Fluopicolide Human Health Risk Assessment D416744

UNITED STATE S ENVIRONMENTAL PROTEC TI ON AGENCY

WASHINGTON, D.C

. 20460



### MEMORANDUM

Date: December 18, 2013 OFFICE OF
CHEMICAL SA FETY AND
POLL U TI ON PREVENTION



### SUBJECT: F luopicolide

. Revised Human Health Risk Assessment for the New Section 3

Tolerances on Rotational Corn.



### PC Code: 027412



### Decision No.: 471299


### Petition No. : 2F8099



### Risk Assessment Type: Single Chemical Aggregate



### TXR No.: NA



### MRJD No.: 48809201,48842201 

### DP Barcode: D416744 

### Registration No.: 59639-140 

### Regulatory Action: Section 3 Registration



### Case No.: N/ A



### CAS No.: 239110-15-7

40 

### CFR: §180.627

## ?~o/h. 

# ·hr-/

Alaa Kamel

, Ph.D.

, Chemi st &

### ~ Alexandra LaMay, Biologi st 

# Iff**~** John Liccion e, Ph.D., Toxico l ogist 

### FROM:

Ri sk Assessment Branch V /V II v Health Effects Division (7509P)

THROUGH: Michael S. Metzger, Chief

# ~**~** Danette Drew, Sen ior Scientist' 

## y**~** Ri sk Assessment Branch V N il

Health Effects Division (750 9P)



### TO: Tony Kish/Dominic Schuler

, 

### RM #22 Fungicide Branch Registration Di v ision (7505P)

This memorandum is th e revised human health ri sk assessment for fluopicolide to support the

n ew tolerances on rotationa l corn. Thi s document reflects revision s to the description of the turf

transfera ble residue data requirement. This memorandum supersedes the previous assessment

d a t ed May 8, 2013

.

Page I of38Fl uo picol ide H uman Health Ri sk Assessme n t D 4 1 6744

1.0 Ex ecutive Summary

. .. . ... ............ .......................... . ...... ....... ... ..... .. .. .. . ..... . . ....... .. ... . . . . .......... 4

2.0 HED Recommendations

... . .................................... . .. . .. . . . .. .. .. ... .. .. ..... ... .. .. .. ... . ... . ........... ..... 

### 6

2.1 Data Deficiencies

..... . ... . . .. ... . .......................... . ............................. ............ ........... .. ... . .. . .. . 6

2.2 Tolerance Co nsiderations

..................................... . ... . ... . ..................... . . .. .. .. .. . . .. .. .. .. .. . .. .. . 7

2.2.1 Enforcement Analytical Method

...................... .......... ................... . ................ . .. .. .. .. .. 7

2.2.2 Recommended T olerances

......................................................................................... 7

2.2.3 Revisions to Petitioned

- For To l erances

............................... . ... . ................................ 8

2.2.4 International Harmonization

............................... ... ................. . ............ ... .. ...... ... .. ..... 8

2.3 Label Recommendations

................................................................................................ 8

2.3.1 Recommendations from Residue Reviews

...... ..... . .. .................................................. 8

2.3.2 Recommendations from Occupation a l Assessment

. .. .. . ... . ... . ... .. ... . ... . ... . . .. .. .. . . ... . ... . . 8

2.3.3 Recommendations from Residential Assessment..

.. . ................ .. . .. .. . . . .. .. .. ... .. . . ......... 8

3.0 Introduction

........... .. .. . .. .......... .............................. .. . .......... ......................... ...... .. ... .. .... ....... 9

3.1 Chemical Identity

...... . .. . ... . ...................................... . ... . .................................... . . . ... .. ... . .. 9

3.2 PhysicaUChemical Characteristics

................ .. .. . ... . ................................... .. ... . ... . ......... 9

3

. 3 Pesticide Use P atte rn

.................................................................................................... 10

3.4 Anticipated E xposure Pathways

..................... . .. .. .. .. ........................... .. ... . ... . ... .. ......... 10

3.5 Consideration of Environmental Justice

............... ....... . .. ........................... .. .. .. ... .. ... .. I 0

4

. 0 Hazard Characterization and Dose-Response Assessment

................ . ......................... 11
4.1 Toxicology Studies Available for Analysis

.. ............... .. .. ... .. ... . . .. .............. ... ... ....... ... . . 11

4.2 Absorption

, Distribution, Metabolism, & Elimination (ADM E )

... . .. .. .. . . ... .. .. . . . .. . . .. . 1 1

5

. 0 Dietary Ex posure and Risk Assessment

......................................................................... 17

5 .1 Metabolite/Degradate Residue Profile

.............. .. . .. .. .. ........... . ... . .................. . . . . . ......... 17

5.1.1 Summary of Plant and Animal Met abo lism Studies

. .. .. ... . ................ . ... . .. ....... ...... 17
5.1.2 Summary of E nvironmental Degradation

.............................................................. 17

5.1.3 Compari so n of Metabolic Pathwa ys

.............. .. .. .. ................................................ . .. 17
5

. 1.4 Residues of Co ncern Summary and Rationale

. .. ............................ . ... .. .. ...... .. .. ... .. 17

5.2 Food Residue Profile

. .... . . . . . .......................................................................................... 18

5.3 Water Residue Profile

..................................... . ... .. .. .. . . .. . .... . ... ...... .. . ... . ... . ..... .. .. .. ... . . .. .. . 1 9

5.4 Dietary Risk Assessment

...... . . . . . .. . . .. .. .. .. ..... ....... . ... . ................ ..... .. .. .. .. .. .. ... .. . ... . ...... . ... . 1 9

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

............................. 20

6.1 Residential Handler Exposure

.......................... ....... . . ................... .. ...... . ... . . .. . . . .. ....... .. 20

6.2 Post-Application Exposure

....................... .. .. .. .. .. .. . . ... . .. .. .. .. .. .. ..................................... 23
6.5 Residential B ys tander Post-application Inha l at i on Exposure

............... .. .. ... . ... .. . .... 27

6.6 Spray Drift

............. .. .. . .. ....... . . ... . .............................................................. . .... . .. ... .. . ....... 27

7.0 Aggregate Exposure/Risk Characterization

............. . .................................................... 28

7.1 Acute Aggregate Risk

................................................................................................... 28

7.2 Short

- Term Aggregate Risk

. .. .. ......................... .......... .. .. ............... . .. ... . ..... .. .. .. . .. .. ...... 28

7.3 Intermed ia te-Term Aggregate Risk

. ............. . . . . . .. .. ... . .. .. .. .. . .. .. . .. ...... ... .. ........ . ........... . 28

7.4 Chronic Aggregate Risk

........ ..................... . .. ... . .. . ................ ... . ... . . ... . ... .. . . .. . . ..... .. .. ...... 29

7.5 Cancer Aggregate Risk

. ... . ..................................... .. . . ... . .. ............................... ... .. .. ... .. . 29

8.0 Cumulative Ex posure/Risk Characterization

. ... . .. .. .. .. .. ... . ... . ............................ . ........... 29

9.0 Occupational Ex posure/Risk Characterization

....................................... ....... . ....... ...... 29

10.0 References

........................... . ................................ .. .. .. .. .. .. .. ... .. .......................................... 29 Appendix A. Toxicology Profile and Executive Summaries

.............................. .. .. ... .. ... . ... .. .. 30

A .l Toxicology Data Requirements

.............. .. . .. .. ... . . . ... . ..... .. ...... .. .. ....................... ..... ....... 30

Pa ge 2 of3 8Fluopicolide Hum an Health Risk Assessment D41 6744

Page 3 of 38 Appendix C. Residue Summary Table ................................................................37Fluopicolide Hum an Health Risk Assessment D41 6744

Page 4 of 38 1.0 Executive Summary

The Health Effects Division (HED) of EPA's Office of Pesticide Programs has evaluated the toxicity and exposure databases for the active ingredient, fluopicolide, 2,6

- dichloro

- N

- [3

- chloro

5

- (trifluoromethyl)

- 2

- pyridylmethyl]benzamide, and has conducted a h uman health risk assessment. The assessment was conducted to support proposed new tolerances on rotation al corn following application to primary crops. Fluopicolide shares a metabolite, 2,6

- dichlorobenzamide (BAM), with another active ingredient, dichloben il. Residues of BAM are considered to be of regulatory concern , and separate toxicity data and endpoints for risk assessment have been selected for BAM. However, since the proposed change in use pattern

do es not add significantly to the BAM dietary exposu re, and residues of BAM due to fluopicolide applications are significantly lower than those from dichlobenil applications, the conclusions from the most recently conducted BAM human health risk assessment (D373401, D. Rate, 3/19/08) remain unchanged and a revised quantitative BAM risk assessment will not be

done to support the proposed tolerances

. Aggregate risks from BAM exposure are not of

concern. This assessment addresses risks from the parent compound fluopicolide and its

metabolites PCA ( 3

- chloro

- 5

- trifluoromethylpyridine

- 2

- carboxylic acid ) and P x 1 ( 3

- methylsulfinyl

- 5

- trifluoromethylpyridine

- 2

- carboxylic acid )

.

Fluopicolide is a fungicide that controls a wide range of diseases including downy mildews, late blight, and some Pythium species and is registered for use on a variety of agricultural crops and for use on turf (lawns, recreational areas, parks, golf courses and athletic fields) and ornamentals. Valent U.S.A. Corporation is petitioning to reduce the plant back interval (PBI) from 18 months to 30 days for rotated field corn on the label for V

- 10161 4 SC (EPA Reg. No. 59639

- 140) and to
establish new inadvertent residue tolerances for fluopicolide on field corn forage

, stover and grain

.

The toxicity database for fluopicolide is comple te. Fluopicolide has low acute toxicity by the oral, dermal and inhalation routes. The subchronic and chronic toxicity studies showed that the primary effects of fluopicolide are in the liver. Developmental toxicity in the rabbit occurred only at doses that caused severe maternal toxicity (including death). In the rat, developmental effects were seen only at high dose levels in the presence of maternal toxicity. Toxicity endpoints and points of departure (PODs) are selected from the rabbit developmental and rat

chronic/cancer studies for all routes (dietary, incidental oral, dermal and inhalation) and durations of exposure (with the exception of acute exposures; there is no endpoint attributable to a single dose). Fluopicolide is not neurotoxic, carcinogenic, or mutagenic. It does not appear to have immunotoxic potential.

T he Food Quality Protection Act (FQPA) safety factor was reduced to 1 × because the toxicity

database is complete , there is no evidence of quantitative susceptibility following in utero and/or postnatal exposure in the rabbit and rat developmental toxicity studies or in the 2

- generation rat reproduction study

, and the exposure assessments are unlikely to underestimat e risk

.

