UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON D.C., 20460 

OFFICE OF 

CHEMICAL SAFETY 

PC Code: 128879 

DP Barcode: D418530 

Date: May 8, 2014 

MEMORANDUM 

SUBJECT: 

TO: 

FROM: 

APPROVED 

BY: 

Refinements to the Triflumizole Preliminary Risk Assessment in Support of Registration 

Review 

Steven Snyderman, Chemical Review Manager 

Avivah Jakob, Team ~eader 

Risk Management and Implementation Branch III 

Pesticide Registration Division (7508P) 

Office of Pesticide Programs ~ ~ 

Stephen Wente, Ph.D., Biologist _s:;.· ;;-::-~ (j!f 1£/' 

Environmental Risk Branch 1 

Environmental Fate and Effects Division (7507P) 

Office of Pesticide Programs 

. c ~ ~ 5\g t \~ l '"_ -0-\r--. j~O-~~~ ) 

Sujatha Sankula, Ph.D., Branch Chief J \ -· =-

Environmental Risk Branch I 

Environmental Fate and Effects Division (7507P) 

Office of Pesticide Programs 

The Environmental Fate and Effects Division (EFED) issued a Preliminary Risk Assessment for 

triflumizole in support ofRegistration Review on June 4, 2013 (D393186). The assessment was 

based on the registered uses. of triflumizole and employed screening level models to identify 

potential risk to multiple taxonomic groups. The assessment identified potential risk concerns 

for: 

• Listed freshwater fish (acute) (ornamental and pineapple uses); 

• Listed estuarine/marine invertebrates (acute) (apples and pears, cherries, and ornamental 

uses); 

• Listed mammals (acute) (apples and pears, cherries, and ornamental uses); 

• Listed and non-listed mammals (chronic) (all uses); 

• Listed birds (acute) (apples and pears, cherries, cucurbits, hops, and ornamental uses); 

and 

• Listed herpatofauna (acute) (cherries and ornamental uses); 

. 1 
2

In this memo, EFED: 

 updates the mammalian risk assessment with a corrected chronic endpoint, 

 provides risk estimates for several alternative application scenarios, and 

 provides further characterization about chronic risk concerns for mammals. 

Updated Chronic Mammalian Risk Quotients 

EFED’s original risk assessment was based on chronic reproduction (rat) endpoints of <30 

mg/kg-diet (NOAEC) and <1.5 mg/kg-bw (NOAEL) (MRID 00162176, 40301602, 47504601). 

Subsequently, EFED was made aware that the DER had been amended to endpoints of 70 

mg/kg-diet (NOAEC) and 3.5 mg/kg-bw (NOAEL). Upper bound Kenaga chronic dose-based 

RQ values (T-REX (v1.4.1), based on the revised chronic mammalian endpoint are provided in 

Table 1 (These RQ values amend the values in Table 26 of the Triflumizole preliminary risk 

assessment). Overall, the RQs decreased because of the higher NOAEC; however this did not 

change the risk conclusions of the original assessment (all scenarios still exceed the chronic 

mammalian LOC). 

Table 1. Upper bound Kenaga chronic dose-based RQ values for mammals for application 

