL was 110 mg/kg/day (250 mg/kg/day

L OAEL) and the mouse subchronic study exceeded the limit dose. For incidental oral intermediate - term exposure to young children, the assessment was based on the rat chronic toxicity

NOAEL of 15 mg/kg/day due to stomach lesions at the L OAEL of 150 mg/kg/day . The finding was reported b y 6 months’ dosing and is therefore the result of an appropriate duration of exposure. Both short - and intermediate - term endpoints are protective of postnatal effects, based on the reproductive toxicity offspring NOAEL of 500 mg/kg/day . A dermal risk assessment is not required for clopyralid. No toxicity was observed in the rabbit 21 - day dermal toxicity

study , which tested up to the limit dose of 1000 mg/kg/day . Because there was no toxicity

observed, and developmental toxicity in the rabbit was only observed in the presence of maternal toxicity (maternal/developmental LOAEL = 250 mg/kg/day), no pre - and/or postnatal toxicity

would be expected from dermal exposure up to the limit dose. There are no inhalation toxicity data on c lopy

ralid; therefore, oral studies were selected with an assumption of 100% absorption (relative to oral). The rat developmental toxicity study NOAELPage 10 of 33

of 75 mg/kg/day

was selected for short - term inhalation exposure and the rat chronic toxicity NOAEL of 15 mg/kg/day was selected for intermediate - term exposure. 3.1.4 FQ PA HED recommends reduction of the FQPA special factor to 1 X . There was no evidence of increased pre - and/or postnatal qualitative or quantitative susceptibility in the developmental rat or rabbit studies, or the rat 2 - generation reproduction study . In the developmental rat study , no developmental effects were seen at doses that caused maternal toxicity . Although acute and subchronic neurotoxicity

studies and an immuno toxicity study have not been submitted and are required under the revised 40 CFR Part 158 guidelines, the available subchronic and chronic studies show no evidence of either neurotoxicity or immunotoxicity

at doses up to or exceeding the limit dose. The e ndpoints selected for risk assessment are therefore considered adequatel y protective of pre - and/or postnatal toxicity . Furthermore, exposure estimates in the risk assessment are health - protective and likel y overestimate exposures. 3.2 Absorption, Distri bution, Metabolism, Excretion (ADME) Metabolism of clopy

ralid was evaluated in the rat. Clopy ralid was essentially

completel y absorbed at both a low (5 mg/kg/day) and a high (150 mg/kg/ day) dose (95 - 115% of administered dose recovered). Excretion was primarily in the urine (91 - 113% of the administered dose at 72 hrs postdosing, with 74 - 98% excreted within 6 - 12 hrs postdosing), whether b y oral or intravenous dosing. Less than 4% of the excretion was via feces. Radioactivity

was not retained in tissues (<0.01% of administered dose at 72 hrs postdosing). There was no evidence of metabolism; only parent compound was identified in the urine and feces. 3.3 FQ PA Considerations 3.3.1 Adequacy of the Toxicity Database Acceptable developmental toxicity studies in rats and rabbits and a two - generation reproduction study in rats are available for FQPA assessment. However, acute and subchronic neurotoxicity in rats and immunotoxicity studies have not been submitted and represent data gaps for clopy ralid under the revised 40 CFR Part 158 guidelines. A 28 - day inhalation toxicity

study in rats is also required fo r assessment of inhalation exposure risk, but the selected oral endpoints, with an assumption of 100% absorption relative to oral absorption, are considered adequatel y protective of pre - and/or postnatal toxicity . 3.3.2 Evidence of Neurotoxicity There are no clinical or micropathological indications of neurotoxicity in the available subchronic and chronic studies in multiple species. Acute and subchronic neurotoxicity studies in the rat have not been submitted but are required under the revised 40 CFR Part 158 guidelines.Page 11 of 33

In the rabbit developmental toxicity study , hydrocephalus was observed at the highest dose tested, 250 mg/kg/day . However, this finding occurred at a dose that caused severe maternal toxici ty , including mortality and decreased body weight gain and food consumption. No evidence of neurodevelopmental toxicity was observed in the rat developmental toxicity study or in the rat two - generation reproductive toxicity study . 3.3.3 Developmental T oxicity and Developmental Neurotoxicity Studies In a developmental toxicity study in the rat (MRID 00127279), pregnant Fischer 344 rats were administered clop yralid (97.0% a.i. ) b y gavage at 0, 15, 75 or 250 mg/kg/day from gestation day s 6 through 15. A repeat study evaluating control and high doses was conducted to assess a low level of malformations in the initial study at the high dose. Maternal toxicity was observed at the LOAEL of 250 mg/kg/day , based on mortality , decreased body weight gains and decreased food consumption. The maternal NOAEL was 75 mg/kg/day . No developmental toxicity was observed; the NOAEL was 250 mg/kg/day and the LOAEL was not established (>250 mg/k g/day). In a second developmental toxicity study (MRID 41649801), pregnant New Zealand White rabbits were administered clopy ralid (96.1 - 96.4% a.i.) by gavage at doses of 0, 50, 110 or 250 mg/kg/day

from gestation day s 7 through 19. Maternal toxicity was observed at the LOAEL of 250 mg/kg/day , based on mortality , clinical signs of toxicity , decreased mean body weight gain and gastric mucosal lesions at the LOAEL of 110 mg/kg/day . Developmental toxicity was observed at the LOAEL of 250 mg/kg/day based on d ecreased mean fetal body weight and hydrocephalus. The NOAELwas 110 mg/kg/day. A developmental neurotoxicity study is not available and is not required. 3.3.4 Reproductive Toxicity Study In a 2 - generation rat reproduction study (MRID 00138155), clopy ralid (96.7% a.i.) was administered in the diet to Fischer 344 rats at 0, 150, 500 or 1500 mg/kg/day for two mating generations (two litters per generation). Parental toxicity was observed at the LOAEL of 1500 m g/kg/day

as decreased body

weights, body weight gains and food consumption in F0 and F1 males and females, and slight focal hyp erkeratotic changes in the gastric squamous mucosa of 1 F0 male and 2 F1 males. The parental toxicity NOAEL was 500 mg/kg/day . Offspring toxicity was observed at the LOAELof 1500 mg/kg/day based on decreased Day