The Agency has reviewed the residue chemistry database , as well as existing feeding studies with both parent compound and t he BAM metabolite, and concluded that tolerances are not
needed for livestock commodities. The new field trial data for rota tion to corn was reviewed andFluopicolide Hum an Health Risk Assessment D41 6744

Page 5 of 38 analyzed using the Organization of Economic Cooperation and Development ( OECD ) maximum residue limit (MRL) calculation procedure . The results of the calculat ion indicated that the proposed tolerance s should be modified for the feed items corn, fiel d forage and corn, field

stover. The livestock dietary burden was unaffected by the new recommended tolerances on field corn forage, stover and grain

.

An acute dietary exposure and risk assessment was not conducted for fluopicolide because an endpoint attributable to a single dose was not identified from the available data. Further, a cancer dietary exposure and risk assessment was not conducted because fluopicolide was classified by

HED as “ not likely to be carcinogenic to humans ”

. A conservative chronic (food plus drinking water) dietary exposure and risk assessment was conducted using tolerance level residues, 100% crop treated assumptions, and empirical or default processing factors. Estimated drinking water concentrations (EDWC s) were derived from conservative modeling programs. Chronic dietary (food and water) estimated risks were well below HED’s level of concern for the U.S. population and all population subgroups.

There are no new residential uses associated with this act ion; however, fluopicolide is registered on residential turf and recreational sites, such as golf courses. Exposure to fluopicolide from these uses was previously assessed

. An updated residential exposure assessment was completed for fluopicolide to reflect updates to HED’s 2012 Residential SOPs 1 along with policy changes for body weight assumptions

. The residential risk estimates impact the aggregate assessment. All residential handler risk estimates are not of concern for fluopicolide

. An updated residential
post

- application exposure assessment was also completed for fluopicolide for use on turf, golf courses, and ornamental plants/trees

. All residential post

- application risk estimates for fluopicolide were not of concern

. Since the proposed chan ge in use pattern does not add significantly to the BAM dietary exposure and there are no new residential uses

, the conclusions from the most recently conducted BAM human health risk assessment remain unchanged and a

revised quantitative BAM risk assessmen t is not required.

In accordance with the FQPA, an aggregate assessment was conducted which considered pesticide exposure and risk from the residential, food, and water pathways. Residential exposures included adults applying fluopicolide in a residenti al setting (dermal and inhalation exposure),
post

- application exposure to adults and children (dermal exposure), and post

- application oral exposure to children (by putting hands or objects in their mouth). The estimated aggregate short

term risks for all o f the exposure scenarios that were calculated were all below HED’s level of

concern.

There are no agricultural or occupational applications associated with this action (there are no direct applications to rotated field corn). Therefore, there is no pote ntial occupational exposure associated with the proposed change in use pattern. Occupational exposure and risk assessments were previously conducted for existing f luopicolide uses

. All handlers and post

- application

MOEs were not of risk concern.

1 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.htmlFluopicolide Hum an Health Risk Assessment D41 6744

Page 6 of 38 Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Lo w

- Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

. For information on human studies s ee Appendix C

.

2.0 HED Recommendations

HED recommends allowing the rotation of field corn 30 days after use of fluopicolide on a primary c rop, and for inadvertent residue tolerances of fluopicolide on field corn grain, stover and forage. Additional data are needed as outlined in Section 2.1 below. The specific tolerance

recommendations are discussed in Section 2.2

.

2.1 Data Deficiencies

The residue chemistry and toxicity data bases are complete and sufficient for characterizing the residues, dietary exposure and hazard of fluopicolide.

In accordance with 40CFR158, turf transferable residue ( TTR ) data are required for all occupational ( e.g., sod farms, golf courses, parks, and recreational areas) or residential turf uses that could result in post

- application exposure to turf. In the absence of chemical

- specific TTR data, EPA uses default values. The 2012 Standard Operating Procedures f or Residential Pesticide Exposure Assessment includes an analysis of all TTR data, available at the time, which resulted in the selection of revised liquid and granular default values for the fraction of the application rate available for transfer after a turf application (F AR ). These values are based on an analysis of 59 TTR studies performed with the Modified California Roller Method (36 studies using liquids, 11 studies using wettable powders/water dispersible granules, and 12 studies using granules). The liquid results (N=131) indicate a range of F AR values from 0.0005% to 6.1% and the granular results (N=37) indicate a range of 0.00064% to 0.69%. In both the liquid and granular data, a large range of transferability is observed and this variability ca n potentially be attributable to many factors such as active ingredient; formulation; field conditions in the studies; weather conditions (e.g., humidity); or many other difficult to quantify factors. Although witnessed across multiple chemicals, this ran ge in F AR values is not expected when considering TTR data for a single chemical. EPA selected 1% and 0.2% as the reasonable, high

- end default values for liquid and granular products, respectively. Because TTR data are not available for fluopicolide , EPA is using the default value of 1%

. Although there may be a small degree of uncertainty in the use of the default TTR value for fluopicolide (i.e., there is a small chance that

the F AR value may exceed the applicable default value ), it is likely that the h ealth

- protective aspects of EPA’s residential postapplication turf assessment methodology will more than compensate for this potential uncertainty). For example, when assessing residential post

application turf exposure, EPA assumes the following: expos ures occur to zero

- day (i.e., day of application ) residues every day of the assessed exposure duration (i.e., EPA assumes that no dissipation or degradation occurs, it doesn’t rain, the grass is not mowed, etc); individuals perform the same postapplicati on activities performed in the turf transfer coefficient study day after day (e.g., tumbling, playing on turf with toys, etc.); and individuals engage in these post

application activities for a high

- end amount of time every day (represented by data reflect ingFluopicolide Hum an Health Risk Assessment D41 6744

Page 7 of 38 time children spend outdoors and not specifically engaged in activities on turf). In actuality, residues will dissipate to some degree depending on the chemical; children do not play on turf every day; children do not spend all of their outdoor time o n turf; and high

- end levels of activity will not occur every day even if children are playing on treated turf.

Given the conservatisms discussed above and the potential compounding nature of these conservatisms, EPA is able to rely upon the calculated ex posure estimates with confidence that exposure is not being underestimated.

Since the estimated residential turf postapplication exposure using default TTR values for fluopicolide is not minimal in comparison to the level of concern (i.e., the calculated MOE is not greater than 10 times higher than the level of concern, MOE = 260 compared to the LOC of 100); EPA is requiring the 40CFR TTR data.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

D 321209, 1/23/2007, A. Acierto , Residue Chemistry Chapter

An acceptable LC/MS/MS enforcement method , RM

- 43C

- 1 “Determination of Fluopicolide and BAM in Crops,” December 11, 2008) is available for the determination of fluopicolide and BAM in corn matrices. Samples are extracted twice with aceton e:water (v:v, 3:1), and the combined

extracts were concentrated to remove the acetone. The extract was mixed with a 5% sodium chloride solution, and the mixture was partitioned twice with methylene chloride. The methylene chloride phases were combined an d concentrated to remove the methylene chloride. The residue was dissolved in hexane and cleaned up on a silica gel cartridge, using hexane:ethyl acetate (80:20, v:v) to elute residues of fluopicolide and hexane:ethyl acetate (2:1, v:v) to elute

residues of BAM. The eluates were combined, evaporated to dryness, and dissolved in methanol:water (3:2, v:v) for LC/MS/MS analysis. For some sample sets, the silica gel column cleanup step was modified as follows: residues were eluted from the silica gel cartri dge using hexane:ethyl acetate (1:1, v:v); the eluate was evaporated to dryness and dissolved in acetonitrile; the acetonitrile was partitioned twice with hexane; and the acetonitrile phases were combined, evaporated to dryness, dissolved in methanol, and diluted with water for LC/MS/MS analysis. Results were reported in analyte equivalents.

Adequate multiresidue method testing data for fluopicolide and its metabolites were previously submitted. Based on the results of the testing, the multiresidue metho ds are not appropriate for determining residues of fluopicolide or its metabolites (D321209, 1/23/2007, A. Acierto).

2.2. 2 Recommended Tolerances

HED recommends that the tolerance expression for fluopicolide be amended under §180.627(d)

to read as follow s: Tolerances are established for residues of the fungicide fluopicolide [2,6

- dichloro

- N

- [[3

- chloro

5

- (trifluoromethyl)

- 2

- pyridinyl]methyl]benzamide], including its metabolites and degradates, inFluopicolide Hum an Health Risk Assessment D41 6744

Page 8 of 38 or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only fluopicolide in or on the commodity.

Tolerances (based on fluopicolide per se ) are not needed for the processed commodities because residues of fluopicolide in grain at the 1× and the 5× exaggerated rate were below LOQ (<0.01 ppm). The proposed and recommended tolerances for residues of fluopicolide are shown in

Table 2.2.3.

Tab le 2.2.3

. Tolerance Summary for Fluopicolide

Commodity Established/Proposed

Tolerance (ppm) Recommended

Tolerance (ppm) Comments

Correct Commodity Definition Corn, field, forage 0.09 0. 08 Corn, field, grain 0.01 0.01
Corn, field, stover 0.30 0. 2

2.2. 3 Revisions to Petitioned

- For Tolerances

The recommended tolerance levels differ from the petition. Recommended tolerances were obtained using the Organization of Economic Cooperation and Development (OECD) calculation procedure. Residue data from the field trial locations (average of duplicate samples) for fluopicolide only were used in the OECD MRL calculation procedure . Censored data were 46%, 100% and 27% for forage, grain and stover respectively. LOQ amounts (0.01 ppm) were entered

if the det ected amount was <LOQ. The petitioner also demonstrated that they used the OECD calculation procedure to calculate the proposed tolerances, however, the sum of fluopicolide +

BAM and moisture content were included in their calculation s . Since the toleran ce expression includes monitoring of residues of fluopicolide only for rotational crops for both food and feed commodities, and that monitored samples will be analyzed without drying, it is not appropriate to

consider residues of BAM and moisture content i n tolerance calculations. The registrant should submit a revised Section F in which the proposed tolerances are the same as those recommended by the HED.

2.2. 4 International Harmonization

A Codex tolerance for fluopicolide has been established at 0.2 pp m for the straw and fodder (dry) of cereal grains. The Codex and U.S. tolerance expressions are harmonized since they both include the parent compound, fluopicolide, only. There are no Canadian or Mexican MRLs for

field corn commodities.

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

None.

2.3.2 Recommendations from Occupational Assessment Not applicable

2.3.3 Recommendations f rom Residential Assessment

NoneFluopicolide Hum an Health Risk Assessment D41 6744

Page 9 of 38 3.0 In troduction

3.1 Chemical Identity

The chemical identity of fluopicolide and its metabolites BAM, PCA and P1 x are shown in Table

3.1.1.

TABLE 3 .1. 1. Test Compound Nomenclature.

