### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON , 

### D.C. 20460

MEMORA ND UM

Date 29-September

- 2015 O FFI C E OF C HEMI CA L SA FET Y A ND POLLUTION PREVENTION



### Subject: Metaflumizone: Human Hea l th Risk Assessment i n Support of Section 3 Registrations for Application of Metaflumizone to Pome Fruit (crop group (CG) 11- 10) and Stone Fruit (CG 12-12); Updating the CG Designation for Citrus to 10-10 and Tree Nuts to 14-12; and Permitting Ae ri al Application to Citrus Fruits

, Grapes

, Tree Nuts, and Nurseries Containing Field- / Conta i ner-Grown Nonbearing Stone and Pome Fruit Trees.

PC Codes : 281250 (E 

### I somer) ; 281251 (Z 

### isomer) DP Barcodes: 0421321; 0425540 

### Decision No.: 492130 

### Registration No.: 7969-270 

### Petition No

. : 4F8286 

### Reg ul atory Action: 

### Section 3 Risk Assessment Type: 

### s in gle chemical airn.regate Case No.: 7446 

### TXR No

. : 

### not appl i cab l e CASNo. : 139968-49-3 

### MRID No: 

### not app li cable



# -

- 

### 40 

### CFR: 180.657



### om Bloem

, Chemist

# l - \ 

### From: T

# ~" ;J /
Anwar Y

. 

### Dunbar,

# .Ph.i?,Ph~acologist**~ "1** **v~ ~**  

# /},1

James S. Miller

, Environmental Engineer

, Public Hct<lth

, Service (PHS) <

## ~A:~ Risk Assessment Branch I/Health Effects Division (RABl/HED; 750 

# ;.

. .

## ~ Through: Thurston Morton

, Chemist

, Acting Branch Chief**~** 

### / George F

. Kramer, Ph.D.

, Senior Chemist**~7'** 

# K--=--5?§
RABI/HED (7509P)

To: 

### Richard Gebken (RM 10) Registration Division (RD; 7505P)

HED of the Office of Pesticide Programs (OPP) is charged w ith estimating the risk to human h e alth from exposure to pesticides. RD of OPP has requested that HED eva lu ate h azard and
exposure data and conduct dietary

, occ u pational

, residential

, and aggregate exposure

asse s sments, as needed

, to estimate the risk to human health that wi ll result from all registered and proposed us e s of metaflumizone (2-[2-( 4-cyanophenyl)-1-[3-(trifluoromethyl)phenyl] ethylidene]

- N -[ 4-(trifluoromethoxy)phenyl]hydraz in ecarboxam id e; E:Z i somer rat i o of > 9:1). A
summary of the findings and an assessment of the human risk resulting from the registered and proposed uses are provided in this document. The risk assessment, dietary risk assessment, and residue chem i stry data review were provided by Tom Bloem (RAB 1 )

, the hazard characterization was provided by Anwar Dunbar (RAB 1 )

, the residential/occupational exposure assessment by James Miller (RAB l )

, and the drinking water assessment by Mohanuned Ruhman

o f th e Environmenta l Fate and Effects Division (EFED).

Page 1 of38Metatlumizon e Human H ea lth Ri s k A ssess ment 0421 321



### Ta b l e o f Co nt e nt s

1.0 Executive S ummar y

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

### 3

2.0 H ED Recommendation s

....... ...... ........ . ... . .......... ..... . .. .. ... .. .. .................... .. .. ............. ... ......... . ..... .......... . .......... . .. . .. . 6 2. 1 Data Defici e nci es / Data Needs

.... ....................... ... .. .. .............................. . .. .... ................. .... . .. ............................ 6 2.2 Tolerance Consideration s

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

### 6 2.2. 1 Enfor cement Ana l y tical Method

.. .. .. .. .................... .. .......... .. .. .. .. ... . ...... ................... ... . .................. . .. ......... 6 2.2.2 R ecommended Tolerances

...... . ................................................. ... . ... . ... .................... ..... . .................. .... .. ... 7 2.2.3 Revision s t o P et iti oned -F or Toleranc es

.............................................................................. .. . ..... . ....... .. . .... 7 2.2.4 International Ham1onization

... .. ........................... ........ ............. ......... ..................................... .... ............... 7 2.3 Label Recomm e ndation s

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

3.0 In g redi e nt Pr ofi l e

.. .. ..... .. .. . ... . ................ . ... .. .. ... .. ... ... . .. ............ .. ... ................... . ... ......... .. ..... ........ . ..................... ..... 8 3

. 1 C hemic a l I dentify

... . . ........... . ........ . . .. .. .... .. ................................... .. . ....... . ....... .. .. . ..................... .. .. .. . .. . .. . .. .. . ........ 8 3

. 2 Proposed Use Pan e rn

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

### 3.3 Ant i cipa t ed Expo s ur e Pathway s

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

### I 0 3 .4 Consideration of Environmental J ustic e

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

4.0 Ha zar d C har ac t erization / A ssess ment

........ ................ .. ...................... ................... .......................... .............. ......... 11 4.1 Tox i cology Studies Available for Analysis

................................. .. .. ... .................................... . .. .............. .... . .... 11 4.2 Absorp ti on , Di s tributi on, Me t abolism, and Excre ti on (A DME )

..... . ............................................ ..... ............... 11 4.3 Tox ic ological E ffects

............. . .. ...... .................................................. .. . ... . .............. ................... .............. ......... 11 4.4 SF for In fants and C hildren ( FQPA SF)

............. ... ....................... . .. ... . . ............................................................ 13 4.4.1 Comple t eness of the Toxicology Dat abase

.. .. ... . ... .. ... ............. . . . ... .. .. . ... .. .. .. .. .. .. . ...... . ..................... .......... 1 4 4.4.2 Evid ence o f Neurotoxic ity

..... . .................. ... .. ... .. .. .. .. ......................... . ... . ...... .. .. .. .. . ............................ ....... 14 4.4.3 Evidence of S en s itivity / Suscept i bi l ity in th e Deve l oping or Young Animal

... . ...... . .. . ........... . ............ ..... 14 4.4.4 Re s idu a l Unce11ainty 

### in the Exposure Databa se

.. ... . .... . ..... .. .. ... .. . . . ... .. .. . ... . .................................... .. . .... .. .. 1 4 4.5 Toxicity E ndp o int a nd P oi nt of Departur e ( POD ) Selec tion s

.................. . ... . ... . .. .. .. . .. .. .. . .. . ................... . .. . .. ..... 1 5



### 5.0 Dietary Exposure a nd Ri s k A ssess ment..

.. ............................... . .... . ....................... . ... ... ....................... ......... . . ....... 19 5.1 Metabolite / D eg rad a te Re si due Profil e

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

### 5.2 Food R esid u e Profil e

................ ............ ................ ... ......................... . ............................ . .................................. 19 5.3 Drinking Water R esid ue Profile

.. ..... ........ .. ... .. ............................. ............... ... . ................. . .. . . ..................... ...... 20 5.4 Dietary (Food + Drinkin g Water) Ri sk Assessment

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

6.0 R es idential ( Non-Occupational) Exposure/Ri s k C h aracterization

.. .. ... . .. ... . .... . . ... . ....... .................. .................... .. . 2 1 

### 6.1 Re si dential B ys t a nd er Post-Application I nhalati o n Exposure

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

### 22 6.2 S pray Drift**··· ··** **······ ··** **~· ·······** **·· -.** **··· ··** **··· ··** **·· ··** **··· ··** **················································ ··** **·· ··** **·· ·····································** **·· ·22**  

# -

. 7 .0 A gg regat e Ex p os ur e/ Ri s k C har ac teri iat ion

............ ... .................................. .. . .. .................................. ........... ....... 23 7. I Acu te Aggr ega t e Ri s k

................. .. .. ... .. .. .. .. ................................ ....... . ... . .. ...................................... ..... . .. . .. . .. .... 23 7.2 Sho rt- Tenn A gg r eg at e Ri s k

.. ... .. ............ .. .. ........................... ................... . ....... ................ .. . ......................... .... 23 7.3 Ch r onic A ggreg at e Ri sk

.................... ... . ..................... .. .... .. ........... ... ............................... ... ........................ .. .... 23 7.4 Cancer Aggregate Ri s k

................................................................................ . ................................................... 23

8.0 Cumulative Exposu r e / Ri s k Characterization

............... .. .... .. ............ .. .. .. ......................... .. .. . ... ........ . .. . ..... ............. 24

9.0 Occupational Expo s ur e / Ri s k Charac terizati on

.................. ...... . ............. . ...... ............................. .............. ............. 24 9.1 Occupational H a ndl er Expos ure / Risk A ssess m e nt

........ .... . ......... . ...... ....................... . ..... ................ . .. ............. 24 

### 9.2 Occupational Po s t -A pplication Exposure/Risk A ssess m e nt

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

### 25

Appendix A

. Toxicolo gy Pr ofile and Exe cutiv e Summar i es

........ .. ... .. . .... . ... . ... ......................................... .. ............... 26
Appendix B. M ethodologies for H EC Calculations

...................... .. ... ................... ............................... . . .. ................... 3 1 Appendix C: Ph ysiochem ical Prop e rties

.... ............................................ ... . .... ......................................... . ................... 36 Appen di x D: Exposure to Metaflumizone in Fish / She ll fish at Co n s umption L eve l s Associated with Subsistence F

ishing

....................... ............ . ............ ...................... ............................. . ... .. .. .. .. .. .. .. . .. .. ..... . ......... ................ .... 37

Pa ge 

### 2 of38Metaflumizone Human Health Risk Assessment D4 2 1321

Page 3 of 38 

### 1.0 Executive Summary

Metaflumizone (2

- [2

- (4

- cyanophenyl)

- 1

- [3

- (trifluoromethyl)phenyl]ethylidene]

- N

- [4

- (trifluoromethoxy)phenyl]hydrazinecarboxamide; E and Z isomers) is a semicarbazone insecticide which blocks the sodium channel and inhibits nerve impulses leading to inhibited feeding and paralysis in susceptible insects (Lepidoptera ; Coleoptera ; fire ants ). The E and Z isomers are typically present at a >9:1 ratio (E:Z). Metaflumizone is currently registered for application to citrus, tree nuts, and grapes with tolerances established for the combined residues of metaflumizone (E and Z isomers) and M320I04 at 0.04 ppm (see Table 3.1.1 for names and structures); tolerances without a U.S. registration are established in/on peppers, eggplant, tomato, and tomato paste at 0.60

- 1.5 ppm. Metaflu mizone is also registered for application around industrial, commercial, agricultural, and recreational facilities/structures / premises. The most recent risk assessment for metaflumizone was conducted on 21

- November

- 2013 (D410219, T. Bloem et al. )

.
BASF i s requesting application of metaflumizone to pome fruit (CG 11

- 10) and stone fruit (CG 12

- 12) and is requesting the establishment of permanent tolerances in/on these crop groups for the combined residues of metaflumizone (E and Z isomers) and M320I04 at 0. 04 ppm (see Table 3.1.1 for names/structures) . BASF is also requesting an update to the CG commodity definitions for citrus (from CG 10 to CG 10

- 10) and tr ee nut (from CG 14 to CG 14

- 12); permitting aerial application to citrus, grape, and tree nut ; and p ermitting aerial application to nonbearing pome fruit and stone fruit.

Hazard Assessment: Hematotoxicity (toxicity of the blood) was the primary toxic effect of concern following subchronic or chronic oral exposures to metaflumizone. Splenic extramedu llary hematopoiesis, increased hemosiderin, and anemia were the most common hematotoxic effects reported after repeated oral dosing with metaflumizone. Chronic oral (gavage) exposures to dogs resulted in slight decreases in mean corpuscular hemoglobin con centration and total hemoglobin, leading to increased plasma bilirubin, increased urinary urobilinogen, and increased hemosiderin in the liver. In a chronic toxicity/carcinogenicity study in mice, anemia was observed in the form of increased hemosiderin i n the spleen, increased mean absolute reticulocyte count, decreased mean corpuscular volume, and mean corpuscular hemoglobin.

The postulated pesticidal mode of action of metaflumizone involves inhibition of sodium channels in target insect species; however, in mammals (rats), there were only clinical signs of neurotoxicity (i.e., piloerection and body temperature variations) with no neuropathology and in the presence of systemic toxicity (e.g., recumbency and poor general state) following acute or re peated exposures. Similarly, several immune system organs seem to be affected following metaflumizone administration via the oral, dermal, and inhalation routes (e.g., the presence of macrophages in the thymus, lymphocyte necrosis in the mesenteric lymph nodes, and diffuse atrophy of the mandibular lymph node ); however, there was no evidence of any functional deficits at the highest dose tested in a g uideline immunotoxicity study. Therefore, the clinical neurotoxicity signs and the effects on the immune system organs following metaflumizone administration are likely to be secondary to the hematotoxic effects.

Metaflumizone induced a malformation ba sed on an absent subclavian artery at a relatively high dose in the developmental toxicity study in rabbits. However, this effect was observed at the same dose as severe maternal toxicity, which included late

- term abortions and other clinical signs of tox icity. There was no evidence (quantitative or qualitative) of increased susceptibility following in utero exposures to rats or ra bbit and following pre

- and post natal exposures to rats. There was no evidence that metaflumizone is genotoxic and carcinogeni city studies with mice and rabbits were negative.Metaflumizone Human Health Risk Assessment D4 2 1321

Page 4 of 38 

### F ood Quality Protection Act (F QPA ) Safety Factor ( SF ) Decision: The metaflumizone risk assessment team recommends that the FQPA SF be reduced from 10x to 3x for all oral exposure scenarios, be retained at 10x for inhalation exposure scenarios, and be reduced to 1x for dermal
exposures. A detailed discussion of these conclusions can be found in Section 4.4.

Dose

- Response Assessment: T able d 4.6 .1 (dietary non

- occupational) and 4.6.2 (occupational)

are a su mmary of the points of departure (PODs) selected for assessment of dietary, inhalation, and /or dermal exposure. R oute

- specific toxicity studies were selected for assessment of short

- /intermediate

- term dermal, inhalation, and oral exposures. Short/intermediate

- term dermal and inhalation exposures can be combined based on the effects on the immune system organs seen a t the lowest

- observed adverse

- effect level ( LOAEL ) in the selected studies. Short/intermediate

term oral, dermal, and inhalation exposures can be combined based on the decreased body weight or decreased body

- weight gain effects seen at the LOAEL in the se lected oral and dermal studies and at doses above the LOAEL in the selected inhalation study. Since the level of concern (LOC) for the different exposure routes are different, the aggregate risks were calculated u sing the aggregate risk index (ARI) approa ch.

