### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON

, D

. C

. 20460

MEMORANDUM

DAT E : F e bruary 25

, 2016 OFFICE OF CHE MICAL SAFETY

AND POLLUTION PR EV ENTION



### SUBJECT: Fluazinam

. Human H ea l th Risk Assessment to S upp ort Sect i on 

### 3 R eg i strat ion

for New Uses on Tuberous and Corm, Subgroup IC

, Mayhaw

, S q uash/Cucumber

S ub g r oup 9B; Amended Uses on Cabbage.

PC Co d e: 129098

Deci s ion Nos.: 499960

Petition Nos.: 5£8349 DP Barcode s: 0426143

Re g istration Nos.: 7 1512-1 Regulatory Act ion: Sec ti o n 3 R egistrat i on Case No .: 7013 Risk Assess m ent Type: Single Che mi cal 

### Aggregate

T XRNo.: 

### NA

MRIDNo.: NA C AS No.: 79622-59-6

40 CFR: §180.574



### F ROM : Elizabeth Holman, Ph ysical Sc ienti st/ Risk Assessor

### ~ Ger a d Thornton,**nvironmentalAr ~c** **tio ~** **~c alist**  

# rJ--1'11 '**~** 

### Karl yn Middleton

,**TOX_icologis ~;~**  J 

# o-rv

Ri s k Asse ss ment B ra n c h II J



### Health Effects Division (7509P)

Sumitra Bose Bi swas
, C h emist

# o.Q~ 

# Jrv

Ri sk Assessment Branch V I

H ealth Effects Di vis ion (7509P)

THROUGH: Chr i st in a Swartz

, Branch Chief

# ~~ Risk Assessment Branch II

Health Effects Division ( 7509P)



### TO: Erik Kraft

, Ri sk Manage r Revi ewer Heather Garvie

, Review Manager # 24

Fun g icid e- H er bi c ide Branch

A

. W ill is E rtman

, Risk Manager Rev i ewer
Barbara Madden

, Minor Use T eam Lea d er
Ri sk Integ r ation

, Minor Use and Emergency Response Branch Regi s tration Di v i s ion (7505 P )

Pa ge 1 of 51

### The R eg istr at ion Divi s ion 

### (RD ) r equeste d th at th e Health Effects Di v i sio n ( HED ) conduct an

exposure and risk assessment for the propo se d new u s es of fluazinam: (1) adding fo li ar

app li catio n to th e existi n g u se pattern on cabbage; (2) p roposed new fo liar u ses on ma y h aw; (3)

n ew foliar and banded so il drench u ses on s quash/ c ucumber subgroup 9 B ; and ( 4 ) an expansion

fro m exist in g foliar uses on potato to tuberous and c orm vege t ab les s ub gro up l 

### C. The attached

human health risk assessment ad dre sses di e tary

, aggregate and occ upati o nal ex po s ure and risk

associated w ith the proposed u ses of fluazinam. With appropriate miti ga tion for the identified

oc cupational risk s, there a re n o ri s k s of concern associated with these proposed u ses.

P age 2 of 51

### Page 3 of 51

1.0 Executive Summary .................................................................................5

2.1 Data Deficiencies/Conditions of Registration

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

2.2 Tolerance Considerations

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

2.2.1 Enforcement Analytical Method

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

2.2.2 International Harmonization

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

2.2.3 Recommended Tolerances

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

2.2.4 Revisions to Petitioned

- For Tolerances

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

2.3 Label Recommendations

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

3. 0 Introduction

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

3.1 Chemical Identity

................................ ................................ ................................ ......... 12

3.2 Physical/Chemical Characteristics

................................ ................................ ............. 12

3.3 Pesticide Use Pattern for Proposed Commodities

................................ ..................... 12

3.4 Anticipated Exposure Pathways

................................ ................................ ................. 13

3.5 Consideration of Environmental Justice

................................ ................................ .... 14

5.0 Dietary Exposure and Risk Assessment

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

5.1 Metabolite/Degradate Residue Profile

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

5.1.1 Summary of Plant and Animal Metabolism Studies

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

5.1.2 Summary of Environmental Degradation

................................ ............................... 19

5.1.3 Comparison of Metabolic Pathways

................................ ................................ ....... 19

5.1.4 Residues of Concern Summary and Rationale

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

5.2 Food Residue Profile

................................ ................................ ................................ .... 21

5.3 Water Residue Profile

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

5. 4 Dietary Risk Assessment

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

5.4.1 Description of Residue Data Used in Dietary Assessment

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

5.4.2 Percent Crop Treated Used in Dietary Assessment

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

5.4.3 Acute Dietary Risk Assessment

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

5.4.4 Chronic Dietary Risk Assessment

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

5.4.5 Cancer Dietary Risk Assessment

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

5.4.6 Summary Table

................................ ................................ ................................ ....... 25

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

............................. 25

6.1 Residential Handler Exposure and Risk

................................ ................................ .... 25

6.2 Residential Post

- application Exposure

................................ ................................ ....... 25

6.3 Combined Residential Risk Estimates

................................ ................................ ........ 26

6.6 Residential Bystander Post

- Application Inhalation Exposure

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

7.0 Aggregate Exposure/Risk Characterization

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

7.1 Acute Aggregate Risk

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

7.2 Short

- /Intermediate

- Term Aggregate Risk Estimates

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

7.3 Chronic Aggregate Risk

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

7.4 Cancer Aggregate Risk

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

8.0 Cumulative Exposure/Risk Characterization

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

9.0 Occupational Exposure/Risk Characterization

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

9.1 Occupational Handler Exposure/Risk Estimates

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

9.2 Occupational Post

- application Exposure/Risk Estimates

................................ ........ 35

9.2.1 Occupational Post

- application Inhalation Exposure/Risk Estimates

...................... 35

9.2.2 Occupational Post

- application Dermal Exposure/Risk Estimates

.......................... 35

10.0 References

................................ ................................ ................................ ......................... 38

### Page 4 of 51

Appendix A. HEC Inhalation Calculations

................................ ................................ ............. 39 Appendix B. International Residue Limit Status Sheet

................................ ......................... 40 Appendix C. Fluazinam Physical/Chemical Properties

................................ ......................... 41 Appendix D. Review of Human Research

................................ ................................ ................ 42 Appendix E. Structures of Fluazinam Metabolites and Degradates of Concern

.................. 43 Appendix F: Fluazinam Toxicology Profile Table s

................................ ................................ 44

### Page 5 of 51

1.0 Executive Summary

T he Interregional Research Project No. 4 (IR

- 4) submitted petitions to establish tolerances

associated with the following proposed new uses of fluazinam: (1) adding foliar application to the existing use pattern on cabbage; (2) proposed new foliar uses on mayhaw; (3) new foliar and banded soil drench uses on squash/cucumber subgroup 9B; and (4) an expansion from existing

fol iar uses on potato to tuberous and corm vegetables subgroup 1C. This human health risk assessment presents HED’s conclusions with respect to the risk estimates associated with the proposed uses for fluazinam.

F luazinam ( 3

- chloro

- N

- [3

- chloro

- 2,6

- dinitro

- 4

- (trifluoromethyl)phenyl]

- 5

- (trifluoromethyl)

- 2

- pyridinamine) i s a preventive contact fungicide with a multi

- site fungicidal mode of action. It disrupts the production of energy at several metabolic sites within the fungal cell. Fluazinam is a

protecta nt fungicide. When it is applied to plants, it remains primarily on the plant surface and kills any fungal spores that come into contact with it. It is not taken up to any extent by the plant

and , unlike systemic fungicides, is not translocated within th e plant.

HED has assessed exposures and risks from the proposed uses of fluazinam. The petition is for a

foliar use on mayhaw ; a foliar use and a banded soil drench use on squash/cucumber subgroup

9B ; a new foliar use on cabbage ( there are existing soil incorporation use and transplant soil

drench use on cabbage); and an expansion of the foliar use on potato to tuberous and corm vegetables 1C

. The uses are for the existing end

- use product Omega® 500F

— an SC containing 40% fluazinam, 4.17 lbs active ingred ient (ai) per gallon of product (EPA Reg. #71512

- 1). The proposed maximum single application rates range from 0.26 to 0.78 lb ai/ acre and may be applied every 7 to 10 days and up to 10 times per growing season depending on the application

rate used and the crop. The preharvest interval (PHI) associated with these uses are 7 days on cabbage and squash/cucumber, and 28 days on mayhaw.

Based on the proposed use pattern, the duration of exposure for the proposed uses are expected

to be short

- term (1 to 30 d ays) and intermediate

- term (1 to 6 months). Long

- term exposures (greater than 6 months) are not anticipated.

Hazard Characterization and Endpoint Selection

The toxicology datab ase for fluazinam is complete. The liver is a primary target organ for fluazinam and numerous liver effects were observed in rats, mice, and dogs after oral and dermal exposure. After inhalation exposure, portal of entry effects (increased lung/bronchial weights, alveolar macrophages and peribronchiola r proliferation) were seen.

Clinical signs and immune related effects were also observed in toxicity studies; however, clear NOAELs have been established for the effects noted and the points of departure (PODs) and endpoints selected f

or risk assessment are protective.

There was no evidence of increased quantitative or qualitative susceptibility in the rabbit developmental or rat reproduction studies. However, quantitative susceptibility was seen in rat developmental and DNT studies where fetal/offspring effects were observed in the absence of

### Page 6 of 51

maternal toxicity. T he concern is low for the increased susceptibility noted in the studies since clear NOAELs are established, and the most sensitive endpoints /PODs are used f or risk

assessment. Therefore, the FQPA safety factor has been reduced to 1x.

Fluazinam is classified as having “Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential,” based on i ncreases in thyroid gland fol licular cell tumors in male rats and increases in hepatocellular tumors in male mice

. The Cancer Assessment

Review Committee ( CARC ) determined that quantification of cancer risk using a non

- linear approach (i.e., RfD) would adequately account for all chro nic toxicity, including carcinogenicity, that could result from exposure to fluazinam. There is no mutagenicity concern for fluazinam.

Since the last risk assessment, the technical ingredient was updated for fluazinam and new acute lethality (LD50) studies were submitted . As a result, the Toxicity Category for acute inhalation toxicity ( II to III ) and primary eye irritation ( I to III ) were revised. For this assessment, the

tox icological endpoints, points of departure (PODs) , and uncertainty factors selected for risk

assessment remain the sam e as in the previous assessment

. However, the inhalation HECs have been updated to incorporate activity specific breathing rates (appendix A ). No other substantive changes have been made to the hazard cha racterization/endpoint selection.

Metabolism/Metabolites and Degradates of Concern

The metabolism of fluazinam in primary crops, rotational crops, and animals has been adequately delineated. The residue of concern for risk assessment in bulb veget ables as well as in root and tuber vegetables is parent fluazinam. For all other plant commodities, the residues of concern in plants for risk assessment are fluazinam and its metabolite AMGT. In drinking water, the degradates of concern for risk assessm ent are parent fluazinam and its transformation products. In livestock commodities, the residues of concern for risk assessment are fluazinam,

the metabolites known as AMPA, DAPA, and their sulfamate conjugates.

Food Residue Profile

The food use profile s for the proposed commodities are complete and adequate for tolerance setting and risk assessment purposes. The number, geographic representation, and the use patterns of the cabbage, cucumber, and squash field trial data are adequate and support the

req uested use patterns. The residue data were generated using a validated data collection method, and are supported by adequate storage stability data. No new field trial data were submitted to support expansion of the current uses of potato to Vegetables, Tuberous, Corm crop subgroup 1C

. Since the requested expansion of the crop groups are for the identical formulation and use pattern, no new residue chemistry data, including processing studies, are required to support these requests. The reco mmended tolerances for the proposed uses are listed in Table

2.2.3.

A dequate analytical methods are available for enforcement of tolerances in plant and livestock commodities. In addition, the FDA Multiresidue Methods ( M RM s ) can serve as a confirmatory

p rocedure for residues of fluazinam , but not for the metabolites

. The necessary a nalytical

### Page 7 of 51

reference standards for fluazinam are available in the EPA National Pesticide Standards Repository

.

Dietary Exposure and Risk

Acute and chronic dietary exposure an d risk assessments were conducted

, including food and drinking water contributions from the existing uses as well as the proposed uses

. T he acute and

chronic assessments a r e based on 100% crop treated assumptions and incorporate modeled estimated drinking water concentrations (EDWCs) that account for both parent fluazinam and its transformation products. D efault processing factors were used for all processed commodities for

which default factors were available

. The acute analysis is based on tolerance

- le vel residues for all commodities and uses high

- end residue estimates for the metabolite AMGT. The chronic analysis is based on tolerance

- level residues for all commodities except apples. For apples, the average field trial value was used. As a result, t he acute and chronic exposure and risk estimates

are considered to be conservative. The acute and chronic dietary risk estimates are below HED’s level of concern for all population subgroups, including those comprised of infants and children.

The acute dietary risk estimate for the general U.S. population is 5. 7 % of the acute Population Adjusted Dose (aPAD). The population subgroup with the highest acute dietary risk estimate is

Females 13

- 49, which uses 32 % of the aPAD. The chronic dietary risk estima te for the general U.S. population is 41 % of the chronic PAD (cPAD). The most highly exposed population subgroup is All Infants (<1 year old), which uses 92 % of the cPAD. As the c hronic dietary endpoint and dose are protective of potential cancer effects , cancer dietary risk is also not of

concern. Because such conservative assumptions were made in the assessments, HED is confident that the acute and chronic dietary exposure assessments do not underestimate risk to the general U.S. population or any popu lation subgroup or life stage

.

Residential Exposure and Risk

The residential exposure database is complete and adequate

. There are no proposed residential uses; however, there is an existing use of fluazinam on golf course turf. I ndividuals can be exposed when they play golf on treated turf, and therefore a residential dermal post

- application assessment was previously conducted for golfers. Residential post

- application exposure to golfers was assessed using the HED Standard Operat ing Procedures (SOPs) for Residential Exposure Assessment (2012), as well as chemical

- specific residue data from the turf transferable residue (TTR) study. Dermal post

- application exposure and risk estimates for golfers resulted in MOEs greater than the L OC of 100

, and were not of concern (e.g., lowest MOE = 780)

.

Aggregate Exposure and Risk

The acute aggregate risk estimate s are equivalent to the corresponding dietary (food plus water)

risk estimate s, which are not of concern. Chronic dietary exposure is considered to be a background exposure level to which the s hort

- term residential exposure is added. The short

- term aggregate risk assessment s resulted in estimated MOEs of 690 to 890 . For fluazinam, the LOC

for short

- term risk is an MOE of 100. As the resulting aggregate MOEs exceed the LOC of 100, aggregate dietary and residential risk estimates are not of concern.

### Page 8 of 51

Occupational

The occupational exposure database is complete and adequate for assessing occupational

exposure to fluazinam for both the registered and proposed uses.