Compound

Common name Fluopicolide

Company experimental name V

- 10161 (Valent); AE C638206 (Bayer)

IUPAC name 2,6

- dichloro

- N

- [3

- chloro

- 5

- (trifluoromethyl)

- 2

- pyridylmethyl]benzamide

CAS name 2,6

- dichloro

- N

- [[3

- chloro

- 5

- (trifluoromethyl)

- 2

- pyridinyl]methyl]benzamide

CAS registry number 239110

- 15

- 7

End

- use product (EP) Presidio Fungicide (4 lb ai /gal suspension concentrate; EPA Reg. No. 59639

- 140)

Compound

Common name BAM

Company experimental name AE C653711

Chemical name 2,6

- dichlorobenzamide

Compound

Common name PCA

Company experimental name AE C657188

Chemical name 3

- chloro

- 5

- trifluoromethylpyridine

- 2

- carboxylic acid

Compound

Common name P 1x

Company experimental name AE 1344122

Chemical name 3

- methylsulfinyl

- 5

- trifluoromethylpyridine

- 2

- carboxylic acid

3.2 Physical/Chemical Characteristics

The physical and chemical properties for fluopicolide are shown in Table 3.2.1Fluopicolide Hum an Health Risk Assessment D41 6744

Page 10 of 38 TABLE 3.2.1

. Physicochemical Properties of the Technical Grade Test Compound Fluopicolide.

Parameter Value Reference 1

Melting point/range 149 C MRID 46474015

pH 6.5 at 22.0 C MRID 46474013

Density 1.65 g/cm 3 at 30 oC MRID 46474016

Water solubility (20 C) 3.02 mg/L 2.86 mg/L at pH 4 2.80 mg/L at pH 7 2.80 mg/L at pH 9 MRID 46474020

MRID 46474021

Solvent solubility (mg/L at 20 C) n

- Hexane: 200

Ethanol: 19,200

Toluene: 20,500 Ethyl acetate: 37,700

Acetone: 74,700

Dichloromethane: 126,000 Dimethylsulfoxide: 183,000 MRID 46474022

Vapor pressure at 25 C 8.03 x 10
- 7 Pa MRID 46474023

Dissociation constant (pKa) No evidence of ionization in the pH range of 1.9 to 9.8 MRID 46474017

Octanol/water partition coefficient Log(K OW ) Log P OW = 3.26 at pH 7.8 and 22 ± 1 C MRID 46474018

Log P OW = 2.9 at pH 4.0, 7.3 and 9.1 and 40 C MRID 46474019

UV/visible absorption spectrum Absorption maxima wavelengths (nm):

In methanol: 203 and 271

In methanol/HCl: 202 and 270

In methanol/NaOH: 219 and 271 MRID 46474014

3.3 Pesticide Use Pattern

The formulation is applied to the primary crop with a 30 day plant back interval on field corn. There are no direct uses of fluopicolide on corn

.

3.4 Anticipated Exposure Pathways

F luopicolide is registered for use on agricultural crops as well as on turf (lawns, golf course, recreational areas) . Exposure to fluopicolide may occur from ingestion of residues in/on foods

and in drinking water, and via the dermal and inhalation routes for adults using fluopicolide products in residential settings. In addition, both adults and children may be exposed dermally in
post

- application scenarios on turf ; children may also be exposed o rally in post

- application

scenarios for turf . There is a potential for post

- application dermal exposure for workers re

entering treated fields.

R isk assessments have been previously prepared for the existing uses of fluopicolide (D384431 D. Davis 12/9/10) . This current risk assessment considers the proposed change in use pattern , as well as the different exposure pathways based on the existing uses of fluopicolide

.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal ActionsFluopicolide Hum an Health Risk Assessment D41 6744

Page 11 of 38 to Address Environmental Justice in Minority Populations and Low

- Income Populatio ns," ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- establ ished procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII ) and /or the CDC under the National Health and Nutrition Examination Survey/What We Eat in America (NHANES/WWEIA), are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able t o assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks

for adult applicators and for toddlers, youths, and adults entering or playing on treated areas
post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized softw are and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

Toxicological effects of fluopicolide were previ ously evaluated in the human health risk assessments conducted in 2007 and 2010 ( D325091, N. Dodd, 11/21/07 and D384431, D. Davis, 12/9/2010). A registration review scoping document was released in 2013 (D. Drew, D405060).

Since that time an i mmunotoxic ity study was submitted and reviewed. The Hazard and Science Policy Council (HASPOC ; TXR. 0056544 ) met on December 19, 2012 to discuss the need for a 28

- day inhalation study. The HASPOC has determined that, based on a weight of evidence ( WOE) approach, a 28

- day inhalation toxicity study is not required at this time.

4.1 Toxicology Studies Available for Analysis

The toxicity database for fluopicolide is complete and sufficient for characterizing the hazard of fluopicolide. The registrant submitted an immunotoxicity study to fulfill the requirement of 40 CFR §158 for pesticide registration. The Agency believes the existing data are sufficient for endpoint selection for exposure/risk assessment scenarios and for evaluation of the requirements

under the FQPA. The toxicity endpoints and points of departure have not changed since the previous risk assessment (D384431, 2010). The immunotoxicity study submitted did not impact the endpoints selected for risk assessment purposes for fluopicolide.

4.2 Absorpt ion, Distribution, Metabolism, & Elimination (ADME)

The results of rat metabolism studies (MRIDs 46474226, 46474239, 46474241, 46474242, and 46474244) ), indicated that fluopicolide was readily absorbed and rapidly excreted within 72 hours following a single oral dose of 10 mg/kg. Fecal elimination accounted for 68.8

- 72.4% ofFluopicolide Hum an Health Risk Assessment D41 6744

Page 12 of 38 the administered radioactivity whereas urinary excretion accounted for only 18.8

- 21.4% of the administered radioactivity. In the bile excretion study (MRID 46474244) , 51.7 % of the administered radioactive dose in both sexes was excreted by the cannulated bile duct indicating a significant portion of the radioactivity recovered in feces is derived from hepatic metabolism of fluopicolide.

Time

- course blood/plasma and tissu e studies revealed rapid absorption and distribution of administered radioactivity to all organs and tissues followed by moderately rapid excretion with reduction to background levels in most tissues and organs within 72 hours. Tissue concentrations peake d at 6

- 7 hours post

- dosing and about 96% of the peak tissue concentrations were dissipated between 6

- 7 hours and 168 hours post

- dose.

Absorption and excretory patterns did not exhibit gender

- related variability, but blood/plasma kinetic studies (MRID 46 474226) suggested a near

- saturation of absorption at the high dose (100 mg/kg bw). Based upon tissue burden data, neither fluopicolide nor its metabolites appear to undergo any significant tissue sequestration. With the exception of transiently higher le vels in the liver, kidneys, and intestines during the elimination phase, radioactivity concentrations in any given tissue consistently represented considerably less than 1% of the administered dose within 24 hours of administration of fluopicolide. The ma jor urinary and fecal metabolites were

oxidative N

- dealkylation cleavage products.

4.2.1 Dermal Absorption

In a dermal penetration study (MRID 46708638), 14 C

- Fluopicolide in a commercial concentrate, or aqueous dilution of a concentrate for the low do se, was applied to the skin of 5 male Sprague

Dawley rats/time point/dose. The dose ( 1.43 or 659 μg/cm 2 skin ) was applied to 12 cm 2 skin and removed after 8 hours. The animals were sacrificed at 8, 24, 72, or 144 hours after application. Dermal absorptio n ranged from 3

- 8% (high dose) to 22

- 37% (low dose). The most conservative value for risk assessment is a dermal absorption of 37% observed at 24 hours after application.

In vitro dermal absorption data suggested that fluopicolide will penetrate human sk in at a substantially lower rate (up to eight times less) than rat skin, providing confidence that a 37% dermal absorption factor is conservative for use in this risk assessment.

4.3 Toxicological Effects

The subchronic and chronic oral toxicity studies in rats and mice revealed liver toxicity in both species. Kidney and thyroid toxicity were observed in rats only. Fluopicolide is not neurotoxic, carcinogenic, nor mutagenic. Fluopicolide does not exhibit immunotoxic potential.

Developmental toxicity i n the rabbit occurred only at doses that caused severe maternal toxicity (including death). In the rat, developmental effects were seen only at high dose levels (700 mg/kg/day) in the presence of maternal toxicity. Similarly, offspring effects (body weig ht, kidney) occurred only at levels causing toxicity in parents of the multi

- generation reproductive toxicity study. There is no evidence of increased quantitative susceptibility of rat or rabbit

fetuses to in utero or post

- natal exposure to fluopicolide.Fluopicolide Hum an Health Risk Assessment D41 6744

Page 13 of 38 No toxic effects were observed in studies in which fluopicolide was administered by the dermal routes of exposure. An inhalation toxicity study is not available. The Hazard and Science Policy Council (HASPOC; TXR. 0056544) met on December 19, 2012 to discuss the need for this inhalation study. The HASPOC has determined that, based on a weight of evidence ( WOE) approach, a 28

- day inhalation toxicity study is not required at this time. This approach considered all of the available hazard and exposure in formation including (1) the physical/chemical properties of fluopicolide, including its potential to volatilize (8.03 x 10 - 7 Pa vapor pressure); (2) the low acute inhalation toxicity; (3) the primary target organs of fluopicolide are the liver and hematopo ietic system following repeat oral exposure; (4) the use of an oral POD for fluopicolide results in screening level occupational/residential inhalation MOEs >40,000.

Te chnical grade fluopicolide has low acute toxicity via oral, dermal and inhalation rout es of exposure. Fluopicolide is not a dermal sensitizer, primary eye irritant, or primary skin irritant.

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

The Agency considers it appropriate to reduce the Food Quality Protection Act (FQPA) safety

factor to 1 × because the toxicity database is complete , there is no evidence of quantitative susceptibility following in utero and/or postnatal exposure in the rabbit and rat developmental toxicity studies or in the 2

- generation rat reproduction study, there is low concern for the qualitative susceptibility observed in the rat developmental toxicity study because the offspring effects (reduced gr owth and skeletal defects) and late

- term abortions are well characterized and accompanied by maternal toxicity near the limit dose, and the exposure assessments are unlikely

to underestimate risk

.

4.4.1 Completeness of the Toxicology Database

The databa se is complete and adequate to characterize potential pre

- and/or post

- natal risk for infants and children. Developmental toxicity studies in rats and rabbits, and a rat reproduction study are available for FQPA assessment.

4.4.2 Evidence of Neurotoxicit y

There are acute and subchronic neurotoxicity studies available. The only neurotoxic effect was a transient lowering of body temperature in the ACN study, but this was observed at a high dose (2000 mg/kg) and not seen in the SCN study.

4.4.3 Evidenc e of Sensitivity /Susceptibility in the Developing Young Animal

T here is no evidence of quantitative susceptibility following in utero and/or postnatal exposure in the rabbit or rat developmental toxicity studies or in the 2

- generation rat reproduction stu dy

. Q ualitative susceptibility observed in the rat developmental toxicity study included offspring effects (reduced growth and skeletal defects) and late

- term abortions which were accompanied by maternal toxicity near the limit dose

.Fluopicolide Hum an Health Risk Assessment D41 6744

Page 14 of 38 4.4.4 Residual Uncer tainty in the Exposure Database

The dietary exposure assessment is based on an exaggerated exposure scenario which assumes that all commodities being consumed retain either tolerance level

- residues or highest field

residues found. The residential exposur e assessment assumes maximum label use rate as well as other conservative assumptions. Moreover, combining the residential incidental oral and dermal

exposure s c enarios is conservative. Therefore, there are no residual uncertainties in the exposure

database and exposure s to fluopicolide will not be underestimated.

