UNITED S TATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION
PC Code: 118204 DP Barcode 425269 Date: February 25

, 2015

MEMORANDUM

SUBJECT: Response to Dow AgroScience Comments on Noviflumuron Problem Formulation

Ed':ard Odenkirchen, Ph.D.,

# Senio~**Sci~e** Advisor

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Qd 1 ) FROM: Chri_stopher M.**~oper,** M.S., Chemist · . 

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E nvuonmental Risk Branch 1 Environmental Fate and Effects Division (7507P)**~** . \ \.

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## I**"().._~~** <9. :J-.=t \ ':) THROUGH : Su ja tha Sankula

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### • Environmental Risk Branch 1 E nvironm ental Fate and E ffects Division (7507P)

TO: Dana Friedman, Chemical Review Manager Tom Myers, Team Leader Kev in Costello, Branch Chief Risk Management and Implementation Branch 2 Pesticide Re

- Evaluation Division (7508P)

Do w Ag roSciences (DAS) submitted comments to the Problem Formulation document posted in the noviflumuron docket for Registration Review. This documen t summarizes the comments and responses by the Environmenta l Fate and Effects Division.

Topic: Application Rates, Labels and Products Currently Registered

DAS Comment: General clarification comments were provided on application rates and status of various label s.

Agency Response : The Agency thanks the registrant for the · clarifications provided and will incorporate t hese findings into the p r eliminary risk asses s ment.

12

Topic: Rationale for waiving the proposed acute oral toxicity study in a passerine bird and avian reproduction studies for an upland game bird and waterfowl species

DAS Comment : “....subterranean termites... spend most of their time underground, and when foraging above ground, they move through enclosed, sturdy tunnels for protection. Therefore the dosed termites will not be readily exposed and available as a food source to predators.”

Agency Response: For predatory taxa other than birds, a consideration of active feeding by burr owing species might still be an issue. In addition, some wildlife species like armadillos could be expected to active ly unearth termites.

In regards to birds and other ground feeding insectivores, subterranean termites do forage at shallow depths in soil (shallow termite monitoring stations show activity within inches of the surface https://flrec.ifas.ufl.edu/pdfs/Su_pub/Su063_Horiz.pdf ), and it is reasonable to expect that they can forage for cellulose right up into the leaf litter or wood mulch surrounding a structure ( http://edis.ifas.ufl.edu/fr075 ). However, the Agency concedes that the species is tied very closely to narrow temperature and moisture requirements. If the litter is dry, or the tempe rature very hot, the termites will be deeper in order to maintain favorable conditions. So, while a complete exposure pathway is possible, the conditions under which ground feeding birds will encounter termites at the surface or shallow litter is governed by season and soil moisture. This comment itself does not obviate the need for understanding passerine toxicity.

DAS Comment : “ US birds primarily feed on termites when they swarm from their nest in the ground....The Agency acknowledges that exposure through this route (alates) is unlikely.”

Agency Response: The registrant has reiterated the Agency position on alate mediated exposure to insectivores. The Agency maintains that exposure through worker consumption is possible

a nd a number of ground feeding insectivorous birds, in addition to herpefauna, for which birds are used as surrogates, may use foraging workers as component of their diet.

DAS Comment: “

Noviflumuron is also practically non-toxic to birds and therefore it is reasonable to assume that in the unlikely situation that passerine birds feed on termites that have been dosed with noviflumuron, the risk posed is very low.” (Comment accompanied by a quantitative assessment of risk to a bobwhite quail using available acute toxicity data and

re ported noviflumuron loads in termites and an analysis of canaries feeding under laboratory

c onditions.)

Age ncy Response: The Agency considered the risk assessment presented and conducted its own version assuming an insectivorous bird of the same weight as the birds in the DAS assessment:

B ird we ight = 20 0 g Termite concentration of chemical = 0.001098 mg/termite (submitted information Dow Report J T112114) Termite fresh weight = 3 mg (submitted information Dow Report JT112114) Concentration in termite diet = 0.001098 mg / 0.000003 kg = 366 mg/kg fresh wt Bird field metabolic rate kcal/day = 2.123 (200) 0.749 = 112.3 kcal/day (USEPA 1993)3

Mass of prey consumed per day = 112.3 kcal/day/(1.7 kcal/g ww X 0.72 AE) = 91.75 g/day (1.7 is energy content of prey item from USEPA 1993; 0.72 is assimilation efficiency from USEPA 1993) Mass of chemical in daily diet = 91.75 g/day X 366 mg chemical /kg-ww insect prey X 0.001 = 33.58 mg/day Daily dose in bird = 33.5 8 mg/day/0.2 = 167.9 mg/kg-bw/day

Compared to a LD50 of 2000 mg/kg/day, there appears sufficient information to absolve concerns for acute effects in a 200 g insectivorous birds.