28 male pup body weight in both F1 litters and increased relative liver weights of male and female F1a pups and male F1b pups. Reproductive toxicity was not observed; th e NOAEL was 1500 mg/kg/day and a LOAEL was not identified (>1500 mg/kg/day). 3.3.5 Additional Information from Literature Sources Additional information from the published literature was not identified for clopy ralid. 3.3.6 Pre - and/or Postnatal ToxicityPage 12 of 33

3.3.6.1 Determination of Susceptibility There was no evidence of increased pre - and/or postn atal qualitative or quantitative susceptibility . In the rat developmental study , no developmental toxicity was observed at a maternall y toxic dose and in the two - generation reproduction study , decreased pup weight (post natal Day 28) and increased relativ e liver weights were observed at the parental L OAEL. In the rabbit, hydrocephalus and decreased mean fetal weight were observed at a dose that caused severe maternal toxicity , including mortality . 3.3.6.2 Degree of Concern Analysis and Residual Uncertain ties for Pre - and/or Postnatal Susceptibility There is low concern for increased pre - and/or postnatal qualitative or quantitative susceptibi lity . In creased susceptibility

was not observed in the developmental toxicity studies, or in the rat reproduction study. There are residual uncertainties due to lack of acute and subchronic neurotoxicity

studies and an immunotoxicity study ; however there was no evidence of neurotoxicity

or immunotoxicity

in the available subchronic and chronic studies, which tested up to doses exceeding the limit dose. Although hydrocephalus was observed in the rabbit developmental toxicity

study , it was onl y observed at a dose that also caused severe maternal toxicity , including mortality . In the rat, there were no fetal effects observed in the developmental study ; in the reproduction study , pup weights (post - natal Day 28) were decreased and relative liver weights incre ased at a maternall y toxic dose that exceeded the limit dose. The endpoints selected for risk assessment provide adequate protection to offspring. Based on these findings, there is low concern for increased pre - and/or postnatal susceptibility . 3.3.7 Re commendation Regarding a Developmental Neurotoxicity Study A developmental neurotoxicity study is not recommended at this time, based on low concern for neurotoxicity . Neuropathology (h ydrocephalus) was only observed in the rabbit developmental study at a dose that caused severe maternal toxicity , and no evidence of neurotoxicity was observed in the rat developmental or reproduction studies or in the available subchronic or chro nic studies. 3.4 FQ PA Safety Factor for Infants and Children HED recommends reduction of the 10 X FQPA safety factor for protection of infants and children to 1 X. In creased qualitative or quantitative pre - and/or postnatal susceptibility was not observ ed in the developmental or 2 - generation reproduction studies. A rat developmental neurotoxicity study is not required at this time, based on lack of evidence of neurotoxicity in subchronic and chronic exposure studies and in the rat developmental and reproduction studies; hydrocephalus in the rabbit developmental study occurred only

in one species and in the presence of severe maternal toxicity, including death. Exposure estimates are based on conservative, health protective assumptions and further suppor t reducing the FQPA safety factor.Page 13 of 33

Data gaps include acute and subchronic neurotoxicity studies. An immunotoxicity study is also required; however, there was no indication in the submitted toxicity studies that there were effects on the immune system. B ased on the lack of concerns for neurotoxicity and immunotoxicity

in the existing database and selection of endpoints which are adequatel y protective of pre - and/or postnatal toxicity , an additional factor for data gaps is not required. 3.5 Hazard Identification and Toxicity Endpoint Selection 3.5.1 Acute Reference Dose (aRfD) Study Selec ted : Developmental Toxicity Study - rat MRID Nos .: 00127279 Dose and Endpoint for Establishing cRfD : maternal NOAEL = 75 mg/kg/day , based on decreased body weight gains and reduced food consumption at the L OAEL of 250 mg/kg/day . Uncertainty Factor(s ): An UF of 100 was applied to account for inter - species extrapolation (10 X) and intra - species variation (10 X) . Comments on Study

/Endpoint/Uncertainty

Factors : The rat developmental toxicity study with a maternal toxicity

NOAEL of 75 mg/kg/day is of an app ropriate route of administration (gavage). The body weight effects in the maternal animals are believed to be due to one or a few doses given at the initiation of the dosing period (gestation day s 6 - 15). The first calculation of maternal weight gain and food consumption was conducted for day s 6 through 9 of gestation (day s 1 - 3 of dosing). The selected dose is also protective of developmental effects seen in the rabbit at 250 mg/kg/day

in the presence of severe maternal toxicity (developmental toxicity NO AEL of 110 mg/kg/day). Acute RfD = 7 5 mg/kg/day (NOAEL) = 0.75 mg/kg/day 100 (UF) 3.5.2 Chronic Reference Dose (cRfD ) Study Selected : Combined Chronic/Carcinogenicity - rat (OPPTS 870 .4300) MRID Nos .: 00162393, 00162434 Dose and Endpoint for Establishing cRfD : NOAEL = 15 mg/kg/day , based on histopathology in the stomach (epithelial hy perplasia and thickening of the limiting ridge) at the L OAEL of 150 mg/kg/day : Uncertainty Factor(s ) : An UF of 100 was applied to account for inter - species extrapolation (10 X) and intra - species variation (10 X) . 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 li miting ridge is 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. Stomach lesions were also observed in the developmental rabbi t study and rat reproduction study . The NOAEL is lower than all endpointsPage 14 of 33

for developmental and reproductive effects and therefore protective of potential pre - and/or postnatal toxicity . Chronic RfD = 15 mg/kg/day (NOAEL) = 0.15 mg/kg/day 100 (UF) 3. 5.3 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 , base d on maternal mortality and decreased body weight gain and food consumption during days 6 - 9 of gestation at the LOAEL of 250 mg/kg/day . Uncertainty Factor(s) : An UF of 100 was applied to account for inter - species extrapolation (10 X) and intra - species variation (10 X) . Comments on Study

