Clopyralid Human Health Risk Assessment DP Nos. D391397, D401055

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION

MEMORANDUM

Date: 6/6/2012

SUBJECT: Clopyralid. Human Health Risk Assessment for New Uses on Apples, Teff, 

Brassica Leafy Greens, and Rapeseed 

PC Code: 117403 (acid)

117401 (alkanolamine salt)

DP Barcode: D391397, D401055

Decision No.: 450262, 463332 Registration Nos.: 62719-73, 62719-80,

62719-81, and 62719-84 

Petition No.: 1E7882, 2E8013 Regulatory Action: Section 3 Registration

Risk Assessment Type: Single Chemical

Aggregate

Case No.: NA 

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

57754-85-5 (monoethanolamine salt)

MRID No.: NA 40 CFR: §180.431

FROM: Douglas A. Dotson, Ph.D., Chemist

Linnea Hansen, Ph.D., Toxicologist

Suku Oonnithan, Ph.D., Biologist

Registration Action Branch II

Health Effects Division (7509P)

THROUGH: Karlyn Middleton, M.S., Toxicologist

Michael A. Doherty, Ph.D., Chemist

Margarita Collantes, M.S., Biologist

Christina Swartz, Branch Chief

Registration Action Branch II

Health Effects Division (7509P)

TO: Laura Nollen/Barbara Madden, RM Team 5

RIMUERB

Registration Division (7505P)
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1.0 Executive Summary.......................................................................................................... 4

2.0 HED Recommendations................................................................................................... 7

2.1 Data Deficiencies/Conditions of Registration............................................................. 7

2.2 Tolerance Considerations............................................................................................. 7

2.2.1 Enforcement Analytical Method ............................................................................. 7

2.2.2 International Harmonization................................................................................... 7

2.2.3 Recommended Tolerances........................................................................................ 8

2.2.4 Revisions to Petitioned-For Tolerances .................................................................. 8

2.3 Label Recommendations.............................................................................................. 8

3.0 Introduction....................................................................................................................... 9

3.1 Chemical Identity.......................................................................................................... 9

3.2 Physical/Chemical Characteristics.............................................................................. 9

3.3 Pesticide Use Pattern .................................................................................................... 9

3.4 Anticipated Exposure Pathways................................................................................ 10

3.5 Consideration of Environmental Justice .................................................................. 11

4.0 Hazard Characterization and Dose-Response Assessment......................................... 17

4.1 Toxicology Studies Available for Analysis................................................................ 11

4.1.1 Sufficiency of Studies/Data..................................................................................... 11

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)............................ 12

4.2.1 Dermal Absorption ................................................................................................. 12

4.3 Toxicological Effects................................................................................................... 12

4.4 Safety Factor for Infants and Children (FQPA Safety Factor).............................. 13

4.4.1 Completeness of the Toxicology Database............................................................ 14

4.4.2 Evidence of Neurotoxicity ...................................................................................... 14

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ...... 14

4.4.4 Residual Uncertainty in the Exposure Database.................................................. 14

4.5 Toxicity Endpoint and Point of Departure Selections............................................. 14

4.5.1 Dose-Response Assessment .................................................................................... 14

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment... 16

4.5.3 Cancer Classification and Risk Assessment Recommendations......................... 16

4.5.4 Summary of Points of Departure and Toxicity Endpoints ................................ 16

5.0 Dietary Exposure and Risk Assessment........................................................................ 17

5.1 Metabolite/Degradate Residue Profile ...................................................................... 17

5.1.1 Summary of Plant and Animal Metabolism Studies ........................................... 18

5.1.2 Summary of Environmental Degradation ............................................................ 18

5.1.3 Comparison of Metabolic Pathways...................................................................... 18

5.1.4 Residues of Concern Summary and Rationale..................................................... 18

5.2 Food Residue Profile................................................................................................... 19

5.3 Water Residue Profile................................................................................................. 20

5.4 Dietary Risk Assessment ............................................................................................ 20

5.4.1 Description of Residue Data Used in Dietary Assessment .................................. 20

5.4.2 Percent Crop Treated Used in Dietary Assessment............................................. 21

5.4.3 Acute Dietary Risk Assessment ............................................................................. 21

5.4.4 Chronic Dietary Risk Assessment ......................................................................... 21

5.4.5 Cancer Dietary Risk Assessment........................................................................... 21

5.4.6 Summary Table....................................................................................................... 21
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6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................ 22

6.1 Residential Handler Exposure and Risk................................................................... 22

6.2 Residential Post-application Exposure ..................................................................... 23

6.3 Combined Residential Risk Estimates...................................................................... 24

6.4 Spray Drift................................................................................................................... 24

7.0 Aggregate Exposure/Risk Characterization................................................................. 24

7.1 Acute Aggregate Risk Estimates................................................................................ 24

7.2 Short-Term Aggregate Risk Estimates..................................................................... 25

7.3 Intermediate-Term Aggregate Risk Estimates ........................................................ 25

7.4 Chronic Aggregate Risk Estimates............................................................................ 26

7.5 Cancer Aggregate Risk Estimates............................................................................. 26

8.0 Cumulative Exposure/Risk Characterization .............................................................. 26

9.0 Occupational Exposure/Risk Characterization ........................................................... 26

9.1 Short-/Intermediate-Term Handler Risk ................................................................. 26

9.2 Occupational/Commercial Post-application Risk.................................................... 29

9.2.1 Post-application Inhalation Exposure................................................................... 29

10.0 References........................................................................................................................ 30

Appendix A. Toxicology Profile and Executive Summaries .................................................. 31

A.1 Toxicology Data Requirements.................................................................................. 31

A.2 Toxicity Profiles .......................................................................................................... 32

A.3 Hazard Identification and Endpoint Selection......................................................... 36

A.4 Executive Summaries.................................................................................................. 39

Appendix B. Clopyralid Physical/Chemical Properties ......................................................... 50

Appendix C. Review of Human Research................................................................................ 51
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1.0 Executive Summary

The Interregional Research Project Number 4 (IR-4) submitted a tolerance petition proposing the 

use of the herbicide clopyralid (3,6-dichloro-2-pyridinecarboxylic acid) on apples. As part of the 

same tolerance petition, IR-4 proposed to amend the Stinger® Herbicide label to expand the 

mustard greens use to the entire Brassica leafy greens subgroup (5B), and to expand the use on 

canola, crambe, and rapeseed to the entire Rapeseed subgroup (20A), except gold of pleasure. In 

addition, IR-4 submitted a separate tolerance petition for the use of clopyralid on teff.

Clopyralid 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. The enduse product that IR-4 proposed for use on these commodities is Stinger® Herbicide (EPA Reg. 

No. 62719-73), which is a 3 lb acid equivalent (ae)/gal emulsifiable concentrate (EC) 

formulation of the monoethanolamine salt of clopyralid.

The toxicology database for clopyralid is considered to be complete for characterizing hazard 

and assessing human health risk. Toxicity was observed in the rat and dog after chronic 

exposure, and the mouse after subchronic and chronic exposure, but consistent target organs 

were not identified. In dogs, reductions in red blood cell parameters, increased liver weight, and 

vacuolated adrenal cortical cells were observed, with skin lesions and clinical chemistry changes

at the highest dose. In rats, stomach lesions were observed at the LOAEL, and decreased body 

weight was observed at the high dose. In mice, the only observed effects were decreased body 

weight and weight gain. No effects were seen in a rabbit 21-day dermal study.

The available studies did not indicate any potential for neurotoxicity, immunotoxicity, or 

reproductive toxicity, and there is no evidence of increased qualitative or quantitative 

susceptibility of fetuses or offspring in developmental and reproduction studies. Additionally, 

the exposure estimates are based on conservative, health-protective assumptions.

Therefore, HED has reduced the required 10x Food Quality Protection Act (FQPA) Safety Factor 

to 1x.

Clopyralid is classified as “not likely to be carcinogenic to humans,” based on the lack of 

treatment-related tumors in the rat and mouse carcinogenicity studies and negative results of the 

genotoxicity assays.

HED selected endpoints for assessment of human health risk for chronic dietary exposure, 

occupational and residential inhalation exposure, and residential incidental oral exposure, based 

on the proposed and existing use patterns and the submitted toxicology studies. Acute dietary

risk was not evaluated because an appropriate endpoint (toxicity from a single dose) was not 

identified. Chronic dietary risk (food and drinking water) was evaluated based on gastric lesions 

in the rat chronic toxicity/carcinogenicity study. Short-term incidental oral exposure of young 

children was evaluated based on decreased maternal body weight gain in the rat developmental 

toxicity study. Dermal exposure was not evaluated because of the lack of toxicity via the dermal 

route. Inhalation exposure was assessed using endpoints and doses obtained from oral studies 

and route-to-route extrapolation. Short-term inhalation exposure was evaluated based on 

decreased maternal body weight gain in the rat developmental toxicity study. Intermediate-term 
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inhalation exposure was evaluated based on gastric lesions observed by six months’ exposure in 

the rat chronic toxicity/carcinogenicity study, which is considered to be protective for potential 

portal-of-entry effects to the lungs. 

The nature of the residue in plants and livestock is adequately understood based on acceptable 

metabolism studies in cabbage, grass, barley, wheat, goats, and poultry. In plants, the major 

residue was the parent compound. In livestock, the major residues are clopyralid and its glycine 

conjugate. No changes to the livestock tolerances are being made as a result of the new uses.

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. Because of 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.

The submitted residue data are adequate to support the proposed uses. The data include adequate 

field trial studies, processing studies, and storage stability data. The data support a tolerance at 

the limit of quantitation (LOQ) of 0.05 ppm for apple fruit. For the other commodities in the 

petition, the tolerances are being translated from other commodities with established tolerances.

There is no acute dietary endpoint for clopyralid and clopyralid is classified as “not likely to be 

carcinogenic to humans.” As a result, an acute dietary exposure assessment was not conducted 

for the chemical, and there is no cancer risk. The chronic dietary exposure assessment is highly 

conservative with regard to protecting human health. The assessment is based on tolerance-level 

residues for all commodities and the assumption that 100% of all commodities with tolerances 

will be treated (i.e., 100% crop treated). Modeled estimates of clopyralid residues in drinking 

water have been incorporated into the analyses. The combined dietary risk estimates from 

exposure to residues of clopyralid in food and drinking water are not of concern for the U.S. 

population or any of the population subgroups. The general U.S. population uses 9.3% of the 

chronic population-adjusted dose (cPAD). The population subgroup Children 1-2 years old is 

estimated to have the highest dietary exposure to clopyralid. This subgroup uses 25% of the 

cPAD. Because such conservative assumptions were made in the assessment, HED is confident 

that the chronic dietary exposure assessment does not underestimate risk to the general U.S. 

population or any population subgroup or life stage. 

Although no new residential uses are being proposed, several clopyralid formulations are 

registered for weed control on lawns, turf, and ornamentals in residential and public areas. For 

the purpose of conducting an aggregate risk assessment, a previous residential exposure 

assessment was updated to incorporate the revisions to the Standard Operating Procedures for 

Residential Exposure Assessment (Residential SOPs, 2012). Scenarios assessed include shortterm inhalation exposure for residential handlers and post-application oral exposure for children 

playing on treated lawns. All residential handler and post-application scenarios resulted in 

estimated MOEs ≥100 and are not of concern.

The chronic aggregate risk estimates are equivalent to the corresponding dietary (food plus 

water) risk estimates, which are not of concern. Short-term aggregate assessments were 
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performed for adults and children. For the adult short-term aggregate risk assessment, the 

residential handler inhalation exposure estimate was aggregated with the chronic dietary

exposure estimate. For children, the incidental oral exposure estimate was aggregated with the 

chronic dietary exposure estimate. The short-term aggregate risk estimates were not of concern

(MOEs ≥100). No specific concerns with respect to environmental justice were identified for 

clopyralid. 

No chemical-specific handler exposure data were submitted in support of this registration. It is 

HED policy to use the best available data to assess handler exposure. Sources of generic handler 

data, used as surrogate data in the absence of chemical-specific data, include the Pesticide 

Handlers Exposure Database Version 1.1 (PHED 1.1), the AHETF database, or other registrantsubmitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), 

and subject to the data protection provisions of FIFRA. Default assumptions established by the 

HED ExpoSAC were used for parameters such as body weight, acres treated, and amount 

handled per day.

Occupational handler assessments are based only on inhalation exposures, because clopyralid 

does not cause systemic toxicity via the dermal route. The short-term handler inhalation risk

estimates are not of concern at the baseline level of personal protective equipment (PPE), which 

consists of long-sleeved shirt, long pants, socks and shoes. Further, for intermediate-term 

exposure, MOEs were ≥180,000 assuming baseline PPE.

As stated above, the label amendments that expand the uses of clopyralid on mustard greens and 

rapeseed commodities to the entire crop subgroups are being proposed without any changes to 

the registered use patterns. As a result, a separate occupational exposure assessment is not 

required to support the proposed label amendments. Also a separate exposure assessment is not 

required for the use of Stinger® Herbicide on teff because the SLN registration is being proposed 

without any change to the use pattern for wheat. 

Dermal post-application exposure is not of concern because there is no hazard associated with 

exposure to clopyralid via the dermal route. Although there is potential for post-application

inhalation exposure, a quantitative post-application inhalation exposure assessment was not 

performed. However, an inhalation exposure assessment was performed for occupational

handlers and the risk estimates were not of concern. This exposure is likely to result in higher 

risk than post-application exposure. Therefore, it is expected that these handler inhalation 

exposure estimates would be protective of occupational post-application inhalation exposure 

scenarios. The submitted parent label for Stinger® Herbicide is for a monoethanolamine salt of 

clopyralid acid and has a restricted entry interval (REI) of 12 hours, which is appropriate.

This risk assessment is based, in part, on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These studies are compliant with 

applicable ethics requirements. Additional information concerning human studies is provided in 

Appendix C.
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2.0 HED Recommendations

HED recommends in favor of granting the requested registrations and establishing the tolerances 

listed in Table 2.2.3. 

