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Clothianidin Registration Review: Response to Comments

1. Comment:

Multiple commenters inquired as to whether the Agency has considered recent publications 

characterizing neonicotinoid exposure to honey bees in laboratory settings; specifically the 2012 

Pettis et al. study with imidacloprid, “Pesticide exposure in honeybees results in increased levels 

of the gut pathogen Nosema.” 

Response:

This study is currently in review and all available data will be considered at the time of risk 

assessment.

2. Comment:

Neonicotinoid particulate matter in seed planter exhaust has been discussed in some recently 

published articles (Krupke CH, et al. 2012; Tapparo et al. 2012). Is the Agency considering seed 

planter exhaust as a route of exposure to neonicotinoid compounds like clothianidin?

Response:

As captured in the conceptual diagram on page 29 of the clothianidin problem formulation, the 

Agency will consider exposure resulting from abraded seed coat particulates in the registration 

review risk assessment for clothianidin.

3. Comment:

Will the Agency consider risks to small birds and mammals exposed via treated seed 

consumption?

Response:

The Agency routinely considers risks to passerines (small birds) and small mammals when 

assessing ecological risk.

4. Comment:

Multiple commenters discussed the toxicity profile of clothianidin in terms of acute exposure to 

bees, wondering how this information will be used in risk assessment.

Response:

The EPA is aware of registrant-submitted studies and other open literature studies regarding the 

potential effects of neonicotinoid insecticides on insect pollinators and specifically on honey 

bees.

As part of the review process, the EPA examines the effects of chemicals on bees based on both 

laboratory and when appropriate, field studies to determine whether individual bees and entire 

bee colonies may be affected by the use of a compound and to support risk mitigation decisions. 
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The EPA is currently revising its process for assessing pesticide risks to bees to reflect 

advancements in the state of the science that underlie bee exposure and effects assessments. 

Interim guidance (USEPA 20111

) on factors to consider when evaluating exposure and effects to 

bees is available to ecological risk assessors. In 2012, the EPA will present to a FIFRA Scientific 

Advisory Panel (SAP) a proposed process for quantifying risks to honeybees and identifying 

exposure and effect studies needed to inform that process. Based on input from the SAP, the 

EPA will incorporate its revised assessment process to quantify risks to bees in a similar manner 

as that used to evaluate risks to other taxa. 

As the EPA’s understanding of the science evolves, its need for data and its evaluation of those 

data will evolve as well. Therefore, as with all taxa, the EPA reserves the right to require 

additional data it deems necessary to inform its understanding of potential ecological risks and 

support its associated risk management decisions. Additional data requirements for pollinators 

may extend beyond those identified in problem formulations and preliminary work plans written 

in support of the registration review process. 

5. Comment:

Roberta Firoved quoted Dr. Luis Espino, a University of California Cooperative Extension 

representative, who provided information on rice and almonds and crop-specific pest 

management practice in California, noting the geographic coincidence of rice growing areas with 

almond orchards in the Sacramento valley region. Seedling pests in rice fields are commonly 

controlled via insecticide application, but these treatments are typically not applied before late 

April, weeks after the completion of almond bloom.

Response:

The Agency will continue to rely on the chemical-specific usage data provided by the California 

Department of Pesticide Regulation to detect trends in both the amount and spatial distribution of 

clothianidin applied in the state of California. The information regarding timing of insecticide 

applications may be useful for exposure characterization in the registration review assessment.

6. Comment:

Bayer CropScience (BCS) requests that section 7.1 Stressors of Concern (page 31) of the PF 

document be amended to omit aquatic invertebrates as species at risk with respect to seed 

treatment uses. The correct screening level aquatic risk assessment indicates minimal chronic 

risk to all aquatic species, including invertebrates, since all RQ’s are less than 1.