Although EPA has required additional data on transferable residues from treated turf for fluopicolide, EPA is confident that it has n ot underestimated turf exposure due to the conservativeness of the default turf transfer value and conservative assumptions in the short

- term turf assessment procedures (e.g., assuming residues do not degrade over the thirty day assessment period and assum ing high

- end activities on turf for every day of the assessment period). The additional data on transferable turf residues have been required in case refinement of exposure assessments is needed in the future and to further EPA’s general understanding of the availability of turf transferable pesticide residues.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose

- Response Assessment

Details of the studies used for selecting toxicity endpoints and points of departure are presented

in A ppen dix A of this assessment.

An acute dietary assessment was not conducted because an endpoint attributable to a single dose has not been identified for fluopicolide. For chronic dietary, incidental oral, dermal and inhalation exposures, t he toxicity endpoints and doses for risk assessment were selected f rom t he rabbit developmental and rat chronic/carcinogenicity studies which were considered co

- critical for endpoint selection. The toxicological profile for fluopicolide suggests that incr eased durations of exposure does not significantly increase the severity of observed effects. The rabbit developmental stud y w as therefore considered for all exposure scenarios , and was considered co

critical with the rat chronic/oncogenicity study for al l scenarios except the incidental oral

scenarios

.

For the rabbit developmental study, the maternal LOAEL was 60 mg/kg/day b ased on death, abortions/premature deliveries (late

- term), decreased food consumption, and decreased body weight gain. The mate rnal NOAEL was 20 mg/kg/day. In the combined chronic toxicity/carcinogenicity study in rats the LOAEL was 109 mg/kg/day based on decreased body weight gain and increased thyroid weight and increased incidence of thyroid lesions with a NOAEL of 31.5 mg/kg/ day. The NOAEL/LOAEL from the rabbit developmental study was used for the point of departure since it is protective of effects observed from similar dosing of the chronic/carcinogenicity rat study.

4.5.2 Recommendation for Combining Routes of Exposures for Risk AssessmentFluopicolide Hum an Health Risk Assessment D41 6744

Page 15 of 38 HED combines risk values resulting from separate routes of exposure when it is likely they can occur simultaneously based on the use pattern and the behavior associated with the exposed population, and if the hazard associated with th e points of departure is similar across routes.

Since dermal , inhalation and incidental oral exposure routes share a common toxicological endpoint for fluopicolide, risk estimates have been combined for those routes.

4.5.3 Cancer Classification and Risk Assessment Recommendation

In accordance with the EPA’s Final Guidelines for Carcinogen Risk Assessment (March

, 2005), the CARC classified Fluopicolide as “Not Likely to be Carcinogenic to Humans” based on convincing evidence that a non

- genotoxic, mitoge nic mode of action for liver tumors was established in the mouse and that the carcinogenic effects were not likely at doses that do not cause perturbations of the liver. Since all risk assessment points of departure were established at dose levels which pr otect for any liver toxicity, people will not be exposed above these levels, and regulating at these levels will protect for any potential carcinogenic effects.

There was no evidence of carcinogenicity in rats

.Fluopicolide Hum an Health Risk Assessment D41 6744

Page 16 of 38 4. 5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk

Assessment

Table 4

. 5

. 4.1. Summary of Toxicological Doses and Endpoints for Fluopicolide for Use in Dietary and Occupational Human Health Risk Assessments
Exposure/

Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors RfD, PAD, Level

of Concern for

Risk Assessment Study and Toxicological Effects

Acute Dietary (all populations) An endpoint attributable to a single dose was not identified from the available data.

Chronic Dietary (all populations) Maternal

NOAEL=20 mg/kg/day UF A =10x

UF H =10x FQPA SF =

1X Chronic RfD =

0.2 mg/kg/day

cPAD = 0.2 mg/kg/day Developmental Toxicity Study in Rabbits

LOAEL (maternal) = 60 mg/kg/day based on death, abortions/ prematu re deliveries, decreased food consumption and body weight gain.

Co

- critical: Chronic/Oncogenicity Study in

Rats NOAEL = 31.5 mg/kg/day. LOAEL = 109.4 mg/kg/day based on decreased body weight gain and increased thyroid weight

and increased incidence of t hyroid lesions.

Incidental Oral Short (1

- 30 days)

and Intermediate

Term s (1

- 6 months) Maternal

NOAEL =

20 mg/kg/day UF A =10x

UF H =10x FQPA SF =

1X MOE = 100

(occupational)

MOE = 100 (residential) Developmental Toxicity Study in Rabbits

LOAEL (maternal) = 60 mg/kg/day based on death, abortions/ premature deliveries, decreased food consumption and body weight gain.

Dermal Short

Intermediate

- and Long

- Term (1

- 30 days, 1

- 6 months, and >6 months) Maternal

NOAEL =

20 mg/kg/day UF A =10x

UF H =10x FQPA SF =

1X

37% dermal absorption MOE = 100

(occupational)

MOE = 100 (residential) Developmental Toxicity Study in Rabbits

LOAEL (maternal) = 60 mg/kg/day based on death, abortions/ premature deliveries, decreased food consumption and body wei ght gain.

Co

- critical: Chronic/Oncogenicity Study in

Rats NOAEL = 31.5 mg/kg/day. LOAEL = 109.4 mg/kg/day based on decreased body weight gain and increased thyroid weight and increased incidence of thyroid lesions.

Inhalation Short

Intermediate

- and Long

- term (1

- 30 days, 1

- 6 months, and >6 months) Maternal

NOAEL =

20 mg/kg/day UF A =10x

UF H =10x FQPA SF =

1X (inhalation

and oral toxicity are

assumed to be equivalent) MOE = 100

(occupational)

MOE = 100 (residential) Developmental Toxicity Study in Rabbits

LOAEL (maternal) = 60 mg/kg/day based on death, abortions/ premature deliveries, decreased food consumption and body weight gain.

Co

- critical: Chronic/Oncogenicity Study in

Rats NOAEL = 31.5 mg/kg/day. LOAEL = 109.4 mg/kg/day based on decreased body weight gain and increased thyroid weight and increased incidence of thyroid lesions.
Cancer (oral, dermal, inhalation) Classification: “Not Likely to be Carcinogenic to Humans”

.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL

= no obs erved adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.Fluopicolide Hum an Health Risk Assessment D41 6744

Page 17 of 3 8 5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Pr ofile

5.1.1 Summary of Plant and Animal Metabolism Studies

Based on acceptable plant metabolism studies, the qualitative nature of the residue in primary plants is adequately understood. In rotation al crop s data demonstrate the potential for quantifiable residues of fluopicolide and its metabolites at a 12 month PBI. The tolerance expression for rotational crops is fluopicolide (parent) only. The residues of concern for the risk assessment for cereal grains as rotational crops are fluopicolide (parent), B AM, PCA, and P1 x in grain for human food, and fluopicolide (parent) and BAM in forage/hay/straw and grain for

livestock feed. In ruminant and poultry metabolism studies, the nature of the residue in livestock is adequately understood.

5.1.2 Summary of Env ironmental Degradation

The Agency has determined, based on two aerobic soil metabolism studies, that the residues of concern in drinking water are parent fluopicolide and the degradate BAM (Fluopicolide Risk Assessment Team, 4/12/07).

5.1.3 Comparison of Metabolic Pathways

The metabolism of fluopicolide in rotational crops appeared to be more extensive than that observed in primary crops (grapes, lettuce, and potato). Four rotational crop metabolites, 3

- OH

BAM, P1x, AE C653598, and AE B102859, were n ot observed in the primary crop metabolism studies, but were found in the rotated crops. The metabolism of fluopicolide is qualitatively similar in primary plants. In ruminants and poultry, the metabolism proceeds in a similar fashion as in plants. In rat

, fluopicolide was readily absorbed and rapidly excreted in the urine and feces.

The major metabolites identified in rat were the same as the plant metabolites BAM, 3

- OH BAM, PCA and P1x indicating that the toxicity of the metabolites consumed by humans i n foods

were evaluated.

5.1.4 Residues of Concern Summary and Rationale

A summary of the fluopicolide residues of concern is shown in Table 5.1.4. 1Fluopicolide Hum an Health Risk Assessment D41 6744

Page 18 of 38 Table 5.1.4.1 . Summary of Fluopicolide Residues of Concern

.

Matrix Residues included in

Risk Assessment Residues included in Tolerance Expression

Plants Primary Crops

All primar y crops except Tuberous and Corm Vegetables Fluopicolide (parent) and

BAM Fluopicolide

Tuberous and Corm Vegetables Fluopicolide (parent), PCA, and BAM

Rotational Crops

All rotational crops except cereal grains Fluopicolide (parent) and

BAM

Fluopicolide Cereal grains

- grain for

human food Fluopicolide (parent), PCA, P1X and BAM

Cereal grains

- forage/hay/straw and grain for livestock feed Fluopicolide (parent) and

BAM

Livestock Fluopicolide (parent) and

BAM Fluopicolide

Drinking Water Fluopicolide (parent) and

BAM Not applicable

5 .2 Food Residue Profile

Adequate data were submitted for tolerance and risk assessments. The residue of concern for tolerance enforcement is fluopicolide per se . Concentration upon processing was not significant; therefore, the tolerance for field corn grain will cover residues in processed commodities. The residues of concern for risk assessment are fluopicolide, BAM, PCA and P1x. Field corn processed commodities may be used for human consumption. The dietary risk assessment for fluopicolide includ ed residues of PCA and P1x. BAM dietary risks were not quantified as part

of this assessment because the contribution of BAM from the use of fluopicolide is negligible compared to its contribution from the use of dichlobenil, another active ingredient sharing the

same metabolite BAM . Residues of fluopicolide, PCA and P1x in the raw agricultural commodities (corn grain) were all below the limit of detection (LOQ), Tolerances are not needed for the processed commodities because residues of fluopicolide in grain in all the crop

field trials at the 1 × and 5× exaggerated rate s were below LOQ (<0.01 ppm). The Agency previously concluded that the presence of r esidues of fluopicolide and BAM in milk, beef fat, kidney and liver are not likely. However, it is possible that quantifiable r esidues of BAM may

be found in beef liver. In poultry, the Agency also concluded that residues are not likely to be present in poultry commodities as a result of feeding feedstuffs containing residues of fluopicolide and BAM. The livestock dietary burden was unaffected by the new recommended

tolerances on field corn forage, stover and grain

.Fluopicolide Hum an Health Risk Assessment D41 6744

Page 19 of 38 5.3 Water Residue Profile “Tier II Drinking Water Exposure Assessment for Fluopicolide and its Major Degradate, 2,6

- Dichlorbenzamide (BAM) for Use on Potatoes, Carro ts, Sugar Beets and Brassica (Cole) Leafy Vegetables ” ( R. Miller, D370764,

6/20/10 )

The Agency conducted a drinking wa t er assessment (R. Miller, D370764, 6/20/10) using PRZM

version 3.12/ EXAMS version 2.98 models and estimated the concentration of fluopicolide in

surface water to be 0.02414 ppm for chronic (non cancer) exposure. For the new use of fluopicolide on rotational corn, EFED has indicated that a new drinking water assessment (DWA) was not needed (Email communication with Michael Lowit, EFED 3/19/2013).