Residue Chemistry and Drinking Water Assessments: Adequate residue chemistry data have been submitted to support the proposed application scenarios. In addition, adequate data are available for the generation of modeled estimated drinking water conc entrations (EDWCs).

Dietary Risk Estimates (Food + Drinking Water ): Acute and chronic dietary (food and drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model

- Food Consumption Intake Database (DEEM

- FC IDTM, ver. 3.16) which incorporates the food consumption data from the United States Department of Agriculture (USDA) National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA; 2003

- 2008). The acute and chronic analyses assume d tolerance

- level residues, 100% crop treated, and modeled drinking water estimates. Since adequate processing studies have been submitted which indicate that tolerances in/on grape raisin, grape juice, citrus juice, tomato puree, and tomato juice are unn ecessary, the DEEM (ver. 7.81) default processing factors for these commodities were reduced to 1. For tomato paste, the DEEM (ver. 7.81) default processing factor was also reduced to 1 as a separate tolerance in/on this commodity is established . For the remaining relevant commodities, the DEEM (ver. 7.81) default processing factors were retained. Based on an assessment by EFED , which concluded that metaflumizone has a high potential to bioaccumulat e in aquatic food webs, the current analysis included the K OW 

### (based) Aquatic Bioaccumulation Model (KABAM; ver. 1.0) piscivorus fish residue estimate for fish/shellfish . The resulting acute (1.6% aPAD; assessment only necessary for females 13

- 49 years old) and chronic (≤ 7.2 % cPAD; children 1

- 2 years old wer e the most highly exposed subgroup) analyses resulted in risk estimates that are not of concern to HED

. Residential (Non

- Occupational) Exposure and Risk Assessment: There are no new residential uses associated with this regulatory action. Metaflumizon e is registered for application as a fire ant bait to lawns, landscapes, golf courses, and other non

- cropland

, and as a granular fly bait around industrial buildings, commercial facilities, agricultural structures / premises , and recreational facilities/area s. As a result of these registered uses, residential handler (short

- term d ermal and inhalation exposures) and post

- application (short

- term dermal and incidental oral) exposures are expected and were previously assessed t o conform with the most recent poli cies and guidance

. No risks of concern were identified for any scenario

.Metaflumizone Human Health Risk Assessment D4 2 1321

Page 5 of 38 

### Aggregate

- Risk Estimates: In accordance with the FQPA, HED aggregate s pesticide exposures and risks from dietary (food and water) and residential (dermal, inhalation, and/or incidental oral) sources. Based on the proposed/registered uses and since inhalation, dermal, and incidental oral exposures can be combined , aggregate acute (dietary) , short

- term (dietary, incidental oral, and/or dermal) , and chronic (dietary) assessments were conducted. All aggregate assessments resulted in risk estimates which are not of concern to HED.

Occupational Exposure and Risk Assessment: Based on the proposed use patterns , types of equipment

, and techniques that can potentially be used, short

- and intermediate

- term dermal and inhalation occupational handler exposure for the following scenarios are expected: (1) mixing/loading a granular f ormulation to support aerial applications, (2) applying granular formulations with aircraft, and (3) flagging to support aerial granular formulation applications. The calculated exposure and risks estimates for occupational handlers wearing the label prescribed personnel protective equipment (PPE; gloves plus baseline) and with engineering controls for aerial applications are not of concern (i.e., aggregate risk index (ARI) ≥ 1)

. The current propose d use s pertains to the applicatio n of a granular formulation via ground or aerial (fixed

- wing aircraft) equipment for the control of fire ants. HED believes that, even when applied aerially, most granules will fall to the orchard or nursery floor and will therefore not present a dermal p ost

- application exposure risk. Also, an occupational handler mixer/loader dermal exposure scenario was assessed and HED believes this to be protective of any post

application dermal exposure. The non

- cancer dermal risk estimate for a commercial aerial mi xer/loader is not of concern (i.e., MOE > 100).

Environmental Justice Considerations: Potential areas of environmental justice concerns, to the extent possible, were considered in this h uman health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations.”

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 the Pesticide Handlers Exposure Database (PHED) 1.1, the Agricultural Handler Exposure Task Force (AHETF) database, and the Agricultural Reentry Task Force (ARTF) database are (1) subje ct 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 data s ources, as well as guidance on their use, can be found at the following Agency websites: http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

.Metaflumizone Human Health Risk Assessment D4 2 1321

Page 6 of 38 

### 2.0 HED Recommendations

Provided the petitioner submits revised Sections B and F, HED concludes that the toxicological and exposure databases are sufficient to support the establishment of permanent tolerances listed in Section 2.2.2. No additional data are required to support t he establishment of these tolerances.

2.1 Data Deficiencies/Data Needs

Toxicology/ORE: None

Residue Chemistry: Revised Sections B (see Section 2.3) and F (see Section 2.2.2).

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

HED previously reviewed method validation and independent laboratory validation (ILV) studies for the BASF high

- performance liquid chromatography (HPLC)/mass spectrometry (MS)/MS analytical method 531/0 and forwarded the method to FDA for tolerance enforce ment (46264221.der; D308394, T. Bloem, 30

- Nov

- 2005; D328915, T. Bloem, 17

- May

- 2006). It is noted that following method validation, BASF incorporated several minor modifications to method 531/0 with this revised method specified as 531/1 (method 531/1 is t he current enforcement method). Based on the similarities of the proposed crops to that currently registered and since the grape, citrus, and tree nut residue samples were analyzed using a method very similar to the current enforcement method and since ad equate validation data were submitted, HED concludes that the current enforcement method is suitable for enforcement of the tolerances recommended herein. The limit of quantitation (LOQ) is 0.01 ppm for metaflumizone (E and Z isomers) and 0.018 ppm for M 320I04 (expressed in parent equivalents).

Analytical standards for metaflumizone (E and Z isomers; expiration date 1

- June

- 2021) and M320I04 (expiration date 01

- July

- 2017) are currently available at the EPA National Pesticide Standards Repository (commun ication from Theresa Cole, BEAD).Metaflumizone Human Health Risk Assessment D4 2 1321

Page 7 of 38 

### 2.2.2 Recommended Tolerances

Table 2.2.2.1 is a summary of the proposed and HED

- recommended tolerances for the combined residues of metaflumizone (E and Z isomers) and M320I04 (expressed in parent equivalents). With the establishment of the tolerances listed in Table 2.2.2.1, the fruit, citrus, group 10 and nut, tree, group 12 tolerances should be deleted.

Table 2.2.2.1: Tolerance Summary.

Commodity Proposed

Tolerance (ppm) HED

Recommended Tolerance (ppm) Comments

Citrus (crop group 10

- 10) 0.04 0.04 commodity definition

– fruit, citrus, group 10

- 10 Tree nut (crop group 14

- 12) 0.04 0.04 commodity definition

– nut, tree, group 14

- 12 Pome fruit (crop group 11

- 10) 0.04 0.04 commodity definition

– fruit, pome, group 11

- 10 Stone fruit (crop group 12

- 12) 0.04 0.04 commodity definition

– fruit, stone, group 12

- 12



### 2.2.3 Revisions to Petitioned

- For Tolerances

A revised Section F is requested which specifies the correct commodity definitions (see comments column of Table 2.2.2.1).

2.2.4 International Harmonization

Canadian

, Codex, and Mexican MRLs are not established in/on the relevant crops; therefore

, harmonization is not an issue for this petition

.

2.3 Label Recommendations

A revised Section B is requested which indicates that only ground equipment may be used for application to bearing pome fruit and stone fruit.Metaflumizone Human Health Risk Assessment D4 2 1321

Page 8 of 38 

### 3.0 Ingredient Profile

3.1 Chemical Identify

The chemical structure and nomenclature of metaflumizone and its metabolites are presented in Tables 3.1.1. The p hysi ochemical p roperties are summarized in Appendix C

.

Table 3.1.1: Metaflumizone, M320I04, and M320I23 Nomenclature.

Chemical structure

Common name Metaflumizone Company experimental name BAS 320 I

IUPAC name ( EZ )

- 2'

- [2

- (4

- cyanophenyl)

- 1

- (α,α,α

- trifluoro

- m

- tolyl)ethylidene]

- 4

- (trifluoromethoxy)carbanilohydrazide

CAS name 2

- [2

- (4

- cyanophenyl)

- 1

- [3

- (trifluoromethyl)phenyl]ethylidene]

- N

- [4

- (trifluoromethoxy)phenyl]hydrazinecarboxamide CAS registry number 139968

- 49

- 3

Metabolite M320I04

4

- [2

- oxo

- 2

- [3

- (trifluoromethoxy)phenyl]ethyl]

- benzonitrile

Metabolite M320I23

4

- [5

- hydroxy

- 3

- oxo

- 4

- [4

- (trifluoromethoxy)phenyl]

- 6

- [3

- (trifluoromethyl)phenyl]

- 2,3,4,5

- tetrahydro

- 1,2,4

- triazin

- 5

- yl]benzonitrile

M320I28 (hydrolysis product of Metaflumizone)

N

- [4

- (trifluoromethoxy)phenyl]

- acetamideMetaflumizone Human Health Risk Assessment D4 2 1321

Page 9 of 38 

### 3. 2 Proposed Use Pattern

The petitioner is proposing application of AltrevinTM Fire Ant Bait Insecticide (EPA Reg. No. 7969

- 270) to pome fruit (CG 11

- 10) and stone fruit (CG 12

- 12); u pdat ing the crop group commodity definitions for citrus (CG 10

- 10) and tree nuts (CG 14

- 12); add ing aer ial application
to citrus, grape, and tree nut ; and adding aerial application to nonbearing pome fruit and stone fruit

. The proposed restricted

- entry interval ( REI ) is 12 hours and the product labels direct mixers, loaders, applicators and other handlers to wear long

- sleeved shirt and long pants, chemical resistant gloves, and shoes plus socks. Table 3.3. 1 is a summary of the proposed end

use product and Table 3.3. 2 is a summary of the proposed application scenarios.

The crop group definitions for citr us, pome fruit, stone fruit, and tree nuts conform to the definitions specified in 40 CFR 180.41 for crop groups 10

- 10, 11

- 10, 12

- 12, and 14

- 12

, respectively . Provided a revised Section B is submitted indicating that only ground equipment may be used for application to bearing pome fruit and stone fruit, the proposed use directions are adequate. For citrus , grape, and tree nuts, application using ground and aerial equipment is permitted (D421322, T. Bloem, 12

- Aug

- 2014).

Table 3.2 .1: Summary of End

- Use Products.

Trade Name Conc. Formulation Label Date Target Crops Target Pests

AltrevinTM Fire Ant Bait Insecticide (EPA Reg. No. 7969

- 270) 0.063% granular not indicated stone fruit imported and native fire ants pome fruit citrus
tree nut

Table 3.2

. 2: Summary of Proposed Directions for Metaflumizone. Applic. Timing; Type; and Equip. Formulation

[EPA Reg. No.] App. Rate Max. No. App. per Y r Max. Yearly App.

Rate PHI

(days) Use Directions and Limitations

Citrus trees: Australian desert lime; Australian finger lime; Australian round lime; Brown River finger lime; Calamondin; Chironja; Citron; Citrus hybrids; Grapefruit; Japanese summer grapefruit; Kumquat; Lemon; Lime; Mediterranean mandarin; Mount White lim e; New Guinea wild lime; Orang e, sour; Orange, sweet; Pummelo; Russell River lime; Satsuma mandarin; Sweet lime; Tachibana orange; Tahiti lime; Tangelo; Tangerine (Mandarin); Tangor; Trifoliate orange; and Uniq fruit Pome fruit trees: Apple; Azarole; Crabapple; Loquat; Mayhaw; Medlar; Pear, Pear, Asian; Quince, Quince, Chinese; Quince, Japanese; and Tejocote Stone fruit trees: Apricot; Apricot, Japanese; Capulin; Cherry, black; Cherry, Nanking; Cherry, sweet; Cherry, tart; Jujube, Chinese; Nectarine; Peach; Plum; Plum, American; Plum, beach; Plum, Canada; Plum, cherry; Plum, Chickasaw; Plum, Damson; Plum, Japanese; Plum, Klamath; Plum, prune; Plumcot; and Sloe Nut trees: African nut

- tree; Almond; Beechnut; Brazil nut; Brazilian pine; Bunya; Bur oak; Butternut; Cajou nut; Candlenut; Cashew; Chestnut; Chinquapin; Coconut; Coquito nut; Dika nut; Ginkgo; Guiana chestnut; Hazelnut (Filbert); Heartnut; Hickory nut; Jap anese horse

- chestnut; Macadamia nut; Mongongo nut; Monkey

- pot; Monkey puzzle nut; Okari nu t; Pachira nut; Peach palm nut; Pecan; Pequi; Pili nut; Pine nut; Pistachio; Sapucaia nut; Tropical almond; Walnut, black; Walnut, English; and Yellowhorn Grape

Postemergence; Broadcast; Ground (also aerial for citrus, tree nuts, and grape) 0.063% G

[796 9

- 270] 0.0007

- 0.001

lb ai/acre 4 0.004 lb ai/acre 5 Broadcast applications are to be made in areas having a mound density of at least 1 mound per 2,000 square feet. Otherwise, individual mound spot treatments are to be made (see below). A minimum RTI of 4 weeks is proposed.

Postemergence; Spot; Ground 0.063% G

[7969

- 270] 0.00004

-

0.00008 lb ai/mound not indicated 0.004 lb ai/acre 5 Spot applications are to be made in areas having a mound density of less than 1 mound per 2,000 square feet. Otherwise, broadcast applications are to be made (see above). A minimum RTI of 4 weeks is proposed.Metaflumizone Human Health Risk Assessment D4 2 1321

Page 10 of 38 

### 3.3 Anticipated Exposure Pathways
Section 3 registrations for application of metaflumizone to citrus, tree nuts, and grape have been established (LOQ

- level tolerances) and tolerances without a U.S. registration have been established in/on tomato, tomato paste, peppers, and eggplant. As a result of these uses and the proposed uses, dietary (food and water) exposure to metaflumizone is possible. Field trial data indicate that the major residue in/on the RACs is parent; however, the tomato processing study indicated that the major residue in/on the tomato processed commodities is M320I04. T he c urrent dietary assessment included residues in fish/shellfish as E FED concluded that metaflumizone has t he potential to bioaccumulate substantially in aquatic food webs (D361157, K. Sappington, 21

- Dec

- 2011 ). Dermal

, inhalation, and incidental oral residential exposure s are also anticipated as a result of the registered fly and fire ant bait application scenarios (handler and post application exposures).