Regarding the canary analysis, the Agency disagrees with the use of laboratory feeding rates to represent free living food consumption. Instead, the Agency used the presented data and conducted an analysis considering the 20 gram bird that the Agency uses as a screen for small birds:

Bird weight = 20 g Termite concentration of chemical = 0.001098 mg/termite (submitted information Dow Report J T112114) Termite fresh weight = 3 mg (submitted information Dow Report JT112114) Concentration in termite diet = 0.001098 mg / 0.000003 kg = 366 mg/kg fresh Bird field metabolic rate kcal/day = 2.123 (20) 0.749 = 20.02 kcal/day (USEPA 1993) Mass of prey consumed per day = 20.02 kcal/day / (1.7 kcal/g ww X 0.72 AE) = 16.4 g/day (1.7 is ene rgy content of prey item from USEPA 1993; 0.72 is assimilation efficiency from USEPA 1993) Mass of chemical in daily diet = 16.4 g/day X 366 mg chemical /kg-ww insect prey X 0.001 = 6 mg/day Daily dose in bird = 6 mg/day/0.02 = 300 mg/kg-bw/day

Compared to a LD50 of >2000 mg/kg/day it appears that the estimated dose would be below the

e mpirically demonstrated no-acute lethality value established for non-passerine species. This would be even lower if the dose were halved based on the assumption that termite concentrations track linearly with bait concentration of noviflumuron. The question is whether passerines would have to be much more sensitive in real testing than the bobwhite quail to alter this conclusion. Upon considering that the available data are non-definitive (LD50 is actually greater than limit dose tested) and allowing for the effects of allometric scaling (a 20 gram bird projects

a cute toxicity thresholds a third to a half of those in tested quail and mallards), the likelihood for

a much disparate acute lethal threshold that would alter acute direct lethal risk predictions for
pa sserines is low. However, EFED has observed poorly tolerated regurgitation responses to otherwise non-toxic compounds since requiring passerine testing. While the analysis above

se ems to indicate that an empirically determined acute LD50 would not likely alter the conclusions reached here, the absence of passerine acute testing precludes a confident statement that regurgitation effects are not of concern.

DAS Comment : “ The comments above (referring to the acute effects analysis) related to exposure potential are also relevant to the rationale for waiving the proposed reproduction studies. In addition, it should be considered that the habitats of upland game birds and4

waterfowl – for which studies are proposed – do not commonly include the environment where

nov iflumuron is used.”

Agency Response: Upland game bird and waterfowl testing are the surrogates commonly tested in t he Agency battery of avian effects protocols. The Agency agrees that these birds themselves are not direct representatives of passerines. If the registrant wish es to develop and submit a passerine reproduction study aimed at developing passerine reproduction data, the Agency urges a protocol to be submitted to for review before commencing the study.

T he Registration Review Problem Formulation for noviflumuron identified a potentially complete exposure pathway for the termiticide use of noviflumuron in insectivorous wildlife through consumption of foraging worker termites accumulating the pesticide when visiting treated bait stations. Consequently, an avian reproduction effects data gap was identified for the pesticide. To help clarify the information benefits, if any, associated with fulfillment of this data
gap, the Agency has explored the potential results of conducting an avian reproduction effects risk a nalysis using the available toxicity data for mammals as a surrogate for avian reproduction.

Screening Approach Using Best Available Toxicological Data and Biologically Relevant Inputs for Small Insectivorous Ground-feeding Passerines

In the absence of a reproduction endpoint for birds, an extrapolation method was applied that uses available acute and chronic data for mammals and the available acute data for birds to estimate a reproduction threshold in birds. The assumption here is that the relationship in mammals is conserved in another vertebrate taxon, birds.

Rat acute oral LD50 >5000 mg/kg (CAL DPR PUBLIC REPORT 2003-5 Noviflumuron Track ing ID Numbers CRR-193920 thru CCR-193923) Rat NOEL Reproduction = 5 mg/kg/day (CAL DPR SUMMARY OF TOXICOLOGY DATA September 26, 2002 Revised: 7/29/03, 7/21/04, 8/22/05) Acute to chronic factor of at least 1000 (highly uncertain but likely not conservative given that the actual LD50 is likely higher than 5000 mg/kg) Bird acute oral LD50 >2000 mg/kg (registrant submitted data) Estimated avian reproduction NOEL = 2000/1000 = 2 mg/kg/day (highly uncertain, compounds uncertainty above by setting limits on the actual LD50 used in extrapolation) Estimated avian reproduction NOEC by chemical analog hexaflumuron=29.4 mg/kg-bw

Ex posure estimates were based on available noviflumuron concentration estimates in termites and an energetics-based model for termite consumption using the house wren as a real world

re ceptor organism. This bird is a small insectivore that is a common species associated with residential areas. For the purposes of this analysis a bodyweight of 10.9 g was assumed (average

va lue, Dunning 1984).

