UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 

OFFICE OF PREVENTION, PESTICIDE

AND TOXIC SUBSTANCES

MEMORANDUM

Date: 3 December 2009

SUBJECT: Clopyralid – Human Health Risk Assessment to Evaluate New Uses on Swiss 

Chard, Bushberry Subgroup (13-07B), and Strawberry (Regional Restriction).

PC Code: 117401 (alkanolamine 

salts), 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

TXR No.: NA CAS Nos.: 1702-17-6 (acid)

57754-85-5 (monoethanolamine salt)

MRID Nos.: 47604401, 47604402, 

47604403

40 CFR: 180.431 

FROM: Michael A. Doherty, Ph.D., Senior Chemist

Linnea Hansen, Ph.D., Toxicologist

Suku Oonnithan, Biologist

Risk Assessment Branch II

Health Effects Division (7509P)

THROUGH: Edward Scollon, Ph.D., Toxicologist

Zaida Figueroa, Industrial 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 Use, 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 Physical 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 Information from Literature 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 Residual Uncertainties for Preand/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 Incidental Oral Exposure (Short-Term)...........................................................14

3.5.4 Incidental Oral Exposure (Intermediate-Term) ...............................................14

3.5.5 Dermal Absorption...........................................................................................14

3.5.6 Dermal Exposure (Short-, Intermediate- and Long-Term)..............................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.............................................. 18
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5.2 Analytical 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 Residential 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 ............................................................ 31
Page 4 of 33

1.0 Executive Summary

The Interregional Research Project No.4 (IR-4) has petitioned the Agency to register clopyralid,

a pyridinoxy 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 system. A use on strawberry grown as a perennial crop has already 

been established. HED has reviewed the available toxicological and residue chemistry studies 

for clopyralid and is recommending that the requested uses be conditionally registered and that 

permanent tolerances be established.

No mammalian target organ was identified in the clopyralid toxicological studies submitted to 

the Agency. Effects were noted in various organs and systems, 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 clopyralid 

as effects in offspring were only observed at doses that caused severe toxicity in the maternal 

animals. There are no indications of neurotoxic or immunotoxic activity and clopyralid has been 

classified as not likely 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 environmental conditions show clopyralid to be 

relatively stable. In animals, the compound is rapidly absorbed and essentially completely 

excreted as the parent compound, although some conjugation to glycine 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 13-07B).

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 clopyralid, 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 Low-Income Populations" 

http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf). As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 
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 analyzed and categorized by subgroups based 

on age, season of the year, ethnic group, and region of the country. Whenever appropriate, nondietary 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 

postapplication are evaluated. Further considerations are currently in development as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary

patterns among specific subgroups.

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 (ethically conducted) for use in risk assessments.

2.0 Ingredient Profile

Clopyralid [3,6-dichloro-2-pyridinecarboxylic acid] is a pyridine herbicide registered for use on 

a variety of food and feed crops in the U.S. for the postemergence control of broadleaf weeds, 

particularly thistles and clover. Permanent tolerances are established for residues of clopyralid 

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 clopyralid in livestock 

commodities at levels ranging from 0.1 ppm in eggs to 36 ppm in meat byproducts, except liver, 

of cattle, goats, horses and sheep. There are currently no tolerances for inadvertent or indirect 

residues of clopyralid.

2.1 Summary of Proposed Uses

In the current petition (PP#8E7481), IR-4 is proposing to expand the use of clopyralid to include 

applications to Swiss chard and bushberries for the postemergence control of various weeds. In 

addition, IR-4 is proposing a regionally restricted use on strawberries grown only in FL and NC 

under an annual-type production system. There is currently a use on strawberries grown as a 

perennial crop (DP# 270507, 8/6/2002, D. Dotson). The proposed end-use product is an 

emulsifiable concentrate containing 3 pounds acid equivalent (ae) clopyralid per gallon.
Page 6 of 33

Table 2.1. 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

(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 minimum 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 10 

gal/A, with a minimum 

RTI of 14 days. Do not 

apply by 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, 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.

2.2 Structure and Nomenclature

Table 2.2. Clopyralid Nomenclature.

Compound

N

Cl

Cl

O

O

OH

NH3

+

Common name Clopyralid, monoethanolamine salt

Company experimental name Dowco 290

IUPAC name 3,6-dichloropyridine-2-carboxylic acid, monoethanolamine salt

CAS name 3,6-dichloro-2-pyridinecarboxylic acid, monoethanolamine salt

CAS registry number 1702-17-6 (acid)

57754-85-5 (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

Table 2.3. Physicochemical Properties of Technical Grade Clopyralid Acid.

