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OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON D.C., 20460 

 

PC Code: 128016 

DP Barcode: 426708

 Date: June 12, 2015

MEMORANDUM 

SUBJECT: Response to Public Comments on the Registration Review Problem Formulation 

for the Ecological Risk Assessment and Drinking Water Exposure Assessment to 

be Conducted for Flonicamid 

TO: Ricardo Jones, Chemical Review Manager 

 Neil Anderson, Chief 

 Risk Management and Implementation Branch 1 

 Pesticide Reevaluation Division (7508P) 

FROM: Colleen M. Rossmeisl, DVM, Biologist 

 Rosanna Louie-Juzwiak, Risk Assessment Process Leader 

 Environmental Risk Branch 3 

 Environmental Fate and Effects Division (7507P) 

PEER Melissa Panger, Ph.D., Senior Biologist 

REVIEW: Environmental Risk Branch 3 

 Environmental Fate and Effects Division (7507P) 

THROUGH: Dana Spatz, Branch Chief

 Environmental Risk Branch 3 

 Environmental Fate and Effects Division (7507P)

 Office of Pesticide Programs 

 

The Office of Pesticide Programs (OPP) received comments from ISK BioSciences relating to 

the Problem Formulation (PF) for the registration review of flonicamid. We appreciate the 

comments and have considered them carefully. The Environmental Fate and Effects Division’s 

(EFED) responses are provided below. 
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Comment a.: “Flonicamid 50 WG (Reg. No. 71512-9) and Technical Flonicamid 

Insecticide (Reg. No. 71512-7) are not Restricted Use pesticides.” 

EFED Response:

These corrections will be considered in the risk assessment. 

Comment b: “The stated maximum single application rate of 0.268 lb a.i./A in the last table 

entry of Table 3 is also incorrect. The maximum single application rate is 0.134 lb a.i./A while 

the maximum seasonal rate is 0.267 lb a.i./A as stated above....” 

EFED Response: 

In referring to application rates, please refer to Table 3, page 4 of the PF regarding ornamental 

rates. Reg. No. 279-3287 has a maximum single application rate of 0.134 lb a.i./A, as noted in 

the ISK comments. However, Reg. No. 279-3277 and No. 279-3264 product labels include the 

maximum single application rate at 0.268 lb a.i./A, as they have a higher volume of finished 

solution listed on the label. 

Comment c: Regarding honey bee and delayed toxicity ISK comments “...On the other hand, 

due to this specific mode of action, non-sucking insects (bees, aquatic invertebrates, etc.) would 

not be expected to be targeted by flonicamid. Thus, flonicamid has been shown to be selective in 

controlling sucking pests while being relatively safe to other beneficial insects, including 

honeybees. Feeding ceases a short time following a single dose of flonicamid. No studies have 

demonstrated a delayed toxicity effect as described in the risk assessment document. The effects 

reported in the bee oral and contact toxicity studies are those that are frequently seen in 

laboratory testing of honeybees, namely coordination problems, apathy and nervousness.” 

EFED Response: Honeybees, butterflies and other invertebrate species feed via a sucking 

mechanism, therefore if the chemical works by impacting the sucking mechanisms of target 

species, there is a potential for these non-target species to also be affected by the chemical. This 

is especially true since flonicamid works on both an oral and a contact exposure. There is 

uncertainty with the potential exposure to terrestrial invertebrates other than the target pests (e.g., 

via feeding on pollen and nectar that may contain flonicamid residues). 

The mechanism of action of flonicamid has been described as a “novel mechanism” and 

speculated to act on potassium regulated type-A channels, but has not been fully elucidated. 

Potassium regulated type-A channels are present in neurons as well as cardiac and smooth 

muscles in invertebrates and vertebrate species.1

 Although the chemical is targeted towards 

insect potassium type-A channels and the product labels specify the target pests as those of 

sucking and piercing insects, this high selectivity has not been clearly demonstrated in the 

available data. 

As the chemical works by causing starvation and dehydration of the organism, delayed mortality 

is the expected course of toxicity. Literature on the efficacy of the product measures the lethality 

of the product at 5 days post exposure. The length of study needed to fully capture mortality due 

 

1

 Cai, S-Q., Li, Wenchao, L and F. Sesti. 2007. Multiple Modes of A-Type Potassium Current Regulation. Current 

Pharmaceutical Design. 13, 3178-3184. 
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to dehydration and starvation could be highly variable both within and across taxa due to 

variability in body stores and supplies, individual hydration status at the time of exposure as well 

as natural biological variability. Extended study durations are aimed to account for this expected 

variation and more accurately quantitate toxicity values. 