Response:

In the Section 3 New Use assessment for clothianidin uses on mustard and cotton (December 

2010; D378994, D377955) an acute level of concern (LOC) was inadvertently used in some 

cases to evaluate the chronic risk to aquatic invertebrates and that this resulted in some erroneous 

LOC exceedences for chronic aquatic invertebrate testing. Despite this, chronic exceedances to 

 1 USEPA. 2011. Pesticides: Science and Policy. Interim Guidance on Honey Bee Data Requirements. 

http://www.epa.gov/pesticides/science/efed/policy_guidance/team_authors/terrestrial_biology_tech_team/hone

ybee_data_interim_guidance.htm
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benthic invertebrates did persist using the chronic LOC of 1.0 based on sediment bound (organic 

carbon normalized) EECs. More importantly; the language describing aquatic invertebrates as a 

taxon at risk was intentionally retained in the problem formulation so as to capture the 

uncertainty surrounding the chronic toxicity of clothianidin to the sediment-dwelling midge,

which available data (MRID 45422414) indicate to be more than three orders of magnitude more 

acutely sensitive than daphnids (MRID 45422338). The EFED’s logic behind a request for 28-

day chronic study with midge using spiked water is that the 10-day midge study (MRID 

46826902) does not assess fecundity, which was the most sensitive endpoint in both chronic 

daphnid and mysid testing. It is noted that the NOAEC in the daphnid chronic test is greater than 

three orders of magnitude more sensitive than the daphnid 48-hour EC50, which indicates that a 

28-day chronic test with the midge could reveal considerably heightened sensitivity compared to 

the 48-hour testing.

7. Comment:

BCS requests that the Agency reconsider its identification of non-guideline midge studies using 

TGAI and the degradates TZNG and TMG as a data gap. The current aquatic data package is 

robust and includes sufficient laboratory and field data to allow the Agency to conclude minimal 

risk for all aquatic organisms, including threatened and endangered species. 

Response:

As described above, uncertainty regarding the chronic sensitivity of midge exists because this 

species has tested to be more acutely sensitive than daphnia. Further, the available 10-day midge 

study (conducted with clothianidin technical) did not evaluate the most sensitive endpoint from 

the daphnid chronic study (i.e., reproduction). The Agency is not aware of an acute midge study 

that indicates equal or lesser toxicity of degradate TMG as compared to daphnia response. Such 

data would likely preclude the need for additional midge chronic testing with TMG. However,

since the publication of the preliminary work plan, EFED has reconsidered the need for further 

midge toxicity testing with degradate TZNG. This is principally because available acute toxicity 

data for midge exposed to TZNG indicate lesser toxicity than acute exposure to clothianidin 

technical. The final work plan will be revised accordingly.

8. Comment:

BCS reiterated comments submitted to the Agency in January 2011. 

• The Agency has mistakenly indicated that the chronic LOC for endangered and threatened species is 

0.05 in Table 13 of the EFED document. The correct chronic LOC is 1.0 as noted in Appendix C, 

page 72 in the EFED document. This error in Table 13 led to a chronic LOC that was 20x lower than 

the appropriate value (1.0 vs. 0.05). Due to this mistake in the process of evaluating the chronic RQ, 

the EFED memo and science chapter incorrectly conclude that there is a major risk to free-swimming 

aquatic invertebrates. These statements should be removed from the memo and removed from 

subsequent related sections of the EFED document. 

• The Agency mistakenly used the lower range of the 95% confidence interval for the mysid 48-hour 

EC50, rather than the EC50 value, itself. 
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Response:

The aquatic invertebrate toxicity characterization errors in the 2010 EFED risk assessment have 

been noted. EFED will revise this risk characterization as appropriate for the registration review 

risk assessment.

EFED has investigated the concern that a lower bound of a 95% confidence interval for an EC50

was used instead of the EC50 value itself. While the endpoint of 22 parts per billion (ppb) is the 

lower bound of the EC50 that was calculated by the study author, the statistical analysis 

completed by the EPA reviewer; described in the Data Evaluation Record (DER) for MRID 

45422414; determined an EC50 of 22 ppb with lower and upper 95% confidence bounds of 18 

and 27 ppb, respectively. 

9. Comment:

BCS opposes the use of the language “degradates of concern” on the grounds that it will be 

misconstrued by the general public as a risk determination rather than a hazard classification. 

Response:

The “degradate of concern” terminology reflects both exposure and hazard components. At this 

time, degradate TMG is of potential concern to the midge, pending submission of additional 

data.