It is HED policy to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical

- specific data, include the

Pesticide Ha ndlers Exposure Database Version 1.1 (PHED 1.1), and the Agricultural Handler Exposure Task Force (AHETF) database. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. Default assumptions establi shed by HED’s Science Advisory Council for Exposure were used for parameters such as body weight, acres treated

, and amount handled.

Occupational handler assessments considered both dermal and inhalation short

- term exposures. The estimates are considered to be protective of intermediate

- term exposure and risk. All occupational handler scenarios for dermal and inhalation exposure, with the exception of dermal exposure for airblast applicator, are not of concern at the label specified PPE or use of an

encl osed cockpit for aerial applications. For airblast applicators, risks of concern for dermal application were identified, but with additional PPE ( e.g., chemically resistant hat) , the dermal exposure MOEs are above the LOC. Risk estimates of concern were a lso identified for mechanically

- pressurized handgun for cabbage and squash/cucumber subgroup 9B, even at the highest level of appropriate mitigation available (e.g., double layer and gloves). However, based on personal communication with RD, the registran t intends to submit a revised label that will prohibit the use of mechanically

- pressurized handgun

.

There is potential for dermal exposure during occupational post

- application activities , such as crop maintenance activities, scouting, irrigation, and ha rvesting . Chemical

- specific dislodgeable foliar residue (DFR) studies were submitted by the registrant and reviewed by HED , and the

results of these studies were incorporated into HED’s review of the existing and proposed uses

. All post

- application derma l scenarios resulted in MOEs greater than the LOC of 100 on day 0, with the exception of hand weeding cabbage, and are not of concern. At 12 and 24 hours after last application, MOEs for hand weeding cabbage increase to 98 and 100 respectively.

Restricted Entry Interval (REI)

Fluazinam is classified as Toxicity Category III via the dermal route

, Toxicity Category IV for skin irritation potential , and Toxicity Category I II for eye irritation potential . It is also a skin

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

- hour REI. In the case of hand weeding activities on cabbage, identified MOEs were 98 a t 12 hours and 100 at 24 hours. However, HED does not consider an MOE of 98 at 12 hours to be of concern, as it is essentially equivalent to an

MOE of 100. All other s hort

- and intermediate

- term post

- application risk estimates were not a concern on day 0

. Therefore, the [156 subpart K] Worker Protection Statement interim REI of

12 hours should be adequate to protect agricultural workers from post

- application exposure to

fluazinam

.

### 2.0 HED Recommendations

HED has no objection to registration of the proposed Section 3 use of fluazinam on mayhaw, cabbage, squash/cucumber, and tuberous and corm vegetables, subgroup 1C

.

Provided a revised section F (as noted in Section 2.2. 4 ) is submitted, there are no residue chemistry considerations that would preclude granting the requested use on cabbage, cucumber, squash as well as the necessary tolerances, as listed in Section 2.2.3, required to support those

uses. HED has no objection to the proposed extrapolation from the apple tolerance to mayhaw and exp ansion of the current use of fluazinam on potato to include all commodities of Vegetables, Tuberous and Corm subgroup 1C.

In addition, HED notes that risks of concern were identified for airblast applicators, but with additional PPE (e.g. chemically resis tant hat), the dermal exposure MOEs are above the LOC (see Section 9.0 for further details).

2.1 Data Deficiencies/Conditions of Registration

None

. In addition, as part of this petition, IR

- 4 submitted previously requested storage stability

on lettuce . This storage stability data was a condition of registration under a previous petition ( PP# 8E7506). The submitted data are adequate and therefore fulfill this previously identified condition of registration.

2.2 Tolerance Considerations

2.2.1 Enf

orcement Analytical Method

An adequate GC/ECD method (6148

- 94

- 0170

- MD

- 001) entitled “Fluazinam: Method for the Analysis in Peanut Nutmeat” (MRID 43521016) is available for enforcing fluazinam tolerances on plant commodities. The method was adequately ra diovalidated and underwent a successful independent laboratory validation (ILV) trial. The method was forwarded to Biological and Economic Analysis Division ’s (BEAD) Analytical Chemistry Branch (ACB) for a TMV trial, and was subsequently determined to be suitable as a tolerance

- enforcement method (Memo, D266802, P. Golden, 6/22/2001). For this method, residues of fluazinam are extracted with methanol:acetic acid (100:2, v/v), filtered, diluted with 0.2 N HCl, and partitioned into hexane.

Residues are the n further partitioned into 0.5 N NaOH, the aqueous phase is acidified, and residues are partitioned back into hexane. The resulting hexane fraction is concentrated, and residues are purified using a Florisil column eluted with hexane:ethyl ether (80:20, v /v). Residues are concentrated to dryness, redissolved in hexane, and analyzed by GC/ECD using external standards for quantitation. The method LOQ is 0.01 ppm for fluazinam in plant commodities. This method is adequate for tolerance enforcement purposes for all the commodities that are subject to this petition.

Adequate FDA multiresidue method ( MRM) testing data are available for fluazinam and its

metabolite AMGT. As fluazinam is partially recovered through Sections 302, 303, and 304 of

PAM Volume I , the M RM s can serve as a confirmatory procedure for residues of fluazinam.

The FDA MRM methods are not suitable for determining residues of AMGT.

### Fluazinam Human Health Risk Assessment DP No. D426143

Page 10 of 51 Conclusion: Acceptable methodology is available for tolerance enforcement purposes for residues of concern in/on all the commodities that are the subject of this assessment.

2.2.2 International Harmonization

There are currently no Codex or Mexican maximum residue limits (MRLs) for residues of

fluazinam on cabbage, mayhaw, squash/ cucumber subgroup 9B

, Vegetable, Tuberous and Corm, Subgroup 1C

, and Veget able, Brassica leafy, Group 5, e xcept cabbage

. The Agency is currently

harmonized with C anada in respect to the residue definition in plant commodities. There are no

Canadian MRLs for both mayhaw and squash/cucumber subgroup 9B. The Canadian MRL for cabbage is lower (0.01 ppm) than the proposed US tolerance (3.0 ppm) due to the proposed new U.S. use pattern for cabbage. For a summary of the international MRLs, please see Appendix B.

2.2.3 Recommended Tolerances

T he recommended tolerances are listed in Table 2.2.3 , and should be added to the table in 40CFR §180.574(a)(1): Tolerances are established for residues of f luazinam, 3

- chloro

- N

- [3

- chloro

- 2,6

- dinitro

- 4

- (trifluoromethyl)phenyl]

- 5

- (trifluoromethyl)

- 2

- pyridinamine ), including its metabolites and degradates, in or on the commodities in the table. Compliance with the tolerance levels is to be determined by measuring only fluazinam.

Table 2.2. 3

. Tolerance Summary for Fluazinam

. Commodity Proposed/Existing

Tolerance (ppm) HED

- Recommended Tolerance (ppm) Comments

( correct commodity definition )
40 CFR 180.574(a) (1) Tolerance for R esidues.

Cabbage 3.0 3.0 None

Mayhaw 2.0 2.0 Extrapolation from current apple tolerance.

S quash/cucumber subgroup 9B 0.05 0.07 Cucurbit Vegetables Crop Group 9 Existing tolerance (0.07 ppm) for melon subgroup 9A can be

removed from 40CFR and replaced by this crop group

tolerance.

Melon subgroup 9A 0.07 Remove Cucurbit Vegetables Crop Group 9 Existing tolerance (0.07 ppm) for melon subgroup 9A can be

removed from 40CFR and replaced by this crop group

tolerance.

Vegetable, Brassica leafy, Group 5, Except cabbage 0.01 0.01 Established tolerance for Vegetable, Brassica leafy, Group 5 can be removed from 40CFR and replaced by this crop group tolerance.

### Fluazinam Human Health Risk Assessment DP No. D426143

Page 11 of 51 2.2.4 Revisions to Petitioned

- For Tolerances

IR

- 4 is requested to submit a revised Section F to reflect the tolerance expression for mayhaw, cabbage and squash/ cucumber subgroup 9B under 40 CFR 180.574 (a) (1) category and remove the request to establish tolerances for the for these crops and crop sub/groups under 40 CFR 180.574 (a) (2) category. According to plant metabolism study, for setting tolerances, the residues of concern in plants include fluazinam and AMGT for wine grapes, but only parent fluazinam for all other plant commodities.

IR

- 4 is requested to submit a revised Section F proposing a single crop group tolerance for crop group 9 at 0.07 ppm instead of separate tolerances for subgroups 9A and 9B. As part of the revised section F, IR

- 4 is requested to remove the existing tolerance for melon sub group 9A and replace it by cucurbit vegetable crop group 9.

2.3 Label Recommend ations

As part of the occupational exposure assessment, HED identified risks of concern associated with the use of mechanically

- pressurized handgun for cabbage and squash/cucumber subgroup 9B, even at the highest level of appropriate mitigation available (e.g., double layer and gloves).

For further details on these risks of concer n, please see Section 9.0 of this assessment

. Based on personal communication with RD, the registrant intends to submit a revised label that prohibits the use of this applicatio n method. HED concurs that with this label revision, the risks of concern will no longer be an issue.

3.0 In troduction Vegetable, Tuberous and Corm, Subgroup

1C 0.02 0.02 Established tolerance for potato can be removed from 40CFR and replaced by this

s ubgroup tolerance.
40 CFR 180.574(a) (2) Tolerance for R esidues

Cabbage 3.0

Remove Remove the request to

establish tolerances for these crops and crop sub/groups under 40 CFR 180.574 (a) (2) category. And Submit a revised

Section F to reflect the tolerance expression for mayhaw, cabbage and squash/cucumber subgroup 9B

under 40 C FR 180.574 (a) (1)

category. According to plant metabolism study, for setting tolerances,

the residues of concern in plants include fluazinam and AMGT for wine grapes, but only parent fluazinam for all other plant commodities. Mayhaw 2.0

Squash/Cucumber Subgroup 9B 0.05

### Fluazinam Human Health Risk Assessment DP No. D426143

Page 12 of 51 3.1 Chemical Identity

T able 3.1. Fluazinam Nomenclature

Compound Chemical Structure

Empirical Formula C 13 H 4 Cl 2 F 6 N 4 O 4 Molecular Weight 465.1

Common Name Fluazinam

Company Experimental Names Fluazinam, IKF

- 1216

IUPAC Name 3

- chloro

- N

- (3

- chloro

- 5

- trifluoromethyl

- 2

- pyridyl)

- α,α,α

- trifluoro

- 2,6

- dinitro

p

- toluidine

CAS Name 3

- chloro

- N

- [3

- chloro

- 2,6

- dinitro

- 4

- (trifluoromethyl)phenyl]

- 5

- (trifluoromethyl)

- 2

- pyridinamine

CAS Number 79622

- 59

- 6

End

- use Product/(EP) Omega ® 500F Fungicide (EPA Reg. No. 71512

- 1) Fluazinam Turf Fungicide (EPA Reg. No. 71512

- 20)



### 3.2 Physical/Chemical Characteristics

Fluazinam has a relatively high octanol/water partition coefficient. T he l og K OW 

### value is 3.56 ( K OW 

### = 3

, 63 0 ). F luazinam has a vapor pressure of 1.7 3 x 10

- 7 

### mm Hg at 2 5 oC

. See Appendix C for a listing of fluazinam ’s p hysical and c hemical properties.

3.3 Pesticide Use Pattern for Proposed Commodities

There is currently a single end

- use product (EP) for fluazinam registered in the U.S. for use on several food and feed crops. This product is Omega ® 

### 500F (EPA Reg. No. 71512

- 1), which is a 4.17 lb/gal soluble

- concentrate (SC) formulation

. The proposed use directions are summarized

in Table 3.3

.

OMEGA ® 

### 500F may be applied as a foliar spray using aerial, chemigation (i.e., sprinkler irrigation system) , ground and handheld equipmen t . The proposed Restricted Entry Interval (REI) is 12 hours for all crops and is considered adequate. The Personal Protective Equipment (PPE) statement on the proposed label requires applicators, flaggers

, and other handlers to wear long

- sleeved shirt and long pants, socks, chemical

- resistant gloves and footwear, and protective eyewear. When mixing and loading also wear a chemical

- resistant apron.

### Fluazinam Human Health Risk Assessment DP No. D426143

Page 13 of 51 The proposed use patterns are shown below in Table 3.3. Fluazinam was previ ously registered for a transplant soil drench and soil incorporation on cabbage. This assessment only considers the current petition for a foliar use on cabbage. Fluazinam spray volume ranges from 20 to 100 gallons per acre for dilute sprays, and 5 to 10 gallons per acre for concentrate ground and aerial

sprays.

Table 3.3 . Summary of Directions for New Uses of Fluazinam

. Applic. Timing, Type, and Equip. Formulation

[EPA Reg.

No. 71512

- 1 ] Max Single

Applic. Rate Max. No.

Applic. per

Season Max. Seasonal

Applic. Rate PHI Use Directions and

Limitations lb ai/A lb ai/A days

Cabbage

Aerial, Chemigation, Groundboom, Mechanically

pressurized Handgun OMEGA ®

500F 40% ai,

Soluble

Concentrate (4.17 lb ai/gal) 0.5

(foliar) 6

(foliar) 3.0

(foliar) 7 Use 20 to 60 gallons of

water per acre for foliar applications. May be retreated every 7 days.

Mayhaw

Aerial, Airblast, Chemigation, Mechanically

pressurized Handgun OMEGA ®

500F 40% ai,

Soluble

Concentrate (4.17 lb ai/gal) 0.45

(foliar) 10

(foliar) 4.5

(foliar) 28 Applications are based on

tree size requiring a dilute spray of 200 gallons per acre. May be retreated every 7 to 10 days.

Squash/Cucumber Subgroup 9B

Aerial, Chemigation, Groundboom, Mechanically

pressurized Handgun OMEGA ®

500F 40% ai,

Soluble

Concentrate (4.17 lb ai/gal) 0.78

(foliar)

0.78 (banded soil drench) 4 (foliar)

1 (banded soil drench) 3.9

(foliar and

banded soil drench) 7 Use 20 to 60 gallons of

water per acre for foliar applications. May be retreated every 7 days.

Tuberous and Corm Vegetables Subgroup 1C

Aerial, Chemigation, Groundboom, Mechanically

pressurized Handgun OMEGA ®

500F 40% ai,

Soluble

Concentrate (4.17 lb ai/gal) 0.26

(foliar) NS 1.8 (foliar) 14 Use 20

- 100 gallons per

acre. May be retreated every 7 to 10 days.