3.4 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 Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations,” ( http://epa .gov/compliance/ej/resources/policy/exec_order_12898.pdf ). As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to populat ion 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 com piled by the USDA under the NHANES/WWEIA (2003

- 2008) and 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 to 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 pestici de 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 experti se to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

B ased on analysis by EFED, metaflumizone has a high potential to bioaccumulate in aquatic food webs. As a result, the dietary risk assessment included a residue estimate for fish/shellfish with the resulting exposures less than HED’s LOC (see Section 5.4). HED also performed a separate analysis for exposure to metafl umizone in fish/shellfish at the consumption level associated with subsistence fishing; the resulting aggregate exposure estimates were also less than HED’s LOC (see Appendix D ).Metaflumizone Human Health Risk Assessment D4 2 1321

Page 11 of 38 

### 4.0 Hazard Characterization/Assessment

Metaflumizone is a semicarbazone insecticide which blocks the voltage

- dependent sodium channels of susceptible insects leading to paralysis

. For toxicity in mammals, metaflumizone seems to operate with a different mode of action leading to primary toxic effects more closely associated w ith hematotoxicity and immunotoxicity

. Clinical signs of neurotoxicity such as piloerection in some studies are likely to be secondary effects to a poor general state.

4.1 Toxicology Studies Available for Analysis

The toxicological database for metaflumizone is adequate for hazard characterization, toxicity endpoint selection, and FQPA SF evaluation

. In the last risk assessment ( D 410219

, T

. Bloem et al.

, 21

- Nov

- 201 3 ), no toxicity studies were noted to be missing

. Neurotoxicity (acute and subchronic), immunotoxicity, and inhalation studies have all been submitted and reviewed by the Agency

. Additionally, toxicity data for the goat/plant/soil metabolite M320I23 have also been submitted and reviewed for hazard charac terization.

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME)

Following administration of a single oral gavage dose of radiolabeled metaflumizone, the fraction absorbed was estimated to be low at <7.5% and even lower at the highest dose tes ted of 1000 mg/kg bw

. The majority of the unabsorbed dose was excreted in feces

. The absorbed radioactivity was distributed quickly to the muscle, liver, kidney, and fat within 0.5

- 2 hours

. Maximum levels in blood (C max 

### ) were attained at about 10 hrs an d were prolonged to about 30 hours at the highest dose tested

. Elimination half

- lives were estimated at about 44 hours for both sexes and increased by more than 2

- fold at the highest dose tested

. Increases in both C max 

### and the area under the plasma

conce ntration

- time curve (AUC) were less than proportional with respect to increases in dose.

In a comparative bioavailability study (oral gavage versus dietary), a difference in absorption was noted between oral gavage and dietary dosing

. Absorption via the diet, a more relevant route of exposure for dietary human risk assessments, was noted to be greater than via gavage by a factor of 2. Therefore, toxicity via the diet can be reasonably expected at doses that are approximately 2

- fold lower than those curre ntly selected for dietary and incidental oral risk assessments, which are based on gavage dosing

.

4.3 Toxicological Effects

Metaflumizone technical (90% E

- isomer and 10% Z

- isomer) : Metaflumizone technical is a mixture of ~90% E

- isomer and 10% Z

- isomer which cause s hematotoxicity (toxicity of the blood) and immunotoxicity as primary toxic effects following subchronic or chronic oral
exposure s

. S light anemia and/or a compensatory extramedullary hematopoiesis in the spleen of rats were observed in a 90

- d ay oral toxicity study , but not in the corresponding chronic toxicity /carcinogenicity study in rats suggestive of an adaptive response to the anemia following long

- term exposure in rats

. In a chronic toxicity study in dog s , anemia was observed in the form of slight decreases in mean corpuscular hemoglobin concentration and total hemoglobin leading to increased plasma bilirubin, increased urinary urobilinogen, and increased hemosiderin in the liver

. Following chronic exposures, anemia was observed in both sexes in mice as increased hemosiderin in the spleen, increased mean absolute reticulocyte count, and decreased mean corpuscular volume and mean corpuscular hemoglobin

.Metaflumizone Human Health Risk Assessment D4 2 1321

Page 12 of 38 

### In a developmental toxicity study in rats, toxicity to the offspring was not observe d at any dose, whereas mild maternal toxicity (decreased body

- weight gain) was observed at the highest dose tested. In rabbits, the malformation absent subclavian artery was observed at the same dose as severe maternal toxicity, which included late

- term a bortions and clinical signs of toxicity. In the
two

- generation reproductive toxicity study in rats, perinatal mortality was observed in offspring. However, the mortality was most likely the result of the improper nursing behavior, as well as the decrease d body weight and clinical signs of toxicity, exhibited by the parents at the same dose. Similar findings were observed in the range

- finding developmental neurotoxicity study in rats, in which pup mortality was observed at the same dose as clinical signs of toxicity and total litter loss in maternal animals.

There was no evidence of neurotoxicity in an acute neurotoxicity study in rats up to the highest dose tested (the limit dose)

. Piloerection and body temperature variations were noted in the subchroni c neurotoxicity study in rats, and salivation and ataxia were observed at the high dose in a chronic study with dogs. However, reduced general condition and/or recumbency, indicators of general systemic toxicity, were also observed in both sexes in both s tudies

. Thus, although metaflumizone is postulated to operate by way of a neurotoxic mechanism of action (sodium channel inhibition) in insect species, it is difficult to separate the clinical signs of neurotoxicity from a general systemic toxic effect in mammals.

Dermal exposure to metaflumizone also resulted in h ematotoxicity and/or immunotoxicity. In a rat 90

- day dermal toxicity study, increased hemosiderin was observed in the livers of females, along with increased macrophages in the thymus, lymphocyte necrosis in the mesenteric lymph nodes, and diffuse atrophy of the mandibular lymph node.

The results of a 28

- day rat inhalation toxicity study also identified l ymphocyte necrosis in the mesenteric lymph node as the critical effect (i.e., obs erved at the lowest dose)

. Although metaflumizone resulted in histopathological findings consistent with immunotoxicity, the results of a 28

- day immunotoxicity study in rats did not indicate any functional deficits in immune response; effects were limited t o deficits in body weight, body

- weight gains, and food consumption.

The concern for genotoxicity following exposure to metaflumizone is low based on the results of

an in vivo mouse micronucleus assay; and there was no evidence of carcinogenecity in the respective studies with mice and rats

. Metaflumizone was classified as Category IV for its low acute toxicity via the oral, dermal, and inhalation routes of exposure. It was neither a dermal irritant, eye irritant, nor a dermal sensitizer.

Dietar y Dosing with Metaflumizone: Five short

- term toxicity studies, in which rats or mice were exposed to metaflumizone in the diet, were submitted to the Agency after the original data package submission. These studies led to the (appropriate) decision by th e registrant to conduct all of its guideline studies using gavage dosing. In every dietary study, decreased body weight and body

- weight gains were observed in the presence of decreased food consumption. Because the decreases in body weight were observed only in the presence of decreased food consumption at the doses tested in these studies (≥3.8 mg/kg bw/day), the effect on body weight could not beMetaflumizone Human Health Risk Assessment D4 2 1321

Page 13 of 38 

### attributed to a direct effect of treatment, but rather was due to the decreased food consumption, which was most likely caused by a lack of palatability of the test substance when administered in the diet. The results from these five studies were supported by two additional studies, also submitted subsequent to the original package , which demonstrated that when given a preference in a free

- choice feeding regimen, rats strongly preferred untreated control feed and avoided diet that was treated with metaflumizone; and when given no preference in an alternate

- day feeding regimen, rats ate less and lost weight on th ose days in which they were forced to eat diet treated with metaflumizone. The results of these seven studies were supported by an eighth study in which no effect on body weight or food consumption was observed when rats were administered metaflumizone by gavage at doses that were similar to the dietary studies. Because the lower body weight observed in the dietary studies was caused by the animals eating less due to the unpalatability of metaflumizone, and not to direct toxicity of the test compound , the y are not relevant for endpoint selection for risk assessment.

Metaflumizone (Z

- isomer alone) : The Z

- isomer of metaflumizone administered alone (99.7%) via oral gavage to rats resulted in m ortality, reduced general condition, piloerection, and decreased overall motor activity in females. In males, decreased overall motor activity was observed at the highest dose tested only. T he Z

- isomer of m etaflumizone was negative for mutagenicity with and without metabolic activation in an in vitro bacterial reverse mutation (Ames) assay.
When these findings for the Z

- isomer alone are compared to those from the subchronic (90

- day) neurotoxicity study in rats using metaflumizone technical ( 90% E

- isomer and 10% Z

- isomer ), it can be concluded that the Z

- isomer is less potent than metaflumizone technical (predominantly E

- isomer), because it caused toxicity at doses that were 2

- fold and 7

- fold higher than the technical active in females and males, respective ly.

Metaflumizone Metabolite M320I23: M320I23 is a metabolite of metaflumizone that is generated in soil, plants (cotton, tomato, white cabbage), and goats, but not in rats. No adverse effects were observed in a 3

- month oral (gavage) study of M320I23 in rats. This metabolite was also negative for mutagenicity in an in vitro bacterial reverse mutation (Ames) test with and without metabolic activation and an in vitro mammalian gene mutation study at the hypoxanthine

- guanine phosphoribosyl transferase (H GPRT) locus in Chinese hamster ovary (CHO) cells without metabolic activation (inconclusive results were obtained in the presence of metabolic activation due to compound precipitation). M320I23 was also negative in an in vitro mammalian chromosomal aberra tion study with V79 cells without metabolic activation. Although the metabolite was positive in this in vitro study with metabolic activation, it was negative in an in vivo mammalian cytogenetic assay (mouse micronucleus test), which would be considered a more relevant test system for clastogenicity since it was tested in a whole animal. The overall weight of the evidence for this metabolite, therefore, indicates that M320I23 is less toxic than metaflumizone technical and non

- mutagenic like the parent com pound.

4. 4 SF for Infants and Children (FQPA SF)

The metaflumizone risk assessment team recommends that the FQPA SF be reduced from 10x to 3x for all oral exposure scenarios, be retained at 10x for inhalation exposure scenarios, and be reduced to 1x for dermal exposures.Metaflumizone Human Health Risk Assessment D4 2 1321

Page 14 of 38 

### 4. 4 .1 Completeness of the Toxicology Database
The toxicological database for metaflumizone is adequate for risk assessment and FQPA SF evaluation. The following acceptable studies are available for FQPA consideration: developmental toxicity studies in rats and rabbits; two

- genera tion reproduction study in rats; and acute neurotoxicity (ACN) and subchronic neurotoxicity (SCN) studies in rats

. An immunotoxicity study has also been submitted and reviewed by the Agency for FQPA SF evaluation.
A difference in absorption was noted bet ween oral gavage and dietary dosing

. Absorption via the diet, a more relevant route of exposure for oral human risk assessments, was noted to be greater than via gavage by a factor of 2. Therefore, toxicity via the diet can be expected at doses that are approximately 2

- fold lower than those currently selected for dietary and incidental oral risk assessments, which are based on gavage dosing. Thus, an FQPA SF of 3x is being retained in the form of a database uncertainty factor (UF) for all oral exposure s cenarios to protect against any toxicity that might result via the dietary (oral) route.
In the case of inhalation exposure scenarios, the FQPA SF of 10x is being re tained as an UF for the use of a LOAEL in the absence of a no

- observed adverse

- effect leve l (NOAEL ) from a 28

- day inhalation study

. The reduction of the FQPA SF from 10x to 1x for dermal exposure scenarios is justified since there is a route

- specific study with a clear NOAEL

.
4. 4 .2 Evidence of Neurotoxicity
Clinical signs indicative of neurotoxicity were observed in several studies; however, these signs were generally observed in the presence of poor animal health (e.g., reduced general health condition, loss of body weight, death). In addition, no neuropathology was observed in any
stu dy with metaflumizone. No signs of abnormal offspring behavior, central nervous system (CNS) malfo r mations, effects on offspring brain weights, or effects on offspring sexual maturation were observed in the developmental or two

- generation reproduction stu dies. No adverse effects were reported on motor activity or in the functional observational battery in the chronic/carcinogenicity study in rats. There was no evidence of neurotoxicity in the acute neurotoxicity test in rat s up to the limit dose.

4

. 4. 3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There are no residual concerns or uncertainties for increased sensitivity/susceptibility in developing animals resulting from pre

- and/or postnatal exposure.

4. 4 .4 Residual Uncertainty in the Exposure Database

The dietary analysis is conservative in that tolerance

- level residues, 100% crop treated, and modeled drinking water estimates were assumed. Therefore, HED concludes that while the submission of data/information by the petitioner addressing the residue chemistry deficiencies identified in a previous petition ( PP#5F6944; D 308394, T. Bloem, 30

- Nov

- 2005 ) may conceivably result in adjustment of the maximum theoretical residue estimate, actual metaflumizone dietary exposu re estimates will not be greater than those generated in the current risk assessment (i.e., incorporation of anticipated residues, percent crop treated estimates, and/or refined drinking water estimates will compensate for any increase in the maximum theor etical residue). The residential analysis is conservative in that health

- protective assumptions were assumed along with the use of the Residential Standard Operating Procedures ( SOPs )

.Metaflumizone Human Health Risk Assessment D4 2 1321

Page 15 of 38 

### 4. 5 Toxicity Endpoint and Point of Departure (POD) Selections

Acut e Dietary Endpoint (General population including infants and children): An acute dietary endpoint was not established for this population group since an endpoint of concern (effect) attributable to a single dose was not identified in the database. Studie s considered for this endpoint included the acute neurotoxicity study for which a LOAEL was not observed.

Acute Dietary Endpoint (Females 13

- 49 years old): This endpoint was established based on a developmental effect observed in the rabbit development al toxicity study that can be potentially due to a single dose of metaflumizone. The effects consisted of an absent subclavian artery in the offspring at the LOAEL of 300 mg/kg bw/day metaflumizone (NOAEL = 100 mg/kg bw/day). The rat developmental toxici ty study was also considered for this endpoint; however, no developmental effects were observed in this study at the highest dose tested of 120 mg/kg bw/day metaflumizone. A combined UF of 300 was applied to account for interspecies (10x) and intraspecies (10x) extrapolation

, and a FQPA SF of 3x was retained because the rabbit developmental toxicity study was performed via oral gavage dosing. Dietary exposures (which are more relevant for human exposures) exhibited an approximately 2

- fold greater absorpti on into the systemic circulation and, thus, can potentially lead to toxicity at 2

- fold lower levels of exposure. Thus, the aPAD for females 13

- 49 years old is estimated to be 0.33 mg/kg bw/day.