10. Comment:

BCS notes that the summary of a field study conducted by researchers at the University of 

Minnesota and University of Guelph inaccurately characterizes several key findings (Appendix 

E). The PF document states “Several effects parameters on honey bees, including mortality, 

pollen foraging activity, mean number of foragers observed, and mean honey yield appeared to 

be negatively impacted by seed treatment, however replicate data for honey bees and hives were 

not provided, so statistical analysis of the data could not be conducted.” This statement 

mischaracterizes the results of the study in question. 

Response:

Submission of the raw data for this study (MRID 45422435) would allow for verification of the 

study authors’ reported results. A statistical re-analysis would necessarily precede any changes 

to study characterization.

11. Comment:

BCS discusses the following: 

• Page 11, Table 3, Aerobic Aquatic Metabolism: There are two studies with acceptable 

data for the assessment of the aerobic aquatic half-life -- MRID 46826903 (half-life = 187 

days; core study with thiazolyl-radiolabel and one water/sediment system) and MRID 

45422324 (half-lives 48 days and 65 days; supplemental study with phenyl-radiolabel 

and two water/sediment systems). All three values should be considered when deriving 

aerobic aquatic half-life used for the aquatic exposure assessment.
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• Page 38, Table 7.1, Aerobic Aquatic Metabolism: The supplemental aerobic aquatic 

metabolism study should be listed (MRID 45422324).

Response:

All data for aerobic aquatic metabolism will be evaluated at the time of risk assessment.

12. Comment:

BCS discusses the following: Exposure Modeling Input Data: In addition to using the 

appropriate aerobic aquatic metabolism half-life, the exposure assessments must also use the 

appropriate aqueous photolysis half-life (half-lives of 0.6 days and 1.1 days for the sterile 

aqueous buffer solution (MRID 45422318) and natural water (MRID 45422318) studies) and 

appropriate application methods for the seed treatment uses (i.e. CAM=8).

Response:

The Agency will use all available data and current guidance on model inputs at the time of risk 

assessment. 

13. Comment:

Valent suggests that the Agency consider harmonizing data requirements for honey bee testing 

with the California Department of Pesticide Regulation (CDPR) and Health Canada’s Pest 

Management Regulatory Agency (PMRA) in order to avoid duplicative or contradictory testing 

requirements.

Response:

The Agency is working with the CDPR and Health Canada’s PMRA to ensure that the necessary 

data will be available for assessing risk to insect pollinators by the time of registration review. It 

is the Agency’s intention to avoid requesting data that is duplicative, contradictory, or otherwise 

unduly burdensome. 

14. Comment:

Valent encourages the EPA to develop and implement a state-of-the-art pollinator risk 

assessment process based on the findings of the SETAC Pellston and FIFRA SAP.

Response:

Comments and recommendations from both the SETAC Global Workshop on Pollinator Risk 

Assessment and the 2012 FIFRA SAP on estimating risk to insect pollinators will influence the 

approach of the clothianidin registration review risk assessment. 

15. Comment:

Both Valent and BCS submitted edits regarding Appendix A, Maximum Labeled Application 

Rates for Clothianidin.
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Response:

EFED will work with the Biological and Economic Analysis Division (BEAD) to insure all use 

rates are accurate at time of risk assessment and BCS and Valent comments will be considered.

16. Comment:

Mass bee die-offs could have far-reaching impacts on the food supply.

Response:

Concerns regarding impacts to pollinators that could potentially affect food security should be 

directed to the United States Department of Agriculture.

17. Comment:

Commenter self-identifies as a commercial beekeeper that has determined varroa mites (Varroa

spp.) to be a major factor in colony health in recent years.

Response:

The USDA and EPA are considering Varroa spp. as a potential contributor among a number of 

stressors that have been implicated in honey bee health issues.

18. Comment:

Beyond Pesticides suggests that the Agency consider a study (Iwasa et al., 2004) with an LD50

value that is lower than the current 0.0439 μg ai/bee endpoint.

Response:

The Agency will consider all available open literature which passes the ECOTOX and OPP

acceptability criteria screens2 at the time of risk assessment.

