Document ID: EPA-HQ-OPP-2012-0009-0012
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-11-07T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                               
                                                                               
                                                      OFFICE OF CHEMICAL SAFETY
\* MERGEFORMAT
                                                       AND POLLUTION PREVENTION

MEMORANDUM

Date:  		9/10/2012
SUBJECT:	Fluazinam.  Human Health Risk Assessment to Support New Uses on Soybeans, the Melon Subgroup (9-A), and the Pepper/Eggplant Subgroup (8-10B), and to Support Registration Review 
 
PC Code:  129098 
DP Barcodes:  D397601, D398687, D398690 
Decision Nos.:  459601, 459565, 459568 
Registration Nos.:  71512-1, 71512-20
Petition Nos.:  1E7959, 2F7977, 8E7506 
Regulatory Action:  Section 3 Registration and Registration Review 
Risk Assessment Type:  Single Chemical Aggregate
Case No.:  7013 
TXR No.:  NA 
CAS No.: 79622-59-6
MRID No.:  NA
40 CFR:  §180.574

FROM:	Douglas A. Dotson, Ph.D., Chemist
		Karlyn Middleton, M.S., Toxicologist
		Zaida Figueroa, M.S., Industrial Hygienist
		Registration Action Branch II
		Health Effects Division (7509P)

THROUGH:	Ed Scollon, Ph.D., Toxicologist
		Dennis McNeilly, Chemist
		Margarita Collantes, M.S., Biologist
		Christina Swartz, Branch Chief
		Registration Action Branch II
		Health Effects Division (7509P)
		
TO:		Andrew Ertman/Barbara Madden, RM Team 5, RIMUERB
		Dominic Schuler/Tony Kish, PM Team 22, Fungicide Branch
		Registration Division (7505P)
			and
		Steven Snyderman/Avivah Jakob, RMIB3
		Pesticide Re-evaluation Division (7508P)

The Health Effects Division (HED) was requested to evaluate tolerance petitions associated with new uses proposed by ISK Biosciences (soybeans) and the Interregional Research Project No. 4 (IR-4, melons and peppers).  The attached human health risk assessment addresses dietary, aggregate and occupational exposure and risk associated with the proposed uses of fluazinam, and there are no risks of concern.

Additional toxicity data required for fluazinam in conjunction with Registration Review have been submitted, evaluated and incorporated into the current hazard characterization, endpoint and dose selection, and Food Quality Protection Act (FQPA) Safety Factor determination.  All of the data HED required to support Registration Review have been submitted and the hazard and exposure databases are complete.

In order to complete a preliminary risk assessment (PRA) for Registration Review, HED has incorporated the new information into the aggregate human health risk assessment for fluazinam.  There are no dietary, residential or aggregate risks of concern associated with the existing and proposed uses.  Further, HED has reassessed occupational exposure and risk for the existing uses of fluazinam, using the most updated policies, surrogate data, transfer coefficients, and chemical-specific data submitted for fluazinam.  In 2009 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 required to support the preliminary risk assessment.

HED is not recommending any label changes or other mitigation for existing uses in conjunction with this risk assessment.  Details regarding the risk assessment to support Registration Review are provided in Appendix F of the attached document.

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 Harmonization	11
2.2.3	Recommended Tolerances	11
2.2.4	Revisions 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	15
4.2	Absorption, Distribution, Metabolism, & Elimination (ADME)	15
4.2.1	Dermal Absorption	15
4.3	Toxicological Effects	16
4.4	Safety Factor for Infants and Children (FQPA Safety Factor)	18
4.4.1	Completeness of the Toxicology Database	18
4.4.2	Evidence of Neurotoxicity	18
4.4.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal	19
4.4.4	Residual Uncertainty in the Exposure Database	19
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 Exposures for Risk Assessment	21
4.5.3	Classification of Carcinogenic Potential	21
4.5.4	Summary of Toxicological 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	Dietary Risk Assessment	29
5.4.1	Description of Residue Data Used in Dietary Assessment	29
5.4.2	Percent 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	31
6.0	Residential (Non-Occupational) Exposure/Risk Characterization	31
6.1	Residential Handler Exposure and Risk	31
6.2	Residential Post-application 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	32
6.6	Residential Bystander Post Application Inhalation Exposure	33
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	Cancer 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-application Exposure/Risk Estimates	37
9.2.1	Occupational Post-application Inhalation Exposure/Risk Estimates	39
9.2.2	Occupational Post-application Dermal Exposure/Risk Estimates	39
10.0	References	41
Appendix A.  Fluazinam Toxicology Profile and Additional Information	43
A.1	Toxicology Profile Tables for Fluazinam	43
A.2	Triple Pack Analysis for Fluazinam	50
A.3	HEC Inhalation Calculations	52
A.4	Hazard Identification and Endpoint Selection	55
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 Registered Uses	66

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 fluazinam.  The toxicity and exposure databases for fluazinam are complete in accordance with the requirements of registration review, and therefore this document also serves as HED's human health risk assessment to support registration review.  The proposed uses on melons and peppers were evaluated under a joint review with Canada's Pesticide Management Regulatory Agency (PMRA).

Fluazinam (3-chloro-N-[3-chloro-2,6-dinitro-4-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2-pyridinamine) is a preventive contact fungicide with a multi-site fungicidal mode of action.  It disrupts the production of energy at several metabolic sites within the fungal cell.  Fluazinam is a protectant fungicide.  When it is applied to plants, it remains primarily on the plant surface and kills any fungal spores that come into contact with it.  It is not taken up to any extent by the plant and, unlike systemic fungicides, is not translocated within the plant.

