Fluazinam Human Health Risk Assessment DP No. D397601

Page 3 of 75 1.0 Executive Summary

................................ ................................ ................................ .......... 5

2.0 HED Recommendations

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

2.1 Data Deficiencies/Conditions of Registration

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

2.2 Tolerance Considerations

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

2.2 .1 Enforcement Analytical Method

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

2.2 .2 International Harmoni zation

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

2.2 .3 Recommended Tolerances

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

2.2 .4 Re visions to Petitioned

- for Tolerances

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

2.3 Label Recommendations

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

3.0 Introduction

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

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

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

3.5 Consideration of Environmental Justice

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

4.0 Hazard Characterization and Dose

- Response Characterization

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

4.1 Toxicology Studies Available for Analysis

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

4.2 Absorption, Distribution, Metabolism, E xcreti on (ADME)

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

4.2.1 Dermal Absorption

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

4.3 Toxicological Effects

................................ ................................ ................................ ... 1 6

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

.............................. 1 8

4.4.1 Completeness of the Toxicology Database

................................ ............................ 1 8

4.4.2 Evidence of Neurotoxicity

................................ ................................ ...................... 1 8

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

...... 1 9

4.4.4 Residual Uncertainty in the Exposure Database

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

4.5 Toxicity Endpoint and Point of Departure Selections

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

4.5.1 Dose Response Assessment

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

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment

..... 2 1

4.5.3 Classification of Carcinogenic Potential

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

4.5.4 Summary of Toxic ological Doses and Endpoints for Fluazinam

....................... 22

5.0 Dietary Exposure and Risk Assessment

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

5.1 Metabolite/Degradate Residue Profile

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

5.1.1 Summary of Plant and Animal Metabolism Studies

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

5.1.2 Summary of Environmental Degradation

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

5.1.3 Comparison of Metabolic Pathways

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

5.1.4 Residues of Concern Summary and Rationale

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

5.2 Food Residue Profile

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

5.3 Water Residue Profile

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

5.4 Di etary Risk Assessment

................................ ................................ ............................ 2 9

5.4.1 Description of Residue Data Used in Dietary Assessment

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

5.4.2 Percen t Crop Treated Used in Dietary Assessment

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

5.4.3 Acute Dietary Risk Assessment

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

5.4.4 Chronic Dietary Risk Assessment

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

5.4.5 Cancer Dietary Risk Assessment

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

5.4.6 Summary Table

................................ ................................ ................................ ....... 30Fluazinam Human Health Risk Assessment DP No. D397601

Page 4 of 75 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

............................ 31

6.1 Residential Handler Exposure and Risk

................................ ................................ ... 31

6.2 Residential Post

- a pplication Exposure

................................ ................................ ..... 31

6 .2.1 Dermal Post

- application Exposure

................................ ................................ ........ 31

6 .2. 2 Inhalation Post

- application Exposure

................................ ................................ ... 32

6.3 Combined Residential Risk Estimates

................................ ................................ ...... 32

6. 4 Residential Risk Estimates for Use in Aggregate Assessment

................................ 32

6.5 Spray Drift

................................ ................................ ................................ ................... 3 3

6.6 Residential Bystander Post Application Inhalation Exposure

................................ 3 3

7.0 Aggregate Exposure/Risk Characterization

................................ ................................ . 33

7.1 Acute Aggregate Risk

................................ ................................ ................................ . 34

7.2 Short

- / Intermediate

- Term Aggregate Risk Estimates

................................ ............ 34

7.3 Chronic Aggregate Risk

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

7.4 C an c er Aggregate Risk

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

8.0 Cumulative Exposure/Risk Characterization

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

9.0 Occupational Exposure/Risk Characterization

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

9.1 Occupational Handler Exposure/ Risk Estimates

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

9.2 Occupational Post

- a pplication Exposure/ Risk Estimates

................................ ....... 3 9

9.2.1 Occupational Post

- application Inhalation Exposure /Risk Estimates

................ 3 9

9.2.2 Occupational Post

- application Dermal Exposure /Risk Estimates

..................... 3 9

10.0 References

................................ ................................ ................................ ........................ 41 Appendix A. Flu a zinam Toxicology Profile and Additional Information

............................ 4 3

A.1 Toxic it y Profile Tables

................................ ................................ ................................ 4 3

A.2 Triple Pack Analysis for Fluazinam

................................ ................................ .......... 50

A.3 HEC Inhalation Calculations

................................ ................................ ..................... 52

A. 4 Hazard Identification and Endpoint Selection

................................ ......................... 5 6 Appendix B

. International Residue Limit Status Sheet

................................ ......................... 60 Appendix C

. Fluazinam Physical/Chemical Properties

................................ ......................... 62 Appendix D . Review of Human Research

................................ ................................ ................ 63 Appendix E

. Structures of Fluazinam Metabolites and Degradates of Concern

................. 64 Appendix F

. Occupational Exposure and Risk Assessment for R egistered Uses

................ 66Fluazinam Human Health Risk Assessment DP No. D397601

Page 5 of 75 1.0 Executive Summary

ISK Biosciences and the Interregional Research Project No. 4 (IR

- 4) submitted petitions to

establish tolerances for the fungicide fluazinam in/on soybeans and the commodities of the melon and pepper/eggplant subgroups (9

- A and 8

- 10B, respectively). This human health risk assessment presents HED’s conclusions with respect to the risk estimates associated with the proposed uses as well as all registered uses for flua zinam. T he toxicity and exposure databases for fluazinam are complete in accordance with the requirements of r egistration r eview

, and

therefore this document also serves as HED’s human health risk assessment to support registration review

. The proposed u ses on melons and peppers were evaluated under a joint review with Canada’s Pesticide Management Regulatory Agency (PMRA).

F luazinam ( 3

- chloro

- N

- [3

- chloro

- 2,6

- dinitro

- 4

- (trifluoromethyl)phenyl]

- 5

- (trifluoromethyl)

- 2

- pyridinamine ) i s a preventive contact f ungicide 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 protectant fungicide . W hen 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 the plant.

HED has assessed exposures and risks from the registered and proposed uses o f fluazinam. T he

end

- use product proposed for use on melons, peppers, and soybeans is OMEGA ® 500F (EPA Reg. No. 71512

- 1), a soluble

- concentrate (SC) formulation containing 40% ai fluazinam (4.17

lb s ai/gal). OMEGA ® 500F may be applied as a foliar spray u sing aerial, ground

, and handheld equipment. It may also be applied via chemigation. The maximum single application rates for the proposed uses range from 0.52

- 0.78 lb ai/A. For melons and peppers, t he label allows up to 6 applications at 0.78 lb ai/A f or a total seasonal application rate of 4.68 lb ai/A. The proposed PHI for these commodities is 30 days. For soybeans, the label allows up to 2 applications at 0.52 lb ai/A for a total seasonal application rate of 1.04 lb ai/A. Occupational e xposure fro m use on soybeans, melons, and peppers is expected to be of short

- to intermediate

- term duration s

.

Hazard Characterization and Endpoint Selection

The 28

- day inhalation and immunotoxicity studies required during registration review were

submitted and evaluated, and t he toxicology datab ase for fluazinam is complete

.

The liver is a primary target organ following dosing with fluazinam . N umerous liver effects were observed in rats, mice, and dogs. Liver effects were also observed in rats following dosi ng via the dermal route. Treatment

- 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.

No signs of neurotoxicity were observed in an acute neurotoxicity study or in two subchronic neurotoxicity studies. However, a neurotoxic lesion described as vacuolization of the white matter of the central nervous system (CNS) was observed in subchronic and chronic studies in mice and dogs, as well as in special studies in rats. After further investigation, it was determined

that an impurity was responsible for the appearance of the white matter vacuol iz ation. A developmental neurotoxicity (DNT) study c ontaining a lower concentration of the impurity wasFluazinam Human Health Risk Assessment DP No. D397601

Page 6 of 75 submitted to address the Agency’s concerns regarding the vacuolization ; i n the study, there was

no evidence of vacuol iz ation of the brain or any other treatment

- related pathology up to the highest dose te sted. Because of the lower concentration of the impurity in the technical used in the DNT, and because of the absence of the lesion in the study, HED concluded that fluazinam,

per se , was not responsible for the induction of th e lesion. Furthermore, HED is not concerned about the presence of the impurity, since the acute and chronic reference doses selected for risk assessment are protective of any possible neurotoxic effects resulting from exposure to the impurity

.

In an immunotoxicity study in mice, significant suppressions of anti sheep red blood cell (anti

SRBC ) antibody

- forming cell assay (AFC) response were demonstrated at the highest dose tested indicating potential immunotoxicity. However, clear NOAELs and LOAELs were identified for

the effects seen in the study and the points of departure (PODs) and endpoints selected for risk assessment are protective of immunotoxic effects.

In a subchronic inhalation toxicity study in rats, pulmonary effects were observed at the mid and high doses. These effects included dose related increases in lung/bronchial weights and increased incidences of alveolar macrophages and peribronchiola r proliferation in both sexes.

There was no evidence of increased quantitative or qualitative susceptibility in a develop mental toxicity study in rabbits or in a 2

- generation reproduction study in rats. In a developmental toxicity study in rats, there was no evidence of increased quantitative susceptibility; however, there was evidence of increased qualitative susceptibilit y. Developmental effects were seen in the presence of minimal maternal toxicity. The registrant submitted a developmental neurotoxicity study (DNT) in rats . There was evidence of increased quantitative susceptibility in the DNT study, i.e., offspring ef fects were seen in the absence of maternal toxicity. The registrant also submitted a series of special studies in order to address the issues of increased susceptibility and the presence of neurotoxic lesions observed in the toxicological database. The concern is low for the increased susceptibility seen in the developmental toxicity and DNT studies because clear NOAELs were established, dose

- responses were well defined, and the most sensitive endpoints were used for risk assessment , in order to be p rotective of the observed susceptibility

. T he required 10x FQPA Safety Factor was reduced to 1x b ased on 1) the completeness of the toxicology database ; 2) the lack of neurotoxicity; 3) the lack of residual uncertainty for pre

- and post natal toxicity ; an d 4) because the exposure assessment is conservative and does not underestimate exposure

.

HED’s Cancer Assessment Review Committee (CARC) classified fluazinam as having “Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential.” The CARC also determined that the quantification of cancer risk using a non

- linear approach (i.e., RfD) would adequately account for all chronic toxicity, including carcinogenicity, that could result from exposure to fluazinam.

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

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

- 49, a developmental toxicity study in rabbits was used , and the endpoint selected was total litterFluazinam Human Health Risk Assessment DP No. D397601

Page 7 of 75 resorptions and skeletal abnormalities. For the chronic dietary risk assessment, the carcinogenicity study in mice and the chronic study in dogs were selected as co

- critical studies. In the mouse, effects seen were mainly in the liver. In dogs, nasal dryness and gastric lymphoid hyperplasia were observed.

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 route, the dermal toxicity and dermal absorption studies were used to determine a refined dermal equivalent dose (RDD) f

or assessing shor t

- and intermediate

- term dermal exposure. For the inhalation route, HED selected the endpoint from the subchronic inhalation toxicity study based

on portal

- of

- entry effects (pulmonary) . I n accordance with current guidance, h uman equivalent concentrations (HECs) and h uman equivalent doses (HEDs) were calculated , with the HEDs being used for risk assessment. The dermal and inhalation studies are prote ctive of the developmental effects seen in rats as well as potential neurotoxicity and immunotoxicity.

The short

- /intermediate

- term toxicological endpoints for fluazinam are the same for the respective routes of exposure . As a result, only short

- term dermal and inhalation exposures were assessed for occupational and residential scenarios . The resulting short

- term risk estimates are considered to be protective of intermediate

- term exposure and risk.

For acute and chronic dietary and dermal risk assess ments, a 100 x uncertainty factor was applied ( 10 x interspecies factor and 10x intraspecies factor). The 100x factor w as used to calculate the

acute and chronic reference doses (RfDs) , which are the same as the respective population adjusted doses (PADs)

. For the dermal assessment, the level of concern (LOC) is a margin of exposure (MOE) of 100, based on the combined uncertainty factors. For inhalation risk assessments, the LOC is an MOE of 30 based on an interspecies factor of 3 x and an intraspecies

fact or 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.

Metabolism/Metabolites and Deg radates 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 vegetables 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 dr inking water, the degradates of concern for risk assessment 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 profiles for the registered and proposed commodities are complete and adequate for tolerance setting and risk assessment purposes , including registration revi ew

. For soybeans, melons, and peppers, the registrants submitted adequate field trial and processing data for parentFluazinam Human Health Risk Assessment DP No. D397601

Page 8 of 75 and the metabolite AMGT. For all crops, a dequate numbers of trials were performed in the recommended NAFTA growing zones. The OECD MRL calcul ation procedures were used for determining appropriate tolerance levels. The recommended tolerances for soybean seed, soybean hulls, the melon subgroup, and the pepper/eggplant subgroup 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 procedure for residues of fluazinam , but not for the metabolites

. The necessary a nalytical

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

.

Dietary Exposure and Risk

Acute and chronic dietary exposure and risk assessments were conducted

, including food and drinking water contributions from the existing uses as w ell 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

- level residues for all commodities and uses high

- end residue estimates for the metabolite AMGT. The chronic

ana lysis is based on tolerance

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

are considered to be conservative. The acute and chronic die tary 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 5.3 % of the acute PAD (aPAD). The population subgroup with the highest acute dietary risk estimate is Females 13

- 49, which

uses 2 8 % of the aPAD. The chronic dietary risk estimate for the general U.S. population is 20 % of the chronic PAD (cPAD). The most hi ghly exposed population subgroup is All Infants (<1 year old), which uses 51 % 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 assumpti ons 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 population subgroup or life stage

.

Residential Exposure and Risk

The residential e xposure 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 Operating 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 LOC of 100

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

.Fluazinam Human Health Risk Assessment DP No. D397601

Page 9 of 75 Aggregate Exposure and Risk

The acute and chronic 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 7 30 to 97 0. 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.

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 Handlers Exposure Database Version 1.1 (PHED 1.1), and the Agricultural Handler Exposure Task Force (AHETF) da tabase. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. Default assumptions established by HED’s Science Advisory Council for Exposure were used for parameters such as body weight, acres trea ted

, 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. For the proposed uses on soybeans, melons

, and pe ppers, all the occupational handler scenarios resulted in MOEs equal to or greater than the respective levels of concern at some level of personal protecti ve equipment ( PPE

, e.g., baseline ( single layer clothing, no respirator ) , chemical

- resistant gloves, double layer clothing), and assuming engineering controls (i.e., en closed cockpit ) for aerial applications

. Based on the dermal and inhalation risk estimates, no additional PPE or other mitigation is need ed on the label , eithe r for the existing or proposed uses

.

Based on the Agency ’ s current practices, a quantitative non

- cancer occupational post

- application inhalation exposure assessment i s not being performed for fluazinam at this time

. Although a quantitative occupational p ost

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational handlers (e.g., flaggers)

. H andler inhalation exposure estimates are considered to be protective of occupational post

applic ation inhalation exposure scenarios. If new policies or procedures are put into place, the Agency m ight revisit the need for a quantitative occupational post

- application inhalation exposure assessment for fluazinam.

There is potential for dermal exposure during occupational post

- application activities , such as crop maintenance activities, scouting, irrigation, and harvesting . 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

. Post

- application dermal exposure and risk estimates for the proposed uses resulted in MOEs greater than the LOC of 100 and are not of concern on Day 0 (i.e., 1 2 hours after application).Fluazinam Human Health Risk Assessment DP No. D397601

Page 10 of 75 Restricted Entry Interval (REI)

The restricted entry interval (REI) for fluazinam is based on the acute toxicity of the technical material. Fluazinam is classified as Toxicity Category I for eye irritation. Under the Worker

P rotection Standard (WPS) for Agricultural Pesticides, active ingredients classified as acute Toxicity Category I for any route is assigned a 48

- hour REI. Based on the acute toxicity profile of fluazinam, the 48

- hour REI specified on the OMEGA ® 500F label is appropriate to protect agricultural workers from post

- application exposures to fluazinam on melons, peppers

, and soybeans.