5.4 Dietary Risk Assessment

D407936, A. Kamel, 4/8/ 2013 “ Fluopicolide

. Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section 3 Tolerances on Rotational Corn. ”

A chronic aggregate dietary (food and drinking water) exposure and risk assessment w as conducted for fluopicolide using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID) Version 3.16 . This software uses 200 3

- 2008 food consumption data from the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). The analysis

was conducted to support Section 3 request for new tolerances for fluopi colide on rotational field

corn

.

5.4.1 Chronic Dietary (Food and Drinking Water) Exposure Results and Characterization

Chronic dietary risk estimate s for the U.S Population and all population subgroups are not of concern. The established and proposed uses of fluopicolide result in an estimated exposure to the U.S. Population equivalent to 7. 6 % of the chronic population adjusted dose (cPAD). The highest exposed subgroup is children 1

– 2 years of age with an estimated exposure equivalent to

1 2 % of the cPAD. This assessment is considered highly conservative as tolerance level residues

, 100% crop treated assumptions , and empirical or default processed fractions were used with the exception of tuberous and corm vegetables (subgroup 1C), and rotational wheat commodities,

where the maximum residues from the field trial data were used

. . Table 5.4.1.1 lists the chronic dietary exposure and risk estimates for fluopicolide.

Acute dietary exposure and cancer risk assessments were not conducted because an end point attributable to a single dose has not been identified for fluopicolide and that it is not a possible carcinogen.Fluopicolide Hum an Health Risk Assessment D41 6744

Page 20 of 38 Table 5 .4.1.1. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Fluopicolide.

Population Subgroup Acute Dietary Chronic Dietary Cancer

Dietary Exposure (mg/kg/day) % aPAD* Dietary Exposure (mg/kg/day) % cPAD* Dietary Exposure (mg/kg/day) Risk

General U.S. Population

N/A N/A 0.015176 7.6

N/A N/A All Infants (<1 year old) 0.010336 5.2

Children 1

- 2 years old 0.024340 12

Children 3

- 5 years old 0.022836 11

Children 6

- 12 years old 0.014425 7.2

Youth 13

- 19 years old 0.011252 5.6

Adults 20

- 49 years old 0.014965 7.5

Adults 50

- 99 years old 0.015368 7.7

Females 13

- 49 years old 0.015252 7.6
*The subpopulation with the highest risk estimate is bolded.

N/A = not available

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no proposed residential uses associated with this petition; however, there are existing residential uses that have been reassessed in this document to reflect updates to HED’s 2012

Residential SOPs 2 along with policy changes for body weight assumptions. The revision of residential exposures will impact the human health aggregate risk assessment for fluopicolide. There are products with uses on residential turfgrass and recreational sites. The prod ucts may be applied to turf at rates up to 0.27 lb ai/A, for two applications at an interval of 14 days. There are also uses on ornamental plants and trees with application rates up to 0.54 lb ai/A

. Since the proposed change in use pattern do es not add s ignificantly to the BAM dietary exposure , and there are no new residential uses, the conclusions from the most recently conducted BAM human health risk assessment remain unchanged and a revised quantitative BAM risk assessment is not required

– aggregate r isks for BAM are not of concern

.

6.1 Residential Handler Exposure

HED believes that there are distinct tasks related to applications and that exposures can vary depending on the specifics of each task. Residential handlers are addressed somewhat differe ntly by HED as homeowners who are assumed to complete all elements of an application without use of any protective equipment. It is possible for residential handlers to apply these products; therefore, residential handlers may receive short

- term dermal an d inhalation exposure to fluopicolide when applying the product. The quantitative exposure/risk assessment developed for residential handlers is based on application of liquid formulation to turf/lawns and gardens/trees using handheld equipment. A series of assumptions and exposure factors served as the basis for completing the residential handler risk assessments. Residential handler exposure is expected to

2 Available: http://www.ep a.gov/pesticides/science/residential

- exposure

- sop.htmlFluopicolide Hum an Health Risk Assessment D41 6744

Page 21 of 38 be short

- term in duration. Intermediate

- term exposures are not likely because of the intermittent nature of applications by homeowners. Dermal and inhalation risk estimates were combined in this assessment, since the toxicological effects for these exposure routes were identical (the same studies / endpoints / PODs were used to quantify risks)

.

All residential handler non

- cancer risk estimates are not of concern (i.e., MOEs are > 100). Combined dermal and inhalation MOEs for residential handlers range from 1,900 (handler applying liquid to lawns and trees with backpack sprayer) to 45,000 (handlers a pplying liquid to lawns with sprinkler can). The results of combined short

- term residential handler exposure and risk estimates for fluopicolide are shown in Table 6.1.1Fluopicolide Hum an Health Risk Assessment D41 6744

Page 22 of 38 Table 6.1.1. Residential Handler Non

- cancer (Short

- Term) Exposure and Risk Estimates for Fluopicolide.

Exposure Scenario Level of

Concern Dermal Unit

Exposure (mg/lb ai) Inhalation Unit

Exposure (mg/lb ai) Maximum

Application

Rate 1 Area Treated

or Amount Handled Daily 2 Dermal Inhalation Total

Dose (mg/kg/day) 3 MOE 4 Dose

(mg/kg/day) 5 MOE 6 MOE 7

Mixer/Loader/Applicator

Gardens/Trees, Liquid, Manually

pressurized handwand

100 63 0.018 0.0025 lb ai/gallon 5 gallons 0.0042 4,700 0.0000033 6,100,000 4,700

Lawns/Tur f, Liquid, Manually

pressurized handwand 0.003 lb ai/gallon 5 gallons 0.0051 3900 0.0000039 5,100,000 3,900

Gardens/Trees, Liquid, Manually

pressurized handwand 0.0000125 lb

ai/ft 2 1200 ft 2 0.0051 3,900 0.0000039 5,100,000 3,900

Gardens/T rees, Liquid, Hose

- end Sprayer/Sprinkler Can

58 0.0014 0.0000125 lb

ai/ft 2 1200 ft 2 0.0047 4,300 0.0000003 66,000,000 4,300

Gardens/T rees, Liquid, Hose

- end

Sprayer 0.0025 lb ai/gallon 11 gallons 0.0086 2,300 0.00000056 36,000,000 2,300

Gardens/Trees, Liquid, Sprinkler

Can 0.0025 lb ai/gallon 5 gallons 0.0039 5,100 0.00000025 79,000,000 5,100

Lawns/Tur f, Liquid, Hose

- end

Sprayer 13.4 0.022 0.27 lb

ai/acre 0.5 acres 0.0097 2,100 0.000043 460,000 2,100

Lawns/Turf, Liquid, Sprinkler

Can 0.0000062 lb

ai/ft 2 1000 ft 2 0.00045 45,000 0.000002 10,000,000 45,000

Gardens/Trees, Liquid, Backpack

130 0.14 0.0000125 lb

ai/ft 2 1200 ft 2 0.01 1,900 0.00003 660,000 1,900

Gardens/Trees, Liquid, Backpack 0.0025 lb ai/gallon 5 gallons 0.0087 2,300 0.000025 790,000 2,300

Lawns/Tur f, Liquid, Backpack 0.003 lb ai/gallon 5 gallons 0.01 1,900 0.00003 660,000 1,900

1 Based on registered labels. Application rate for turf is 0.27 lb ai/acre, or 0.0000062 lb ai/ft 2 . The label states that a volume of 2 gallons treats 1000 sq. ft, which is equiv alent to 87 gallons per acre. Therefore, the turf rate is 0.003 lb ai/gallon. Application rate for ornamental plants is 0.54 lb ai/a cre, which is equivalent to 0.0000125 lb ai/ft 2 . The label states that 100 gallons treats 20,000 sq ft, which is equivale nt to 218 gallons per acre. Therefore, the ornamental plant rate is 0.0025 lb ai/gallon.

2 Based on HED’s 2012 Residential SOPs ( http://www.epa.gov/pesticides/science/reside ntial

- exposure

- sop.html ).

3 Dermal Dose = Dermal Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A/day or gallons/day) × Dermal Absorption Factor (%) ÷ Body Weight (kg).

4 Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day).

5 Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A/day or gallons/day) ÷ Body Weight (kg).

6 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

7 Total MOE = NOAEL (mg/kg/day) ÷ (Dermal Dose + Inhalation Dose)Fluopicolide Hum an Health Risk Assessment D41 6744

Page 23 of 38 6.2 Post

- Application Exposure

There is the potential for short

- term post

- application exposure to fluopicolide for individuals

expose d as a result of being in an environment that has been previously treated with fluopicolide.

T here is also a potential for exposure to BAM during post

- application activities on fluopicolide

treated turf and plants ; however, foliar residues and therefore e xposures to BAM are expected to be insignificant and were therefore not included in this risk assessment. The quantitative exposure/risk assessment for residential post

- application exposures includes the following

scenarios:

Adults and children (1 to < 2 years old) dermal exposure to treated turf during high

contact lawn activities. Children (1 to < 2 years old) incidental oral exposure to treated turf. Adult and children (11 to < 16 years old) dermal exposure to treated turf during mowing and golfing a ctivities. Children (6 to < 11 years old) dermal exposure to treated turf during golfing activities. Adult and children (6 to < 11 years old) dermal exposure to treated gardens.

The exposure assessment for dermal exposure to treated gardens is protective of exposure to treated ornamental trees. The lifestages selected for each post

- application scenario are based on an analysis provided as an Appendix in the 2012 Residential SOPs. These lifestages are not the only lifestages that could be potentially expo sed for these post

- application scenarios; however, the assessment of these lifestages is health protective for the exposures and risk estimates for any other potentially exposed lifestages.

A series of assumptions and exposure factors served as the basis for completing the residential
post

- application risk assessment. Each assumption and factor is detailed in the 2012 Residential SOPs. Because turf transferable residue (TTR) data were not available fluopicolide, turf residues were estimated using default assumptions. A dislodgeable foliar residue (DFR) study for fluopicolide use on leaf lettuce was submitted (MRID 46708641) and reviewed by the Agency for use in assessing post

- application activities. The target application rate for each application

was 0.119 lb ai/A; 3 applications were completed at an approximate re

- treatment interval of 5 days. The total target application was 0.3575 lb ai/A. A linear regression analysis was conducted using the natural logarithm of the individual DFR values. The maxi mum predicted day 0 residue from the DFR study is 0.36 μg/cm 2 . For risk assessment purposes, this residue value is scaled from the study application rate of 0.12 lb ai/acre to the maximum registered application rate on ornamental trees of 0.54 lb ae/acre; the residue value for risk assessment is 1.62 μg/cm 2 on day 0.