of triflumizole on food and non-food crops 

Crop and Application 

Rate Functional Feeding Group 

Dietary Item 

15 g mammals 35 g mammals 1000 g mammals 

Chronic Chronic Chronic 

Grapes – 0.25 lb a.i./A 

@ 4 apps/14-d interval 

Herbivores/Insectivores 

 Short Grass 18.22 15.57 8.34 

 Tall Grass 8.35 7.13 3.82 

 Broadleaf plants/ sm insects 10.25 8.76 4.69 

 Fruits/pods/lg insects 1.14 0.97 0.52 

Granivore—Seeds 0.25 0.22 0.12 

Apples and Pears – 0.5 

lb a.i./A @4 apps/10-d 

interval

Herbivores/Insectivores 

 Short Grass 41.16 35.16 18.85 

 Tall Grass 18.87 16.11 8.64 

 Broadleaf plants/ sm insects 23.15 19.78 10.60 

 Fruits/pods/lg insects 2.57 2.20 1.18 

Granivore—Seeds 0.57 0.49 0.26 

Cherries – 0.5 lb a.i./A 

@ 6 apps /7-d interval

Herbivores/Insectivores 

 Short Grass 58.00 49.54 26.56 

 Tall Grass 26.58 22.71 12.17 

 Broadleaf plants/ sm insects 32.62 27.87 14.94 

 Fruits/pods/lg insects 3.62 3.10 1.66 

Granivore—Seeds 0.81 0.69 0.37 

Cucurbits – 0.25 lb 

a.i./A @ 5-apps /7-d 

interval

Herbivores/Insectivores 

 Short Grass 26.18 22.36 11.99 

 Tall Grass 12.00 10.25 5.49 

 Broadleaf plants/ sm insects 14.73 12.58 6.74 

 Fruits/pods/lg insects 1.64 1.40 0.75 
3

Crop and Application 

Rate Functional Feeding Group 

Dietary Item 

15 g mammals 35 g mammals 1000 g mammals 

Chronic Chronic Chronic 

Granivore—Seeds 0.36 0.31 0.17 

Hazelnuts – 0.1875 lb 

a.i./A @ 6 apps/ 10-d 

interval

Herbivores/Insectivores 

 Short Grass 18.67 15.95 8.55 

 Tall Grass 8.56 7.31 3.92 

 Broadleaf plants/ sm insects 10.50 8.97 4.81 

 Fruits/pods/lg insects 1.17 1.00 0.53 

Granivore—Seeds 0.26 0.22 0.12 

Strawberries – 0.25 lb 

a.i./A @ 8 apps/ 14-d 

interval

Herbivores/Insectivores 

 Short Grass 18.22 15.57 8.34 

 Tall Grass 8.35 7.13 3.82 

 Broadleaf plants/ sm insects 10.25 8.76 4.69 

 Fruits/pods/lg insects 1.14 0.97 0.52 

Granivore—Seeds 0.25 0.22 0.12 

Leafy Greens – 0.25 lb 

a.i./A @3 apps/ 14-d 

interval

Herbivores/Insectivores 

 Short Grass 15.90 13.58 7.28 

 Tall Grass 7.29 6.23 3.34 

 Broadleaf plants/ sm insects 8.95 7.64 4.10 

 Fruits/pods/lg insects 0.99 0.85 0.46 

Granivore—Seeds 0.22 0.19 0.10 

Hops – 0.375 lb a.i./A 

@ 3 apps/ 14-d 

interval

Herbivores/Insectivores 

 Short Grass 23.85 20.38 10.92 

 Tall Grass 10.93 9.34 5.01 

 Broadleaf plants/ sm insects 13.42 11.46 6.14 

 Fruits/pods/lg insects 1.49 1.27 0.68 

Granivore—Seeds 0.33 0.28 0.15 

Papaya – 0.3125 lb 

a.i./A @ 3 apps/ 14-d 

interval

Herbivores/Insectivores 

 Short Grass 19.88 16.98 9.10 

 Tall Grass 9.11 7.78 4.17 

 Broadleaf plants/ sm insects 11.18 9.55 5.12 

 Fruits/pods/lg insects 1.24 1.06 0.57 

Granivore—Seeds 0.28 0.24 0.13 

Ornamentals - 1 lb 

a.i./A @ 3 apps/ 7-d 

interval

Herbivores/Insectivores 

 Short Grass 74.42 63.57 34.08 

 Tall Grass 34.11 29.14 15.62 

 Broadleaf plants/ sm insects 41.86 35.76 19.17 

 Fruits/pods/lg insects 4.65 3.97 2.13 

Granivore—Seeds 1.03 0.88 0.47 

Bolded RQ values exceed the chronic LOC of 1 

Chronic Mammalian Risk Quotients for Alternate Application Scenarios

Based on a request for additional characterization from the Pesticide Re-registration Division 

(PRD), EFED explored additional application scenarios to further characterize chronic risks of 

triflumizole to mammals (Table 2). 
4

Table 2. Alternate Foliar Application Scenarios for T-REX Modeling

Crop 

Original or 

Alternate 

Scenario 

Application Rate 

(lb a.i./A) No. Applications

Minimum 

Application 

Interval (Days) 

Apples and Pears 

Original 0.5 4 10 

Alternate 0.4 2 12 

0.4 2 28 

Cherries 

Original 0.5 6 7 

Alternate 0.4 2 12 

0.4 2 28 

Hazelnuts Original 0.1875 6 10 

Alternate 0.1875 2 28 

Table 3 provides the upper bound Kenaga chronic dose-based RQs for the alternative application 

scenarios (scenarios described in Table 2). The alternative application scenarios reduce RQs 

relative to the original scenarios (Table 1), but still exceed the chronic mammalian LOC for all 

of the alternative application scenarios. 