2.0 HED Recommendations

HED recommend s in favor of granting the proposed Section 3 use of fluazinam on soybeans, the Melon subg roup (9

- A), and the Pepper/ e ggplant subgroup (8

- 10 B)

.

2.1 Data Deficiencies/Conditions of Registration

None

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate GC/ECD method (6148

- 94

- 0170

- MD

- 001) is available for enforcing fluazinam tolerances on plant commodities. The method was adequately radiovalidated and underwent a successful ILV trial. The method was forwarded to BEAD’s Analytical Chemistry Branch (ACB) for a TMV trial, and was subsequently determined to be suitable as a tolerance

enforcement method. The method LOQ is 0.01 ppm for fluazinam in plant commodities. An adequate enforcement method for determination of AMGT is also available. The method is an HPLC/UV method entitled “Method Evaluation for the Analysis o f AMGT in Grapes.” The registrant submitted an adequate ILV for the method. The range of fortification levels and the percent recovery values were acceptable.

ISK Biosciences Corporation’s analytical method en titled “ Enforcement Method for the Analysis

of Fluazinam and its Metabolites AMPA and DAPA in Milk and Meat ” is adequate as an enforcement method for residues of fluazinam, AMPA, and DAPA and their sulfamate conjugates in kidney, liver, and fat. The method was successfully validated for f luazinam, AMPA, and DAPA in beef kidney

, beef liver , and beef fat.

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. D397601

Page 11 of 75 2.2.2 International Harmonization

There are no harmonization issues between the U.S., Cod ex, Canada, and Mexico. There are currently no Codex MRLs for fluazinam on any commodities including melons, bell peppers,

non

- bell peppers, or soybeans. There are no Canadian or Mexican MRLs for melons or peppers. The petition for melons and peppers is being evaluated jointly by the EPA and PMRA , and the MRLs for melons and peppers will be harmonized between the two countries. There are no harmonization issues between the U.S. and Canada with respect to soybean commodities. There

is a Canadian MRL of 0.10 ppm for edible

- podded soybean. There is no need to harmonize this MRL with HED’s recommended tolerance of 0.01 ppm for soybean seed because edible

- podded soybean and soybean seed are different commodities. Edible

- podded soybean is an immature

seed t hat includes the pod. It is likely to have a higher residue level than soybean seed, which is

the dried seed alone.

The U.S. and Canadian MRLs are harmonized for all other commodities for which both countries have established MRLs ( potatoes (0.02 ppm), b ushberries (7.0 ppm)

, Brassica leafy vegetables (0.01 ppm), dried shelled peas and beans (Subgroup 6C, except pea, 0.02 ppm)

, and edible podded peas and beans (Subgroup 6A, except pea, 0.10 ppm)

. Mexico adopts U.S. tolerances and/or Codex MRLs for its export purposes.

For the purpose of registration review, no additional tolerance changes are needed to achieve

harmonization.

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 de gradates, 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 F luazinam

Commodity as Proposed by Registrant Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity

Definition

Melon subgroup 9A 0.08 0.07

Pepper/eggplant subgroup 8

- 10B 0.10 0.09

Soybean, Seed 0.01 0.01 Soybean, seed

Soybean, Hulls 0.02 0.05 Soybean, hulls

2.2.4 Revisions to Petitioned

- For Tolerances

T he proposed tolerances for soybean hulls, melons, and peppers are different from the tolerances recommended by HED. The reason for the differences is that the registrant determined the proposed tolerances using the NAFTA tolerance calculator , while Canada and the U.S. agreed to

use the OECD calculat ion procedures for melons and peppers

. The U.S. is also using the OECDFluazinam Human Health Risk Assessment DP No. D397601

Page 12 of 75 calculation procedures for soybean commodities. R evised Section s F should be submitted by IR

4 and the registrant, to reflec t HED’s tolerance recommend ations

. No changes are needed to the tolerance expressions.

2.3 Label Recommendations

None

3.0 In troduction

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 aFluazinam Human Health Risk Assessment DP No. D397601

Page 13 of 75 4.17 lb/gal soluble

- concentrate (SC) formulation

. ISK Biosciences and IR

- 4 are proposing to add uses on soybeans, the melon subgroup (9A)

, and the pepper/eggplant subgroup (8

- 10B) to the registered label . The prop osed 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 48 hours for all c rops. 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. Mixers/Loaders must wear a dust/mist filtering respirator (MSHA/NIOSH TC

- 21C) or a NIOSH approved respirator with an N, R, P or

HE filter.

Table 3.3 . Summary of Directions for Proposed Use of Fluazinam on Melons, Peppers and Soybean s

Applic. Timing, Type, and Equip. Formulation

[ EPA Reg.

No. 71512

- 1 ] Max. Single

Applic ation

Rate (lb ai/A) † Max. No. of

Applic ations per Season Max. Seasonal

Applic ation Rate (lb ai/A) PHI

(days) Use Directions and

Limita tions

Melons (Crop Sub g roup 9A)

Broadcast ; Ground, Chemigation (Sprinkler System). OMEGA ® 500F

40% ai, Soluble

Concentrate (4.17 lb ai/gal) 0.78 lb ai/A

(24 fl oz/A) 6 4.68 lb ai/A ( 144 fl oz/A) 30 Re

- treatment Interval = 7

- 10 days

. Apply when disease symptoms first appear. Peppers (Crop Sub g roup 8

- 10B)

Broadcast; Ground, Chemigation (Sprinkler System), Soil Drench (at transplanting). OMEGA ® 500F 40% ai, Soluble

Concentrate (4.17 lb ai/gal) 0.78 lb ai/A

(24 fl oz/A) (0.013 lb ai/gal) 6 4.68 lb ai/A ( 144 fl oz/A) 30 Re

- treatment Interval = 7

- 14 days

. Apply as a soil drench at transplanting. Foliar applications should begin 7 days after transplanting. Soybean

Apply at early bloom to full bloom stage of development. Broadcast; Aerial,

Ground. OMEGA ® 500F

40% ai, Soluble

Concentrate (4.17 lb ai/gal) 0.52 lb ai/A

(16 fl oz/A) 2 1.04 lb ai/A (32 fl oz/A) Growth

Stage

R33 Re

- treatment Interval = 10

- 14 days (at early pod formation). For preventive treatment or low disease pressure use low rate. Do not feed hay from treated

field to livestock or allow livestock to graze on treated

areas. Do not apply after early pod

formation. † Maximum Single Application Rate for Soybeans (lb ai/A) = (1 pint/A)(16 fl oz/1 pint) (4.17 lb ai/gal)(1 gal/128 fl oz) = 0.52 lb ai/A. Maximum Single Application Rate for Melons & Peppers (lb ai/A) = (24 fl oz/A) (4.17 lb ai/gal)(1 gal/128 fl oz) = 0.78 lb ai/A. Maximum Single Application Rate for Peppers (lb ai/gal) = ( 0 .78 lb ai/A)/(60 gal/ A) = 0.0 13 lb ai/gal.

T he proposed (and current) product label for the 4.17 lb/gal soluble

- concentrate (SC)

formulation specifies that a pplications are allowed through the following types of irrigation systems: center pivot, motorized lateral move, traveling gun, solid set

, or portable (wheel move, side roll, end tow, or hand move). The label contains the following rotational crop restriction s :Fluazinam Human Health Risk Assessment DP No. D397601

Page 14 of 75 “A ll crops on the label may be replanted immediately after treatment . A ll other crops may be replanted 30 days after the last app lication. ”

The recommended spray volumes are 20

- 100 gal/A (20

- 60 gal A for field/row crops) for dilute spray applications and 5

- 10 gal/A for ground and aerial spray applications. As the proposed supplemental label states that chemigation (i.e., sprinkler irrigation) will be permitted on melons and peppers, chemigation was assessed for the proposed uses.

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

. The only residential exposure scenario expected for fluazinam is dermal post

- application exposure to treated golf course turf. The registered and proposed use s also result in the potential for occupational (handler/p ost

application) exposures. In a ddition, applicators might be exposed 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 assessment, in accordance with U.S. Executive Order 12898, “ Federal Actions to Address Environmental Justice in Minority Populations and Lo w

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

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups accor ding 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 r isk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups

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

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths

, and adults entering or playing on treated areas post

- application are evaluated. Further considerations are currently in development

, as OPP has committed resources and expertise to the development of specialized software and models that consider exposur e 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 takenFluazinam Human Health Risk Assessment DP No. D397601

Page 15 of 75 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.

4.1 Toxicology Studies Av ailable for Analysis

T he toxicology database for fluazinam is complete . The available studies include: subchronic oral toxicity studies in rats, mice, and dogs ; a chronic oral toxicity study in dogs ; carcinogenicity

studies in rats and mice ; developmenta l and reproduction studies in rats and a developmental study in rabbits ; subchronic dermal and inhalation toxicity studies in rats ; and an immunotoxicity study in mice . There is also a metabolism study in the rat

, a complete mutagenicity battery, and

acut e LD50 and neurotoxicity studies (acute, subchronic, and developmental).

4.2 Absorption, Distribution, Metabolism, Excretion (ADME)

In the rat metabolism study, o verall recovery of the administered radioactivity was acceptable (93.10

- 103.55%). Excretion via the urine was minor. AMPA mercapturate and DAPA, the major urinary metabolites, represented only 0.05

- 0.39% of the administered dose. Radioactivity

in the fe ces represented most of the administered dose (88.78

- 100.0%). Identified fecal metabolites, however, represented from 11.20

- 68.59% of the administered dose. For all dose groups, most of the fecal radioactivity appeared to reside with unextractable compon ents in the

post

- extraction solids (PES). Further analysis of the PES components using base hydrolysis indicated that most of this radioactivity could be attributed to hydrolysis products of AMPA and DAPA. PES radioactivity was also greatest for the low

- dose group

, which was consistent with the lower overall accounting of identified metabolites for this group. Approximately 20

- 25% of the aqueous phase of the fecal extraction was identified as a cysteine conjugate of DAPA and represented <1% of the admini stered dose. With the exception of the low

- dose group, parent compound represented most of the identified radioactivity in the feces. AMPA and DAPA were identified in the feces from all dose groups

, but these metabolites never represented more than

5% of the administered dose (except for high

- dose female rats where AMPA accounted for 10.22%).

DAPA glucuronide and AMPA mercapturate were the major biliary metabolites

, but represented <4% of the administered dose. Total biliary radioactivity, however rep resented 25

- 34% of the

administered dose

. Analysis of chromato grams indicated that numerous other metabolites were present in the bile

, but were individually of insufficient quantity to allow for characterization.

Metabolite profiles from administrati on of different label positions (pyridyl and phenyl) indicated that there was no metabolic cleavage of the ring structures. Minor quantitative differences in metabolite recovery were observed between genders

, but not of sufficient magnitude to suggest bio logically relevant differences in the metabolism of fluazinam

.

4.2.1 Dermal Absorption

An in vivo d ermal absorption study in rats is available for fluazinam that demonstrates low dermal absorption of 4%. Additionally, in vitro dermal data are available in rat and human skin, along with a dermal toxicity study in rats . In the rat study, liver effects were seen at the lowestFluazinam Human Health Risk Assessment DP No. D397601

Page 16 of 75 observed adverse effects level (LOAEL) of 100 mg/kg/day , with a no observed adverse effects level ( NOAEL ) of 10 mg/kg/day. In an e ffort to refine the dermal point of departure selected for risk assessment, the dermal absorption data and dermal toxicity study were used to calculate a refined human dermal equivalent dose that was used for short

- and intermediate

- term dermal risk

assess ments. To calculate a RDD, in vitro results using rat skin are corrected for any differences

between in vitro and in vivo absorption rates and species differences between rats and humans. This refinement in dermal absorption is important because absorpti on by human skin is usually lower than that by rat skin. Accordingly, the combined use of the data from the three studies and two testing systems offers greater precision in estimating human dermal absorption, which strengthens the reliability of the derm al risk assessment ( see Appendix A.2).

4.3 Toxicological Effects

In subchronic and chronic oral and dermal studies in rats, dogs

, and mice, the liver was a primary

target organ. In rats, subchronic exposure resulted in increased liver weights and liver histopathology (hepatocyte hypertrophy, sinusoidal chronic inflammation , and necrosis). In dogs, increased liver enzymes (alkaline phosphatase), increased liver weights, and histop athology (hepatic coagulative necrosis, and bile duct hyperplasia) were observed. In mice, increased liver weights, and liver hypertrophy were seen. Liver histopathology (hypertrophy, necrosis, brown pigment, and apoptosis) was also noted in maternal ani mals in a preliminary developmental toxicity study in rabbits. Chronic exposure in rats led to similar liver effects, along with gross lesions ( pale, enlarged, pitted, and mottled livers

, and accentuated markings on the liver) and more pronounced liver hi stopathology ( eosinophilic or basophilic hepatocytes, rarefied or vacuolated hepatocytes, altered foci, single cell necrosis, hypertrophy, and fatty change ). In dogs, liver effects were limited to increased alkaline phosphatase and liver weights

after lon g

- term exposure. In mice, basophilic and/or eosinophilic vacuolated hepatocytes, hepatitis, and brown pigmented macrophages were observed after chronic exposure, with the addition of hepatocellular adenomas/carcinomas at the HDT

.

T re atment

- re lated effects were also observed in other organs in subchronic and chronic oral,

dermal

, and inhalation studies in rats, dogs

, and mice, but these effects were not regularly noted in all three species or in all studies in a given species. In rats, effects obser ved were decreased body weight gain, decreased food consumption, mild anemia, and clinical chemistry alterations ( increased serum cholesterol, phospholipid, and aspartate aminotransferase ). T esticular atrophy

and increased test icular weights (inhalation s tudy), pancreatic exocrine atrophy, increased lung weights and increased alveolar adenomatosis, epithelialization

, and macrophages were also observed. Additionally , thyroid gland follicular cell hyperplasia and an increased incidence of thyroid gland foll icular cell tumors in male rats, but not in female rats , were seen . In dogs,

effects included increased salivation and increased nasal dryness, grey mottling of the retina, mild anemia, and gastric lymphoid hyperplasia. In mice, increased mortality (at h igh doses), decreased body weight gain, increased serum glucose, increased kidney weights, cystic thyroid follicles, and an increased incidence of hepatocellular adenoma/carcinoma (males) were seen. In a subchronic inhalation toxicity study in rats, pulmo nary effects were observed at the mid and high doses. These effects included dose related increases in lung/bronchial weights and increased incidences of alveolar macrophages and peribronchiolar proliferation in both sexes.Fluazinam Human Health Risk Assessment DP No. D397601

Page 17 of 75 In a developmental toxicity study in rats

, there was evidence of increased qualitative susceptibility of fetuses to fluazinam; however, there was no evidence of increased quantitative susceptibility. D ecrease d body weights, placental weights, and increased incidences of facial/pala te clefts, diaphragmatic hernia and delayed ossification ( several bone types ) were

observed in fetuses at the HDT

. There was also greenish amniotic fluid and increases in late resorptions, as well as post

- implantation loss. Maternal effects observed at the same dose level

were decrease d body weight gain and food consumption, increase d water consumption, and increased urogenital staining.

There was no evidence of increased quantitative or qualitative susceptibility in a developmental toxicity study in ra bbits or in a 2

- generation reproduction study in rats. In rabbits, increased incidences of total litter resorptions and a slight ly increased incidence of fetal skeletal

abnormalities (e

. g. kinked tail tip, fused or incompletely ossified sternebrae, and ab normalities of head bones) were seen in fetuses at the HDT. At the same dose, abortions, resorptions, placental anomalies, decreased body weight gain and food consumption, and significant liver histopath

ology were seen in maternal animals. Additionally, treatment

- related effects were seen at lower

doses in maternal animals in the absence of fetal effects. In the rat reproduction study, decreased pup weight gain was seen at the HDT in the presence of decreased food consumption and liver histopathology in parental animals.