/Endpoint : This endpoint is based on an oral study of an appropriate duration. Effects in the maternal animal are believed to be due to one or a few doses given at the initiation of the dosing period (gestation day s 6 throu gh 15). The first calculation of maternal weight gain and food consumption was determined for gestation day s 6 - 9. The selected dose is protective of potential postnatal toxicity based on the offspring NOAEL of 500 mg/kg/day in the rat reproduction study . 3.5.4 Incidental Oral Exposure (Intermediate - Term) Study Selected : Combined Chronic/Carcinogenicity - rat (OPPTS 870.4300) MRID Nos .: 00162393, 00162434 Dose and Endpoint for Establishing cRfD : 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 : Uncertainty Factor(s ): An UF of 100 was applied to account for inter - species extrapolation (10 X) and intra - species variation (10 X) . Comments on Study

/Endpoint/Uncertainty

Factors : See 3.5.2. Stomach lesions in the rat were observed at 6 months of oral dosing and are therefore an appropriate endpoint for this risk assessment. The selected dose is protective of potential postnatal toxicity based on the offspring NOAEL of 500 mg/kg/day in the rat reproduction study . 3.5.5 Dermal Absorption Dermal absorption data are not available for clop yralid. A 21 - day dermal to xicity

is available and was considered for dermal exposure endpoints of all durations (see below). 3.5.6 Dermal Exposure (Short - , Intermediate - and Long - Term) Dermal absorption data are not available for clop yralid. No 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 only

in the presencePage 15 of 33

of severe maternal toxicity (decreased maternal body weight, clinical signs of toxicity and mortality). Therefore, since no body weight or other effects were 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; based on comparison of the two studies, risk from exposure via the dermal route is not a concern . 3.5.7 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 LOAEL of 250 mg/kg/day . Uncertainty Factor(s) : An UF of 100 was applied to account for inter - species extrapolation (10 X) and intra - species variation (10 X) . 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 developmental study and endpoint were selected because they are protective of effects observed in all the available studies, including hydrocephalus as ob served 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. 3.5.8 Inhalation Exposure (Intermediate - Term) Study Selected : Chronic toxicity /carcinogenicity i n rats MRID No .: 00162393, 0016243 4 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. Uncertainty Factor(s) : An UF of 100 was applied to account for inter - species extrapolatio n (10 X) and intra - species variation (10 X) . Comments about the Study /Endpoint : No inhalation studies are available. Therefore, an oral study is selected to estimate risk using route - to - route extrapolation. The study and endpoint were selected because the y are protective of effects observed in all available studies, including developmental effects in the rabbit (hydrocephalus, decreased fetal weight), which were seen at a dose that caused severe maternal effects including mortality (250 mg/kg/day). The en dpoint is of appropriate duration, as the effect may be a result of intermediate - or longer - 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. 3.5. 9 Level of Concern for Margin of Exposure Table 3.5.9 . Summary of Levels of Concern for Risk Assessment. Route Short - Term (1 - 30 Days) Intermediate - Term (1 - 6 Months) Long - Term (> 6 Months) Occupational (Worker) Exposure Dermal 100 100 N/APage 16 of 33

Inhalation 100 100 N/A Residential Exposure Dermal 100 100 N/A Inhalation 100 100 N/A Incidental Oral 100 100 N/A 3.5. 10 Recommendation for Aggregate Exposure Risk Assessments According to FQPA (1996), when there are potential residual exposures to a pesticide, an aggregate risk assessment must consider exposures from 3 major routes: oral, dermal and inhalation. Although d ermal exposure is anticipated from residential use of clopy ralid, a dermal assessment was not performed, and therefore dermal exposure is not included in the aggregate assessment, because an appropriate endpoint was not identified (no toxicity up to the limit dose of 1000 mg/kg/day). Exposures to clopy

ralid may be aggregated as follows: (1) for acute dietary exposure, drinking water and dietary

exposures may

be combined; (2) for short - term exposure, drinking water and dietary exposures may

be combined with inhalation exposure for adult applicators and residential incidental oral exposures for young children; and (3) for intermediate - term exposure, drinking water and dietary

exposures may

be combined with residential incidental oral exposures for yo ung chil dren. An adult aggregate exposure estimate for intermediate exposure is not required because intermediate - term inhalation exposure is not anticipated from residential uses and a dermal assessment is not required. 3.5.1 1 Classification of Carcinogenic Pot ential There was no evidence of treatment - related increases in tumor incidence in the 2 - ye ar rat and mouse dietary

studies. Both studies included a high dose that exceeded the limit dose. Genotox icity

studies were negative. 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.” 3.5.1 2 Summary of Toxicological Doses and Endpoints for Use i n Human Risk Assessments Table 3.5.12a. Toxicological Doses and Endpoints for Clopyralid for Use in Dietary and Residential Human Health Risk Assessments. E xposure/ 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) NOAEL = 75 mg/kg UF A= 10X

UF H = 10X SF FQPA=1 aRfD=0.75

mg/kg/day aPAD=0.75 mg/kg/day Developmental Toxicity (oral)

– rat

Maternal LOAEL = 250 mg/kg/day, based on decreased body weight gain and food consumption during GD 6 - 9. 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 thePage 17 of 33

Table 3.5.12a. Toxicological Doses and Endpoints for Clopyralid for Use in Dietary and Residential Human Health Risk Assessments. E xposure/ Scenario Point of

Departure Uncertainty/FQP

A Safety Factors Level of Concern

for Risk Assessment Study and Toxicological Effects

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. Incidental Oral, Intermediate - term

(1 - 6 months) NOAEL = 15

mg/kg/day 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. 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 rabbit

21 - day d ermal toxicity study and there are no developmental or reproductive concerns. No quantification of risk is required. Inhalation, Short term (1 - 30 days) Oral study

NOAEL = 75 mg/kg/day (inhalation absorption rate = 100% of oral) 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. Inhalation Intermediate - term

(1 - 6 months) Oral study

NOAEL= 1 5 mg/kg/day (inhalation absorption rate = 100% of oral) 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 o f 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 observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. SF FQPA = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. Table 3.5.12b. Summary 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. No quantification of risk is required.
Inhalation, Short - term (1 - 30 days) NOAEL = 75

mg/kg/day (default inhalation absorption UF A= 10X

UF H = 10X SF FQPA=1 Occupational

LOC for MOE = 100 Developmental Toxicity (oral)