### 3.4 Anticipated Exposure Pathways

Humans m ight be exposed to fluazinam i n food and drinking water because fluazinam may be applied directly to row crops and golf course turfgrass

. Residential exposure may occur due to contact with treated golf course turf. The registered and proposed use s also result in the potential

for occupational (handler/post

- application) exposures. In a ddition, applicators might be exposed

### Fluazinam Human Health Risk Assessment DP No. D426143

Page 14 of 51 while handling the pesticide prior to application, mixing/loading the pesticide, a nd during application.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this

human health risk assessm ent, in accordance with U.S. Executive Order 12898, “ Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations, ” ( http://www.eh.doe.gov/oepa/g uidance/justice/eo12898.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 population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA)

, 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 d ietary exposure to smaller, specialized subgroups

, and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicat ors and for toddlers, youths, and adults entering or playing on treated areas post

- application are evaluated. Further considerations are currently in development

, as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Characterization

Fluazinam is a preventive contact fungicide with a multi

- site mode of action. The fungicidal mode of action involves disruption of the production of energy at several metabolic sites within the fungal cell. Fluazinam is a protectant fungicide . U n like sy stemic fungicides

, i t is not taken up to any extent by the plant, and is not translocated within the plant. When applied to plants it remains primarily on the plant surface. The mammalian mode of action is unknown at this time.

With the exception of upd ated h uman equivalent concentrations (HECs) for inhalation exposure to incorporate activity specific breathing rates (see Appendix A) , there have been no changes in the fluazinam hazard characterization or toxicology database. Therefore, only a brief summary of this hazard characterization is provided below. For a detailed fluazinam hazard

characterization and dose

- response characterization, please see the most recent fluazinam risk assessment ( D397601, D. Dotson, 09/10/2012 ). Since the last risk ass essment, the technical product was updated and n ew acute lethality studies (Appendix F, Table F.1) were submitted for

the fluazinam technical

. As a result, t he acute inhalation toxicity category changed from II to III

and primary eye irritation changed fr om I to III ( D407410, C. Swartz, 02/14/2013 ).

The toxicology datab ase for fluazinam is complete. The liver is a primary target organ for fluazinam and numerous liver effects were observed in rats, mice, and dogs after oral and dermal

### Fluazinam Human Health Risk Assessment DP No. D426143

Page 15 of 51 exposure. Treatme nt

- related effects were also noted in other organs; however, these effects were not regularly observed in all three species or in all studies in a given species. After inhalation exposure, portal of entry effects were observed including increases in lung/ bronchial weights and increased incidences of alveolar macrophages and peribronchiola r proliferation.

Decreased motor activity was seen at the limit dose in an acute neurotoxicity study

. However,

n o signs of neurotoxicity were observed in two subchroni c neurotoxicity studies. A neurotoxic lesion was observed in subchronic and chronic studies in mice and dogs, as well as in special

studies in rats. However, a series of special studies were submitted to address the lesions and they were found to be rever sible and attributed to an impurity (impurity

- 5).

There was no evidence of increased quantitative or qualitative susceptibility in a rabbit developmental toxicity study or rat reproduction studies. In a rat developmental toxicity study,

there was evid ence of increased quantitative susceptibility (when endpoints are updated to current policy). Skeletal abnormalities/facial/palate clefts were seen in fetuses in the absence of treatment related maternal toxicity (decreased body weight gain/food consumption seen). In the DNT study, increased quantitative susceptibility was also observed ; offspring effects (decreased pup weight and delayed preputial separation) were seen in the absence of maternal toxicity. However, the concern is low for the incr eased susceptibility seen in the developmental studies since clear NOAELs are established, and the most sensitive endpoints are used for risk

assessment. Therefore, the FQPA safety factor has been reduced to 1x.

S ignificant suppressions of anti

- sheep red blood cell (anti

- SRBC ) antibody

- forming cell assay (AFC) response were demonstrated at the highest dose tested in a mouse immunotoxicity study. However, clear NOAELs have been established for the effects and the points of departure (PODs) and e ndpoints selected for risk assessment are protective of potential immunotoxicity.

Fluazinam is classified as having “Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential,” based on i ncreases in thyroid gland follicular cell tumors in male rats and increases in hepatocellular tumors in male mice

. The CARC determined that quantification of cancer risk using a non

- linear approach (i.e., RfD) would adequately account for all chronic toxicity, including carcinogen icity, that could result from exposure to fluazinam. There is no mutagenicity concern for fluazinam.

The dose and endpoint for acute dietary risk assessment (general population) w ere selected from an acute neurotoxicity study in which clinical signs inc luding decreased motor activity and soft

stools were observed at high doses. For acute dietary risk assessment for females 13

- 49, a developmental toxicity study in rabbits was used , and the endpoint selected was total litter resorptions and skeletal abnor malities. For the chronic dietary risk assessment, the carcinogenicity study in mice and the chronic study in dogs were selected as co

- critical studies.

Route

- specific toxicity studies were available for assessing both dermal and inhalation risks. In the dermal study, the endpoint consisted of liver effects, while in the inhalation study the effects observed were lung histopathology and increased lung and bronchial weights. For the dermal risk assessment, the dermal toxicity and dermal absorption stud ies were used to determine a refined dermal equivalent dose (RDD) f or assessing shor t

- and intermediate

- term dermal

### Fluazinam Human Health Risk Assessment DP No. D426143

Page 16 of 51 exposure. For inhalation exposure, h uman equivalent concentrations (HECs) and h uman equivalent doses (HEDs) were calculated for use in the inhalation risk assessments.

For dietary risk assessments, the conventional 100 x uncertainty factor was applied (10 x interspecies factor and 10x intraspecies factor). For the dermal assessment, the level of concern (LOC) is a margin of exposure (MOE) of 100 (10 x interspecies factor and 10x intraspecies factor)

. For inhalation risk assessments, the LOC is an MOE of 30 based on an interspecies

factor of 3 x and an intraspecies factor of 10 x; the interspecies factor was reduced from 10x to 3x,

since calculation of human equivalent calculations (HECs) accounts for pharmacokinetic (not pharmacodynamic) interspecies differences between animals and humans.

Table 4

. 0 .a. Toxicological Doses and End points for Fluazinam for Use in Dietary and Non

- Occupational Human

Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors RfD, PAD, Level of

Concern for Risk

Assessment Study and Toxicological Effects

Acute Dietary (General population) NOAEL=

50 mg/kg/day UF: 100 x

UF A = 10x

UF H =10x FQPA SF=1x Acute RfD =0.5

mg/kg/day

aPAD= 0.5mg/kg/day Acute Neurotoxicity

- Rats. LOAEL = 1000 mg/kg/day based on decreased motor activity and soft stools on day of dosing.

Acute Dietary (Females 13

- 49 years of age) NOAEL

(developmental) = 7 mg/kg/day UF: 100 x

UF A = 10x

UF H =10x FQPA SF=1x Acute RfD =0.07

mg/kg/day

aPAD = 0.07mg/kg/day Developmental Toxicity

- Rabbits. Developmental LOAEL = 12 mg/kg/day

based on increased incidence of total litter resorptions and possibly increased

incidence of fetal skeletal abnormalities.

Chronic Dietary (All Populations) NOAEL=

1.1 mg/kg/day (mouse study) UF: 100 x

UF A = 10x

UF H =10x FQPA SF=1x Chronic RfD =0.011

mg/kg/day

cPAD = 0.011mg/kg/day Co

- c ritical: Carcinogenicity

- Mice.

LOAEL = 10.7 mg/kg/day based on liver histopathology and increased liver weight

. Chronic Dog.

LOAEL = 10 mg/kg/day based on marginal increases in the incidence of nasal dryness in females and the incidence/severity of gastric lymphoid hyperplasia in both sexes.

Dermal Short

Term (1

- 30 days) Dermal POD =

24.4 mg/kg/day UF: 100 x

UF A =10x

UF H =10x Residential LOC :

MOE = 100 21

- Day Dermal Toxicity

- R ats LOAEL= 100 mg/kg/day based on liver effects (increased AST and cholesterol levels). Dermal NOAEL=10 mg/kg/day

A Refined Dermal Equivalent Dose (RDD) of 24.4 mg/kg/day was calculated using the dermal NOAEL and dermal absorption data

.

### Fluazinam Human Health Risk Assessment DP No. D426143

Page 17 of 51 Table 4

. 0 .a. Toxicological Doses and End points for Fluazinam for Use in Dietary and Non

- Occupational Human

Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors RfD, PAD, Level of

Concern for Risk

Assessment Study and Toxicological Effects

Inhalation

Short

- Term (1

- 30 days) NOAEL=

0.003 mg/L

(See HEC/HED

calculations in Appendix A ) UF: 30 x

UF A =3 x UF H =10x Residential LOC:

MOE = 30 4 week inhalation study in the rat. LOAEL = 0.020 mg/L based on a dose

related increase in absolute and relative lung/bronchial weights in both sexes. At 0.100 mg/L, increased lung/bronchial weights were also seen , along with lung histopathology (alveolar macrophages, peribronchiolar proliferation) in both

sexes.

Cancer (oral, dermal, inhalation) Classification: “Suggestive Evidence of Carcinogenicity, but not sufficient to assess human carcinogenic

potential

. ”

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

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed a dverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). PAD = p opulation adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. HEC = human equivalent concentration; HED = human equivalent dose

. RDD = Dermal NOAEL x (animal in vitro 
h uman in vitro ); RDD = 10 mg/kg/day x (40.17%  16.49%) = 24.4 mg/kg/day

.

Table 4

. 0

. b Summary of Toxicological Doses and End points for Fluazinam for Use in

Occupational Human Health Risk Assessments

Exposure/

Scenario Point of Departure Uncertainty/ FQPA Safety

Factors Level of Concern for

Risk Assessment Study and Toxicological Effects

Dermal

Short

- Term (1

- 30 days);

Intermediate

- Term (1

- 6 months) Dermal POD =

24.4 mg/kg/day UF=100 x

UF A =10x

UF H =10x Occupational LOC for

MOE = 100 21

- Day Dermal Toxicity

- R ats LOAEL= 100 mg/kg/day based on liver effects (increased AST and cholesterol levels) . Dermal NOAEL=10 mg/kg/day

A Refined Dermal Equivalent Dose (RDD) of 24.4 mg/kg/day was calculated using the dermal NOAEL and dermal absorption data

.

### Fluazinam Human Health Risk Assessment DP No. D426143

Page 18 of 51 Table 4

. 0

. b Summary of Toxicological Doses and End points for Fluazinam for Use in

Occupational Human Health Risk Assessments

Exposure/

Scenario Point of Departure Uncertainty/ FQPA Safety

Factors Level of Concern for

Risk Assessment Study and Toxicological Effects

Inhalation

Short

- Term (1

- 30 days);

Intermediate

- Term (1

- 6 months) NOAEL=

0.003 mg/L
(See HEC/HED

calculations in Appendix A ) UF=30X

UF A =3 x UF H =10x Occupational LOC:

MOE = 30 4 week inhalation study in the rat. LOAEL = 0.020 mg/L based on a dose

related increase in absolute and relative lung/bronchial weights in both sexes. At 0.100 mg/L, increased lung/bronchial weights were also seen, along with lung histopathology (alveolar macrophages, peribronchiolar proliferation) in both

sexes.

Cancer (o ral, dermal, inhalation) Classification: “Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic

potential”

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

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of

concern. HEC = human equivalent concentration; HED = human equ ivalent dose

. RDD = Dermal NOAEL x (animal

in vitro  human in vitro ); RDD = 10 mg/kg/day x (40.17%  16.49%) = 24.4 mg/kg/day

.



### 5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The nature of fluazinam residues in plants is adequately understood based on metabolism studies

on potatoes, peanuts, apples, and grapes. The residue of concern in peanuts and root and tuber vegetables is parent fluazinam for purposes of both dietary risk assessment and tolerance

enforcement (D272624, W. Cutchin, 4/23/2001) . For all other crops, the residues of concern include both fluazinam and its metabolite AMGT for purposes of dietary risk assessment. For

tolerance enforcement , th e residues of concern in plants include fluazinam and AMGT for wine grapes, but only fluazinam for all other plant commodities.

The nature of fluazinam residues in rotational crops is adequately understood. Based on the absence of metabolites containing the intact fluazinam nucleus, HED has determined that the residue of concern in rotational crops is the parent compound, and that rotational crop tolerances are not required for fluazinam. The available confined field rotational crop stud y supports the

30

- day plantback interval (PBI) that is currently listed on the label for crops without direct uses

of fluazinam.

### Fluazinam Human Health Risk Assessment DP No. D426143

Page 19 of 51 The nature of the residue in livestock is also understood based on acceptable goat and hen metabolism studies. The fluazinam residues of regul atory interest in animal commodities are parent plus the metabolites AMPA and DAPA and their sulfamate conjugates.

5.1.2 Summary of Environmental Degradation

The environmental fate studies for fluazinam indicate that the parent compound forms

transformati on compounds that, in most cases, are similar in structure to the parent. Fluazinam does not undergo degradation. Instead, it undergoes transformation into a series of products, all

of which are structurally similar to the parent compound . For modeling drinking water residues, the Environmental Fate and Effects Division (EFED) assumed that the physicochemical characteristics were similar for both the parent and its products (i.e.

, the total toxic residue approach).

5.1.3 Comparison of Metabolic Pathways

Fluazinam is a secondary amine whose substituents are substituted phenyl and pyridinyl ring s. The primary metabolic and degradation pathways involve reduction of nitro groups on the phenyl ring followed by hydrolysis or conjugation of the various substit uents on both rings . Two of the primary metabolites and degradates are AMPA and DAPA, and their hydrolysis or conjugation products . These compounds are primary metabolites in plants, ruminants, poultry, drinking water, and rats.

In plants, fluazinam undergoes reduction of one of the nitro groups to an amine, forming AMPA. AMPA can then be conjugated with glutathione, with subsequent degradation of the glutathione moiety to cysteine. The AMPA

- cysteine conjugate then undergoes transamination, reductio n, and conjugation with glucose to form AMGT. In addition, both rings of fluazinam appear to be labile to ring cleavage, and subsequent degradation of the rings into small fragments occurs. These fragments can then be incorporated into a variety of natur al plant components.

I n ruminants and poultry

, t he metabolism of [ 14 

### C]

- fluazinam is comparable , and involves reduction of one or both nitro groups on the phenyl ring to form AMPA, MAPA, or DAPA. Fluazinam also undergoes dehalogenation and hydroxylation of the chlorine on the phenyl ring to form HYPA. These compounds can then undergo conjugation w ith glutathione, and subsequent degradation of the glutathione component yields a variety of polar compounds. Although the ring structure of the parent molecule remains intact, fluazinam per se was only a minor component (≤2.7% TRR) of the [ 14 

### C]

- residues in poultry tissues and eggs, and was not

detect ed in ruminant tissues or milk.

In drinking water, the primary degradates include DCPA, CAPA, DAPA, HYPA, and AMPA.

Although there are metabolites and degradates in plants, livestock, and drinking water th at were not found in the rat, these compounds are structurally similar to the parent compound. The toxicity of these compounds is considered to be comparable to that of the parent. The toxicological endpoints that were selected for fluazinam are expected to be protective for the metabolites and degradates.