Clinical signs were observed in an acute oral neurotoxicity study in rats ; decreases in motor activity and soft stools were seen on the day of dosing at the limit dose . These effects were

attributed to systemic toxicity and were not co nsidered to be evidence of frank neurotoxicity. In two subchronic neurotoxicity studies (evaluated together) in rats

, no evidence of neurotoxicity

was observed up to and including the HDT

. A neurotoxic lesion described as vacuolization of

the white matte r of the CNS was observed initially in long

- term studies i n mice and dogs ; however, the lesion is reversible and was later attributed to the presence of an impurity in the technical material. The developmental neurotoxicity study was conducted with a technical with significantly less of the impurity, and there were no lesions or developmental neurotoxicity

concerns (see section 4.4.2)

.

In an immunotoxicity study in mice, significant suppressions of anti

- SRBC AFC assay response were demonstrated at the HDT indicating potential immunotoxicity. However, clear NOAELs and LOAELs were identified for the effects seen in the study and the points of departure (PODs)

and end points selected for risk assessment are protective of immunotoxic effects.

Fluazinam is classified as having “Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential.” This classification was based on some ev idence of th yroid

tumors in male rats and evidence of liver tumors in male mice. 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 coul d result from exposure to fluazinam.

Fluazinam (technical) has low or mild acute toxicity (Categories III and IV), except for acute eye irritation (I) and acute inhalation toxicity (II).Fluazinam Human Health Risk Assessment DP No. D397601

Page 18 of 75 4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

The proposed and exi sting use patterns for fluazinam will result in dietary and residential exposure to infants and children. Thus, FQPA hazard and exposure considerations were

addressed in HED’s evaluation of the database. HED recommends that the 10x FQPA Safety Factor ( for the protection of infants and children ) be reduced to 1x. This recommendation is supported by the following: 1) the t oxicological database for fluazinam is complete with regard

to pre

- and postnatal toxicity , including the required immunotoxicity and neurotoxicity studies and the developmental neurotoxicity study, 2) the endpoints and doses selected for risk assessment are protective of the qualitative and quantitative susceptibility observed in the developmental rat and DNT studies , respectively, and the degree of concern for the susceptibility is low, 3) although indications of neurotoxicity and immunotoxicity were observed in the database, there were clear NOAELs for these effects, and the endpoints and doses for risk

assessment a re protective of the potential effects, 4) t he dietary exposure assessment s are based

on high

- end health protective residue levels and processing factors for foods, and upper

- bound assumptions were used to determine exposure through drinking water , and 5) the residential assessments were conducted in accordance with standard practices that ensure exposures were

not underestimated , and further, no residential exposure is expected for children.

4.4.1 Completeness of the Toxicology Database

T he available toxici ty studies are adequate for assessing and characterizing potential pre

- and/or

post

- natal susceptibility for infants and children , and the database is complete in accordance with the Part 158 data requirements, including route

- specific toxicity studies

. Acceptable/guideline developmental toxicity studies in rats and rabbit s, a reproduction study in rats , and a DNT study

in rats are all available for FQPA assessment

.

4.4.2 Evidence of Neurotoxicity

N o evidence of neurotoxicity was observed in an acute neurotoxicity study in rats up to 1000 mg/kg/day. D ecreases in motor activity and soft stools were observed on the day of dosing. These findings are attributed to systemic toxicity and are not considered to be evidence of frank neurotoxicity. However, a neurotoxic lesion described as vacuolization of the white matter of the central nervous system (CNS) was observed in subchronic and chronic studies in mice and dogs, as well as special studies in rats. After further investigation, it was determined that one single impurity, Impurity

- 5, was solely responsible for the appearance of the white matter

vacuolization . A developmental neurotoxicity (DNT) study containing a lower concentration of Impurity

- 5 was submitted to address the concerns regarding the vac uolization observed. In the study, there was no evidence of vacuolization of the brain or any other treatment

- related pathology up to the highest dose tested. The DNT study contained a lower concentration of Impurity

- 5 than the maximum concentration of Impurity

- 5 in technical grade fluazinam. Therefore, it was concluded that fluazinam, per se , was not responsible for the induction of this lesion. A NOAEL for Impurity

- 5 was determined that is equivalent to a NOAEL for CNS effects of 20 mg/kg/day for tec hnical grade fluazinam. The current acute and chronic reference doses selected for risk assessment are lower than the determined NOAEL and protective of any possible neurotoxic effects resulting from exposure to Impurity

- 5.Fluazinam Human Health Risk Assessment DP No. D397601

Page 19 of 75 4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

No evidence of increased quantitative or qualitative susceptibility was seen in a developmental toxicity study in rabbits or a reproduction study in rats. However, there was eviden ce of

i ncreased qualitative susceptibility of fetuses in the developmental toxicity study in rats.

I ncreased incidences of facial/palate clefts and other rare deformities were seen in fetuses in the presence of minimal maternal toxicity. A DNT study in r ats was submitted to address the increased susceptibility as well as the presence of neurotoxic lesions observed after fluazinam exposure. In the DNT study, decreases in body weight and body weight gain a s well as delay ed

preputial separation were observe d in pups. These effects were seen in the absence of maternal effects, suggesting increased quantitative susceptibility of the offspring.

Although there is evidence of increased qualitative susceptibility in the developmental toxicity study in rats, th ere are no residual uncertainties with regard to pre

- and/or postnatal toxicity following in utero exposure to rats or rabbits and pre and/or post

- natal exposures to rats. Considering the overall toxicity profile and the doses and endpoints selected for ri sk assessment, the degree of concern for the effects observed in the developmental rat study is low. There is a clear NOAEL for the fetal effects seen, the effects occurred in the presence of maternal toxicity, and they were only seen at the highest dose tested. Additionally, the fetal NOAEL of 50 mg/kg/day identified in th e developmental toxicity study in rats is significantly higher than the NOAEL used ( 7 mg/kg/day) to establish the acute r eference d ose (aRfD

, females 13

- 49); therefore, the aRfD is prot ective of any observed fetal effects.

As previously stated, i ncreased quantitative susceptibility was seen in the DNT study in rats

. Although the NOAEL determined for the DNT study (2 mg/kg/day) is lower than the NOAEL used for acute dietary risk assessment for females 13

- 49 (7 mg/kg/day), the effects noted in the

DNT study are attributable to multiple doses and are considered to be post

- natal effects. Therefore, the study endpoint is not appropriate for assessing acute dietary exposure and risk

. Additionally, the NOAEL (1.1 mg/kg/day) used for the chronic dietary assessment is lower, and

is considered to be protective of the effects observed in the DNT study

.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertaint ies with respect to dietary and residential exposure. T he dietary

exposure assessment s are based on high

- end health protective residue levels (that account for parent and metabolites of concern), and processing factors. Actual risk from exposure to
fluaz inam will likely be much lower than HED’s risk estimates conducted for the proposed and existing uses

. Furthermore, conservative, upper

- bound assumptions were used to determine exposure through drinking water and residential sources, such that these expos ures have not been

underestimated.Fluazinam Human Health Risk Assessment DP No. D397601

Page 20 of 75 4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose

- Response Assessment

T he detailed description s of the toxicity studies used for selecting toxicity endpoints and points of departure for various exposure scenarios are presented in A ppendix A.3 of this assessment

. For acute dietary assessment for females 13

- 49

, the endpoint selected for risk assessmen t was increased incidence of total litter resorptions and increased incidence of fetal skeletal

abnormalities at the LOAEL of 12 mg/kg/day, and the point of departure (POD) was the NOAEL

of 7 mg/kg/day . For the general population, the acute dietary endpoi nt was clinical signs ( soft stools and decreased motor activity ) observed at the LOAEL of 1000 mg/kg/day; the POD was the study NOAEL of 50 mg/kg/day. The effects observed in the selected studies are considered

to be attributable to a single dose of fluaz inam

.

For chronic dietary exposure and risk assessment , the carcinogenicity study in mice and the chronic study in dogs were selected as co

- critical studies. In both studies, the NOAELs determined were approximately 1 mg/kg/day and the LOAELs approximate ly 10 mg/kg/day. In the mouse, effects seen were mainly in the liver ( increased pigmented macrophages

, eosinophilic vacuolated hepatocytes , and liver weights). In dogs, nasal dryness and gastric lymphoid hyperplasia were seen. The rat carcinogenicity study was also considered; however, the mouse and dog studies provided a lower point of departure. The POD for the chronic dietary assessment was the NOAEL of 1.1 mg/kg/day from the carcinogenicity study in mice.

For s hort

- and intermediate

- term dermal exposure, a refined dermal dose of 24.4 mg/kg/day was calculated based on the dermal toxicity study and dermal absorption data. In the dermal toxicity study, liver effects were seen at the LOAEL of 100 mg/kg/day. Develo pmental effects were noted in developmental toxicity studies at ≥ 12 mg/kg/day . Although the RDD is 24 mg/kg/day, it is based on an oral NOAEL that is lower than the dose at which developmental effects were seen. The comparable dermal equivalent dose (DE D) for the developmental study, using the developmental NOAEL of 7 mg/kg/day and a DAF of 4.47% is 155 mg/kg/day. Therefore, the RDD is considered protective of potential developmental effects. Additionally, the RDD is protective of immunotoxic effects s een in an immunotoxicity study in mice at the LOAEL of 231 mg/kg/day.

For short

- and intermediate

- term inhalation exposure, a route

- specific 4 week inhalation toxicity study was used for endpoint and dose selection

. In previous risk assessments, the syst emic liver

effects observed in a 7

- day inhalation study served as the basis for endpoint and dose selection. However, i n the 4

- week study, a dose related increase in lung and bronchial weights in both sexes was observed at the LOAEL of 0.020 mg/L/day. At 0.100 mg/L, there were also increased lung and bronchial weights, along with histopathology of the lung (alveolar macrophages, peribronchiolar proliferation) in both sexes. The NOAEL is 0.003 mg/L/day. In accordance with current guidance, h uman equivale nt concentrations (HECs) and h uman equivalent doses (HEDs) were calculated , with the HEDs being used for risk assessment. The occupational

inhalation HED is 0.048 mg/kg/day

, and the residential inhalation HED is 0.043 mg/kg/day

. The inhalation POD and en dpoint are protective of the developmental effects seen in rats as wellFluazinam Human Health Risk Assessment DP No. D397601

Page 21 of 75 as potential neurotoxicity and immunotoxicity since significantly lower PODs were determined in the inhalation study

.

The occupational HED is based on an 8

- hour working day, and a corresponding 8 hours of inhalation exposure. The residential HED takes into account the potential for 24

- hour bystander exposure via the inhalation route. At the current time, there are no data to quantitatively assess inhalation exposure to residential bystanders, and there are no other residential inhalation exposure scenarios based on the existing and proposed uses. If sufficient exposure data become available to assess potential bystander exposure and risk, the residential HED would be used.

Based on the proposed use pattern for fluazinam , long

- term dermal and inhalation exposures are not anticipated.

For acute and chronic dietary and dermal risk assessments, a 100 x uncertainty factor was applied (interspecies factor of 10 x and intraspecies f actor of 10 x ). For dietary assessments, the acute and chronic population adjusted doses are therefore For dermal risk assessment, the level of concern (LOC) is a margin of exposure (MOE) of 100, based on the combined interspecies and intraspecies uncertai nty factors. For inhalation risk assessments, the LOC is an MOE of 30 (interspecies factor of 3 x and intraspecies factor of 10 x ) since human equivalent calculations (HECs) were used for risk assessment. The interspecies factor was reduced from 10 x to 3 x because the HEC calculation accounts for pharmacokinetic (not pharmacodynamic) interspecies

differenc es between animals and humans.

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment

When there are potential occupational and reside ntial exposures to a pesticide, the risk assessment must address exposures from three major sources: incidental oral, dermal

, and

inhalation . It must be determine d whether or not the individual exposures have the same toxicological effects. If they do, then they can be combined. For fluazinam, inhalation and

dermal routes can not be combined because the t oxicological effects are different

.

4.5.3 Classification of Carcinogenic Potential

In accordance with EPA’s Draft Guidelines for Carcinogen R isk Assessment (July, 1999), the Cancer Assessment Review Committee (CARC) classified (HED Doc. No.: 014512, March 29, 2001) fluazinam 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

. Although there is evidence of thyroid tumors in male rats and liver tumors in male mice, the NOAEL used (1.12 mg/kg/day) for establishing th e chronic reference dose is approximately 3

- fold lower than the lowest dose that induced tumors (3.8 mg/kg/day). The Agency has determined that quantification of cancer risk using a non

- linear approach would adequately account for all chronic toxicity, in cluding carcinogenicity, that could result from exposure to fluazinam.Fluazinam Human Health Risk Assessment DP No. D397601

Page 22 of 75 The cancer classification is based on the following weight

- of

- evidence considerations:

(i) There was some evidence that fluazinam induced an increase in thyroid gland follicular cell tumors in male rats, but not in female rats at ≥ 100 ppm (3.8 mg/kg/day). In one study in mice, there was clear evidence that an increased incidence of hepatocellular

tumors observed in male mice was treatment

- related at 1000 ppm (107 mg/kg/day). In another study in mice, there was equivocal/some evidence that fluazinam m ight have induced an increase in hepatocellular tumors in the male mice at ≥ 3000 ppm (377mg/kg/day). Increases in hepatocellular tumors observed in the female mice in the

latter st udy were not statistically significant

, and some occurred at an excessively toxic dose level. The thyroid gland follicular cell tumors of concern were seen only in the

male rats

, and the hepatocellular tumors of concern were seen only in the male mice.

(ii) Fluazinam was negative in mutagenicity assays. In a combined chronic/carcinogenicity study in rats, increased incidences of thyroid gland follicular cell tumors were observed

in male rats only. Additionally, i n two carcinogenicity studies in mice, increa sed incidences of hepatocellular tumors were observed in male mice only. The CA RC concluded that there was some evidence that the thyroid tumors observed in the male rats

were treatment

- related . For the liver tumors in mice, the CARC concluded that there was clear evidence of treatment

- related increases in both benign and malignant liver tumors in one study; however, it was concluded that there was only equivocal/some evidence for hepatocellular tumors in the other study. There was no evidence of mutagen icity in the available mutagenicity battery.

4.5.4 Summary of Toxicological Doses and Endpoints for Fluazinam for Use in Human

Health Risk Assessments

Table 4 .5

. 4. a. Toxicological Doses and End points for Fluazinam for Use in

Dietary and Non

- Occupational H uman 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.Fluazinam Human Health Risk Assessment DP No. D397601

Page 23 of 75 Table 4 .5

. 4. a. Toxicological Doses and End points for Fluazinam for Use in

Dietary and Non

- Occupational H uman Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors RfD, PAD, Level of

Concern for Risk

Assessment Study and Toxicological Effects

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 NOAEL =

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).

A Refined Dermal Equivalent Dose (RDD) of 24.4 mg/kg/day was calculated using the dermal POD and dermal absorption data (see Appendix A.2)

Inhalation

Short

- Term (1

- 30 days) NOAEL=

0.003 mg/L

HEC= 0.0003 mg/L

HED =
0.043 mg/kg/day 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.Fluazinam Human Health Risk Assessment DP No. D397601

Page 24 of 75 Table 4 .5

. 4. b

. Summary of Toxicolog ical 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 NOAEL =

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)

A Refined Dermal Equivalent Dose (RDD) of 24.4 mg/kg/day was calculated using the dermal POD and dermal absorption data (see Appendix A.2)

Inhalation

Short

- Term (1

- 30 days);

Intermediate

- Term (1

- 6 months) NOAEL=

0.003 mg/L

HEC= 0.001mg/L

HED =
0.048 mg/kg/day 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 (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 a nd 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 = ext rapolation 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 equivalen t dose

.

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, and grapes. The residue of concern in peanuts and root and tuber vegetables is parent fluazinam for purposes of both dietary risk assessm ent 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 pla nts include fluazinam and AMGT for wine grapes, but only fluazinam for all other plant commodities.Fluazinam Human Health Risk Assessment DP No. D397601

Page 25 of 75 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.