19. Comment:

From the Beyond Pesticides letter: “The application rates for clothianidin and thiamethoxam on 

corn range from 0.25 to 1.25 mg/kernel. A single kernel contains several orders of magnitude of 

active ingredient more than the published LD50 values for honey bees.”

Response:

The exposure routes that are relevant to the seed treatment coating and that the EFED is planning 

to evaluate at the time of risk assessment are captured by the terrestrial organism exposure and 

effects conceptual models (See Figures 6.2 and 6.3 on page 29 of the Problem Formulation for 

the Ecological Risk, Endangered Species, and Drinking Water Exposure Assessments in Support 

of the Registration Review of Clothianidin). Those media include: nectar, pollen, guttation 

droplets/dew, abraded seedcoat dust, and puddled surface water.

 2

Evaluation Guidelines for Ecological Toxicity Data in the Open Literature:

http://www.epa.gov/pesticides/science/efed/policy_guidance/team_authors/endangered_species_reregistra

tion_workgroup/esa_evaluation_open_literature.htm
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Please note that no response to comments 20 through 24 is included in this document

On March 20, 2012, the EPA received an emergency citizen petition seeking suspension of 

registration for clothianidin. The petition requested action within 90 days. The agency is 

reviewing the petition and plans to respond to the petitioners' allegation that clothianidin poses 

an imminent hazard to pollinators. Many of the comments received in the March 20, 2012 

petition were also received during the 60 day comment period. Comments received in both the 

petition and during the comment period for the PWP such as comments 20 through 24 below will 

not be responded to in this document but instead will be posted in the Clothianidin Petition for 

Emergency Suspension Docket (EPA-HQ-OPP-2012-0334) at www.regulations.gov. 

20. Comment:

From the Beyond Pesticides letter: “Lethal and sublethal exposures have been shown to decrease 

foraging activity, along with olfactory learning performance and decrease hive activity.”

21. Comment:

From the Beyond Pesticides letter: “One of the greatest sources for exposure is from the exhaust 

of the tractor-drawn planters that spew small residues (dust) of treated seeds into the air while 

sowing. One Italian study found that bee mortality increased right after seed sowing and 

confirmed these findings with post mortem chemical analysis that found high concentrations of 

neonicotinoid insecticides (imidacloprid and clothianidin) as high as 500 nanograms active 

ingredient /bee (Girolami V, et al. 2011). A similar study involving the seed sower found 

comparable results of increased bee mortality on the day of sowing and decreased foraging days 

after sowing, this time with thiamethoxam (Tremolada P, et al. 2010).”

22. Comment:

From the Beyond Pesticides letter: “Clothianidin residues remain present in the surface soil of 

agricultural fields long after treated seed had been planted, as long as two growing seasons 

(Krupke CH, et al. 2012).”

23. Comment:

From the Beyond Pesticides letter: “The rapid disappearance of the honey bees, also dubbed 

“Colony Collapse Disorder” or CCD, has been observed in the U.S. since 2006. Even though 

researchers have indicated that there may be several variables associated with CCD, clothianidin, 

and other chemicals in its class, cannot be ruled out as a major contributor and this must be 

factored into the agency’s assessment.”

24. Comment:

From the Beyond Pesticides letter: “Looking at SETAC’s recommendations and EPA’s data 

requirements, pesticide risks to honey bees have not been extensively studied and the agency is 

playing catch-up with bee data. Much remains unknown about the effects of pesticide 

contaminants and exposure pathways on the honey bee and other bee and pollinator populations. 

The members of the SETAC workshop agreed that the most significant routes of exposure for 

both honey bees and other bees (from foliar and systemic seed treatments), are through dermal 

contact and oral exposure of foraging adults, hive adults, and larvae to contaminated pollen, 
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nectar, and processed food (honey, bee bread, etc) (Krupke CH, et al. 2012). Contact with 

contaminated soil, sprayed leaves and petals were also notable exposure pathways, especially for 

other bees. In light of this and independent studies demonstrating that these routes of exposures 

do occur resulting in bee mortality and impaired bee health, serious action is warranted. Thus far 

the agency has not sufficiently reviewed pertinent honey bee data regarding clothianidin. As a 

result, the agency has not fulfilled its statutory mandate under FIFRA to pose no unreasonable 

adverse effect on the environment.”