Chronic Dietary Endpoint: This endpoint was based on results of a chronic toxicity study in dogs via capsule administration. The effects at the LOAEL of 30 mg/kg bw/day (NOAEL = 12 mg/kg bw/day) consisted of reduced general health condition, slight to severe ataxia, recumbency, an d severe salivation, decreases in MCHC and total Hb and increased bilirubin, increased urobilinogen, and increased hemosiderin in the liver. A combined UF of 300 was applied to account for interspecies (10x) and intraspecies (10x) extrapolation

, and an FQ PA factor of 3x was retained for the higher absorption observed with dietary exposures to metaflumizone (see above). Thus, the cPAD is estimated to be 0.040 mg/kg bw/day.

Incidental Oral (Short

- and Intermediate

- Term): This endpoint was selected on the basis of the
matern al effects observed in the rat two

- generation reproductive toxicity study at the LOAEL of 50 mg/kg bw/day metaflumizone (NOAEL = 20 mg/kg bw/day). Maternal toxicity consisted of poor general health and body

- weight deficits that were als o associated with improper nursing behavior. Similar effects were also noted in a developmental neurotoxicity study (gavage, range finding) also considered for this endpoint

. In this study, poor maternal health was also observed at the LOAEL of 120 mg/kg bw/day metaflumizone (NOAEL = 80 mg/kg bw/day). Both studies considered for this endpoint achieved a clear NOAEL for the offspring effects, but the NO AEL of 20 mg/kg bw/day for the two

- generation reproductive toxicity study is considered more protective. A combined UF of 300 was applied to account for interspecies (10x) and intraspecies (10x) extrapolation

, and an FQPA SF of 3x to account for the 2

- fold greater absorption observed in dietary versus oral gavage exposures (see above). The LOC is 300.

Der mal (Short

- and Intermediate

- Term): This endpoint was based on a rat 90

- day dermal toxicity study in which deficits in body weight, body

- weight gain and food consumption (in males and females); anogenital smearing; increased macrophages in the thymus; ly mphocyte necrosis in the mesenteric lymph nodes; diffuse atrophy of the mandibular lymph node; and increased hemosiderin in the liver (females only) were observed at the LOAEL of 300 mg/kg bw/day (NOAEL = 100 mg/kg bw/day). The LOC , for both occupational and residential exposure, is 100 based on a combined UF of 100 for interspecies (10x) and intraspecies (10x) extrapolation.Metaflumizone Human Health Risk Assessment D4 2 1321

Page 16 of 38 

### Inhalation (Short

- and Intermediate

- Term): There is a 28

- day inhalation study that is adequate for both exposure durations. There was no NOAEL identified for female rats. At the LOAEL of 0.10 mg/L metaflumizone (NOAEL = 0.03 mg/L), histopathology of the nasal tissues, lungs, thymus, prostate, and adrenal cortex was observed in males. The LOAEL of 0. 0 3 mg/L identified in females re sulted in lymphocyte necrosis in the mesenteric lymph node.

The methods and dosimetry equations described in EPA’s reference concentration (RfC) guidance (1994) are suited for calculating HECs (human

- equivalent concentration) based on the inhalation tox icity point of departure ( N OAEL, LOAEL, or BMDL) for use in MOE calculations (See Appendix B ) . The regional

- deposited

- dose ratio (RDDR), which accounts for the particulate diameter (mass median aerodynamic diameter [MMAD] and geometric standard deviation [  g 

### ] of aerosols), can be used to estimate the different dose fractions deposited along the respiratory tract. The RDDR is also based on interspecies differences in ventilation and respiratory

- tract surface areas

. Thus, the RDDR can be used to adjust an observed inhalation particulate exposure of an animal to the predicted inhalation exposure for a human. For the subchronic inhalation toxicity study with metaflumizone, an RDDR wa s estimated at 2.81 based on systemic effects ( lymphocyte necrosis in the me senteric lymph node) in females at the LOAEL of 0.03 mg/L (no NOAEL established) and a MMAD of 1.7  m and  g 

### of 2.7.

For this action with metaflumizone, residential and occupational handler scenarios are being assessed

. F or residential handler scenarios, 2

- hr/day inhalation exposures are assumed. Adjustment to shorter exposure scenarios relative to the animal toxicity study duration ( e.g., 2 hr residential exposures) should only be made if there is time

- course information th at would support a shorter time

- frame

. Since there is no such information available for metaflu mizone, the unadjusted animal PO D w as used to assess the shorter duration residential handler exposures

. Thus, the HEC equals the LOAEL from the study was calc ulated to be 0.084 mg/L

. The FQPA SF of 10x is being retained for lack of a NOAEL for females in the study. The standard interspecies extrapolation UF can be reduced from 10 x to 3 x due to the HEC calculation accounting for pharmacokinetic (not pharmacodynamic) interspecies differences

. The intraspecies UF remains at 10 x

. Therefore, the LOC for this scenario is 300

, which includes the FQPA SF of 10x, interspecies (3 x ), and intraspe cies (10 x ) extrapolation.

For occupational exposure, the HEC is 0.063 23 mg/L. Three HEDs were subsequently calculated based upon the ventilation rates of 8.3, 16.7 and 29 L/min (3.6 , 7.24 and 12.57 mg/kg/day fo r respectively ). The safety factors, LOC i s 300 similar to that for the residential inhalation exposure scenarios. For details regarding the calculation of the HECs and HEDs, see Appendix B . These HEDs are protective of the systemic effects observed through the inhalation route. This study is t hus appropriate for the route and duration of exposure, and is protective of adults in occupational and residential settings.Metaflumizone Human Health Risk Assessment D4 2 1321

Page 17 of 38 

### 4.6 Recommendation for Combining Routes of Exposure for Risk Assessment

HED notes that route

- specific toxicity studies were selected for assessment of short

- /intermediate

- term dermal, inhalation, and oral exposures. Short/intermediate

- term dermal and inhalation exposures can be combined based on the immunotoxic effects seen a t the LOAEL in the selected studies. Short/intermediate

- term oral, dermal, and inhalation exposures can be combined based on the decreased body weight or decreased body

- weight gain effects seen at the LOAEL in the selected oral and dermal studies and at d oses above the LOAEL in the selected inhalation study. Tables 4.6.1 is a summary of the toxicological doses and endpoints selected for dietary and non

- occupational risk assessment and Table 4.6.2 is a summary of the toxicological doses and endpoints selec ted for occupational risk assessment.

Table 4

. 6 .1: Summary of Toxicological Doses and Endpoints for Metaflu mizone for Use in Dietary and Non

Occupational Human Health Risk Assessments

. 1
Exposure Scenario Dose Used in Risk

Assessment, UF FQPA SF or LOC for Risk Assessment Study and Toxicological Effects

Acute Dietary

general population, including infants and children N/A N/A An endpoint of concern (effect) attributable to a single dose was not identified in the database. Quantification of acute risk to general population including infants and children is not required. Acute Dietary

females 13

- 49 years old NOAEL = 100

mg/kg/day UF = 100 FQPA SF = 3x

aPAD = aRfD = 0.33 mg/kg/day Developmental toxicity (rabbit; gavage dosing); Offspring LOAEL = 300 mg/kg/day based on absent subclavian artery.

Chronic Dietary

general population, including infants and children NOAEL = 12 mg/kg/day

UF = 100 FQPA SF = 3x

cPAD =c RfD = 0.04 mg/kg/day Chronic toxicity (dog; capsule dosing); LOAEL = 30 mg/kg/day based on reduced general health condition, slight to severe ataxia, recumbency, and severe salivation, decreases in MCHC and total Hb and increased bilirubin, increased urobilinogen, and increased hemosiderin in the liver. Short

- (1

- 30 days) and Intermediate

- (1

- 6 months) Term Incidental Oral NOAEL = 20 mg/kg/day LOC (residential) = MOE < 300 Two

- generation reproduction (rat); Maternal LOAEL = 50 mg/kg/day based on poor general health and decreased body weight.

Short

- (1

- 3 0 days) and Intermediate

- (1

- 6 months) Term Dermal NOAEL = 100

mg/kg/day LOC (residential) = MOE < 100 90

- day dermal (rat); LOAEL = 300 mg/kg/day based on decreased BW gain and food consumption (M&F); anogenital smearing, decreased BW, increased macrophage s in the thymus, lymphocyte necrosis in the mesenteric lymph nodes, diffuse atrophy of the mandibular lymph node, and increased hemosiderin in the liver (F).

Short

- (1

- 30 days) and Intermediate

- (1

- 6 months) Term Inhalation LOAEL = 0.030 mg/L

NOAEL not observed LOC (residential) = MOE < 300 28

- day inhalation (rat); LOAEL = 0.03 mg/L * based lymphocyte necrosis in the mesenteric lymph node (F). HEC = 0.084 mg/L 2 HED = 2.4 mg/kg/day 3
Cancer (oral, dermal, inhalation) Classification: Not likely to be carcinogenic to humans.

1 UF = uncertainty factor, FQPA SF = FQPA Safety Factor, NOAEL = no

- observed adverse

- effect level, LOAEL = lowest

observed adverse

- effect level, RfD = reference dose (a = acute, c = chronic), PAD = population

- adjusted dose, MOE = margin of exposure, LOC = level of concern, N/A = n ot a pplicable, UF L = uncertainty factor for lack of a NOAEL and extrapolation of a 28

- day study for longer durations.

2 HEC = LOAEL x RDDR = 0.030 x 2.809 = 0.084
3 H ED = human

- equivalent dose = HEC x human specific conversion factor (CF) x relative activity factor (AF) x exposure duration = 0.084 mg/L x 11.8 L/hr/kg BW x 1.2 x 2 hrs = 2.4 mg/kg/dayMetaflumizone Human Health Risk Assessment D4 2 1321

Page 18 of 38 Table 4.6.2

. Summary of Toxicological Doses and Endpoints for Metaflumizone for Use in Occupational Hu man Health Risk Assessments

. 1

Exposure Scenario Dose Used in Risk Assessment, UF FQPA SF or LOC for

Risk Assessment Study and Toxicological Effects

Short

- (1

- 30 days) and Intermediate

- (1

- 6 months) Term Dermal NOAEL = 100 mg/kg/day LOC ( occupational) = MOE < 100 90

- day dermal (rat); LOAEL = 300 mg/kg/day based on decreased BW gain and food consumption (M&F); anogenital smearing, decreased BW, increased macrophages in the thymus, lymphocyte necrosis in the mesenteric lymph nodes, diffuse atrophy of the ma ndibular lymph node, and increased hemosiderin in the liver (F).

Short

- (1

- 30 days) and Intermediate

- (1

- 6 months) Term Inhalation LOAEL = 0.030 mg/L NOAEL not observed LOC ( occupational) = MOE < 300 (includes 10x FQPA SF in form of UF L ) 28

- day inhalation (rat); LOAEL = 0.03 mg/L * based lymphocyte necrosis in the mesenteric lymph node (F). HEC = 0.063 23 mg/L 2 HEC (8.3 L/min) = POD of 3.6 HEC (16.7 L/min) = POD of 7.24 HEC (29 L/min) = POD of 12.57 Cancer (oral, dermal, inhalation) Classification: Not likely to be carcinogenic to humans.

1 UF = uncertainty factor, FQPA SF = FQPA Safety Factor, NOAEL = no

- observed adverse

- effect level, LOAEL = lowest

- observed adverse

effect level, MOE = margin of exposure, LOC = level of concern, UF L = uncertainty factor for lack of a NOAEL

2 Human equivalent doses (HEDs) corresponding to the ventilation rates of 8.3, 16.7, and 29 L/min were calculated as 3.6, 7.24, and 12.57 mg/kg/day, respectively, for occupational activities. Human Equivalent Conce ntration (HEC).The human concentration (for inhalation exposure) or dose (for other routes of exposure) of an agent that is believed to induce the same magnitude of toxic effect as the experimental animal species concentration or dose.Metaflumizone Human Health Risk Assessment D4 2 1321

Page 19 of 38 

### 5.0 Dietary Expo sure and Risk Assessment D421322, T. Bloem, 12

- Aug

- 2014 (aerial application to citrus, grape, and tree nuts) D4 25292 , T. Bloem

, 29

- Sep

- 201 5 ( pome fruit and stone fruit) D4 25293 , T. Bloem, 29

- Sep

- 201 5 (dietary exposure analysis)



### 5.1 Metabolite/Degradate Residue Profile

HED has previously reviewed cabbage, cotton, tomato, ruminant

, and poultry metabolism studies as well as a confined rotational crop study. Based on these data, HED concluded that the residues of concern are as defined in Table 4.0.1. The available data are adequate to support the proposed uses. HED notes that future petitions, depending on the proposed use pattern, may require additional metabolism data.

Table 4.0.1: Residues of Concern for Tolerance Expression and Risk Assessment.

Matrix Residues I ncluded in Risk Assessment Residues I ncluded in Tolerance Expression
P lants 1 metaflumizone (E and Z isomers) and M320I04 metaflumizone (E and Z isomers) and M320I04
L ivestock (excluding ruminant liver) 2 metaflumizone (E and Z isomers) metaflumizone (E and Z isomers)
Livestock ruminant liver 2 metaflumizon e (E and Z isomers) and M320I28 3 metaflumizone (E and Z isomers)
R otational crops metaflumizone (E and Z isomers) and M320I04 metaflumizone (E and Z isomers) and M320I04

1 D304496, R. Mitkus et al. , 24

- Jan

- 2006; D421320 , T. Bloem, 6

- Aug

- 2014

2 For future petitions, these conclusions will be re

- evaluated; see Section 5.1.6 of D304496 (R. Mitkus et al. , 24

- Jan

- 2006).
3 Acetonitrile and acetic acid microwave extraction of the methanol extracted liver residues results in the formation of M320I28 (microwave

- assisted cleavage and/or derivatization; common moiety method).



### 5.2 Food Residue Profile

Pome Fruit and Stone Fruit: The petitioner is proposing application of AltrevinTM to pome fruit and stone fruit. No new residue data were submitted in conjunction with this request. Instead, the petitioner is proposing t ranslation of the previously submitted/reviewed citrus (47235703.de1; 47235703.de2), grape (47235702.der), and tree nut (47235701.der) metaflumizone residue data to pome fruit and stone fruit.