The nature of the residue in livestock is also understood based on acceptable goat and hen metabolism studies. The fluazinam residues of regulatory interest in animal com modities 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 transformation 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,

th e 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 substitu ents 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 unde rgoes 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, reduction,

a nd 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 natural p lant 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 th e chlorine on the phenyl ring to form HYPA. These compounds can then undergo conjugation with glutathione, and subsequent degradation of the glutathione component yields a variety of polar compounds. Although the ring structure of the parent molecule rem ains 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.Fluazinam Human Health Risk Assessment DP No. D397601

Page 26 of 75 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 that 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 tha t of the parent. The toxicological endpoints that were selected for fluazinam are expected to be protective for the metabolites and degradates.

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 misuse

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 (PB I) 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 metabolit es. Their toxicity is assumed to be comparable to that of the parent compound (D272624, W. Cutchin, 4/23/2001).

Table 5.1.4

. Summary 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 fluazinamFluazinam Human Health Risk Assessment DP No. D397601

Page 27 of 75 Table 5.1.4

. Summary 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

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

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 measuring only fluazinam. The existing tolerances for residues in grapes and livestock commodities are listed Under 40 CFR §18 0.574(a)(2) and (a)(3), respectively, including the relevant coverage and compliance statements. No changes are needed in conjunction with the proposed uses or to support registration review.

5 .2 Food Residue Profile

The food use profile for the proposed and registered commodities is adequate and complete for tolerance setting and risk assessment purposes (D 397721, D. Dotson, 9 /7 /2012 ) . For soybeans, melons, and peppers, the registrants submitted adequate field trial data for parent and the

metabolite AMGT. For head and leaf lettuce, IR

- 4 submitted adequate field trial data for the

metabolite AMGT , which were requ ested in a previous review ( D360840, D. Dotson,

3/31/2010 ). Adequate storage stability data were submitte d for melons, peppers, and soybean forage, hay, and seed. The data indicated that residues were stable over the storage durations

used in the field trial and processing studies.

For all crops, a dequate numbers of trials were performed in the recommended NAFTA growing

zones. Residues of parent fluazinam were below the LOQ of 0.01 ppm in all samples of soybean seed. Quantifiable residues of fluazinam were found in soybean forage, soybean hay, melons, and peppers. The ranges of residues in the samples of these commodities can be found in Table 5.2. No quantifiable residues of AMGT were found in any samples of any commodities tested, including head and leaf lettuce.Fluazinam Human Health Risk Assessment DP No. D397601

Page 28 of 75 The registrant submitted a processing study for soybeans. Residues concentrated in soy bean

hulls , and a separate tolerance for the commodity will be needed. Separate tolerances will not be needed for soybean oil or meal.

Although soybean seed and hulls are livestock feed items, the current tolerances for livestock commodities (0.05 ppm fo r the fat and meat byproducts of cattle, goats, horses, and sheep) are adequate.

Table 5.2 provides a summary of the soybean, cantaloupe, pepper, and lettuce field trial data.

TABLE 5.2 . Summary of Fluazinam Field Trial Residue Data

Commodity Analyte Total

Rate (lb ai/A) PHI

(days) Residue Levels (ppm)

n Sample

Min. Sample

Max. LAFT 1 HAFT 2 Median Mean Std

. Dev.

Soybeans

Soybean Forage Fluazinam 0.99

- 1.17 29

- 35 16 0.021 3.73 0.034 3.06 0.427 0.63 0.74

AMGT <0.01 <0.01 <0.01 <0.01 0.01 0.01 NA

Soybean Hay Fluazinam 29

- 35 16 <0.017 5.21 0.028 5.21 0.868 1.41 1.48

AMGT <0.01 < 0.01 <0.01 <0.01 0.01 0.01 NA

Soybean Seed Fluazinam 56

- 94 16 <0.01 <0.01 <0.01 <0.01 0.01 0.01 NA

AMGT <0.01 <0.01 <0.01 <0.01 0.01 0.01 NA

Cantaloupes

Cantaloupe Fluazinam 5.18

- 5.35 27

- 32 22 <0.01 0.077 <0.01 0.048 0.01 0.017 0.015

AMGT < 0.01 <0.01 <0.01 <0.01 0.01 0.01 NA

Peppers (Bell and Non

- Bell)

Bell Pepper Fluazinam 4.47

- 5.45 28

- 31 18 <0.01 0.038 <0.01 0.030 0.01 0.014 0.007

AMGT <0.01 <0.01 <0.01 <0.01 0.01 0.01 NA

Non

- Bell Pepper Fluazinam 5.10

- 5.29 28

- 31 8 <0.01 0.053 < 0.01 0.045 0.01 0.02 0.016

AMGT <0.01 <0.01 <0.01 <0.01 0.01 0.01 NA

Lettuce

Head Lettuce AMGT 0.95

- 1.02 46

- 52 14 <0.02 <0.02 <0.02 <0.02 0.02 0.02 NA

Leaf Lettuce AMGT 0.97

- 1.05 20

- 32 14 <0.02 <0.02 <0.02 <0.02 0.02 0.02 NA

1 LAFT = lowest average field trial

2 HAFT = highest average field trial result. NA = not applicable

T he OECD MRL calculation procedures were used for determining appropriate tolerance levels. The recommended tolerances for soybean seed, soybean hulls, the melon subgroup, and the pepper/eggplant subgroup are listed in Table 2.2.3.

5.3 Water Residue Profile

Th e drinking water assessment performed by EFED provides E DWC s of fluazinam in surface water and in groundwater. The drinking water residue used in the dietary risk assessment was provided by EFED ( D3 9 7602 , J. Meléndez, 7 / 17 /201 2 ) 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 itsFluazinam Human Health Risk Assessment DP No. D397601

Page 29 of 75 transformation products, including DCPA, CAPA, DAPA, HYPA, and AMPA. The acute and

chronic EDWCs are based on ground application of fluazinam to turf. The turf use results in higher EDWCs t han uses on the proposed crops (as well as all other crops). The values are provided in Table 5.3, below. The groundwater value was generated using the Screening Concentration in Groundwater (SCI

- GROW) Model and the surface water values were generated

us ing the FQPA Index Reservoir Screening Tool (FIRST) Model. The surface water estimates were used for both the acute and chronic assessments because they were higher than the groundwater value. For the acute assessment, a value of 226 ppb was used. This value includes both parent and degradates. For the chronic assessment, a value of 37.8 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 Based on Ground

Application of Fluazinam to Turf at a Seasonal Rate of 8.4 lb a.i./A

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

Surface Water/FIRST 217 2 1.47 226 2 37.8

Groundwater/SCI

- GROW 0.404

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

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 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.Fluazinam Human Health Risk Assessment DP No. D397601

Page 30 of 75 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 level 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 es timate for the general U.S. population is 5. 3 % of the acute PAD (aPAD). The population subgroup with the highest acute dietary risk estimate is Females 13

- 49, which uses 2 8 % of the

aPAD. Although Females 13

- 49 use the greatest percent of the aPAD, the po pulation subgroup with the highest exposure estimate is Children 1

- 2. This subgroup uses 2 1 % of the aPAD. The reason this subgroup has a higher exposure but a lower estimated risk than Females 13

- 49 is that it has a higher aPAD value than Females 13

- 49 ( 0.5 mg/kg/day for Children 1

- 2 a s opposed to 0.07 mg/kg/day for Females 13

- 49). Since the assessment 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 Ta ble 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 20 % of the chronic PAD (cPAD). The most highly exposed popu lation subgroup is All Infants (<1 year old), which uses 51 % of the cPAD. The chronic dietary risk estimates are given in Table 5.4.6.

5.4.5 Cancer Dietary Risk Assessment

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.Fluazinam Human Health Risk Assessment DP No. D397601

Page 31 of 75 5.4.6 Summary Table

Table 5.4.6. Summary of Acute and Chronic Dietary Ex posure 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 0.02 6393 5.3 0.011 0.00 2145 20

All infants 0.5 0.0 83776 1 7 0.011 0.004928 45

Children 1

- 2 yrs * 0.5 0. 106710 2 1 0.011 0.005635 51

Children 3

- 5 yrs 0.5 0.06 4022 13 0.011 0.00 3751 34

Children 6

- 12 yrs 0.5 0.0 31323 6.3 0.011 0.00 2031 18

Youth 13

- 19 yrs 0.5 0.01 7332 3.5 0.011 0.00 1171 11

Adults 20

- 49 yrs 0.5 0.01 9148 3.8 0.011 0.001 936 18

Adults 50

- 99 yrs 0.5 0.01 7495 3.5 0.011 0.00 2118 19

Females 13

- 49 yrs * 0.07 0.01 9721 2 8 0.011 0.001 996 18

* The subpopulation s with the highest acute or chronic risk estimate s

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, Fluazinam 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 ol d, 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

Ass essments, (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

- application Exposure

Short

- term r esidential post

- application dermal exposures resulting in MOEs greater than or equal

to 100 are not of concern. Sh ort

- term dermal post

- application exposure and risk analys e s for golfers resulted in MOE s greater than the LOC 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 t he residential short

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

.Fluazinam Human Health Risk Assessment DP No. D397601

Page 32 of 75 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 = ( NOAEL ( 24 .4 mg/kg/day) ) ÷ ( Dermal Dose (mg/kg/day) )

.

6.2.2 Inhalation Post

- application Exposure

Based on the Agency ’ s current practices, a quantitative post

- application inhalation exposure

assessment i s not being performed for fluazinam at this time primarily because of its vapor

pressure of 1.73 x 10 - 7 m m Hg . However, volatilization of pesticides can be a potential source of

post

- application inhalation exposure to individuals in close proximit y to 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. The Agency received the SAP’s final report on March 2, 2 010 ( http://www.epa.gov/scipoly/SAP /meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and m ight , as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

- application inhalation exposure into the Agency ’ s risk assessments. If new policies or procedures are put into place, the Agency m ight revisit the need for a quantitative post

- application inhalation expos ure assessment for fluazinam.

6.3 Combined Residential Risk Estimates

HED combines risk values resulting from separate exposure scenarios when it is likely they can occur simultaneously based on the use pattern and when the toxicological effects are the same across different routes of exposure. Since inhalation post

- application exposure is expected to be negligible outdoors

, and the application of fluazinam is only directed for golf course, incidental oral post

- application exposure for children i s also expected 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 A ggregate Assessment

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 cours es for adults (MOE = 1,100 ) and for children 6 to < 11yrs old (MOE = 780).Fluazinam Human Health Risk Assessment DP No. D397601

Page 33 of 75 6. 5 Spray Drift

Spray drift is always a potential source of exposure to residents in close proximity to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for fluazinam

. The Agency has been working with the Spray Drift Task Force, EPA Regio nal Offices

, State Lead Agencies for pesticide regulation

, and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a ch emical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast

, and ground hydraulic methods. After the p olicy is in place, the Agency m ight impose further refinements in spray drift management practices to reduce off

- target drift with specific products with significant risks

associated with drift.

Although a quantitative residential post

- application inhalat ion exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers. This exposure scenario is representative of a worse case inhalation (drift ) exposure and may be considered protective of most outdoor agricultural and commercial post

- application inhalation exposure scenarios

.

6. 6 Residential Bystander Post

- Application Inhalation Exposure

Based on the Agency ’ s current practices, a quantitative post

- application inhalation exposure

assessment is not being performed for fluazinam at this time primarily because of its vapor pressure ( 1.73 x 10 - 7 mm Hg ), and the proposed use rates (0.52

- 0.78 lb ai/A). However,

volatilization of pesticides m ight be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues

related t o 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.h tml ). The Agency is in the process of evaluating the SAP report and m ight , as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

application inhalation exposure into the Agency ’ s risk assessments. If new policies or procedures are developed, the Agency m ight revisit the need for a quantitative post

- application inhalation exposure assessment 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 estim ates of hazard (e.g., a NOAEL or PAD), or the risk estimate s themselves canFluazinam Human Health Risk Assessment DP No. D397601

Page 34 of 75 be aggregated. When aggregating 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 both 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

For 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, the dietary groups did not directly overlap with the representative residential life stages

. Specifically, the closest dietary subgroup

to the residenti al 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 7 30 to 9 7 0 . 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 rela tive to the dermal exposure estimates, the short

- term aggregate MOEs are the similar to those estimated 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

NOAEL 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 0.00 2031 0.031 356 0.033 3 87 7 30

Youth 11

- <16 24. 4 100 0.244 0.001 171 0.026 709 0.027 880 8 8 0

Adults 24.4 100 0.244 0.00 2118 0.0 2292 3 0.0 2 5041 9 7 0

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) = NOAEL/LOC

3

. Residential Exposure = Dermal exposure from treated turf (see table 6.2.2).

4

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

5

. Aggregate MOE = [NOAEL ( 24.4 mg/kg/day) ÷ ( Avg Food & Water Exposure + Residential Exposure ( mg/kg/day) ) ]Fluazinam Human Health Risk Assessment DP No. D397601

Page 35 of 75 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 expos ure 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 Cancer 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 was not performed.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pest icides 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

metabol ite 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 released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substanc es found to have

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

.

9.0 Occupational Exposure/Risk Characterization

9.1 Occupational Handler Exposure/Risk Estimates

Based on the anticipated use patterns

, current labeling, and the types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses. The quantitative exposure/risk assessment developed for occupation al handlers is

based on the following scenarios:

• Mixing/Loading Liquids for Groundboom Application,

• Mixing/Loading Liquids for Aerial Application,

• Mixing/Loading Liquids for Chemigation,

• Applying Sprays with Groundboom Equipment,

• Applying Sprays with Aerial Equipment,

• F lagging for Aerial Applications, and

• M ixing/ L oading/ A pplying L iquids with M echanically

- P ressurized H andgun S prayer.Fluazinam Human Health Risk Assessment DP No. D397601

Page 36 of 75 No handler exposures are expected from applying sprays via chemigation systems.

The maximum s ingle application rate on the proposed label was used to assess all handler exposure scenarios ( 0. 52

- 0.78 lb ai/A ) . The maximum application rate per acre per season ranges from 1.04

- 4.68 lb ai/A/yr. The number of applications per year at the maximum single application rate ranged from 2

- 6 depending on the use site

.

No data on the number of exposure days per year were provided. For fluazinam, based on the proposed use patterns and directions (e.g., 2

- 6 applications per season with a minimum 7

- 14 day spray interval depending on the use ), short

- and intermediate

- term exposures are expected for

handlers. The estimates are considered to be protective for intermediate

- term exposure and risk

. Long

- term expos ures 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. When mixing and loading

, handlers must wear a chemical

resistant apron and a dust/mist filtering respirator (MSHA/NIOSH T C

- 21C) or a NIOSH approved respirator with an N, R, P or HE filter.

Detailed descriptions of the occupational handler assessment are available in Z. Figueroa (D 397723

, 9 / 7 /2012 ) . The occupational hander exposure and risk estimates rely on generic data from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), and the Agricultural Handler Exposure Task Force (AHETF) database. Some of these data are pro prietary (e.g., AHETF data) and subject to the data protection provisions of FIFRA. The sta ndard values recommended for use in predicting handler exposure that are used in this assessment, known as “unit exposures

, ” are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (http://www.epa.gov/opp00001/science/h andler

- exposure

- table.pdf), which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at : http ://www.epa.gov/pesticides/science/handler

- exposure

data.html

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

adul t 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. Exposure estimates for the

o c cupational handler scenarios described above resulted in MOEs greater than the respectiveFluazinam Human Health Risk Assessment DP No. D397601

Page 37 of 75 levels of concern (dermal LOC = 100; inhalation LOC = 30) at some level of PPE and with the assumption of a n en closed cockpit (i.e., engineering controls ) for aerial applicato r s.