HED combines risk values resulting from separate routes of exposure when it is likely they can occur simultaneously based on the use pattern and the behavior associated with the exposed popul ation, and if the hazard associated with the points of departure is similar across routes. Since dermal and incidental oral exposure routes share a common toxicological endpoint for fluopicolide, risk estimates have been combined for those routes. The i ncidental oral scenarios (i.e., hand

- to

- mouth and object

- to

- mouth) should be considered inter

- related and it is likely that they occur interspersed amongst each other across time. Combining all of these scenarios with the dermal exposure scenario would be overly

- conservative because of the conservative nature ofFluopicolide Hum an Health Risk Assessment D41 6744

Page 24 of 38 each individual assessment. Therefore, for fluopicolide, the post

- application exposure scenarios that were combined for children 1 < 2 years old are the dermal and hand

- to

- mouth scenarios.

This c ombination is a protective estimate of children’s exposure to pesticides used on turf. All residential post

- application risk estimates for fluopicolide were found to be “not of concern” (MOEs > LOCs) for all exposure scenarios and all lifestages. Table 6. 2.1 summarizes the residential post application exposure and risk estimates for fluopicolide.

Table 6.2.1. Residential Post

- application Non

- cancer (Short

- Term) Exposure and Risk Estimates for Fluopicolide.

Lifestage Post

- application Exposure

Scenario Application

Rate 1 Dose

(mg/kg/day) 2 MOEs 3 Combined Routes
(X indicates included in Combined MOE) Combined MOEs

Use Site Route of Exposure

Adult Turf Dermal

– High

Contact

0.27 lb

ai/acre for turf, 0.54 lb

ai/acre for garden/trees 0.043 460

N/A N/A Garden Dermal 0.161 120

Turf Dermal

- Mowing 0.00089 23,000

Dermal

- Golfing 0.0034 5,900

11 to < 16 year

old Dermal

- Mowing 0.00088 23,000

Dermal

- Golfing 0.0034 5,800

6 to < 11 year

old Dermal

- Golfing 0.0040 5,000

Garden Dermal 0.095 210

1 to < 2 year

old Turf Dermal 0.074 270 X 260 Hand

- to

- Mouth 0.0041 4,900 X
Object

- to

- Mouth 0.00012 160,000

N/A N/A Incidental Soil Ingestion 9.1E

- 06 2,200,000

1 Based on registered label.

2 Dose (mg/kg/day) equations can be found in Appendix A.

3 MOE = POD (mg/kg/day) ÷ Dose (mg/kg/day).

4 Combined MOE = 1 ÷ (1/dermal MOE) + (1/inhalation MOE) + (1/incidental oral MOE), where applicable.

6.3 Combined Residential Risk Estimates (Multiple Exposure Scenarios)

Residential handler and post

- application scenarios should generally not be combined. Although there is potential for the same individual (i.e., adult) to apply a pesticide in and around the home and be exposed by reentering a treated area in the same day this is unlikely to occur day after day for 30 days. Combining both of these exposure scenarios would also be inappropriate because of

the unrealistically conservative nature of each individual assessment.

B ecause of the conservative nature of the individual turf and ornamental plants/trees assessments, these scenarios were not combined.

6.4 Residential Risk Estimates for Use in Aggregate Assessment

Table 6.4.1 reflects the residential risk estimates for use in the aggregate assessment for fluopic olide , which represent the highest exposure and highest risk scenarios for the fluopicolide

residential uses.Fluopicolide Hum an Health Risk Assessment D41 6744

Page 25 of 38 The recommended residential exposure for use in the adult aggregate assessment reflects dermal post

- application exposure to treated gardens.

The recommended residential exposure for use in the children (11 to < 16 years old) aggregate assessment reflects dermal post

- application exposure from golfing. The recommended residential exposure for use in the children (6 to < 11 years old)
aggregate assess ment reflected dermal post

- application exposure to treated gardens. The recommended residential exposure for use in the children (1 to <2 years old) aggregate assessment reflects dermal and hand

- to

- mouth exposures from post

- application turf scenario (i.e., post

- application exposure to treated turf).Fluopicolide Hum an Health Risk Assessment D41 6744

Page 26 of 38 Table 6 .4.1. Residential Exposures for the Fluopicolide Aggregate Assessment. 1

Lifestage Residential Handler Residential Post

- application

Dose (mg/kg/day) 2 MOE 3 Dose (mg/kg/day) 4 MOE 5

Dermal Inhalation Total Dermal Inhalation Total Dermal Inhalation Oral Total Dermal Inhalation Oral Total

Short

- Term

Adult 0.01 0.00003 0.010

- - 1,900 0.161 N/A N/A 0.161 120 N/A N/A 120 Child (11 to < 16 years old)

N/A 0.0034 N/A N/A 0.0034 5,800 N/A N/A 5,800

Child (6 to < 11 years old) 0.095 N/A N/A 0.095 210 N/A N/A 210

Child (1 to < 2 years old) 0.074 N/A 0.0041 0.078 270 N/A 4,900 260

1 Bolded risk estimates should contribute to the residential exposure portion of the aggregate assessment.

2 Residential Handler Dose = the highest handler dose for each applicable lifestage of all scenarios assessed. Total = dermal + inhalation.

3 Residen tial Handler MOE = the MOEs associated with the highest doses identified. Total = 1 ÷ (1/Dermal MOE) + (1/Inhalation MOE).

4 Residential Post

- application Dose = the highest post

- application dose for each applicable lifestage of all scenarios assessed. To tal = dermal + inhalation + incidental oral, where applicable.

5 Residential Post

- application MOE = the MOEs associated with the highest doses identified. Total = 1 ÷ (1/Dermal MOE) + (1/Inhalation MOE) + ( 1/Incidental oral MOE).Fluopicolide Human Health Risk Assessment D 416744

Page 27 of 38 6.5 Residential Bystander Post

- application Inhalation Exposure

Although there are no agricultural applications associated with this action, there are registered uses of fluopicolide on agricultural crops.

Based on the Agency's current practices, a quantita tive post

- application inhalation exposure assessment was not performed for fluopicolide at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV) and low vapor pressure (6 x 10 - 9 mm Hg at 25° C). However, volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rode nticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 Available at: http://www.epa.gov/scipoly/sap/meetings/2009/120 109meeting.html . The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

- application inhalation exposure into the Agency's r isk assessments. If new policies or procedures are developed, the Agency may revisit the need for a quantitative post

- application inhalation exposure assessment for fluopicolide.

Although a quantitative residential post

- application inhalation exposure as sessment was not performed, an inhalation exposure assessment was performed for handlers. This exposure scenario is representative of a wors t case inhalation exposure and should be considered protective of post

- application inhalation exposure scenarios fo r fluopicolide

.

6.6 Spray Drift

Although there are no agricultural applications associated with this action, there are registered uses of fluopicolide on agricultural crops. Spray drift is always a potential source of exposure to residents nearby to sp raying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for fluopicolide. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information (Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm ). The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further

refinements i n spray drift management practices to reduce off

- target drift with specific products with significant risk estimates associated with drift. It is noted that the 0.27 lb ai/acre application rate for turf was modeled to estimate post

application residential exposure of children. As this rate is equal to or higher than many of agricultural application rates, this scenario is protective of any exposure of children via spray drift from agricultural fluopicolide applications.Fluopicolide Human Health Risk Assessment D 416744

Page 28 of 38 7.0 Aggregate Exposure/Risk Characteriza tion

In accordance with the FQPA, HED must aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks fr om various sources, HED considers both the route and duration of exposure. Fluopicolide is registered f or use in residential settings as well as for use on food; therefore, an aggregate risk was conducted which combined average food residues with

non

- occupational estimates of exposure.

7.1 Acute Aggregate Risk

An acute aggregate assessment was not conducted because an endpoint attributable to a single dose was not identified from the available data for fluopicolide.

7.2 Short

- Term Aggregate Risk

Short

- term aggregate assessments include exposures that will occur from one to thirty days and

include the most protective short

- term residential exposure scenarios along with chronic food and water exposures

. The exposure scenario used for adults and children was post

- application exposure to treated gardens. Table 7.2 .1 presents the most conservative scenario for aggregate

food and water as well as short

- term residential risk calculations

. The short

- term aggregate risk

estimates were not of concern for adults or children.

Table 7.2 .1 Short

- Term Aggregate Risk Calculations

Population Short

- Term Scenario

NOAEL mg/kg/d

ay LOC 1 Max

Allowable Exposure 2
mg/kg/day Average

Food and

Water Exposure mg/kg/day Residential

Exposure mg/kg/day 3 Total

Exposure mg/kg/day 4 Aggregate

MOE (food, water, and residential) 5

Adult Male

20 100 0.2 0.015368 0.161 0.176368 110

Adult Female 0.015252 0.161 0.176252 110

Child (6

- < 11yr) 6 0.014425 0.095 0.109425 183

1 For LOC calculation a 10 × standard inter

- species, 10 × intra

- species and 1 × FPQA uncertainty factors are

included.

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure]. Values from Table 6 .4.1

4 Total Exposure = Avg Food & Water Exposure + Residential Exposure)

5 (Avg Food & Water Exposure + Residential Exposure)]

6 This age group represents the m ost conservative exposure residential scenario among children . The average food and water exposure daily dose was selected for the corresponding age group (6

- 12 yr.) from Table 5.4.1.1.

7.3 Intermediate

- Term Aggregate Risk

Intermediate

- term exposures are not likely because of the intermittent nature of applications by

homeowners.Fluopicolide Human Health Risk Assessment D 416744

Page 29 of 38 7.4 Chronic Aggregate Risk

Chronic or long

- term aggregate assessments include exposures that will exceed six months.

Since there are no chronic non

- occupational (residential) exposures, the chornic aggregate assessment includes food and drinking water only. Refer to section 5.4. 1 for a detailed discussion of the chronic dietary assessment.

7.5 Cancer Aggregate Risk

HED has considered fluopicolide to be classified as “not likely to be carcinogenic to humans” ; no quantification of cancer risks is required.

8.0 Cumulative Exposure/Ri sk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as

to fluopicolide and any other substances

. Although fluop icolide shares a common metabolite, BAM, with dichlobenil, quantification of risks for residues of BAM resulting from fluopicolide was not done as part of this assessment since they contribute an insignificant amount to the total BAM exposure. Furthermore, aggregate risks to BAM are not of concern. For the purposes of this tolerance action, EPA has not assumed that fluopicolide has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which

chemicals hav e a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substa nces found to have a common mechanism on EPA’s website at : http://www.epa.gov/pesticides/cumulative /.

9.0 Occupational Exposure/Risk Characterization

There are no agricultural or occupational applicatio ns associated with this action. Therefore, there is no potential occupational exposure associated with the proposed change in use pattern.

