1 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

August 27, 2014 

PC Code: 117401, 117403, 117404, 117423 

MEMORANDUM DP Barcode: 422307

SUBJECT: Addendum to the EFED Registration Review Problem Formulation for Clopyralid 

Regarding Tier I Honey Bee Toxicity Testing 

FROM: Elyssa Arnold, Biologist 

 Environmental Risk Branch II 

Environmental Fate and Effects Division (7507P) 

THROUGH: Brian Anderson, Branch Chief 

Environmental Risk Branch II 

 Environmental Fate and Effects Division (7507P) 

 

TO: Steven Snyderman, Chemical Reviewer Manager 

 Avivah Jakob, Team Leader 

 Patricia Parrott, Branch Chief 

Risk Management and Implementation Branch III 

Pesticide Re-Evaluation Division (7508P) 

This addendum addresses changes to the data gaps identified in the preliminary problem 

formulation (USEPA, 2014b) and Preliminary Work Plan (USEPA, 2014a) prepared in support 

of the Registration Review of clopyralid. Specifically, this document identifies additional data 

gaps for clopyralid with respect to toxicity tests on honey bees (Apis mellifera). 

Since the preliminary problem formulation was published, the Agency has issued guidance for 

assessing the potential risks of pesticides to bees and the data needed to support such 

assessments (USEPA et al., 2014). The guidance document indicates that if exposure of bees to a 

pesticide is expected, a Tier I screening-level risk assessment is conducted. The Tier I 

assessment is intended to be sufficiently conservative that chemicals that pass the screen are 

considered to represent a relatively low risk of adverse effects to bees. Tier I toxicity data that 

are needed to complete screening-level risk assessments include a suite of laboratory-based 

studies of individual bees and include the following tests: acute contact toxicity data to adult 

honey bees (honey bees serving as a surrogate for all bee species), acute and chronic oral toxicity 

to adult honey bees, and acute and chronic oral toxicity to honey bee larvae. If risk concerns are 

identified in the screening-level assessment, the assessment may be refined using data that 
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further define exposure or through additional toxicity data from Tier II semi-field or Tier III fullfield studies conducted with whole colonies. 

Clopyralid uses include aerial applications to multiple agricultural crops, pastures, rangeland, 

agricultural fallow/idleland/conservation reserve, forest trees, and nonagricultural uncultivated 

areas/soils where spray drift may land on blooming non-target plants and could result in residues 

in pollen and nectar. This pollen and nectar could then be transported to hives by adult forager 

bees. Additionally, clopyralid is highly persistent and, like other members of the picolinic acid 

family, is systemic and can move in both xylem and phloem tissue. Although clopyralid uptake 

is primarily through the foliage, root uptake is also possible. Therefore, clopyralid residues may 

be present in pollen and nectar either through transport from leaf tissues affected by spray drift or 

from root uptake from plants grown where clopyralid was previously applied. Residues may also 

contaminate pollen and/or nectar through foliar applications. Residues can in turn be brought 

back to bee colonies where in-hive bees including young adult and developing brood (i.e., eggs, 

larvae and pupae) may be exposed. Therefore, exposure at all bee life stages would be expected. 

Since exposure of bees to clopyralid residues is expected, Tier I honey bee laboratory toxicity 

data are needed to conduct the screening-level risk assessment. Acute contact and oral toxicity 

data are available that indicate clopyralid residues are practically non-toxic to adult honey bees 

on an acute contact and oral exposure basis. However, no data are available to evaluate 

clopyralid’s toxicity from the oral exposure route to larval bees on an acute or chronic basis or to 

adult bees on a chronic basis. 

Therefore, the Environmental Fate and Effects Division (EFED) recommends requesting Tier I 

laboratory toxicity data on the technical grade active ingredient (TGAI) for acute and chronic 

oral toxicity for larval honey bees and for chronic oral toxicity for adult honey bees in order to 

complete the risk assessment for bees, as is further detailed in the attached data rationale tables. 

Should the screening level risk assessment identify that there are risk concerns to bees, 

mitigation measures may need to be considered or the registrant may be required to conduct 

more refined studies under semi-field or full-field conditions (e.g. OCSPP guideline 850.3040) 

that reduce uncertainty by characterizing clopyralid’s effects at the whole-colony level. 

References 

USEPA, 2014a. Clopyralid Preliminary Work Plan. Registration Review: Initial Docket, Case 

Number 7212. Pesticide Re-evaluation Division, Office of Pesticide Programs, USEPA, 

Washington D.C. March 20, 2014. 

USEPA, 2014b. EFED Registration Review Problem Formulation for Clopyralid. 

Environmental Fate and Effects Division, Office of Pesticide Programs, USEPA, Washington 

D.C. February 25, 2014. DP Barcode 416098. 

USEPA, PMRA, and CDPR, 2014. Guidance for Assessing Pesticide Risks to Bees. Office of 

Pesticide Programs, USEPA, Washington D.C. Health Canada Pest Management Regulatory 

Agency, Ottawa, ON, Canada. California Department of Pesticide Regulation, Sacramento, CA. 