### Fluazinam Human Health Risk Assessment DP No. D426143

Page 20 of 51 5.1.4 Residues of Concern Summary and Rationale

HED has concluded that t he residue of concern in peanuts and root and tuber vegetables is parent fluazinam for purposes of both dietary risk assessment and tolerance enforcement (D272624, W. Cutchin, 4/23/2001) . For all other crops, the residues of concern include both fluazinam and its metabolite AMGT for purposes of dietary risk assessment. For tolerance enforcement , the residues of concern in plants include fluazinam and AMGT for wine grapes, but only fluazinam for all other plant commodities. AMGT is included in the tolerance for wine grapes becaus e it is the only adequate measure of misuse for residues in wine. The parent does not serve as a misus e measure in wine because it degrad es during the fermentation process. Based on structural similarity, AMGT is assumed to have comparable toxicity as the parent and

, therefore

, is included for dietary risk assessment in those crops where it is present at significant levels.

Based on the absence of metabolites containing the intact fluazinam nucleus in rotational crop

studies , HED has determined that the residue of concern in rotational crops is the parent compound, and that rotational crop tolerances are not required for fluazinam. The available confined field rotational crop stud y supports the 30

- day plant

- back interval (PBI) that is currently listed on the label for crops without direct uses of fluazinam.

The fluazinam residues of regulatory interest in animal commodities are parent plus the metabolites AMPA and DAPA and their sulfamate conjugates. These metabolites were the primary metabolites in the ruminant and poultry metabolism studies. AMPA and DAPA are structurally similar to fluazinam. They are the products formed by reduction of one or both nitro groups on the phenyl ring to form the mono

- and di

- amino metabolites. Their toxicity is assumed to be comparable to that of the parent compound (D272624, W. Cutchin, 4/23/2001).

Table 5.1.4

. Sum mary of Metabolites and D egradates to be included in the

Risk Assessment and Tolerance Expression

Matrix Residues included in Risk

Assessment Residues included in Tolerance Expression

Plants Primary Crop : grapes Parent fluazinam and AMGT Parent fluazinam and AMGT

Primary Crop : peanuts, root/tuber vegetables, bulb vegetables Parent fluazinam Parent fluazinam

Primary Crop : all

others Parent fluazinam and AMGT Parent fluazinam

Rotational Crop N/A Note: Tolerances are not required based on the absence of residues in rotational crops at the requested plant back

interval.

Livestock Ruminant Parent fluazinam, AMPA, and DAPA, and their sulfate conjugates Parent fluazinam, AMPA, and DAPA, and their sulfate conjugates

### Fluazinam Human Health Risk Assessment DP No. D426143

Page 21 of 51 Table 5.1.4

. Sum mary of Metabolites and D egradates to be included in the

Risk Assessment and Tolerance Expression

Matrix Residues included in Risk

Assessment Residues included in Tolerance Expression

Poultry Parent fluazinam, AMPA, and DAPA, and their sulfate conjugates Parent fluazinam, AMPA, and DAPA, and their sulfate conjugates

Drinking Water Fluazinam, CAPA, DAPA,

DCPA , HYPA, and AMPA Not Applicable



### Under 40 CFR §180.574(a)(1), t olerances are established for residues of f luazinam, 3

- chloro

- N

- [3

- chloro

- 2,6

- dinitro

- 4

- (trifluoromethyl)phenyl]

- 5

- (trifluoromethyl)

- 2

- pyridinamine ), including its metabolites and degradates, in or on the commodities in the table. Compliance with the tolerance levels is to be determined by me asuring only fluazinam. The existing tolerances for residues in grapes and livestock commodities are listed Under 40 CFR §180.574(a)(2) and (a)(3), respectively, including the relevant coverage and compliance statements. No changes to these tolerance exp ressions are needed in conjunction with the proposed uses.

5 .2 Food Residue Profile

The food use profile for the proposed commodities is adequate and complete for tolerance setting and risk assessment purposes ( D426241

, S. Biswas

, 09/18/2015 )

. The submitted field trial data for fluazinam on cabbage, cucumber, and summer squash are acceptable and support the proposed uses. Adequate numbers of trials were conducted in the appropriate geographic regions at approximately 1x the maximum proposed rate, a nd the appropriate samples were collected from each test at, or close to, the proposed PHI. Adequate storage stability data were submitted

for cabbage, cucumber, and summer squash . The data indicated that residues were stable over the storage durations u sed in the field trial and processing studies.

In addition, as part of this petition, IR

- 4 submitted previously requested storage stability on lettuce. This storage stability data was a condition of registration under a previous petition ( PP# 8E7506). T he submitted data are adequate and therefore fulfill this previously identified condition of registration.

Quantifiable residues of fluazinam were found in cucumber, summer squash, and cabbage . The ranges of residues in the samples of these commodi ties can be found in Table 5.2. No quantifiable residues of AMGT were found in any samples of any commodities tested.

No new field trial were submitted for mayhaw, an existing member of pome fruit group 11

- 10.

The tolerance for residues on mayhaw was r equested based on the June 20 th 

### , 2013 ChemSAC decision that provides an allowance for extrapolating apple residue data to mayhaw. The proposed label and the available field trial data for fluazinam residues in/on apple are adequate for the proposed transl ation of apple data to mayhaw.

### Fluazinam Human Health Risk Assessment DP No. D426143

Page 22 of 51 Similarly, no new field trial data were submitted to support the requested expansion of the current use on potatoes to the Vegetable, tuberous and corm, subgroup 1C

. The representative commodity for crop subgroup 1C is potato. Since a potato use is already on the label (Omega® 500F) for which expansion to crop subgroup 1C is requested, and since the expansion to crop subgroup 1C is for the identical use pattern currently registered for potato, no new data are required t o support the requested use on the crop subgroup 1C. The newly requested use on crop subgroup 1C commodities is considered adequately supported by the residue data previously submitted to establish the potato use.

There are no processed food or feed commodities associated with the requested use on cabbage, cucumber and summer squash ; therefore, a discussion of processed foods or feeds is not appropriate to this petition. Although there are processed commodities asso ciated with potatoes

, processing studies were not required since the p etitioner has requested a crop group expansion

which is supported with previously submitted data, including processing studies.

There are no livestock feedstuffs associated with the pro posed new use on cabbage, cucumber and summer squash

. Therefore, the proposed new uses have no impact on the existing tolerances for livestock commodities (0.05 ppm for the fat and meat byproducts of cattle, goats, horses, and sheep) and these existing li vestock tolerances are adequate.

Table 5.2 provides a summary of the cabbage, summer squash, and cucumber field trial data.

Table 5.2 . Summary of Fluazinam Field Trial Residue Data

. Crop

Matrix Analyte Total Application Rate (lb ai/A) PHI

(days) n 1 Residues (ppm)

Min. 2 Max. 2 LAFT 3 HAFT 3 Median 3 Mean 3 SD 3

Cucumbers Fluazinam 3.90

- 3.96 5.68 (1 trial) 6

- 7 6 <0.01 0.0316 <0.01 0.0267 0.01 0.0128 0.0068

AMGT <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

Combined 4 <0.02 <0.0416 <0.02 <0.0367 0.020 0.0228 0.0068

Summer squash Fluazinam 3.62

- 3.95 6

- 7 6 <0.01 0.0165 <0.01 <0.0132 0.010 0.0109 0.0014

AMGT <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

Combined 4 <0.02 <0.0265 <0.02 <0.0232 0.020 0.0209 0.0014
Cabbage Fluazinam 2.964

- 3.583 6

- 7 8 0.124 1.67 0.12 9 1.4 5 0.457 0.635 0.521

AMGT <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A

Combined 4 < 0.134 < 1.68 < 0.13 9 < 1.4 6 0.467 0.64 5 0.521

1 n = number of field trials.

2 Values based on total number of samples.

3 Values based on per

- trial averages. LAFT = lowest average field trial, HAFT = highest average field trial, SD = standard

deviation. N/A = Not applicable.

4 Combined residues of fluazinam and AMGT.



### The Organization for Economic Cooperation and Developme nt (OECD) MRL calculator was used to determine appropriate tolerance levels for the residues of fluazinam (parent only) for cabbage, cucumber, squash, and mayhaw

. Both cucumber and squash are representative crops of crop subgroup 9B. Based on the results from the OECD calculator, the tolerance level for cucumber (0.04 ppm) is higher than that of squash (0.02 ppm). Based on HED’s policy, since the differences between the recommended tolerances is <5x, then it is appropriate to recommend

for a tolerance fo r the crop subgroup 9B based on the highest calculated value. However, b oth squash and cucumber are also representative crops for cucurbit vegetables crop group 9 and a

### Fluazinam Human Health Risk Assessment DP No. D426143

Page 23 of 5 1 tolerance is currently established for melon subgroup 9A at 0.07 ppm which is higher t han the proposed tolerance (0.05 ppm) for subgroup 9B. Based on the residue data review and HED’s policy, it is appropriate to recommend a tolerance for a crop group based on highest tolerance value. Therefore, HED is recommending a single crop group tol erance for crop group 9 at 0.07 ppm instead of separate tolerances for subgroups 9A and 9B. The recommended tolerances for proposed new uses are listed in Table 2.2.3.

5.3 Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by the Environmental Fate and Effects Division (EFED; D 426144, J. Meléndez, 10 / 6 /201 5) and incorporated directly into this dietary assessment into the food categories “water, direct, all sources” and “water, indirect, all sources.” The residues of concern in drinking water for risk assessment are parent fluazinam and its transformation prod ucts, including DCPA, CAPA, DAPA, HYPA, and AMPA.

The estimated acute and chronic EDWCs are based on ground application of fluazinam to turf.

The values are provided in Table 5. 3, below. The groundwater value was generated using the

Pesticide Root Zone Model for Groundwater (PRZM

- GW) Model and the surface water values were generated using the FQPA Index Reservoir Screening Tool (FIRST) Model. The surface water estimate was used for the acute assessment because this estimate was higher than the groundwat er value. In contrast, the groundwater estimate was used for the chronic assessment, because this estimate was higher than the surface water value. Both acute and chronic estimates included parent and degradates. For the acute assessment, a value of 226 ppb was used, and for the chronic assessment, a value of 119 ppb was used. This value also includes both parent and degradates. For more information about EFED’s drinking water models, see http ://www.epa.gov/oppefed1/models/ water

.

Table 5.3 . Maximum Tier 1 Estimated Drinking Water Concentrations B ased on G round

A pplication of F luazinam t o T urf at a S easonal R ate of 8.4 lb a.i./A

Source/Model Fluazinam Total Residues of Fluazinam 1
Acute/ppb Chronic/ppb Acute/ppb Chronic/ppb

Surface Waters/FIRST 217 2 1.47 226 2 37.8

Groundwater/PRZM

- GW 0.538 0.319 137 2 119 2

1. Including the following transformation products: DCPA, HYPA, CAPA, DAPA and AMPA.

2

. Exceeds the solubility of fluazinam at pH 7 (71 ppb), but not the solubility at pH 11 (350 ppm).



### 5.4 Dietary Risk Assessment

D429506

, E. Holman

, 02/25/2016

5.4.1 Description of Residue Data Used in Dietary Assessment

Acute and chronic dietary (food and drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model DEEM

- FCIDTM, Version 3.16 which uses food consumption data from the U.S. Department of Agriculture’s National Health and

### Fluazinam Human Health Risk Assessment DP No. D426143

Page 24 of 51 Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). This dietary survey was conducted from 2003 to 2008.

The acute analysis is based on tolerance

- level residues for all commodities and uses high

- end

residue estimates for the metabo lite AMGT. In addition, the acute assessment assumes 100% crop treated and incorporates modeled EDWCs that account for both parent fluazinam and its transformation products. D efault processing factors were used for all relevant processed

commodities with out separate tolerances

. Therefore, the resulting exposure and risk estimates are considered to be very conservative.

The chronic analysis is based on tolerance

- level residues for all commodities except apples. For apples, the average field trial value was used. As with the acute assessment, it incorporates high

end estimates for AMGT, 100% crop treated assumptions

, d efault processing factors for all

relevant processed commodities without a separate tolerance

, and modeled EDWCs that account for both par ent and transformation products. Again, the resulting exposure and risk estimates are

considered to be conservative.

Because such conservative assumptions were made in the assessments, the resulting exposure

and risk estimates are considered to be conser vative as well. HED is confident that the acute and chronic dietary exposure assessments significantly over estimate risk to the general U.S. population an d its various population subgroup s

.

5.4.2 Percent Crop Treated Used in Dietary Assessment

T he acute and chronic assessments were both based on the assumption that 100% of all

commodities with fluazinam tolerances will be treated.

5.4.3 Acute Dietary Risk Assessment

The acute risk estimates at the 95 th 

### percentile of exposure are below HED’s leve l of concern for all population subgroups, including those comprised of infants and children. Generally, HED is concerned when risk estimates exceed 100% of the population

- adjusted dose (PAD). The acute risk estimate for the general U.S. population is 5. 7 % of the acute PAD (aPAD). The aPAD is lower for females 13 to 49 years old. Although Children 1

- 2 years old have the highest exposure estimate (0. 112064 mg/kg/day; 22 % aPAD), the population subgroup with the highest risk

estimate is females 13 to 49 ye ars old, with 3 2 % of the aPAD ( 0.022220 mg/kg/day). Since the

asses sment used an assumption of 100 % CT, the risk estimates are being reported at the 95 th


### percentile of exposure. The acute dietary risk estimates are given in Table 5.4.6.

5.4.4 Chronic Dietary Risk Assessment

Chronic risk estimates are also below HED’s level of concern for all population subgroups. The risk estimate for the general U.S. population is 41 % of the chronic PAD (cPAD). The most highly exposed population subgroup is All Inf ants (<1 year old), which uses 92 % of the cPAD. The chronic dietary risk estimates are given in Table 5.4.6.

5.4.5 Cancer Dietary Risk Assessment

### Fluazinam Human Health Risk Assessment DP No. D426143

Page 25 of 51 Fluazinam is classified as having “suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential.” The CARC determined that quantification of risk using a

non

- linear approach (i.e., RfD) will adequately account for all chronic toxicity, including carcinogenicity, that could result from exposure to fluazinam. As a result, a separate dietary exposure assessment for cancer risk was not performed.