HED has assessed exposures and risks from the registered and proposed uses of fluazinam.  The end-use product proposed for use on melons, peppers, and soybeans is OMEGA[(R)] 500F (EPA Reg. No. 71512-1), a soluble-concentrate (SC) formulation containing 40% ai fluazinam (4.17 lbs ai/gal).  OMEGA[(R)] 500F may be applied as a foliar spray using 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, the label allows up to 6 applications at 0.78 lb ai/A for 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 exposure from use on soybeans, melons, and peppers is expected to be of short- to intermediate-term durations. 

Hazard Characterization and Endpoint Selection

The 28-day inhalation and immunotoxicity studies required during registration review were submitted and evaluated, and the toxicology database for fluazinam is complete.

 The liver is a primary target organ following dosing with fluazinam.  Numerous liver effects were observed in rats, mice, and dogs.  Liver effects were also observed in rats following dosing 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 vacuolization.  A developmental neurotoxicity (DNT) study containing a lower concentration of the impurity was submitted to address the Agency's concerns regarding the vacuolization; in the study, there was no evidence of vacuolization of the brain or any other treatment-related pathology up to the highest dose tested.   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 the 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 peribronchiolar proliferation in both sexes.
 
There was no evidence of increased quantitative or qualitative susceptibility in a developmental 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 susceptibility.  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 effects 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 protective of the observed susceptibility.  The required 10x FQPA Safety Factor was reduced to 1x based 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; and 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) were 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 dietary risk assessment for females 13-49, a developmental toxicity study in rabbits was used, and the endpoint selected was total litter resorptions and skeletal 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) for assessing short- 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).  In accordance with current guidance, human equivalent concentrations (HECs) and human equivalent doses (HEDs) were calculated, with the HEDs being used for risk assessment.  The dermal and inhalation studies are protective 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 assessments, a 100x uncertainty factor was applied (10x interspecies factor and 10x intraspecies factor).  The 100x factor was 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 3x and an intraspecies factor of 10x; 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 Degradates of Concern

The metabolism of fluazinam in primary crops, rotational crops, and animals has been adequately delineated.  The residue of concern for risk assessment in bulb 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 drinking 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 review.  For soybeans, melons, and peppers, the registrants submitted adequate field trial and processing data for parent and the metabolite AMGT.  For all crops, adequate numbers of trials were performed in the recommended NAFTA growing zones.  The 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.

Adequate analytical methods are available for enforcement of tolerances in plant and livestock commodities.  In addition, the FDA Multiresidue Methods (MRMs) can serve as a confirmatory procedure for residues of fluazinam, but not for the metabolites.  The necessary analytical 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 well as the proposed uses.  The acute and chronic assessments are based on 100% crop treated assumptions and incorporate modeled estimated drinking water concentrations (EDWCs) that account for both parent fluazinam and its transformation products.  Default 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 analysis 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 dietary risk estimates are below HED's level of concern for all population subgroups, including those comprised of infants and children.   The acute dietary risk estimate for the general U.S. population is 5.3% of the acute PAD (aPAD).  The population subgroup with the highest acute dietary risk estimate is Females 13-49, which uses 28% of the aPAD.  The chronic dietary risk estimate for the general U.S. population is 20% of the chronic PAD (cPAD).  The most highly exposed population subgroup is All Infants (<1 year old), which uses 51% of the cPAD.  As the chronic dietary endpoint and dose are protective of potential cancer effects, cancer dietary risk is also not of concern.  Because such conservative assumptions were made in the assessments, HED is confident that the acute and chronic dietary exposure assessments do not underestimate risk to the general U.S. population or any population subgroup or life stage.

Residential Exposure and Risk 

The residential exposure database is complete and adequate.  There are no proposed residential uses; however, there is an existing use of fluazinam on golf course turf.  Individuals 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).

Aggregate Exposure and Risk

 The acute and chronic aggregate risk estimates are equivalent to the corresponding dietary (food plus water) risk estimates, which are not of concern.  Chronic dietary exposure is considered to be a background exposure level to which the short-term residential exposure is added.  The short-term aggregate risk assessments resulted in estimated MOEs of 730 to 970.  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) database.  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 treated, and amount handled.

Occupational handler assessments considered both dermal and inhalation short-term exposures.  The estimates are considered to be protective of intermediate-term exposure and risk.  For the proposed uses on soybeans, melons, and peppers, all the occupational handler scenarios resulted in MOEs equal to or greater than the respective levels of concern at some level of personal protective equipment (PPE, e.g., baseline (single layer clothing, no respirator), chemical-resistant gloves, double layer clothing), and assuming engineering controls (i.e., enclosed cockpit) for aerial applications.  Based on the dermal and inhalation risk estimates, no additional PPE or other mitigation is needed on the label, either for the existing or proposed uses.

Based on the Agency's current practices, a quantitative non-cancer occupational post-application inhalation exposure assessment is not being performed for fluazinam at this time.  Although a quantitative occupational post-application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational handlers (e.g., flaggers).  Handler inhalation exposure estimates are considered to be protective of occupational post-application inhalation exposure scenarios.  If new policies or procedures are put into place, the Agency might 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., 12 hours after application).
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 Protection 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[(R)] 500F label is appropriate to protect agricultural workers from post-application exposures to fluazinam on melons, peppers, and soybeans. 

2.0	HED Recommendations

HED recommends in favor of granting the proposed Section 3 use of fluazinam on soybeans, the Melon subgroup (9-A), and the Pepper/Eggplant subgroup (8-10B).

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 of 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 entitled "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 fluazinam, 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 MRMs can serve as a confirmatory procedure for residues of fluazinam.  The FDA MRM methods are not suitable for determining residues of AMGT.