Te rmite concentration of chemical = 0.001098 mg/termite (submitted information Dow Report J T112114) Termite fresh weight = 3 mg (submitted information Dow Report JT112114) Concentration in termite diet = 0.001098 mg / 0.000003 kg = 366 mg/kg fresh5

Bird field metabolic rate kcal/day = 2.123 (10.9) 0.749 = 12.7 kcal/day (USEPA 1993) Mass of prey consumed per day = 12.7 kcal/day/(1.7 kcal/g ww X 0.72 AE) = 10.38 g/day (1.7 is energy content of prey item from USEPA 1993; 0.72 is assimilation efficiency from USEPA 1993) Mass of chemical in insect diet = 366 mg/kg- ww Mass of chemical in daily diet = 10.38 g/day X 366 mg chemical /kg-ww insect prey X 0.001 = 3.80 mg/day Daily dose in bird = 3.80 mg/day/0.0109 = 348.6 mg/kg-bw/day

The integration of exposure and effects was accomplished using the risk quotient method. A ssuming 100% of the diet consumed by wrens is termites (very conservative), the best guess reproduction RQ would be: RQ = 348.6 /2 = 174.3

If the hexaflumuron NOEC (29.4 mg/kg-diet) is used as the effects endpoint for reproduction, it can be compared to a noviflumuron concentration in the diet of 366 mg/kg for an RQ of 366/29.4

= 12.45.

Contextual Considerations

How many termites in a day constitute 10.9 g of die t? (10.9 X 1000 mg/g)/3 mg = 3633 termites Th i s is a very conservative daily termite ingestion number and not likely achieved by such a small bird foraging in and around the areas surrounding structures.

To test the risk conclusions further, one can dete rmine how many termites need be consumed to trigger a concern (i.e., reach the NOEL for an RQ of 1, which is the threshold for concern for BOTH listed and non-listed species). This is can be determined by taking the 100% termite diet RQ (above) and calculating the percent reduction in diet that would be needed to produce an exposure equivalent to an RQ of 1.

Analysis Based on Noviflumuron Bird/Mammal Extrapolation RQ The target percentage of diet = (1/174.3)(100) = 0.574% How much termite mass is that? 10.9 x 0.00574 = 0.063 g How many termites is that in a day? (0.063 g X 1000 mg/g)/3 mg = 21 termites

. Consequently, 21 termites (less than 1 percent of a small insectivorous bird’s diet), with the registrant-reported concentration of noviflumuron in them, consumed in a day, is sufficient to trigger a concern under the construct of the model. Assuming that application rate scales linearly
to re sidues, a lower percentage of noviflumuron (say by one-half) would result in lower termite concentrations and about twice the number of termites consumed to reach the reproduction concern threshold.

Analysis Based on Hexaflumuron Avian Reproduction RQ Using the dietary-based RQ of 12.45, the percentage of diet necessary to reach an exposure equivalent to an RQ of 1.

The target percentage of diet = (1/12.45)(100) = 8%6

How much termite mass is that? 10.9 x 0.08 = 0. 872 g How many termites is that in a day? (0.872 g X 1000 mg/g)/3 mg = 291 termites.

Under the hexaflumuron dietary endpoint scenario, the percentage of the diet necessary to reach a concern is approximat 14 times greater than for the mammal tox extrapolation approach 85 versus 0.574%). Again, assuming that application rate scales linearly to residues, a lower percentage of noviflumuron (say by one-half) would result in lower termite concentrations and about twice the number of termites consumed to reach the reproduction concern threshold. As these numbers of termites required gets higher, the arguments about termite availability, predation frequency, and contaminated versus uncontaminated prey base become more compelling. However, there is little quantitative evidence to suggest that one of the assessment approaches is preferable to the other.

DAS Comment : Reference was made to the proposed interim registration review decision for he xaflumuron (EOA- HQ -OPP-2009-0568-0023 as a rational for waiving the avian reproduction study requirement. The comment included statements regarding:

 Hexaflumeron being only a fraction of the total bait pesticide mass at any one time

 No n -target organisms will consume both tainted and untainted termites

 Window for exposure to chemical is short given the intended purpose to kill
ter mites

 Accessibility to contaminated termites may be considered low as they are not

ac cessible prey most of the time

 Wildlife are not associated with man-made structures, the site of use for hexaflumuron

Agency Response:

The argument that the pesticide’s intent is to kill termites therefore limiting exposure is spurious for insect growth regulators. These chemicals kill organisms in their molting phases. The

e ffectiveness of noviflumuron as a termite nest destroyer lies in the slow nature of the effect and in the expected ability of worker termites to transport the pesticide within their bodies to the metamorphosing life stages. These properties, along with the registrant’s supplied residue data for noviflumuron suggest that the exposure pathway is complete up to residues within potential
prey.