Handler d ermal exposure and risk estimates were not of concern (LOC = 100) with baseline PPE

, except for the following scenarios which required additional PPE to attain and MOE equal to o r greater than 100 ; however, HED notes that these additional PPE are already required on the proposed label :

mixing/loading liquids for groundboom applications to soybeans

, which require s the use

of chemical

- resistant gloves, mixing/loading liquids for ae rial applications to soybeans

, which require s the use of

chemical

- resistant gloves + double layer clothing, and mixing/loading liquids for chemigation for melons and peppers

, which require s the use of

chemical

- resistant gloves.

Handler i nhalation exposure and risk estimates were not of concern (LOC = 30) at the baseline

PPE (i.e., no respirator) for all of the scenarios. The dermal and inhalation handler risk estimates do not require any changes to the PPE listed on the proposed label.

The Agency has evaluated scenarios that m ight be limited in nature such as flagging during aerial applications because engineering controls (i.e., Global Positioning Satellite technology) are now predominantly used as indicated by the 1998 National Agricultural Aviat ion Association (NAAA) survey of their membership. It appears, however, that flaggers are still used in approximately 10 to 15 percent of aerial application operations. In cases like these, the Agency strongly encourages the use of the engineering contro l system

, but will continue to evaluate risks for flaggers and any other population where a clear exposure pathway exists until the potential for exposure is eliminated. The Agency is aware that NAAA is conducting another survey on exposure issues and wil l consider those results as are timely and appropriate.

HED has no data to assess exposure for pilots using open cockpits. The only data available

represent exposure for pilots in enclosed cockpits. Therefore, pilot exposure and risk estimates

are deter mined assuming use of engineering control (enclosed cockpits) and baseline attire ( i.e., long

- sleeve shirt, long pants, shoes, and socks) . P ilots are not required to wear protective gloves. With this level of protection, there are no risk estimates of co ncern for aerial applicators treating melons, peppers

, and soybeans with fluazinam in accordance with the proposed label.Fluazinam Human Health Risk Assessment DP No. D397601

Page 38 of 75 Table 9 .1. Short

- Term Occupational Handler Exposure and Risk Estimates for Fluazinam

Exposure Scenario Crop or Target Dermal Unit

Exposure ( μ g/lb ai) 1 Inhalation Unit

Exposure ( μ g/lb ai) 1 Maximum

Application

Rate 2 Area

Treated or

Amount

Handled Daily 3 Dermal Inhalation

Mitigation Level Mitigation Level Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7

Mixer/Loader

Liquids for Groundboom Applications

(AHETF) Melons, Peppers 220

(Baseline) 0.219

(No respirator) 0.78 lb ai/A 80 A 0.171 140 0.000171 280

Soybeans 37.6

(Gloves) 0.219

(No respirator) 0.52 lb ai/A 200 A 0.0489 500 0.000285 170

Liquids for Aerial Application

(AHETF) Soybeans 29.1
(Double Layer, Gloves) 0.219
(No respirator) 0.52 lb ai/A 1,200 A 0.228 110 0.00171 30

Liquids for Chemigation

(AHETF) Melons, Peppers 37.6

(Gloves) 0.219

(No respirator) 0.78 lb ai/A 350 A 0.129 190 0.000748 60

Applicator

Sprays for Groundboom Applications

(AHETF) Melons, Peppers 78.6

(Baseline) 0.34

(No respirator) 0.78 lb ai/A 80 A 0.061 400 0.000265 180

Soybeans 78.6

(Baseline) 0.34

(No respirator) 0.52 lb ai/A 200 A 0.102 240 0.000443 110

Sprays for Aerial Application

(AHETF) Soybeans 5
(Engineering Controls

- Enclosed cockpit) 0.068

(Engineering Controls

- Enclosed cockpit) 0.52 lb ai/A 1,200 A 0.039 630 0.000530 90

Flagger

Flagging for Aerial Applications

(PHED) Soybeans 11

(Baseline) 0.35

(No respirator) 0.52 lb ai/A 350 A 0.025 980 0.000796 60

Mixer/Loader/Applicator

Mechanically

- pressurized Handgun Sprayer

( PHED ) Peppers (Soil

Drench) 1,300

( Baseline ) 3.9

( No respirator) 0.013 lb ai/gal 1,000 gal 0.211 120 0.000634 80

1 Based on “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March, 2012); includes data from PHED/ORETF/AHETF (Level of Mitigation: Baseline, Gloves, Double Layer, Eng. Controls).

2 Based on the proposed crops listed on the registered label ( EPA Reg . No. #71512

- 1)

. 3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure ( μ g/lb ai) x Conversion Factor (0.001 mg/ μ g) x Applicati on Rate (lb ai/A) x Area Treated or Amount Handled (A/day or gal/day) /BW ( 80 kg).

5 Dermal MOE = Dermal NOAEL ( 24.4 mg/kg/day)/Dermal Dose (mg/kg/day) ; LOC = 100

. 6 Inhalation Dose = Dermal Unit Exposure ( μ g/lb ai ) x Conversion Factor (0.001 mg/ μ g) x Application Rate (lb ai/ A ) x Area Treated or Amount Handled (A/day or gal/day) /BW ( 80 kg).

7 Inhalation MOE = Inhalation NOAEL ( 0.048 mg/kg/day)/ Inhalation Dose (mg/kg/day) ; LOC = 30

.Fluazinam Human Health Risk Assessment DP No. D397601

Page 39 of 75 9

. 2 Occupational Post

- application Exposure/Risk Estimates

9 .2.1 Occupational Post

- application Inhalation Exposure/Risk Estimates

Based on the Agency ’ s current practices, a quantitative post

- application inhalation exposure

assessment is not being performed for fluazinam a t this time primarily because of its vapor pressure ( 1.73 x 10 - 7 mm Hg ), and the proposed use rates (0.52

- 0.78 lb ai/A). However , there are multiple potential sources of post

- application inha lation 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.go v/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available post

- application inhalation exposure data generated by the Agricultural Reentry Task Force and m ight , as appropriate, develop

p olicies and procedures to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the Agency ’ s risk assessments. If new policies or procedures are put into place, the Agency m ight revisit the need for a quantitative occupational post

- application inhalation exposure assessment for fluazinam

.

Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial

handlers , including flaggers . 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 expos ure 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 Z. Figueroa, (D 397723

, 9 / 7 /2012 )

.

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

info rmation about the ARTF data, can be found at : http://www.epa.gov/pesticides/science/post

app

- exposure

- data.html

.Fluazinam Human Health Risk Assessment DP No. D397601

Page 40 of 75 Dislodgeable Foliar Residues : Chemical

- specific dislodgeabl e 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 . Furthermore, H ED concluded that t he peanut DFR data serve as the best surrogate to assess post

- application exposure for all crops when no crop

- specific DFR data

are available

, based on available information about the study conditions , region of use, use pattern, etc. ( M. Collantes, 03/18/2008, D349315 ).

Therefore, d ermal post

- application exposure resulting from application of fluazinam on melons,

peppers
, and soybeans was estimated using the best available surrogate DFR predicted Day

- 0 residue value from treated peanu ts (0.987 ug/cm 2 ) calculated by a first

- order dissipation kinetics and decay model. Maximum single application rates were used in this assessment. Day

- 0 DFR values were adjusted by application rate.

Dermal exposures during post

- application activities were estimated using : 1) the maximum single application rate on the proposed label for each crop ( 0.52

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

.

Occupational Po st

- 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. b

. Only risk estimates for the highest contact activity are shown below. Post

application dermal exposure and risk estimates for the scenarios shown below resulted in MOEs greater than 100 on the day of application, and are not of concern

. All other scenarios involving lower contact activities would have higher MOEs and are also not of concern.

Table 9 .2. 2. b

. Short

- term Occupational Post

- application Exposure and Risk Estimates for Fluazinam

Crop/Site Activities DFR 1 Day 0 Dose 2 Day 0 MOE 3 Day at which
MOE ≥ LOC

Melons Irrigation (hand set) 0.975 0.1850 130 0 Peppers Irrigation (hand set) 0.975 0.1850 130 0 Soybeans Scouting 0.650 0.0715 340 0

1

. Dislodgeable Foliar Residue (DFR) from Treated Peanuts = 0.987 ug/cm 2 is based on predicted day 0 residue value calculated from chemical

specific data (MRID No. 455842

- 01) and then adjusted by application rate. 2. Daily Dermal Dose = [DFR (μg/cm 2 ) x TC x 0.001 mg/μg x 8 hrs/day] BW (kg). 3. MOE = NOAEL (24.4 mg /kg/day) / Daily Dermal Dose.

Restricted Entry Interval

The restricted entry interval (REI) for fluazinam is based on the acute toxicity of technical material. Fluazinam is classified as Toxicity Category I for eye irritation. Under the Worker Protection Standard (WPS) for Agricultural Pesticides, active ingr edients classified as acute Toxicity Category I for any of the routes are assigned a 48

- hour REI. Based on the acute toxicity profile of fluazinam, the 48

- hour REI specified on the OMEGA ® 500F label is appropriate to protect agricultural workers from post

- application exposures to fluazinam on melons, peppers

, and soybeans.Fluazinam Human Health Risk Assessment DP No. D397601

Page 41 of 75 10.0 References

D. Dotson, K. Middleton, Z. Figueroa, 3 / 31 /201 0

, D365940

, Fluazinam. Human Health Risk Assessment for the Proposed Uses on Apples, Carrots, Lettuce, and the Bulb Onion Subgroup (3

- 07A), and a Request for a Reduced Tolerance on the Bushberry Subgroup (13

- 07B)

D. Dotson, K. Middleton, Z. Figueroa, 2 / 7 /201 2, Fluazinam . Human Health Risk Assessment

for the Section 3 Registration Action on Turfgrass

D. Dotson, 9 / 7 /2 012

, Fluazinam. Petitions for the Establishment of Tolerances and Registration of New Uses on Soybeans, the Melon Subgroup (9

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

- 10B). Summary of Analytical Chemistry and Residue Data

D. Dotson, 9 / 7 /2012

, D397722

, Fluazinam

, Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 Registration Action on Soybeans, the Melon Subgroup (9A), and the Pepper/Eggplant Subgroup (8

- 10B)

Z. Figueroa

, 2 / 7 /2012

, D387284

, Flu azinam: Occupational and Residential Exposure Assessment for the Proposed Use on Golf Course Turf

J. Melendez

, 7 / 17 /201 2 , D3 9 7602

, Tier I Estimated Drinking Waters Concentrations of

Fluazinam and its Transformation Products for the Use in the Human Health Risk Assessment for the Registration of the New Uses on Peppers, Eggplant (Subgroup 8

- 10B)

, Melons (Subgroup 9A) , and Soybeans

Z. Figueroa, 9/7 /2012

, D397723 , Fluazinam: Occupational and Residential Exposure and Risk Assessment for Registration Re view and to Support the Registration of Proposed Uses on Melons, Peppers, and Soybeans

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

D. Dotson, K. Middleton, S. Oonnithan, 9/2/2009, D 362190, Fluazinam Human Health Assessment Scoping Document in Support of Registration Review

Fluazinam Final Work Plan for Registration Review

, Fluazinam Registration Review Docket ID

EPA

- HQ

- OPP

- 2009

- 0039

Y. Yang

, 4/17/2012, D398060. Fluazinam : Immunotoxicity Study in Mice.

K. Middleton

, D393912

, Fluazinam: Toxicology Data Evaluation Record for Inhalation Toxicity StudyFluazinam Human Health Risk Assessment DP No. D397601

Page 42 of 75 List of Appendices

Appendix A

. Toxicology Profile and Additional Data Appendix B. International Residue Limit Status Sheet Appendix C. F luazinam Physical/Chemical Properties Appendix D

. Review of Human Research Appendix E

. Structures of Fluazinam Metabolites and Degradates of Concern Appendix F

. Occupational Exposure and Risk Assessment t o Support Registr ation ReviewFluazinam Human Health Risk Assessment DP No. D397601

Page 43 of 75 Appendix A: Fluazinam Toxicology Profile and Additional Data

A.1. Toxicity Profile Tables

Table A.1

. 1. 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 A.1. 2. Acu te Toxicity Data on Fluazinam

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

Acute inhalation toxicity : rats Fluazinam 50% WP a (51.3% fluazinam) 42311001 M: LC 50 = 3.0 mg/L

F: LD 50 = 3.4 mg/L IV

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.Fluazinam Human Health Risk Assessment DP No. D397601

Page 44 of 75 Table A.1. 3. Subchronic, Chronic and Other Toxicity Studies (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

Prenatal developmental toxicity

rats F: 0,10, 50, 250

mg/kg/day

Acceptable/guideline 42248613 (1985) Maternal NOAEL = 50 mg/kg/day LOAEL = 250 mg/kg/day based on decreased body weight gain and food 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 F: 0, 2, 4, 7, 12

mg/kg/day 42248616 (1988) Materna l NOAEL = 4 mg/kg/day LOAEL = 7 mg/kg/day based on decreased food consumption andFluazinam Human Health Risk Assessment DP No. D397601

Page 45 of 75 Table A.1. 3. Subchronic, Chronic and Other Toxicity Studies (Technical)

Guideline / Type of Study Study Title/

Classification /Doses MRID Results toxicity

rabbits Acceptable/guideline 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 site s and decreased litter sizes 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

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 tumo rs) in male rats, 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 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 onFluazinam Human Health Risk Assessment DP No. D397601

Page 46 of 75 Table A.1. 3. Subchronic, Chronic and Other Toxicity Studies (Technical)

Guideline / Type of Study Study Title/

Classification /Doses MRID Results

Acceptable/guideline 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 (hep atocellular tumors) 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

femal es

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)

Acceptable/Guideline 42270604 (1989) Negative with and without S9 up to cytotoxic concentrations.

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 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 inFluazinam Human Health Risk Assessment DP No. D397601

Page 47 of 75 Table A.1. 3. Subchronic, Chronic and Other Toxicity Studies (Technical)

Guideline / Type of Study Study Title/

Classification /Doses MRID Results cells) 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.

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 gFluazinam Human Health Risk Assessment DP No. D397601

Page 48 of 75 Table A.1. 3. Subchronic, Chronic and Other Toxicity Studies (Technical)

Guideline / Type of Study Study Title/

Classification /Doses MRID Results 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 s ystemic 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 inclu des the absorbed 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 using a flow through diffusion cell system. A Suspension Concentrate

and a Diluted Suspension Concentrate

were used and the

formulations were 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 respectivel y. 48361515 (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 equiv. 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 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 Main: 0 and 3000 ppm

for 7 days and sacrificed 48361510 (2005) Decreases in T3 and T4 and an increasing trend in TSH in the mainFluazinam Human Health Risk Assessment DP No. D397601

Page 49 of 75 Table A.1. 3. Subchronic, Chronic and Other Toxicity Studies (Technical)

Guideline / Type of Study Study Title/

Classification /Doses MRID Results on Thyroid

Function and its Reversibility in Rats (0 and 222 mg/kg/day)

Recovery: 0 and 3000ppm then reversibility for 7 days

Acceptable/Non

- guide

line 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 PROD, 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.Fluazinam Human Health Risk Assessment DP No. D397601

Page 50 of 75 A. 2. Triple Pack Analysis for Fluazinam

Using the available dermal a bsorption data for fluazinam, a refined dermal dose (RDD) for human skin was calculated. A RDD is calculated from a dermal point of departure (POD) and triple pack dermal absorption data ( in vivo rat, in vitro rat skin, and in vitro human skin) as

follows:

R efined Dermal Dose (R DD ) = Dermal Equivalent Dose (DED) x (animal in vitro human in

vitro )

POD= DED=Dermal NOAEL= 10 mg/kg/day

RDD = 10 mg/kg/day x ( 40.17 % 16.49 %) = 24.4 mg/kg/day

Additional details of the study results supporting these calculations are shown in the table below:Fluazinam Human Health Risk Assessment DP No. D397601

Page 51 of 75 Table A.2. Fluazinam Triple Pack Data

Parameters In Vivo Rat In Vitro Rat In Vitro Human Comments

Study ID MRID No. 48361513

TXR No. 0055733 MRID No.48361514

TXR No. 0055733 MRID No.48361515

TXR No. 0055733 Same formulation products were tested in

all three studies.