2.2.2	International Harmonization

There are no harmonization issues between the U.S., Codex, 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 that 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), bushberries (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

The 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 fluazinam, 3-chloro-N-[3-chloro-2,6-dinitro-4-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2-pyridinamine), including its metabolites and degradates, in or on the commodities in the table.  Compliance with the tolerance levels is to be determined by measuring only fluazinam. 

Table 2.2.3.  Tolerance Summary for Fluazinam
Commodity 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

The 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 calculation procedures for melons and peppers.  The U.S. is also using the OECD calculation procedures for soybean commodities.  Revised Sections F should be submitted by IR-4 and the registrant, to reflect HED's tolerance recommendations.  No changes are needed to the tolerance expressions.

2.3	Label Recommendations

None

3.0	Introduction

3.1	Chemical Identity

Table 3.1.   Fluazinam Nomenclature
Compound
Chemical Structure
                              

Empirical Formula

C13H4Cl2F6N4O4
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[(R)] 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.  The log KOW value is 3.56 (KOW = 3,630).  Fluazinam has a vapor pressure of 1.73 x 10[-][7] mm Hg at 25ºC.  See Appendix C for a listing of fluazinam's physical and chemical 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[(R)] 500F (EPA Reg. No. 71512-1), which is a 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 proposed use directions are summarized in Table 3.3.

OMEGA[(R)] 500F may be applied as a foliar spray using aerial, chemigation (i.e., sprinkler irrigation system), ground and handheld equipment.  The proposed Restricted Entry Interval (REI) is 48 hours for all crops.  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 Soybeans
                       Applic. Timing, Type, and Equip.
                      Formulation [EPA Reg. No. 71512-1]
                         Max. Single Application Rate 
                                 (lb ai/A)†
                      Max. No. of Applications per Season
                   Max. Seasonal Application Rate (lb ai/A)
                                  PHI (days)
                        Use Directions and Limitations
Melons (Crop Subgroup 9A)
Broadcast; Ground, Chemigation (Sprinkler System).
OMEGA(R) 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 Subgroup 8-10B)
Broadcast; Ground, Chemigation (Sprinkler System), Soil Drench (at transplanting).
OMEGA(R) 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(R) 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) = 0.013 lb ai/gal.

The proposed (and current) product label for the 4.17 lb/gal soluble-concentrate (SC) formulation specifies that applications 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 restrictions:  "All crops on the label may be replanted immediately after treatment.  All other crops may be replanted 30 days after the last application."

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 might be exposed to fluazinam in 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 uses also result in the potential for occupational (handler/post-application) exposures.  In addition, applicators might be exposed while handling the pesticide prior to application, mixing/loading the pesticide, and 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 Low-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 according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture's National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA), and are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess 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 exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0	Hazard Characterization and Dose-Response Characterization

Fluazinam is a preventive contact fungicide with a multi-site mode of action.  The fungicidal mode of action involves disruption of the production of energy at several metabolic sites within the fungal cell.  Fluazinam is a protectant fungicide.  Unlike systemic fungicides, it is not taken up to any extent by the plant, and is not translocated within the plant.  When applied to plants it remains primarily on the plant surface.  The mammalian mode of action is unknown at this time.

4.1	Toxicology Studies Available for Analysis

The 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; developmental 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 acute LD50 and neurotoxicity studies (acute, subchronic, and developmental). 

4.2	Absorption, Distribution, Metabolism, Excretion (ADME)

In the rat metabolism study, overall 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 feces 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 components 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 administered 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 represented 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 administration 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 biologically relevant differences in the metabolism of fluazinam.

4.2.1	Dermal Absorption	

An in vivo dermal 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 lowest 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 effort 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 assessments.  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 absorption 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 dermal 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 histopathology (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 animals 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 histopathology (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 long-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. 

Treatment-related 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 observed were decreased body weight gain, decreased food consumption, mild anemia, and clinical chemistry alterations (increased serum cholesterol, phospholipid, and aspartate aminotransferase).  Testicular atrophy and increased testicular weights (inhalation study), 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 follicular 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 high 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, 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 peribronchiolar proliferation in both sexes.  
 
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.  Decreased body weights, placental weights, and increased incidences of facial/palate 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 decreased body weight gain and food consumption, increased water consumption, and increased urogenital staining.

There was no evidence of increased quantitative or qualitative susceptibility in a developmental toxicity study in rabbits or in a 2-generation reproduction study in rats.  In rabbits, increased incidences of total litter resorptions and a slightly increased incidence of fetal skeletal abnormalities (e.g. kinked tail tip, fused or incompletely ossified sternebrae, and abnormalities 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 considered 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 matter of the CNS was observed initially in long-term studies in 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 endpoints 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 evidence of thyroid 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 could 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).  

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

The proposed and existing 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 toxicological 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 are protective of the potential effects, 4) the dietary exposure assessments 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.  

1.1.1 Completeness of the Toxicology Database 

The available toxicity 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 rabbits, a reproduction study in rats, and a DNT study in rats are all available for FQPA assessment. 

4.4.2 	Evidence of Neurotoxicity
 
No evidence of neurotoxicity was observed in an acute neurotoxicity study in rats up to 1000 mg/kg/day.  Decreases 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 vacuolization 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 technical 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.
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 evidence of increased qualitative susceptibility of fetuses in the developmental toxicity study in rats.  Increased incidences of facial/palate clefts and other rare deformities were seen in fetuses in the presence of minimal maternal toxicity.  A DNT study in rats 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 as well as delayed-preputial separation were observed 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, there 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 risk 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 the developmental toxicity study in rats is significantly higher than the NOAEL used (7 mg/kg/day) to establish the acute reference dose (aRfD, females 13-49); therefore, the aRfD is protective of any observed fetal effects.  