Regarding the non-specific effects seen in honeybees, the effects seen in the honeybees in the 

study, were the same as those noted in aphids. From Morita et al. 2007 “... Most treated aphids 

displayed uncoordinated locomotion, and some aphids walked staggeringly with their legs 

stretched immediately after treatment. From these results it appears that the effect of flonicamid 

on aphids is via the nervous system.”2

 These effects in aphids were followed by nearly 100 % 

mortality, with the LD50 based on lethality measured 5 days after exposure. 

Comment d: Regarding concerns of delayed toxicity in aquatic invertebrates, “... Feeding 

cessation in sucking insects occurs as a result of their inability to pierce the leaf surfaces upon 

which they feed. This is what causes death, not the mere exposure to flonicamid. There is no 

reason to extrapolate this behavior to aquatic insects such as daphnids and mysids. The exposure 

pattern and feeding conditions are quite different between sucking insects and aquatic 

invertebrates, so it is not reasonable to extrapolate the delayed toxicity observed in sucking 

insects to aquatic insects.... Even so, mortality at 25 mg/L was limited to 10%. Twenty-five 

mg/L is an extremely high dose for which to have 90% survival in a study of this type. Even if 

the EC50 of the chronic study were substituted for the acute toxicity, the risk would be 

considered no more than slightly toxic. In addition, running the acute study for up to 21 days 

would not lead to greater toxicity than that seen in the chronic study.” 

EFED Response: Currently, there are insufficient data to demonstrate that flonicamid exhibits 

high selectivity to only terrestrial plant piercing or sucking insects. Aquatic hemiptera have 

piercing and sucking mouthparts and therefore could feed in a similar way as targeted terrestrial 

invertebrates. As previously discussed, toxicity is from oral but also from contact exposure, so 

other aquatic organisms are also susceptible to chemical effects. 

Effects on weight and anorexia have been seen in other studies submitted by the registrant for 

other taxa. The available acute oral and sub-acute dietary bird studies reported anorexia and 

weight loss at the end of study durations, and although a non-specific finding, suggests the 

possible conservation of the toxic mechanism of action across species. This also suggests the 

independence of this mechanism from an organism necessarily being a sucking or piercing insect 

in order for feeding effects to be seen. 

In the acute daphnia study, the test was terminated at 48 hours, which would potentially not 

capture mortality from the chemical. The proposed mechanism of immediate irreversible feeding 

cessation on exposure, leading to death due to starvation, would suggest that an extended study 

duration would help to fully capture and more accurately quantify mortality based on an acute 

exposure. In studies that establish LC50 values for this compound for target organisms3

, acute 

toxicity values are based on mortalities recorded 5 days after exposure. Although mysid and 

 

2

 Masayuki Morita, Tsuyoshi Ueda, Tetsuo Yoneda, Tohru Koyanagi and Takahiro Haga. 2007. Flonicamid, a novel 

insecticide with a rapid inhibitory effect on aphid feeding. Pest Manag Sci 63:969–973. 3

 Ibid 
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daphnia are not sucking organisms, deaths did not occur in these studies, even at higher 

concentrations, until later in the study. However, as an acute exposure with an extended 

observation period would not be expected to result in a lower LC50 than the one provided in the 

chronic study with a 21 day exposure period, EPA will use the LC50 generated from the chronic 

study (LC50 = 42.1 mg a.i./L; MRID 45863812) as a conservative estimate if an extended 

duration acute study is not provided. 

Comment e. Regarding marine/estuarine invertebrate concerns, “The existing acute toxicity 

study on mysid shrimp followed constant exposure over a 96 hour period.... A delayed mortality 

period of 2 to 5 days would certainly be apparent within a 96 hour (4 day) continuous dosing 

period. In addition, the extremely low toxicity seen in the acute estuarine/marine test precludes 

the need for a chronic toxicity study according to the criteria in 40CFR158.630.” 

EFED Response: In the 96 hour mysid shrimp acute study, delayed effects were seen in the 

highest concentration groups, with the first mortality not occurring until 48 hours after study 

initiation. In both of the highest treatment groups, new mortalities and effects were continuing to 

occur at the termination of the test at 96 hours. While there continue to be concerns for effects to 

estuarine/marine invertebrates (e.g., delayed mortality and impaired reproduction), the daphnid 

(freshwater) appears to be more sensitive; thus, a new chronic estuarine/marine invertebrate 

study was not requested. In the acute daphnia study, the test was terminated at 48 hours, which 

would potentially not capture mortality from the chemical. 