Parameter Value Reference

Melting point/range 149.6 Data were obtained from the 

FOOTPRINT Pesticide 

Properties DataBase, 

(http://www.eufootprint.org/ppdb.html).

pH Not available

Density (specific gravity) 1.76 g/mL

Water solubility (g/L) at 20°C 143

Solvent solubility (g/L) at 20°C Acetone – 250

Ethyl acetate – 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 absorption spectrum Not available

3.0 Hazard Characterization/Assessment

This hazard characterization updates the previously prepared assessment of September 26, 2002 

(D270885). No additional toxicology studies 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 considered 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

Clopyralid is an herbicide of the pyridinoxy 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 metabolism 

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 toxicology database for clopyralid 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 (§870.6200a 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 

DCI Tables (see Appendix A.3). 

3.1.2 Toxicological Effects

The acute toxicity of clopyralid is low (Toxicity Category IV) via oral, inhalation and dermal 

exposure and it is not a dermal irritant or sensitizer. In its acid form, clopyralid is a severe eye 

irritant (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 systemic toxicity or local dermal irritation was observed in rabbits following 

dermal exposure to the limit dose for 21 days. Subchronic inhalation data are not available.

Toxicity was observed in the rat and dog following chronic exposure, but consistent target 

organs were not identified. In a 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 hyperplasia 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 decreased 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 lesions. 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).

Acute 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-year bioassays at doses 

exceeding the limit dose. No positive findings for mutagenicity or clastogenicity were observed 

in a battery of mutagenicity studies (bacterial reverse gene mutation, in vitro and in vivo host 
Page 9 of 33

mediated assays in Salmonella and Saccharomyces, in vivo chromosomal aberrations, 

unscheduled DNA synthesis, dominant lethal activity). Clopyralid is therefore classified as “not 

likely to be carcinogenic to humans.”

Clopyralid is rapidly 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 endpoints selected for this human health risk assessment of clopyralid 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 days of dosing 

(gestation days 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 chronic 

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 were 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 LOAEL) 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 LOAEL of 150 

mg/kg/day. The finding was reported by 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 clopyralid; therefore, oral studies were selected with an 

assumption of 100% absorption (relative to oral). The rat developmental toxicity study NOAEL 
Page 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 FQPA

HED recommends reduction of the FQPA special factor to 1X. 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 immunotoxicity 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 endpoints selected for risk assessment are therefore considered adequately 

protective of pre- and/or postnatal toxicity. Furthermore, exposure estimates in the risk 

assessment are health-protective and likely overestimate exposures.

3.2 Absorption, Distribution, Metabolism, Excretion (ADME)

Metabolism of clopyralid was evaluated in the rat. Clopyralid was essentially completely 

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 by 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 FQPA 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 

clopyralid under the revised 40 CFR Part 158 guidelines. A 28-day inhalation toxicity study in 

rats is also required for assessment of inhalation exposure risk, but the selected oral endpoints, 

with an assumption of 100% absorption relative to oral absorption, are considered adequately 

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 

toxicity, 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 Toxicity and Developmental Neurotoxicity Studies

In a developmental toxicity study in the rat (MRID 00127279), pregnant Fischer 344 rats were 

administered clopyralid (97.0% a.i.) by gavage at 0, 15, 75 or 250 mg/kg/day from gestation days 

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/kg/day).

In a second developmental toxicity study (MRID 41649801), pregnant New Zealand White 

rabbits were administered clopyralid (96.1-96.4% a.i.) by gavage at doses of 0, 50, 110 or 250 

mg/kg/day from gestation days 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 decreased mean fetal body weight and 

hydrocephalus. The NOAEL was 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), clopyralid (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 

mg/kg/day as decreased body weights, body weight gains and food consumption in F0 and F1 

males and females, and slight focal hyperkeratotic 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 LOAEL of 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; the 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 clopyralid.

3.3.6 Pre-and/or Postnatal Toxicity
Page 12 of 33

3.3.6.1 Determination of Susceptibility

There was no evidence of increased pre- and/or postnatal qualitative or quantitative 

susceptibility. In the rat developmental study, no developmental toxicity was observed at a 

maternally toxic dose and in the two-generation reproduction study, decreased pup weight (postnatal Day 28) and increased relative liver weights were observed at the parental LOAEL. 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 Uncertainties for Pre- and/or Postnatal 

Susceptibility

There is low concern for increased pre- and/or postnatal qualitative or quantitative susceptibility. 