As previously stated, increased 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 uncertainties with respect to dietary and residential exposure.  The dietary exposure assessments 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 fluazinam 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 exposures have not been underestimated.

1.4       Toxicity Endpoint and Point of Departure Selections

4.5.1	Dose-Response Assessment

The detailed descriptions of the toxicity studies used for selecting toxicity endpoints and points of departure for various exposure scenarios are presented in Appendix A.3 of this assessment.
For acute dietary assessment for females 13-49, the endpoint selected for risk assessment 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 endpoint 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 fluazinam.

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 approximately 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 short- 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.  Developmental 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 (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.

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 systemic liver effects observed in a 7-day inhalation study served as the basis for endpoint and dose selection.  However, in 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, human equivalent concentrations (HECs) and human 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 endpoint are protective of the developmental effects seen in rats as well 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 100x uncertainty factor was applied (interspecies factor of 10x and intraspecies factor of 10x).  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 uncertainty factors.  For inhalation risk assessments, the LOC is an MOE of 30 (interspecies factor of 3x and intraspecies factor of 10x) since human equivalent calculations (HECs) were used for risk assessment.  The interspecies factor was reduced from 10x to 3x because the HEC calculation accounts for pharmacokinetic (not pharmacodynamic) interspecies differences between animals and humans.

4.5.2	Recommendation for Combining Routes of Exposure for Risk Assessment

When there are potential occupational and residential exposures to a pesticide, the risk assessment must address exposures from three major sources:  incidental oral, dermal, and inhalation.  It must be determined 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 cannot be combined because the toxicological effects are different.
 
1.4.3 Classification of Carcinogenic Potential

In accordance with EPA's Draft Guidelines for Carcinogen Risk 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 increases 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 the 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, including carcinogenicity, that could result from exposure to fluazinam.  

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 might 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 study 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, in two carcinogenicity studies in mice, increased incidences of hepatocellular tumors were observed in male mice only.  The CARC 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 mutagenicity in the available mutagenicity battery. 

1.4.4 Summary of Toxicological Doses and Endpoints for Fluazinam for Use in Human Health Risk Assessments  

Table 4.5.4.a.  Toxicological Doses and Endpoints for Fluazinam for Use in 
          Dietary and Non-Occupational Human Health Risk Assessments
                              Exposure/ Scenario
                              Point of Departure
                                 Uncertainty/
                              FQPA Safety Factors
                RfD, PAD, Level of Concern for Risk Assessment
                        Study and Toxicological Effects
Acute Dietary (General population)
NOAEL=
50 mg/kg/day

UF: 100x
UFA= 10x
UFH=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: 100x
UFA= 10x
UFH=10x
FQPA SF=1x

Acute RfD =0.07 mg/kg/day

aPAD = 0.07mg/kg/day
Developmental Toxicity- Rabbits.
Developmental LOAEL = 12 mg/kg/day based on increased incidence of total litter resorptions and possibly increased incidence of fetal skeletal abnormalities.
Chronic Dietary (All Populations)
NOAEL=
1.1 mg/kg/day (mouse study)

UF: 100x
UFA= 10x
UFH=10x
FQPA SF=1x

Chronic RfD =0.011 mg/kg/day

cPAD
= 0.011mg/kg/day
Co-critical: 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: 100x
UFA=10x
UFH=10x

Residential LOC:
MOE = 100 

21-Day Dermal Toxicity-Rats
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 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: 30x
UFA=3x
UFH=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 adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  PAD = population 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.

Table 4.5.4.b.  Summary of Toxicological Doses and Endpoints 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=100x
UFA=10x
UFH=10x

Occupational LOC for MOE = 100 

21-Day Dermal Toxicity-Rats
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 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
UFA=3x
UFH=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 and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = 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 equivalent 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 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.

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 study 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 commodities are parent plus the metabolites AMPA and DAPA and their sulfamate conjugates.

5.1.2	Summary of Environmental Degradation
      
The environmental fate studies for fluazinam indicate that the parent compound forms 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, the Environmental Fate and Effects Division (EFED) assumed that the physicochemical characteristics were similar for both the parent and its products (i.e., the total toxic residue approach).

5.1.3	Comparison of Metabolic Pathways

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

In plants, fluazinam undergoes reduction of one of the nitro groups to an amine, forming AMPA.  AMPA can then be conjugated with glutathione, with subsequent degradation of the glutathione moiety to cysteine.  The AMPA-cysteine conjugate then undergoes transamination, reduction, and conjugation with glucose to form AMGT.  In addition, both rings of fluazinam appear to be labile to ring cleavage, and subsequent degradation of the rings into small fragments occurs.  These fragments can then be incorporated into a variety of natural plant components.

In ruminants and poultry, the metabolism of [[14]C]-fluazinam is comparable, and involves reduction of one or both nitro groups on the phenyl ring to form AMPA, MAPA, or DAPA.  Fluazinam also undergoes dehalogenation and hydroxylation of the chlorine on the phenyl ring to form HYPA.  These compounds can then undergo conjugation with glutathione, and subsequent degradation of the glutathione component yields a variety of polar compounds.  Although the ring structure of the parent molecule remains intact, fluazinam per se was only a minor component (<=2.7% TRR) of the [[14]C]-residues in poultry tissues and eggs, and was not detected in ruminant tissues or milk.

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

Although there are metabolites and degradates in plants, livestock, and drinking water 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 that 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 the residue of concern in peanuts and root and tuber vegetables is parent fluazinam for purposes of both dietary risk assessment and tolerance enforcement (D272624, W. Cutchin, 4/23/2001).  For all other crops, the residues of concern include both fluazinam and its metabolite AMGT for purposes of dietary risk assessment.  For tolerance enforcement, 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 because 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 degrades 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 study supports the 30-day plant-back interval (PBI) that is currently listed on the label for crops without direct uses of fluazinam.