Comment f. Regarding the need for pollinator Tier I and Tier II testing, “...It seems premature 

to recommend conducting both Tier I and Tier II tests simultaneously, when the need for Tier II 

studies may be obviated. The more appropriate course of action, while involving more time, 

would appear to be conducting the necessary Tier I tests followed by an evaluation according to 

the new guidelines before requiring the higher tier testing, in this case, the Tier II semi-field 

honeybee study.” 

EFED Response: The potential Tier I and Tier II tests are outlined in Table 12 of the PF. The 

need for additional Tier II studies will be dependent on the Tier I results. As outlined in Table 12 

of the Problem Formulation, Tier I study protocols will need to be evaluated and potentially 

modified to capture the delayed mortality effects of flonicamid. 

Comment g. Regarding stressors of concern, “the degradates are identified as TFNA, TFNAAM, TFNG, TFNG-AM and TFNA-OH. These were also identified in the Flonicamid Human 

Health Scoping Document in Support of Registration Review as drinking water residues of 

concern. In that same document, the available laboratory toxicity studies on these degradates are 

summarized as shown below. While not a complete toxicity profile, these results provide 

justification for the assumption that flonicamid degradates will have similar or less toxicity than 

the parent. In relation to the oral toxicity, all five degradates are less toxic than parent 

flonicamid.” 

EFED Response: As discussed in the Problem Formulation, there is limited information 

available to show that these degradates are of significantly lower toxicity to exclude them as part 

of the residues of concern for the aquatic modeling. EPA welcomes any additional information 
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the registrant may have regarding the toxicity of any of these major degradates, and will be 

considered at the time of the ecological risk assessment. 

Comment h. Review of Incident Data, Incident #I021090-014. “According to records of the 

registrant (ISK) and distributor company (FMC), the Incident # 102109-14 reported in the EPA 

document (page 29,12/24/2914 EFED Memorandum Registration Review-Preliminary Problem 

Formulation for the Ecological Risk Assessment and Drinking Water Exposure Assessment to 

conducted for Flonicamid (PC Code 12896; DP Barcode 421510) could not be substantiated. 

Neither company has any knowledge of an incident occurring in 2009. FMC records indicate that 

only one incident occurred and that it occurred on July 5, 2011. The primary allegation was that 

flonicamid applications had damaged cotton. This claim could not be substantiated and FMC 

personnel reported that the damage closely resembled 2,4-D. According to the BEAD Chemical 

Profile (BCP) for Registration Review: Flonicamid (128016), dated November 17, 2014, also 

included in the initial docket opening, cotton is the largest crop on which flonicamid is used, 

with a total acreage of 1,300,000 acres over the 2006-2012 time period. This sustained usage 

would not be seen if flonicamid was injurious to the crop. Since it is extremely unlikely that the 

damage is the result of a Flonicamid application, ISKBC recommends that the incident report 

classification be changed from possible to unlikely and that it not be used as a basis for 

requesting additional non-target plant testing.” 

EFED Response: This incident was reported to EPA and entered in the EIIS database on August 

1, 2009. The correct incident number is IO21090-14 (incorrectly reported in comments). It was 

reported through the Merced County Agriculture Commissioner's office after the known 

application of Carbine 50 WG / FMC (i.e. flonicamid), Britz natural oil and Pix to five cotton 

sites. As per guidelines used to qualify incidents as likely, probable, possible and unlikely in 

EIIS, this incident was classified as possible. 

Although providing supplementary information, this incident was not the sole basis for 

requesting additional vegetative vigor studies. This request was based primarily on the need for 

vegetative vigor studies tested at the maximum labeled rate. 

Comment i. Regarding uncertainties and maximum number of applications per year; “In certain 

cases it is very straightforward to state the number of applications per year, e.g. the number of 

crop cycles for perennial crops (hops, stone fruit, pome fruit, etc.) equals the number of 

applications per year. In other cases it’s not possible to give a definitive answer to the request. 