Doses are identical in in

vivo and in vitro rat and

human studies

Comparable exposure periods

DED not required since dermal toxicity study

used.

Calculated a Refined Dermal Dose (RDD) to modify the dermal

POD. Test

Material Suspension Concentrate (SC) Diluted Spray Concentrate

(DSC) Suspension Concentrate (SC) Diluted Spray Concentrate

(DSC) Suspension Concentrate (SC) Diluted Spray Concentrate

(DSC) Exposure (hours) 6, 24, and 48 hrs post dose 24 24

Doses tested Low (DSC)

-

24 hrs Hi (SC)

- 24 hrs Low (DSC) Hi (SC) Low (DSC) Hi (SC)

5 μ g/ cm 2 5000 μ g/ cm 2 5 μ g/ cm 2 5000 μ g/ cm 2 5 μ g/ cm 2 5000 μ g/ cm 2

% Dermal Delivery (Absorbed +

absorbable dose)

24 hrs 4.47 0.52 40.17 2.36 16.49 1.61

Risk Values POD = 21 day dermal study

- dermal NOAEL of 10 mg/kg/day (LOAEL =100 mg/kg/day) used

to assess short

- , and intermediate

- term dermal exposure. Long

- term dermal exposure not anticipated

.

Dermal Equivalent Dose (DED) Dermal toxicity study was used for risk assessment (10 mg/kg/day).

Therefore, DED=POD=10mg/kg/day

Refined

Dermal Dose (based on

dermal delivery values) Diluted Suspension Concentrate (5 μ g/ cm 2 )

POD=Dermal NOAEL= 10mg/kg/day DAF ( In Vivo rat)= 4.47%

In vitro human dermal absorption= 16.49%)

In vitro rat dermal absorption= 40.17%

* Refined Dermal Equivalent Dose(RDD)= DED x (animal in vitro/human in vitro)

POD=DED

RDD = 10 mg/kg/day x 40.17% = 24.4 mg/kg/day

16.49%

Information taken from “ Interim Guidance: Estimating Dermal Absorption Factors for Use In Human Health Risk Assessments, Office of Pesticide Programs, June 2010 ”Fluazinam Human Health Risk Assessment DP No. D397601

Page 52 of 75 A.3 HEC Inhalation Calculations

In response to the data requirements for registration 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 exposures), 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 both sexes. The NOAEL is 0.003 mg/L.

RDDR for Fluazinam Because the respired material used in the inhalation study is an aerosol, the RD DR ratio, which incorporates MMAD and σ, is appropriate to use for HEC calculation (table below)

. The “RDDR.exe” software program was used to obtain the RDDR value of 3.1 based on pulmonary

effects as shown below. The inputs for the program are : MMAD =4.7; σ =2.7; BW for CD Rats from study report=150g; S tandard human BW information (i.e., 70 kg ).

Table A.3. HEC Array for Non

- Occupational and Occupational Risk Assessment

Relevant Study LOAEL (mg/ L ) NOAEL

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

Short

- & Intermediate

- Term Occupational Exposure

Inhalation

– Rat (4 week) ( MRID 48571410 ) Pulmonary 0.020 0.003 6 8 5 5 0.486 0.001 3 10 NA

Short

- & Intermediate

- Term Non

- Occupational (Residential) Exposure

Inhalation

– Rat (4 week) ( MRID 48571410 ) Pulmonary 0.020 0.003 6 24 5 7 0.486 0.0 003 3 10 NA

Long Term Exposure: Not appropriate

Key for Array Tables

LOAEL : Lowest observed adverse effect level

Da : Daily animal exposure (hrs/day)

Wa : Weekly animal exposure (days/week)

RRDR : Regional Deposited Dose Ratio

inter : interspecies extrapolation uncertainty factor Dh : Anticipated daily human exposure (hrs/day)

Wh : Anticipated weekly human exposure (days/week)

HC: Human Concentration

HEC : Human Equivalent Concentration

intra : intraspecies variation uncertainty factor

UF : Other uncertainty factor(s)Fluazinam Human Health Risk Assessment DP No. D397601

Page 53 of 75 Calculation of the Human Equivalent Concentration (HEC) and Human Equivalent Dose

Human Equivalent Concentrations

Human Equivalent Doses

Using the HEC s calculated

, a conversion of the inhalation concentration to a dose (mg/L to mg/kg/day) was conducted as follows:

D ose (systemic HEC value) mg/L x A x CF (L/hr/kg) x D (hours) x AF = mg/kg;

Occupational: (0.001 mg/L) x 1 x 6 x 8 x 1 = 0.048 mg/kg/day

Residential : (0.0003 mg/L) x 1 x 6 x 24 x 1 = 0.043 mg/kg/day

Where:

A A bsorption: ratio of deposition and absorption in respiratory tract compared to absorption by the oral route.

CF Conversion Factor: A L/hr/kg factor which accounts for respiratory volume and body weight for a given species and strain (Table 1 of guidance document).

D Duration: Duration of daily animal or human exposure (hours).

AF Activity Factor: Animal default is 1.

When conducting inhalation risk assessments, the magnitude of the UFs applied is dependent on the methodology used to calculate risk. For studies in this risk assessment with inhalation animal data, UFs are based on the RfC methodology developed by the Office of Research and Development (ORD) for the derivation of inhalation reference concentration s (RfCs) and human equivalent concentrations (HECs) for use in MOE calculations. As the RfC methodology takes into consideration the pharmacokinetic (PK) differences but not p harmacodynamic (PD)

differences , the UF for interspecies extrapolation may be reduced to 3 x (to account for the PD

differences between animals and humans which are not accounted for in the RfC methodology ) while the UF for intraspecies variation is retaine d at 10 x . Thus, the UF when using the RfC methodology is customarily 30 x

.

For fluazinam , HED believes exposures can be short

- (1

- 30 days) or intermediate

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

- term exposures are n ot anticipated for fluazinam

.Fluazinam Human Health Risk Assessment DP No. D397601

Page 54 of 75 For the short

- and intermediate

- term scenarios, inhalation data from the 4

- week inhalation rodent study was most appropriate for determining HECs. In the RfC methodology, different HECs can be calculated for the same experimental NOAEL because d ifferent algorithms are used to derive HECs for systemic versus port

- of

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

- of

- entry effect. For fluazinam

, pulmonary effects were observed and

, therefore, only pulmonary HECs were deri ved. 

### Ti me adjustments are traditionally needed for

non

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

non

- occupational exposure are based on the number of hours an individual m ight be at home. Therefore, the mos t conservative estimate of hours spent at home would be 24 hours/day and 7 days/week. In comparison, the average work week for an occupational worker is 8 hours/day and 5 days/week. The HEC array table reflects the time adjustment in the calculations.

M ethodologies for Human

- Equivalent Concentration (HEC) Calculations.

The RfC methodology applies a dosimetric adjustment that takes into consideration not only the differences in ventilation rate (MV) but also the physicochemical properties of the inhaled compound, the type of toxicity observed ( e.g. systemic vs. port of entry) and the pharmacokinetic (PK) but not pharmacodynamic (PD) differences between animals and humans. Based on the EPA’s RfC guidance (1994), the methodology for RfC derivation is an es timate of the quantitative dose

- response assessment of chronic non

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

- specific relationships of exposure concentration to deposited/delivered dose. This adjustment is influenced by the physicochemical properties of the inhaled compound as well as the type of toxicity observed ( e.g. systemic vs. port of entry), and takes into consideration the PK differences between animals

and humans. Though the RfC methodology was developed to estimate toxicity of inhaled chemicals over a lifetime, it can be used for other inhalation exposures ( e.g. acute and short

- term exposures) since the dosimetric adjustment incorporates mechanistic determinants of disposition

t hat can be applied to shorter duration of exposures provided the assumptions underlying the methodology are still valid. These assumptions, in turn, vary depending on the type of toxicity observed. Thus the derivation of a HEC for inhaled gases is descri bed by the following equation:

Where:

POD study : Point of departure identified in the critical toxicology study

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

D anticipated exposure : Anticipated human duration of exposure (hrs/day; days/w k) RGDR: Regional Gas Dose Ratio

Calculations used to estimate the inhalation risk to humans from aerosols are dependent not on the RGDR as for gases, but on the regional deposited dose ratio (RDDR). Inhalation studies using aerosols characterize particu late exposure by defining the particulate diameter (mass median aerodynamic diameter [MMAD]) and the geometric standard deviation (σ g ), which is then used to determine the RDDR. The RDDR is a multiplicative factor used to adjust an observed inhalation par ticulate exposure concentration of an animal (A) to the predictedFluazinam Human Health Risk Assessment DP No. D397601

Page 55 of 75 inhalation particulate exposure concentration for a human (H) that would be associated with the same dose delivered to the region or target tissue.

RDDR

r = (RDD

r

/Normalizing Factor) A

(RDD

r /Normalizing Factor) H

As wit h calculations for gases, the regions and potential target tissues are the three respiratory regions (ET, TB, PU). The RDDR is easily calculated by using a software program designed specifically for computing the RDDR from the MMAD and σ g defined from an aerosol inhalation study. The values for the species

- specific parameters used to calculate the RDDR are provided in the EPA document “Methods for Derivation of Inhalation Reference Concentrations and Application o f Inhalation Dosimetry.”Fluazinam Human Health Risk Assessment DP No. D397601

Page 56 of 75 A. 4

. Hazard Identification and Endpoint Selection

Acute Reference Dose (aRfD)

- Females age 13

- 49

Study Selected: Developmental T oxicity S tudy in R abbits

MRID No: 46578987 Dose and Endpoint for Risk Assessment : NOAEL= 7 mg/kg/day Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability

, 1x FQPA Safety Factor )

Comments about Study/Endpoint/Uncertainty Factors: A developmental toxicity study in

rabbits was used to select the dose and endpoint for establishing the aRfD of 0.07 mg/kg/day. The NOAEL of 7 mg/kg/day and the LOAEL of 12 mg/kg/day were based on increased incidence of total litter resorptions and a possibl e increased incidence of fetal skeletal abnormalities (including k inked tail tip, fused or incompletely ossified sternebrae, and abnormalities of head bones). The skeletal abnormalities observed are considered to be effects that could occur after a single dose of fluazinam; thus, the route and duration of exposure are

a ppropriate for this population.

Acute RfD (females 13

- 49) = = 0.07 mg/kg/day

Acute Reference Dose (aRfD)

- General Population

Study Selected: Acute N eurotoxicity S tudy in R ats
MRID No: 44807210 Dose and Endpoint for Risk Assessment : NOAEL= 50 mg/kg/day Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability

, 1x FQPA Safety Factor )

Study/Endpoint/Uncertainty Factors: An acute oral neurotoxicity study in rats was used to
select the dose an d endpoint for establishing the aRfD of 0.5 mg/kg/day. The NOAEL of 50 mg/kg/day and the LOAEL of 1000 mg/kg/day were based on soft stools and decreased motor activity. I n this study there was a large dose spread between the NOAEL (50 mg/kg/day) and the LOAEL (1000 mg/kg/day) . T he true NOAEL is probably much higher than 50 mg/kg/day. This study, however, provides the best data available for determining an acute RfD for the general population ( including infants and children). T he route and duration of e xposure are appropriate for this population.

Acute RfD (females 13

- 49) = = 0.5 mg/kg/dayFluazinam Human Health Risk Assessment DP No. D397601

Page 57 of 75 Chronic Reference Dose (cRfD)

Studies Selected: A 2

- y ear carcinogenicity study in mice and a 1

- y ear chronic oral study in dogs (co

- critical studies) were selected to establish the cRfD. The 2

- y ear carcinogenicity study in mice, rather than the 1

- year chronic oral study in dogs, was used to establish the RfD because

the treatment

- related effects at the LOAEL in the mouse study wer e related to liver toxicity (the regularly observed target organ for fluazinam in many studies); whereas the effects at the LOAEL in the dog study were unrelated to liver toxicity. The effects seen in the dog study were increased incidence of nasal drynes s in females and increased incidence/severity of gastric lymphoid hyperplasia in males and females

. The NOAELs in the mouse (1.12 mg/kg/day in males and 1.16 mg/kg/day in females) and the dog (1 mg/kg/day in males and females) studies

and the LOAELs in th e mouse (10.72 mg/kg/day in males and 11.72 mg/kg/day in females) and dog (10 mg/kg/day in males and females) studies were similar.

1 st Study: 2

- Year C arcinogenicity S tudy in M ice

MRID No s : 42208405, 44807220, 44807212 Dose and Endpoint for Risk Assessment : NOAEL= 1.12 mg/kg/day Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability

, 1x FQPA Safety Factor )

Study/Endpoint/Uncertainty Factors: A 2

- y ear carcinogenicity study in mice was one of two

co

- critical studies used in selecting the dose and endpoint for establishing the cRfD of 0.11 mg/kg/day. The NOAEL of 1.12 mg/kg/day and the LOAEL of 10.72 mg/kg/day were based on

increased incidences of br own pigmented macrophages in the liver of both sexes, increased incidences of eosinophilic vacuolated hepatocytes in males, and increased liver weights in

females

. The route and duration of exposure are appropriate for this population.

2 nd Study: 1

- Yea r C hronic O ral T oxicity S tudy in D ogs MRID No s : 42270603, 44807219 Dose and Endpoint for Risk Assessment : NOAEL= 1 mg/kg/day Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability

, 1x FQPA safety factor )

Study/Endpoin t/Uncertainty Factors: A 1

- y ear chronic oral toxicity study in dogs was one of

two co

- critical studies used in selecting the dose and endpoint for establishing the cRfD of 0.11 mg/kg/day. The NOAEL of 1 mg/kg/day and the LOAEL of 10 mg/kg/day were based on marginal increases in the incidence of nasal dryness in females and the incidence/severity of gastric lymphoid hyperplasia in both sexes. The route and duration of exposure are appropriate for this population.

Chronic RfD = = 0.011 mg/kg/day

Comments: A 2

- year chronic feeding/carcinogenicity study in rats (MRID 42248620, 44807223) was also considered for establishing the cRfD based on a lower NOAEL of 0.38 mg/kg/day. The next highest dose level tested in this study was 3.8 mg/kg/day in males and 4.9Fluazinam Human Health Risk Assessment DP No. D397601

Page 58 of 75 mg/kg/day in females (a 10 fold higher dose). A second 2

- year chronic feeding study in rats (MRID s 44839901 and 44807213) was subsequently performed with 2 intermediate dose levels. The doses used in the study were 0, 1.0, 1.9, and 3.9 mg/kg/day for male s; 0, 1.2, 2.4, and 4.9 mg/kg/day for females. The NOAEL observed in the second study was 1.9 mg/kg/day for males and 4.9 mg/kg/day for females, which is higher than the NOAEL (1.1 mg/kg/day) selected for establishing the chronic RfD. Therefore, this stu dy was not chosen for risk assessment.

Dermal Exposure (Short

- , Intermediate

- Term)

Stud ies Selected: 21

- Day D ermal T oxicity S tudy in R ats

, In Vivo Dermal Penetration Study in Rats, and In Vitro Dermal Penetration Study in Human and Rat Skin

MRID No s : 42270602 , 48361513

- 15 Dose and Endpoint for Risk Assessment : Refined human dermal NOAEL= 24.4 mg/kg/day Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability

, 1x FQPA Safety Factor )

Study/Endpoint/Uncertainty Factors: A 21

- day dermal toxicity study in rats was used , along with dermal absorption data to refine the point of departure for short

- and intermediate

- term
dermal risk assessment

. In the dermal toxicity study, t he NOAEL of 10 mg/kg/day and the

LOAEL of 100 mg/ kg/day were based on increased aspartate aminotransferase ( AST ) and

increased cholesterol levels in males. The route and duration of exposure are appropriate for this population. A refined dermal dose of 24.4 mg/kg/day was calculated considering data fr om the available dermal penetration studies in human and rat skin. The data suggests that human skin is less permeable than rat skin (see A.2).