5.4.6 Summary Table

Table 5

. 4.6 Summary of Acute and Chronic Exposure and Risk Estimates for Fluazinam

Population Subgroup Acute Assessment (95 th Percentile) Chronic Assessment

aPAD, mg/ kg/ day Exposure

Estimate, mg/ kg/ day % aP AD cPAD, mg/ kg/ day Exposure Estimate,

mg/ kg/ day %

cP AD

U.S Population 0.5 0.028533 5.7 0.011 0.004521 41

All infants * 0.5 0.085186 1 7 0.011 0.010122 92

Children 1

- 2 yrs 0.5 0.112064 22 0.011 0.009750 89

Children 3

- 5 yrs 0.5 0.065310 13 0.011 0.006614 60

Children 6

- 12 yrs 0.5 0.034218 6.8 0.011 0.004161 38

Youth 13

- 19 yrs 0.5 0.019517 3.9 0.011 0.002981 27

Adults 20

- 49 yrs 0.5 0.021791 4.4 0.011 0.004243 39

Adults 50

- 99 yrs 0.5 0.019444 3.9 0.011 0.004490 41

Females 13

- 49 yrs * 0.07 0.022220 32 0.011 0.004338 39

* The subpopulation with the highest acute or chronic risk estimate



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

6.1 Residential Handler Exposure and Risk

The Agency uses the term “Handlers” to describe those individuals who are involved in the pesticide application process. A residential handler assessment has not been conducted for fluazinam, since the end

- use product, Fluazina m Turf Fungicide

, limits the application site to golf courses only

. The proposed label also includes the following statement in the use

restrictions section: “Do not apply product to home lawns (turf) or any other residential turf

. ”

6.2 Residential Post

- a pplication Exposure

Fluazinam residential post

- application scenarios include individuals playing golf on treated turf.

C hildren 6 to <11 years old, youths 11 to <16 years old, and adults can potentially be exposed when they play golf on treated turf

. Post

- application residential exposure was assessed using default assumptions and transfer coefficients from the HED SOPs for Residential Exposure Assessments, (20 12 ), as well as chemical

- specific residue data from a t urf transferable residue (TTR) study (MRID No. 48361527)

. Although HED typically assesses oral (hand

- to

- mouth)

post

- application exposure and risk for toddlers playing on treated turf, these exposures are not expected for golf course turf, and were therefore not assessed.

6.2.1 Dermal Post

- a pplication Exposure

### Fluazinam Human Health Risk Assessment DP No. D426143

Page 26 of 51 Short

- term r esidential post

- application dermal exposures resulting in MOEs greater than or equal

to 100 are not of concern. Short

- term dermal post

- application exposure and risk analys e s for golfers resulted in MOE s greater than the LO C and are not of concern. The highest risk estimate (lowest MOE) was for youth golfers aged 6 to <11 year s old, with an MOE of 780. A summary

of the residential short

- term dermal ex posure and risk estimates is shown in Table 6.2. 1

.

Table 6.2. 1

. Residential Post

- application Short

- term Dermal Exposure and Risk Estimate s for Fluazinam

Scenario Application

Rate (lb ai/A) TTR 1

(μg/cm 2 ) CF T C

(cm 2 /hr) ET

(hrs) BW (kg) Dose 2 (mg/kg/day) Dermal

MOE 3

Golfer
6 to < 11 yrs old 0.7 0.0865 0.001 2,9 00 4 32 0.0 31356 780
11 to < 16 yrs old 0.7 0.0865 0.001 4,400 4 57 0.0267 09 9 1 0

Adult 0.7 0.0865 0.001 5,300 4 80 0.022923 1,100

1. Turf Transferable Residues (TTR) = 0.0865 ug/cm 2 is based on predicted day 0 residue value calculated from chemical

specific data (MRID No. 48361527). 2. Dermal Dose (mg/kg/day) = [TTR (μg/cm 2 ) x 0.001 (mg/μg) x TC (cm 2 /hr) x ET (hr/day)]/ BW (kg)

. 3. Dermal MOE = ( POD ( 24 .4 mg/kg/day) ) ÷ ( Dermal Dose (mg/kg/day) )

.



### 6.2.2 Inhalation Post

- application 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 pesticides 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 evaluated the SAP report and has develo ped 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

fluazinam

.

6.3 Combined Residential Risk Estimates

HED combines risk values resulting from separate exposure scenarios when it is likely they can

occur simultan eously based on the use pattern and when the toxicological effects are the same across different routes of exposure. Since the application of fluazinam is only directed for golf

course s , incidental oral post

- application exposure for children is also expec ted to be negligible.

T he only route of exposure is through the dermal route (i.e., dermal post

- application exposure)

. Therefore, combined residential exposure assessment for golfers i s not required

.

6.4.2 Residential Risk Estimates for Use in Aggregate Ass essment

T he residential scenarios and risk estimates identified for use in performing an aggregate exposure assessment as part of the fluazinam human health risk assessment are: dermal post

application exposure resulting from treated golf courses for adults (MOE = 1,100 ) and for children 6 to < 11yrs old (MOE = 780).

### Fluazinam Human Health Risk Assessment DP No. D426143

Page 27 of 51 6. 5 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, spr ay drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for fluazinam. 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 informa tion). 1 

### 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 is currently quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently. However, fluazinam recently completed a registration review assessment ( D397601, D. Dotson, 09/10/2012 ) prior to the finalization of this spray drift policy. The approach is outlined in the revised (2012) Standard Operating Procedures For Residential Risk Assessment (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.

Therefore, given that this was not assessed during registration review, as part of this assessment, HED has used the procedures described in this document to assess the potential for spray drift

exposure. Fluazinam products have existing labels for use on golf course turf, thus it was considered whether the risk assessment for that use may be considered protective of any type of exposure that would be associated with spray drift. It should be noted that t he registered

residential uses on turf result in ex posure greater than potential exposure from spray drift; therefore, no new residential assessment needs to be completed. If the maximum application rate on crops adjusted by the amount of drift expected is less than or equal to existing turf application

r ates, the existing turf assessment is considered protective of spray drift exposure. The currently registered maximum single application rate of fluazinam for Brassica vegetables is 1.3 lb ai/A

. The highest degree of spray drift noted for any application method immediately adjacent to a treated field (Tier 1 output from the aerial application using fine to medium spray quality) results in an deposition fraction of 0.26 of the application rate. A quantitative spray drift assessment for

fluazinam is not re quired because the max imum application rate to a crop/ta rget site multiplied by the adjustment factor for drift of 0.26 is less than the maximum direct spray residential turf application rate [( 0.70 lb ai/A )] 2 

### for any fluazinam products . The turf post

- application MOEs have been previously assessed and are based on the revised SOPs for Residential Exposure Assessment (i.e., see above in Section 6.2 ).

It is noted that the use rates proposed for this petition are 0.26

- 0.78 lb ai/A/appli cation; therefore, the spray drift assessment associated with the registered use rates is protective of the anticipated exposure from this new use action.

1 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm

2 1.3 lb ai/A x 0.26 ≤ 0.70 lb ai/A

### Fluazinam Human Health Risk Assessment DP No. D426143

Page 28 of 51 6. 6 Residential Bystander Post

- Application Inhalation Exposure

Volatilization of pesticides may b e a source of post

- application inhalation exposure to individuals nearby pesticide applications. The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act

Scien tific 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 evaluated 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 t oxicological studies) or further analysis is required for

fluazinam

.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposure and

risk estimate s from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risk estimate s themselves can be aggregated. When aggregatin g exposures and risks from various sources, HED considers both the route and duration of exposure.

7.1 Acute Aggregate Risk

Acute aggregate risk result s from exposure to residues in food and drinking water. The acute dietary exposure analysis included b oth food and drinking water . Therefore, acute aggregate risk

estimates are equivalent to the acute dietary risk estimates

, as discussed in Section 5.4.3, above.

All risk estimates are not of concern.

7.2 Short

- /Intermediate

- Term Aggregate Risk Estimates

Fo r the short

- term aggregate risk assessment, the only relevant residential exposure scenario,

dermal post

- application

, was combined with background exposure from food and water.

The chronic dietary exposure estimate s are the background exposure level s that w ere added directly to the residential dermal post

- application exposure estimate s

. Of the population subgroups comprised of adults, the subgroup Adults 50

- 99 had the highest dietary exposure estimate. For the child and youth population subgroups, t he dietary groups did not directly overlap with the representative residential life stages

. Specifically, the closest dietary subgroup

to the residential life stage children 6

- <11 was children 6

- 12, and the closest dietary subgroup to

the residential life stage youth 12

- <16 was youth 13

- 19.

The short

- term aggregate risk assessment s resulted in estimated MOE s of 690 to 890 . For fluazinam, the LOC for short

- term risk is an MOE of 100. As the resulting aggregate MOE s

e xceed the LOC of 100, aggregate dietary and residential risk estimates are not of concern. Because the background exposure from food and water is so low relative to the dermal exposure

### Fluazinam Human Health Risk Assessment DP No. D426143

Page 29 of 51 estimates, the short

- term aggregate MOEs are the similar to those esti mated for the dermal route

alone. The aggregate risk estimates are given in Table 7.2.

Table 7.2. Residential Short

- /Intermediate

- Term Aggregate Risk Calculations

Population Short

- or Intermediate

- Term Scenario

POD mg/kg/day LOC 1 Max

Allowable Exposure 2 mg/kg/day Average

Food and

Water Exposure mg/kg/day Residential Post

application Dermal Exposure mg/kg/day 3 Total

Exposure 4 mg/kg/day Aggregate

MOE (food, water, and

residential ) 5

Children 6

- <11 24.4 100 0.244 0.004161 0.031356 0.035517 690

Youth 11

- <16 24.4 100 0.244 0.002981 0.026709 0.02969 0 820

Adults 24.4 100 0.244 0.004490 0.022923 0.027413 890

1. An UF of 100x was applied to account for interspecies extrapolation (10x) and intraspecies variation (10x). No additional uncertainty factors/safety factors are required.

2

. Maximum Allowable Exposure (mg/kg/day) = POD /LOC

3

. Residential Exposure = Dermal exposure from treated turf (see table 6.2. 1 ).

4

. Total Exposure = Avg Food & Water Exposure + Residential Exposure

5

. Aggregate MOE = [ POD ( 24.4 mg/kg/day) ÷ ( Avg Food & Water Exposure + Residential Exposure ( mg/kg/day) ) ]



### 7. 3 Chronic Aggregate Risk

There are no residential scenarios that result in long

- term exposure. As a result, t he chronic aggregate risk assessment result s from long

- term exposure to residues in food and drinking water only

. The chronic dietary exposure analysis included both food and drinking water and, therefore, the chronic aggregate risk assessment is equivalent to the chronic dietary assessment discussed in Section 5.4.4, above. All risk estimates are below HED’s level of concern.

7. 4 Canc er Aggregate Risk

Fluazinam is classified as having “suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential.” The CARC determined that quantification of risk using a

non

- linear approach (i.e., RfD) will adequately account for all chronic toxicity, including carcinogenicity, that could result from exposure to fluazinam. As a result, a separate dietary exposure assessment for cancer risk w as not performed.

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 fluazinam and any other substances

, and fluazinam does not appear to produce a toxic metabolite produced by other substances. For the purposes of this risk assessment , therefore,

EPA has not assumed that fluazinam has a common mechanism of toxicity with other

substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements release d by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have

a common mechanism on EPA’s website at http://w ww.epa.gov/pesticides/cumulative/

.

### Fluazinam Human Health Risk Assessment DP No. D426143

Page 30 of 51 9.0 Occupational Exposure/Risk Characterization

9.1 Occupational Handler Exposure/Risk Estimates

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, oc cupational handler exposure is expected from the proposed uses. The quantitative exposure/risk assessment developed for occupational handlers is ba sed on the following scenarios:

 Mixing and loading liquids for aerial, airblast, chemigation, and groundboom applications;

 Applying sprays with aerial, airblast, and groundboom equipment;

 Flagging for aerial applications; and

 Mixing, loading, and applying liquids via mechanically

- pressurized handgun for foliar applications.

As per the label instructions, fluazinam may be applied every 7 days multiple times throughout the growing season. Using the maximum application rates for all new uses, the maximum number of times fluazinam may be applied ranges from 4 for cabbage, to 10 times for m ayhaw. Based on these proposed new uses, short

- and intermediate

- term exposures are expected. Long

term exposures are not expected.

Estimates of dermal and inhalation exposure were calculated for various levels of personal protective equipment (PPE). Results are presented for “baseline,” defined as a single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator, as well as baseline with various levels of PPE as necessary (e.g ., gloves, respirator, etc). The fluazinam product label directs mixers, loaders, applicators and other handlers to wear : baseline clothing (i.e., long

- sleeved shirt and long pants, socks), chemical

- resistant gloves and

footwear

, and protective eyewear. Those who are mixing, loading, or cleaning equipment must also wear a chemical resistant apron.

Detailed descriptions of the occupational handler assessment are available in G. Thornton (D 430208

, 02/25/2016 )

. It is the policy of HED to use the best ava ilable data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical

specific data, include PHED 1.1, the AHETF database, the Outdoor Residential Exposure Task Force (ORETF) database, or other registra nt

- submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting handler exposure that are used

in this assess ment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table 3 

### ”, which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website 4



### .

3 Available: http://www2.epa.gov/sites/production/files/2015

- 09/documents/handler

- exposure

- table

- 2015.pdf

4 Available: http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/occupational

- pesticide

- handler

exposure

- data

### Fluazinam Human Health Risk Assessment DP No. D426143

Page 31 of 51 In addition to the generic exposure data to assess occupational exposure and risk, HED used standard assumptions with respect to the area treated, the hours worked in a day, and the average adult body weight (80 kg).

Occupational Handler Non

- Cancer Exposure and Risk Estimates

Table 9 .1 presents the short

- term dermal and inhalation risk estimate s for handlers

. Since the endpoints selected for risk assessment are different for dermal (liver effects) and inhalation (lung effects) routes of exposure, the exposure and risk cannot be combined. Therefore, dermal and inhalation risks were calculated and presented sepa rately.

The occupational handler exposure and risk estimates indicate that the short

- and intermediate

term dermal (LOC < 100) and inhalation (LOC < 30) MOEs are not of concern at or below the level of personal protection specified on the label (double layer and gloves), with the exception of dermal exposure during the use of airblast applicator and mechanically

- pressurized handgun. Based on personal email communication with RD, the registrant intends to submit a revised label that prohibits the use of m echanically

- pressurized handgun, thus mitigating the risks of concern associated with this application method. For airblast applicators, risks of concern for dermal application were identified, but with additional PPE (e.g., chemically resistant hat), the dermal exposure MOEs are above the LOC. All inhalation exposure and risk estimates pass at baseline protection. All scenarios resulting in aerial applicator exposure are assumed to occur using engineering controls for this assessment. Risk estimates, d ermal exposure, and mitigation levels

are included below in Table 9.1.

HED has no data to assess exposures to pilots using open cockpits. The only data available is for exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed usi ng the engineering control (enclosed cockpits) and baseline attire (long

- sleeve shirt, long pants, shoes, and socks); per the Agency’s Worker Protection Standard stipulations for engineering controls, pilots are not required to wear protective gloves for t he duration of the application. With this level of protection, there are no risk estimates of concern for applicators.

The Agency matches quantitative occupational exposure assessment with appropriate characterization of exposure potential. While HED pre sents quantitative risk estimates for human flaggers where appropriate, agricultural aviation has changed dramatically over the past two decades. According the 2012 National Agricultural Aviation Association (NAAA) survey of their membership, the use of GP S for swath guidance in agricultural aviation has grown steadily from the mid 1990’s. Over the same time period, the use of human flaggers for aerial pesticide applications has decreased steadily from ~15% in the late 1990’s to only 1% in the most recent ( 2012) NAAA survey. The Agency will continue to monitor all available information sources to best assess and characterize the exposure potential for human flaggers in agricultural aerial applications.