2.1 Data Deficiencies/Conditions of Registration

None

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Plant Commodity Enforcement Method

The Pesticide Analytical Manual (PAM) Vol. II lists a GC/ECD method for determining 

clopyralid residues in/on plant commodities (Method I or Method ACR 75.6). For this method, 

residues are extracted with dilute NaOH (0.25% or 0.1%) and filtered. The extract is then 

acidified and salinized, and residues are partitioned into ethyl ether. Residues are then 

methylated using diazomethane and cleaned up on an activated alumina column. Residues are 

then determined by GC/ECD using external standards. The reported LOQs are 0.5 ppm for 

grains and 2.0 ppm for green forage. The data gathering method used in the apple field trials is 

almost identical to the analytical enforcement method, the only difference being the type of 

alumina column used for sample clean-up. The method was adequately validated in conjunction 

with analysis of field trial samples. The method LOQ and LOD are 0.05 ppm and 0.02 ppm, 

respectively.

Livestock Commodity Enforcement Method

The Pesticide Analytical Manual (PAM) Vol. II lists a GC/ECD method for the determination of 

clopyralid residues in animal commodities (Method II or Method ACR 86.1). Method II is 

essentially the same as Method I, except that aqueous potassium hydroxide is used for extraction 

instead of sodium hydroxide. The reported detection limits are 0.1 ppm for milk and eggs, and 

0.2 ppm for liver.

Multiresidue Methods

The FDA Pestrak database (PAM Vol. I, Appendix dated 11/6/90) indicates that the existing 

FDA multiresidue methods are not likely to recover clopyralid. Clopyralid does appear to be 

adequately recovered by the “QuEChERS” multiresidue method (http://www.quechers.com).

2.2.2 International Harmonization

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

the proposed commodities. However, there is a Canadian MRL for residues of clopyralid in or 

on flax at 0.2 ppm. This MRL does not harmonize with the existing U.S. tolerance of 3.0 ppm 
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for flax seed (or the proposed tolerance of 3.0 ppm for the Rapeseed subgroup). Based on the 

differing use patterns and the available residue data, the recommended tolerance for the 

Rapeseed subgroup cannot be harmonized with the Canadian MRL on flax.

2.2.3 Recommended Tolerances

Table 2.2.3 provides a summary of the proposed tolerances, the recommended tolerances, and 

the correct commodity definitions.

Table 2.2.3. Tolerance Summary for Clopyralid

Commodity as Proposed by Registrant

Proposed 

Tolerance 

(ppm)

Recommended 

Tolerance 

(ppm)

Comments

(correct commodity definition)

40 CFR §180.431(a)

Apple 0.05 0.05 Adequate field trial data are available.

Leafy Brassica greens subgroup 5B 5.0 5.0 Based on the existing tolerance for mustard 

greens, the representative commodity of the 

Leafy Brassica greens subgroup

(Brassica, leafy greens, subgroup 5B)

Rapeseed subgroup 20A, except Gold of 

pleasure, seed

3.0 3.0 Based on the existing tolerance of 3.0 ppm 

for rapeseed, canola, and flax seed

(Rapeseed, subgroup 20A, except gold of 

pleasure)

Rapeseed subgroup 20A, except Gold of 

pleasure, meal

6.0 6.0 Based on the existing tolerance of 6.0 ppm 

for canola meal and flax meal

(Rapeseed, meal)

Rapeseed subgroup 20A, except Gold of 

pleasure, forage

3.0 None Tolerance is not needed because rapeseed 

forage is not a significant livestock feed 

item.

Teff, forage 9.0 9.0 Based on wheat forage (9.0 ppm)

Teff, grain 3.0 3.0 Based on wheat and barley grain (3.0 ppm)

Teff, hay 9.0 9.0 Based on barley hay (9.0 ppm)

Teff, straw 9.0 9.0 Based on wheat and barley straw (9.0 ppm)

2.2.4 Revisions to Petitioned-For Tolerances

None

2.3 Label Recommendations

The submitted supplemental labels for apples, teff, Brassica leafy greens, and the Rapeseed 

subgroup are adequate. HED has no label recommendations.

 
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3.0 Introduction

3.1 Chemical Identity

Table 3.1. Clopyralid Nomenclature

Compound

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 Products (EUP) Stinger® Herbicide (EPA Reg. No. 62719-73), 3 lb ae/gal EC

3.2 Physical/Chemical Characteristics

Clopyralid has a relatively low octanol/water partition coefficient. The log KOW value is -1.81 at 

a pH of 5 (KOW = 0.015). Based on this value, the chemical would not bioaccumulate to any 

great extent. The relatively low KOW value also decreases clopyralid’s potential for dermal 

absorption. Clopyralid has a vapor pressure of 1.0 x 10-5 mm Hg at 25oC. As a result, there is 

the potential for inhalation exposure. See Appendix B for a table of clopyralid’s physical and 

chemical properties. 

3.3 Pesticide Use Pattern

A 3.0 lb ae/gal EC formulation of clopyralid is currently registered to Dow AgroSciences 

(Stinger®; EPA Reg. No. 62719-73) for control of postemergence weeds in: (1) mustard greens, 

(2) canola (rapeseed) and crambe, and (3) barley, oats, and wheat. IR-4 submitted supplemental 

labels for the Brassica leafy greens subgroup and the Rapeseed subgroup. The use directions on 

those supplemental labels are consistent with the use directions for the commodities from which 

the tolerances are being extended. IR-4 also submitted a supplemental label for apples. Finally, 

IR-4 submitted a FIFRA 24(c) SLN label for teff. The use directions are based on the use 

directions on the Stinger®label for barley, oats, and wheat. The proposed use directions are 

summarized below in Table 3.3.

N

Cl

Cl

O

O

OH

+ NH3
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Table 3.3. Summary of Directions for Use of Clopyralid

Applic. Timing, Type, and 

Equip. 1

Formulation

[EPA Reg. 

No.]

Applic. 

Rate 

(lb ae/A)

Max. No. 

Applic. 

per 

Season

Max. 

Seasonal 

Applic. Rate

(lb ae/A)

PHI Use Directions and 

Limitations 2

Apple

Apply to non-bearing (wellestablished, 1 year or older) 

and bearing trees. Apply to 

actively growing weeds. 

Apply with ground 

equipment only.

Stinger, 3.0 

lb ae/gal EC 

[62719-73]

0.094-

0.25 1 0.25 30days

Apply in a minimum of 

10 gal/A. Do not use in 

Florida or in Nassau or 

Suffolk Counties, New 

York. Do not apply by 

aircraft.

Leafy Brassica Greens Subgroup 5B

3

Apply to actively growing 

weeds. Apply with ground 

equipment only.

Stinger, 3.0 

lb ae/gal EC 

[62719-73]

0.06-0.25 2 0.5 30

days

Apply in a minimum of 

10 gal/A, with a 

minimum RTI of 14 

days. Do not apply by 

aircraft.

Rapeseed Subgroup 20A, Except Gold of Pleasure

Apply in the 2- to 6-leaf stage 

of crop growth. Apply to 

actively growing weeds. 

Apply with ground and aerial 

equipment only.

Stinger, 3.0 

lb ae/gal EC 

[62719-73]

0.113-

0.25 1 0.25 7days

Use in the State of 

Oregon only. Apply in 

a minimum of 20 gal/A. 

Do not use with a 

surfactant. Apply with 

ground and aerial 

equipment only.

Teff

Apply when crop is from 3-

leaf stage up to early boot 

stage of growth.

Stinger, 3.0 

lb ae/gal EC 

[62719-73]

0.094-

0.125 1 0.125

Not 

Specified

Do not harvest hay from 

treated grain fields.

4

1 Do not apply through any type of irrigation system.

2 The label for the 3 lb ae/gal EC contains the following rotational crop restrictions: barley, canola, cole crops, flax, 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.

3

For use and distribution only in the states of AZ, AR, CA, CO, DE, FL, GA, MD, MI, MO, NJ, NM, NY, NC, OH, OK, PA, 

SC, TX, VA and WI. Not for sale or distribution in Nassau and Suffolk Counties in New York State.

4 Do not permit lactating dairy animals or meat animals being finished for slaughter to forage or graze treated grain fields within 

one week after treatment.

The PPE for applicators and other handlers on the registered Stinger® Herbicide label is baseline 

clothing (long-sleeved shirt, long pants, and shoes plus socks), chemical-resistant gloves made of 

any waterproof material, and protective eyewear. 

 
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3.4 Anticipated Exposure Pathways

The Registration Division requested that HED perform an assessment of human health risk to 

support the proposed new uses of clopyralid. Humans could be exposed to clopyralid residues 

through dietary intake of apples, teff, Brassica leafy greens, rapeseed commodities, and drinking 

water. The proposed use also results in the potential for occupational (handler/post-application)

exposures.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions 

to Address Environmental Justice in Minority Populations and 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, 

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 

Surveys 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. Additionally, OPP is able to 

assess dietary exposure to smaller, specialized subgroups, and exposure assessments are 

performed when conditions or circumstances warrant. Whenever appropriate, non-dietary

exposures based on home use of pesticide products and associated risks for adult applicators and 

for toddlers, youths, and adults entering or playing on treated areas post-application are 

evaluated. Further considerations are 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.

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

4.1.1 Sufficiency of studies/data

The toxicology database for clopyralid is considered to be complete. Studies submitted include a 

21-day dermal toxicity study in the rabbit and the following oral studies: subchronic toxicity in 

the mouse, chronic toxicity in the dog, chronic toxicity/carcinogenicity in the rat, carcinogenicity

in the mouse, prenatal toxicity in the rat and rabbit, reproductive toxicity in the rat, metabolism 

in the rat, and immunotoxicity in the rat. In addition, there is a complete battery of genotoxicity

studies. Subchronic studies for rats and dogs are not available; however, requirements for these

studies were satisfied by the chronic studies. 
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Based on the toxicology data requirements outlined in the recently revised 40 CFR Part 158, 

acute and subchronic neurotoxicity studies in the rat are required for food use chemicals. 

However, HED’s Hazard and Science Policy Council (HASPOC) concluded that these studies 

are not required for clopyralid, based on the lack of evidence of neurotoxicity in the available 

studies conducted with clopyralid as well as with other structurally related compounds. 

HASPOC also determined that a 28-day inhalation toxicity study in the rat (§870.3465) is not 

required, based on the low volatility, low acute inhalation toxicity, and selection of conservative, 

adequately protective points of departure from oral studies.

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

Metabolism of clopyralid following oral dosing was evaluated in the rat. Clopyralid was 

essentially completely absorbed (95-115% of administered dose, or AD) at both low (5 

mg/kg/day) and high (150 mg/kg/day) doses. There were no significant differences in metabolic 

disposition between males and females or dose groups. Excretion was primarily via the urine 

(91-113% AD at 72 hrs post-dosing, with 74-98% AD excreted within 6-12 hrs post-dosing), 

whether by oral or intravenous dosing. Less than 4% of the excretion was via feces. 

Radioactivity was not retained in tissues (<0.01% AD at 72 hrs post-dosing). Plasma 

pharmacokinetic parameters were not evaluated. There was no evidence of metabolism; only

parent compound was identified in the urine and feces.

4.2.1 Dermal Absorption

A dermal absorption study was not required or submitted for clopyralid. However, absorption 

appears to be low, based on the lack of toxicity observed at the limit dose in the 21-day rabbit 

dermal study. This is consistent with the low Kow identified for clopyralid.

4.3 Toxicological Effects

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. However, the mode of action for mammalian toxicity has 

not been characterized. 

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

organs were not identified. In a one-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 was observed at 

the highest dose. Only decreased body weight/weight gain and food efficiency in males were 

observed in the mouse carcinogenicity study at doses exceeding the limit dose. 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 
Clopyralid Human Health Risk Assessment DP Nos. D391397, D401055

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the limit dose for 21 days. A rat immunotoxicity study showed no treatment-related effects on 

the immune system, and immunotoxicity was also not observed in other studies. 

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

susceptibility. No developmental toxicity was observed in the rat at doses that caused maternal 

mortality and decreased maternal body weight gain. Decreased fetal body weight and 

hydrocephalus were observed in the rabbit but only at a dose that caused significant maternal 

toxicity, including mortality, clinical signs of toxicity, decreased body weight gain, and gastric 

mucosal lesions. Reproductive toxicity was not observed in the rat, but mean pup weights (Day

28) were reduced, and relative liver weights were increased at doses that caused parental toxicity

(decreased body weight/weight gain and food consumption; gastric lesions).

There were no direct clinical or histopathological indications of neurotoxicity in the available 

studies at doses up to or exceeding the limit dose. Hydrocephalus was observed in the young in 

the rabbit developmental study in the presence of significant maternal toxicity, including a high 

rate of mortality. However, no indications of neurotoxicity were observed in maternal animals at 

the same dose, in other species, or in studies on other structurally related chemicals. Therefore, 

acute and subchronic neurotoxicity studies in the rat are not required based on lack of evidence 

of neurotoxicity for clopyralid and related chemicals. 

Clopyralid is classified as “not likely to be carcinogenic to humans.” No evidence of 

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 (in vitro and in vivo host mediated assays in Salmonella and 

Saccharomyces, in vivo chromosomal aberrations, unscheduled DNA synthesis, and dominant 

lethal assay). 

Clopyralid is rapidly absorbed and excreted, predominantly as parent compound, and primarily 

in the urine with very low fecal excretion. It is not retained in tissues (see Section 4.2, above).

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

dermal exposure, and it is not a dermal irritant or sensitizer. However, in its acid form, 

clopyralid is a severe eye irritant (Category I).