– rat

Maternal LOAEL = 250 mg/kg/day,Page 18 of 33

Table 3.5.12b. Summary 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 rate = 100% of oral absor ption) based on decreased body weight gain and food consumption during GD 6 - 9. Inhalation, Intermediate term (1 - 6 months) NOAE L = 15

mg/kg/day (default inhalation absorption rate = 100% of oral absorption) UF A = 10X

UF H = 10X SF FQPA = 1 Occupational

LOC for MOE = 100 2 - Year Combined Chronic

Toxicity/Carcinogenicity (oral)

– rat LOAEL = 150 mg/kg/day, based on increased epithelia l 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 = extrapolation from animal to human (interspecies). UF H = potenti al 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. N/A = not applicable 3.6 Endocrine disruption EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances (including all pesticide active and other ingredients) may have an effect in humans that is similar to an effect produced b y a naturall y occurring estrogen, or other such endocrine effects as the Administrator may designate. Following the recommendations of its Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC), EPA determined that there was scientific basis for including, as part of the program, the androgen and thy

roid hormone sy stems, in addition to the estrogen hormone sy stem. EPA also adopted EDSTAC’s recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may

help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluatio ns. As the science develops and resources allow, screening of additional hormone sy stems may be added to the Endocrine Disruptor Screening Program (EDSP). When the appropriate screening and/or testing protocols being considered under the Agency ’s EDSP have been developed, clop yralid may be subjected to additional screening and/or testing to better characterize effects related to possible endocrine disruption. To the extent that new or revised tests are developed in connection with the EDSP that can provi de more information on endocrine effects, EPA will consider whether further testing of clop yr alid is appropriate. 4.0 Public Health and Pesticide Epidemiology Data Public health and pesticide ep idemiology data were not used for this risk assessment. 5.0 Dietary Exposure/Risk Characterization 5.1 Pesticide Metabolism and Environmental DegradationPage 19 of 33

The nature of the residue in plants is adequatel y understood for purposes of this petition based on the acceptable cabbage, grass, barley and wheat metabolism studies. In each of these studies, the major 14 C - residue was determined to be only parent compound. Although the available crop metabolism data all indicate that the parent compound is the only major residue, the data are from only two dissimilar crops (leafy vegetable and cereal grain) . Therefore, HED concludes that the residue of concern in plants for purposes of this petition is clopy ralid. Addi tional metabolism studies may

be required in the future should the petitioner request the establishment of clopy ralid tolerances for additional crops. In livestock, the major residues are the parent clopyralid as well as its glycine conjugate (3,6 - DCPA - gl ycine). HED notes that the current petition does not involve livestock feed items. In the environment, clopyralid has a low rate of soil sorption, is stable to photoly sis and anaerobi c metabolism and is moderatel y stable to aerobic metabolism. Due to its stability and high 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 Clopyral id Clopyralid

Rotational Crop Clopyralid Clopyralid Livestock Ruminant Clopyralid + Glycine Conjugate Clopyralid

Poultry Clopyralid + Glycine Conjugate Clopyralid Drinking Water Clopyralid Not Applicable 5.2 Analytical Methodology An adequate gas chromatograph y/ electron - capture detection ( GC/ECD ) method (Method ACR 75.6) is available for enforcing the proposed tolerances and collecting data on residues of clopy ralid in Swiss chard, blueberries and strawberries. R esidues are extracted with 0.5% NaOH and centrifuged. The resulting extract is acidified with HCl and salinized with NaCl; the residues are then partitioned into ethyl ether. Residues are then m ethylated using diazomethane, concentrated to dry

ness, re - dissolved in toluene, cleaned up using an activated Alumina A column , and eluted with toluene . The meth yl ated residues are analyzed by GC /ECD using external standards . Residues are expressed in terms of parent clop y ralid using a conversion factor of 0.93 . The lowest level of method validation (LLMV) for clopy ralid in each commodity i s 0.05 ppm. 5.3 Food Residue Profile Adequate supervised crop field trials have been conducted to support tolerances for clopy ralid in/on swiss chard, bushberry , and strawberry . The trials resulted in quantifiable residues of clopy ralid in all three crops, with maximum values of 1.9 ppm (swiss chard), 0.42 ppm (blueberry), and 3.0 ppm (strawberry) at the 1X use rate. Residue data at the 0 .5X use rate for S wiss chard and strawberry show a proportionate relationship between application rate andPage 20 of 33

residue levels. 5.3.1 Anticipated Residue and Percent Crop Treated (%CT) Information This assessment is based on tolerance - level residues and assumes 100% crop treated for all crops with registered or proposed uses on clop yr alid labels. 5.3.2 International Residue Limits There are no Code x or Mexican maximum residue limits (MRL s) for residues of clopy ralid in/on the requested commodities (Appendi x I). However, there are Canadian MRL s for residues of clopy ralid at 1.0 mg/kg on strawberry and 0.1 mg/kg on blueberry . The Canadian MRLfor strawberry

harmonizes with the existing tolerance for strawberry . Based on the proposed use on strawberry

and bushberries, and the available residue data, the recommended tolerances on strawberry

and bushberries (subgroup 13 - 07B) cannot be harmoni zed with the Canadian MRL s. 5.4 Drinking Water Residue Profile The Environmental Fate and Effects Division (EFED) provided a Tier I drinking water assessment that uses modeling and available monitoring data to estimate the ground water and surface water concentrations of pesticides in drinking water source water (pre - treatment) resulting from clop yralid use on sites that are highly vulnerable (D361314, A. Shelby, 9 September 2009). Of the requested uses, bushbe rry had the greatest single application rate and was used to model estimated drinking water concentrations (EDWCs) of clopy ralid. Non - crop uses of clop yralid have greater application rates than those of bushberry and were also used to obtain EDWCs (Table 5.4). HED ha s used the maximum acute and chronic EDWCs (45.0 and 11.9 ppb, respectivel y) from non - crop uses of clopy ralid in its dietary