The fluazinam residues of regulatory interest in animal commodities are parent plus the metabolites AMPA and DAPA and their sulfamate conjugates.  These metabolites were the primary metabolites in the ruminant and poultry metabolism studies.  AMPA and DAPA are structurally similar to fluazinam.  They are the products formed by reduction of one or both nitro groups on the phenyl ring to form the mono- and di-amino metabolites.  Their toxicity is assumed to be comparable to that of the parent compound (D272624, W. Cutchin, 4/23/2001). 

Table 5.1.4.  Summary of Metabolites and Degradates to be included in the
         Risk Assessment and Tolerance Expression
Matrix
Residues included in Risk Assessment
Residues included in Tolerance Expression
Plants

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

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

Primary Crop: all others
Parent fluazinam and AMGT
Parent fluazinam

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

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

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), tolerances are established for residues of fluazinam, 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 §180.574(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 (D397721, 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 requested in a previous review (D360840, D. Dotson, 3/31/2010).  Adequate storage stability data were submitted 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, adequate 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.  

The registrant submitted a processing study for soybeans.  Residues concentrated in soybean 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 for 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

The 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

The drinking water assessment performed by EFED provides EDWCs of fluazinam in surface water and in groundwater.  The drinking water residue used in the dietary risk assessment was provided by EFED (D397602, J. Meléndez, 7/17/2012) and incorporated directly into this dietary assessment into the food categories "water, direct, all sources" and "water, indirect, all sources."  The residues of concern in drinking water for risk assessment are parent fluazinam and its transformation 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 than 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 using 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-FCID(TM), 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 metabolite AMGT.  In addition, the acute assessment assumes 100% crop treated and incorporates modeled EDWCs that account for both parent fluazinam and its transformation products.  Default processing factors were used for all relevant processed commodities without 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, default processing factors for all relevant processed commodities without a separate tolerance, and modeled EDWCs that account for both parent and transformation products.  Again, the resulting exposure and risk estimates are considered to be conservative.

Because such conservative assumptions were made in the assessments, the resulting exposure and risk estimates are considered to be conservative as well.  HED is confident that the acute and chronic dietary exposure assessments significantly overestimate risk to the general U.S. population and its various population subgroups.

5.4.2	Percent Crop Treated Used in Dietary Assessment

The 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 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 28% of the aPAD.  Although Females 13-49 use the greatest percent of the aPAD, the population subgroup with the highest exposure estimate is Children 1-2.  This subgroup uses 21% 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 as 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 Table 5.4.6.

5.4.4	Chronic Dietary Risk Assessment

Chronic risk estimates are also below HED's level of concern for all population subgroups.  The risk estimate for the general U.S. population is 20% of the chronic PAD (cPAD).  The most highly exposed population 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.

5.4.6	Summary Table
 
 Table 5.4.6.  Summary of Acute and Chronic Dietary Exposure and Risk Estimates for Fluazinam
                                        
                              Population Subgroup
                      Acute Assessment (95[th] Percentile)
                               Chronic Assessment
 
                                aPAD, mg/kg/day
                          Exposure Estimate, mg/kg/day
                                     % aPAD
                                cPAD, mg/kg/day
                          Exposure Estimate, mg/kg/day
                                     % cPAD
U.S. Population
0.5
0.026393
5.3
                                     0.011
0.002145
20
All infants
0.5
0.083776
17
                                     0.011
0.004928
45
Children 1-2 yrs*
0.5
0.106710
21
                                     0.011
0.005635
51
Children 3-5 yrs
0.5
0.064022
13
                                     0.011
0.003751
34
Children 6-12 yrs
0.5
0.031323
6.3
                                     0.011
0.002031
18
Youth 13-19 yrs
0.5
0.017332
3.5
                                     0.011
0.001171
11
Adults 20-49 yrs
0.5
0.019148
3.8
                                     0.011
0.001936
18
Adults 50-99 yrs
0.5
0.017495
3.5
                                     0.011
0.002118
19
Females 13-49 yrs*
0.07
0.019721
28
                                     0.011
0.001996
18
 *The subpopulations with the highest acute or chronic risk estimates
 
 
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-application Exposure

Fluazinam residential post-application scenarios include individuals playing golf on treated turf.  
Children 6 to <11 years old, youths 11 to <16 years old, and adults can potentially be exposed when they play golf on treated turf.  Post-application residential exposure was assessed using default assumptions and transfer coefficients from the HED SOPs for Residential Exposure Assessments, (2012), as well as chemical-specific residue data from a turf 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 residential post-application dermal exposures resulting in MOEs greater than or equal to 100 are not of concern.  Short-term dermal post-application exposure and risk analyses for golfers resulted in MOEs greater than the LOC and are not of concern.  The highest risk estimate (lowest MOE) was for youth golfers aged 6 to <11 years old, with an MOE of 780.  A summary of the residential short-term dermal exposure and risk estimates is shown in Table 6.2.1.