### Fluazinam Human Health Risk Assessment DP No. D426143

Page 32 of 51 Table 9 .1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Fluazinam.

Exposure

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

Exposure (μg/lb ai) 1 Maximum

Application

Rate 3 Area Treated

or Amount

Handled Daily 4 Dermal

LOC = 100 Inhalation

LOC = 30

[ Level of PPE or Engineering

Control ] 2 [ Level of PPE or

Engineering

Control ] 2 Dose (mg/kg/day) 5 MOE 6 Dose (mg/kg/day) 7 MOE 8

Mixer/Loader

Aerial Tuberous and Corm

Subgroup 1C 37.6 [SL/G] 0.219

[Baseline] 0.26

lb ai/acre 1200 Acres 0.146 170 0.000854 150

Cabbage 37.6

[SL/G] 0.219

[Baseline] 0.5

lb ai/acre 350 Acres 0.0823 300 0.000479 260

Squash/Cucumber Subgroup 9B 37.6 [SL/G] 0.219

[Baseline] 0.78

lb ai/acre 350 Acres 0.129 190 0.000748 170

Mayhaw 37.6

[SL/G] 0.219

[Baseline] 0.45

lb ai/acre 350 Acres 0.074 330 0.000431 290

Airblast Mayhaw 220 [Baseline] 0.219

[Baseline] 0.45

lb ai/acre 40 Acres 0.0495 490 0.0000493 2500

Chemigation Tuberous and Corm

Subgroup 1C 37.6 [SL/G] 0.219

[Baseline] 0.26

lb ai/acre 350 Acres 0.0428 570 0.000249 500

Cabbage 37.6

[SL/G] 0.219

[Baseline] 0.5

lb ai/acre 350 Acres 0.0823 300 0.000479 260

Squash/Cucumber Subgroup 9B 37.6 [SL/G] 0.219

[Baseline] 0.78

lb ai/acre 350 Acres 0.129 190 0.000748 170

Mayhaw 37.6

[SL/G] 0.219

[Baseline] 0.45

lb ai/acre 350 Acres 0.074 330 0.000431 290

Groundboom Tuberous and Corm

Subgroup 1C 220

[Baseline] 0.219

[Baseline] 0.26

lb ai/acre 200 Acres 0.143 170 0.000143 870

Cabbage 220

[Baseline] 0.219

[Baseline] 0.5

lb ai/acre 80 Acres 0.11 220 0.00011 1100

Squash/Cucumber Subgroup 9B 220

[Baseline] 0.219

[Baseline] 0.78

lb ai/acre 80 Acres 0.171 140 0.000171 730

Applicator

### Fluazinam Human Health Risk Assessment DP No. D426143

Page 33 of 51 Table 9 .1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Fluazinam.

Exposure

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

Exposure (μg/lb ai) 1 Maximum

Application

Rate 3 Area Treated

or Amount

Handled Daily 4 Dermal

LOC = 100 Inhalation

LOC = 30

[ Level of PPE or Engineering

Control ] 2 [ Level of PPE or

Engineering

Control ] 2 Dose (mg/kg/day) 5 MOE 6 Dose (mg/kg/day) 7 MOE 8

Aerial Tuberous and Corm

Subgroup 1C 2.08 [EC] 0.0049

[EC] 0.26

lb ai/acre 1200 Acres 0.00811 3000 0.0000191 3200

Cabbage 2.08

[EC] 0.0049

[EC] 0.5

lb ai/acre 350 Acres 0.00455 5400 0.0000107 5800

Squash/Cucumber Subgroup 9B 2.08 [EC] 0.0049

[EC] 0.78

lb ai/acre 350 Acres 0.0071 3400 0.0000168 3700

Mayhaw 2.08

[EC] 0.0049

[EC] 0.45

lb ai/acre 350 Acres 0.0041 6000 0.00000965 6400

Airblast Mayhaw 1480 [DL/G] 4.71

[Baseline] 0.45

lb ai/acre 40 Acres 0.333 73

0.00106 58 215 [SL/G/CRH] 0.0484 500

Groundboom Tuberous and Corm

Subgroup 1C 78.6

[Baseline] 0.34

[Baseline] 0.26 lb ai/acre 200 Acres 0.0511 480 0.000221 280

Cabbage 78.6

[Baseline] 0.34

[Baseline] 0.5

lb ai/acre 80 Acres 0.0393 620 0.00017 360

Squash/Cucumber Subgroup 9B 78.6

[Baseline] 0.34

[Baseline] 0.78

lb ai/acre 80 Acres 0.0613 400 0.000265 230

Flagger

Aerial Tuberous and Corm

Subgroup 1C 11

[Baseline] 0.35

[Baseline] 0.26

lb ai/acre 1200 Acres 0.0125 200 0.000399 540

Cabbage 11

[Baseline] 0.35

[Baseline] 0.5

lb ai/acre 350 Acres 0.0241 1000 0.000766 280

Squash/Cucumber Subgroup 9B 11

[Baseline] 0.35

[Baseline] 0.78

lb ai/acre 350 Acres 0.0375 650 0.0012 180

Mayhaw 11

[Baseline] 0.35

[Baseline] 0.45

lb ai/acre 350 Acres 0.0216 1100 0.000689 310

Mixer/Loader/Applicator

### Fluazinam Human Health Risk Assessment DP No. D426143

Page 34 of 51 Table 9 .1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Fluazinam.

Exposure

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

Exposure (μg/lb ai) 1 Maximum

Application

Rate 3 Area Treated

or Amount

Handled Daily 4 Dermal

LOC = 100 Inhalation

LOC = 30

[ Level of PPE or Engineering

Control ] 2 [ Level of PPE or

Engineering

Control ] 2 Dose (mg/kg/day) 5 MOE 6 Dose (mg/kg/day) 7 MOE 8

Mechanically

pressurized Handgun Tuberous and Corm

Subgroup 1C 6050

[Baseline] 8.68

[Baseline] 0.013

lb ai/gal 1000 Gallons 0.984 25

0.00141 150 1360 [DL/G] 0.221 110

Cabbage 6050

[Baseline] 8.68

[Baseline] 0.025

lb ai/gal 1000 Gallons 1.89 13

0.00271 80 1360 [DL/G] 0.425 57

Squash/Cucumber Subgroup 9B 6050

[Baseline] 8.68

[Baseline] 0.039

lb ai/gal 1000 Gallons 2.95 8.3

0.00424 51 1360 [DL/G] 0.663 37

Mayhaw 6050

[Baseline] 8.68

[Baseline] 0.00225

lb ai/gal 1000 Gallons 0.17 140 0.000244 890

1. Unit exposures and description of mitigation leve l s are found in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table ” (September 2015)

2. Level of PPE or Engineering controls : Baseline is considered single layer, no gloves, and no respirator; SL/G is single layer and gloves; DL/G is double layer and gloves; PF5 R is "Protection Factor 5" respirator assuming an 80% reduction in exposure; SL/G/CRH is single layer, gloves, and chem ical resistant hat. The label PPE is considered to be DL/G. 3. Based on registe red or proposed label (Reg. No. 71512

- 1 ). 4. Exposure Science Advisory Council Policy #9.1. 5. 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 Daily (A or gal/day) ÷ BW ( 80 kg).

6. Dermal MOE = Dermal POD (mg/kg/day) ÷ Dermal Dose (mg/kg/d ay).

7. Inhalation Dose = Inhalation Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW (kg). 8. Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

### Fluazinam Human Health Risk Assessment DP No. D426143

Page 35 of 51 9

. 2 Occupational Post

- application Exposure/Risk Estimates

9 .2.1 Occupational Post

- application Inhalation Exposure/Risk Estimates

There are multiple potential sources of post

- application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The agency sought expert advice and input on issues related to volatilization of pesticides 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/2 009/120109meeting.html ). The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( ht tp://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 f or fluazinam.

In addition, the Agency is continuing to evaluate the available post

- application inhalation exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the Agency will continue to identify the need for and, subs equently, the way to incorporate occupational post

- application inhalation exposure into the agency's risk assessments.

Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessmen t was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post

- application exposure. Therefore, it is expected that these handler inhalation exposu re estimates would be protective of most occupational post

- application inhalation exposure scenarios.

9

. 2 .2 Occupational Post

- application Dermal Exposure/Risk Estimates

Occupational workers who enter treated fields to perform post

- application activities such as hand weeding and scouting m ight be exposed to fluazinam residues. Based on the use pattern,

workers m ight be exposed to short

- and intermediate

- term exposure durations. Detailed descriptions of the occupational post

- application dermal assessment are available in G. Thornton

, ( D 430208

, 02/25/2016 )

.

Transfer Coefficients: It is the policy of HED to use the best available data to assess post

application exposure. Sources of generic post

- application data, used as surrogate data in the

absence of chemical

- specific data, are derived from ARTF exposure monitoring studies, and, as proprietary data, are subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting post

- application exposure that are used in t his assessment, known as “transfer coefficients”, are presented in the ExpoSAC Policy 3” ( http://www.epa.gov/pesticides/science/exposac_policy3.pdf ), which, along with additional

### Fluazinam Human Health Risk Assessment DP No. D426143

Page 36 of 51 in formation about the ARTF data, can be found at : http://www.epa.gov/pesticides/science/post

app

- exposure

- data.html

.

Dislodgeable Foliar Residues : Chemical

- specific dislodg eable foliar residue (DFR) s tudies on apples (MRID#: 455842 03), potatoes (MRID # : 455842 02), and peanuts (MRID#: 45584201 ) were submitted and reviewed by HED. The studies demonstrated that dislodgeable foliar residue

values declined over time

.

The pean ut DFR study was used to assess post

- application exposure and risk estimates from contact with cabbage and crops in the squash/cucumber subgroup 9B because it was the most conservative DFR value. As apple and potato are the representative commodities for t he proposed crops, mayhaw and tuberous and corm vegetables subgroup 1C respectively, the apple DFR and potato DFR studies were used to assess post

- application exposure and risk estimates from contact with mayhaw and tuberous and corm vegetables subgroup 1C

.

Dermal exposures during post

- application activities were estimated using : 1) the maximum single application rate on the proposed label for each crop ( 0.26

- 0.78 lb ai/acre ), 2) a standard body weight for the general population (80 kg), and 3) an average occupational workday of 8 hours per day

.

Occupational Post

- application Non

- Cancer Dermal Risk Estimates

A summary of the post

- application exposure and risk estimates for the proposed uses is provided

in Table 9 .2. 2

. Only risk estimates for the highest contact activity are shown below. All scenarios resulted in MOEs greater than the LOC of 100 on day 0, with the exception of hand weeding cabbage, and are not of concern. At 12 and 24 hours after last application, MOE s for hand weeding cabbage increase to 98 and 100 respectively.

Table 9.2

. 2. Occupational Post

- application Non

- Cancer Exposure and Risk Estimates for Fluazinam.

Crop/Site Activities Transfer

Coefficient (cm 2 /hr) DAT 1 DFR/TTR

(μg/cm

2 ) Dermal Dose 2

MOE 3 (mg/kg/day)

Short

- and Intermediate

- term

Cabbage Hand Weeding 4200 0.5 0.59 4 0.249 98

1 0.56 4 0.236 100

Mayhaw Thinning Fruit 3600 0 0.05 5 0.017 1400

Squash/Cucumber Subgroup 9B Irrigation

(hand set) 1900 0 0.98 4 0.186 130

Tuberous and

Corm Vegetables Subgroup 1C Irrigation

(hand set) 1900 0 0.23 6 0.044 550

1 DAT = Day(s) after treatment

2 Daily Dermal Dose = [DFR (μg/cm 2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day]  BW ( 80 kg).

3 MOE = POD ( POD = 24.4 mg/kg/day) / Daily Dermal Dose. 4 Fluazinam Peanut DFR data used (MRID# 45584201) 5 Fluazinam Apple DFR data used (MRID# 45584203)

### Fluazinam Human Health Risk Assessment DP No. D426143

Page 37 of 51 6 Fluazinam Potato DFR data used (MRID# 45584202)



### Restricted Entry Interval

Fluazinam is classified as Toxicity Category III via the dermal route and Toxicity Category IV for skin irritation potential. It is a skin sensitizer. Under 40 CFR 156.208 (c) (2), ai’s classified as Acute III or IV for acute dermal, eye irritation and primary skin irritation are assigned a 12

- hour REI. In the case of hand weeding activities on cabbage, identified MOEs were 98 at 12 hours and 100 at 24 hours. However, HED does not consider an MOE of 98 at 12 hours to be of concern, as it is essentially equivalent to an MOE of 100. All other s hort

- and intermediate

- term
post

- application risk estimates were not a concern on day 0

. Therefore, the [156 subpart K]

Worker Protection Statement interim REI of 12 hours should be adequate to protect agricultural workers from post

- application exposure to fluazinam

.

### Fluazinam Human Health Risk Assessment DP No. D397601

Page 38 of 51 10.0 References

D. Dotson, K. Middleton, Z. Figueroa, 9/10/2012

, D3 97601

, Fluazinam. Human Health Risk

Assessment to Support New Uses on Soybeans, the Melon Subgroup (9

- A), and the Pepper/Eggplant Subgroup (8

- 10 B) , and to Support Registration Review

C Swartz , M Doherty, 2/14/2013, D407410. Fluazinam. Addendum to the Human Health Risk Assessment for New Uses and Registration Review: Incorporation of New Acute Toxicity Data and Updated Restricted Entry Interval (REI).

S. Biswas, 09/18/2015 , D426241. Fluazinam. Petition for the Establishment of Permanent Tolerances and Registration for New Uses on Tuberous and Corm, Subgroup 1C, Mayhaw, Squash/Cucumber Subgroup 9B; Amended Uses on Cabbage; and Removal of Cabbage from Vegetable, Brassica leafy, group 5 . Summary of Analytical Chemistry and Residue Data.

E. Holman

, 02/25/2016

, D429506

, Fluazinam. Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 Registration Action for New

U ses on Tuberous and Corm, Subgroup 1C, Mayhaw, Squash/Cucumber Subgroup 9B; Amended Uses on Cabbage; and Removal of Cabbage from Vegetable, Brassica leafy, group 5.

G. Thornton

, 02/25/2016

, D430208

, Fluazinam. Occupational and Residential Exposure Assessment for Proposed Uses on Cabbage (foliar), Mayhaw, Squash/Cucumber Subgroup 9B and to Expand the Existing use on Potatoes to Tuberous and Corm Vegetables Subgroup 1C.