assessment. Table 5.4 . Maxim umTier I Estimated Drinking Water Concentrations (EDWCs) for drinking water assessment based on ground application of Clopyralid. Drinking Water Source (Model Used) Use (Rate Modeled) Maximum Estimated Drinking Water Concentration (EDWC) (ppb) Groundwater (SCIGROW) Bushberry (0.25 lbs a.i./A) Ac ute and Chronic 0.39 Groundwater (monitorin g) NAWQA, Alabama Ac ute 13 Surface water (FIRST) Bushberry (0.25 lbs a.i./A) Ac ute 41.1 Bushberry (0.25 lbs a.i./A) Chronic 10.8 Non - crop (0.5 lbs a.i./ A) Ac ute 45.0 Non - crop (0.5 lbs a.i./ A) Chronic 11.9 5. 5 Dietary Exposure and Risk Acute and chronic combined dietary (food + drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model DEEM - FCIDTM, Version 2.03 which use 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 acute and chronic assessments are highl y conservative with regard to protecting humanPage 21 of 33

health. Both assessments assume 100% crop treated and are b ased on tolerance - level residues for all commodities. Modeled estimates of clop yr alid residues in drinking water have been incorporated into the analy ses. Children 1 - 2 years old are estimated to have the highest dietary exposure to clopy

ralid. The screening - level estimates for that subpopulation are 9% of the acute population - adjusted dose (aPAD) and 2 3 % of the chronic population - adjusted dose (cPAD). Generally , HED is concerned about dietary risk when the exposure estimate exceeds 100% of the PAD. The refore, the combined dietary risk from residues of clop yr alid in food and drinking water are below HED’s level of concern for all population groups (Table 5.5). Table 5.5. Summ ary of the Combined Dietary (Food + Drinking Water) Exposure and Risk Estimate s for Clopyralid. Population Subgroup Ac ute ( 95th Percentile) Chronic Cancer Dietary Exposure (mg/kg/day) %

aPAD* Dietary Exposure

(mg/kg/day) % cPAD* Dietary Exposure (mg/kg/day) Risk General U.S. Population 0.035084 5 0.013212 9
N/A N/A All Infants (< 1 year old) 0.043768 6 0.012778 9 Children 1 - 2 years old 0.070616 9 0.035056 23 Children 3 - 5 years old 0.060428 8 0.031908 21 Children 6 - 12 years old 0.042390 6 0.021317 14 Youth 13 - 19 years old 0.025842 3 0.012669 8 Adults 20 - 49 years ol d 0.022783 3 0.010403 7 Adults 50+ years old 0.019576 3 0.008967 6 Females 13 - 49 years old 0.021362 3 0.009685 7 The % PAD values for the highest exposed population for each type of risk assessment are bolded . 6.0 Residential (Non - Occupational) E xposure/Risk Characterization There are no new residential uses for clop yralid associated with the subject petition and HED has used the previous residential exposure estimates (D 270 507 , W. G. Sproat , 26 September 2002) to assess non - occupational risk as well as aggregate risk (Section 7). Residential exposure and risk estimates from the 2002 assessment are summarized below. Note that risks via the dermal route of exposure are no t of concern for clopy ralid; therefore, residential risks result solely from incidental oral and inhalation exposures. 6.1 Residential Handler Exposure Inhalation e xposures were estimated for homeowners using pus h - ty pe granular spreaders, low pressure hand sprayers and garden hose - end sprayers. The maximum exposure estimate from these scenarios is 0.000034 mg/kg/day (garden hose - end sprayers) , with an associated MOE of 2.2×10 6 . The level of concern for residenti al risk is an MOE of less than 100; therefore, the MOE for garden hose - end sprayers represents a risk below HED’s level of concern. 6.2. Residential Postapplication Exposure Short - term hand - to - mouth expo sure of clop yralid by toddlers from turf treated with L ontrel Turf and Ornamental (EPA Reg. No. 62719 - 305) at an application rate of 0.5 lb ae/A amounted to 0.0075 mg/kg/day

with an MOE of 10,000. Additionally , there is a potential for toddlers to ingest granular formulations of clopy ralid directly from treated turf. The incidental oralPage 22 of 33

ingestion of granules from turf treated with Lawn Fertilizer Plus Confront Weed Control (EPA Reg. No. 62719 - 263) resulted in a dose of 0.024 mg/kg/day and a corresponding MOE of 3,100. All of these MOEs are greater than 100 and represent risks below HED’s level of concern. Note that due to the episodic nature of granule ingestion, it is not appropriate to include this source of exposure in aggregate assessments. 6.3 Oth er (Spray Drift, etc .) Spray drift is alway s a potential source of exposure to residents living in close proximity to spraying operations. This situation is particularly the case with aerial application. However, t o a lesser extent, spray

drift resulting from the ground application of clop yr alid could also be a potential source of exposure. The Agency has been working with the Spray Drift Task Force (a membership of U.S. pesticide registrants), EPA Regional Offices , State Lead Agencies for pesticide regulation, and other parties to develop the best spray drift management practices. The Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Ag ency has completed its evaluation of the new database submitted by

the Spray

Drift Task Force, and is developing a policy on how to apply appropriatel y the data and the AgDRIFT computer model to its risk assessments for pesticides applied by

air, orchard airblast, and ground h ydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off - target drift risks associated with pesticide application. 7.0 Aggregate Risk Assessments and Risk Characterization 7.1 Acute Aggregate Risk There are no non - dietary

exposure scenarios appropriate for assessing via an acute risk assessment; theref

ore, acute aggregate risk estimates are equivalent to the acute dietary risk estimates discussed in Section 5.5 and are below HED’s level of concern. 7.2 Short - and Intermediate - Term Aggregate Risk Residential risks associated with short - term exposures were discussed in Section 6. These residential exposures may coincide with dietary

exposure to clopy

ralid, resulting in aggregate exposure. HED has evaluated short - and intermediate - term aggregate risk by combining the short - or intermediate - term MOEs for residential exposures with dietary MOEs (based on chronic exposures from food plus water as measure s of background dietary exposure). The aggregate MOEs are summarized in Table 7.2 and represent ri sks that are below HED’s level of concern. Table 7.2. Summ ary of Short - and Interm ediate - Term Aggregate Risks for Clopyralid. Population NOAEL , mg/kg/day LOC Dietary