4.4 Safety factor for Infants and Children (FQPA Safety Factor)

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

to 1x. This recommendation is based on the following considerations: 1) the toxicity database is 

complete, with required studies either submitted or waived; 2) there is no evidence of increased 

qualitative or quantitative pre- and/or postnatal susceptibility in the developmental or 2-

generation reproduction toxicity studies; 3) there is no evidence of neurotoxicity, and a 

developmental neurotoxicity study is not required; and 4) the exposure assessments are based on 

conservative, health-protective assumptions that will not underestimate exposure and risk.
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4.4.1 Completeness of the Toxicology Database

The database for clopyralid is considered to be adequate for FQPA assessment. Acceptable 

developmental toxicity studies in the rat and rabbit and a two-generation reproduction study in 

the rat are available for FQPA assessment. As previously discussed (Section 4.1.1), the required 

acute and subchronic neurotoxicity and 28-day inhalation studies in the rat have been waived. 

Therefore, no additional uncertainty factors are needed to account for missing data. 

4.4.2 Evidence of Neurotoxicity

There are no direct clinical or micropathological indications of neurotoxicity in the available 

subchronic and chronic studies in multiple species. Hydrocephalus was observed in the young in 

the rabbit developmental study in the presence of significant maternal toxicity, including 

mortality. However, no indications of neurotoxicity were observed in maternal animals at the 

same dose, in other species, or in structurally related chemicals. Therefore, acute and subchronic 

neurotoxicity studies in the rat are not required based on lack of evidence of neurotoxicity for 

clopyralid and related chemicals. 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There was no evidence of increased qualitative or quantitative sensitivity/susceptibility in the 

developing or young animal. In the rat developmental toxicity study, no developmental toxicity

was observed at a maternally toxic dose. In the rat two-generation reproductive toxicity study, 

decreased pup weight (postnatal day 28) and increased relative liver weights were observed at 

the parental LOAEL. As noted above, hydrocephalus and decreased mean fetal weight were 

observed in the rabbit developmental study, but at a dose that also caused significant maternal 

toxicity, including mortality: the fetal findings were therefore considered to be comparable to 

those of adult animals.

 

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties with regard to dietary and residential exposure. The dietary

exposure assessment is based on conservative, health-protective assumptions that ensure that 

exposures to clopyralid are not underestimated. These assumptions include tolerance-level 

residues and 100% crop treated estimates for all commodities. Actual exposures and risk 

estimates from the use of clopyralid will likely be lower. Furthermore, conservative, upperbound assumptions were used to determine exposure through drinking water and residential 

sources, such that these exposures have not been underestimated. 

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

For acute oral exposure, an endpoint resulting from a single exposure was not identified. As a

result, an aRfD was not determined. The finding of hydrocephalus in the young in the rabbit 

developmental study was not considered to be an appropriate endpoint because it was observed 
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only at the highest dose tested in the presence of severe maternal toxicity, including a high rate 

of mortality.

For chronic dietary exposure, the NOAEL of 15 mg/kg/day from the rat chronic toxicity/carcinogenicity study was selected, based on increased epithelial hyperplasia and thickening of the 

limiting ridge of the stomach in both sexes at the LOAEL of 150 mg/kg/day. The study was 

selected because it was of the appropriate route and duration. This histological finding was 

considered to be the result of direct irritation of the stomach by the test material, and it provided 

the most sensitive NOAEL for this risk assessment scenario.

 

For incidental oral short-term exposure, the maternal toxicity NOAEL of 75 mg/kg/day from the 

rat developmental toxicity study was selected based on mortality, decreased maternal body

weight gain, and decreased food consumption at the LOAEL of 250 mg/kg/day. This study was 

selected because it was of the appropriate duration and route, and it provided the most sensitive 

NOAEL.

For short- and intermediate-term dermal exposure, an appropriate endpoint was not identified. 

No systemic toxicity was observed in a 21-day rabbit dermal study which tested up to the limit 

dose of 1000 mg/kg/day. Developmental toxicity in the rabbit was only seen in the presence of 

significant maternal toxicity (maternal/developmental NOAEL = 250 mg/kg/day), and in the rat

developmental study was not observed up to a maternally toxic dose (250 mg/kg/day). In the rat 

reproduction study, fetal body and liver weight effects were seen at doses causing decreased 

maternal body weight. Therefore, no pre- and/or postnatal toxicity would be expected at dermal 

doses up to and including the limit dose. 

A 28-day inhalation toxicity study is not available or required; therefore, oral studies were 

considered for use with route-to-route extrapolation for inhalation exposure assessment. For 

short-term inhalation exposure, the maternal toxicity NOAEL of 75 mg/kg/day from the rat 

developmental toxicity study was selected based on mortality, decreased maternal body weight 

gain, and decreased food consumption at the LOAEL of 250 mg/kg/day. This study was selected 

because it was of the appropriate duration and route, and it provided the most sensitive NOAEL. 

This endpoint is protective of pre- and/or postnatal toxicity because developmental toxicity in the 

rabbit was only seen in the presence of significant maternal toxicity (maternal/developmental 

NOAEL = 250 mg/kg/day), and developmental toxicity in the rat was not observed up to a 

maternally toxic dose.

For intermediate-term inhalation exposure, the NOAEL of 15 mg/kg/day from the rat dietary

chronic toxicity/carcinogenicity study was selected based on increased epithelial hyperplasia and 

thickening of the limiting ridge of the stomach in both sexes at the LOAEL of 150 mg/kg/day. 

Although it is of chronic duration, it was selected to be protective of gastric irritation that might

result from oral exposure of intermediate duration because it was observed at the interim 

sacrifices (6 and 12-month) in some animals. As such, it is considered to be a conservative 

endpoint for this exposure scenario.
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4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

HED has considered oral, dermal, and inhalation routes of exposure in its assessment of 

clopyralid. It is appropriate to combine routes of exposure when such exposures are expected to 

co-occur and result in the same toxicological effects. For aggregate assessments, adults are only 

exposed via the inhalation and oral (food + water) routes, and these exposures should be 

combined and compared to the short-term inhalation endpoint and dose. For children, the only 

relevant exposures consist of postapplication oral exposure to residues on lawns and oral dietary

(food + water) exposure. These exposures should be combined and compared to the short-term 

incidental oral endpoint and dose. For occupational workers, only inhalation exposure and risk 

are being assessed.

4.5.3 Cancer Classification and Risk Assessment Recommendation

In accordance with the EPA’s Final Guidelines for Carcinogen Risk Assessment (March, 2005), 

clopyralid is classified as “not likely to be carcinogenic to humans.” There was no evidence of 

treatment-related increases in tumor incidence in the 2-year rat and mouse dietary studies. Both 

studies included a high dose that exceeded the limit dose. Genotoxicity studies were negative. 

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

Table 4.5.4.1. Toxicological Doses and Endpoints for Clopyralid for Use in Dietary and Residential 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) 

An appropriate endpoint for a single exposure was not identified.

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 

stomach in both sexes.

Incidental Oral, Shortterm (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.

Dermal, Short-term

(1-30 days) 

No dermal or systemic toxicity was observed at the limit dose (1000 mg/kg/day) in a rabbit 21-day

dermal toxicity study and there are no developmental or reproductive concerns.

Inhalation, Short-term

(1-30 days)

Oral study

NOAEL = 75 

mg/kg/day

(inhalation 

toxicity assumed 

to be equivalent 

to toxicity via the 

oral route)

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.
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Table 4.5.4.1. 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

Inhalation Intermediateterm (1-6 months)Oral study 

NOAEL= 15 

mg/kg/day 

(inhalation 

toxicity assumed 

to be equivalent 

to toxicity via 

the oral route)

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). SFFQPA = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = 

reference dose. MOE = margin of exposure. LOC = level of concern. 

Table 4.5.4.2. 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, 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 21-day dermal 

toxicity study and there are no developmental or reproductive concerns.

Inhalation, Shortterm

(1-30 days)

NOAEL = 75 

mg/kg/day (inhalation 

toxicity assumed to be 

equivalent to toxicity 

via the oral route)

UFA= 10X

UFH= 10X

Occupational 

LOC for MOE

= 100

Developmental Toxicity (oral) – rat

Maternal LOAEL = 250 mg/kg/day, based on 

decreased body weight gain and food 

consumption during GD 6-9.

Inhalation, 

Intermediate- term

(1-6 months)

NOAEL = 15 

mg/kg/day (inhalation 

toxicity assumed to be 

equivalent to toxicity 

via the oral route)

UFA = 10X

UFH = 10X

Occupational 

LOC for MOE

= 100

2-Year Combined Chronic

Toxicity/Carcinogenicity (oral) – rat

LOAEL = 150 mg/kg/day, based on increased 

epithelial hyperplasia and thickening of the 

limiting ridge of the stomach in both sexes.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and used to 

mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL 

= no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = 

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

population (intraspecies). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile
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5.1.1 Summary of Plant and Animal Metabolism Studies

The nature of the residue in plants is adequately understood based on acceptable cabbage, grass, 

barley, and wheat metabolism studies. In each of these studies, the major 14C-residue was 

determined to be only parent compound. HED concludes that the residue of concern in plants for 

purposes of this petition is clopyralid. 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). Additional metabolism studies might be required in the future 

should the petitioner request the establishment of clopyralid tolerances for additional crops.

The nature of the residue in livestock commodities is adequately understood based on acceptable 

goat and poultry metabolism studies. In livestock, the major residues are the parent clopyralid 

and its glycine conjugate (3,6-DCPA-glycine).

5.1.2 Summary of Environmental Degradation

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. Because of 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.

5.1.3 Comparison of Metabolic Pathways

Data depicting the metabolism of clopyralid in plants and animals have been submitted to the 

Agency. In rats, there was no evidence of metabolism. Only parent compound was identified in 

the rat urine and feces. Clopyralid was essentially completely absorbed at both low and high 

doses (5 and 150 mg/kg/day, respectively). Excretion was primarily via the urine. Less than 4% 

of the excretion was via feces. Radioactivity was not retained in tissues (<0.01% AD at 72 hrs 

postdosing). Plant metabolism studies were performed on cabbage, grass, barley, and wheat. In 

all of these studies, the major residue was determined to be parent compound. Livestock 

metabolism studies were performed on goats and poultry. In livestock, the major residues are the 

parent clopyralid and its glycine conjugate (3,6-DCPA-glycine). Finally, parent clopyralid is 

also the predominant compound found in drinking water. In effect, parent clopyralid is the 

predominant compound in rats, plants, livestock, and drinking water. In livestock, glycine 

conjugates of clopyralid are also found. As a result, the primary metabolites and degradates to 

which humans would be exposed are accounted for in the rat metabolism study. 

5.1.4 Residues of Concern Summary and Rationale

As stated above, the nature of the residue in plants is adequately understood for purposes of this 

petition based on acceptable cabbage, grass, barley, and wheat metabolism studies. In each of 

these studies, the major residue was determined to be only parent compound. HED concludes

that the residue of concern in plants for purposes of this petition is clopyralid. In livestock, the 

major residues are the parent clopyralid as well as its glycine conjugate (3,6-DCPA-glycine). 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. Because of its stability and high 
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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 Food Residue Profile

The only study that IR-4 submitted in support of the current tolerance petition was a combined 

field trial/processing study for apples. For the other commodities, IR-4 is proposing that 

currently established tolerances be extended to the proposed commodities. As a result, no new 

field trial data were submitted for the Brassica leafy greens subgroup, the Rapeseed subgroup, or 

teff.

The submitted apple field trial data are adequate and support the proposed use. IR-4 performed 

an adequate number of trials and they were performed in the recommended EPA growing zones. 

The application rate was 1x the maximum proposed rate, and the samples were collected at the 

proposed PHI. Residues of clopyralid in/on each commodity were determined using an adequate 

GC/ECD method, and the duration and conditions of sample storage are supported by the 

available storage stability data. The available field trial data support an LOQ tolerance of 0.05 

ppm for apple fruit. Table 5.2 provides a summary of the apple field trial data.

Table 5.2. Summary of Residue Data from Crop Field Trials with Clopyralid

Commodity Total Applic. 

Rate2

(lb ae/A)

PHI

(days)

Residue Levels (ppm)1

n Min. Max. HAFT3 Median Mean Std. 

Dev.

Apple Fruit 0.244–0.275 28-30 25 <0.05 < 0.05 < 0.05 < 0.05 < 0.05 NA4

1 These values represent residues of clopyralid

2 One foliar application of Stinger Herbicide at approximately 0.25 lb ae/A was made.

3 HAFT = Highest Average Field Trial.

4NA = Not applicable

In the apple processing study, no detectable residues were found in the samples of apple fruit, 

apple juice, or wet apple pomace. Because of phytotoxicity concerns, IR-4 did not perform an 

exaggerated rate study. No residues were found in the processed commodities; which indicates 

that if concentration did occur, it was not to a considerable extent.
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5.3 Water Residue Profile

The estimated drinking water concentrations (EDWCs) used in the dietary risk assessment were 

provided by the Environmental Fate and Effects Division (EFED) in the following 

memorandum: “Tier I Drinking Water Assessment for Proposed New Use of Clopyralid on 

Apple, Leafy Brassica Greens Subgroup 5B, and Rapeseed Subgroup 20A, except Camelina 

(Gold of Pleasure)” (D391398, W. Shaughnessy, 12/19/2011) and incorporated directly into the 

dietary assessment. Water residues were incorporated in the DEEM-FCID into the food 

categories “water, direct, all sources” and “water, indirect, all sources.” 

A modeled upper-bound estimate of the clopyralid concentration in surface water (11.9 ppb) 

from the FQPA Index Reservoir Screening Tool (FIRST) Model was used for the assessment 

(Table 5.3). This estimate is greater than that for groundwater from the Screening Concentration 

in Ground Water (SCIGROW) Model. The same value was used in the previous dietary

exposure assessment. The drinking water models and their descriptions are available at the EPA 

internet site: http://www.epa.gov/oppefed1/models/water/. 