The HED Chemistry Science Advisory Council (ChemSAC) was consulted concerning the proposed residue translation. The ChemSAC concluded that provided the proposed pome fruit and stone fruit application scenarios were identical to that employed in the citrus, grape, and tree nut magnitude of the residue studies and b ased on the available field trial, processing, and rotational crop data, the proposed residue translation was accept able (ChemSAC minutes 23

- Oct

2013). Since the proposed application scenarios are identical to that preformed in the referenced field trials and based on these data, HED is recommending for the establishment of a 0.04

- ppm tolerance in/on pome fruit and sto ne fruit (tolerances in/on the processed commodities are unnecessary). In addition, since the representative crops for the updated citrus and tree nut crop groups are identical to that for the old crop groups, HED concludes that the proposal to update the crop group commodity definitions is also acceptable. No additional data are required.

Aerial Application to Citrus, Grape, and Tree Nuts: The petitioner is proposing a label amendment permitting aerial application of AltrevinTM to citrus, tree nut, and grape . The proposed application scenario is identical to the currently

- registered with the exception that the label will permit aerial application. Th e ChemSAC was consulted concering the need for additional data and concluded that the currently avai lable data and toelrances were adequate (ChemSAC minutes 29

- Jan

- 2014 ). The ChemSAC did note that for crops where granules may get lodged in the edible portion of the plant (e.g., around an apple stem), this type of translation may not be appropriate.Metaflumizone Human Health Risk Assessment D4 2 1321

Page 20 of 38 

### 5. 3 Drinking Water Residue Profile

Table 5 .3.1 is a summary of metaflumizone surface water and groundwater estimated drinking water concentrations (EDWCs) provided by EFED (D421741, M. Ruhman, 30

- Mar

- 2015). The EDWCs were generated using the following mod els: Surface Water Concentration Calculator (SWCC) and the Pesticide Root Zone Model

– Groundwater (PRZM

- GW). The modeled application scenario yields the highest EDWCs and these estimates were incorporated into the current assessment. The water models and their description are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/

.

Table 5.3.1 : Maximum Tier I Flutriafol EDWCs. 1

Model Yearly Application Rate Concentration (ppb) Groundwater ( PRZM

- GW) fly bait (26 x 0.0137 lb ai/acre) acute and chronic 1.09 x 10

- 12
Surface water ( SWCC ) fly bait (26 x 0.0137 lb ai/acre) acute 1.03 chronic 0.487

1 Bolded estimates were incorporated into the current analyses.



### 5.4 Dietary (Food + Drinking Water) Risk Assessment
Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using DEEM

- FCID TM ( ver. 3.16) which incorporates food consumption data from the USDA NHANES/WWEIA ( 2003

- 2008). The acute and chronic analyses assumed tolerance

- level residues

, 100% crop treated, and modeled drinking water estimates. Since adequate processing studies have b een submitted which indicate that tolerances in/on grape raisin, grape juice, citrus juice, tomato puree, and tomato juice are unnecessary, the DEEM (ver. 7.81) default processing factors for these commodities were reduced to 1. F or tomato paste, the DEEM (ver. 7.81) default processing factor was also reduced to 1 because a separate tolerance for this commodity is established. For the remaining relevant commodities, the DEEM (ver. 7.81) default processing factors were retained. Based on an assessment by the Environmental Fate and Effects Division (EFED) which concluded that metaflumizone has a high potential to bioaccumulate in aquatic food webs, the current analysis included the KABAM ( ver. 1.0 ) piscivorus fish estimate for fish/shellfish.

An acute en dpoint of concern was not identified in the toxicological database for the general U.S. population including infants and children; however an acute toxicological endpoint was identified for females 13

- 4 9 years of age. The resulting acute ( 1.6 % a PAD) and c hronic (≤ 7.2 % cPAD; children 1

- 2 years old were the most highly exposed subgroup) analyses resulted in risk estimates that are not of concern to HED (see Table 5.4.1)

.

Table 5.4.1 : Summary of the Acute and Chronic Dietary Exposure and Risk.

Population aPAD

(mg/kg/day) Exposure

(mg/kg/day) 1 %aPAD cPAD (mg/kg/day) Exposure

(mg/kg/day) %cPAD

General U.S. Population

An endpoint of concern (effect) attributable to a single dose was not identified in the database. Quantification of acute risk to these populations is not required. 0.04 0.001527 3.8 All Infants 0.000840 2.1 Children 1

- 2 years old 0.002864 7.2 Children 3

- 5 years old 0.002433 6.1 Children 6

- 12 years old 0.001663 4.2 Youth 13

- 19 years old 0.001095 2.7 Adults 20

- 49 years old 0.001466 3.7 Adults 50

- 99 years old 0.001498 3.7 Females 13

- 49 years old 0.33 0.005288 1.6 0.001264 3.2

1 95 th percentile (tier 1 analysis)Metaflumizone Human Health Risk Assessment D4 2 1321

Page 21 of 38 

### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no new residential uses associated with this regulatory action. Metaflumizone is registered for application as a fire ant bait to lawns, landscapes, golf courses, and other non

cropland and as a granular fly bait around industrial buildings, com mercial facilities, agricultural
structures /

premises , and recreational facilities / areas. Res idential exposure resulting from these exist i ng uses were reassessed to conform with the most recent policies and guidance (D414616, K. Lowe, 21

- Nov

- 2013).

As a result of these registered uses, residential handler ( s hort

- term d ermal and inhalation
exposures ) and post

- application ( short

- term dermal and incidental oral ) exposures are expected and were assessed (see Table 6.0.1 and 6.0.2)

. No risks of concern w ere identified for any scenario

. Table 6.0.3 is a summary of the residential exposure scenario s which should be included in the aggregat e risk assessment

.

Table 6.0.1 : Residential Handler Exposure and Risk Estimates for Existing Residential Uses.

Scenario Formulation Equipment Dose (mg/kg/day) 1 MOE 2 ARI 3 Dermal Inhalation Dermal (LOC < 100) Inhalation

(LOC < 300 )

Lawns/ Turf Granule Push

- type rotary spreader 5.1E

- 06 1.6E

- 08 2.0E+07 1.5 E+08 140,000 Belly Grinder 1.2E

- 04 1.3E

- 08 8.1E+05 1.8 E+08 7,900
Spoon 1.8E

- 07 2.5E

- 09 5.6E+08 9.6 E+0 8 2,000,000

3.9E

- 05 5.4E

- 07 2.6E+06 4.4 E+0 6 9,400
Cup 3.2E

- 09 3.7E

- 10 3.2E+10 6.4 E+ 9 20,000,000

6.9E

- 07 8.1E

- 08 1.5E+08 3.0 E+07 92,000

1 See D414616 (K. Lowe, 21

- Nov

- 2013) for determination of the dose . Application rates = 0.001 lb ai/ acre , 2.3 x 10

- 8 lb ai/ft 2 , or 0.0001 lb ai/mound based on fire ant bait product (see Table 4.1 in D414616 ).

2 MOE = POD (mg/kg/day) ÷ Dose (mg/kg/day) , where dermal POD = 100 mg/kg/day (LOC for MOEs < 100) and inhalation POD = 2.4 mg/kg/day ( LOC for MOEs < 300 )

. 3 ARI = 1 ÷ ( (Dermal LOC ÷ Dermal MOE) + (Inhalation LOC ÷ Inhalation MOE) ) , where dermal L OC = 100 and inhalation LOC = 3 00

. LOC for ARI s < 1.

Table 6.0.2 : Residential Post

- application Exposure and Risk Estimates for Existing Residential Uses. Use/Target Lifestage Post

- application Exposure Scenario Dose 1 (mg/kg/day) MOE 2 A RI 3

Tur f Adult Dermal

- High

- contact (playing) 0.0012 86,000

N/A 0.00008 1,200,000 Dermal

- Mowing 1.5E

- 06 65,000,000 Dermal

- Golfing 5.9E

- 06 17,000,000

Child 11<16 yrs Dermal

- Mowing 1.8E

- 06 57,000,000

Dermal

- Golfing 6.9E

- 06 15,000,000 Child 6<11 yrs Dermal

- Golfing 8.1E

- 06 12,000,000

Child 1<2 yrs Dermal (high

- contact play) 0.0023 44,000 380

I ncidental o ral

- Hand to Mouth 2.1E

- 05 950,000
I ncidental o ral

- Object to Mouth 1.3E

- 06 15,000,000 N/A I ncidental o ral

- Incidental Soil Ingestion 4.7E

- 07 42,000,000

1 Dose (mg/kg/day) equations provided in D414616 (K. Lowe, 21

- Nov

- 2013) . Application rates = 0.001 lb ai/A based on fire ant bait product (see Table 4.1 ) and 0.014 lb ai/A based on the fly bait product (see Table 4.1 in D414616 )

. 2 MOE = POD (mg/kg/day) ÷ Dose (mg/kg/day), where dermal POD = 100 mg/kg/day (LOC for MOEs < 100) and incidental oral POD = 20 mg/kg/day ( LOC for MOEs < 300 )

. 3 ARI = Aggregate Risk Index = 1÷ ( (Dermal LOC ÷ Dermal MOE) + ( Incidental oral LOC ÷ Incidental o ral MOE) ) , where dermal LOC = 10 0 and incidental oral LOC = 300

. LOC for ARI s < 1.Metaflumizone Human Health Risk Assessment D4 2 1321

Page 22 of 38 Table 6.0.3 : Recommendations for the Residential Exposures for Aggregate Assessment. 1 ,2

Lifestage (Scenario) Dose (mg/kg/day) MOE

Dermal Inhalation Oral Dermal (LOC < 100) Inhalation

(LOC < 300) Oral

(LOC < 300) Total 3

Residential Handler Adult Male (Belly Grinder) 1.2E

- 04 1.3E

- 08 N / A 8 10,000 59 0,000,000 N/A ARI = 7,900

Residential Post

- application
Adult Male ( h igh

contact activity on turf

) 0.0012 N/A N/A 86,000 N/A N/A MOE = 86,000 Child ( high

- contact activity on turf) 0.0023 N / A 2.1E

- 05 44,000 N / A 950,000 ARI = 380

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

2 Listed are the highest are the highest handler and post

- application dose/MOEs for each applicable lifestage of all residential scenarios assessed.

3 ARI = 1÷ ( (Dermal LOC ÷ Dermal MOE) + (Incidental oral LOC ÷ Incidental oral MOE) )

. LOC for ARI < 1.



### 6.1 Residential Bystander P ost

- Application Inhalation Exposure

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 pestic ides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The agency has eval uated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219 ). During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is required for metaflumizone.

6.2 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application method s (e.g., groundboom and airblast) employed for metaflumizone

. The agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call

- In issued by EPA), 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 ; http:/

/www.epa.gov/opp00001/factsheets/spraydrift.htm ). The agency has also developed a policy on how to appropriately consider spray drift as a potential source of exposure in risk assessments for pesticides. The potential for spray drift will be quantitative ly evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures For Residential Risk Assess ment (SOPs)

- Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification of indirect non

- occupational exposure to drift.Metaflumizone Human Health Risk Assessment D4 2 1321

Page 23 of 38 

### 7.0 Aggregate Exposure/Risk Characterizati on
In accordance with the FQPA, HED aggregate s pesticide exposures and risks from dietary (food and water) and residential (dermal, inhalation, and/or incidental oral) sources. Based on the proposed/registered uses and since inhalation, dermal, and incid ental oral exposures can be combined , aggregate acute (dietary) , short

- term (dietary, incidental oral, and/or dermal) , and chronic (dietary) assessments were conducted.

7.1 Acute Aggregate Risk

Since there are no registered/proposed uses that result in acute residential exposure to females 13

- 49 years old (acute endpoint was not identified for the remaining populations), the acute aggregate exposure assessment consists of exposure from only food and water. The acute dietary exposure estimate for fema les 13

- 49 years old was 1 .6 % the aPAD and, therefore, does not exceed HED’s LOC (see Section 5. 4 ).

7 .2 Short

- Term Aggregate Risk

As indicated above, short

- term dermal, incidental oral, and/or inhalation residential exposures are anticipated and exposure via these routes can be combined based on a common toxic effect (see Section 4.6)

. Since the L OC for the various routes of exposure differ

, the aggregate risk estimates were calculated using the ARI approach (LOC for ARI < 1)

. The short

- term aggregate assessment combine d food and drinking water exposure with the highest potential residential exposure as outlined in Table 6.0.3 . Table 7 .2.1 is a summary of the short

- term aggregate risk estimates for metaflumizone . The aggregate ARIs are > 1 an d are

, therefore, no t of concern to HED (the populations assessed provide the worst

- case short

- term exposure estimates )

. It is noted that although only short

- term residential exposure is anticipated, the short

- term assessment is protective on intermediate

- term exposure as the short and intermediate

- term PODs/LOCs are identical.

Table 7 .2.1: Short

- and Intermediate

- Term Aggregate Risk

.

Population Background Dietary + Incidental Oral Exposures Residential Exposures ARI 4

Oral LOC Chronic Dietary Exp

. (mg/kg/day) 1 Incidental Oral

Exp

. (mg/kg/day) 1 Oral

MOE 2 Dermal

LOC Dermal Exp. (mg/kg/day) 1 Dermal

MOE 3

Adults 50

- 99 years old 300 0.001498 NA 13,000 100 0.0012 8 6 ,000 42

Children 1

- 2 years old 0.00 2864 0.000 0 21 7,000 0.00 23 44,000 22

1 See Table 5.4.1 (dietary) and Table 6 .0. 3 (residential)

. 2 Oral MOE = NOAEL (20 mg/kg/day) ÷ (chronic food/water exposure + incidental oral exposure).

3 Dermal MOE = NOAEL (100 mg/kg/day) ÷ (dermal exposure).

4 ARI ( Aggregate Risk Index) = 1 ÷ (( Oral LOC ÷ Oral MOE) + ( Dermal LOC ÷ Dermal MOE)); ARI > 1 indicates an acceptable exposure.



### 7.3 Chronic Aggregate Risk

Since there are no registered/proposed uses that result in chronic residential exposure, the chronic aggregate exposure assessment consists of expos ure from food and water. The chronic dietary exposure estimate was ≤ 7.2 % the cPAD and, therefore, does not exceed HED’s LOC (see Section 5. 4 ).

7.4 Cancer Aggregate Risk

An aggregate cancer risk assessment was not performed because metaflumizone is no t considered to be a carcinogen.Metaflumizone Human Health Risk Assessment D4 2 1321

Page 24 of 38 

### 8.0 Cumulative Exposure/Risk 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 metaflumizone and any other substances and metaflumizone does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that metaflumizone has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to dete rmine which chemicals have 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 cumul ating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization D421322, J. Miller, 2 0

- Nov

- 2014



### 9.1 Occupational Handler Exposure/Risk Assessment

Based on the proposed use patterns, types of equipment

, and techniques that can potentially be used, short

- and intermediate

- term dermal and inhalation occupational handler exposure for the following scenarios are expected: (1) m ixing/ l oading a granular formulation to support aerial applications, (2) a pplying granular formulations with aircraft, and (3) f lagging to support aerial granular formulation applications.

