Page 1 of 7 OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION UNITED STATES ENVIRONMEN TAL PROTECTION AGENCY WASHINGTON D.C., 20460

PC Code: 128016

DP Barcode: 426708

Date: June 12, 2015

MEMORANDUM

SUBJECT: Response to Public Comments on the Re gistration 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) receive d comments from ISK BioSciences relating to the Problem Formulation (PF) for the registra tion review of flonicamid. We appreciate the comments and have considered them carefully. The Environmental Fate and Effects Division’s (EFED) responses are provided below.Page 2 of 7 Comment a.: “Flonicamid 50 WG (Reg. No. 71 512-9) 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 applic ation 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 toxici ty ISK comments “...On the other hand, due to this specific mode of action, non-sucking in sects (bees, aquatic inve rtebrates, etc.) would not be expected to be targeted by flonicamid. Thus, flonicamid has been shown to be selective in controlling sucking pests while be ing relatively safe to other be neficial insects, including honeybees. Feeding ceases a short time following a single dose of flonicamid. No studies have demonstrated a delayed toxicity effect as descri bed in the risk assessment document. The effects reported in the bee oral and contact toxicity st udies are those that are frequently seen in laboratory testing of honeybees, namely coor dination problems, apathy and nervousness.”

EFED Response: Honeybees, butterflies and other invert ebrate species feed via a sucking mechanism, therefore if the chemical works by impacting the sucking mechanisms of target species, there is a potential for th ese non-target species to also be affected by the chemical. This is especially true since flonicamid works on bot h an oral and a contact exposure. There is uncertainty with the potential e xposure to terrestrial i nvertebrates 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 b een 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 pres ent 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 organi sm, 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.Page 3 of 7 to dehydration and starvation co uld be highly variable both w ithin and across taxa due to variability in body stores and supplies, individual hydr ation status at the time of exposure as well as natural biological variability. Extended study du rations are aimed to account for this expected variation and more accurately quantitate toxicity values.

Regarding the non-specific effects seen in honeyb ees, the effects seen in the honeybees in the study, were the same as those noted in aphids. Fr om Morita et al. 2007 “... Most treated aphids displayed uncoordinated locomotion, and some ap hids walked staggeri ngly 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 LD 50 based on lethality measured 5 days after exposure.

Comment d: Regarding concerns of delayed toxi city 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 behavi or 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 extrap olate the delayed toxicity observed in sucking insects to aquatic insects.... Even so, mortal ity 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 th an that seen in the chronic study.”

EFED Response: Currently, there are insufficient data to demons trate that flonicamid exhibits high selectivity to only terrestrial plant pierci ng or sucking insects. Aquatic hemiptera have piercing and sucking mouthparts and therefore could feed in a simila r way as targeted terrestrial invertebrates. As previously disc ussed, toxicity is from oral but also from contact exposure, so other aquatic organisms are also su sceptible 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 suck ing or piercing insect in order for feeding effects to be seen.

In the acute daphnia study, the test was termin ated 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 LC 50 values for this compound for target organisms 3 , acute toxicity values are based on mortalities reco rded 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 IbidPage 4 of 7 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 ex pected to result in a lower LC 50 than the one provided in the chronic study with a 21 day exposure period, EPA will use the LC 50 generated from the chronic study (LC 50 = 42.1 mg a.i./L; MRID 45863812) as a c onservative 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 exposur e over a 96 hour period.... A delayed mortality period of 2 to 5 days would certainly be appa rent 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 st udy, 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 te st at 96 hours. While there continue to be concerns for effects to estuarine/marine invertebrates ( e.g. , delayed mortality and impair ed 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 mo rtality 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 te sts 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 th e necessary Tier I tests followed by an evaluation according to the new guidelines before requiri ng the higher tier testi ng, 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 protoc ols will need to be evaluated and potentially modified to capture the delayed mortality effects of flonicamid.

Comment g . Regarding stressors of c oncern, “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 Regist ration Review as drinki ng water residues of concern. In that same document, the available labo ratory toxicity studies on these degradates are summarized as shown below. While not a comple te toxicity profile, these results provide justification for the assumption that flonicamid degr adates will have similar or less toxicity than the parent. In relation to the or al toxicity, all five degradates are less toxic than parent

flonicamid.”

EFED Response: As discussed in the Problem Formul ation, there is limited information available to show that these degrad ates are of significantly lower t oxicity to exclude them as part of the residues of concern for the aquatic modeling. EPA welcomes any additional informationPage 5 of 7 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 di stributor 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 Ba rcode 421510) could not be substantiated. Neither company has any knowledge of an incident occurring in 2009. FMC r ecords 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 rese mbled 2,4-D. According to the BEAD Chemical Profile (BCP) for Registration Review: Fl onicamid (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 extr emely unlikely that the damage is the result of a Flonicamid applica tion, ISKBC recommends that the incident report classification be changed from possible to unlik ely 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 (i ncorrectly reported in comments). It was reported through the Merced County Agricult ure Commissioner's office after the known application of Carbine 50 WG / FMC (i.e. flonica mid), Britz natural oil and Pix to five cotton sites. As per guidelines used to qualify incide nts as likely, probable, possible and unlikely in EIIS, this incident was cl assified as possible.

Although providing supplementary information, th is 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 applicat ions per year; “In certain cases it is very straightforward to state the num ber of applications per year, e.g. the number of crop cycles for perennial crops (hops, stone frui t, pome fruit, etc.) equals the number of applications per year. In other cases it’s not po ssible to give a definitive answer to the request. This is due primarily to geographi c restrictions in certain areas that limit the growing season that are not limitations in other areas, such as Florid a 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 flonicam id 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-liv es of 3 to 10 days, th e 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 gr oundwater to be 0.000753 ug/L based on flonicamid alone and 0.00132 ug/L based on total residues (flonicamid + degradation products). There is noPage 6 of 7 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 ab sence 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 fl onicamid, “...As stated above (Response to point 3a), the delayed mortality that is refere nced from registrant-submitted efficacy studies is selective to sucking insects (homopterans) such as aphids and whiteflies a nd is associated with almost immediate feeding cessation . Since this response is selectiv e 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 spectr um 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. a norexia, etc.), there is uncertain ty 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 befo re the current guidelin e 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 st udies at the maximum seasonal application rate in or der 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 violati on 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. 279-326 4 and 279-3277. With the reported ‘possible’ plant toxicity incident, as well as the available terrestrial plant t oxicity studies having tested only up to the 0.134 lb a.i./A rate, ther e continues to be uncertainty w ith potential eff ects 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 ri sk to estuarine/marine anim als are not expected based on the information already at hand. Even taking the worst case assumpti on that the LC and EC 50 values for freshwater species are equal to th e highest dose tested (t hey were all greater than the highest dose), the risk is estimated to be extremely low ...”Page 7 of 7 EFED Response: There is uncertainty associated with the toxicity endpoints for estuarine/marine species since th ey are based on the assumption that flonicamid is equally toxic

to freshwater and estuarine/marine invertebrate species. The concern of de layed mortality effects and the potentially inadequate durat ion 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 F eeding Tests; OCSPP 850.4100; and, OCSPP 850.4150.”

EFED Response: For the reasons stated above, EPA conti nues 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 measur ed in existing toxicity studies conducted with

flonicamid.