Table 6.2.1.  Residential Post-application Short-term Dermal Exposure and Risk Estimates for Fluazinam
                                   Scenario
                               Application Rate
                                   (lb ai/A)
                                    TTR [1]
                                  (ug/cm[2])
                                      CF
                                      TC
                                  (cm[2]/hr)
                                   ET (hrs)
                                    BW (kg)
                              Dose 2  (mg/kg/day)
                                 DermalMOE [3]
                                    Golfer
6 to < 11 yrs old
                                      0.7
                                    0.0865
0.001
                                     2,900
                                       4
                                      32
                                   0.031356
                                      780
11 to < 16 yrs old
                                      0.7
                                    0.0865
0.001
                                     4,400
                                       4
                                      57
                                   0.026709
                                      910
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 (ug/cm[2]) x 0.001 (mg/ug) 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 is not being performed for fluazinam at this time primarily because of its vapor pressure of 1.73 x 10[-7] mm Hg.  However, volatilization of pesticides can be a potential source of post-application inhalation exposure to individuals in close proximity 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, 2010 (http://www.epa.gov/scipoly/SAP /meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report and might, 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 might revisit the need for a quantitative post-application inhalation exposure 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 is also expected to be negligible.  The only route of exposure is through the dermal route (i.e., dermal post-application exposure).  Therefore, combined residential exposure assessment for golfers is not required.  

6.4 Residential Risk Estimates for Use in Aggregate Assessment
The residential scenarios and risk estimates identified for use in performing an aggregate exposure assessment as part of the fluazinam human health risk assessment are: dermal post-application exposure resulting from treated golf courses for adults (MOE = 1,100) and for children 6 to < 11yrs old (MOE = 780).

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 Regional 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 chemical 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 policy is in place, the Agency might 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 inhalation 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 might be a source of post-application inhalation exposure to individuals nearby pesticide applications.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report and might, 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 might 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 estimates from three major sources: food, drinking water, and residential exposures.  In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risk estimates themselves can 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 results 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 estimates are the background exposure levels that were added directly to the residential dermal post-application exposure estimates.  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 residential life stage children 6-<11 was children 6-12, and the closest dietary subgroup to the residential life stage youth 12-<16 was youth 13-19.    
 
 The short-term aggregate risk assessments resulted in estimated MOEs of 730 to 970.  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.  Because the background exposure from food and water is so low relative 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
                                    0.002031
                                    0.031356
                                    0.033387
                                      730
 Youth 11-<16
                                      24.4
                                      100
                                     0.244
                                    0.001171
                                    0.026709
                                    0.027880
                                      880
 Adults
                                      24.4
                                      100
                                     0.244
                                    0.002118
                                    0.022923
                                    0.025041
                                      970
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))]

7.3	Chronic Aggregate Risk

There are no residential scenarios that result in long-term exposure.  As a result, the chronic aggregate risk assessment results from long-term exposure to residues in food and drinking water only.  The chronic dietary exposure analysis included both food and drinking water and, therefore, the chronic aggregate risk assessment is equivalent to the chronic dietary assessment discussed in Section 5.4.4, above.  All risk estimates are below HED's level of concern.

7.4	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.

6.0 Cumulative Exposure/Risk Characterization
Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to fluazinam and any other substances, and fluazinam does not appear to produce a toxic metabolite produced by other substances.  For the purposes of this risk assessment, therefore, EPA has not assumed that fluazinam has a common mechanism of toxicity with other substances.  For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.

7.0 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 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,
::	Applying Sprays with Groundboom Equipment,
::	Applying Sprays with Aerial Equipment, 
::	Flagging for Aerial Applications, and
::	Mixing/Loading/Applying Liquids with Mechanically-Pressurized Handgun Sprayer.

No handler exposures are expected from applying sprays via chemigation systems.

The maximum single 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 exposures are not expected.

Estimates of dermal and inhalation exposure were calculated for various levels of personal protective equipment (PPE).  Results are presented for "baseline," defined as a single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator, as well as baseline with various levels of PPE as necessary (e.g., gloves, respirator, etc).  The fluazinam product label directs mixers, loaders, applicators and other handlers to wear: baseline clothing (i.e., long-sleeved shirt and long pants, socks), chemical-resistant gloves and footwear, and protective eyewear.  When mixing and loading, handlers must wear a chemical-resistant apron and a dust/mist filtering respirator (MSHA/NIOSH TC-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 (D397723, 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 proprietary (e.g., AHETF data) and subject to the data protection provisions of FIFRA.  The standard values recommended for use in predicting handler exposure that are used in this assessment, known as "unit exposures," are outlined in the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (http://www.epa.gov/opp00001/science/handler-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 adult body weight (80 kg).

Occupational Handler Non-Cancer Exposure and Risk Estimates

Table 9.1 presents the short-term dermal and inhalation risk estimates 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 separately.  Exposure estimates for the occupational handler scenarios described above resulted in MOEs greater than the respective levels of concern (dermal LOC = 100; inhalation LOC = 30) at some level of PPE and with the assumption of an enclosed cockpit (i.e., engineering controls) for aerial applicators.

Handler dermal 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 or 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 requires the use of chemical-resistant gloves,
   * mixing/loading liquids for aerial applications to soybeans, which requires the use of chemical-resistant gloves + double layer clothing, and
   * mixing/loading liquids for chemigation for melons and peppers, which requires the use of chemical-resistant gloves. 

Handler inhalation 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 might 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 Aviation 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 control 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 will 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 determined assuming use of engineering control (enclosed cockpits) and baseline attire (i.e., long-sleeve shirt, long pants, shoes, and socks).  Pilots are not required to wear protective gloves.  With this level of protection, there are no risk estimates of concern for aerial applicators treating melons, peppers, and soybeans with fluazinam in accordance with the proposed label.

 Table 9.1.  Short-Term Occupational Handler Exposure and Risk Estimates for Fluazinam
                               Exposure Scenario
                                Crop or Target
                      Dermal Unit Exposure (μg/lb ai)[1]
                    Inhalation Unit Exposure (μg/lb ai)[1]
                                    Maximum
                              Application Rate[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 (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application 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 (μg/lb ai) x Conversion Factor (0.001 mg/μg) 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.