J. Melendez

, 10/6/2015 , D 426144

, Tier I Estimated Drinking Waters Concentrations of

Fluazinam and its Tra nsformation Products for Use in the Human Health Risk Assessment for the Registration of the New Uses on Mayhaw, Cabbage and Chinese cabbage, Cucurbit Vegetables, Squash/Cucumber Subgroup 9B, and Root and Tuber Vegetables, Tuberous and Corm Subgroup 1C

W. Cutchin, 4/23/2001, D272624, Fluazinam . Decision by Metabolism Assessment Review Committee (MARC)

List of Appendices

Appendix A

. HEC Inhalation Calculations Appendix B. International Residue Limit Status Sheet Appendix C. Fluazinam Physical/Chemical Properties Appendix D

. Review of Human Research Appendix E

. Structures of Fluazinam Metabolites and Degradates of Concern Appendix F. Toxicity Profile Tables

### Fluazinam Human Health Risk Assessment DP No. D397601

Page 39 of 51 A ppendix A. HEC Inhalation Calculations

In response to the data requirements for registratio n review, a 4 week repeated dose rat inhalation toxicity study (MRID 48571410) was conducted to assess the effects of fluazinam via the

inhalation route. Fluazinam was administered to 10/sex CD rats (nose only) for a total of 6 hours/day (two 3 hr exposur es), 5 days/week, as an aerosol with an average mass medium aerodynamic diameter (MMAD) of 4.7 and a geometric standard deviation (σ) of 2.7

. The LOAEL of 0.020 mg/L is based on a dose related increase in absolute and relative lung/bronchial weights in bo th sexes. The NOAEL is 0.003 mg/L.

Fluazinam: HECs and HEDs: 4 Week Subchronic Inhalation Study in Rats ( MRID 48571410 )

Short and

intermediate

- term
Inhalation Inhalation NOAEL =

0.003 mg/L (See

HEC/HED calculations below) UF A = 3X

UF H =10X Residential

and Occupational

LOC for MOE

= 30 Inhalation LOAEL =

0.020 mg/L is based on a dose related increase in

absolute and relative lung/bronchial weights in

both sexes.
Exposure Scenario HECs HEDs

Occupationa

l Handler

HECs and

HEDs Ventilation rate=8.3

L/min 0.00109 mg/L 0.062mg/kg/day

Ventilation rate=16.7

L/min 0.125 mg/kg/day

Ventilation rate=29 L/min 0.217 mg/kg/day

### Fluazinam Human Health Risk Assessment DP No. D397601

Page 40 of 51 Appendix B. International Residue Limit Status Sheet

Fluazinam (PC Code 129098; Date of Request 8/10/2015) Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 2 Codex

40 CFR 180.574

Plants: Fluazinam, 3

- chloro

- N

- [3

- chloro

- 2,6

- dinitro

- 4

- (trifluoromethyl)phenyl]

- 5

- (trifluoromethyl)

- 2

- pyridinamine 3

- chloro

- N

- [3

- chloro

2,6

- dinitro

- 4

- (trifluoromethyl)phen yl]

- 5

- (trifluoromethyl)

- 2

- pyridinamine None



### Commodity 1 

### Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 2 

### Codex
Mayhaw 2.0 Cabbage 3.0 0.01 Squash/cucumber subgroup

9B 0.05

Vegetable, Brassica leafy, group 5, except cabbage 0.01 0.01 bok choy Chinese cabbages, broccoli, broccoli raab, Brussels sprouts, cabbages, cauliflower, Chinese broccoli, chinese mustard cabbages, collards, kale, kohlrabi, mustard greens, mustard spina ch, napa Chinese cabbages, rape

leaves Vegetable, Tuberous and corm, Subgroup 1C 0.02 0.02 potatoes

Completed by: M. Negussie; 08/14/15

1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant. 2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

### Fluazinam Human Health Risk Assessment DP No. D397601

Page 41 of 51 Appendix C

. Fluazinam Physical/ Chemical Properties

Table C .1. Physicochemical Properties of Fluazinam

Parameter Value Reference

Melting Point/Range 115 .5 °C MRID 42208401

pH 5.85 MRID 43521001

Density (2 0 °C) 1. 74 g/cm 3 MRID 42208401

Water Solubility (25°C) (pH 5 .5): 25 ppb (pH 7) : 71 ppb (pH 11 ) : 350 ppm MRID 42208401

Solvent Solubility (25°C) Solvent Solubility (g /L ) MRID 42208401

acetone
dichloroethane ethyl acetate ethyl ether

hexane

methanol

toluene 645

485

624

168

6.7

1 6 2

51 2

Vapor Pressure (25°C) 1.7 3 x 10

- 7 mm Hg
( 2.3 x 10

- 5 Pa ) LSS 2000_1973_2LS_rev

Dissociation Constant (pK

a ) Average pKa = 7.22 in 50% ethanol/water (v/v) MRID 42208401

Octanol/Water Partition Coefficient ( K OW ) 3,630
(Log K
ow = 3.56 ) MRID 42208401

UV/Visible Absorption Spectrum pH λ

max (nm) PMRA Regulatory Note REG2003

- 12 5

7

>10 238

239, 342 260, 343, 482

### Fluazinam Human Health Risk Assessment DP No. D397601

Page 42 of 51 Appendix D

. 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 Datab ase Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database; the Outdoor Residential Exposure Task Force (ORETF) database; the Agricultural Re

- entry Task Force (ARTF) database; and other registrant

submitted studies (MRID Nos. 46991302, 45584203, 45584202

, and 48361527); are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements. For certain studies

, that review m ight have included review by the Human Studies Review Board. Descriptio ns of data sources as well as guidance on their use

can be found at http://www.epa.gov/pesticides/science/handler

- exposure

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

- app

- exposure

- data.html

.

### Fluazinam Human Health Risk Assessment DP No. D397601

Page 43 of 51 A ppendix E

. Structures of Fluazinam Metabolites and Degradates of Concern

Table E. 1. Structures of Fluazinam Metabolites and Degradates of Concern

Compound Common N ame Structure

Fluazinam

AMGT

Plant Metabolite

AMPA

Livestock Metabolite Drinking Water Degradate

DAPA

Livestock Metabolite Drinking Water Degradate

### Fluazinam Human Health Risk Assessment DP No. D397601

Page 44 of 51 Table E. 1. Structures of Fluazinam Metabolites and Degradates of Concern

Compound Common N ame Structure

CAPA

Drinking Water Degradate

DCPA

Drinking Water Degradate

HYPA

Drinking Water Degradate



### Appendix F: Fluazinam Toxicology Profile Tables

Table F.1. Acute Toxicity Data on Fluazinam

- Updated Technical Ingredient

Guideline No./ Study Type Test Substance MRID No. Results Toxicity Category

870.1000 Acute oral toxicity

rats Technical grade fluazinam

(Batch No. 080204; 96.53% a.i ) 48361502 F: LD50 > 5000 mg/kg IV

870.1200

Acute dermal toxicity rats Technical grade fluazinam

(Batch No. 080204; 96.53% a.i) 48361503 M: LD50 > 2000 mg/kg F: LD50 > 2000 mg/kg

Combined LD50> 2000 mg/kg III

870.1300

Acute inhalation toxicity: rats Technical grade fluazinam (Lot

No.: A629/1995; 97.3% a.i.) 48361504 M: LC50 > 1.1 mg/L

F: LC50 > 1.1 mg/L

Combined LC50 > 1.1 mg/L III

870.1300

Acute inhalation toxicity: rats Technical grade fluazinam

(Batch No. 080204; 96.53% a.i) 48361505 M: LC50 > 1. 08 mg/L

F: LC50 > 1. 08 mg/L III

### Fluazinam Human Health Risk Assessment DP No. D397601

Page 45 of 51 Table F.1. Acute Toxicity Data on Fluazinam

- Updated Technical Ingredient

Guideline No./ Study Type Test Substance MRID No. Results Toxicity Category

Combined LC50 > 1. 08 mg/L

870.2400 Acute eye irritation

rabbits Technical grade fluazinam

(Batch No. 080204; 96.53% a.i) 48361506 Moderately irritating III

870.2500 Acute

dermal irritation

rabbits Technical grade fluazinam

(Batch No. 080204; 96.53% a.i) 48361507 Non irritating IV

870.2600 Dermal

sensitization guinea pigs Technical grade fluazinam

(Batch No. 080204; 96.53% a.i) 48361508 Positive NA

Table F. 2

. Acute Toxicity Data on Fluazinam Technical

Guideline No./ Study Type Test Substance MRID No. Results Toxicity Category

870.1100 Acute oral toxicity

rats Technical grade fluazinam

(lot #109; 95.3%) 42248603 M: LD50 = 4500 mg/kg F: LD50 = 4100 mg/kg III

Technical grade fluazinam (lot #8412

- 20; 95.3%) 42248602 M: LD50 >5000 mg/kg F: LD50 >5000 mg/kg IV

Technical grade fluazinam (lot #1/87; 97.9%) 42248604 M: LD50 > 5000 mg/kg F: LD50 >5000 mg/kg IV

870.1200 / Acute dermal toxicity : rats Technical grade fluazinam

(lot #8303

- 2; 98.5%) 42248605 M: LD50 >2000 mg/kg F: LD50 >2000 mg/kg III

870.1300

Acute inhalation toxicity : rats Technical grade fluazinam

(lot #109; 95.3%) 42270601 M: LC50 = 0.463 mg/L F: LD50 = 0.476 mg/L II

870.2400 Acute eye irritation

rabbits Technical grade fluazinam

(lot # SNPE B

- 1216, No. 1006; 97.9%) 42248606 Extremely irritating. Corneal opacity did NOT reverse in 21 days. I

870.2500 Acute

dermal irritation

rabbits Technical grade fluazinam

(lot # SNPE B

- 1216, No. 1006; 97.9%) 42248607 Slightly irritating IV

870.2600 Dermal

sensitization guinea pigs Technical grade fluazinam

(lot # 1030/91; 96.7%) 42274401 Positive NA

Ultra

- purified fluazinam (lot #Y910401; 100%) 42248608 Negative NA

Table F.3 Acu te Toxicity Data on Fluazinam Formulations

Guideline No./ Study Type Test Substance MRID No. Results Toxicity Category

870.1100 Acute oral toxicity

rats Omega 500F (40% fluazinam) 42974907 M: LD 50 >5000 mg/kg

F: LD 50 >5000 mg/kg IV

870.1200 Acute dermal toxicity

rabbits Omega 500F (40% fluazinam) 42974908 M: LD 50 >2000 mg/kg

F: LD 50 >2000 mg/kg III

870.1300 Fluazinam 50% WP a 42311001 M: LC 50 = 3.0 mg/L IV

### Fluazinam Human Health Risk Assessment DP No. D397601

Page 46 of 51 Table F.3 Acu te Toxicity Data on Fluazinam Formulations

Acute inhalation toxicity : rats (51.3% fluazinam) F: LD 50 = 3.4 mg/L

870.2400 Acute eye irritation

rabbits Omega 500F (40% fluazinam) 42974910 Slightly irritating III

870.2500 Acute

dermal irritation

rabbits Omega 500F (40% fluazinam) 42974911 Moderately irritating II

870.2600 Dermal

sensitization guinea pigs Omega 500F (40% fluazinam) 42974912 Positive NA

a Study satisfies requirement for testing on Omega 500F.

Table F.4

. Subchronic, Chronic and Other Toxicity Studies for Fluazinam Technical

Guideline / Type of Study Study Title/

Classification /Doses MRID Results

870.3100

90

- Day oral toxicity

rats M : 0, 0.15, 0.77, 3.8, 38

mg/kg/day; F: 0, 0.17, 0.86, 4.3, 44 mg/kg/day

Acceptable/guideline 42248610 (1984); 44807214 (1998) NOAEL: Males: 3.8 mg/kg/day;

Females: 4.3 mg/kg/day LOAEL Males = 38 mg/kg/day; Females = 44 mg/kg/day based on increased liver weights and liver histopathology in males, and increased lung and uterus weights in females.

870.3150

90

- Day oral toxicity dogs M & F: 0, 1, 10, 100

mg/kg/day

Acceptable/guideline 42248611 (1991); 44807215 (1998) NOAEL = 10 mg/kg/day

LOAEL = 100 mg/kg/day based on retinal effects, increased relative liver weight, liver histopathology and possible increased serum alkaline phosphatase in females and possible marginal vacuolization of the cerebral white matter (equivocal)

870.3200

21

- Day dermal toxicity

rats M & F: 0, 10, 100, 1000

mg/kg/day

Acceptable/guideline 42270602 (1985) Systemic NOAEL = 10 mg/kg/day LOAEL = 100 mg/kg/day based on

increased AST and cholesterol levels in clinical chemistry determinations (males)

Dermal NOAEL = not identified LOAEL = 10 mg/kg/day based on erythema, acanthosis, and dermatitis

870.3465

4 week inhalation toxicity Concentrations of 0,

0.003, 0.020

, or 0.100 mg/L

Acceptable/guideline 48571410 NOAEL = 0.003 mg/L LOAEL = 0.020 mg/L based on a dose

related increase in absolute and relative lung/bronchial weights in both sexes. At 0.100 mg/L, increased lung/bronchial weights were also seen, along with lung histopathology (alveolar macrophages, peribronchiolar proliferation) in both

sexes.
870.3700a F: 0,10, 50, 250

mg/kg/day 42248613 (1985) Maternal NOAEL = 50 mg/kg/day LOAEL = 250 mg/kg/day based on decreased body weight gain and food

### Fluazinam Human Health Risk Assessment DP No. D397601

Page 47 of 51 Table F.4

. Subchronic, Chronic and Other Toxicity Studies for Fluazinam Technical

Guideline / Type of Study Study Title/

Classification /Doses MRID Results

Prenatal developmental toxicity

rats Acceptable/guideline consumption and increased water consumption and urogenital staining Developmental NOAEL = 50 mg/kg/day LOAEL = 250 mg/kg/day based on decreased fetal body weights and placental weights, increased facial/cleft palates, diaphragmatic hernia, and delayed ossification in several bone types, greenish amn iotic fluid and possible increased late resorptions and postimplantation loss

870.3700b

Prenatal developmental toxicity

rabbits F: 0, 2, 4, 7, 12

mg/kg/day

Acceptable/guideline 42248616 (1988) Materna l NOAEL = 4 mg/kg/day LOAEL = 7 mg/kg/day based on decreased food consumption and increased liver histopathology. Developmenta l NOAEL = 7 mg/kg/day LOAEL = 12 mg/kg/day based on an increase in total litter resorptions and possible fetal skeletal abnormalities

870.3700b

Prenatal developmental toxicity

rabbits F: 0, 0.3, 1, 3 mg/kg/day

Unacceptable/guideline 42248615 (1985); 42248614 (1984); 42248617 (1984) Materna l NOAEL = 3 mg/kg/day

LOAEL = not identified (>3 mg/kg/day) Developmenta l NOAEL = 3 mg/kg/day LOAEL = not identified (>3 mg/kg/day)

870.3800 Reproduction and fertility effects

rats F 0 males: 0, 1.5, 7.3,

36.6 mg/kg/day

F 0 females: 0, 1.7, 8.4, 42.1 mg/kg/day

F 1 males: 0, 1.9, 9.7, 47.3 mg/kg/day

F 1 females: 0, 2.2, 10.6, 53.6 mg/kg/day

Acceptable/guideline 42248619 (1987);

42208406 (1985); 42248618 (1986) Parental/Systemic NOAEL = 1.9

mg/kg/day LOAEL = 9.7 mg/kg/day based on liver pathology in F 1 males Reproductive NOAEL = 10.6 mg/kg/day LOAEL = 53.6 mg/kg/day based on decreased number of implantation sites

and decreased litter size s to day 4 post

partum for F 1 females (F 2 litters). Offspring NOAEL = 8.4 mg/kg/day LOAEL = 42.1 mg/kg/day based on

reduced F 1 and F 2 pup body weight gains during lactation.

