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 

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Environmental Risk Branch 1 Environmental Fate and Effects Division (7507P) Office of Pesticide Programs



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# ) Sujatha Sankula , Ph.D., Branch Chief 

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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 w ith a corrected chronic endpoint,

 provides risk estimates for several alte rnative application scenarios, and

 provides further characteri zation 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 th e 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 revi sed 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 a ssessment (all scenarios still exceed the chronic mammalian LOC).
Table 1. Upper bound Kenaga chronic dose-bas ed 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 fo r Alternate Application Scenarios
Based on a request for additional characterization from the Pesticide Re-registration Division (PRD), EFED explored additional application scenarios to furthe r characterize ch ronic 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 ap plication scenarios reduce RQs relative to the original scenarios (Table 1), but still exceed the chronic mammalian LOC for all of the alternative a pplication scenarios.
Table 3. Upper bound Kenaga chronic dose-bas ed 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 50 th 

### 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. Aver age 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 re production study is not designed to distinguish between the duration of, or timing of, an exposure th at 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 valu es. The black values are for the original scenarios, and the red values are the PRD-reque sted scenarios. Again, RQs exceed the Agency’s LOCs for all of the original and altern ative 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

Chronic 1 Chronic 1 Chronic 1

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

Chronic 1 Chronic 1 Chronic 1
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 Eff ects 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 ba sed on mortality, decreased pup body weight, reduced litter size, and increas ed 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. Consequent ly, it is unknown if these eff ects 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 thes e 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 (a nd at similar doses), then it would be logical to expect that shorter-term exposure windows c ould be reasonably expected to produce similar effects to those observed in the multi-gene ration study under field c onditions. The HED DER indicates that a consideration of all three ava ilable shorter-term studies suggests a developmental LOAEL of 35 mg/kg-bw/day based on decreased nu mbers 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 repr oduction study observations to shorter-term developmental observations it is clear the fetal survival, resorp tions, and late resorptions in the developmental study are reasonably similar to the reduced litte r 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 repr oduction study. Therefore this comparison between shorter-term and longer-term chronic mammalia n effects provides additional support to, and increases the Agency’s confidence in, the mamm alian wildlife risk assessment conclusions.