10.0 References

Residue Chemistry Summary (A. Kamel, 4/17 /2013, D410652) Dietary Exposure Assessment (A. Kamel, 4/8/2013, D407936) Occupational/Residential Exposure Assessment (A. LaMay, 4/2/2013, D040413) Human Health Risk Assessment (D. Davis, 12/09/2010, D384431) and references therein.Fluopicolide Human Health Risk Assessment D 416744

Page 30 of 38 Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ .................. 870.1300 Acute Inhalation Toxicity

................................ .............. 870.2400 Primary Eye Irritation

................................ .................... 870.2500 Primary Dermal Irritation

................................ .............. 870.2600 Dermal Sensitization

................................ ...................... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

................................ ............... 870.3150 Oral Subchronic (nonrodent)

................................ ......... 870.3200 21

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 90

- Day Inhalation

................................ .......................... yes

yes

yes

yes

yes yes

yes

yes

yes

yes

870.3700a Developmental Toxicity (rodent)

................................ ... 870.3700b Developmental Toxicity (nonrodent)

............................. 870.3800 Reproduction

................................ ................................ . yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

................................ .............. 870.4100b Chronic Toxicity (nonrodent)

................................ ........ 870.4200a Oncogenicity (rat)

................................ .......................... 870.4200b Oncogenicity (mouse)

................................ .................... 870.4300 Chronic/Oncogenicity

................................ .................... yes

yes

yes

yes

yes yes

yes

yes

yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

..................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

................ 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations

... 870.5xxx Mutagenicity

— Other Genotoxic Effects

....................... yes

yes

yes

yes yes

yes

yes

yes 870.6100a Acute Delayed Neurotoxicity (hen)

............................... 870.6100b 90

- Day Neurotoxicity (hen)

................................ ........... 870.6200a Acute Neurotoxicity Screening Battery (rat)

................. 870.6200b 90

- Day Neurotoxicity Screening Battery (rat)

............... 870.6300 Develop. Neurotoxicity

................................ ................. no

no

yes

yes

no -

-

yes

yes

-

870.7485 General Metabolism

................................ ...................... 870.7600 Dermal Penetration

................................ ........................ 870.7800 Immunotoxicity

................................ ............................. yes

yes

yes yes

yes

yesFluopicolide Human Health Risk Assessment D 416744

Page 31 of 38 A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile

- Test Substance

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [rat] Fluopicolide

Technical 98.3% (AE C638206) Formulation SC 40 (AE C638206) Formulation SC61 (AE B066752) 46708601

46709903

46709803 LD50≥ 2000 mg/kg (f)

LD50 ≥ 2000 mg/kg (m/f) LD50 ≥ 2000 mg/kg (m/f) III

III

III

870.1200 Acute dermal [rat]

Technical 97.7% (AE C638206) Formulation SC40 (AE C638206) Formulation SC61 (AE B066752) 46708605

46709904

46709804 LD50 ≥ 5000 mg/kg

LD50 ≥ 4000 mg/kg LD50 ≥4000 mg/kg IV

III

III

870.1300 Acute inhalation [rat]

Technical (AE C638206) Formulation SC40 (AE C638206) Formulation SC61 (AE B066752) 46708606

46709905

46709805 LC50 ≥ 5.16 mg/L

LC50 ≥ 1.789 mg/L LC50 ≥ 3.195 mg/L IV

III

IV

870.2400 Acute eye irritation [rabbit]

Technical 97.7% (AE C638206) Formulation SC40 (AE C638206) Formulation SC61 (AE B066752) 46708607

46709906

46709806 slight conjuctival irritation

chemosis/corneal opacity in

both studies IV

III

III

870.2500 Acute dermal irritation [rabbit]

Technical 97.7% (AE C638206) Formulation SC40 (AE C638206) Formulation SC61 (AE B066752) 46708650

46709907

46709807 None (PDII = 0.00)

slight (PDII = 0.08) slight (PDII = 0.25) IV

IV

IV

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3050 28

- day dietary

toxicity (mouse) 46708609 (2000)

Acceptable/Guideline M/F: 0/0, 0.95/1.19, 10.4/12.9, 100/129, 980/1242 mg/kg/day NOAEL = 980/1242 mg/kg/day; the limit dose).

The LOAEL was not observed.

870.3050 28

- day dietary

toxicity (rat) 46708610 (2000)

Acceptable/Guideline M/F: 0/0, 1.8/1.8, 17.4/17.9, 174/184, and 1720/1820 mg/kg/day NOAEL = 17.4/17.9 mg/kg/day in males/females). The LOAEL = 174/184 mg/kg/day (M/F) based on decreased body weight gain and food conversion in

females an d nephrotoxicity in males.

870.3050 28

- day dietary

toxicity (rat)

AE 1344122 (Fluopicolide metabolite) 46708611 (2003)

Acceptable/Guideline M/F: 0/0, 1.5/1.7, 14.9/16.8, 151.6/167.1, 1495.3/1615.5 mg/kg/day NOAEL = 151.6/167.1 mg/kg/day. LOAEL = 1495.3/1615.5 mg/kg/day based on decreased body weights and body weight gains in both sexes, and nephrotoxicity in females.

870.3050 28

- day dietary

toxicity (rat) AE C657378 (a Fluopicolide metabolite) 46708612 (2003)

Acceptable/Guideline

M/ F: 0/0, 1.6/2.1, 16.2/20.4, 159.2/230.6,

and 1775.0/1930.8 mg/kg/day NOAEL = 159.2/230.6 mg/kg/day.

LOAEL = 1775.0/1930.8 mg/kg/day based on decreases in body weight and body weight gain (males); increased absolute (females) and relative liver weight (bo th sexes) and relative kidney weight (males); increased cholesterol (both sexes); and histopathological effects in the liver (females), theFluopicolide Human Health Risk Assessment D 416744

Page 32 of 38 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

kidneys (males), and thyroid (both sexes).

870.3050 28

- day oral

toxicity (dog) 46708613 (2000)

Acceptable/Non

- guideline 0, 10, 100, 1000 mg/kg/day NOAEL = 1000 mg/kg/day (limit dose).

LOAEL was not observed.

870.3100 90

- Day oral

toxicity (rat) 46474112 (2000)

Acceptable/guideline M: 0, 7.4, 109, 1668 mg/kg/d F: 0, 8.4, 119, 1673 mg/kg/day NOAEL = 109 mg/kg/day for males; 8.4 mg/kg/day

for females LOAEL = 1668 mg/kg/day for males and 119 mg/kg/day for females based on hypertrophy of the zona glomerulosa in the adrenal gland (M/F), decreased cellularity of the bone marrow (M/F), and

trabecu lar hyperostosis of the bone joint (M)

870.3100 90

- Day oral

toxicity (mouse) 46474114 (2000)

Acceptable/guideline M/F: 0, 5.5, 53, 545 or 1092 mg/kg/day NOAEL = 1092 mg/kg/day (M/F)

LOAEL = not identified

870.3100 90

- Day oral

toxicity (mouse) 46474116 (2001)

Acceptable/guideline M: 0, 10.4, 37.8, 161, 770 mg/kg/d F: 0, 12.6, 52.8, 207, 965 mg/kg/day NOAEL = 770 mg/kg/day for males; 207 mg/kg/day for females LOAEL = not identified for males; 965 mg/kg/day

for females based on increased inci dence of liver

oval cell proliferation

870.3150 90

- Day oral

toxicity (dog) 46474118 (2000)

Acceptable/guideline M&F: 0, 5, 70, 1000 mg/kg/day NOAEL = 1000 mg/kg/day (M/F) LOAEL = not identified (M/F)

870.3200 21/28

- Day dermal

toxicity (species) 46708614 (2003)

Acceptable Guideline 0, 100, 250, 500, 1000 mg/kg/day NOAEL = 1000 mg/kg/day LOAEL > 1000 mg/kg/day No local or systemic toxicity observed

870.3700a Prenatal

developmental in (rat) Pilot study 46708615 (2000)

Acceptable/non

- guideline F: 500, 1000 mg/kg/day (GD 7

- 20) NOAEL/LOAEL not determined. Only four

animals/group. Purpose of study was to determine high

- dose level for 46474120.

870.3700a Prenatal

developmental in (rat) 46474120 (2001)

Acceptable/guide line F: 0, 5, 60, 700 mg/kg/day (GD 7

- 20) Maternal NOAEL = 60 mg/kg/day

LOAEL = 700 mg/kg/day based on decreased body

weight gain Developmental NOAEL = 60 mg/kg/day LOAEL = 700 mg/kg/day based on delayed fetal growth and delayed ossification

870.3700b Prenatal

developmental in (rabbit) Pilot study 46708616 (2000)

Acceptable/non

- guideline F: 25, 50, 100, 250, 500, or 1000 mg/kg bw/day (GD 6

- 28) Maternal NOAEL = 25 mg/kg/day LOAEL = 50 mg/kg/day based on reduced

defecation and abortion i n a single dose Developmental NOAEL = 1000 mg/kg/day

LOAEL = not observed

870.3700b Prenatal

developmental in 46474122 (2001)

Acceptable/guideline Maternal NOAEL = 20 mg/kg/day LOAEL = 60 mg/kg/day based on death, late

- termFluopicolide Human Health Risk Assessment D 416744

Page 33 of 38 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

(rabbit) F: 0, 5, 20, 60 mg/kg/day

(GD 6

- 28) abortion/premature delivery, decreased food consumption and weight gain Developmental NOAEL = 20 mg/kg/day LOAEL = 60 mg/kg/day based on abortion/premature delivery, decreased fetal body weight and crown

- rum p length

870.3800 Reproduction and

fertility effects (rat) 46474124 (2003)

46474125 (additional data, 2004) 46474126 (range

- finding,

2002) Acceptable/guideline M: 0, 7.4, 36.4, 144.6 mg/kg/d F: 0, 8.1, 41.0, 159.7 mg/kg/day Parental/Systemic NOAEL = 36.4/41.0 mg/kg/day (M/F) LOAEL = 144.6/159.7 mg/kg/day (M/F) based on kidney toxicity in males and females and decreased

weight gain in females. Reproductive NOAEL = _144.6/159.7 mg/kg/day

(M/F)

LOAEL = not identified. Offspr ing NOAEL = 36.4/41.0 mg/kg/day (M/F) LOAEL = 144.6/159.7 mg/kg/day (M/F) based on decreased body weight and weight gain.