Table 5.3. Maximum Tier 1 Estimated Drinking Water Concentrations

Drinking Water Source Model Used and Rate EDWC (ppb)

Groundwater NAWQA (Oregon) 0.2588

Surface Water (Acute) FIRST (non-food crop, one application per year 

@ 0.5 lb ai/A)

45

Surface Water (Chronic) FIRST (non-food crop, one application per year 

@ 0.5 lb ai/A)

11.9

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

There is no acute dietary endpoint for clopyralid. As a result, an acute dietary exposure 

assessment was not conducted for the chemical. A chronic dietary (food + drinking water) 

exposure and risk assessment was conducted for clopyralid using the Dietary Exposure 

Evaluation Model DEEM-FCIDTM, Version 2.03 which uses food consumption data from the 

U.S. Department of Agriculture’s Continuing Surveys of Food Intakes by Individuals (CSFII) 

from 1994-1996 and 1998. The assessment is highly conservative with regard to protecting 

human health. The assessment is based on tolerance-level residues for all commodities. DEEM 

Version 7.81 default processing factors were used for all processed commodities for which they

were available. Modeled estimates of clopyralid residues in drinking water have been 

incorporated into the analyses. Because such conservative assumptions were made in the 

assessment, the resulting exposure and risk estimates are considered to be conservative as well. 

HED is confident that the chronic dietary exposure assessment significantly overestimates risk to 

the general U.S. population and its various population subgroups.
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Clopyralid is classified as “not likely to be carcinogenic to humans.” As a result, cancer risk is 

not an issue for this chemical.

5.4.2 Percent Crop Treated Used in Dietary Assessment

The chronic dietary exposure assessment was based on the assumption that 100% of all 

commodities with clopyralid tolerances will be treated.

5.4.3 Acute Dietary Risk Assessment

An acute dietary endpoint was not selected for clopyralid. As a result, an acute dietary exposure 

assessment was not performed.

5.4.4 Chronic Dietary Risk Assessment

Chronic risk estimates are below HED’s level of concern for the general U.S. population and all 

population subgroups. The U.S. population uses 9.3% of the cPAD. The population subgroup 

Children 1-2 years old has the highest estimated dietary exposure to clopyralid. This subgroup 

uses 25% of the cPAD. Generally, HED is concerned about dietary risk when the exposure 

estimate exceeds 100% of the PAD. The combined dietary risk from exposure to residues of 

clopyralid in food and drinking water are not of concern for the general U.S. population or any of 

the population subgroups. The chronic dietary risk estimates are given in Table 5.4.6.

5.4.5 Cancer Dietary Risk Assessment

Clopyralid is classified as “not likely to be carcinogenic to humans.” As a result, cancer risk is 

not an issue for clopyralid.

5.4.6 Summary Table

Table 5.4.6. Summary of the Combined Dietary (Food + Drinking Water) Exposure and Risk Estimates

for Clopyralid

Population Subgroup

Acute Chronic Cancer

Dietary Exposure 

(mg/kg/day)

% 

aPAD

Dietary Exposure

(mg/kg/day) % cPAD

Dietary Exposure

(mg/kg/day) Risk

General U.S. Population

NA NA

0.013895 9.3

N/A N/A

All Infants (< 1 year old) 0.013726 9.2

Children 1-2 years old* 0.037039 25

Children 3-5 years old 0.033869 23

Children 6-12 years old 0.022590 15

Youth 13-19 years old 0.013383 8.9

Adults 20-49 years old 0.010847 7.2

Adults 50+ years old 0.009407 6.3

Females 13-49 years old 0.010170 6.8

*The most highly exposed population subgroup
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6.0 Residential (Non-Occupational) Exposure/Risk Characterization

No new residential uses for clopyralid are being proposed at this time. However, for the purpose 

of performing an aggregate human health risk assessment, the previous residential exposure and 

risk estimates (D270507, S. Wang, 9/26/2007) were updated in accordance with the Revised 

Standard Operating Procedures for Residential Exposure (Residential SOPs, 2012).

Several clopyralid formulations are registered for weed control on residential lawns and/or 

professionally maintained turf areas. HED previously reviewed two clopyralid formulations for 

residential exposures: Lawn Fertilizer Plus Confront® Weed Control (EPA Reg. No. 62719-

263), a granule plus fertilizer mix containing 0.18 % clopyralid (0.12 % ae) and Lontrel®Turf 

and Ornamental (EPA Reg. No. 62719-305), an EC formulation containing 40.9% clopyralid (or 

3.0 lb ae/gal). The granule has an application rate of 15.55 lbs of product per 4,500 sq. ft. (0.19 

lb ae/A) and the EC has a maximum single application rate of 11⁄3 pt./A (0.5 lb ae/A) on turf.

6.1 Residential Handler Exposure and Risk

Based on the use pattern on home lawns, homeowners would be exposed via dermal and 

inhalation routes for a short-term duration only. A quantitative short-term dermal residential 

handler exposure assessment was not conducted because of the lack of toxicity via the dermal 

route. The estimated short-term inhalation handler MOEs ranged from 340,000 to 24,000,000. 

All residential handler scenarios resulted in estimated MOEs greater than 100, with no risks of 

concern (Table 6.1).

Table 6.1. Summary of Residential Handler Exposure and Risk Estimates for Clopyralid1

Exposure 

Scenario

Application 

Rate 2

Area Treated 

or Gallons 

Used/Day) 3

Unit Exp.

(mg/lb ae) 3

Short-term Inhalation

Dose

(mg/kg/day) 4 MOE 5

Granule: Applied with 

push-type spreader

0.19 lb

ae/A 0.5 A 0.0026 3.1x10-6

24,000,000

EC: Mixing and applying 

spray with hose-end 

sprayer

0.5

lb ae/A 0.5 A 0.022 6.9x10-5

1,100,000

EC: Mixing and applying 

spray with back-pack 

sprayer

0.025

lb ae/gal 5 Gallons 0.14 2.2x10-4

340,000

EC: Mixing and applying 

with manually pressurized 

handwand sprayer

0.025

lb ae/gal 5 Gallons 0.018 2.8x10-5

2,700,000

1. The previous estimate (S. Wang, D270507, 9/26/2007) was recalculated using unit exposures and area treated 

from the revised Residential SOP (2012).

2. Application rate is expressed either in lb ae/A or in lb ae/gal. The EC formulation (Lontrel Turf and Ornamental, 

(EPA Reg. No. 62719-305) recommends a minimum spray volume of 20 gal/A. Therefore, for back-pack and 

handwand sprayers, the application rate was calculated in lb ae/gal (0.5 lb ae/A/20 gal=0.025 lb ae/gal).

3. Area treated/A or spray vol. used/day assumptions are from the Lawn and Turf, Residential SOP (2012).

4. Inhalation Dose (mg/kg/day) = [Appl. Rate (lb ae/A or lb ae/gal) * Area Treated/day (acres or spray volume

 * Inhal. Unit Exp. (mg/lb ae) * Inhalation Absorption (100%)] / body wt (80 kg).

5. Short-term Inhalation MOE = Short-term NOAEL (75 mg/kg/day) / Inhalation Dose (mg/kg/day).
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6.2 Residential Post-application Exposure

The only short-term residential post-application exposure quantitatively assessed was for 

children playing on treated lawns, and in the absence of a dermal endpoint, only incidental oral 

exposure was included in the assessment.

There is a potential for post-application inhalation exposure to both adults and children following 

applications to lawns. However, based on the Agency’s current practices, a quantitative 

residential postapplication inhalation exposure assessment was not performed for clopyralid 

primarily because it has low inhalation toxicity and is applied as a soil directed spray to control 

broadleaf weeds. However, volatilization of pesticides may be a potential source of 

postapplication inhalation exposure to individuals nearby to agricultural pesticide applications. 

The Agency sought expert advice and input on issues related to volatilization of pesticides from 

its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in 

December 2009. The Agency received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report and may, as appropriate, develop policies and procedures to 

identify the need for and, subsequently, the way to incorporate postapplication inhalation 

exposure into the Agency’s risk assessments. If new policies or procedures are put into place, 

the Agency may revisit the need for a quantitative postapplication inhalation exposure 

assessment for clopyralid.

Provided in Table 6.2, below, are risk estimates associated with incidental oral post-application

exposure (i.e., hand to mouth, object to mouth, and soil and granule ingestion) for children 

following use of clopyralid granules and liquids on recreational and home lawns. All MOEs 

range from 10,000 to 4,600,000, and are not of concern.

Table: 6.2. Summary of Children’s Post-application Exposure and Risk Estimates for Clopyralid.1

Formulation 

Type

Exposure 

Scenario

Application

Rate

lb/AE/A

Short-term incidental oral

Dose

(mg/kg/day) 2 MOE 3

EC

Hand-to-mouth 0.5 0.00745 10,000

Objects-to-mouth 0.5 0.00023 330,000

Soil ingestion 0.5 0.000016 4,600,000

Granule

Hand-to-mouth 0.19 0.00028 270,000

Objects-to-mouth 0.19 0.00009 860,000

Granule ingestion (episodic) - - Not applicable 4

1. Revised estimates based on new Residential SOP for Exposure (2012). Original estimates: D270507, S. Wang, 

9/26/2007

2. Oral doses were calculated based on new Residential SOP for Exposure (2012).

3. Short-term incidental oral MOE = NOAEL 75 (mg/kg/day) / oral dose (mg/kg/day).

4. Granule ingestion is viewed as an acute oral exposure. As there is no acute dietary endpoint for clopyralid, 

exposure from granule ingestion was not assessed.
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6.3 Combined Residential Risk Estimates

HED believes that combining children’s post-application exposures, such as hand-to-mouth, 

object-to-mouth, and soil and granule ingestion resulting from EC and granule formulations of 

clopyralid on home lawns, would be overly conservative. Although these exposures might occur 

simultaneously based on the use pattern of the pesticide and the behavior associated with the 

exposed population, the inputs used in calculating the risk estimates are conservative, and 

combining these conservative exposure and risk estimates would result in an unrealistically high

estimate of exposure and risk. In the case of clopyralid on turf, the scenario with the highest oral 

exposure for children (hand-to-mouth, MOE=10,000) is considered to be protective of all 

children’s post-application exposure and risk, and should be used in the aggregate exposure and 

risk calculations.

6.4 Spray Drift

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

operations. This is particularly the case with aerial application, but, to a lesser extent, could also 

be a potential source of exposure from the ground application method employed for clopyralid. 

The Agency has been working with the Spray Drift Task Force, EPA Regional Offices, State 

Lead Agencies for pesticide regulation, and other parties to develop the best spray drift 

management practices (see the Agency’s Spray Drift website for more information at 

http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the 

Agency is now requiring interim mitigation measures for aerial applications that must be placed 

on product labels/labeling. The Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is 

developing a policy on how to appropriately apply 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 with specific products with significant risks 

associated with drift.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

risk estimates from three major sources: food, drinking water, and residential exposures. In an 

aggregate assessment, exposures from relevant sources are added together and compared to

quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risk estimates themselves can 

be aggregated. When aggregating exposures and risks from various sources, HED considers 

both the route and duration of exposure.

7.1 Acute Aggregate Risk Estimates

Acute aggregate risk results from exposure to residues in food and drinking water alone. An 

acute dietary endpoint was not selected for clopyralid. As a result, an acute aggregate risk 

assessment was not performed.
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7.2 Short-Term Aggregate Risk Estimates

For a short-term aggregate risk assessment, exposures from the oral, dermal, and inhalation 

routes need to be added. A dermal endpoint was not selected for clopyralid; as a result, only 

exposures from the oral and inhalation routes need to be aggregated. The incidental oral and 

inhalation endpoints were selected from the same study: the rat developmental toxicity study. 

The toxicological effects were decreased body weight gain and food consumption during 

gestation days 6 through 9. The LOC for short-term aggregate risk is an MOE of 100.

Adults are exposed to clopyralid through the residential handler inhalation route of exposure; 

however, they are not exposed through the incidental oral route. As a result, the residential 

handler inhalation exposure estimate only needs to be aggregated with the chronic dietary

exposure estimate, which serves as a background exposure level. As the oral and inhalation 

endpoints are the same, the additive dose approach can be used for aggregating adult short-term 

exposures. The adult population subgroup with the highest exposure estimate is Adults 20-49;

however, the general U.S. population has a higher dietary exposure estimate. As a result, the 

dietary exposure estimate for the general U.S. population was used to determine aggregate risk. 

The residential exposure estimate that resulted in the lowest MOE was that for 

mixing/loading/applying sprays with a backpack sprayer, so exposure from this scenario was 

combined with exposure from food and water. The resulting aggregate exposure estimate yields 

an MOE of 5,300, which exceeds the LOC of 100 and is not of concern. 

Children are exposed to clopyralid through the incidental oral route of exposure. The incidental 

oral exposure estimate was aggregated with the chronic dietary exposure estimate, which serves 

as a background exposure level. As the oral route is the only route of exposure, the additive dose 

approach can be used for aggregating children’s short-term exposures. The population subgroup 

with the highest exposure estimate is Children 1-2, so this exposure was combined with the oral 

hand-to-mouth exposure estimate. The resulting aggregate risk estimate is an MOE of 1,700, 

which exceeds the LOC of 100 and is not of concern. 

The aggregate risk estimates for adults and children are given in Table 7.2. As stated in the two 

preceding paragraphs, the MOEs given in the table are worst-case scenarios because the shortterm MOEs for any other population subgroups would be higher than those given in Table 7.2. 

In effect, short-term aggregate risk estimates are not of concern for any population subgroup.

Table 7.2. Residential Short-Term Aggregate Risk Calculations

Population

Short-Term Scenario

NOAEL

mg/kg/day LOC1

Average Food and 

Water Exposure 

mg/kg/day

Residential 

Inhalation

Exposure 

mg/kg/day

Hand-toMouth 

Exposure

mg/kg/day

Total 

Exposure2

mg/kg/day

Aggregate 

MOE (food, 

water, and 

residential)3

Children 1-2 75 100 0.037039 NA 0.00745 0.044489 1,700

U.S. Population 75 100 0.013895 0.000218 NA 0.010916 5,300

1. An UF of 100x was applied to account for interspecies extrapolation (10x) and intraspecies variation (10x). No 

additional uncertainty factors/safety factors are required.