870.4100a Chronic toxicity

rats M: 0, 1.0, 1.9, 3.9

mg/kg/day F: 0, 1.2, 2.4, 4.9 mg/kg/day

Acceptable/guideline 44839901 (1993);

44807213 NOAEL = Males: 1.9 mg/kg/day;

Females: 4.9 mg/kg/day LOAEL = Males: 3.9 mg/kg/day; Females: not identified (>4.9 mg/kg/day) based on increased testicular atrophy in males and no

effects in females

870.4100b Chronic toxicity dogs M & F: 0, 1, 10, 50

mg/kg/day

Acceptable/guideline 42270603 (1987); 44807219 (1998) NOAEL = 1 mg/kg/day

LOAEL = 10 mg/kg/day based on gastric lymphoid hyperplasia in both sexes and nasal dryness in females

### Fluazinam Human Health Risk Assessment DP No. D397601

Page 48 of 51 Table F.4

. Subchronic, Chronic and Other Toxicity Studies for Fluazinam Technical

Guideline / Type of Study Study Title/

Classification /Doses MRID Results

870.4300

Combined chronic toxicity/carcino

genicity

rats M: 0, 0.04, 0.38, 3.8, 40

mg/kg/day F: 0, 0.05, 0.47, 4.9, 53 mg/kg/day

Acceptable/guideline 42248620 (1988); 44807223 (1999); 45150201 (2000) NOAEL = Males: 0.38 mg/kg/day;

Females: 0.47 mg/kg/day LOAEL = Males: 3.8 mg/kg/day; Females: 4.9 mg/kg/day based on liver toxicity in both sexes, pancreatic exocrine atrophy in females and testicular atrophy in males. Some evidence of carcinogenicity (thyroid gland follicular cell tumors)

in male ra ts, but not in females

. 870.4200b Carcinogenicity

mice M: 0, 0.12, 1.1, 10.7,

107 mg/kg/day
F: 0, 0.11, 1.2, 11.7, 117 mg/kg/day

Acceptable/guideline 42208405 (1988);

4 4807220 (1996) NOAEL = Males:1.1 mg/kg/day;

Females: 1.2 mg/kg/day

LOAEL = Males: 10.7 mg/kg/day; Females: 11.7 mg/kg/day based on

increased incidences of brown macrophages in the liver of both sexes, eosinophilic vacuolated hepatocytes in males, and increased liver weight in

females Clear evidence of carcinogenicity (hepatocellular tum ors) in male mice,

but not in females

870.4200b Carcinogenicity

mice M: 0, 126, 377, 964

mg/kg/day F: 0, 162, 453, 1185 mg/kg/day

Acceptable/guideline 44807222 (1996); 44807221 (1998); 45201301 (2000) NOAEL = Males:<126 mg/kg/day,

Females: <162 mg/kg/day LOAEL = Males: 126 mg/kg/day; Females: 162 mg/kg/day based on increased liver weights and liver and brain histopathology in both sexes Equivocal/some evidence of carcinogenicity (hepatocellular tumors) in male mice, but not in

females

870.5100

Bacterial reverse mutation assay (Ames test) Up to 2 μg/plate for S.

typhimurium strains and up to 250 μg/plate for E.

coli (

- S9). Up to 100 μg/plate for S. typhimurium strains and Up to 500 μg/plate for E.

coli (+ S9)

Acceptable/Guideline 42270605 (1988) Negative with and without S9 up to cytotoxic concentrations.

870.5100

Bacterial reverse mutation assay (Ames test) Up to 1μg/plate for S.

typhimurium strains and up to 250 μg/plate for E.

coli (

- S9) and up to 100 μg/plate for S. typhimurium strains and up to 500 μg/plate for E.

coli (+S9) 42270604 (1989) Negative with and without S9 up to cytotoxic concentrations.

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. Subchronic, Chronic and Other Toxicity Studies for Fluazinam Technical

Guideline / Type of Study Study Title/

Classification /Doses MRID Results Acceptable/Guideline

870.5300

In vitro mammalian gene mutation assay Up to 9 μg/m L (+S9), up

to 0.3 μg/m L (

- S9)

Acceptable/guideline 45261801 (2000) Negative with S9 activation up to 9 μg/ mL . Negative without S9 activation up to 0.3 μg/ mL

. Compound tested to cytotoxic

concentrations.

870.5300

In vitro mammalian gene mutation assay Up to 5 μg/m L (+/

- S9)

Acceptable/guideline 45156902 (1986) Negative with and without S9 activation up to 5 μg/ mL

. Compound tested to cytotoxic

concentrations.

870.5375

In vitro mammalian

chromosome aberration (CHL cells) Up to 9.5 μg/m L (+S9)

up to 4 μg/ mL (

- S9)

Acceptable/guideline 42270606 (1988) Negative with and without S9 up to cytotoxic concentrations. Cells

harvested at 24 and 48 hours in

nonactivated studies and at 24 hours in

activated studies.

870.5395

Mammalian erythrocyte

micronucleus test 500, 1000, 2000 mg/kg

(oral gavage)

Acceptable/guideline 44807224 (1999) Negative at 24 hour sacrifice (500, 1000, 2000 mg/kg). Negative at 24, 48, and 72 hour sacrifices (2000 mg/kg).

870.5550 UDS in primary rat hepatocytes Unacceptable/guideline

0.05 to 6.25 μg/m L 45156901 (1984) Negative; however there were several serious study deficiencies: treatment time shorter than recommended, no data supporting the claim of cytotoxicity, data variability for major endpoints.

870.5550

Differential killing/growth

inhibition in B.

subtilis 0.003 to 0.3 μg/disk

(

- S9) 0.3 to 30 μg/disk (+S9)

Unacceptable/guideline 42270607 (1988) Negative, however only one replicate plate/dose was used.

870.6200a Acute neurotoxicity screening battery

rats M & F: 0, 50, 1000,

2000 mg/kg

Acceptable/guideline 44807210 (1995) Systemic NOAEL = 50 mg/kg LOAEL = 1000 mg/kg based on soft stools and decreased motor activity on day of dosing. Neurotoxicity NOAEL = 2000 mg/kg LOAEL = not identified (>2000 mg/kg)

870.6200b

Subchronic neurotoxicity screening battery

rats M :0, 21, 69, 74, 149,

233 mg/kg/day; F: 0, 23, 81, 89, 175, 280 mg/kg/day

Acceptable/guideline 44807217 (1998); 44807218 (1998) Neurotoxicity NOAEL = Males: 233

mg/kg/day; Females: 280 mg/kg/da y LOAEL = not identified (Males: >233 mg/kg/day; Females: > 280 mg/kg/day)

870.6300 Developmental neurotoxicity 0, 2, 10 or 50 mg/kg/day

Acceptable/Non

Guideline 46534401,

47018301 and

47037001. Maternal:

NOAEL not established. No toxicity at highest dose tested.

Developmental: NOAEL = 2 mg/kg/day. LOAEL = 10 mg/kg/day based on decreased pup weight and gain and delayed balano

- preputial separation.

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. Subchronic, Chronic and Other Toxicity Studies for Fluazinam Technical

Guideline / Type of Study Study Title/

Classification /Doses MRID Results

870.7485

Metabolism and pharmacokinetics

rats 0.5, 50 mg/kg

Acceptable/guideline 44807233 (1995);

43521004 thru 43521008,

43553001 (1993

- 1995) Only 33

- 40% of the administered dose

was absorbed. Most of the administered dose was recovered in the feces (>89%).

Excretion via the urine was minor (<4%). Total biliary radioactivity, however, represented 25

- 34% of the administered dose, indicating considerable enterohepatic circulation.

870.7600 Dermal Absorption

Rat 500 g/L (Fluazinam SC)

and 0.5 g/L (diluted Fluazinam SC) for 6

hours Acceptable/Guideline 48361513 (2001) The mean absorbed dose for Fluazinam SC at 24 hours was 0.38% (18.67 μg equiv.cm

- 2 ). The dermal delivery was 0.52% (25.72 μg equiv.cm

- 2 ). The mean

absorbed dose for diluted Fluazinam SC at 24 hours was 4.08% (0.153 μ g equiv.cm

- 2 ). The dermal delivery dose was 4.47% (0.169 μ g equiv.cm

- 2 ).

870.7800 Immunotoxicity

Mouse Acceptable/Guideline

0, 1000, 3000 or 7000 ppm (0, 217.7, 679.0 or 1684.6 mg/kg/day) MRID 48708702

and 48708703 (2011) Under conditions of the combined

studies, the immunotoxicity NOAEL is 50 ppm (equivalent to 11 mg/kg/day); the LOAEL is 1000 ppm (equivalent to 231 mg/kg/day) based on decreased

anti

- SRBC AFC response.

The systemic toxicity NOAEL is 7000 ppm (1684.6 mg/ kg/day); the LOAEL

was not established

. Non

- guideline

In Vitro

Percutaneous Absorption of

Radiolabeled

Fluazinam in Two

Formulation s Through Rat Skin Fluazinam applied to 13

rat dermatomed skin

membranes in vitro in 2 test formulations;

Fluazinam SC and

Diluted Fluazinam SC (Fluazinam Suspension using in vitro flow through diffusion cell system. The

formulations were applied to skin for 24

hours at 10 u L

/cm 2 giving the nominal dose levels of 5000 μg/cm 2 and 5 μg/ cm. 2 48361514 (2000) Dermal delivery of Fluazinam from the Fluazinam SC (5000 μg/cm 2 ) was 119 μg equiv/cm 2 or 2.36% of the applied dose. Of this, only 58 μg equiv/cm 2 or 1.16% of the applied dose was absorbed. Dermal delivery of Fluazinam from the

Diluted Fluazinam SC (5 μg/cm 2 ) was 1.88 μg equiv/cm 2 or 40.17% of the applied dose. Of this, only 0.75 μg equiv/cm 2 or 15.95% of the applied dose

was absorbed. For risk assessment purposes the dermal delivery dose at 24

hours will be used since it includes the

a bsorbed dose as well as any material potentially absorbed (absorbable dose).

Non

- guideline

In Vitro

Percutaneous Absorption of

Radiolabeled

Fluazinam in Two

Formulation Through Human

Skin Fluazinam applied to

human dermatomed skin

membranes in vitro

us ing a flow through diffusion cell system. A Suspension Concentrate

and a Diluted Suspension Concentrate

were used and the

formulations were 483615 15 (2000) Dermal delivery of Fluazinam from the Fluazinam SC was 81 ug equiv.cm 2 or 1.61% of the applied dose. Of this, only 8 ug equiv. cm 2 or 0.15% of the applied dose was absorbed. Dermal delivery of

Fluazinam from the Diluted Fluazinam SC was 0.83 ug e quiv. cm

- 2 or 16.49% of the applied dose. Of this, only 0.10 ug equiv. cm 2 or 2.08% of the applied

dose was absorbed. For risk assessment

### Fluazinam Human Health Risk Assessment DP No. D397601

Page 51 of 51 Table F.4

. Subchronic, Chronic and Other Toxicity Studies for Fluazinam Technical

Guideline / Type of Study Study Title/

Classification /Doses MRID Results applied to the skin at 10

μ L .cm - 2 giving the

nominal dose levels of 5000 μg.cm

- 2 and 5

μg.cm, - 2 respectively. purposes the dermal delivery dose at 24

hours will be used since it includes the absorbed dose as well as any material potentially absorbed (absorbable dose).

Non

- guideline Mechanistic Study on Thyroid

Function in Rats 0 50, 1000 and 3000

ppm for 7 days (0, 3.58, 71.1, and 212 mg/kg/day)

Acceptable/Non

- guide

line 48361509 (2004) Decrease in T4 and an increase or increasing trend in TSH at 1000 and 3000 ppm groups. Increase in UDPGT activity toward 4

- nitrophenol in all treated groups. Thyroid hypertrophy and proliferation at 1000 and 3000 ppm.

Non

- guideline Mechanistic Study on Thyroid

Function and its Reversibility in Rats Main: 0 and 3000 ppm

for 7 days and sacrificed (0 and 222 mg/kg/day) Recovery: 0 and 3000ppm then reversibility for 7 days

Acceptable/Non

- guide

line 48361510 (2005) Decreases in T3 and T4 and an increasing trend in TSH in the main group after treatment at 3000 ppm. In the 3000 ppm recovery group after 7 days, decrease in T3 noted at almost the same level, but no changes in T4 or TSH. Increase in UDPGT activity

toward 4

- nitrophenol in main group, similar changes in recovery group.

T hyroid proliferation in main group @ HDT, no proliferation in recovery group

Non

- guideline Effects on Hepatic Drug

- Metabolizing Enzyme induction,

Cell Proliferation

and Oxidative

Stress in Mice 0 10, 100 and 1000 ppm

for 3, 7, and 14 days (0, 1.38, 13.9, and 140 mg/kg/day) Acceptable/Non

- guide

line 48361511 (2001) I ncreases in cytochrome P

- 450 content, ECOD and PROD in the 1000 ppm group. The 100 ppm group showed an increase in ECOD and an increasing

trend in PROD. Increases in CYP1A were seen in the 1000 ppm group. The 100 ppm group also exhibited an

increase in CYP2B and an increasing trend in CYP1A. Hepatic proliferation in1000 ppm group after 7 and 14 days.

No effect on oxidative stress markers.

Non

- guideline

Additional Mechanistic Study on Hepatic Drug

Metabolizing Enzyme induction,

Cell Proliferation

and th e Reversibility of its

Toxic Effects in

Mice Main: 0 and 1000 ppm

for 14 days and sacrificed (0 and 137 mg/kg/day) Recovery: 0 and 1000ppm (0 and 139 mg/kg/day) then reversibility for 14 days Acceptable/Non

- guide

line 48361512 (2005) Increases in P

- 450 PR OD, ECOD after 14 days at 1000 ppm. Returned to normal in the satellite group after 14 days of recovery at 1000ppm. Increase in CYP1A and an increasing trend in CYP2B in the main group after 14 days at 1000 ppm. In the satellite group after 14 days at 1000 ppm, still a significant increase (but lower) in CYP1A. CYP2B returned to normal. No changes in hepatic proliferation observed in any

group.