Comments: Developmental effects were noted in developmental toxicity studies at ≥ 12 mg/kg/day . Although t he RDD is 24 mg/kg/day, it is based on an oral NOAEL that is lower than the dose at which developmental effects were seen. The comparable dermal equivalent dose (DED) for the developmental study, using the developmental NOAEL of 7 mg/kg/day and a

DAF of 4 .47% is 155 mg/kg/day. Therefore, the RDD is considered protective of potential developmental effects. Additionally, the RDD is protective of immunotoxic effects seen in an immunotoxicity study in mice at the LOAEL of 231 mg/kg/day.

Inhalation Exposure (Short

- , Intermediate

- Term)

Study Selected: 4 Week Inhalation Study in Rats (test material: Frowncide WP, containing 51.9% fluazinam)

MRID No: 48571410 Dose and Endpoint for Risk Assessment : NOAEL= 0.003 mg/kg/day Uncertainty Factor: 30x (3x interspecies extrapolation, 10x intraspecies variability, 1x FQPA Safety Factor ) Inhalation absorption factor (IAF): 100%

Study/Endpoint/Uncertainty Factors: A 4 week inhalation study in rats was used to select the dose and endpoint for short

- and intermediate

- term inhalation exposure. The NOAEL of 0.003 mg/L and the LOAEL of 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 wereFluazinam Human Health Risk Assessment DP No. D397601

Page 59 of 75 also seen, along with lung histopathology (alveolar macrophages, peribronchiolar proliferation)

in both sexes.

Occupational and Residential Long

- Term Dermal and Inhalation Exposures

Based on the proposed use pattern for fluazinam , long

- term dermal and inhalation exposures are not anticipated.Fluazinam Human Health Risk Assessment DP No. D397601

Page 60 of 75 Appendix B. International Residue Limit Status Sheet

Table B.1. Summary of U

. S

. and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 2 Codex [40 CFR § 180.574 (a)(1)] Plant: fluazinam ( 3

- chloro

- N

- [3

- chloro

- 2,6

- dinitro

- 4

- (trifluoro

methyl)phenyl]

- 5

- (trifluoromethyl)

- 2

- pyridinamine ) 3

- chloro

- N

- [3

- chloro

- 2,6

- dinitro

- 4

- (trifluoromethyl)phenyl]

- 5

- (trifluoromethyl)

- 2

- pyridinamine None

Commodit

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

US Canada Mexico 2 Codex

Apple 2.0 Apple, wet pomace 5.0

Bushberry subgroup 13

- 07B 7.0 7.0 aronia berries, buffalo currants, Chilean guavas, currants, elderberries, European barberries, gooseberries, highbush blueberries highbush cranberries honeysuckle, huckleberries, jostaberries, lingonberries, lowbush blueberries, native currants, salal berries, saskatoon berries (juneberries), sea buckthorn
Carrot, roots 0.70 Ginseng 4.5
Lettuce, head 0.02
Lettuce, leaf 2.0 Onion, bulb, subgroup 3

- 07A 0.20
Pea and bean, dried shelled, except soybean, subgroup 6C,

except pea 0.02 0.02 Dry (adzuki beans, beans, blackeyed peas, broad beans, catjang seeds, chickpeas, cowpea seed, guar seeds, kidney beans, lablab beans, lima beans, moth beans, mung beans, navy beans, pink beans, pinto beans, rice beans, southern peas, tepary beans, urd beans); grain lupin
Pea and bean, succulent shelled, subgroup 6B, except pea 0.04

Peanut 0.02

Potato 0.02 0.02 Turnip, greens 0.01 Vegetable, Brassica leafy, group

5 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 spinach, napa Chinese cabbages, rape greens Vegetable, legume, edible

podded, subgroup 6A, except

pea 0.10 0.1edible podded ( jackbeans, moth beans, runner beans, snap beans, soybeans, sword beans, wax beans, yardlong beans) Proposed MRLs

Melon subgroup 9A 0.08 Pepper/Eggplant Subgroup 8

- 10B 0.10

Soybean, Seed 0.01 0.1 edible

- podded soybeans Soybean, Hulls 0.05Fluazinam Human Health Risk Assessment DP No. D397601

Page 61 of 75 Table B.1. Summary of U

. S

. and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 2 Codex [40 CFR §180.574(a)(2)]
fluazinam and its metabolite AMGT (3

- [[4

- amino

- 3

- [[3

- chloro

- 5

- (trifluoromethyl)

- 2

- pyridinyl]amino]

- 2

- nitro

- 6

- (trifluoromethyl) phenyl]thio]

- 2

- (beta

- D

- glucopyranosyloxy) propionic acid). Same as above None

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

US Canada Mexico 2 Codex

Grape, wine 1 3.0 [40 CFR §180.574(a)(3)] Canada Mexico 2 Codex fluazinam, AMPA (2

- (6

- amino

- 3

- chloro

- α,α,α

- trifluoro

- 2

- nitro

- p

toluidino)

- 3

- chloro

- 5

- (trifluoromethyl) pyridine), DAPA (3

- chloro

- 2

- (2,6

- diamino

- 3

- chloro

α,α,α.

- trifluoro

- p

- toluidino)

- 5

- (trifluoromethyl)pyridine), and their sulfamate conjugates. Same as above None

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

US Canada Mexico 2 Codex

Cattle, fat 0.05 Cattle, meat byproducts 0.05
Goat, fat 0.05 Goat, meat byproducts 0.05
Horse, fat 0.05 Horse, meat byproducts 0.05 Sheep, fat 0.05 Sheep, meat byproducts 0.05 Proposed MRLs

Milk 0.01
Meat of Cattle, Goat, Horse, and Sheep 0.03

Meat Byproducts of Cattle, Goat, Horse, and Sheep 0.10

Completed: : M. Negussie; 08/03/2012

1 No US registration as of March 15, 2002 (grape, wine)

. 2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.Fluazinam Human Health Risk Assessment DP No. D397601

Page 62 of 75 Appendix C

. Fluazinam Physical/Chemical Properties

Table B.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, 482Fluazinam Human Health Risk Assessment DP No. D397601

Page 63 of 75 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 64 of 75 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 DegradateFluazinam Human Health Risk Assessment DP No. D397601

Page 65 of 75 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 DegradateFluazinam Human Health Risk Assessment DP No. D397601

Page 66 of 75 Appendix F.

Occupational Exposure and Risk Assessment to Support Registration Review

With the submission of the two toxicity studies required during registration review, as well as additional conditional data requested in conjunction with previously evaluated new use petitions,

t he toxicity and exposure database s for fluazinam are complete . Therefore, the new use

aggr egate human health risk assessment, in combination with the information presented below, serves as HED’s risk assessment to support registration review. The new toxicity data have been evaluated and incorporated into the hazard characterization, endpoint and dose selection, and FQPA Safety Factor determination.

The residue data submitted as a condition of registration are acceptable, and have been incorporated in to the dietary exposure and risk estimates, which are not of concern when both existing and p roposed uses are taken into consideration. In addition, the largely unrefined dietary assessments incorporated high end modeled estimates of drinking water exposure.

The only potential residential exposure scenario results from dermal contact with treat ed golf course turf, and no dermal risks of concern were identified; the most recent policies and procedures for assessing residential exposure were used to estimate post

- application risk for youth and adult golfers. When these exposures were aggregated w ith background exposure from food and water, there were no aggregate risks of concern.

In 2009 HED consulted the OPP Incident Data System (IDS) for poisoning incident data on fluazinam to identify potential patterns on the extent and severity of the healt h effects attributed to fluazinam exposure. The IDS includes reports of incidents from various sources, including mandatory Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Section 6 (a) (2) reports from registrants, other federal and state heal th and environmental agencies and individual consumers. HED concluded that because of the relatively low volume of incidents , and the lack

of moderate or severe health effects potentially related to fluazinam exposure, no further investigation was require d to support the preliminary risk assessment.

There were 5 major changes that required HED to reassess occupational exposure and risk for the existing uses of fluazinam, for the purpose of registration review:

1) The inhalation endpoint changed from systemi c liver effects to the portal

- of

- entry effects for the respiratory system. Based on the results of the new inhalation study, the Reference Concentration methodology developed by the Office of Research and Development (ORD) was used to calculate human equi valent concentrations (HECs) and doses (HEDs) for inhalation risk assessment ; 2) Since the effects observed via the inhalation route are different from the effects observed following dermal dosing, dermal and inhalation exposures are no longer combined in the

risk assessment ; 3) HED has updated the surrogate unit exposures for occupational handlers, which have been incorporated in to the risk assessment for occupational handlers ( see Occupational Pesticide Handler Unit Exposure Surrogate Reference Table )

. No changes to the labelFluazinam Human Health Risk Assessment DP No. D397601

Page 67 of 75 PPE , or other types of mitigation, are required in conjunction with the revised risk

estimates ; 4) HED has used an updated approach to incorporation of dislodgeable foliar residue (DFR)

data ( i.e., use of predicted vs. measured day 0 r esidue values ) . Further, HED has revised the post

- application exposure and risk assessment to reflect the use of the available DFR data to assess all registered crops; and 5) HED has incorporated updated transfer coefficients to assess post

- application exposure

associated with re

- entry activities such as harvesting, thinning, weeding, and scouting. No label changes or mitigation are needed in conjunction with the revised post

application exposure and risk assessment.

A summary of the occupational scenarios assessed, as well as the updated handler and post

application exposure and risk estimates for the registered uses

, is presented below. The detailed assessment, including ass umptions used for DFR studies, is presented in Z. Figueroa ( D 397723

, 9/7/2012)

.

Table F. 1. Summary of Occupational Exposure Scenarios for Fluazinam Registered Uses

EPA Reg.

No. Crop Application Equipment Max. rate/appl. (lb ai/A) No. appl./season

(Re

- Treatment Interval)

71512

- 1

O mega 500F (40% ai; 4.17

lb a.i. /ga l ) Dry B ean & S ucculent

Bean Crop

Edible

- podded Legume Vegetables Groundboom 0.44 2 (7 days)

Brassica vegetables (pre

- transplant soil

spray band or bed ; post

- transplant soil

drench ) Groundboom 1.36 (0.024 lb ai/gal) 1

- 2 (none)

B ushberry Groundboom, airblast 0.65 6 (7 days)

Carrots Groundboom, aerial, chemigation 0.52 4 (7 days)

Lettuce Groundboom, a erial chemigation 0.78 1 (none)

Onions Groundboom, aerial, chemigation 0.52 6 (7 days)

Apples A erial

, chemigation , airblast 0.45 10 (7 days)

G inseng Groundboom 0.78 4 (7 days)

P eanut s Groundboom 0.78 2 (21 days)

P otato es Groundboom, a erial chemigation 0.26 7 (7 days)

CO 070003

O mega 500F P otato es

seed pieces (at

- plant in

- furrow over seed piece) Groundboom 1.8 1 (none)

71512

- 20

Fluazinam

Turf Fungicide (40% ai; X) Turf (Golf Course) Groundboom, handheld (b ackpack , m anually

- pressurized

h andwand , and m echanically

pressurized h andgun s prayer s) 0.70 12 (14 days)Fluazinam Human Health Risk Assessment DP No. D397601

Page 68 of 75 Occupational Handler Exposure and Risk Estimates

Based on the registered use patterns and current labeling, and the types of equipment and techniques use for application, the following occupational handler exposures are expected from the registered uses. The quantitative exposure/risk assessment develop ed for occupational handlers is based on the following scenarios:

• Mixing/Loading Liquids for Groundboom Application,

• Mixing/Loading Liquids for Aerial Application,

• Mixing/Loading Liquids for Chemigation,

• Mixing/Loading Liquids for Airblast,

• Applying Sprays with Groundboom Equipment,

• Applying Sprays with Aerial Equipment,

• Applying Sprays with Airblast,

• Flagging for Aerial Applications,

• Mix er

/Load er/Applicator for Mechanically

- P ressurized Handgun Sprayer,

• Mix er

/Load er/Applicator for Backpack Sprayer, and

• Mix er

/Load er/Applicator for Manually

- pressurized Handwand

No handler exposures are expected from applying sprays via chemigation systems. The maximum single application rate on the registered label was used to assess all handler e xposure scenarios.

No data on the number of exposure days per year were provided. Based on the registered use patterns and directions, short

- and intermediate

- term exposures are expected for handlers. As

short

- and intermediate

- term endpoints and PODs a re the same for each exposure route, only

short

- term handler exposures were estimated . The estimates are considered to be protective of

intermediate

- term exposure and risk. Long

- te rm exposures are not expected.

Table F.2 presents the short

- term dermal a nd inhalation risk estimates for occupational handlers.

T he occupational handler scenarios for the existing uses resulted in estimated MOEs greater than

the respective levels of concern (dermal LOC = 100; inhalation LOC = 30) at some level of PPE (e.g., c hemical

- resistant gloves, double l ayer clothing with chemical

- resistant h at ) and assuming

use of engineering controls (i.e., en closed cockpit) for aerial applications

. Based on the risk estimates shown below, no additional PPE or other mitigation is neede d on registered label s

.Fluazinam Human Health Risk Assessment DP No. D397601

Page 69 of 75 Table F.2. Short

- Term Occupational Handler Exposure and Risk Estimates for Fluazinam Registered Uses

.

Exposure Scenario Crop or Target Dermal Unit Exposure

( μ g/lb ai) 1 Inhalation Unit

Exposure ( μ g/lb ai) 1 Maximum

Application

Rate 2 Area

Treated or Amount

Handled 3 Dermal Inhalation

Mitigation Level Mitigation Level Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7

Mixer/Loader

Liquids for Groundboom Applications

(AHETF) Turf (Golf Course) 220

(Baseline) 0.219

(No respirator) 0.70 lb ai/A 40 0.0770 320 0.000077 620

Potatoes
(Spray) 220

(Baseline) 0.219

(No respirator) 0.26 lb ai/A 80 0.0573 430 0.000057 84 0

Potatoes
(at plant in

- furrow over seed piece) 37.6

(Gloves) 0.219

(No respirator) 1.8 lb ai A 80 0.0676 360 0.00034 120

Dry Bean & Succulent Bean Crop,

Edible

- podded Legume Vegetable 220

(Baseline) 0.219

(No respirator) 0.4 4 lb ai/A 80 0.0968 250 0.0000964 500

Carrots, Onions 220

(Baseline) 0.219

(No respirator) 0.52 lb ai/A 80 0.114 0 210 0.000114 420

Bushberry 220

(Baseline) 0.219

(No respirator) 0.65 lb ai/A 80 0.143 0 170 0.000143 340

Ginseng, Peanut s, Lettuce (Head and Leaf) 220

(Baseline) 0.219

(No respirator) 0.78 lb ai/A 80 0.171 0 140 0.000171 280

Brassica (Cole) Leafy Vegetables 37.6

(Gloves ) 0.219

(No respirator) 1.36 lb ai/A 80 0.0511 480 0.000298 160

Liquids for Aerial Application

(AHETF) Potatoes 220

(Baseline) 0.219

(No respirator) 0.26 lb ai/A 350 0.250 100 0.000249 190

Apples 37.6

(Gloves ) 0.219

(No respirator) 0.45 lb ai/A 350 0.074 330 0.000431 110

Carrots, Onions 37.6

(Gloves ) 0.219

(No respirator) 0.52 lb ai/A 350 0.085 290 0.000499 100

Lettuce (Head and Leaf) 37.6

(Gloves ) 0.219

(No respirator) 0. 78 lb ai/A 350 0.129 190 0.000748 60

Liquids for Chemigation

(AHETF) Potatoes 220

(Baseline) 0.219

(No respirator) 0.26 lb ai/A 350 0.250 100 0.000249 190Fluazinam Human Health Risk Assessment DP No. D397601

Page 70 of 75 Table F.2. Short

- Term Occupational Handler Exposure and Risk Estimates for Fluazinam Registered Uses

.