Exposure, mg/kg/day Dietary

MOE Residential

Activity Residential

MOE Aggregate

MOE * Sh ort - Term Adult Handler 75 100 0.013 212 5, 6 00 Application (Inhalation) 2,200,000 5, 5 00Page 23 of 33

Children 1 - 2 year s old 75 100 0.03 5056 2,100 Incidental Oral ( H and - to - M outh) 10,000 1,700 Intermediate - Term Childre n 1 - 2 years old 15 100 0.03 5056 4 2 0 Incidental Oral ( H and - to - M outh) 5,800 39 0 * Aggregate MOE = 1÷ [(1÷MOE Dietary) + (1÷MOE Residential )] 7. 3 Long - Term Aggregate Risk There are no non - dietary

exposure scenarios appropriate for assessing via a chronic risk assessment; therefore, chronic aggregate risk estimates are equivalent to the chronic dietary risk estimates discussed in Section 5.5 and are below HED’s level of concern. 7. 4 Cancer Risk Clopy ralid has been classified as “Not Likel y to be Carcinogenic to Humans.” Therefore, cancer risk is not a concern for this chemical. 8.0 Cumulative Risk Characterization/Assessment 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 clopy ralid and an y other substances and clop yr alid does not appear to produce a toxic metabolite produced b y other substances. For the pur poses of this tolerance action, therefore, EPA has not assumed that clopy 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 evaluat e the cumulative effects of such chemicals, see the policy statements released by

EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/. 9.0 Occupational Exposure/Risk Pathway An occupational risk assessment to address the requeste d uses of clop yr alid is being developed ( D367967, S. Oonnithan, in preparation) . Based on the previous assessment (D270885, D. Dotson, 26 September 2002) , in which occupational MOEs ranged from 17,000 to 470,000 assuming baseline personal protective equip ment (PPE) , o ccupational risk estimates are expected to be below HED’s level of concern. 10.0 Data Needs and Label/Regulatory Recommendations 10.1 Toxicology In ord er to satisfy

recently revised pesticide registration data requirements (40 CFR Part 158), the following toxicity

studies are required (see Appendix A3) :  870.3465

– 28 - or 90 - Day Inhalation Toxicity  870.6200

– Acute and Subchronic NeurotoxicityPage 24 of 33

 870.7800

– Immunotoxicity 10.2 Residue Chemistry No data deficiencies were noted in the submission or in the residue chemistry database for clopy ralid. Prior to registration, the label should be modified to prohibit application of clopy ralid to low - bush varieties of bushberry . The tolerance definition for clopy ralid should be revised to read as follows: Tolerances are established for residues of the herbicide clopy ralid, including its metabolites and degradates, in or on the commodities in the table below from its application in the acid form or in the form of its salts . Compliance with the tolerance levels specified below is to be determined b y measuring only

clopy ralid [3,6 - dichloro - 2 - py

ridinecarbox yl ic acid] in or on the commodi ty . HED is recommending that tolerances for residues of clopy ralid be established as summarized in Table 10. Table 10 . Tolerance Summary for Clopyralid. Commodity Proposed/Existing

Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity Definition 40 CFR §180.431(a) Swiss Chard 5.0 3.0 Adequate field tri al data are available. B ushberry subgroup 13 - 07B 6.0 0.50 Adequate field tri al data are available *

. Cranberry 4.0 4.0 The tolerance for cranberries should remain due to differences i n use pattern and residue level versus the currently proposed use on bushberry . Straw berry 4.0 4.0 Adequate field trial data are available to support a 7 - day PHI for straw

berries grown under an annual - ty pe production system in FL and NC only. This tolerance will supersede the existing 1.0 - ppm tolerance already established for straw berry (grown under a perennial production system). * The Summary of Analytical Chemistry and Residue Data (D361787, M. Doherty, 27 October 2009) recommends that the tolerance b e for Subgroup 13 - 07B, except for low - growing varieties. After further review, HED is recommending that the tolerance be for residues in/on all of Subgroup 13 - 07B and has determined that label language prohibiting application to low - growing varieties will be sufficient. 10.3 Occupational and Residential Exposure None. References: D 270885, D. Dotson, 26 September 2002. PP No. 4F4379: Human Health Risk Assessment for

Clopy ralid U ses on garden beets, crambe, mustard seed, rapeseed, cranberry, flax , canola, mustard greens, head and stem brassica, hops, spinach, strawberries, turnips, stone fruit crop group, sweet corn, and popcorn.Page 25 of 33

D361787, M. Doherty, 27 October 2009 . Clopy ralid

– Petition for Tolerances on Swiss chard, Bushberry

Subgroup 13 - 07B, and Strawberry (Regional Restriction). Summary of Analy tical Chemistry

and Residue Data . PP No. 8E7481. D 368855, M. Doherty, 27 October 2009 . Clopy ralid

– Acute and Chronic Combined D ietary (Food + Drinking Water) Exposure and Risk Assessments .Page 26 of 33

Appendix A: Toxicology Assessment A.1 Toxicology Data Requirements The requirements (40 CFR 158.340) fo r non - food use for clopyralid are shown in Table A.1 and are based on the revised 40 CFR, Part 158 guidelines (March, 2009). Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used. Test Technical Required Sati sfied 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 y es 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 yes yes

yes 1 yes

- no 870.3700a Developmental Toxicity (ro dent) ................................ ... 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 ................ 870.5300 Mutagenicity

— Structural Chromosomal Aberrations ... 870.5550 Mutage nicity

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

yes yes yes 870.6100a Acute Delayed Neuroto x icity (hen) ............................... 870.6100b 90 - Day

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

Neuro toxicity Screening Battery (rat) ............... 870.6300 Develop. Neur otoxicity ................................ ................. no no yes yes no -

- no no

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

- 870.7800 Immunotoxicity ............................................. yes no Special Studies for Ocular Effects

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

-

- 1 Satisfied by 870.4100 b, chronic dog 2 Satisfied by 870.4300, rat combined chronic toxicity/carcinogenicity 3 Satisfied by overall negative genotoxicity database including h ost - mediated assay of S. typhimurium A.2 Toxicity ProfilesPage 27 of 33