Increased 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 only 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 increased at a maternally 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 Recommendation Regarding a Developmental Neurotoxicity Study

A developmental neurotoxicity study is not recommended at this time, based on low concern for 

neurotoxicity. Neuropathology (hydrocephalus) 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 

chronic studies. 

3.4 FQPA Safety Factor for Infants and Children

HED recommends reduction of the 10X FQPA safety factor for protection of infants and children 

to 1X. Increased qualitative or quantitative pre- and/or postnatal susceptibility was not observed 

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, healthprotective assumptions and further support 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. Based on the lack of concerns for neurotoxicity and 

immunotoxicity in the existing database and selection of endpoints which are adequately 

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 Selected: 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 LOAEL of 250 mg/kg/day.

Uncertainty Factor(s): An UF of 100 was applied to account for inter-species extrapolation 

(10X) and intra-species variation (10X). 

Comments on Study/Endpoint/Uncertainty Factors: The rat developmental toxicity study with a 

maternal toxicity NOAEL of 75 mg/kg/day is of an appropriate 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 days 6-15). The first calculation of 

maternal weight gain and food consumption was conducted for days 6 through 9 of gestation 

(days 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

NOAEL of 110 mg/kg/day).

Acute RfD = 75 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 hyperplasia and 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 

(10X) and intra-species variation (10X). 

Comments on Study/Endpoint/Uncertainty Factors: The 2-year rat chronic 

toxicity/carcinogenicity study 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 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 rabbit study and rat reproduction study. The NOAEL is lower than all endpoints 
Page 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, based 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 (10X) 

and intra-species variation (10X).

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 days 6 through 15). The first calculation of maternal 

weight gain and food consumption was determined for gestation days 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 hyperplasia, 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 

(10X) and intra-species variation (10X). 

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 clopyralid. A 21-day dermal toxicity 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 clopyralid. 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 presence 
Page 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 (10X) 

and intra-species variation (10X).

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 

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.

3.5.8 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 

hyperplasia 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 extrapolation (10X) 

and intra-species variation (10X).

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 they 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 endpoint 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/A
Page 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 dermal exposure is anticipated from residential use of clopyralid, 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 clopyralid 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 

young children. 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.

3.5.11 Classification of Carcinogenic Potential

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 exceeded the limit dose. 

Genotoxicity studies were negative. In accordance with the EPA’s Final Guidelines for 

Carcinogen Risk Assessment (March, 2005), clopyralid is classified as “not likely to be 

carcinogenic to humans.” 

3.5.12 Summary of Toxicological Doses and Endpoints for Use in Human Risk 

Assessments

Table 3.5.12a. Toxicological Doses and Endpoints for Clopyralid for Use in Dietary and Residential Human 

Health Risk Assessments.

Exposure/

Scenario

Point of 

Departure

Uncertainty/FQP

A Safety Factors

Level of Concern 

for Risk Assessment

Study and Toxicological Effects

Acute Dietary (All 

populations including 

infants and children) 

NOAEL = 75 

mg/kg

UFA= 10X

UFH= 10X

SFFQPA=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

UFA= 10X

UFH= 10X

SFFQPA=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 
Page 17 of 33

Table 3.5.12a. Toxicological Doses and Endpoints for Clopyralid for Use in Dietary and Residential Human 

Health Risk Assessments.

Exposure/

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

UFA= 10X

UFH= 10X

SFFQPA=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

UFA= 10X

UFH= 10X

SFFQPA=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 

months, respectively) 

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. No 

quantification of risk is required.

Inhalation, Shortterm (1-30 days)Oral study

NOAEL = 75 

mg/kg/day

(inhalation 

absorption rate = 

100% of oral)

UFA= 10X

UFH= 10X

SFFQPA=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= 15 

mg/kg/day

(inhalation 

absorption rate = 

100% of oral)

UFA= 10X

UFH= 10X

SFFQPA=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 observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = 

extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human 

population (intraspecies). UFL = use of a LOAEL to extrapolate a NOAEL. SFFQPA = 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 

Human Health Risk Assessments.

Exposure/

Scenario

Point of Departure Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Dermal, Shortand 

Intermediateterm (1-30 

days and 1-6 

months, 

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 

UFA= 10X

UFH= 10X

SFFQPA=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 

Human Health Risk Assessments.

