UNITED STATES 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 ~~ .2-I :J I Qd 

1 FROM: ) 

Chri_stopher M. ~oper, M.S., Chemist · . 2-{7.-T(fr 

Envuonmental Risk Branch 1 

Environmental Fate and Effects Division (7507P) ~ . \ \. -

A . ' . I "().._~~ <9. :J-.=t \ ':) 

THROUGH: Sujatha Sankula, Ph.D., Branch Chief _1~""-J-.'---- ~ • 

Environmental Risk Branch 1 

Environmental Fate and Effects Division (7507P) 

TO: Dana Friedman, Chemical Review Manager 

Tom Myers, Team Leader 

Kevin Costello, Branch Chief 

Risk Management and Implementation Branch 2 

Pesticide Re-Evaluation Division (7508P) 

Dow AgroSciences (DAS) submitted comments to the Problem Formulation document posted in 

the noviflumuron docket for Registration Review. This document summarizes the comments 

and responses by the Environmental 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 labels. 

Agency Response: The Agency thanks the registrant for the· clarifications provided and will 

incorporate these findings into the preliminary risk assessment. 

1 
2 

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 

burrowing species might still be an issue. In addition, some wildlife species like armadillos 

could be expected to actively 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 

temperature 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 

and 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 

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

conditions.) 

Agency 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: 

Bird weight = 200 g

Termite concentration of chemical = 0.001098 mg/termite (submitted information Dow Report 

JT112114) 

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 = 33.58 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 

JT112114) 

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 energy 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 

empirically 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 

acute 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 

passerines is low. However, EFED has observed poorly tolerated regurgitation responses to 

otherwise non-toxic compounds since requiring passerine testing. While the analysis above 

seems 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 and 
4 

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

noviflumuron is used.”

Agency Response: Upland game bird and waterfowl testing are the surrogates commonly tested 

in the Agency battery of avian effects protocols. The Agency agrees that these birds themselves 

are not direct representatives of passerines. If the registrant wishes 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. 

The 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 analysis 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 

Tracking 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

Exposure 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 

receptor 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 

value, Dunning 1984). 

Termite concentration of chemical = 0.001098 mg/termite (submitted information Dow Report 

JT112114) 

Termite fresh weight = 3 mg (submitted information Dow Report JT112114) 

Concentration in termite diet = 0.001098 mg / 0.000003 kg = 366 mg/kg fresh 
5 

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. 

Assuming 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 diet? (10.9 X 1000 mg/g)/3 mg = 3633 termites 

This 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 determine 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 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. 

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 

hexaflumuron (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

 Non-target organisms will consume both tainted and untainted termites 

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

termites

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

accessible 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 

effectiveness 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, an 

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. Subterranean termites do forage at shallow depths in 
7 

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 

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. 

Given the small percentage of the diet required to raise a concern for noviflumuron as calculated 

by one method, the argument in the hexaflumuron decision that both tainted and non-tainted 

termites 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 

States 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 

predicted 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 

quantitative assessment performed in this response) acceptable in the face of the 

toxicological uncertainties (e.g. the range in proportion of the diet (<1% to 8 %) 

necessary to reach reproduction concerns in insectivorous birds)? 

2. How will the uncertainties relate to listed species concerns, knowing that it is likely that 

many Federally-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 

reach 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 

chemical; an analog (hexaflumuron) that recently underwent assessment for Registration Review 

has a toxicity endpoint for avian reproduction of 29.4 mg/kg-diet. The analysis above used 
8 

BOTH an extrapolation approach based on: 1) the best information available for noviflumuron 

mammalian acute and reproduction endpoints and available avian acute data to estimate a 

reproduction effect endpoint in birds; and 2) an endpoint using the hexaflumuron avian 

reproduction 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) 

necessary 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 

endpoint) 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 

limitations, 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.