2. Total Exposure = Avg Food & Water Exposure + Residential Exposure

3. Aggregate MOE = [NOAEL (75 mg/kg/day)/ (Avg Food & Water Exposure + Residential Exposure)]
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7.3 Intermediate-Term Aggregate Risk Estimates

There are no residential uses for clopyralid that result in intermediate-term exposures. As a 

result, no intermediate-term aggregate risk assessments were performed.

7.4 Chronic Aggregate Risk Estimates

There are no residential scenarios that result in long-term exposure. As a result, the chronic 

aggregate risk assessment includes long-term exposure to residues in food and drinking water

only. The chronic dietary exposure analysis included both food and drinking water and, 

therefore, the chronic aggregate risk assessment is equivalent to the chronic dietary risk 

assessment discussed in Section 5.4.4, above. All risk estimates are not of concern.

7.5 Cancer Aggregate Risk Estimates

Clopyralid is classified as “not likely to be carcinogenic to humans.” As a result, cancer risk is 

not an issue for the chemical.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to clopyralid and any other substances, and clopyralid does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this risk assessment, 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 Characterization

9.1 Short-/Intermediate-Term Handler Risk

Occupational Handlers

The proposed use pattern for apples is expected to result in short-term (1-30 days) exposure for 

most handlers. However, as commercial applicators might apply Stinger® Herbicide at several 

locations during the crop season, intermediate-term (1-6 months) handler exposure could occur,

and therefore an intermediate-term assessment was also conducted.

The label amendment to expand uses on individual crops to entire crop subgroups are based on 

registered use patterns. The proposed use pattern for the Brassica leafy greens subgroup is the 
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same as the registered use pattern on mustard greens, and the proposed use pattern for the 

Rapeseed subgroup is the same as the registered use pattern for canola, crambe, and rapeseed. 

Similarly the request to register the use of clopyralid on teff is based on the registered use pattern 

for wheat. Because these actions are being proposed without changes to the registered use 

patterns, separate occupational exposure assessments are not required.

Potential Exposure Scenarios: Exposure scenarios describe the handler activities (mixer, loader

and applicator) and type of application equipment. Based on the proposed use pattern, the 

following exposure scenarios were identified:

• mixing of EC formulation and loading diluted spray in groundboom sprayer

• applying the spray using groundboom equipment

• mixing, loading and applying the EC formulation using a back-pack sprayer for spot 

treatment.

The registrant has not submitted a chemical-specific exposure study to select unit exposures 

required for estimating handler exposure. HED’s policy is to use the best available data to assess 

handler exposure. Sources of generic handler data, used as surrogate data in the absence of 

chemical-specific data, include the PHED Version 1.1, AHETF, Outdoor Residential Exposure 

Task Force (ORETF) databases, or other registrant-submitted occupational exposure studies. 

Some of these data are proprietary (e.g., AHETF data), and are subject to the data protection 

provisions of FIFRA. The standard values recommended for use in predicting handler exposure 

that are used in this assessment, known as “unit exposures,” are outlined in the “Occupational 

Pesticide Handler Unit Exposure Surrogate Reference Table” 

(http://www.epa.gov/opp00001/science/handler-exposure-table.pdf), which, along with 

additional information on HED policy on use of surrogate data, including descriptions of the 

various sources, can be found at http://www.epa.gov/pesticides/science/handler-exposuredata.html.

Other inputs from ExpoSAC’s Policy No. 9.1 (Standard Values of Daily Acres Treated) were

used to estimate handler exposure. Regardless of what the proposed label stipulates for PPE, 

HED typically conducts an initial assessment at the baseline level of personal protection 

consisting of a long-sleeve shirt, long pants, shoes and socks (no gloves and no respirator). 

Additional PPE and mitigation measures, such as gloves, respirators, engineering, and

administrative controls are added, if required, to obtain a risk level that does not exceed HED’s 

LOC. 

Table 9.1 summarizes the short- and intermediate-term inhalation risk estimates for handlers 

resulting from the proposed use of Stinger®EC Herbicide on apples applied as broadcast and 

spot treatments. No dermal endpoint and dose were selected for clopyralid because of the lack of 

dermal toxicity and, therefore, there is no risk associated with exposure via the dermal route. At 

baseline PPE, the short-term (MOE ≥ 880,000) and intermediate-term (MOE ≥ 180,000) 

inhalation risk estimates are significantly above HED’s LOC of an MOE of 100, and are not of 

concern.
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Table 9.1. Occupational Handler Inhalation Exposure and Risk Estimates from Applying Clopyralid in Apple Orchards.

Handler Scenario

Used for Apple 1

Application

Rate 2

Area Treated

or Gallons

Used/day 3

Risk

Mitigation 

Level 4

Inhalation

Unit Exp. 

(μg/lb ae) 5

Inhalation Dose

(mg/kg/day) 6

Short- term 

Inhalation

MOE 7

Interm.-term

Inhalation

MOE 8

Mixing/Loading Liquids for 

Groundboom (AHETF) 0.25 lb ae/A 80 acres Baseline 0.219 5.5E-5 1,400,000 270,000

Applying by Groundboom 

(AHETF) 0.25 lb ae/A 80 acres Baseline 0.34 8.5E-5 880,000 180,000

Mixing/Loading/Applying by 

backpack Sprayer (MRID 

44339801) (ground-directed -

orchards)

0.025 lb ae/gal) 40 gals Baseline 2.58 3.2E-5 2,300,000 470,000

1. Occupational Pesticide Handler Unit Exposure Surrogate Reference Table used for each scenario is indicated in parenthesis.

2. The parent label (62719-73 recommends a minimum spray volume of 10 gal/A for ground application and therefore, for back-pack sprayer, application rate 

was calculated as 0.25 lb ae/A/10 gal/A = 0.025 lb ae/gal. 

3. Area treated per day assumptions are from ExpoSAC (SOP No. 9.1). 

4. Baseline PPE includes long-sleeved shirt, long pants, shoes and socks, and no respirator. 

5. From http://www.epa.gov/pesticides/science/handler-exposure-data.html

6. Inhalation Dose (mg/kg/day) = [Appl. Rate (lb ae/A or lb ae/gal) * Area Treated/day (acres or spray volume) * Inhal. Unit Exp. (μg/lb ae/1000) * Inhalation 

Absorption (100%)] / Body Wt (80 kg). 

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

8. Intermediate-term Inhalation MOE = intermediate-term NOAEL (15 mg/kg/day) / Inhalation Dose (mg/kg/day).
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9.2 Occupational/Commercial Post-application Risk

Post-application workers can be exposed to residues of clopyralid through dermal and inhalation 

routes when they enter treated areas to perform post-application activities, such as thinning, 

irrigation, scouting, etc. As there is no systemic toxicity associated with dermal exposure to 

clopyralid, a dermal post-application exposure assessment was not conducted, and there is no 

risk associated with post-application exposure via the dermal route. 

9.2.1 Post-application Inhalation Exposure

Based on the Agency’s current practices, a quantitative post-application inhalation exposure 

assessment is not being performed for clopyralid at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV) of the end-use product formulation (M. Hashim, 

D291712, 10/16/2003), low vapor pressure, and the low proposed use rate (0.25 lb ae/A). 

However, there are multiple potential sources of post-application inhalation exposure to 

individuals performing post-application activities in previously treated fields. These potential 

sources include volatilization of pesticides and re-suspension of dusts and/or particulates that 

contain pesticides. The Agency sought expert advice and input on issues related to volatilization 

of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory

Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate occupational 

post-application inhalation exposure into the Agency’s risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for clopyralid.

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides to crops is likely to result in 

higher exposure than exposure to workers if they enter treated fields. Therefore, it is expected 

that the handler inhalation exposure estimates are protective of most occupational postapplication inhalation exposure scenarios.

The registrant has provided supplemental labels for Stinger® Herbicide (EPA Reg. No. 62719-

73) with this submission. The active ingredient in Stinger®is the monoethanolamine salt of 

clopyralid acid and has a 12-hour REI, which is appropriate.
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10.0 References

D361316, M. Doherty, et al., 12/3/2009, Clopyralid – Human Health Risk Assessment to 

Evaluate New Uses on Swiss Chard, Bushberry Subgroup (13-07B), and Strawberry (Regional 

Restriction)

D391747, D. Dotson, 6/6/2012, Clopyralid. Petition for the Section 3 Registration and the 

Establishment of Tolerances on Apples, Brassica Leafy Greens (Subgroup 5-B), Teff, and 

Rapeseed (Subgroup 20-A) Except Gold of Pleasure. Summary of Analytical Chemistry and 

Residue Data

D399390, D. Dotson, 6/6/2012, Clopyralid Chronic Aggregate Dietary (Food and Drinking 

Water) Exposure and Risk Assessment for the Section 3 Registration Action on Apples, Teff, the 

Leafy Brassica Greens Subgroup (5-B), and the Rapeseed Subgroup (20-A) 

D391398, W. Shaughnessy, 12/19/2011, Tier I Drinking Water Assessment for Proposed New 

Use of Clopyralid on Apple, Leafy Brassica Greens Subgroup 5B, and Rapeseed Subgroup 20A, 

Except Camelina (Gold of Pleasure)

D391748, S. Oonnithan, 4/30/2012, Clopyralid: Occupational Exposure Assessment for a New 

Use on Apples; Expansion of Crop Group 5B; and Revised Residential Exposure Assessment for 

use on Turf.

List of Appendices

Appendix A. Clopyralid Toxicology Profile and Executive Summaries

Appendix B. Clopyralid Physical/Chemical Properties

Appendix C. Review of Human Research
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Appendix A: Toxicology Profile and Executive Summaries

Appendix A.1. Toxicology Data Requirements

The requirements (40 CFR 158.340) for food use for clopyralid are in the table below. Use of the new guideline 

numbers does not imply that the new (1998) guideline protocols were used.

Study

Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

870.1200 Acute Dermal Toxicity ..................................................

870.1300 Acute Inhalation Toxicity..............................................

870.2400 Primary Eye Irritation....................................................

870.2500 Primary Dermal Irritation ..............................................

870.2600 Dermal Sensitization......................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)...............................................

870.3150 Oral Subchronic (nonrodent).........................................

870.3200 21-Day Dermal ..............................................................

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

870.3465 28-Day Inhalation..........................................................

yes

yes

yes

no

no4

yes

yes1

yes

-

-

870.3700a Developmental Toxicity (rodent)...................................

870.3700b Developmental Toxicity (nonrodent).............................

870.3800 Reproduction .................................................................

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)..............................................

870.4100b Chronic Toxicity (nonrodent)........................................

870.4200a Oncogenicity (rat)..........................................................

870.4200b Oncogenicity (mouse)....................................................

870.4300 Chronic/Oncogenicity....................................................

yes

yes

yes

yes

yes

yes2

yes

yes2

yes

yes

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

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

870.5xxx Mutagenicity—Structural Chromosomal Aberrations...

870.5xxx Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

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 

no4

no4

no

-

-

-

-

-

870.7485 General Metabolism ......................................................

870.7600 Dermal Penetration........................................................

870.7800 Immunotoxicity .............................................................

yes

no

yes

yes

-

yes

Special Studies for Ocular Effects

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

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

Six-month Oral (dog)..................................................

no

no

no

-

-

-

1 Satisfied by 870.4100b, chronic dog

2 Satisfied by 870.4300, rat combined chronic toxicity/carcinogenicity

3 Satisfied by overall negative genotoxicity database including host-mediated assay of S. typhimurium and S. 

cerevisia

4 Requirement waived by HED HASPOC based on a weight of evidence consideration of hazard, exposure, 

physicochemical properties, and structurally-related chemicals. 
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Appendix A.2. Toxicity Profiles

Table A.2.1. Acute Toxicity Profile for Clopyralid

Guideline 

Number

Study Type

Classification

MRID

Number

Results Toxicity 

Category

870.1100 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 41848301 LC50 (M/F) > 1 mg/L III

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.2.2 Subchronic, Chronic and Other Toxicity Profile for Clopyralid

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3100 90-Day oral 

toxicity (rat)

An acceptable study is not available. Requirement satisfied by combined 

chronic oral toxicity/carcinogenicity study in the rat (870.4300).

870.3100 90-Day oral 

toxicity (mouse) 

00127276 (2003)

Acceptable/guideline

0, 200, 750, 2000 or 5000 

mg/kg/day

NOAEL = 2000 mg/kg/day

LOAEL = 5000 mg/kg/day based on decreased 

body weight gain.

870.3150 90-Day oral 

toxicity (dog)

An acceptable study is not available. Requirement satisfied by chronic oral 

study in the dog (870.4100).

870.3200 21-Day dermal 

toxicity (rabbit)

41790701 (1990)

Acceptable/guideline

0, 100, 500 or 1000 

mg/kg/day

Systemic NOAEL = 1000 mg/kg/day (limit 

dose)

Systemic LOAEL = not established (>1000 

mg/kg/day).

Local dermal NOAEL < 100 mg/kg/day 

(LDT)

Local dermal LOAEL = 100 mg/kg/day, 

based on epithelial hyperplasia at application 

site

870.3250 90-Day dermal 

toxicity 

Study not required,

870.3465 28- Day inhalation 

toxicity (rat)

Study not required.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Clopyralid

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3700a Prenatal 

developmental in 

(rat)

00127279 (1981)

Acceptable/guideline

0, 15, 75 or 250 

mg/kg/day

Maternal NOAEL = 75 mg/kg/day

LOAEL = 250 mg/kg/day based on mortality, 

decreased body weight gains and reduced food 

consumption.

Developmental NOAEL = 250 mg/kg/day 

(HDT)

LOAEL = not established (>250 mg/kg/day).