Table 3. Upper bound Kenaga chronic dose-based RQ values for mammals for application 

of triflumizole on food and non-food crops 

Crop and Application 

Rate Functional Feeding Group 

Dietary Item 

15 g mammals 35 g mammals 1000 g mammals 

Chronic Chronic Chronic 

Apples and Pears – 0.4 

lb a.i./A @2 apps/12-d 

interval 

Herbivores/Insectivores 

 Short Grass 20.43 17.45 9.35 

 Tall Grass 9.36 8.00 4.29 

 Broadleaf plants/ sm insects 11.49 9.82 5.26 

 Fruits/pods/lg insects 1.28 1.09 0.58 

Granivore—Seeds 0.28 0.24 0.13 

Apples and Pears – 0.4 

lb a.i./A @2 apps/28-d 

interval

Herbivores/Insectivores 

 Short Grass 17.37 14.84 7.95 

 Tall Grass 7.96 6.80 3.65 

 Broadleaf plants/ sm insects 9.77 8.35 4.47 

 Fruits/pods/lg insects 1.09 0.93 0.50 

Granivore—Seeds 0.24 0.21 0.11 

Cherries – 0.4 lb a.i./A 

@ 2 apps /12-d 

interval 

Herbivores/Insectivores 

 Short Grass 20.43 17.45 9.35 

 Tall Grass 9.36 8.00 4.29 

 Broadleaf plants/ sm insects 11.49 9.82 5.26 

 Fruits/pods/lg insects 1.28 1.09 0.58 

Granivore—Seeds 0.28 0.24 0.13 

Cherries – 0.4 lb a.i./A 

@ 2 apps /28-d 

interval

Herbivores/Insectivores 

 Short Grass 17.37 14.84 7.95 

 Tall Grass 7.96 6.80 3.65 

 Broadleaf plants/ sm insects 9.77 8.35 4.47 

 Fruits/pods/lg insects 1.09 0.93 0.50 

Granivore—Seeds 0.24 0.21 0.11 

Hazelnuts – 0.1875 lb 

a.i./A @ 2 apps/ 28-d 

Herbivores/Insectivores 

 Short Grass 8.14 6.96 3.73 
5

Crop and Application 

Rate Functional Feeding Group 

Dietary Item 

15 g mammals 35 g mammals 1000 g mammals 

Chronic Chronic Chronic 

interval Tall Grass 3.73 3.19 1.71 

 Broadleaf plants/ sm insects 4.58 3.91 2.10 

 Fruits/pods/lg insects 0.51 0.43 0.23 

Granivore—Seeds 0.11 0.10 0.05 

Bolded RQ values exceed the chronic LOC of 1 

Chronic Mammalian Risk Quotients Based on 50th Percentile Data

For additional characterization, risk quotients were calculated using average Kenaga EECs (50th 

percentile) rather than the more conservative upper bound Kenaga EECs (90th percentile), which 

are typically used in EFED modeling. Average Kenaga EECs may more accurately capture 

long-term concentrations that are expected to be found in the environment. The average 

provides additional information on the frequency, likelihood, and magnitude of exposure for 

varied situations. A weakness of using average Kenaga EECs is that they will not capture shortterm spikes, which could be important if the elevated concentration occurs during a sensitive 

developmental window (the two-generation rat reproduction study is not designed to distinguish 

between the duration of, or timing of, an exposure that is needed to cause an adverse effect). 

These values are not typically provided in EFED risk assessments. Table 4 provides chronic RQs 

for mammals, based on the average Kenaga values. The black values are for the original 

scenarios, and the red values are the PRD-requested scenarios. Again, RQs exceed the Agency’s 

LOCs for all of the original and alternative application scenarios considered. 

Table 4. Average Kenaga chronic dose-based RQ values for mammals for application of 