The metaflumizone product label directs mixers, loaders, applicators and other handlers to wear chemical

- resistant gloves and baseline PPE (long

- sleeved shirt, long pants, shoes plus socks, and no respirator). A summary of the risk estimate s representative of label

- prescribed PPE for mixers and loaders and with engineering controls for aerial applicator are provided in Table 9.1.1. The resulting exposure and risk estimates indicate that the re is no risks of concern fr om the proposed uses.

Table 9.1. 1 : Occupational Handler Non

- Cancer Exposure and Risk Estimates for Metaflumizone.

Exposure Scenario Crop or Target Dermal Unit Exposure (μg/lb ai) 1 Inhalation

Unit Exposure (μg/lb ai) 1 Max.

App. Rate 2 (lbs ai/ a cre) Area Treated

or Amount Handled Daily 3 ( a cres) Dermal

(LOC = 100) Inhalation (LOC = 300) Total

Dose (mg/kg/day) 4,9 MOE 5,9 Dose 6,9 (mg/kg/day) MOE 7,9 ARI 8,9

Mixer/Loader (Aerial

- Fixed Winged)

Orchards Citrus, Tree Nuts,

Stone/Pome fruit and Grapes 6.9

(BL/gloves) 2 1.7

(No Resp.) 0.001 350 0.000031 3,200,000 0.0000077 1,600,000 4,600

Nurseries 60 0.0000053 19,000,000 0.0000013 9,600,000 27,000 Applicator (Aerial

- Fixed Winged)

Orchards Citrus, Tree Nuts,

Stone/Pome fruit and Grapes 1.7

(Eng control) 1.3

(Eng. control) 0.001 350 0.0000077 13,000,000 0.0000059 2,100,000 6,600

Nurseries 60 0.0000013 76,000,000 0.0000010 130,000 41,000Metaflumizone Human Health Risk Assessment D4 2 1321

Page 25 of 38 Table 9.1. 1 : Occupational Handler Non

- Cancer Exposure and Risk Estimates for Metaflumizone.

Exposure Scenario Crop or Target Dermal Unit Exposure (μg/lb ai) 1 Inhalation

Unit Exposure (μg/lb ai) 1 Max.

App. Rate 2 (lbs ai/ a cre) Area Treated

or Amount Handled Daily 3 ( a cres) Dermal

(LOC = 100) Inhalation (LOC = 300) Total

Dose (mg/kg/day) 4,9 MOE 5,9 Dose 6,9 (mg/kg/day) MOE 7,9 ARI 8,9

Flagger (Aerial

- Fixed Winged)

Orchards Citrus, Tree Nuts,

Stone/Pome fruit and Grapes 2.73

(BL/gloves) 2 0.15

(No Resp.) 0.001 350 0.000012 8,100,000 0.00000068 19,000,000 36,000

Nurseries 60 0.0000021 47,000,000 0.00000012 110,000,000 21,0000

1 B ased on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table”; Level of mitigation: Baseline, PPE, Eng. Controls.

2 PPE and Maximum application rates are based on proposed label (Reg. No. 7969

- 270).
3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) ÷ BW (80 kg).
5 Dermal MOE = Dermal POD (mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal ) × Area Treated or Amount Handled (A or gal/day) ÷ BW (80 kg).

7 Inhalation MOE = Inhalation POD (mg/kg/day) ÷ Inhalation Dose ( mg/kg/day).
8 ARI = Aggregate Risk Index = 1÷ [(Dermal LOC ÷ Dermal MOE) + (Inhalation LOC ÷ Inhalation MOE)] ; LOC for ARIs < 1

. 9 Dermal and inhalation dose, MOE and ARI calculations for aerial application in orchards and nurseries are based on enginee ring control PPE.



### 9.2 Occupational Pos t

- Application Exposure/ Risk Assessment

The current proposes pertains to the application of a granular formulation via ground or aerial (fixed

- wing aircraft) equipment for the control of fire ants. HED believes that , even when applied aerially, most granules will fall to the orchard or nursery floor and will therefore not present a dermal post

- application exposure risk. Also, an occupational handler mixer/loader dermal exposure scenario was assessed and HED believes this to be protective of any post

application dermal exposure. The non

- cancer dermal risk estimate for commercial aerial mixer/loader application is not of concern (i.e., MOE > 100).

Restricted Entry Interval: The REI specified on the proposed label (12 hours) is based on the acute toxicity of metaflumizone. Metaflumizone is classified as Toxicity Category IV via the dermal route and Toxicity Category IV for skin irritation potential. It is not a skin sensitizer. Short

- and intermediate

- term post

- a pplication risk estimates were not a concern on day 0 (12 hours following application) for all post

- application activities. Under 40 CFR 156.208 (c) (2) (iii), ai’s classified as Acute III or IV for acute dermal, eye irritation and primary skin irritation are assigned a 12

- hour REI. Therefore, the [156 subpart K] Worker Protection Statement interim REI of 12 hours is adequate to protect agricultural workers from post

- application exposures to metaflumizone

.
RDI: RAB1 ( 7

- Apr

- 201 5 )

Appendix A. Toxicology Profile and Executive Summaries

. Appendix B. Methodologies for HEC Calculations. Appendix C : Physiochemical Properties Appendix D : Exposure to Metaflumizone in Fish/Shellfish at Consumption Levels Associated with Subsistence Fishing

.Metaflumizone Human Health Risk Assessment D4 2 1321

Page 26 of 38 

### Appendix A. Toxicology Profile and Executive Summaries

.

Table A.1: Acute Toxicity Profile

- M etaflumizone Technical (96% ai), Z

- isomer, and Metabolite M320I23.
Guideline No./Study Type MRID No. Results Toxicity Category
M etaflumizone Technical (96% ai) 870.1100/Acute oral toxicity rat 46264232 LD 50 => 5,000 mg/kg (males, females combined) IV 870.1100/Acute oral toxicity mouse 46264234 LD 50 => 5,000 mg/kg (males, females combined) IV 870.1200/Acute dermal toxicity rat 46264235 LD 50 > 5,000 mg/kg (males, females combined) IV 870.1300/Acute inhalation toxicity rat 46264236 LC 50 > 5.2 mg/L (males, females combined) IV 870.2400/Primary eye irritation rabbit 46264238 Conjunctivitis in 2/3, 1/3, 0/3 at 1, 24, and 48 hours, resp.;

no positive effects IV 870.2500/Primary dermal irritation rabbit 46264237 non

- irritant PII = 0 IV 870.2600/Dermal sensitization guinea pig 46264239 is not a sensitizer N/A Z

- isomer 870.1100/Acute oral toxicity rat 46264231 LD 50 => 5,000 mg/kg (males, females combined) IV Metabolite M320I23 870.1100/Acute oral toxicity rat 46264233 LD 50 => 2,000 mg/kg (HDT 1 ) (females) III
1 HDT=Highest Dose Tested

Table A.2: Subchronic and Chronic Toxicity and Genotoxicity Profile

– M etaflumizone Technical, Z

- isomer, and Metabolite M320I23. Guideline No./ Study Type MRID No. (Year)/Doses/ Classification Results

M etaflumizone Technical

4

- day palatability rats (Alternate

- day feeding regimen) 47036907 (2007)

Un acceptable/non

- guideline (individual animal data not submitted) Reduced food consumption and corresponding body weight losses occurred when treated diet was offered compared to control diet, indicating poor palatability of the diet when the test material i s incorporated as an admixture in feed.

5

- day palatability rats (Free

- choice regimen) 47036908 (2007)

Un acceptable/non

- guideline (individual animal data not submitted) When offered a choice of control feed or diet treated with 400 ppm of the test materi al, rats exhibited a strong preference for the control feed by avoidance of the treated diet. This avoidance indicates poor palatability of the diet when the test material is incorporated as an admixture in feed.

7

- day rats (gavage) 47036909 (2007)

0, 6, 16, or 28 mg/kg bw/day

Un acceptable/non

- guideline (individual animal and dose analysis data not submitted) No effects on food consumption or body

- weight gain. In contrast, significant decreases in food consumption and body

- weight gain were observed af

ter 7 days of treatment at similar doses via the diet (MRID 47036902)

90

- day oral rats (dietary) 47036902 (1999/2007)

0, 50, 100, 200, or 400 ppm (equivalent to 0, 3.8, 7.2, 13.7, or 26.3 mg/kg/day)

Acceptable (non

- guideline) NOAEL not established LOAEL = 50 ppm (3.8 mg/kg/day) based on decreased food consumption, body weights, and body

- weight gains, due to poor palatability of the test substance

28

- day oral rats (dietary) 47036903 (1999/2007)

0, 10, 20, or 40 ppm (equivalent to 0, 1.1, 2.2, or 4. 3 mg/kg/day)

Acceptable (non

- guideline) NOAEL = 20 ppm (2.2 mg/kg/day) LOAEL = 40 ppm (4.3 mg/kg/day) based on decreased food consumption, body

- weight gains, and body weights, due to poor palatability of the test substance

28

- day oral rats (dietary) 4703 6904 (2000) 0, 250, 1000, 5000, or 10,000 ppm (equivalent to 0/0, 27.2/23.8, 86.4/83.2, 417.5/360.6, or 798.1/783.0 mg/kg/day [M/F] Acceptable (non

- guideline) NOAEL not established LOAEL = 250 ppm ( 27.2/23.8 mg/kg/day) based on decreased food consumption, body

- weight gains, and body weights, due to poor palatability of the test substanceMetaflumizone Human Health Risk Assessment D4 2 1321

Page 27 of 38 Table A.2: Subchronic and Chronic Toxicity and Genotoxicity Profile

– M etaflumizone Technical, Z

- isomer, and Metabolite M320I23. Guideline No./ Study Type MRID No. (Year)/Doses/ Classification Results

28

- day oral mice (dietary) 47036905 (1999/2007)

0, 50, 200, or 800 ppm (equivalent to 0, 10, 42, or 101 mg/kg/day

Acceptable (non

- guideline) NOAEL = 50 ppm (10 mg/kg/da y) LOAEL = 200 ppm ( 42 mg/kg/day) based on decreased food consumption, body

- weight gains, and body weights, due to poor palatability of the test substance

28

- day oral mice (dietary) 47036906 (2001/2007)

0, 10, 20, or 40 ppm (equivalent to 0, 2.0, 4.3, or 8.2 mg/kg/day) Acceptable (non

- guideline) NOAEL = 40 ppm (8.2 mg/kg/day) LOAEL not established

870.3100 90

- day oral rats (gavage) 46264241 (2002)

0, 100, 500 or 1000 mg/kg/day

Unacceptable (guideline) NOAEL (28

- day) = 100 mg/kg/day LOAEL (28

- day) = 500 mg/kg/day based on decreased BW, BW gain and food consumption, and splenic extramedullary hematopoiesis and hepatocellular hypertrophy

NOAEL (90

- day) = not established LOAEL (90

- day) = not established It is noted that treatment

- related effects were no t identified in either sex at 100 mg/kg/day after 90 days.

870.3250 90

- day dermal rats 46264303 (2004)

0, 100, 300 or 1000 mg/kg/day

Acceptable (guideline) NOAEL = 100 mg/kg/day LOAEL = 300 mg/kg/day based on decreased BW gain and food consumption (M& F); anogenital smearing, decreased BW, increased macrophages in the thymus, lymphocyte necrosis in the mesenteric lymph nodes, diffuse atrophy of the mandibular lymph node, and increased hemosiderin in the liver (F)

870

. 3465 28

- day inhalation
rats 478393 01 (2004)

0, 0.03, 0.10, or 0.70 mg/L

Acceptable (non

- guideline) NOAEL= 0.03 mg/L (M) and not observed (F) LOAEL = 0.10 mg/L based on histopathology of the nasal tissues, lungs, thymus, prostate, and adrenal cortex (M); and 0.03 mg/L based on lymphocyte necrosis in the mesenteric lymph node (F).

870.3700 Developmental toxicity rats (gavage) 46264316 (2004)

0, 15, 40 or 120 mg/kg/day

Acceptable (guideline) Maternal NOAEL = 40 mg/kg/day Maternal LOAEL = 120 mg/kg/day based on decreased corrected BW gain (corrected for uterine weights)

Developmental NOAEL = 120 mg/kg/day (HDT) Developmental LOAEL > 120 mg/kg/day

870.3700 Developmental toxicity rabbits (gavage) 46264317 (2004) 0, 30, 100 or 300 mg/kg/day

Acceptable (guideline) Maternal NOAEL = 100 mg/kg/day Maternal LOAEL = 300 mg/kg/day based on abortions (GD 22 and 28), ataxia (GD 23

- 28), lateral recumbency (GD 26

- 29), and poor health state (GD 27

- 29) Developmental NOAEL = 100 mg/kg/day Developmental LOAEL = 300 mg/kg/day, based on absent subclavian artery

870.3800 2

- generation reproduction rats (gavage) 46264315 (2004)

P generation: 0, 12, 30 or 75 mg/kg/day (mid and high doses reduced to 20 and 50 mg/kg/day, resp., after 17 weeks of treatment)

F1 generation: 0, 12, 20 or 50 mg/kg/day

Acceptable (guideline) Parental NOAEL = 20 mg/kg/day Parental LOAEL = 50 mg/kg/day based on poor health state and decreased BW

Reproductive NOAEL = 20 mg/kg/day Reproductive LOAEL = 50 mg/kg/day based on improper nursing behavior

Offspring NOAEL = 20 mg/kg/day Offspring LOAEL = 50 mg/kg/day based on mortality (from birth to weaning)

870.4100 Chronic toxicity dogs (capsule) 46264302 (2004) 0, 6, 12 or 30 (60/40/30) mg/kg/day (dose level altered in high dose group) Acceptable (guideline) NOAEL = 12 mg/kg/day LOAEL = 30 mg/kg/day based on reduced general health condition, slight to severe ataxia, recumbency, and severe salivation (all clinical signs observed on ≥day 191); decreases in MCHC and total Hb and inc reased bilirubin, increased urobilinogen, and increased hemosiderin in the liverMetaflumizone Human Health Risk Assessment D4 2 1321

Page 28 of 38 Table A.2: Subchronic and Chronic Toxicity and Genotoxicity Profile

– M etaflumizone Technical, Z

- isomer, and Metabolite M320I23. Guideline No./ Study Type MRID No. (Year)/Doses/ Classification Results

870.4200 Carcinogenicity mice (gavage) 46264314 (2003)

0, 100, 250 or 1000 mg/kg/day

Acceptable (guideline) NOAEL = 250 mg/kg/day LOAEL = 1000 mg/kg/day (limit dose), based on incr. hemosiderin in the spleen, increased mean absolute reticulocyte count, and decreased mean corpuscular volume and mean corpuscular hemoglobin (M&F); and decreased BW gain (M). No evidence of carcinogenicity.