Table A . 2 .a. Acute Toxicity Profile for Clopyralid Guideline Number Study Type

Classification MRID

Number Results Toxicity Category 870.1100 Ac ute - oral - rat 4164 1301 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 41848300 LC 50 (M/F) > 5mg/L IV 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.b. Subchronic, Chronic and Other Toxicity Prof ile for Clopyralid GDLN Study Type/

Classification Dose Levels MRID Results 870.31 0 0 13 Week Feeding Mouse (1983) Acceptable/Guideline 0, 2 00, 7 50, 2 000 , 5000 mg/kg/day 00127276 NOAEL = 2000 mg/kg/day (M/F) LOAEL = 5000 mg/kg/day (M/F ) , based on decreased body weight gain 870.3100 13 Week Feeding - Rat No study available. Requirement satisfied by subchronic study in mo use (870.3100) and chronic/carcinogenicity study in rat (870.4300) 870.3150 13 Week Capsule Dog No study available. Requirement satisfied by chronic dog study (870.3200b) . 870.3200 21 - day Dermal

Toxicity

– Rabbit (1990) Acceptable/Guideline 0, 100, 500, 1000 mg/kg/day 41790701 NOAEL ≥ 1000 mg/kg/day (limit dose) LOAEL = not attained (>1000 mg/kg/day) No local dermal irritation wa s observed 870.3465 28 - Day Inhalation Toxicity - Rat No study available. Study required under revised 40 CFR Part 158 Guidelines. 870.3700 Developmental

Toxicity - Rat (gavage) (1981) Acceptable/guideline 0, 15, 75, 250 mg/kg/day 00127279 Maternal NOAEL = 75 mg/kg/day LOAEL = 250 mg/kg/day, based on mortality, reduced body weight gains and reduced food consumption Developmental NOAEL ≥ 250 mg/kg/d ay LOAEL = not attained (>250 mg/kg/day).Page 28 of 33

Table A . 2.b. Subchronic, Chronic and Other Toxicity Prof ile for Clopyralid GDLN Study Type/

Classification Dose Levels MRID Results 870.3700 Developmental

Toxicity - Rabbit (gavage) (1990) Acceptable/Guideline 0, 15 , 11 0, 250 mg/kg/day 41649801, - 02 Maternal NOAEL = 110 mg/kg/day LOAEL = 250 mg/kg/day , based on mo rtality, decreased body weight gains and food consumption and lesions in the gastric mucosa Developmental NOAEL = 110 mg/kg/day LOAEL = 250 mg/kg/day , based on decreased fetal body weight and hydrocephalus 870.3800 2 - Generation

Reproduction - Rat ( feeding ) (1983) Acceptable/Guidelin e 0, 150, 500, 1 500 mg/kg/day 00138155 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 = not 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 . 870.4100 and 870.4200 104 Week Chronic

Toxicity and 104 Week Carcinogenicity in Rat, respectively Requirement satisfied by 870.4300Page 29 of 33

Table A . 2.b. Subchronic, Chronic and Other Toxicity Prof ile for Clopyralid GDLN Study Type/

Classification Dose Levels MRID Results 870.4100 52 Week Capsule - Dog

(1984) Ac ceptable/ Guideline 0, 100, 320, 1000 mg/kg/day 00158256 NOAEL = 100 mg/kg/day (M/F ): LOAEL = 320 mg/kg/day (M/F ) , 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 observed at high dose. 870.4200 24 - mo nth

C arcinogenicity

– Mice (feeding) (1984) Acceptable/Guideline 0, 100, 500, 2000 mg/kg/day 00157783 NOAEL = 500 mg/kg/day (males); 2000 mg/kg/day (females) LOAEL = 2000 mg/kg/day (males ) , based on decreased body weight/weight gain and decreased food efficiency. No e vidence of carcinogenicity 870.4300 104 Week Combined

Chronic Toxicity/ Carcinogenicity - Rat ( feeding ) (1986) Acceptable/Guideline 0, 15, 150 or 1500 mg/kg/day 00162393 ,

00162434 NOAEL = 15 mg/kg/day

(M/F) LOAEL = 150 mg/kg/day (M/F), based on gastric lesions (epithelial hyperplasia and thickening of the limiting ridge). At 1500 mg/kg/day, decreased body weight gains and food consumption was observed. No e vidence of car cinogenicity 870.5100 Bacterial Reverse

Mutation Assay Study not submitted. Not required due to lack of tumorigenicity in rat/mouse bioassays and negative findings in all other genotoxicity assays. 870.5300 In Vitro and In Vivo

Host Mediated Assay ( Sa lmonella strains TA 1530, G - 46 and Saccharomyces strain D - 3) (1973) In vivo assays were conducted using mice 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 000 57086 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.Page 30 of 33

Table A . 2.b. Subchronic, Chronic and Other Toxicity Prof ile for Clopyralid GDLN Study Type/

Classification Dose Levels MRID Results 870.53 8 5 In V

iv o M icronucleus assay, Rat (1973) A cceptable/Guideline 0, 4, 40 or 4 00 mg/kg for one day or for 5 days to male rats; sacrifice at 6, 24 or 48 hrs postdosing for all groups. 00073638 Negative

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

870.5450 Domin ant Lethal

Assay in Rats (1973) Acceptable/Guideline 4, 40 or 400 mg/kg/day for 5 days to male rats prior to mating 00059053,

00099100 Negative

– no evidence of

treatment - related resorptions. 870.5550 Unscheduled DNA

Synthesis, Rat Hepatocytes (1985, 1 990) 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 00156387

41790702 Negative

– no evidence of

increased unscheduled DNA synthesis in the initial or supplementary assays testing up to insoluble/toxic concentrations. 870.6200 Ac ute Gavage

Neurotoxicity - Rat Study not submitted. Required under revised 40 CFR Part 158 . 870.6200 Subchronic Dietary

Neurotoxicity

–Rat Study not submitted. Required under revised 40 CFR P art 158. 870.7485 Metabolism