870.3700b Prenatal 

developmental in 

(rabbit)

41649801, -02 (1990)

Acceptable/guideline

0, 50, 110 or 250 

mg/kg/day by gavage

Maternal NOAEL = 110 mg/kg/day

LOAEL = 250 mg/kg/day based on mortality, 

decreased body weight gains, reduced food 

consumption and lesions in the gastric mucosa.

Developmental NOAEL = 110 mg/kg/day

LOAEL = 250 mg/kg/day based on decreased 

fetal body weight and hydrocephalus.

870.3800 Reproduction and 

fertility effects

(rat)

00138155 (1983)

Acceptable/guideline

0, 150, 500 or 1500 

mg/kg/day in diet

Parental 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.

870.4100a Chronic toxicity

(rat)

Requirement satisfied by 870.4300.

870.4100b Chronic toxicity 

(dog)

00158256 (1984)

Acceptable/guideline

0, 100, 320 or 1000 

mg/kg/day by capsule

NOAEL = 100 mg/kg/day

LOAEL = 320 mg/kg/day based on decreases 

in RBC parameters, increased liver weight 

(males) and vacuolated adrenal cortical cells 

(females). Clinical chemistry changes 

(decreased serum albumin, globulin, protein) 

and skin lesions were observed at high dose.

870.4200a Carcinogenicity

(rat)

Requirement satisfied by 870.4300.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Clopyralid

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.4200b 24-month 

Carcinogenicity

(mouse)

00162393, 00162434 

(1984)

Acceptable/guideline

0, 100, 500 or 2000 

mg/kg/day in the diet (24 

months)

NOAEL = 500 mg/kg/day

LOAEL = 150 mg/kg/day based on decreased 

body weight/weight gain and reduced food 

efficiency.

(no) evidence of carcinogenicity

870.4300 Chronic 

toxicity/carcinoge

nicity (rat)

00162393, 00162434 

(1986)

Acceptable/guideline

0, 15, 150 or 1500 

mg/kg/day in the diet (104 

weeks)

NOAEL = 15 mg/kg/day

LOAEL = 150 mg/kg/day based on gastric 

lesions (epithelial hyperplasia and thickening of 

the limiting ridge). At 1500 mg/kg/day, 

decreased body weight gains and food 

consumption were also observed.

(no) evidence of carcinogenicity

Gene 

Mutation

870.5100

Study not submitted. Not required due to lack of tumorigenicity in rat and mouse bioassays and 

negative findings in all other genotoxicity assays, including host-mediated assays in Salmonella

and Saccharomyces.

Gene 

Mutation

870.5300

In Vitro and In 

Vivo Host 

Mediated Assay 

(Salmonella 

strains TA 1530, 

G-46 and 

Saccharomyces

strain D-3) (1973)

In vivo assays 

were conducted 

using mice

00057086 (1973)

Acceptable/guideline

In vitro testing: without 

S9 activation at 5% w/v 

solution

In vivo testing: 0, 4, 40 or 

400 mg/kg by gavage to 

10 mice

Negative – no evidence of induced mutant 

colonies over background levels in Salmonella

or Saccharomyces strains tested in either the in 

vitro or the in vivo assays.

Cytogenetics

870. 5385

In Vivo

Micronucleus 

assay, Rat

00073638 (1973)

Acceptable/guideline

0, 4, 40 or 400 mg/kg for 

one day or for 5 days to 

male rats; sacrifice at 6, 

24 or 48 hrs postdosing 

for all groups.

Negative – no evidence of an increase in the 

formation of chromosomal aberrations in bone 

marrow at any dose tested. 

Other 

Effects

870.5450

Dominant Lethal 

Assay in Rats

00059053, 00099100 

(1973)

Acceptable/guideline

4, 40 or 400 mg/kg/day 

for 5 days to male rats 

prior to mating

Negative – no evidence of treatment-related 

resorptions.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile for Clopyralid

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

Other 

Effects

870.5550

Unscheduled 

DNA Synthesis, 

Rat Hepatocytes

00156387 (1985), 

41790702 (1990)

Acceptable/guideline

5x10-5, 1.56x10-4, 5x10-4, 

1.56x10-3, 5x10-3, 

1.56x10-2, 5x10-2 M, 

incubated for 18-20 hrs

Negative – no evidence of increased 

unscheduled DNA synthesis in the initial or 

supplementary assays testing up to 

insoluble/toxic concentrations.

870.6200a Acute 

neurotoxicity 

screening battery 

(rat)

Study not required.

870.6200b Subchronic 

neurotoxicity 

screening battery 

(rat)

Study not required.

870.6300 Developmental 

neurotoxicity

Study not required.

870.7485 Metabolism and 

pharmacokinetics

(rat)

41790703 (1991)

Acceptable/guideline

5.0 and 50 mg/kg, single 

oral dose; 5.0 mg/kg, 

single IV dose and 5.0 

mg/kg/day, repeated daily 

dose for 14 days

Clopyralid was rapidly and completely 

absorbed and eliminated with 95 to 115% of the 

administered dose recovered by 72 hr, most 

within 6-12 hrs postdosing. Almost all 

radioactivity was eliminated via the urine 

irrespective of dose or route of administration 

(91 to 113% of AD), with <4% excreted in the 

feces. Tissue retention was negligible (<0.01% 

AD). There was essentially no metabolism of 

clopyralid: only parent compound was 

identified. No significant gender, dose or 

exposure route differences were identified.

870.7600 Dermal 

penetration 

Study not available.

870.7800 Immunotoxicity 

(rat)

48300001 (2011)

Acceptable/guideline

0, 158, 530, or 1062 

mg/kg/day

Systemic NOAEL = 1062 mg/kg/day (limit 

dose)

Systemic LOAEL = not established (>1062 

mg/kg/day)

Immunotoxicity NOAEL = 1062 mg/kg/day

Immunotoxicity LOAEL = not established 

(>1062 mg/kg/day)
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Appendix A.3. Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD) – All Populations (Including Females Age 13-49 and 

Infants and Children)

This risk assessment was not performed. An appropriate endpoint for acute oral exposure was 

not identified. Although hydrocephalus was observed, it occurred only in the presence of severe 

maternal toxicity, including a high rate of mortality (considered treatment-related in 8/29 

females), and was therefore not selected for this exposure scenario. 

A.3.2 Chronic Reference Dose (cRfD) – All Populations (Including Females Age 13-49 and 

Infants and Children)

Study Selected: Combined Chronic/Carcinogenicity - rat (OPPTS 870.4300)

MRID Nos.: 00162393, 00162434

Dose and Endpoint for Risk Assessment: NOAEL = 15 mg/kg/day, based on histopathology in 

the stomach (epithelial hyperplasia and thickening of the limiting ridge) at the LOAEL of 150 

mg/kg/day: 

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. The finding was observed in some interim 

sacrifice animals at 6 and 12 months, as well as at terminal (24-month) sacrifice. The endpoint is 

considered conservative because only 1-2 animals/sex were affected at 6 months. Stomach 

lesions were also observed in the developmental rabbit study and rat reproduction study. The 

NOAEL is lower than all endpoints for developmental and reproductive effects and therefore 

protective of potential pre- and/or postnatal toxicity. An UF of 100 was applied to account for 

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

Chronic RfD = 15 mg/kg/day (NOAEL) = 0.15 mg/kg/day

100 (UF)

A.3.3 Incidental Oral Exposure (Short-Term) 

Study Selected: Developmental Toxicity Study – rat (OPPTS 870.3700a) 

MRID No.: 00127279

Dose and Endpoint for Risk Assessment: NOAEL = 75 mg/kg/day, based on maternal 

mortality and decreased body weight gain and food consumption during days 6-9 of gestation at 

the LOAEL of 250 mg/kg/day. 

Comments on Study/Endpoint: This endpoint is based on a study of an appropriate duration 

and route. The selected dose is protective of potential prenatal toxicity because fetal effects were 

seen only at the maternal LOAEL, and of potential postnatal toxicity based on the offspring 
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NOAEL of 500 mg/kg/day in the rat reproduction study. An UF of 100 was applied to account 

for inter-species extrapolation (10X) and intra-species variation (10X).

A.3.4 Incidental Oral Exposure (Intermediate-Term) 

Study Selected: Combined Chronic/Carcinogenicity - rat (OPPTS 870.4300)

MRID Nos.: 00162393, 00162434

Dose and Endpoint for Risk Assessment: NOAEL = 15 mg/kg/day, based on histopathology in 

the stomach (epithelial hyperplasia, thickening of the limiting ridge) at the LOAEL of 150 

mg/kg/day: 

Comments on Study/Endpoint/Uncertainty Factors: This study was of an appropriate route 

and effects were observed by six months’ exposure duration. An UF of 100 was applied to 

account for inter-species extrapolation (10X) and intra-species variation (10X). 

A.3.5 Dermal Absorption

Dermal absorption data are not available for clopyralid; however, a 21-day dermal toxicity study

was available and showed no systemic toxicity up to the limit dose of 1000 mg/kg/day (see 

below).

A.3.6 Dermal Exposure (Short- and Intermediate-Term)

This risk assessment was not performed. No systemic 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 of 

severe maternal toxicity (decreased maternal body weight, clinical signs of toxicity and 

mortality). Therefore, these findings were not observed following dermal exposure in the same 

species, developmental effects would not be expected at the limit dose. The 21-day study

indicates that dermal absorption is low. Based on comparison of the two studies, risk from 

exposure via the dermal route is not a concern.

A.3.7 Inhalation Exposure (Short-Term)

Study Selected: Developmental toxicity in rat

MRID No.: 00127276

Dose and Endpoint for Risk Assessment: Maternal NOAEL = 75 mg/kg/day based on 

mortality, decreased body weight gain and food consumption at the LOAEL of 250 mg/kg/day. 

Comments about the Study/Endpoint: This endpoint is based on an oral study because no 

inhalation studies are available. Therefore, an oral study is selected to estimate risk using a 

route-to-route extrapolation. The rat developmental study and endpoint were selected because 

they are protective of pre- and/or postnatal effects, including hydrocephalus as observed in the 

rabbit developmental study at 250 mg/kg/day (maternal and developmental NOAEL = 110 

mg/kg/day). The observed effects are a result of short-term exposure. Absorption via inhalation 

is assumed to be equivalent to absorption via the oral route, i.e., 100% inhalation absorption is 

assumed in risk assessment. An UF of 100 was applied to account for inter-species extrapolation 

(10X) and intra-species variation (10X). An additional 10x UFDB was not applied for lack of the 
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inhalation study because an inhalation study is not required, and the oral study is considered 

protective based on low vapor pressure and high inhalation MOEs estimated using the oral 

endpoint.

A.3.8 Inhalation Exposure (Intermediate-Term)

Study Selected: Chronic toxicity/carcinogenicity in rats

MRID No.: 00162393, 00162434

Dose and Endpoint for Risk Assessment: The NOAEL = 15 mg/kg/day, based on epithelial 

hyperplasia and thickening of the limiting ridge of the stomach in both sexes.

Comments about the Study/Endpoint: No inhalation studies are available. Therefore, an oral 

study was selected to estimate risk using route-to-route extrapolation. The study and endpoint 

were selected because they were observed by six months’ exposure and are protective of effects 

observed in all available studies, including maternal and developmental effects in the rabbit. 

Absorption via inhalation is assumed to be equivalent to absorption via the oral route, i.e., 100% 

inhalation absorption is assumed in risk assessment. An UF of 100 was applied to account for 

inter-species extrapolation (10X) and intra-species variation (10X). An additional 10x UFDB was 

not applied for lack of the inhalation study because an inhalation study is not required and the 

oral study is considered to be protective based on low vapor pressure and high inhalation MOEs 

estimated using the oral endpoint.
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Appendix A.4. Executive Summaries

A.4.1 Subchronic Toxicity

870.3100 90-Day Oral Toxicity - Rat

Satisfied by 870.4300 (Chronic Oral Toxicity/Carcinogenicity – Rat)

870.3100 90-Day Oral Toxicity - Mouse

In a subchronic toxicity study (MRID #00127276) 3,6- dichloropicolinic acid (technical, 97% 

purity) was administered to groups of 10/sex/dose BSC3F1 mice at dietary levels of 0, 200, 750, 

2000, or 5000 mg/kg body weight/day for approximately 13 weeks.

There was a statistically significant decrease in body weight in both sexes at 5000 mg/kg/day. 

Relative (to body) liver weight was significantly increased in both sexes at 5000 mg/kg/day. 

Males and females at 5000 mg/kg/day and females at 2000 mg/kg/day had centrilobular 

hepatocellular hypertrophy with altered tinctorial properties. The increased liver weight and 

hepatocellular histopathology were considered reversible, adaptive effects resulting from the 

increased metabolic activity due to dietary intake of clopyralid. 

The LOAEL is 5000 mg/kg/day, based on decreased body weight in both sexes. The 

NOAEL is 2000 mg/kg/day.

This subchronic toxicity study is classified Acceptable/guideline and does satisfy the guideline 

requirement for a subchronic oral study (§870.3100) in the rodent (mouse).

870.3150 90-Day Oral Toxicity - Dog

Satisfied by 870.4100b (Chronic Oral Toxicity – Dog)

870.3200 21-Day Dermal Toxicity – Rat

In a 21-day repeated dose dermal toxicity study (MRID 41790701), groups of 5 male and 5 

female New Zealand white rabbits were treated with Clopyralid (technical, 95.78%, Lot No. not 

given) at doses of 0, 100, 500, or 1000 mg/kg/day as a powder under moistened gauze. Animals 

were treated by dermal occlusion for 6 hours/day, 5 days/week for 3 weeks.