Arguments that termites are not a ready source of diet might be persuasive if a large percentage of the diet was needed to raise concerns but, the above quantitative assessment shows that as little as 1 to 2% of the diet (21 to 42 termites depending on assumptions of residues and linearity of application rate to termite residue) consisting of contaminated termites is sufficient to raise a reproduction concern. To place these numbers in the perspective of foraging termite density, a n Eastern subterranean termite colony can contain many thousands to over a million foraging termites in areas up to 12,000 square feet ( http://www.termite.com/termites/eastern-subterraneantermite.html ) after several years of growth. S ubterranean termites do forage at shallow depths in7

soil (shallow termite monitoring stations show activity within inches of the surface https://flrec.ifas.ufl.edu/pdfs/Su_pub/Su063_Horiz.pdf ), and it is reasonable to expect that they can forage for cellulose right up into the leaf litter or wood mulch surrounding a structure ( http://edis.ifas.ufl.edu/fr075 ). However, the species is tied very closely to narrow temperature and moisture requirements. If the litter is dry, or the temperature very hot, the termites will be de eper in order to maintain favorable conditions. So, while a complete exposure pathway is possible, the conditions under which ground feeding birds will encounter termites at the surface or shallow litter is governed by season and soil moisture.

Given the small percentage of the diet required to raise a concern for noviflumuron as calculated b y one method, the argument in the hexaflumuron decision that both tainted and non-tainted
ter mites will be consumed is not persuasive as a waiver justification. The assessment conducted above, considering the noviflumuron assessment would have to be below 8% to the diet as treated termites to be below reproduction risk considerations.

The argument that large populations of wildlife are not associated with areas surrounding manmade structures is a value judgement. Certainly, many home owners actively attract avifauna to their yards. In fact, market researchers report that the wild bird feeding industry in the United S tates encompassed 3.22 billion dollars in bird feed and 1.18 billion dollars in bird feeders in 2013 and that the practice is well distributed among rural, urban and suburban areas and
pre dicted to grow ( http://www.ectownusa.net/wbfi/docs/WBFI_2013_US_and_Canada_Market_Research_presenta tion.pdf ). It would seem that such money spent on attracting populations of wildlife to residential areas would tend to contradict the assertion that no appreciable populations of wildlife exist in those areas.

Questions for Risk Management Consideration

1. For non -listed species, is the range in the level of potential concern (illustrated in the
qua ntitative assessment performed in this response) acceptable in the face of the
tox icological uncertainties (e.g. the range in proportion of the diet (<1% to 8 %)

ne cessary to reach reproduction concerns in insectivorous birds) ? 2. How will the uncertainties relate to listed species concerns, knowing that it is likely that

man y Federal ly -listed ground-feeding insectivorous birds in and around houses might be larger than the wren modelled? This would increase the number of termites needed to

re ach an RQ of 1 or more. However, owing to the non-linear nature of calculations for food ingestion, a bird twice the size of a wren would have an increased termite consumption to reach the concern threshold at less than double the wren’s 21 or 291 termites.

Data to Clarify the Risk Picture

One of the principal areas of uncertainty associated with the risk model employed above is the assumption of the reproduction toxicity threshold for birds. Currently no data exist for this chemi cal ; an analog (hexaflumuron) that recently underwent assessment for Registration Review ha s a toxicity endpoint for avian reproduction of 29.4 mg/kg-diet. The analysis above used8

BOTH an extrapolation approach based on: 1) the best information available for noviflumuron mammalian a cute and reproduction endpoints and available avian acute data to estimate a reproduction effect endpoint in birds; and 2) an endpoint using the hexaflumuron avian

re production NOEC. The extrapolation result yields concerns for reproduction and establishes a low number (21) of contaminated termites necessary for consumption to reach concerns. The use of the hexaflumuron surrogate also yields risk concerns, though the number of termites (291)

ne cessary for consumption is an order of magnitude higher than the extrapolation method. Because the available acute data are indeterminate (i.e., not producing a definitive median lethal

e ndpoint) the degree to which extrapolations based on these data are highly uncertain, yet the use of a surrogate, is also uncertain because the indeterminate acute toxicity precludes a definitive relationship between noviflumuron and hexaflumuron toxic potency. In light of these li mitations, a good deal of uncertainty in the above findings would be eliminated by provision of an empirically-based avian reproduction endpoint. If this uncertainty is an important limitation to a confident risk management decision, then EFED would recommend fulfillment of the avian reproduction data gap.