– Rat

(1991) Acceptable/Guideline 5.0 and 50 mg/kg, single oral doses; 5.0 mg/kg, single IV dose and 5.0 mg/kg/day, repeated daily dose for 14 days 41790703 Clopyralid was rapidly and completely absorbed and eliminated, with 95 - 115% of the total administered dose recovered by 72 hr, and most of that within 6 - 12 hrs postdosing. Almost all radioactivity was eliminated via urine regardless of dose or route of administration (91 - 113% of dose), with <4% excreted in the feces. Tissue retenti on was negligible (<0.01% of dose). There was essentially no metabolism of clopyralid; only parent compound was identified. No significant gender, dose or exposure route differences were identified. 870.7800 Immunotoxicity Study not submitted. Require d under revised 40 CFR Part 158.Page 31 of 33

A.3 Rationale for Toxicology Data Requirements Table A. 3.a Guideline Number: 870.3465 Study Title: 28 - or 90 - Day Inhalation Toxicity Rationale for Requiring the Data This study is required if there is the likelihood of significant repeated inhalation exposure to the pesticide as a gas, vapor or aerosol. The Agency has determined that there are potential inhalation exposures to mixers, loaders and applicators, as we ll as potential postapplication exposures, associated with clopyralid applications. The inhalation study may potentially be shortened (i.e., 28 - day exposure) as appropriate to exposures from current use patterns. Because toxicity via the inhalation route may differ from that observed following oral dosing, the study is required to better assess potential effects resulting from inhalation exposure and provide a refined assessment of risk from inhalation exposure. Practical Utility of the Data How did the Agency make its re - registration decision without these data? In the absence of inhalation toxicity studies on a pesticide , The Agency estimates occupational risk from inhalation exposure by using the most sensitive oral endpoint appropriate for a given exposure scenario. To account for route - to -route extrapolation, 100% absorption is assumed . How will the data be used? An inhalation study may result in changes to the endpoints and how the risks are quantified. These animal studies can be use d to select endpoints and doses for use in risk assessment of all exposure scenarios and are considered a primary data source for reliable reference dose calculation. How could the data impact the Agency’s future decision - making? The Agency does not have a full picture of the potential effects which could occur as a result of exposure via the inhalation route. In some cases, toxicity observed via the inhalation route is higher than toxicity observed via oral exposure, which means that route - to -route extra polation could result in an underestimation of risks from inhalation. The study may be used to confirm that no further mitigation is needed for uses where inhalation exposure occurs.Page 32 of 33

Table A . 3.b Guideline Number: 870.6200 Study Title: Acute & Sub chronic Neurotoxicity Rationale for Requiring the Data The acute and subchronic neurotoxicity studies are a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide (food and non - food uses). The Neur otoxicity Test Guideline (OPPTS 870.6200) prescribes functional and structural neurotoxicity testing and is designed to evaluate the potential of a repeated chemical exposure to produce adverse effects on the nervous system. Although some information on n eurotoxicity may be obtained from standard guideline toxicity study data, studies not specifically conducted to assess neurotoxic endpoints may be inadequate to characterize a pesticide’s potential neurotoxicity. While data on clinical signs of toxicity o r histopathology in routine chronic or subchronic toxicity studies may offer useful information on potential neurotoxic effects, these endpoints alone may be insufficient to detect more subtle neurological effects. Practical Utility of the Data How wil l the data be used? Neurotoxicity studies provide critical scientific information needed to characterize potential hazard to the human population on the nervous system from pesticide exposure. Since epidemiologic data on the effects of chemical exposures on neurologic parameters are limited and may be inadequate to characterize a pesticide’s potential neurotoxicity in humans, animal studies are used as the most sensitive endpoint for risk assessment. These animal studies can be used to select endpoints an d doses for use in risk assessment of all exposure scenarios and are considered a primary data source for reliable reference dose calculation. How could the data impact the Agency's future decision - making? If the neurotoxicity studies show that the test material poses either a greater or a diminished risk than that given in the interim decision’s conclusion, the risk assessments for the test material may need to be revised to reflect the magnitude of potential risk derived from the new data. If the Agen cy does not have these data, a 10X database uncertainty factor may be applied for conducting a risk assessment from the available studies.Page 33 of 33

Table A.3.b Guideline Number: 870.7800 Study Title: Immunotoxicity Rationale for Requiring the Data The immun otoxicity study is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide (food and non - food uses). The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity testing and is designed to evaluate the potential of a repeated chemical exposure to produce adverse effects (i.e., suppression) on the immune system. Immunosuppression is a deficit in the ability of the immune system to respond to a challenge of bacterial or viral infections such as tuberculosis (TB), Severe Acquired Respiratory Syndrome (SARS), or neoplasia. Because the immune system is highly comple x , studies not specifically conducted to assess immunotoxic endpoints are inadequate to characterize a pesticide’s potential immunotoxicity. While data from hematology, lymphoid organ weights, and histopathology in routine chronic or subchronic toxicity studies may offer useful information on potential immunotoxic effects, these endpoints alone are insufficient to pre dict immunotoxicity. Practical Utility of the Data How will the data be used? Immunotoxicity studies provide critical scientific information needed to characterize potential hazard to the human population on the immune system from pesticide exposure. S ince epidemiologic data on the effects of chemical exposures on immune parameters are limited and are inadequate to characterize a pesticide’s potential immunotoxicity in humans, animal studies are used as the most sensitiv e endpoint for risk assessment. These animal studies can be used to select endpoints and doses for use in risk assessment of all exposure scenarios and are considered a primary data source for reliable reference dose calculation. For example, animal studi es have demonstrated that immunotoxicity in rodents is one of the more sensitive manifestations of TCDD (2,3,7,8 - tetrachlorodibenzo -p - dioxin) among developmental, reproductive, and endocrinologic toxicities. Additionally, the EPA has established an oral reference dose (RfD) for tributyltin oxide (TBTO) based on observed immunotoxicity in animal studies (IRIS, 1997). How could the data impact the Agency's future decision - making? If the immunotoxicity study shows that the test material poses either a great er or a diminished risk than that given in the interim decision’s conclusion, the risk assessments for the test material may need to be revised to reflect the magnitude of potential risk derived from the new data. If the Agency does not have these data, a 10X database uncertainty factor may be applied for conducting a risk assessment from the available studies.