870.4300 Chronic Toxicity/Carcinogenic ity rats (gavage) 46264240 (2003)

0, 30, 60 or 300/200 mg/kg/day (high dose reduced to 200 mg/kg/day in females after 2 weeks of treatment)

Acceptable (guideline) NOAEL = 30 (M) and 60 mg/kg/day (F) LOAEL = 60 mg/kg/day based on basophilic hepatocellular alterations and hepatocellular hypertrophy (M); 200 mg/kg/day based on decreased BW, BW gain, and food consumption (F). No evidence of carcinogenicity.

870.5100 In Vitro bacterial reverse mutation (S. typhimurium/E. coli) 46264304 (2001)

15, 50, 150, 500, or 5000  g/plate (std. plate test) (

- /+ activation)

Acceptable (guideline) Negative.

870.5300 In Vitro mammalian gene mutation (CHO/HGPRT) 46264307 (2002)

0, 25.0, 50.0, 100.0, 156.3, 200.0, 312.5, 400.0, 625.0, 800.0, 1250.0, 2500.0 or 5000.0 μ g/mL (

- activation)

0, 50.0, 100.0, 156.3, 200.0, 312.5, 400.0, 625.0, 800.0, 1200.0, 1250.0, 2500.0 or 5000.0 μg/mL (+ activation)

Unacceptable (guideline) Inconclusive without metabolic activation due to compound precipitation at all concen trations tested

.

870.5375 In Vitro mammalian chromosomal aberration (V79) 46264309 (2002)

0, 3.125, 6.25, 12.5, 25.0 or 50.0 μ g/mL (

- activation);

0, 25.0, 50.0 or 100.0 μ g/mL (+ activation)

Acceptable (guideline) Positive without metabolic activation at soluble (12.5 μ g/mL) and insoluble (≥ 25 μ g/mL) concentrations.

Negative with metabolic activation.

870.5395 In Vivo mammalian cytogenetics (mouse micronucleus) 46264311 (2002)

0, 500, 1000 or 2000 mg/kg

Acceptable (guideline) Negative.

870.5550 UDS in mammalian cells 46264313 (2003)

0, 1000 or 2000 mg/kg

Acceptable (guideline) Negative.

870.6200 Acute neurotoxicity rats (gavage) 46264318 (2003)

0, 125, 500, or 2000 mg/kg/day Acceptable (guideline) NOAEL = 2000 mg/kg/day (HDT) LOAEL > 2000 mg/kg/day

870.6200 Subchronic neurotoxicity rats (gavage) 46264319 (2003)

0, 12, 36, 150 or 300 mg/kg/day Acceptable (guideline) NOAEL = 36 mg/kg/day LOAEL = 150 mg/kg/day, based on death, reduced general condi tion, and piloerection (M&F); hyperthermia (M); abnormal squatting posture, hypothermia, decreased BW, BW gain, and food consumption (F)Metaflumizone Human Health Risk Assessment D4 2 1321

Page 29 of 38 Table A.2: Subchronic and Chronic Toxicity and Genotoxicity Profile

– M etaflumizone Technical, Z

- isomer, and Metabolite M320I23. Guideline No./ Study Type MRID No. (Year)/Doses/ Classification Results

870.6300 Developmental Neurotoxicity rats (gavage) (range

finding) 47839302 (2005)

0, 50, 80, or 120 mg/kg bw/day Maternal NOAEL = 80 mg/kg/day Maternal LOAEL = 120 mg/kg/day, based on poor general state and total litter loss in both cohorts.

Offspring NOAEL = 80 mg/kg/day Offspring LOAEL = 120 mg/kg/day based on pup mortality

870.7485 Metabolism rats (gavage) 46264 230 (2002)

30 and 1000 mg/kg (single dose)

30 mg/kg (14

- day repeated dosing)

Acceptable (guideline) Following a single oral dose of [benzonitrile ring

- U

14 C] and [trifluoromethoxyphenyl ring

- U

14 C] metaflumizone, the amount of absorption was < 7.5% for the 30 mg/kg dose group and <2% for the 1000 mg/kg dose group after 72 hours. The majority (>90%) of the two doses

were excreted in the feces. Biliary excretion accounted for <5% of the low dose and <2% of the high dose. Urinary excretion was al so low at 1

- 2%. The absorbed doses were distributed quickly to the muscle, liver, kidney, and fat within 0.5

- 2 hours. Total radioactivity in muscle, liver, kidney, blood, and plasma reached maximal levels at or near the blood T max irrespective of sex or dose. Near the blood T max , radioactivity was highest in fat or liver, followed by kidney and blood/plasma/muscle. Unchanged parent accounted for the majority of radioactive residue in muscle, liver, kidney, fat and plasma. BAS 320I was metabolized via h ydroxylation of the aniline or benzonitrile ring and hydrolysis of the central hydrazine carboxamide group to yield the aniline derivatives and phenacyl benzoylnitrile derivatives. The trifluoromethoxyaniline was shown to conjugate with malonic and oxalic acids. Glycine conjugation occurred at the carboxyl group of the cyanobenzoic acid. Glutathione conjugation occurred by displacement of one of the fluorine atoms of the trifluoromethyl or trifluoromethoxy group to form S

- (N

- (N

- γ

- glutamyl))

- cysteinyl

- , gl ycyl

- conjugate.

After 14 days of daily dosing at 30 mg/kg/day, metaflumizone concentrations were up to 26 (muscle), 13 (liver), 13 (kidney), 43 (fat), and 26 (plasma) times higher than those found after a single oral dose. [Trifluoromethoxyphenyl ring

- U

14 C]

- labeled parent/metabolite(s) appeared to partition into RBCs, rather than plasma, in both sexes after 14 days of dosing.

Single, low

- dose absorption study (gavage vs dietary) 47249001 (2007)

0.73 mg/kg bw (single

- dose gavage) 0.76 mg/kg bw (single

- dose dietary) Unacceptable/non

- guideline (biliary excretion not measured) 10.8% absorption via gavage 23.0% absorption via diet

Although measurement of radioactivity excreted into the bile was not made and is necessary for a complete characterization of absorption, study data indicate that the relative percentage of administered dose excreted into bile under either dosing regimen would be similar 870.7800 Immunotoxicity 28 days (oral gavage) 48448601(2011) 0, 15, 40, or 75 mg/kg/day Immunotoxicity: NOA EL = 75 mg/kg bw/day LOAEL = not identified Systemic toxicity: NOAEL = 40 mg/kg bw/day LOAEL = 75 mg/kg bw/day based on decreases in body weights, body

weight gains, and food consumption. Z

- isomer

870.3100 3

- month oral
rats

- gavage 46264301 (2004)

0, 100, 300 or 1000 mg/kg/day

Acceptable (guideline) NOAEL = 100 (F) and 300 (M) mg/kg/day LOAEL = 300 (F) and 1000 (M) mg/kg/day, based on mortality, clinical signs (reduced general condition and piloerection), and lymphocyte necrosis in the mesenteric lymph node (F) and decreased motor activity (M&F)

870.5100 In Vitro bacterial reverse mutation (S. typhimurium/E. coli) 46264305 (2002)

20

- 5000 μ g/plate (std. plate test) (

- /+ activation)

4

- 2500 μ g/plate (preincubation assay) (

- /+ activation) Acceptable (guideline) Negative with and without metabolic activation.Metaflumizone Human Health Risk Assessment D4 2 1321

Page 30 of 38 Table A.2: Subchronic and Chronic Toxicity and Genotoxicity Profile

– M etaflumizone Technical, Z

- isomer, and Metabolite M320I23. Guideline No./ Study Type MRID No. (Year)/Doses/ Classification Results

Metabolite M320I23

870.3100 3

- month oral rats

- gavage 46264242 (2004)

0, 50, 200, or 1000 mg/kg/day

Acceptable (guideline) NOAEL = 1000 mg/kg/day (HDT) LOAEL > 1000 mg/kg/day

870.5100 In vitro bacterial reverse mutation (S. typhimurium, E. coli) 46264306 (2003)

20, 100, 500, 2500, or 5000 μg/plate (std. plate test) (

- /+ activation)

62.5, 125, 250, 500, 1500 μg/plate (preincubation assay) (

- /+ activation)

Acceptable (guideline) Negative with and without metabolic activation.

Negative with and without metabolic activation.

870.5300 In Vitro mammalian gene mutation (CHO/HGPRT) 46264308 (2004)

0, 0.125, 0.25, 0.5, 1.0, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, or 6.0 μ g/mL (

- activation)

0, 1.25, 2.5, 3.125, 5, 6.25, 10, 12.5, 15, 20, 25, 30, 40, 50, or 100 μ g/mL (+ activation)

Unacceptable (guideline) Negative without metabolic activation.

Inconclusive with metabolic activation due to compound precipitation at all concentrations tested

870.5375 In Vitro mammalian chromosomal aberration (V79) 46264310 (2004)

0, 0.25, 0.5 or 1.0 μg/mL (

- activation)

0, 1.0, 5.0, 7.5, 10.0 or 12.5 μg/mL (+ activation)

Acceptable (guideline) Negative without metabolic activation.

Positive with metabolic activation.

870.5395 In Vivo mammalian cytogenetics (mouse micronucleus) 46264312 (2004)

0, 500, 1000 or 2000 mg/kg

Acceptable (guideline) Negative.Metaflumizone Human Health Risk Assessment D4 2 1321

Page 31 of 38 

### Appendix B . Methodologies for HEC Calculations.

The RfC methodology applies a dosimetric adjustment that takes into consideration not only the differences in ventilation rate (MV) but also the physicochemical properties of the inhaled compound, the type of toxicity observed ( e.g., systemic vs. portal

- of

- entry) and the phar macokinetic (PK) but not pharmacodynamic (PD) differences between animals and humans. Based on the EPA’s RfC guidance (1994), the methodology for RfCs derivation is an estimate of the quantitative dose

- response assessment of chronic non

- cancer toxicity fo r individual inhaled chemicals and includes dosimetric adjustment to account for the species

specific relationships of exposure concentration to deposited/delivered dose. This adjustment is influenced by the physicochemical properties of the inhaled compo und as well as the type of toxicity observed ( e.g. , systemic vs. portal

- of

- entry), and takes into consideration the PK differences between animals and humans. Though the RfC methodology was developed to estimate toxicity of inhaled chemicals over a lifeti me, it can be used for other inhalation exposures ( e.g. , acute and short

- term exposures) since the dosimetric adjustment incorporates mechanistic determinants of disposition that can be applied to shorter duration of exposures provided the assumptions unde rlying the methodology are still valid. These assumptions, in turn, vary depending on the type of toxicity observed. Thus the derivation of a HEC for inhaled gases is described by the following equation:

Where: POD study 

### : Point of departure identified in the critical toxicology study D animal exposure 

### : Duration of animal exposure (hrs/day; days/wk) D anticipated exposure 

### : Anticipated human duration of exposure (hrs/day; days/wk) RGDR: Regional Gas Dose Ratio

Calculations used to estimate the inhalatio n risk to humans from aerosols are dependent not on the RGDR as for gases, but on the regional deposited dose ratio (RDDR). Inhalation studies using aerosols characterize particulate exposure by defining the particulate diameter (mass median aerodynamic d iameter [MMAD]) and the geometric standard deviation (σ g 

### ), which is then used to determine the RDDR. The RDDR is a multiplicative factor used to adjust an observed inhalation particulate exposure concentration of an animal (A) to the predicted inhalation particulate exposure concentration for a human (H) that would be associated with the same dose delivered to the rth region or target tissue.

RDDR r 

### = (RDD r



### /Normalizing Factor) A 

### (RDD r 

### /Normalizing Factor) H


### As with calculations for gases, the r reg ions and potential target tissues are the three respiratory regions (ET, TB, PU). The RDDR is easily calculated by using a software program designed specifically for computing the RDDR from the MMAD and σ g 

### defined from an aerosol inhalation study. The va lues for the species

- specific parameters used to calculate the RDDR are provided in the EPA document “Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry.”Metaflumizone Human Health Risk Assessment D4 2 1321

Page 32 of 38 

### Regional Deposited Dose Ratio (RDDR) for Metaflumizone

MMAD = 1.7 Sigma g = 2.7

Body Minute SPECIES Weight (g) Ventilation (VE, ml)

----------------------------------------------------------------------------- rat 15 6 1 22.1 human 70000 13800.0

-----------------------------------------------------------------------------

Extra respiratory SA (m^2) deposited fraction

------------------------------------- ------------------------------------------- rat 15 6 0. 453 human 7000 0. 626

-------------------------------------------------------------------------------- RATIO 0.0 02 0.723

RDDR = (VE/ BW ) animal 

### /(VE/ BW ) human 

### * deposited fraction animal 

### /deposited fraction human 

### = (1 22.1 /15 6 ) animal 

### /(13800/ 70000 ) human 

### * 0.439/0. 626

= 2.77

The magnitude of the UFs applied is dependent on the methodology used to calculate risk. The RfC methodology takes into consideration the PK differences but not the PD differences

. Consequently, the UF for interspecies extrapolation may be reduced to 3X (to account for the PD differences) while the UF for intraspecies variation is retained at 10X. Thus, the UF when using the RfC methodology is customarily 30X.

B .1. HEC Calculations for Short

- and Intermediate

- term Residential Exposure:

Assume residents will be exposed for 24 hrs/day and 7 days/week:

HEC = NOAEL study 

### * (daily duration of exposure animal 

### /daily duration of exposure human 

### ) * (days/week of exposure animal 

### /days/week of exposure human 

### ) * RDDR

Residential Handler Outdoor HEC = 0. 03 mg/L * 2

. 8 = 0.0 8 4 mg/LMetaflumizone Human Health Risk Assessment D4 2 1321

Page 33 of 38 Table B .1. HEC Array for Residential Risk Assessment.
Relevant Study LOAEL (mg/L) NOAEL

(mg/L) Da Dh Wa Wh RDDR HEC (mg/L) inter intra UF

Short

- & Intermediate

- Term Exposure

Inhalation

– Rat (MRID 4 47839301 ) 2 8

- day E R 0

. 03

- See equations listed above table 2

. 8 Handler/Out door Postapp.