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 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, there are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously-treated fields.  These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/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 might, as appropriate, develop policies 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 might 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 exposure 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 might be exposed to fluazinam residues.  Based on the use pattern, workers might be exposed to short- and intermediate-term exposure durations.  Detailed descriptions of the occupational post-application dermal assessment are available in Z. Figueroa, (D397723, 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 this 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 information about the ARTF data, can be found at: http://www.epa.gov/pesticides/science/post-app-exposure-data.html.  

Dislodgeable Foliar Residues:  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 studies demonstrated that dislodgeable foliar residue values declined over time.  Furthermore, HED concluded that the 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, dermal 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 peanuts (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 Post-application Non-Cancer Dermal Risk Estimates

A summary of the post-application exposure and risk estimates for the proposed uses is provided in Table 9.2.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 (ug/cm[2]) x TC x 0.001 mg/ug 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 ingredients 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[(R)] 500F label is appropriate to protect agricultural workers from post-application exposures to fluazinam on melons, peppers, and soybeans.  

10.0	References

D. Dotson, K. Middleton, Z. Figueroa, 3/31/2010, 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, 2/7/2012,  Fluazinam.  Human Health Risk Assessment for the Section 3 Registration Action on Turfgrass

D. Dotson, 9/7/2012, 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, Fluazinam:  Occupational and Residential Exposure Assessment for the Proposed Use on Golf Course Turf

J. Melendez, 7/17/2012, D397602, 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 Review 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, D362190, 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 Study
 
 
 
 List of Appendices
 
Appendix A.	Toxicology Profile and Additional Data 
Appendix B.	International Residue Limit Status Sheet
Appendix C.	Fluazinam Physical/Chemical Properties
 Appendix D.	Review of Human Research
 Appendix E.	Structures of Fluazinam Metabolites and Degradates of Concern
 Appendix F.	Occupational Exposure and Risk Assessment to Support Registration Review

                                       
              Appendix A:  Toxicology Profile and Additional Data

A.1. Toxicity Profile Tables for Fluazinam

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.  Acute 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: LD50 >5000 mg/kg
F: LD50 >5000 mg/kg

                                      IV

870.1200 
Acute dermal toxicity
rabbits

                                  Omega 500F
                                (40% fluazinam)

                                   42974908

M: LD50 >2000 mg/kg
F: LD50 >2000 mg/kg

                                      III

870.1300
Acute inhalation toxicity
rats

                             Fluazinam 50% WP [a]
                               (51.3% fluazinam)

                                   42311001

M: LC50 = 3.0 mg/L
F: LD50 = 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.

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 amniotic fluid and possible increased late resorptions and postimplantation loss
870.3700b
Prenatal developmental toxicity
rabbits
F: 0, 2, 4, 7, 12 mg/kg/day 

Acceptable/guideline

42248616 (1988)

Maternal NOAEL = 4 mg/kg/day
LOAEL = 7 mg/kg/day based on decreased food consumption and increased liver histopathology.
Developmental 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)

Maternal NOAEL = 3 mg/kg/day
LOAEL = not identified (>3 mg/kg/day)
Developmental NOAEL = 3 mg/kg/day
LOAEL = not identified (>3 mg/kg/day)
870.3800
Reproduction and fertility effects
rats
F0 males: 0, 1.5, 7.3, 36.6 mg/kg/day
F0 females: 0, 1.7, 8.4, 42.1 mg/kg/day
F1 males: 0, 1.9, 9.7, 47.3 mg/kg/day
F1 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 F1 males
Reproductive NOAEL = 10.6 mg/kg/day
LOAEL = 53.6 mg/kg/day based on decreased number of implantation sites and decreased litter sizes to day 4 post-partum for F1 females (F2 litters).
Offspring NOAEL = 8.4 mg/kg/day
LOAEL = 42.1 mg/kg/day based on reduced F1 and F2 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 tumors) 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

Acceptable/guideline

42208405 (1988); 44807220 (1996)

NOAEL =  Males:1.1 mg/kg/day; Females: 1.2 mg/kg/day
LOAEL = Males: 10.7 mg/kg/day; Females: 11.7 mg/kg/day based on increased incidences of brown macrophages in the liver of both sexes, eosinophilic vacuolated hepatocytes in males, and increased liver weight in females
Clear evidence of carcinogenicity (hepatocellular 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 females
870.5100
Bacterial reverse mutation assay (Ames test)
Up to 2 μg/plate for S. typhimurium strains and up to 250 μg/plate for E. coli (-S9).  Up to 100 μg/plate for S. typhimurium strains and Up to 500 μg/plate for E. coli (+ S9)

Acceptable/Guideline
42270605 (1988)

Negative with and without S9 up to cytotoxic concentrations. 
870.5100
Bacterial reverse mutation assay (Ames test)
Up to 1μg/plate for S. typhimurium strains and up to 250 μg/plate for E. coli (-S9) and  up to 100 μg/plate for S. typhimurium strains and up to 500 μg/plate for E. coli (+S9) 

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/mL (+S9), up to 0.3  μg/mL (-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/mL (+/-S9) 

Acceptable/guideline

45156902 (1986)

Negative with and without S9 activation up to 5 μg/mL.   
Compound tested to cytotoxic concentrations.
870.5375
In vitro mammalian chromosome aberration (CHL cells)
Up to 9.5 μg/mL (+S9) up to 4 μg/mL (-S9) 

Acceptable/guideline

42270606 (1988)

Negative with and without S9 up to cytotoxic concentrations.  Cells harvested at 24 and 48 hours in nonactivated studies and at 24 hours in activated studies.
870.5395
Mammalian erythrocyte micronucleus test
500, 1000, 2000 mg/kg (oral gavage) 