June 23, 2014. 
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Guideline Number: Non-Guideline 

Study Title: Adult Honey Bee Chronic Oral Toxicity

Rationale for Requiring the Data 

This study is needed to evaluate the potential effects of technical grade active ingredient (TGAI) on young 

adult honey bees from repeat exposure. Clopyralid uses include aerial applications to multiple agricultural 

crops, pastures, rangeland, agricultural fallow/idleland/conservation reserve, forest trees, and 

nonagricultural uncultivated areas/soils where spray drift may land on blooming non-target plants and 

result in residues in pollen and nectar (which could then be transported to the hive). Additionally, 

clopyralid is highly persistent and, like other members of the picolinic acids family, is systemic and can 

move in both xylem and phloem tissues into pollen and/or nectar. Although clopyralid uptake is primarily 

through the foliage, root uptake is also possible. Therefore, clopyralid residues may be present in pollen 

and nectar either through transport from leaf tissues affected by spray drift or from root uptake from plants 

grown where clopyralid was previously applied. Residues can in turn be brought back to bee colonies 

where in-hive bees including young adult and developing brood (i.e., eggs, larvae and pupae) may be 

exposed. Therefore, exposure at all bee life stages may occur. 

Since the preliminary Problem Formulation and Preliminary Work Plan for clopyralid were signed, the 

Agency finalized its guidance for assessing the risk of pesticides to bees (USEPA et al., 2014). EPA now 

requires this study for all use sites where potential exposure to pollinators may occur. Although EPA has 

not developed a guideline for this study and OECD has yet to finalize test guidance for chronic studies, 

efforts are currently underway to develop standardized guidelines for assessing effects from chronic (10-

day) exposures to adult bees in the laboratory. Until a guideline is finalized, a protocol should be 

submitted to the Agency for review before study initiation. Clopyralid acid (PC 117403) technical grade 

active ingredient (TGAI) should be used in this study and will be assumed to be representative of the 

toxicity of the three registered clopyralid salts (PC 117401, PC 117404, PC 117423). 

Practical Utility of the Data 

How will the data be used and how could the data impact the Agency’s future decision-making? 

The 10-day toxicity study with young adult bees provides data that will be used in estimating chronic risk 

to individual adult bees. Risk estimates based on these data will be considered along with other lines of 

evidence to determine whether higher-tier studies are needed at the whole colony level. 

These data are needed for risk assessments written in support of Registration Review as well as for future 

endangered species assessments. These data would allow the Agency better characterize the potential for 

risk to insects (including beneficial pollinators) from the use of picolinic acids-class chemicals. These data 

may help the Agency determine whether any mitigation is needed. If the Registration Review and any 

future endangered species risk assessments are performed without these data, the Agency would have to 

assume that picolinic acids-class chemicals "may affect" insects, including bees and beneficial pollinators, 

directly (and threatened or endangered species from other taxa indirectly), and uses of clopyralid might 

need to be restricted in areas where pollinators could be exposed. 

 
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Guideline Number: Non-Guideline 

Study Title: Larval Honey Bee Acute and Chronic Oral Toxicity

Rationale for Requiring the Data 

These studies are needed to evaluate the potential effects of technical grade active ingredient (TGAI) on 

honey bee larvae from repeat exposure. Clopyralid uses include aerial applications to multiple agricultural 

crops, pastures, rangeland, agricultural fallow/idleland/conservation reserve, forest trees, and 

nonagricultural uncultivated areas/soils where spray drift may land on blooming non-target plants and 

result in residues in pollen and nectar (which could then be transported to the hive). Additionally, 

clopyralid is highly persistent and, like other members of the picolinic acids family, is systemic and can 

move in both xylem and phloem tissues into pollen and/or nectar. Although clopyralid uptake is primarily 

through the foliage, root uptake is also possible. Therefore, clopyralid residues may be present in pollen 

and nectar either through transport from leaf tissues affected by spray drift or from root uptake from plants 

grown where clopyralid was previously applied. Residues can in turn be brought back to bee colonies 

where in-hive bees including young adult and developing brood (i.e., eggs, larvae and pupae) may be 

exposed. Therefore, exposure at all bee life stages may occur. 

Since the preliminary Problem Formulation and Preliminary Work Plan for clopyralid were signed, the 

Agency finalized its guidance for assessing the risk of pesticides to bees (USEPA et al., 2014). EPA now 

requires these studies for all use sites where potential exposure to pollinators may occur. Although EPA 

has not developed a guideline for this study, the 21-day larval toxicity study currently under development 

by OECD provides a draft guidance protocol for potentially assessing both the acute and chronic toxicity 

to developing brood (larvae and pupae) from repeat exposure to pesticides. Until a guideline is finalized, 

protocols should be submitted to the Agency for review before study initiation. Registrants may choose to 

submit a separate acute (single dose) larval toxicity study following OECD TG 237 as well as the 21-day 

repeat dose chronic toxicity study. Clopyralid acid (PC 117403) technical grade active ingredient (TGAI) 

should be used in this study and will be assumed to be representative of the toxicity of the three registered 

clopyralid salts (PC 117401, PC 117404, PC 117423). 

Practical Utility of the Data 

How will the data be used and how could the data impact the Agency’s future decision-making? 

The 21-day toxicity study provides data on the effects of technical grade active ingredient (TGAI) on 

developing bees from acute (short-term) and chronic (longer term) exposure and will be used for 

estimating risk to individual (solitary) bees as well as bee colonies (social bees). Risk estimates based on 

these data will be considered along with other lines of evidence to determine whether higher-tier studies 

are needed at the whole colony level. 

These data are needed for risk assessments written in support of Registration Review as well as for future 

endangered species assessments. These data would allow the Agency better characterize the potential for 

risk to insects (including beneficial pollinators) from the use of picolinic acids-class chemicals. These data 

may help the Agency determine whether any mitigations are needed. If the Registration Review and any 

future endangered species risk assessments are performed without these data, the Agency would have to 

assume that picolinic acids-class chemicals "may affect" insects, including bees and beneficial pollinators, 

directly (and threatened or endangered species from other taxa indirectly), and uses of clopyralid might 

need to be restricted in areas where pollinators could be exposed.