Exposure/

Scenario

Point of Departure Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

rate = 100% of oral 

absorption)

based on decreased body weight gain and 

food consumption during GD 6-9.

Inhalation, 

Intermediateterm

(1-6 months)

NOAEL = 15 

mg/kg/day (default 

inhalation absorption 

rate = 100% of oral 

absorption)

UFA = 10X

UFH = 10X

SFFQPA = 1

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. UFA = 

extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human 

population (intraspecies). SFFQPA = 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 by a naturally 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 thyroid hormone systems, in addition to the estrogen hormone system. 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 evaluations. As the science develops and resources allow, 

screening of additional hormone systems 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, clopyralid 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 provide more information on 

endocrine effects, EPA will consider whether further testing of clopyralid is appropriate.

4.0 Public Health and Pesticide Epidemiology Data

Public health and pesticide epidemiology data were not used for this risk assessment.

5.0 Dietary Exposure/Risk Characterization

5.1 Pesticide Metabolism and Environmental Degradation
Page 19 of 33

The nature of the residue in plants is adequately understood for purposes of this petition based on 

the acceptable cabbage, grass, barley and wheat metabolism studies. In each of these studies, the 

major 14C-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 clopyralid. Additional 

metabolism studies may be required in the future should the petitioner request the establishment 

of clopyralid tolerances for additional crops.

In livestock, the major residues are the parent clopyralid as well as its glycine conjugate (3,6-

DCPA-glycine). 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 photolysis and 

anaerobic metabolism and is moderately stable to aerobic metabolism. Due to its stability and 

high mobility, clopyralid 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. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance 

Expression

Matrix Residues included in Risk 

Assessment

Residues included in 

Tolerance Expression

Plants 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 Analytical Methodology

An adequate gas chromatography/electron-capture detection (GC/ECD) method (Method ACR 

75.6) is available for enforcing the proposed tolerances and collecting data on residues of 

clopyralid in Swiss chard, blueberries and strawberries. Residues 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 methylated using diazomethane, 

concentrated to dryness, re-dissolved in toluene, cleaned up using an activated Alumina A 

column, and eluted with toluene. The methylated residues are analyzed by GC/ECD using 

external standards. Residues are expressed in terms of parent clopyralid using a conversion 

factor of 0.93. The lowest level of method validation (LLMV) for clopyralid in each commodity

is 0.05 ppm.

5.3 Food Residue Profile

Adequate supervised crop field trials have been conducted to support tolerances for clopyralid 

in/on swiss chard, bushberry, and strawberry. The trials resulted in quantifiable residues of 

clopyralid 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 

Swiss chard and strawberry show a proportionate relationship between application rate and 
Page 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 clopyralid labels.

5.3.2 International Residue Limits

There are no Codex or Mexican maximum residue limits (MRLs) for residues of clopyralid in/on 

the requested commodities (Appendix I). However, there are Canadian MRLs for residues of 

clopyralid at 1.0 mg/kg on strawberry and 0.1 mg/kg on blueberry. The Canadian MRL for 

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 harmonized with the Canadian MRLs.

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 clopyralid use on sites that are highly vulnerable (D361314, A. Shelby, 9 

September 2009). Of the requested uses, bushberry had the greatest single application rate and 

was used to model estimated drinking water concentrations (EDWCs) of clopyralid. Non-crop 

uses of clopyralid have greater application rates than those of bushberry and were also used to 

obtain EDWCs (Table 5.4). HED has used the maximum acute and chronic EDWCs (45.0 and 

11.9 ppb, respectively) from non-crop uses of clopyralid in its dietary assessment.

Table 5.4. Maximum Tier 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) Acute and Chronic 0.39

Groundwater (monitoring) NAWQA, Alabama Acute 13

Surface water (FIRST) Bushberry (0.25 lbs a.i./A) Acute 41.1

Bushberry (0.25 lbs a.i./A) Chronic 10.8

Non-crop (0.5 lbs a.i./ A) Acute 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 Surveys of 

Food Intakes by Individuals (CSFII) from 1994-1996 and 1998.

The acute and chronic assessments are highly conservative with regard to protecting human 
Page 21 of 33

health. Both assessments assume 100% crop treated and are based on tolerance-level residues 

for all commodities. Modeled estimates of clopyralid residues in drinking water have been 

incorporated into the analyses. Children 1-2 years old are estimated to have the highest dietary

exposure to clopyralid. The screening-level estimates for that subpopulation are 9% of the acute 

population-adjusted dose (aPAD) and 23% of the chronic population-adjusted dose (cPAD). 