This is due primarily to geographic restrictions in certain areas that limit the growing season that 

are not limitations in other areas, such as Florida or the Southwest. Therefore, for some crops 

there may be multiple plantings in some areas but a single season planting in others in a single 

year. Due to the rapid degradation of flonicamid and its degradates in aerobic systems, 

accumulation over multiple growing seasons would not be expected to lead to high levels in the 

environment. Given field soil degradation half-lives of 3 to 10 days, the levels in soil would 

certainly not accumulate from one growing season to the next. Regarding the potential to 

accumulate in groundwater, the most recent EFED assessment in April 2012 showed estimated 

drinking water levels in groundwater to be 0.000753 ug/L based on flonicamid alone and 

0.00132 ug/L based on total residues (flonicamid + degradation products). There is no 
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expectation that flonicamid would accumulate even following multiple seasonal uses in a single 

calendar year.” 

EFED Response: The ecological risk assessments are based on modeling the maximum labeled 

rate stated on the product labels. In the absence of such label information, conservative 

assumptions will be made based on the available information on the number of potential crop 

cycles, retreatment intervals and other label information not explicitly stated. 

Comment j. Uncertainties, delayed mortality of flonicamid, “...As stated above (Response to 

point 3a), the delayed mortality that is referenced from registrant-submitted efficacy studies is 

selective to sucking insects (homopterans) such as aphids and whiteflies and is associated with 

almost immediate feeding cessation. Since this response is selective for this insect class, it is 

inappropriate to generalize it to all invertebrates. It is possible to predict the effect across species, 

and the effect is limited to the homopteran species of sucking insects, which is why flonicamid 

labels claim a narrow spectrum of insect control.” 

EFED Response: As discussed above, the mechanism of action of flonicamid has not been well 

defined and is considered novel. To date, there are insufficient data (e.g., observation periods 

were too short to measure the potentially delayed mortalities resulting from feeding cessation) to 

demonstrate that this delayed mortality would not be observed in other insects (including nonsucking). Given the appearance of delayed effects in the chronic studies and some of the clinical 

signs noted in other taxa (e.g. anorexia, etc.), there is uncertainty with how this mechanism may 

be conserved within and across taxa, and testing should therefore be designed to account for this 

possible delayed effect. 

Comment k. Regarding uncertainties, “...Both the seedling emergence and vegetative vigor 

studies were conducted approximately 10 years before the current guideline requirements were in 

place. Under the guidance available at the time, the studies were conducted at the maximum 

application rate and no adverse results were seen. Conducting new studies at the maximum 

seasonal application rate in order to see potential toxicity would only provide information 

concerning the potential misuse of the product, since applying a full seasonal application in one 

dose would clearly be a violation of the label directions...” 

EFED Response: As discussed above, the maximum labeled application rate of 0.268 lb a.i./A is 

currently registered on EPA Reg. Nos. 279-3264 and 279-3277. With the reported ‘possible’ 

plant toxicity incident, as well as the available terrestrial plant toxicity studies having tested only 

up to the 0.134 lb a.i./A rate, there continues to be uncertainty with potential effects to nontarget 

plants associated with the highest registered single application rate. 

Comment l. Regarding uncertainties, chronic data for estuarine/marine fish and invertebrates 

“...Chronic testing on estuarine/marine species is not triggered according to the criteria listed in 

40CFR158.630. ISKBC agrees that risk to estuarine/marine animals are not expected based on 

the information already at hand. Even taking the worst case assumption that the LC and EC50 

values for freshwater species are equal to the highest dose tested (they were all greater 

than the highest dose), the risk is estimated to be extremely low...” 
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EFED Response: There is uncertainty associated with the toxicity endpoints for 

estuarine/marine species since they are based on the assumption that flonicamid is equally toxic 

to freshwater and estuarine/marine invertebrate species. The concern of delayed mortality effects 

and the potentially inadequate duration of the acute study adds to this uncertainty. However, as 

noted in the PF, EFED is not recommending that these data be requested at this time. 

Comment m. Regarding requested studies. “...For the reasons stated in points 3 a. to 3 g. above, 

ISK Biosciences does not agree that data are needed for risk assessment for the following 

guideline requirements: OCSPP 850.1010; OCSPP 850.1025; 850.1035 OCSPP Non-guideline 

Tier II Bee Semi-field, Tunnel and Feeding Tests; OCSPP 850.4100; and, OCSPP 850.4150.” 

EFED Response: For the reasons stated above, EPA continues to believe that these studies are 

still needed to inform on the uncertainties described in the PF, as well as the concerns for 

potential delayed mortality not adequately measured in existing toxicity studies conducted with 

flonicamid.