25. Comment:

Steve Ellis of Old Mill Honey looks to update a previously submitted incident report by 

specifying the number of hives affected.

Response: The Agency will consider all available incident information at the time of risk 

assessment.

26. Comment:

Steve Ellis claims to speak for other beekeepers in Minnesota who have experienced bee kill 

incidents in early spring. Mr. Ellis suspects pesticide poisoning may be the cause.

Response:

All available incident reports will be considered at the time of risk assessment. The following 

information, taken from the National Pesticide Information Center (NPIC) website

(http://npic.orst.edu/reportprob.html#env), explains how to report a pesticide incident. NPIC is a 

cooperative agreement between Oregon State University and the U.S. Environmental Protection 

Agency.

Reporting an Environmental Incident (wildlife, air, soil or water):

1. If a pesticide incident has occurred involving wildlife, air, soil or water, contact your State 

Environmental Agency to report the problem.

2. Next, call the National Pesticide Information Center (NPIC) at 1-800-858-7378 to report the 

incident. NPIC provides these reports to the EPA under a cooperative agreement. Trained 

pesticide specialists are available to document the incident and provide information that could be 

helpful in your unique situation. NPIC is open from 7:30am - 3:30pm PST.

3. Also, consider reporting the incident to the product's manufacturer. Manufacturers are required by 

law to submit reports of adverse effects to the US EPA.

Attention government organizations, academia, wildlife rehabilitation centers, conservation 

societies, and bee keepers:

If you want to report pesticide-related illness in wildlife or an environmental problem associated with a 

pesticide, please submit a report using our quick and easy Ecological Pesticide Incident Reporting portal 

(http://pi.ace.orst.edu/erep/). Reports will improve the quality of environmental incident data the EPA 

receives.
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27. Comment:

Northern tier beekeepers rely on early spring blooming plants such as dandelion for colony 

build-up. The persistence of clothianidin in the soil, in conjunction with the compound’s 

systemic nature, could affect the quality of this type of forage.

Response:

EFED risk assessments consider both the treatment area and surrounding habitat that may be 

affected as a result of pesticide application. Potential impacts to edge habitat and coincident 

forage resources resulting from clothianidin use will be characterized in the registration review 

risk assessment.

28. Comment:

Could the Agency consider a different toxicological paradigm to address the mode of action of 

systemic compounds like clothianidin, rather than continued reliance on the LD50 methodology? 

The commenter further expressed concern of unintended consequences resulting from the 

concurrent use of systemic pesticides and plant-incorporated protectants (PIPs).

Response:

The Agency intends to convene a Scientific Advisory Panel meeting to obtain expert scientific 

advice regarding risk assessment methodology for systemic compounds which may effect 

pollinators. The registration review risk assessment for clothianidin is expected to be conducted 

in 2017 after submission of clarifying toxicity and exposure information. For the registration 

review risk assessment, EPA will consider clothianidin exposure and hazard issues in a manner 

consistent with the recommendations of the FIFRA SAP.

It is likely that EPA will continue to rely on tradition measures of acute toxicity which are 

consistent with those used with other taxa. While the use of LD50 data may not be confined to 

acute contact studies with young adult bees, this measure of toxicity remains a recognized 

standard in toxicity testing whether it is based on contact toxicity or oral toxicity and it is used 

extensively by other regulatory partners globally, particularly for screening-level assessments. 

Where there are sufficient data to indicate that a compound is toxic, higher tiered studies will be 

required to address specific uncertainties and these tests will typically be conducted to examine 

effects at the whole colony level. Such tests may be conducted under controlled environmental 

conditions such as semi-field studies where colonies are confined to tented enclosures or they 

may extend to full field studies where exposure conditions are intended to reflect actual usage 

patterns of the chemical. However, as ecological effect testing is refined, the studies are 

intended to focus on specific uncertainties which have been determined through the lower tier 

studies; the need for such studies will also depend on the risk managers' need for additional 

information to support decision making efforts.