There were no treatment-related deaths or signs of systemic toxicity and no treatment-related 

effects on body weight, hematology, clinical chemistry, or organ weight. No evidence of skin 

irritation was observed in control rabbits; however, very slight erythema was observed on 1 midand 1 high-dose male and 1 mid-dose female at the end of the study. Treatment-related diffuse 

epidermal hyperplasia was observed on 1/5, 3/5, and 5/5 low-, mid- and high-dose males and 2/5, 

1/5, and 5/5 low-, mid-, and high-dose females, respectively, at the end of the study. The effect 

was not observed in any control animals. 
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The local dermal LOAEL was 100 mg/kg/day (LDT) based on diffuse epidermal 

hyperplasia on the skin of both males and females. A dermal NOAEL was not identified

(<100 mg/kg/day).

The systemic NOAEL is 1000 mg/kg/day based on a lack of biologically significant systemic 

toxicity. A systemic LOAEL was not identified (>1000 mg/kg/day).

This study is classified as Acceptable/Guideline and does satisfy the guideline requirements for a 

repeated-dose dermal study (§870.3200) in rabbits. Although a dermal NOAEL was not 

identified based on epithelial hyperplasia (1-5 animals affected) at all dose levels, no systemic 

toxicity was reported at any dose level.

870.3465 28-Day Inhalation – Rat

Not required.

A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study - Rat

In a developmental toxicity study (MRID 00127279), 29-30 presumed pregnant Fischer 344 rats 

per group were administered Clopyralid (technical, 97.0%; Lot/Batch No. not provided) by

gavage in cottonseed oil at doses of 0, 15, 75, and 250 mg/kg/day on gestation days (GD) 6-15, 

inclusive (Phase I). When a low number of malformations were observed at the highest dose 

tested in Phase I, additional control and high-dose groups (of 25 animals apiece) were evaluated 

later in Phase II. Controls were treated with cottonseed oil (vehicle). On GD 21, dams were 

sacrificed, maternal liver, kidney, and thymus weights were recorded, and all fetuses examined 

externally. Approximately one-half of each litter was processed for visceral examination, and all 

carcasses and the heads of the remaining one-half were processed for skeletal examination.

During Phase I, one rat in the 250 mg/kg/day group died on GD 11. Moistening of the hair of the 

perineal region, a thymus slightly decreased in size, and a gastrointestinal tract devoid of feed or 

fecal material were observed in this animal. During Phase II, two rats in the 250 mg/kg/day

group died on GD 10. Both animals exhibited substantial weight loss and exudative material 

from the nares. Definitive diagnoses as to cause of death could not be made for any of these 

animals. No other treatment-related clinical signs of toxicity were observed in any other animals. 

Maternal necropsy was unremarkable. In Phase I, absolute body weights of the high-dose dams 

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

statistically significant (p ≤0.05) on GD 10 and 16. Weight gain by the Phase I high-dose dams 

was significantly decreased (p ≤ 0.05) to 25-75% of the control group level during the treatment 

period. In Phase II, absolute body weights of the high-dose dams were statistically significantly 

decreased (p ≤ 0.05) to 94- 97% of controls on GD 10, 16, and 21. Weight gain by the Phase II 

high-dose dams was significantly decreased (p ≤ 0.05) to 42-74% of the control group level 

during the treatment period. In both Phase I and II, animals of the 250 mg/kg/day group had 

significantly (p ≤0.05) lower food consumption as compared with the controls during the 
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treatment interval. No treatment- related differences in water consumption were observed 

between the treated and control groups.

The maternal toxicity LOAEL is 250 mg/kg/day, based on death, reduced body weight 

gains, and reduced food consumption, and the maternal toxicity NOAEL is 75 mg/kg/day.

There were no differences between the control group and the 15, 75, or 250 mg/kg/day groups 

during Phase I or Phase II for number of corpora lutea, number of implantation sites, live 

fetuses/dam, pre- and post-implantation losses, or fetal sex ratios. During Phase I, the mean fetal 

body weight in the 75 mg/kg/day group was slightly, but statistically significantly (p ≤0.05), 

increased to 104% of control group level. No other statistically or biologically differences 

between treated and control animals were noted. In Phase I, the overall incidence rates for liners 

containing fetuses with major external, visceral, and/or skeletal malformations in the 0, 15, 75, 

and 250 mg/kg/day groups were 0/29, 0/22, 0i25, and 2/26, respectively. In Phase II, the overall 

incidence rates for liners containing fetuses with major external, visceral, and/or skeletal 

malformations in the 0 and 250 mg/kg/day groups were 1/20 and 0/21. No single malformation 

occurred at a statistically or biologically significant greater incidence in the treated groups, and 

the incidence of total major malformations was also not significantly increased for any of the 

treated groups as compared to controls.

The developmental toxicity NOAEL is 250 mg/kg/day. A developmental toxicity LOAEL 

was not determined (>250 mg/kg/day).

This study is classified as Acceptable/Guideline and satisfies the requirements for a 

developmental toxicity study (§83-3a) in rats. Despite numerous deficiencies in the conduct of

this study, an assessment of the developmental toxicity potential of the test article was possible.

870.3700b Prenatal Developmental Toxicity Study - Rabbit

In a developmental toxicity study (MRID 41649801, 41649802), 26-34 presumed pregnant New 

Zealand White rabbits per group were administered Clopyralid (technical, 96.1-96.4% a.i., Lot 

No. AGR 233257) by gavage at doses of 0, 50, 110, and 250 mg/kg/day on gestation days (GD) 

7-19, inclusive. The controls were given vehicle (corn oil) only for the same dosing period. On 

GD 28, all does were sacrificed, necropsied to assess gross pathology, and uteri and ovaries were 

removed. All fetuses were sexed, weighed, and examined for external malformations/variations 

prior to sacrifice. All of the fetuses were opened and checked viscerally then processed for 

skeletal examination.

Clinical signs of toxicity consisting of labored breathing, rales, shallow respiration, and/or 

coughing were observed in 11/29 does at 250 mg/kg/day. Eight of 13 deaths occurring at 250 

mg/kg/day were considered treatment-related. Mean body weight gain was statistically

significantly (p 0.05) decreased during the treatment period (GD 7-20) which correlates with a 

significant reduction in absolute body weight at GD 20 for 250 mg/kg/day animals. 

Histopathologic lesions of the gastric mucosa were observed in does (8/33) of the 250 mg/kg/day

treatment group.
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The maternal toxicity LOAEL is 250 mg/kg/day, based on clinical signs of toxicity, 

mortality, reduction in mean body weight, and lesions of the gastric mucosa during the 

treatment period. The maternal toxicity NOAEL is 110 mg/kg/day.

A statistically significant (p≤0.05) reduction in fetal body weight (13.2%), observed at 250 

mg/kg/day of Clopyralid, was considered treatment-related. Also at 250 mg/kg/day, 3/15 litters 

contained fetuses (total of eight) with hydrocephaly compared with 0/19 controls (n.s.).

The developmental toxicity LOAEL is 250 mg/kg/day, based on decreased fetal body 

weight and malformations. The developmental NOAEL is 110 mg/kg/day.

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a 

developmental toxicity study in rabbits (§83-3b). No deficiencies were noted which would 

adversely affect the interpretation of this study.

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects - Rat

In a multigeneration reproduction study (MRID 00138155), DOWCO®290 (96.7% a.i.; 

Identification No. ARG-l92532) was administered to groups of 30 Fischer-344 rats/sex/dose at 

dietary concentrations of 0, 150, 500, or 1500 mg/kg/day for two generations. Two litters were 

produced in both generations. F1 adults were chosen from the F1b pups and weaned onto the 

same diet as their parents. Test or control diets were administered to the F0 parental animals for 

up to 14 weeks and to the F1 parental animals for up to 17 weeks before the animals were mated 

within the same dose group. All animals were continuously exposed to test material either in the 

diet or via lactation until sacrifice.

Death of two F0 females and two F1 females was considered incidental to treatment; all other F0 

and F1 males and females survived to terminal sacrifice. No treatment-related clinical signs of 

toxicity were observed in males or females of either generation at any time during the study. 

Gross necropsy and histological examination of the parental animals revealed a treatment-related 

effect in the gastric squamous mucosa in high dose males of both generations. Histopathology

revealed slight focal hyperkeratotic changes in the gastric squamous mucosa of 1 of 30 F0 males 

and 2 of 30 F1 males of the high dose. Body weights, body weight gains, and food consumption 

of the low- and mid-dose F0 and F1 males and females were not affected in a biologically

relevant manner.

Absolute body weights of the high-dose F0 males were significantly (p ≤ 0.05) decreased (96-

97% of controls) during the premating interval. Overall weight gain by the high-dose males was

95 % (p≤0.05) of the control group mean. Food consumption by the high-dose male group was 

significantly (p ≤ 0.05) less than the controls for much of the premating interval. High-dose F0 

females had significantly (p ≤ 0.05) lower absolute body weights (96-97% of the control levels). 

Overall mean body weight gain by the high-dose females was slightly reduced (88% of controls) 

during the premating interval. Food consumption by the high-dose female group was 

significantly (p ≤0.05) less than the controls for a only few weeks of the premating interval. 
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Mean body weight among high-dose F0 females was also decreased during the lactation intervals 

of both litters (93-97% of control).

Mean body weight among F1 males fed 1500 mg/kg/day was significantly (p ≤ 0.05) decreased 

(93 - 94 % of control values) beginning with day 27 and continuing throughout the study; mean 

overall body weight gain was 96 % (n.s.) of the control. Mean food consumption was 

significantly (p ≤ 0.05) decreased among males receiving 1500 mg/kg/day during a few weeks of 

the premating interval, values for this group were 92 - 95% of control. Mean body weight among 

females fed 1500 mg/kg/day was significantly (p ≤ 0.05) decreased beginning with day 55 of the 

premating exposure period; mean body weight for this group was consistently 96 % of the 

control means. Mean food consumption among F1 females fed 1500 mg/kg/day was not effected 

during the premating interval. Lactational body weight of dams was only sporadically affected 

during the nursing of either the F2a, or F2b litters. 

The LOAEL for parental systemic toxicity is 1500 mg/kg/day based on decreased body 

weights, body weight gains, and food consumption in the F0 and F1 males and females and 

slight focal hyperkeratotic changes in the gastric squamous mucosa of 1 of 30 F0 males and 

2 of 30 F1 males. The parental systemic toxicity NOAEL is 500 mg/kg/day.

Mating, fertility, gestation, and parturition indices, and mean gestation length were similar 

between the treated and control female groups of both generations. 

The NOAEL for reproductive toxicity is 1500 mg/kg/day (HDT). A LOAEL for 

reproductive toxicity was not determined (>1500 mg/kg/day).

Mean litter size, live births, and pup survival were also similar between the treated and control 

groups for both generations. No treatment-related clinical signs of toxicity were observed in the 

F1a, F1b, F2a, or F2b pups during lactation. Body weight was significantly decreased by 8-10% 

in Day 28 male pups of the high dose of the F1a and F1b litters of the F1 generation, but not the 

F2 generation in comparison to the controls. Relative liver weight was significantly increased in 

F1a pups (both sexes) and F1b males at the high dose in comparison to controls. No treatmentrelated effects were observed among treated pups compared to the controls upon 

histopathological examination.

The LOAEL for offspring toxicity is 1500 mg/kg/day based on the decreased Day 28 body 

weight of male pups of both litters of the F1 generation and the increased relative liver 

weight of F1a pups (both sexes) and F1b males of the F1 generation. The offspring toxicity 

NOAEL is 500 mg/kg/day.

This study is classified as Acceptable/Guideline and satisfies the requirements for a reproduction 

study (§870.3800) in rats.
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A.4.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity – Rat

In a chronic toxicity/carcinogenicity study (MRID 00162393 and 00162434), DOWCO® 290 

(Clopyralid technical, 96.7% a.i.; lot number not reported) was administered in the diet to groups 

of 70 male and 70 female Fischer-344 rats at concentrations delivering doses of 0, 15, 150, or 

1500 mg/kg/day. Groups of 10 rats per sex per dose were killed at 6 and 12 months for interim 

evaluations; the remaining 50 rats per sex per dose were maintained on treated or control diets 

for up to 24 months.

No treatment-related effects were observed on mortality or clinical signs of toxicity at any dose. 

Mean body weights were significantly decreased by 2-5% (p≤0.05) in male rats fed 1500 

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

mg/kg/day group females compared with the weights of controls. Males in the 1500 mg/kg/day

group gained 5% less weight than controls during the first year of the study and 7% less weight 

overall, whereas 1 500-mg/kg/day group females gained 11% less during the first year and 1:6% 

less weight overall. Food consumption by 1500 mg/kg/day group male and female rats was 

significantly decreased by as much as 8% and 7%, respectively, at sporadic time points during 

the study. No treatment-related effects were observed on body weights or food consumption in 

the 15 or 150 mg/kg/day groups.

Statistically significant changes were observed for hematologic parameters, serum chemistry

parameters, and relative organ weights, but none were considered treatment related. The changes 

showed no dose-related trend, were transient in duration, or the magnitude of the change was not 

considered biologically significant. The primary target for DOWCO® 290 was the limiting 

ridge of the stomach. No gross or microscopic lesions affecting the limiting ridge were observed 

in 15 mg/kg/day groups. Gross examination showed that the limiting ridge was increased in size 

in almost all male and female rats receiving 1500 mg/kg/day for 12 or 24 months. Microscopic 

examination showed epithelial hyperplasia of the limiting ridge in almost all 1500 mg/kg/day

group male and female rats at 6, 12, and 24 months. The same lesion was observed in one or two 

male or female rats receiving 150 mg/kg/day for 6 and 12 months and in 52% of males and 42% 

of females at 24 months. The limiting ridge was thickened in two to seven male and female rats 

receiving 1500 mg/kg/day for 6 and 12 months and in 80% of males and 58% of females at 24 

months. The limiting ridge was also thickened in one or two males or females receiving the 150

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

mg/kg/day included chronic active inflammation in 6/10 males at 12 months compared with 0/10 

in the control group, and mononuclear cell aggregates in the stomach mucosa in 23/50 (p>0.05) 

males and 25/50 (p≤0.05) females compared with 12/50 controls of each sex. In addition, a 

statistically significant increase in the incidence of mononuclear cell aggregates in the 

lacrimal/Harderian gland was observed in males receiving 1500 mg/kg/day (21/50 vs 9/50 for 

controls, p≤0.05).