Generally, HED is concerned about dietary risk when the exposure estimate exceeds 100% of the 

PAD. Therefore, the combined dietary risk from residues of clopyralid in food and drinking 

water are below HED’s level of concern for all population groups (Table 5.5).

Table 5.5. Summary of the Combined Dietary (Food + Drinking Water) Exposure and Risk Estimates for 

Clopyralid.

Population Subgroup

Acute (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 old 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) Exposure/Risk Characterization

There are no new residential uses for clopyralid associated with the subject petition and HED has 

used the previous residential exposure estimates (D270507, 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 not of concern for clopyralid; therefore, residential risks result solely from 

incidental oral and inhalation exposures.

6.1 Residential Handler Exposure

Inhalation exposures were estimated for homeowners using push-type granular spreaders, lowpressure 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 

2.2×106. The level of concern for residential 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 exposure of clopyralid by toddlers from turf treated with Lontrel 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 clopyralid directly from treated turf. The incidental oral 
Page 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 Other (Spray Drift, etc.)

Spray drift is always a potential source of exposure to residents living in close proximity to 

spraying operations. This situation is particularly the case with aerial application. However, to a 

lesser extent, spray drift resulting from the ground application of clopyralid 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 Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, and is developing a policy on how to apply

appropriately the data and the AgDRIFT computer model to its risk assessments for pesticides 

applied by air, orchard airblast, and ground hydraulic methods. After the policy is in place, the 

Agency may impose further refinements in spray drift management practices to reduce off-target 

drift 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; therefore, 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 clopyralid, 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 measures of background dietary exposure). The 

aggregate MOEs are summarized in Table 7.2 and represent risks that are below HED’s level of 

concern.

Table 7.2. Summary of Short- and Intermediate-Term Aggregate Risks for Clopyralid.

Population NOAEL, 

mg/kg/day

LOC Dietary 

Exposure, 

mg/kg/day

Dietary 

MOE

Residential

Activity

Residential

MOE

Aggregate 

MOE*

Short-Term

Adult Handler 75 100 0.013212 5,600 Application

(Inhalation)

2,200,000 5,500
Page 23 of 33

Children 1-2 years old 75 100 0.035056 2,100 Incidental Oral 

(Hand-to-Mouth)

10,000 1,700

Intermediate-Term

Children 1-2 years old 15 100 0.035056 420 Incidental Oral

(Hand-to-Mouth)

5,800 390

* Aggregate MOE = 1÷ [(1÷MOEDietary) + (1÷MOEResidential)]

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

Clopyralid has been classified as “Not Likely 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 clopyralid and any other substances and clopyralid does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 

EPA has not assumed that clopyralid has a common mechanism of toxicity with other 

substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Pathway

An occupational risk assessment to address the requested uses of clopyralid 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 equipment (PPE), occupational risk estimates are expected 

to be below HED’s level of concern.

10.0 Data Needs and Label/Regulatory Recommendations

10.1 Toxicology

In order 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 Neurotoxicity
Page 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 

clopyralid. Prior to registration, the label should be modified to prohibit application of 

clopyralid to low-bush varieties of bushberry.

The tolerance definition for clopyralid should be revised to read as follows:

Tolerances are established for residues of the herbicide clopyralid, 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 by 

measuring only clopyralid [3,6-dichloro-2-pyridinecarboxylic acid] in or on the commodity.

HED is recommending that tolerances for residues of clopyralid 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 trial data are available.

Bushberry 

subgroup 13-07B

6.0 0.50 Adequate field trial data are available*.

Cranberry 4.0 4.0 The tolerance for cranberries should remain due to 

differences in use pattern and residue level versus the 

currently proposed use on bushberry.

Strawberry 4.0 4.0 Adequate field trial data are available to support a 7-

day PHI for strawberries grown under an annual-type 

production system in FL and NC only. This 

tolerance will supersede the existing 1.0-ppm

tolerance already established for strawberry (grown 

under a perennial production system).

* The Summary of Analytical Chemistry and Residue Data (D361787, M. Doherty, 27 October 2009) recommends 

that the tolerance be 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:

D270885, D. Dotson, 26 September 2002. PP No. 4F4379: Human Health Risk Assessment for 

Clopyralid Uses 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. Clopyralid – Petition for Tolerances on Swiss chard, 

Bushberry Subgroup 13-07B, and Strawberry (Regional Restriction). Summary of 

Analytical Chemistry and Residue Data. PP No. 8E7481.