Exposure Scenario Crop or Target Dermal Unit Exposure

( μ g/lb ai) 1 Inhalation Unit

Exposure ( μ g/lb ai) 1 Maximum

Application

Rate 2 Area

Treated or Amount

Handled 3 Dermal Inhalation

Mitigation Level Mitigation Level Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7

Appl es 37.6

(Gloves ) 0.219

(No respirator) 0.45 lb ai/A 350 0.074 330 0.000431 110

Carrots, Onions 37.6

(Gloves ) 0.219

(No respirator) 0.52 lb ai/A 350 0.085 290 0.000499 100

Lettuce (Head and Leaf) 37.6

(Gloves ) 0.219

(No respirator) 0. 78 lb ai/A 350 0.1 29 190 0.000 748 60

Liquids for Airblast (AHETF) Apples 220

(Baseline) 0.219

(No respirator) 0.45 lb ai/A 40 0.0495 490 0.0000493 970

Bushberry 220

(Baseline) 0.219

(No respirator) 0.65 lb ai/A 40 0.0715 340 0.0000711 680

Applicato r

Sprays for Groundboom Applications

(AHETF) Turf (Golf Course) 78.6

(Baseline) 0.34

(No respirator) 0.70 lb ai/A 40 0.02751 890 0.000119 400

Potatoes
(Spray Treatment) 78.6

(Baseline) 0.34

(No respirator) 0.26 lb ai/A 80 0.0204 1

, 200 0.0000884 540

Potatoes
(at plant in

- furrow over seed piece) 78.6

(Baseline) 0.34

(No respirator) 1.8 lb ai/A 80 0.141 170 0.000613 80

Dry Bean & Succulent Bean Crop,

Edible

- podded Legume Vegetable 78.6

(Baseline) 0.34

(No respirator) 0.4 4 lb ai/A 80 0.0346 710 0.00015 320

Carrots, Onions 78.6

(Baseline) 0.34

(No respirator) 0.52 lb ai/A 80 0.0409 600 0.000176 270

Bushberry 78.6

(Baseline) 0.34

(No respirator) 0.65 lb ai/A 80 0.0511 480 0.000221 220

Ginseng, Peanuts

, Lettuce (Head and Leaf) 78.6

(Baseline) 0.34

(No respirator) 0.78 lb ai/A 80 0.061 3 400 0.000265 180

Brassica (Cole) Leafy Vegetables 78.6

(Baseline) 0.34

(No respirator) 1.36 lb ai/A 80 0.1070 230 0.000463 100

Sprays for Aerial Application Potatoes 5
(Engineering Controls

- 0.068
(Engineering Controls

- 0.26 lb ai/A 350 0.00569 4

, 300 0.0000774 620Fluazinam Human Health Risk Assessment DP No. D397601

Page 71 of 75 Table F.2. Short

- Term Occupational Handler Exposure and Risk Estimates for Fluazinam Registered Uses

.

Exposure Scenario Crop or Target Dermal Unit Exposure

( μ g/lb ai) 1 Inhalation Unit

Exposure ( μ g/lb ai) 1 Maximum

Application

Rate 2 Area

Treated or Amount

Handled 3 Dermal Inhalation

Mitigation Level Mitigation Level Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7

(AHETF) Enclosed cockpit) Enclosed cockpit)

Apples 5

(Engineering Controls

- Enclosed cockpit) 0.068

(Engineering Controls

- Enclosed cockpit) 0.45 lb ai/A 350 0.00985 2,500 0.000134 360

Carrots, Onions 5

(Engineering Controls

- Enclosed cockpit) 0.068

(Engineering Controls

- Enclosed cockpit) 0.52 lb ai/A 350 0.01140 2,100 0.000155 310

Lettuce (Head and Leaf) 5

(Engineering Controls

- Enclosed cockpit) 0.068

(Engineering Controls

- Enclosed cockpit) 0. 78 lb ai/A 350 0.0171 1,400 0.0002 33 210

Sprays fo r Airblast Applications

( AHETF ) Apples 1,480
(Double Layer +

Chemical

- resistant Hat, Gloves) 4.71

(No respirator) 0.45 lb ai/A 40 0.333 500 0.00106 50

Bushberr y 1,480

(Double Layer +

Chemical

- resistant Hat, Gloves) 4.71

(No respirator) 0.65 lb ai/A 40 0.481 350 0.00153 30

Flagger

Flagging for Aerial Applications

(PHED) Potatoes 11

(Baseline) 0.35

(No respirator) 0.26 lb ai/A 350 0.0125 2

, 000 0.000399 120

Apples 11

(Baseline) 0.35

(No respirator) 0.45 lb ai/A 350 0.0216 1,100 0.000689 70

Carrots, Onions 11

(Baseline) 0.35

(No respirator) 0.52 lb ai/A 350 0.025 0 980 0.000796 60

Lettuce (Head and Leaf) 11

(Baseline) 0.35

(No respirator) 0. 78 lb ai/A 350 0.0375 650 0.0012 40

Mixer/Loader/Applicator

Backpack Sprayer

(MRID 44339801) Turf, G olf C ourse 826 0

(Baseline) 2

. 58

(Baseline) 0.0175 lb ai/gal 5 gals 0.00903 2,700 0.00000282 17,000

Manually

- pressurized

Handwand

(PHED) Landscape, Outdoor

A reas 100 000

(Baseline) 30

(Baseline) 0.0175 lb ai/gal 5 gals 0.109 220 0.0000328 1,500

Mechanically

- pressurized Turf, Golf Courses 114 0 1

. 9 0.70 lb ai/A 5 A 0.050 490 0.0000831 580Fluazinam Human Health Risk Assessment DP No. D397601

Page 72 of 75 Table F.2. Short

- Term Occupational Handler Exposure and Risk Estimates for Fluazinam Registered Uses

.

Exposure Scenario Crop or Target Dermal Unit Exposure

( μ g/lb ai) 1 Inhalation Unit

Exposure ( μ g/lb ai) 1 Maximum

Application

Rate 2 Area

Treated or Amount

Handled 3 Dermal Inhalation

Mitigation Level Mitigation Level Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7

Handgun Sprayer (Liquids)

(ORETF) (Broadcast) (Baseline) (Baseline)

Mechanically

- pressurized Handgun Sprayer (Liquids)

( PHED ) Brassica (Cole) Leafy

Vegetables (Soil Drench) 390

( Single Layer, Gloves) 3.9

( No respirator) 0.024 lb ai/gal 1,000 gal 0.117 210 0.00117 40

1 Based on “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March, 2012); includes data from PHED/ORETF/AHETF (level of mitigation: Baseline, Gloves, Eng. Controls).

2 Based on the registered labels (EPA Reg. No. 71512

- 1 and EPA Reg. No. 71512

- 20).

3 Exposure Science Advisory Council Po licy #9.1.

4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/A) x Area Treated o r Amount Handled (A/day or gal/day)/BW (80 kg).

5 Dermal MOE = Dermal NOAEL (24.4 mg/kg/day)/Dermal Dose (mg/kg/day); LOC = 100.

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

7 Inhalat ion MOE = Inhalation NOAEL (0.048 mg/kg/day)/ Inhalation Dose (mg/kg/day); LOC = 30.Fluazinam Human Health Risk Assessment DP No. D397601

Page 73 of 75 Occupational Post

- A pplication Exposure and Risk Estimates

Post

- Application Inhalation

Based on the Agency ’ s current practices, a quantitative non

- can cer occupational post

- application inhalation exposure assessment for the existing uses i s not being performed for fluazinam at this time; handler inhalation exposure estimates are considered to be protective of occupational post

application inhalation expo sure scenarios. If new policies or procedures are put into place, the Agency m ight revisit the need for a quantitative occupational post

- application inhalation exposure assessment for fluazinam.

Post

- Application Dermal

S hort

- and intermediate

- term derm al exposures are expected for workers conducting post

application activities on agricultural crops. The standard values recommended for use in predicting post

- application exposure that are used in this assessment, known as “transfer

coefficients

, ” are pre sented in the ExpoSAC Policy 3 (http://www.epa.gov/pesticides/science/exposac_policy3.pdf), which, along with additional information about the ARTF data, can be found at: http://www.epa.gov/pesticides/science/post

app

- exposure

- data.html

.

Chemical

- specific dislodgeable foliar residue (DFR) studies on apples (MRID 45584203), potatoes (MRID 45584202), and peanuts (MRID 45584201) were submitted and reviewed by

HED. The stud ies demonstrated that dislodgeable foliar residue values declined over time.

HED concluded that the peanut DFR data would serve as the best surrogate to assess post

application exposure for all crops when no crop

- specific DFR data w ere available based on information about the study conditions, region of use, use pattern, etc. (M. Collantes, 03/18/2008, D3 49315). Therefore, the peanut DFR data w ere used as a surrogate t o assess dermal post

- application exposure resulting from application of fluazinam on ginseng, B rassica (cole) leafy vegetables, succulent edible podded and dry beans, carrots, bushberr ies , lettuce, onions, and peanuts. The apple and potato DFR studies were used to assess post

- application exposure for the respective crops, and a chemical

- specific turf

- transferable residue (TTR) study was used to assess dermal exposure to treated turf.

Maximum single application rates were used b ased on the registered labels (EPA Reg. No.

#71512

- 1 and EPA Reg. No. #71512

- 20). Residue valu es were adjusted by application rate, when applicable.

Post

- application Exposure and Risk Estimate s

– Agricultural Crops

A summary of the post

- application exposure and risk estimates for the registered agricultural uses is provided in Table F

. 3

.Fluazinam Human Health Risk Assessment DP No. D397601

Page 74 of 75 T able F

. 3 . Short

- term Occupational Post

- application Exposure and Risk Estimates for Fluazinam Registered Uses

.
Crop/Site Activities DFR 1
( μg/cm 2 ) Day 0 Dose 2

(mg/kg/day) Day 0 MOE 3 Day at which MOE ≥ LOC

DFR Data on Treated Peanuts (MRID 45584201)

Brassica (Cole) Leafy Vegetables Transplanting 1.70 0.0391 620 0

Scouting 1.70 0.0561 430 0 Hand Weeding 1.70 0.2380 100 0 Irrigation (hand set) 1.36 0.2580 100 2

Ginseng Weeding, Hand 0.975 0.0068 3,600 0

Scouting 0.975 0.0205 1,200 0 Harvesting, Hand 0.975 0.1070 230 0 Irrigation (hand set) 0.975 0.1850 130 0

Succulent Edible Podded and Dry

Beans Hand weeding 0.550 0.00385 6,300 0

Scouting 0.550 0.01160 2,100 0 Scouting 0.550 0.06050 400 0 Irrigation (hand set) 0.550 0.10500 230 0

Carrots Hand Weeding 0.650 0.00455 5,400 0

Scouting 0.650 0.01370 1,800 0 Harvesting, Hand 0.650 0.0715 340 0 Irrigation (hand set) 0.650 0.1240 200 0

Bushberry Hand Weeding 0.812 0.00568 4,300 0

Transplanting 0.812 0.01870 1,300 0 Harvesting, Hand 0.812 0.08930 270 0 Irrigation (hand set) 0.812 0.1540 160 0

Lettuce Hand Weeding 0.975 0.00683 3,600 0

Scouting 0.975 0.02050 1,200 0 Transplanting 0.975 0.02240 1,100 0 Harvesting, Hand 0.975 0.10700 230 0 Irrigation (hand set) 0.975 0.18500 130 0

Onions Scouting 0.650 0.0215 1,100 0

Hand Weeding 0.650 0.0910 270 0 Irrigation (hand set) 0.650 0.1240 200 0 Weeding, Hand 0.582 0.2440 100 1

Peanuts Hand Weeding 0.975 0.0068 3,600 0

Scouting 0.975 0.0205 1,200 0 Irrigation (hand set) 0.975 0.1850 130 0

DFR Data on Potatoes (MRID 45584202)

Potatoes Hand Weeding 0.232 0.00162 15,000 0

Scouting 0.232 0.00405 5,000 0 Irrigation (hand set) 0.232 0.00441 550 0

DFR Data on Apple Trees (MRID 45584203)

Apples Orchard

M aintenance

, Propping, Hand Weeding, Thinning Fruit, Bird Control 0.017 0.00017 140,000 0

Transplanting 0.017 0.00039 62,000 0 Scouting, Hand Pruning, Training 0.017 0.00099 25,000 0

Harvesting, Hand 0.017 0.00238 10,000 0 Thinning, Fruit 0.017 0.00061 4,000 0

1

. Dislodgeable Foliar Residue (DFR) from Treated Peanuts = 0.987 μ g/cm 2 is based on predicted day 0 residue value calculated from chemical

specific data (MRID No. 455842 01) and then adjusted by application rate. Dislodgeable Foliar Residue (DFR) from Potatoes = 0.429 μ g/cm 2

is based on predicted day 0 residue value calculated from chemical

- specific data (MRID No. 455842 0 2 ) and then adjusted by application rate. Dislodge able Foliar Residue (DFR) from Apples = 0.0471 μ g/cm 2 is based on predicted day 0 residue value calculated from chemical

- specific data (MRID No. 455842 0 3 ) and then adjusted by application rate. 2. Daily Dermal Dose = [DFR (μg/cm 2 ) x TC x 0.001 mg/μg x 8 hrs/day] BW ( 80 kg). 3. MOE = NOAEL (24.4 mg /kg/day) / Daily Dermal Dose.Fluazinam Human Health Risk Assessment DP No. D397601

Page 75 of 75 Short

- and intermediate

- term post

- application risk estimates were not a concern on day 0 ( i.e., 12 hours following application) for most activities. Ba sed on HED’s post

- application exposure calculations, the following crops reached a dermal MOE of 100 within 48 hours of applicati o n
, which is in accordance with the current label REI :

• Onions resulted in a MOE of 100 or greater within 1 day (24 hours after application ) for hand weeding activities;

• Brassica ( c ole) l eafy v egetables resulted in a n MOE of 100 or greater within 2 days (48 hours after application) for irrigation (hand set) activities.

The REI specified on the proposed label is based on the acute toxicity of f luazinam technical

material

. Fluazinam is classified as Toxicity Category I for eye irritation. Under the Worker Protection Standard for Agricultural Pesticides, active ingredient s classified as acute toxicity category I for any of these routes are assigned a 48

- hour REI. Based on the acute toxicity profile of fluazinam, the 48

- hour REI specified on the OMEGA ® 500F label is appropriate to protect agricultural workers from post

- application exposures to fluazinam.

Dermal Post

- appli cation Exposure and Risk Estimate

– Turf (Golf Course)

Dermal post

- application exposure for turf was previously assessed ( D398546

, Z. Figueroa

, 2/7/2012). A summary of the post

- application exposure and risk estimate for turf is provided in

Table F

. 4

. The p ost

- application dermal exposure estimate resulted in a n MOE greater than 100

and was not of concern.

Table F

. 4 . Short

- Term Occupational Post

- application Exposure and Risk Estimate Using Chemical

- Specific

Data for Fluazinam on Turf (Golf Course)

Crop/Site Activities TTR 1
( μg/cm 2 ) Day 0 Dose 2

(mg/kg/day) Day 0 MOE 3 Day X at which MOE ≥

LOC

Turf/Sod Maintenance,

Harvesting, Slab
Transplanting/
Planting 0.0865 0.0320 760 0

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

- specific data (MRID No. 48361527).

2. Chemical

- Specific Dermal Dose = [TTR ( μg/cm 2 ) x TC (cm 2 /hr) x 0.001 mg/ug x 8 hrs/day] BW (80 kg).

3. Chemical

- Specific MOE = NOAEL (24.4 mg/kg/day)/Dermal Dose (mg /kg/day); LOC = 100.

The Worker Protection Standard (WPS) requirements, such as REI, apply when this product is used on agricultural crops

. However, t urf grasses on golf cours es are not within the scope of WPS. Therefore, HED concurs with the non

- agricultural use requirement listed on the label

which states: “Do not enter or allow others to enter the area until treatments have dried.” The statement included in the proposed la bel is considered to be appropriate.