- 0.0 8 4 mg/L 3 10 10

Long

- Term Exposure: Not appropriate for metaflumizone

.

Key for Array Tables LOAEL : Lowest

- observed adverse

- effect level NOAEL : No

- observed adverse

- effect level Da : Daily animal exposure (hrs/day) Dh : Anticipated daily human exposure (hrs/day) Wa : Weekly animal exposure (days/week) Wh : Anticipated weekly human exposure (days/week) RRDR : Regional Deposited Dose Ratio HEC : Human

- Equivalent Concentration inter : Interspecies extrapolation UF intra : Intraspecies variation U F UF : Other UF(s) ET: Extra

- thoracic region



### Route

- to

- Route Extrapolation

More information and details in: Memo, “Route

- to

- Route Extrapolations” J. Whalen and H. Pettigrew, 10/10/98.

HED’s route

- to

- route extrapolation converts human and animal values from mg/L concentrations to mg/kg oral equivalent doses. The equation uses a single conversion factor to account for default body weights and respiratory volumes. An activity factor is u sed to account for increased exposure resulting from increased respiration.

Using the HEC calculated (based upon terminal airway inflammation in males), a conversion of the inhalation concentration to a dose (mg/L to mg/kg/day) was conducted as follows: HED (mg/kg/day) = Dose (systemic HEC value, mg/L) x A x CF (L/hr/kg) x D (hours) x AF = mg/kg

Where: A = absorption: ratio of deposition and absorption in respiratory tract compared to

absorption by the oral route. CF = conversion factor; a L/hr/kg fa ctor which accounts for respiratory volume and

body weight for a given species and strain (Table 1 of J. Whalen and H. Pettigrew, 10/10/98). D = duration; duration of daily animal or human exposure (hours). AF = activity factor; animal default is 1. For h umans with a ventilation rate of 16.7

L/min, the value is 1.2.

Therefore, the residential HED for metaflumizone is calculated as follows:

Residential Handler and Outdoor Post

- application HED: (0.0 8 mg/L) x 1.2 x 11.8 L/hr/kg xMetaflumizone Human Health Risk Assessment D4 2 1321

Page 34 of 38 

### 2 hr x 1 = 2.413 mg/kg/day

B .2. HEC Calculations for Short

- and Intermediate

- term Occupational Exposure: Assume workers will be in the field for 8 hrs/day and 5 days/week:

HEC = NOAEL study 

### * (daily duration of exposure animal 

### /daily duration of exposure human 

### ) * (days/week of exposure animal 

### /days/week of exposure human 

### ) * RDDR

HEC = 0. 03 mg/L * (6/8) * (5/5) * 2

. 8 = 0. 6323 mg/L.

Table C .1. HEC Array for Occupational Risk Assessment.
Relevant Study LOAEL (mg/L) NOAEL

(mg/L) Da Dh Wa Wh RDDR HEC (mg/L) inter intra UF

Short

- & Intermediate

- Term Exposure

Inhalation

– Rat (MRID 47839301 ) 2 8

- day ET 0.03

- 6 8 5 5 2.8 0.0 6 3 10 10

Long

- Term Exposure: Not appropriate for metaflumizone

.

Key for Array Tables LOAEL : Lowest

- observed adverse

- effect level NOAEL : No

- observed adverse

- effect level Da : Daily animal exposure (hrs/day) Dh : Anticipated daily human exposure (hrs/day) Wa : Weekly animal exposure (days/week) Wh : Anticipated weekly human exposure (days/week) RRDR : Regional Deposited Dose Ratio HEC : Human

- Equi valent Concentration inter : Interspecies extrapolation UF intra : Intraspecies variation UF UF : Other UF(s) ET: Extra

- thoracic region



### Route

- to

- Route Extrapolation

More information and details in: Memo, “Route

- to

- Route Extrapolations” J. Whalen and H. Pettigrew, 10/10/98.

HED’s route

- to

- route extrapolation converts human and animal values from mg/L concentrations to mg/kg oral

- equivalent doses. The equation uses a single conversion factor to account for default body weights and respiratory volumes. A n activity factor is used to account for increased exposure resulting from increased respiration.

Using the HEC calculated (based upon terminal airway inflammation in males), a conversion of the inhalation concentration to a dose (mg/L to mg/kg/day) was conducted as follows:

HED (mg/kg/day) = Dose (systemic HEC value, mg/L) x A x CF (L/hr/kg) x D (hours) x AF = mg/kg

Where:

A = absorption; ratio of deposition and absorption in respiratory tract compared to

absorption by the oral route.Metaflumizone Human Health Risk Assessment D4 2 1321

Page 35 of 38 

### CF = convers ion factor; a L/hr/kg factor which accounts for respiratory volume and

body weight for a given species and strain (Table 1 of J. Whalen and H. Pettigrew, 10/10/98). D = duration; duration of daily animal or human exposure (hours). AF = activity fact or; animal default is 1. For humans, the value varies with ventilation

rates determined by occupational/restidential scientists; 0.6 (8.3L/min), 1.2 (16.7 L/min) and 2.1 (29 L/min)

Therefore, the occupational HED for metaflumizone is calculated as follows:

Occupational HED, Ventilation Rate, 8.3 L/min: (0.0 6323 mg/L) x 1 x 0.6 x 11.8 L/hr/kg x 8 hr = 3.6 mg/kg/day Occupational HED, Ventilation Rate, 16.7 L/min: 0.0 632 mg/L) x 1 x 1.2 x 11.8L/hr/kg x 8 hr = 7.2 mg/kg/day Occupational HED, Ventilation Rate, 29 L/min: (0.0 6323 mg/L) x 1 x 2.1 x 11.8 L/hr/kg x 8 hr = 12.57 mg/kg/day

Based on the current metaflumizone label, HED believes exposures can be short

- (1

- 30 days) or intermediate

- (1 to 6 months) term in duration. Long

- term exposure s are not anticipated for metaflumi zone based on proposed labeled uses. For the short

- and intermediate

- term scenar ios, inhalation data from the 28

- day inhalation rodent study was most appropriate for determining HECs. In the RfC methodology, different H ECs may be calculated for the same experimental NOAEL due to the following:

1. Different algorithms are used to derive HECs for systemic versus portal

- of

- entry effects. Typically, HECs are calculated separately for systemic versus portal

- of

- entry effect. For metaflumizone , portal

- of

- entry irritation was observed and, therefore, onl y portal

- of

- entry HECs were derived. 2. Time adjustments are traditionally needed for non

- occupational (bystander) versus occupational exposure scenarios. Traditionally, HECs for non

- occupational exposure are based on the number of hours an individual may be at home. Therefore, the most conservative estimate of hours spent at home would be 24 hours/day and 7 days/week. In comparison, the average workweek for an occupational worker is 8 hours/day and 5 days/week. The HEC array table reflects the time adju stment in the calculations.Metaflumizone Human Health Risk Assessment D4 2 1321

Page 36 of 38 

### Appendix C : Physiochemical Properties

Table 3.2.1 is a summary of the physical/chemical properties for metaflumizone. Metaflumizone has a low vapor pressure and a high Log K ow 

### .

Table B.1 : Physicochemical Properties of Met aflumizone. Melting points Two melting points observed at approximately 127 oC and 186 oC. MRID 46264204 pH 6.48 at 25 oC (1% aqueous suspension) MRID 46264524 Density (20 oC) 1.461 g/cm 3 MRID 46264204

Water solubility (20 oC) D.I. water 1.79 μg/L pH 5 1.35 μg/L pH 7 1.81 μg/L pH 9 1.73 μg/L MRID 46264208

Solvent solubility (20 oC) Acetone 142.7 mg/L Acetonitrile 60.3 mg/L DCM 92.7 mg/L EtOAc 159.7 mg/L Heptane 0.0084 mg/L Methanol 13.95 mg/L Toluene 3.96 mg/L MRID 46264212

Vapor pressure 1.24 x 10

- 8 Pa at 20 oC MRID 46264206 Dissociation constant, pK a None in pH range 2

- 12 MRID 46264217 Octanol/water partition coefficient, Log(K OW ) Log P OW = 5.1 (Z isomer) Log P OW = 4.4 (E isomer) MRID 46264213

UV/visible absorption spectrum Molar absorptivity: 3.81×10 4 L/Mcm at 234 nm; 1.93×10 4 L/Mcm at 280 nm. MRID 46264207Metaflumizone Human Health Risk Assessment D4 2 1321

Page 37 of 38 

### Appendix D : Exposure to Metaflumizone in Fish /Shellfish at Consumption Levels Associated with Subsistence Fishing

. Based on an assessment by EFED which concluded that metaflumizone has a high potential to bioaccumulate in aquatic food webs, the dietary risk assessment conducted in support of the current uses included the KABAM ( ver. 1.0 ) piscivorus fish resi due estimat e for fish/shellfish; the resulting exposure estimates are less than HED’s LOC (see Section 5.4)

. However, th e s e analys e s d id not consider fish/shellfish consumption rates associated with subsistence fishing. To account for these consumption rates, the a ssessment summarized below was conducted.

Consumption rates associated with subsistence fishing were attained from the Fish Consumption Rates Technical Support Document (ver. 2.0) from the State of Washington Department of Ecology ( https://fortress.wa.gov/ecy/publications/publications/1209058.pdf ). The report addresses fish consumption in the State of Washington among the general population, tribal popul ations, and other groups such as Asian and Pacific Islanders and recreational anglers. Based on the consumption rates from this document

, and the KABAM (ver. 1.0) piscivorus fish residue estimate, exposure estimates were calculated and added to the DEEM

- F C ID estimates (see Table C .1). T he resulting aggregate exposure estimates are less than HED’s LOC (see Table C.2)

. HED notes that the exposure estimates presente d in Table C .1 can be considered conservative for the following reasons: ( 1 ) the KABAM (ver. 1.0) model assumes a farm pond ecosystem receiving runoff from an adjacent treated field (highest registered/proposed rate assumed) ; this scenario is not typical for subsistence fishing; ( 2) the analysis assumes that all consumed fish/she llfish have the KABAM piscivor us fish metaflumizone residue estimate ; and (3 ) the DEEM

- FCID TM exposure estimates considered residues in fish/shellfish and adding the s e estimate s to the exposure estimates from subsistence fishing results in fish/shellfish co nsumption levels great er than figures indicated in Table D.1

.

It is noted that t he lindane subsistence diet exposure analysis (D282455, T. Morton, 17

- Apr

2002) utilized consumption data from the Alaska Department of Fish and Game

- Division of Subsistenc e

- Community Profile Database (ver. 3.11; 27

- Mar

- 2001)

. Based on lindane ’s d emonstrated properties for long

- range transport and the documented concentrations in terrestrial, freshwater, and marine habitats, the lindane analysis selected the three Alaskan communities with the highest consumption of seal, whale, or walrus. In contrast to lindane,

m etaflumizone is anticipated to a ffect only water bodies in the vicinity of the application site (long range transport is not anticipated ; communication fr om EFED ). Therefore, it was concluded that the consumption estimates used in the lindane analysis were not applicable to the
current assessment.Metaflumizone Human Health Risk Assessment D4 2 1321

Page 38 of 38 Table C .1 : Summary of Subsistence Dietary Input s and Risks.

Population Fish/Shellfish Residue

Estimate 1 (ppm) Body

Weight (kg) Subsistence DEEM

- FCIDTM Exposure 4 combined %PAD 5

Consumption ( g /day ) 2 Exposure (mg/kg/day) 3

Acute Chronic Acute Chronic Acute Chronic Acute Chronic
Children 1

- 2 years old

3.5 10
acute assessment is
unnecessary 25
acute assessment is
unnecessary 0.008750
acute assessment is
unnecessary 0.002864
acute assessment is
unnecessary 2 9
Children 3

- 5 years old 20 25 0.004375 0.002433 1 7
Children 6

- 12 years old 30 113 0.013183 0.001663 37
Adults 7 0 214 0.010700 0.001498 30
Adult Females 6 0 797 214 0.046492 0.012483 0.00528 8 0.001264 1 6 34

1 As part of EFED’s ecological risk assessment associated with the registered fly bait application scenario, a residue estimate for piscivorus fish of 3.5 ppm was generated using KABAM (ver. 1.0; D361157, K. Sappington, 21

- Dec

- 2011).

2 Consumption rates derived from the Fish Consumption Rates Technical Support Document (ver. 2.0; https://fortress.wa.gov/ecy/publications/publications/1209058.pdf ) from the State of Washington Department of Ecology. The adult consumption figures were taken from Table 1 and the children (<6 years old) consumption figures were taken from Table A.1. The referenced document did not include consumption figures for children (6

- 12 years old). The 113 g/day consumption figure for children 6

- 12 years old was derived by adjusting the adult consumption figure by 0.53 with the 0.53 factor based on the following reference: Heller, C., 1966. Meat Consumption at Three Northern Eskimo Villages. Environment of the Cape Thompson Region, Alaska. Wilimovsky, Norman, & Wolfe, John, Editors. United States Atomic Energy Commission. pp. 1109

- 1111.
3 E xposure = consumption (g/day) ÷ body weight x fish residues (ppm) x (1 mg/1000 μg)

. 4 See Table 5.4.1.
5 C ombine d %PAD = (subsistence exposure + DEEM

- FCIDTM exposure ) ÷ PAD (aPAD = 0.33 mg/kg/day; cPAD = 0.04 mg/kg/day)

.

Table C.2 : Short

- and Intermediate

- Term Aggregate Risk

Population Background Dietary + Incidental Oral Exposures Residential Exposures
ARI 4

Oral LOC Dietary Exp

.

(mg/kg/day) 1 Incidental Oral

Exp

. (mg/kg/day) 1 Oral MOE 2 Dermal LOC Dermal Exp. (mg/kg/day) 1 Dermal MOE 3

Adults 50

- 99 years old 300 0.058975 NA 1,500 100 0.0012 86,000 4.8

Children 6

- 12 years old 0.014846 0.000 0 21 1,300 0.00 23 44,000 4.4

1 See Table C.1 (dietary) and Table 6 .0. 3 (residential)

. 2 Oral MOE = NOAEL (20 mg/kg/day) ÷ (chronic food/water exposure + incidental oral exposure).

3 Dermal MOE = NOAEL (100 mg/kg/day) ÷ (dermal exposure).

4 ARI ( Aggregate Risk Index) = 1 ÷ (( Oral LOC ÷ Oral MOE) + ( Dermal LOC ÷ Dermal MOE)); ARI > 1 indicates an acceptable exposure.