870.4100b Chronic toxicity

(dog) 44674128 (2002)

Acceptable/guideline M&F: 0, 70, 300, 1000 mg/kg/day NOAEL = 300 mg/kg/day (M); _1000 mg/kg/day (F) LOAEL = 1000 mg/kg/day based on decreased body weight gain (M); not identified (F)

870.4200b Carcinogenicity

(mouse) 46474130 (2003)

Acceptable/guideline M: 0, 7.9, 64.5, 551.0 mg/kg/d F: 0, 11.5, 91. 9, 772.3 mg/kg/day NOAEL = 64.5/91.9 mg/kg/day (M/F)

LOAEL = 551.0/772.3 mg/kg/day (M/F) based on decreased body weight and weight gain and liver

lesions. no evidence of carcinogenicity

870.4300 Chronic/

Carcinogenicity (rat) 46474139 (2003)

Acceptable/guideline M: 0, 2.1, 8.4, 31.5, 109.4 mg/kg/day F: 0, 2.8, 10.8, 41.0, 142.2 mg/kg/day NOAEL = 31.5/41.0 mg/kg/day (M/F) LOAEL = 109.4/142.2 mg/kg/day based on decreased body weight gain (M/F) and thyroid

toxicity (M).

no evidence of carcin ogenicity

870.5100 Gene Mutation

(Salmonella typhimurium) 46474146 (2001)

Unacceptable/guideline

1.6

- 5000 μg/plate 46474202 (2001) Acceptable/guideline

1.6

- 5000 μg/plate 46474148 (2001) Acceptable/guideline

1.6

- 5000 μg/plate 46474144 (2001) Acceptable/guideline

1.6

- 5000 μg/plate 46474142 (2004) Acceptable/guideline AE638206 (batch mixture

of PP/241067/1 and PP/241024)

5

- 5000 μg/plate negative (non

- mutagenic) Upgradeable if purity for test material is given. negative (non

- mutagenic) negative (non

- mutagenic) negative (non

- mutagenic positive (mutagenic)Fluopicolide Human Health Risk Assessment D 416744

Page 34 of 38 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.5300 Gene mutation

(Chinese hamster lung cells) 46474204 (2000)

Acceptable/guideline AE638206 (batch mixture

of PP/241067/1 and PP/241024)

1.2

- 3820 μg /mL negative (non

- mutagenic)

870.5375 Cytogenetics 46474208 (2001) Acceptable/guideline 1.22 to 625 μg/mL 46474206 (2004) Acceptable/guideline AE638206 (batch mixture

of PP/241067/1 and PP/241024) 3.2 to 100 μg/mL negative for chromosome aberrations positive for aberrations without S9

870.5395 Micronucleus

(mouse) 46474214 (2003)

Acceptable/guideline 150, 300 or 600 mg/kg/day 46474210 (2005) Acceptable/guideline AE638206 (batch mixture

of PP/241067/1 and PP/241024) 200, 600 or 2000 mg/kg/day 46474212 (2005) Acceptable guideline AE C638206 (Batch No. OP

2050046 at 2000 mg/kg/day negative at doses up to 600 mg/kg negative at doses up to 2000 mg/kg negative at dose of 2000 mg/kg

870.5550 Unscheduled

DNA Synthesis (rat hepatocytes) 42169839 (1989)

Acceptable/guideline negative at concentration up to 300 μg/mL in cultured rat hepatocytes

(no OPPTS

no./ FIFRA

test guideline

84

- 2) Other

Genotoxicity

Unscheduled DNA synthesis (rat hepatocytes) 46474216 (2000)

Acceptable/guideline AE638206 (batch mixture

of PP/241067/1 and PP/241024) 600 or 2000 mg/kg negative at concentrations up to 2000 mg/kg in hepatocytes from treated rats

870.6200a Acute

ne urotoxicity screening battery (rat) 46474218 (2002)

46474219 (range

- finding,

2002) Acceptable/guideline M/F: 0, 10, 100, 2000 mg/kg NOAEL = 100 mg/kg (M/F)

LOAEL = 2000 mg/kg (M/F) based on transiently

lowered body temperature.

870.6200b Subchronic

neurotoxicity screening battery 46474221 (2002)

46474222 (positive control, 2002) Acceptable/guideline M: 0, 15.0, 106.6, 780.6 NOAEL = 106.6/18.0 mg/kg/day (M/F) LOAEL = 780.6/125.2 mg/kg/day based on decreased body weight gain, food consumption, and

food efficiency.Fluopicolide Human Health Risk Assessment D 416744

Page 35 of 38 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

mg/kg/day F: 0, 18.0, 125.2, 865.8 mg/kg/day

870.6300 Developmental

neurotoxicity None

870.7485 Metabolism and

pharmacokinetics (rat) 46474242 (2004)

- main

studies 46474241 (2001) 46474244 (2003) 46474226 (2003) 46474239 (2003) rapid absorption, metabolism and excretion; main

metabolites were oxidative N

- dealkylation cleavage products. Primary route of excretion is fecal and urinary with little accumulation in the tissues.

870.7485 Metabolism and

pharmacokinetics (rat) 46708632 (2002)

Acceptable Non

- guideline Most of the metabolites observed were derivatives of AE C638206 fitting well with the prior known metabolites, implying cysteine or N

- acetyl

- cysteine introduction on the phe nyl ring from gluthione conjugation, hydroxylation, or other conjugations.

870.7485 Metabolism and

pharmacokinetics (rat)

AE C657188 (PCA) 46708636 (2002)

Acceptable Guideline AE C657188 (PCA) showed high (87%) absorption but low (14

– 21%) metabolism. Excretion is mainly through the urine, with a minor portion in

the feces.

870.7485 Metabolism and

pharmacokinetics (rat) AE C653711 (2,6

- dichloro

benzamide 46708633 (2003)

46708634 (2003) 46708635 (2003) Acceptable Guideline Absorption: 50

- 79%. Metabolized extensively to 18 identified compounds. The majority of the radioactivity was associated with a mercapturic acid conjugate of hydroxyl

- chlorobenzamide (15

- 5

- 26.2%), present in the urine Excretion mainly

through urine and feces.

870.7600 Dermal

penetration (rat) 46708638 (2003)

Acceptable Guideline 1.43, 659 ug/cm2 skin In vivo study

Dermal Penetration rate: 37%

870.7600 Dermal

penetration (comparative) 46708637 (2003)

Acceptable Non

- guideline 1.9, 744 ug/cm2 skin In vitro study Rat skin dermal penetration rate is 7.8 times greater

than human skin.

A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD)

- Females age 13

- 49 Study Selected: None.

Comments: No appropriate endpoint attributable to a single exposure (dose) was identified

from the database.

A.3. 2 Chronic Reference Dose (cRfD)

Study Selected: Developmental Toxicity Study in Rabbits MRID No: 46474122 Dose and Endpoint for Risk Assessment: NOAEL = 20 mg/kg/day based on death, abortions/premature deliveries, decreased food consumption and body weight gain at 60 mg/kg/day. Uncertainty Factor : 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA)Fluopicolide Human Health Risk Assessment D 416744

Page 36 of 38 Comments on Study/Endpoint/Uncertainty Factors: This study is considered to be the most appropriate for chronic dietary dose and endpoint selection with support of the

chroni c/oncogenicity study in rats (co

- critical study). In the latter study, the NOAEL was 31.5 mg/kg/day based on decreased body weight gain and increased thyroid weight and increased incidence of thyroid lesions at 109.4 mg/kg/day.

A.3.4 Incidental Oral Exposure (Short

- and Intermediate

- Term)

Study Selected: Developmental Toxicity Study in Rabbits MRID No: 46474122 Dose and Endpoint for Risk Assessment: NOAEL = 20 mg/kg/day based on death, abortions/premature deliveries, decreased food consumption an d body weight gain at 60 mg/kg/day. Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA)

Comments on Study/Endpoint/Uncertainty Factors: The endpoint of concern in this study is appropriate for the populati on (infant and children) and duration of concern.

A.3.5 Dermal Exposure (Short

- , Intermediate

- and Long

- Term)

Study Selected: Developmental Toxicity Study in Rabbits MRID No: 46474122 Dose and Endpoint for Risk Assessment: NOAEL = 20 mg/kg/day bas ed on death, abortions/premature deliveries, decreased food consumption and body weight gain at 60 mg/kg/day. Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA)

Comments on Study/Endpoint/Uncertainty Factors: The developmental study is selected since developmental endpoints are not examined in dermal toxicity studies. It is also protective of effects observed in the chronic toxicity studies, i.e., decreased body weight gain and increased thyroid weight and increased incidence of thyroid lesions.

A.3.6 Inhalation Exposure (Short

- , Intermediate

- and Long

- Term)

Study Selected: Developmental Toxicity Study in Rabbits MRID No: 46474122 Dose and Endpoint for Risk Assessment: NOAEL = 20 mg/kg/day based on death, abortions/premature deliveries, decreased food consumption and body weight gain at 60 mg/kg/day. Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA)

Co mments on Study/Endpoint/Uncertainty Factors: Th e developmental toxicity study is protective of any potential developmental effects. It is also protective of effects observed in the chronic toxicity studies, i.e., decreased body weight gain and increas ed thyroid weight and increased incidence of thyroid lesions.Fluopicolide Human Health Risk Assessment D 416744

Page 37 of 38 Appendix B

. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database ; the ARTF database; and the Outdoor Residential Exposure Task Force (ORETF) database

, are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of d ata sources, as well as guidance on their use, can be found at the Agency website 3

3 http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/opp00001/science/residential

- exposure

- sop.htmlFluopicolide Human Health Risk Assessment D 416744

Page 38 of 38 Appendix C . Residue Summary Table

Appendix E

. Summary of Residue Data in Rotational Crops Following Primary Treatment with

Fluopicolide

. Commodity Total Applic.

Rate (lb ai/A) [g ai/ha] PBI

(days) Residue Levels 1
(ppm fluopicolide equivalents)

n Sample

Min. Sample

Max. LAFT 2 HAFT 2 Median Mean Std.

Dev.

Fluopicolide

Forage 0.366

- 0.387

[410

- 433] 28

- 41 19 <0.010 0.071 <0.010 0.069 0.010 0.017 0.014

Grain 20 < 0.010 <0.010 <0.010 <0.010 0.010 0.010 N/A

Stover 21 <0.010 0.174 <0.010 0.158 0.016 0.028 0.034

Forage 0.749

- 0.771

[840

- 864] 29

- 33 3 0.018 0.048 0.021 0.044 0.026 0.030 0.012

Grain 3 <0.010 <0.010 <0.010 <0.010 0.010 0.010 N/A

Stover 3 0.058 0.124 0.062 0.113 0.074 0.083 0.026

Forage 1.917 [2149] 31 1 0.236 0.299 0.268 0.268 0.268 0.268 N/A

Grain 1 <0.010 <0.010 <0.010 <0.010 0.010 0.010 N/A

Stover 1 0.322 0.419 0.371 0.371 0.371 0.371 N/A

1 Except for sample min/max, values reflect per trial averages; n = no. of field trials. For calculation of median, mean, and standard deviation, the LOQ in fluopicolide equivalents (0.0 10 ppm for fluopicolide, 0.0 2 0 ppm for BAM, 0.034 ppm for PCA, and 0.030 ppm for P1x) was used for any results reported as <LOQ in . N/A = Not applicable.

2 LAFT = lowest average field trial; HAFT = highest average field trial.