triflumizole on food and non-food crops 

Crop and Application 

Rate Functional Feeding Group 

Dietary Item 

15 g mammals 35 g mammals 1000 g mammals 

Chronic1 Chronic1 Chronic1

Apples and Pears – 0.5 

lb a.i./A @4 apps/10-d 

interval

Herbivores/Insectivores 

 Short Grass 14.58 12.45 6.67 

 Tall Grass 6.17 5.27 2.83 

 Broadleaf plants/ sm insects 7.72 6.59 3.53 

 Fruits/pods/lg insects 1.20 1.03 0.55 

Granivore—Seeds 0.27 0.23 0.12 

Apples and Pears – 0.4 

lb a.i./A @2 apps/12-d 

interval 

Herbivores/Insectivores 

 Short Grass 7.24 6.18 3.31 

 Tall Grass 3.06 2.62 1.40 

 Broadleaf plants/ sm insects 3.83 3.27 1.75 

 Fruits/pods/lg insects 0.60 0.51 0.27 

Granivore—Seeds 0.13 0.11 0.06 

Apples and Pears – 0.4 

lb a.i./A @2 apps/28-d 

interval

Herbivores/Insectivores 

 Short Grass 6.15 5.26 2.82 

 Tall Grass 2.61 2.23 1.19 

 Broadleaf plants/ sm insects 3.26 2.78 1.49 
6

Crop and Application 

Rate Functional Feeding Group 

Dietary Item 

15 g mammals 35 g mammals 1000 g mammals 

Chronic1 Chronic1 Chronic1

 Fruits/pods/lg insects 0.51 0.43 0.23 

Granivore—Seeds 0.11 0.10 0.05 

Cherries – 0.5 lb a.i./A 

@ 6 apps /7-d interval

Herbivores/Insectivores 

 Short Grass 20.54 17.55 9.41 

 Tall Grass 8.70 7.43 3.98 

 Broadleaf plants/ sm insects 10.87 9.29 4.98 

 Fruits/pods/lg insects 1.69 1.44 0.77 

Granivore—Seeds 0.38 0.32 0.17 

Cherries – 0.4 lb a.i./A 

@ 2 apps /12-d 

interval 

Herbivores/Insectivores 

 Short Grass 7.24 6.18 3.31 

 Tall Grass 3.06 2.62 1.40 

 Broadleaf plants/ sm insects 3.83 3.27 1.75 

 Fruits/pods/lg insects 0.60 0.51 0.27 

Granivore—Seeds 0.13 0.11 0.06 

Cherries – 0.4 lb a.i./A 

@ 2 apps /28-d 

interval

Herbivores/Insectivores 

 Short Grass 6.15 5.26 2.82 

 Tall Grass 2.61 2.23 1.19 

 Broadleaf plants/ sm insects 3.26 2.78 1.49 

 Fruits/pods/lg insects 0.51 0.43 0.23 

Granivore—Seeds 0.11 0.10 0.05 

Hazelnuts – 0.1875 lb 

a.i./A @ 6 apps/ 10-d 

interval

Herbivores/Insectivores 

 Short Grass 6.61 5.65 3.03 

 Tall Grass 2.80 2.39 1.28 

 Broadleaf plants/ sm insects 3.50 2.99 1.60 

 Fruits/pods/lg insects 0.54 0.47 0.25 

Granivore—Seeds 0.12 0.10 0.06 

Hazelnuts – 0.1875 lb 

a.i./A @ 2 apps/ 28-d 

interval

Herbivores/Insectivores 

 Short Grass 2.88 2.46 1.32 

 Tall Grass 1.22 1.04 0.56 

 Broadleaf plants/ sm insects 1.53 1.30 0.70 

 Fruits/pods/lg insects 0.24 0.20 0.11 

Granivore—Seeds 0.05 0.05 0.02 

Bolded RQ values exceed the chronic LOC of 1 

1 Chronic RQ = (upper bound dose-based EEC, mg/kg-bw) / (NOAEL; mg/kg-bw).

Additional Mammalian Chronic Exposure Information 

EFED routinely uses information from the two-generation rat reproduction study to assess 

chronic effects to mammals. The Human Effects Division (HED) DER for the multi-generation 

study (MRID 00162176, 40301602, 47504601) reports a LOAEL of 8.5 mg/kg-bw/day and 

NOAEL of 3.5 mg/kg-bw/day with effects based on mortality, decreased pup body weight, 

reduced litter size, and increased incidence of hydroureter and space between the body wall and 

organs. The two-generation rat study is not designed to determine the duration of time needed to 
7

produce adverse effects. Consequently, it is unknown if these effects were the result of a short 

exposure during a critical developmental window, or if they required a longer-term exposure. It 

is likely that exposures in the field will be more punctuated and variable than organisms 

experience in the multi-generation reproduction study. 

To more fully characterize the risk predicted using the multi-generation study endpoints, EFED 

considered the results available for short-term developmental studies in the rat (MRIDs 4548001, 

00157075, and 00164384). The goal of considering these developmental study results was to 

determine if short-term windows of exposure could be biologically significant. If similar effects 

are seen in the shorter-term developmental study (and at similar doses), then it would be logical 

to expect that shorter-term exposure windows could be reasonably expected to produce similar 

effects to those observed in the multi-generation study under field conditions. The HED DER 

indicates that a consideration of all three available shorter-term studies suggests a developmental 

LOAEL of 35 mg/kg-bw/day based on decreased numbers of viable fetuses, increased dead or 

resorbed fetuses, increased numbers of late resorptions, decreased fetal body weight, and 

increases in the incidents of cervical rib formation. The NOAEL for these endpoints is 10 

mg/kg-bw/day. 

Comparing the longer-term reproduction study observations to shorter-term developmental 

observations it is clear the fetal survival, resorptions, and late resorptions in the developmental 

study are reasonably similar to the reduced litter size that was seen in the reproduction study. 

The NOAEL for the developmental study (10 mg/kg-bw/day) is slightly higher that the NOAEL 

for the reproduction study (3.5 mg/kg-bw/day), but these differences may be more a factor of the 

dose progression selection for each study rather than actual toxicological differences. 

On balance, it is reasonable to conclude that short-term exposures can produce offspring effects 

at doses proximate to the longer-term reproduction study. Therefore this comparison between 

shorter-term and longer-term chronic mammalian effects provides additional support to, and 

increases the Agency’s confidence in, the mammalian wildlife risk assessment conclusions.