The LOAEL is 150 mg/kg/day for male and female rats based on histopathologic findings 

in the stomach (epithelial hyperplasia and thickening of the limiting ridge). The 

corresponding NOAEL is 15 mg/kg/day.
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There was no evidence of potential carcinogenicity of the test material at the doses given in this 

study. No neoplastic lesions occurred in treated groups at incidences significantly higher than the 

incidences in control animals. The doses administered were adequate for testing carcinogenicity 

as evidenced by histopathologic lesions in the stomach at the 150 and 1500 mg/kg/day doses. In 

addition, the high dose of 1500 mg/kg/day exceeded EPA’s limit dose of 1000 mg/kg/day.

This chronic toxicity/carcinogenicity study in the rat is Acceptable/Guideline and it satisfies the 

guideline requirement for a chronic toxicity/carcinogenicity oral study [OPPTS §870.4300] in 

rats. Deficiencies were noted, but none affected the interpretation of the results.

870.4100b Chronic Toxicity - Dog

In a chronic oral feeding toxicity study (MRID 00158256), Clopyralid (Batch No. AGR 192532, 

95.8% purity) was administered to groups of six male and six female beagle dogs for 52 weeks at 

doses of 0, 100, 320, or 1000 mg/kg/day in the diet.

No animals died as a result of treatment, and no treatment-related clinical signs of toxicity were 

observed. There were no treatment-related effects on mean body weight, body weight gain, or 

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

statistically significant reduction in both sexes of mid- and high-dose dogs. These changes are 

judged to be adverse and toxicologically significant, based on their magnitude (10-28% 

reduction in RBCs). Clinical chemistry changes (decreased albumin, globulin, or serum protein 

at one or more sampling times) at the high dose in both sexes were highly statistically significant 

and considered treatment related. Highly significant increased absolute and relative liver weight 

in both sexes of high dose dogs and absolute liver weight in mid dose males was considered 

toxicologically significant although in the absence of associated findings. Gross and histological 

changes seen in the lungs of treated dogs were evidently an inflammatory response to inhaled 

food particles, caused by the dogs “mouthing” their food, and not the result of systemic toxicity. 

Microscopically observed skin findings were increased in incidence and severity at the high dose 

in both sexes and included acanthosis (m,f), hyperkeratosis (m), and acute ulcerative dermatitis 

(f) and were considered treatment related. A dose-related increase in both incidence and severity

of slight to mild focal vacuolation of adrenal cortical cells at the mid dose of females and high 

dose of both sexes was considered a significant toxicological effect.

The chronic oral toxicity LOAEL for dogs is 320 mg/kg/day for both sexes, based on a 

reduction in the hematological parameters, increased absolute liver weight in males, and 

vacuolated adrenal cortical cells in females. The NOAEL is 100 mg/kg/day.

This chronic oral toxicity study is classified as Acceptable/Guideline and satisfies the guideline 

requirement for a chronic oral toxicity study (§870.4100b) in dogs.

A.4.5 Carcinogenicity

870.4200a Carcinogenicity Study - rat

See 870.4100a (870.4300)(Chronic oral toxicity/carcinogenicity – rat)
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870.4200b Carcinogenicity (feeding) - Mouse

In an oncogenicity study (MRID 00157783), DOWCO®290 (technical, 96.7% a.i., batch/lot no. 

not supplied) was administered to groups of 70 male and 70 female B6C3F1 mice in the diet at 

concentrations providing 0, 100, 500, or 2000 mg/kg/day for up to 24 months. The dietary

concentrations were adjusted weekly or monthly to maintain the target dose level using the food 

intake and body weights. Ten animals per sex per group were utilized for 6 month and for 12 

month interim studies.

Treatment with DOWCO®290 did not result in a significant decrease in survival or increases in 

clinical signs in treated groups compared with the control groups. Group mean body weights of 

males at 2000 mg/kg/day were decreased by 5% to 13% (p ≤0.05) from treatment days 91 to 708 

compared to the controls. The mean overall body weight gain in males was decreased by about 

15% at 2000 mg/kg/day and by 8% at 100 and 500 mg/kg/day compared to the control group. 

The overall food efficiency in males was also 18% lower at 2000 mg/kg/day than that of the 

control group. The body weight and weight gain in females were not affected by treatment with 

DOWCO®290 and the food efficiency in females was higher in the treated groups than in the 

control.

No treatment-related changes were seen in hematology parameters. Group mean blood glucose 

levels were increased in males by 20% and 27% (p ≤0.05) at 500 and 2000 mg/kg/day, 

respectively, after 6 months of treatment, and by 42% and 36% (p ≤ 0.05) after 24 months. Blood 

glucose levels were also increased in females by 28%, 9%, (NS) and 34% (p ≤0.05) at 100, 500, 

and 2000 mg/kg/day, respectively, after 6 months, but were not significantly increased at 12 or 

24 months. The toxicological significance of the changes in blood glucose levels in treated 

animals is compromised by the use of non-fasted animals, the lack of a clear dose effect in 

females at 6 months and males at 24 months, and the lack of significant changes at 12 months in 

both sexes and at 24 months in females. A decrease in alkaline phosphatase activity of 51% was 

seen in females at 2000 mg/kg/day compared to the control after 24 months of treatment. The 

decreased activity appears to be associated, at least in part, with a decrease in the incidence of 

bone fibrous osteodystrophy in high-dose females (control, 35/50; 2000 mg/kg/day, 26/50, NS). 

A slight decrease in the incidence of sciatic nerve axon degeneration was seen in high-dose 

males at 24 months (control, 16/50; 2000 mg/kg/day, 8/50, p ≤0.05). No treatment- related 

adverse effects were seen during the histopathologic examinations.

The LOAEL is 2000 mg/kg/day based on decreased body weight, body weight gain, and 

food efficiency for males. The LOAEL was not identified for females (>2000 mg/kg/day). 

The NOAEL was 500 mg/kg/day for males; 2000 mg/kg/day for females.

There was no evidence of oncogenic potential under the conditions of this study. Major organs 

examined included liver, kidney, testes, lung, ovary, bladder, brain, and thyroid. The dosing 

based on toxic response was marginal in males and inadequate in females. The high dose of 2000 

mg/kg/day was above the limit dose for non-toxic agents and, therefore, was considered adequate 

for the oncogenicity study. This study is classified as Acceptable/guideline and does satisfy the 

guideline requirement for an oncogenicity study (§870.4200b) in mice.
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A.4.6 Mutagenicity

Gene Mutation

870.5300, in vitro (Salmonella and 

Saccharomyces) and in vivo (mouse) 

host-mediated gene mutation assay

MRID 00057086

Acceptable/Guideline

Negative for evidence of induction of mutant colonies over background levels 

in Salmonella or Saccharomyces strain D-3 at doses in the presence or 

absence of S9. Mice exposed to 4, 40 or 400 mg/kg by gavage.

Cytogenetics

870.5385, in vivo micronucleus assay in 

the rat

MRID 00073638

Acceptable/guideline

Negative for evidence of increased incidence of treatment-related bone 

marrow chromosomal aberrations at 4, 40 or 400 mg/kg/day.

Other Genotoxicity

870.5450, dominant lethal assay in the 

rat

MRID 00059053, 00099100

Acceptable/guideline

Negative for evidence of increased incidence of treatment-related resorptions 

at 4, 40 or 400 mg/kg/day for 5 days prior to mating.

870.5550, unscheduled DNA synthesis 

in the rat

MRID 00156387, 41790702

Acceptable/guideline

Negative for evidence of increased unscheduled DNA synthesis up to

insoluble concentrations when tested at concentrations between 9.6 to 9600 

μg/mL for 18 to 20 hrs.

A.4.7 Neurotoxicity

870.6200 Subchronic Neurotoxicity Screening Battery (Acute and Subchronic)

Not required.

A.4.8 Metabolism

870.7485 Metabolism - Rat

In a metabolism study (MRID 41790703), groups of five male and five female rats were given a 

single oral dose of [144C]-Clopyralid (5 or 150 mg/kg; Lot no. 805 [ref. no. GHD-2775-l0a, 

purity >96%), a single intravenous dose (5 mg/kg) of radiolabeled test article, or 14-day repeated 

5 mg/kg/day oral doses of non-radiolabeled Clopyralid (Lot no. AGR 233257; radiochemical 

purity >99%) followed by a single 5 mg/kg oral dose of radiolabeled test article. Additionally, a 

pretest experiment to assess pulmonary excretion was performed in which two male and two 

female rats were given a single oral dose (5 mg/kg). An untreated control group consisted of one 

male and one female rat.

There were no deaths or overt signs of toxicity reported. Radioactivity inventory indicated an 

acceptable recovery (95-115%) of the administered dose among the experimental groups in the 
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definitive phase of the study. Clopyralid was nearly completely absorbed at the doses tested. 

Under the conditions of this study, tissue and carcass burdens were negligible for all groups, 

suggesting little potential for accumulation. Minimal radioactivity (≤0.0 1% at 72 hours) was 

found in the gastrointestinal tract and organs associated with excretion (e.g., liver, kidneys). 

Urinary excretion accounted for most (91-113% at 72 hours postdose) of the administered test 

material regardless of the administration route or dose. There did not appear to be any

biologically relevant gender- dependent differences in total urinary excretion or excretion rates.

Most urinary excretion (74-98% of administered dose) occurred within 6 hours after 

administration for all low dose groups and within 12 hours for the repeated-dose group. Fecal 

excretion was negligible and, at 72 hours, accounted for <4% of the administered dose in all 

treatment groups. HPLC and TLC analysis of urine and fecal samples indicated that the 

radioactivity inventory represented only parent compound. There was no evidence of 

metabolites.

This metabolism study in rats is classified as Acceptable/Guideline and satisfies the guideline 

requirement for a Metabolism and Pharmacokinetics study in the rat (§870.7485).

A.4.9 Immunotoxicity

870.7800 Immunotoxicity

In an immunotoxicity study (MRID 483000001) Clopyralid (95.9% a.i., Lot No. 910905 5P) was 

administered to male F344/DuCrl rats in the diet designed to give nominal dose levels of 0 

(vehicle control and positive control), 150, 500, or 1000 mg/kg bw/day (actual dose levels of 0, 

158, 530, and 1062 mg/kg bw/day, respectively) (10 animals/dose) for 29 days (Day 1-29). On 

Day 25, animals in all groups were immunized with a suspension of sheep red blood cells 

(SRBC) by intravenous injection (2x108SRBC/animal, 0.5 mL/animal dose volume). Animals 

in the positive control group received an intraperitoneal injection of cyclophosphamide on Days 

24-28 at a dose of 20 mg/kg bw (1 mL/kg bw dose volume). All animals were evaluated for 

mortality, clinical signs, body weight changes, and gross pathology. The vehicle control and test 

substance treatment groups also were evaluated for food consumption, hematologic parameters, 

and histopathology. Immunotoxicity was assessed for all animals by ELISA assay; spleen and 

thymus weights were determined at necropsy. 

There were no test substance-related effects on mortality, clinical signs, body weight changes, 

food consumption, hematologic parameters, histopathology or gross pathology. A LOAEL for 

systemic toxicity could not be determined for Clopyralid in male rats (i.e., greater than the 

nominal dose of 1000 mg/kg bw/day, actual dose of 1062 mg/kg bw/day, highest dose tested) 

based on the evaluated parameters. The NOAEL for systemic toxicity is 1000 mg/kg 

bw/day (actual dose of 1062 mg/kg bw/day), highest dose tested and the limit dose.

There were no test substance-related effects on serum anti-SRBC IgM antibody levels as 

measured by ELISA assay, on thymus and spleen weights, or on hematologic parameters. A 

LOAEL for immunotoxicity could not be determined for Clopyralid in male rats (i.e., 

greater than the nominal dose of 1000 mg/kg bw/day, actual dose of 1062 mg/kg bw/day, 

highest dose tested) based on the evaluated parameters. The NOAEL for immunotoxicity is 
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1000 mg/kg bw/day (actual dose of 1062 mg/kg bw/day), highest dose tested and the limit 

dose.

This immunotoxicity study is classified as acceptable/guideline and satisfies the guideline 

requirement for an immunotoxicity study (OPPTS 870.7800) in the rat. Information regarding 

the stability of the test substance, storage conditions of the test substance and dietary

formulations, and references for the historical control thymus weight data should be submitted.
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Appendix B. Clopyralid Physical/Chemical Properties

Physicochemical Properties of the Technical Grade Clopyralid

Parameter Value References

Physical State Solid A world Compendium, 

The Pesticide Manual, 

14th Edition. C.D. S 

Tomlin (Editor), 2006.

Color Colorless

Melting Point/Range 151-152°C

Dissociation Constant (pKa) 2

Density at 20°C 1.57 g/cm3 

Vapor Pressure at 25°C 1.0 x 10-5 mm Hg (1.33 mPa)

Water Solubility at 20°C 7.85 g/L

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

Ethyl acetate: 102

Xylene: 4.6

Hexane: 6.0

Octanol/water partition coefficient, 

Log (KOW)

-1.81 (pH 5) 

-2.63 (pH 7) 

-2.55 (pH 9)
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Appendix C. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These data, which include studies from 

the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler 

Exposure Task Force (AHETF) database; and other registrant-submitted exposure monitoring 

studies (MRID 44339801), are subject to ethics review pursuant to 40 CFR 26, have received 

that review, and are compliant with applicable ethics requirements. For certain studies, that 

review may have included review by the Human Studies Review Board. Descriptions of data 

sources as well as guidance on their use can be found at: http://www.epa.gov/pesticides/ 

science/handler-exposure-data.html and http://www.epa.gov/pesticides/science/post-appexposure-data.html.