D368855, M. Doherty, 27 October 2009. Clopyralid – Acute and Chronic Combined Dietary

(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) for 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 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

yes

yes

yes1

yes

-

no

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

yes2

yes 

yes2

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial.....................

870.5300 Mutagenicity—Gene Mutation - mammalian................

870.5300 Mutagenicity—Structural Chromosomal Aberrations...

870.5550 Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

yes3

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

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

Acute Oral (rat)...........................................................

Subchronic Oral (rat) ..................................................

Six-month 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 host-mediated assay of S. typhimurium

A.2 Toxicity Profiles
Page 27 of 33

Table A.2.a. Acute Toxicity Profile for Clopyralid

Guideline 

Number

Study Type

Classification

MRID

Number

Results Toxicity Category

870.1100 Acute-oral-rat 41641301 LD50 (M/F) >5,000 

mg/kg 

IV

870.1200 Acute-dermal-rat 41641302 LD50 (M/F) > 5000 

mg/kg

IV

870.1300 Acute-inhalation-rat 41848300 LC50 (M/F) > 

5mg/L

IV

870.2400 Acute-eye irritationrabbit41641304 Severe irritation at 

7 days (corrosive)

I

870.2500 Acute-dermal 

irritation-rabbit

41641305 Not an irritant IV

870.2600 Skin sensitization -

guinea pig

41641306 Not a sensitizer -

Table A.2.b. Subchronic, Chronic and Other Toxicity Profile for Clopyralid

GDLN Study Type/ 

Classification

Dose Levels MRID Results

870.3100 13 Week FeedingMouse (1983)

Acceptable/Guideline

0, 200, 750, 2000, 

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 

mouse (870.3100) and chronic/carcinogenicity study in rat (870.4300)

870.3150 13 Week CapsuleDogNo 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 

was 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/day

LOAEL = not attained

(>250 mg/kg/day).
Page 28 of 33

Table A.2.b. Subchronic, Chronic and Other Toxicity Profile for Clopyralid

GDLN Study Type/ 

Classification

Dose Levels MRID Results

870.3700 Developmental 

Toxicity-Rabbit 

(gavage) (1990)

Acceptable/Guideline

0, 15, 110, 250 

mg/kg/day

41649801, -02 Maternal NOAEL = 110 

mg/kg/day

LOAEL = 250 mg/kg/day,

based on mortality, 

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/Guideline

0, 150, 500, 1500 

mg/kg/day 

00138155 Parental NOAEL = 500 

mg/kg/day

(M/F)

LOAEL = 1500 

mg/kg/day(M/F), based on 

decreased body weights 

and body weight gain in F0

and F1 males; body 

weights in F1 and F2

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 F1

male pups and increased 

relative liver weights of 

F1a male and female pups 

and F1b male pups.

870.4100 and 

870.4200

104 Week Chronic 

Toxicity and 104 

Week Carcinogenicity 

in Rat, respectively

Requirement satisfied by 870.4300
Page 29 of 33

Table A.2.b. Subchronic, Chronic and Other Toxicity Profile for Clopyralid

GDLN Study Type/ 

Classification

Dose Levels MRID Results

870.4100 52 Week Capsule-Dog

(1984)

Acceptable/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-month 

Carcinogenicity –

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 evidence 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 evidence of 

carcinogenicity

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 

(Salmonella 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

00057086 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 Profile for Clopyralid

GDLN Study Type/ 

Classification

Dose Levels MRID Results

870.5385 In Vivo Micronucleus 

assay, Rat (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.

00073638 Negative – no evidence of 

an increase in the formation 

of chromosomal aberrations 

in bone marrow at any dose 

tested. 

870.5450 Dominant 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, 

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

00156387

41790702

Negative – no evidence of 

increased unscheduled 

DNA synthesis in the initial 

or supplementary assays 

testing up to insoluble/toxic 

concentrations.

870.6200 Acute 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 Part 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 retention 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. Required 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 well 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 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.

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 extrapolation 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 & Subchronic 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 Neurotoxicity 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 neurotoxicity 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 or 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 will 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 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? 

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 Agency 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 immunotoxicity 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 complex, 

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 predict 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. Since 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 sensitive 

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 studies 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 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 Agency does not have these data, a 10X database uncertainty factor may be applied for 

conducting a risk assessment from the available studies.