Acceptable/guideline
44807224 (1999)

Negative at 24 hour sacrifice (500, 1000, 2000 mg/kg).
Negative at 24, 48, and 72 hour sacrifices (2000 mg/kg).
870.5550
UDS in primary rat hepatocytes
Unacceptable/guideline
0.05 to 6.25 μg/mL
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/day
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 μg equiv.cm[-2]).  The dermal delivery dose was 4.47% (0.169 μg equiv.cm[-2]).
870.7800
Immunotoxicity-Mouse
Acceptable/Guideline
0, 1000, 3000 or 7000 ppm (0, 217.7, 679.0 or 1684.6 mg/kg/day)
MRID 48708702 and 48708703 (2011)
Under conditions of the combined studies, the immunotoxicity NOAEL is 50 ppm (equivalent to 11 mg/kg/day); the LOAEL is 1000 ppm (equivalent to 231 mg/kg/day) based on decreased anti-SRBC AFC response. 
 
The systemic toxicity NOAEL is 7000 ppm (1684.6 mg/kg/day); the LOAEL was not established.
Non-guideline

In Vitro Percutaneous Absorption of Radiolabeled Fluazinam in Two Formulations 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 uL/cm[2] giving the nominal dose levels of 5000 ug/cm[2] and 5 ug/cm.[2]
48361514 (2000)
Dermal delivery of Fluazinam from the Fluazinam SC (5000 ug/cm[2]) was 119 ug equiv/cm[2]or 2.36% of the applied dose. Of this, only 58 ug equiv/cm[2] or 1.16% of the applied dose was absorbed. Dermal delivery of Fluazinam from the Diluted Fluazinam SC (5 ug/cm[2]) was 1.88 ug equiv/cm2 or 40.17% of the applied dose. Of this, only 0.75 ug equiv/cm2 or 15.95% of the applied dose was absorbed.  For risk assessment purposes the dermal delivery dose at 24 hours will be used since it includes the 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 μL.cm[-2] giving the nominal dose levels of 5000 μg.cm-2 and 5 μg.cm,[-2] respectively.
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 on Thyroid Function and its Reversibility in Rats
Main: 0 and 3000 ppm for 7 days and sacrificed (0 and 222 mg/kg/day)
Recovery: 0 and 3000ppm then reversibility for 7 days

Acceptable/Non-guide-line 
48361510 (2005)
Decreases in T3 and T4 and an increasing trend in TSH in the main group after treatment at 3000 ppm.  In the 3000 ppm recovery group after 7 days, decrease in T3 noted at almost the same level, but no changes in T4 or TSH. Increase in UDPGT activity toward 4-nitrophenol in main group, similar changes in recovery group. Thyroid 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)
Increases 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 the 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. 

A.2. Triple Pack Analysis for Fluazinam

Using the available dermal absorption 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:  

Refined Dermal Dose (RDD) = 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:

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 ug/cm2
                                       
                                 5000 ug/cm2
                                   5 ug/cm2
                                       
                                 5000 ug/cm2
                                   5 ug/cm2
                                       
                                 5000 ug/cm2

% 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 ug/cm2)

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" 

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 RDDR 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; Standard 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
                                    0.0003
                                       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)	

Calculation of the Human Equivalent Concentration (HEC) and Human Equivalent Dose

Human Equivalent Concentrations

Human Equivalent Doses

Using the HECs calculated, a conversion of the inhalation concentration to a dose (mg/L to mg/kg/day) was conducted as follows:
 
Dose (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	Absorption:  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 pharmacodynamic (PD) differences, the UF for interspecies extrapolation may be reduced to 3x (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 retained at 10x.  Thus, the UF when using the RfC methodology is customarily 30x.

For fluazinam, HED believes exposures can be short- (1-30 days) or intermediate- (1 to 6 months) term in duration.  Long-term exposures are not anticipated for fluazinam.  
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 different 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 derived.  Time adjustments are traditionally needed for non-occupational (bystander) versus occupational exposure scenarios.  Traditionally, HECs for non-occupational exposure are based on the number of hours an individual might be at home.  Therefore, the most conservative estimate of hours spent at home would be 24 hours/day and 7 days/week.  In comparison, the average 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.

Methodologies 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 estimate 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 that 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 described by the following equation:

Where:
PODstudy: Point of departure identified in the critical toxicology study
Danimal exposure: Duration of animal exposure (hrs/day; days/wk)
Danticipated exposure: Anticipated human duration of exposure (hrs/day; days/wk)
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 particulate exposure by defining the particulate diameter (mass median aerodynamic diameter [MMAD]) and the geometric standard deviation (σg), which is then used to determine the RDDR.  The RDDR is a multiplicative factor used to adjust an observed inhalation particulate exposure concentration of an animal (A) to the predicted inhalation particulate exposure concentration for a human (H) that would be associated with the same dose delivered to the region or target tissue.

	RDDRr = (RDDr/Normalizing Factor)A

		     (RDDr/Normalizing Factor)H  

As with 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 σg 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 of Inhalation Dosimetry."
 

A.4.  Hazard Identification and Endpoint Selection

Acute Reference Dose (aRfD) - Females age 13-49

Study Selected:  Developmental Toxicity Study in Rabbits	
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 possible increased incidence of fetal skeletal abnormalities (including kinked 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 appropriate for this population.

                 Acute RfD (females 13-49) =  = 0.07 mg/kg/day

Acute Reference Dose (aRfD) - General Population

Study Selected:  Acute Neurotoxicity Study in Rats	
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 and 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.  In this study there was a large dose spread between the NOAEL (50 mg/kg/day) and the LOAEL (1000 mg/kg/day).  The 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).  The route and duration of exposure are appropriate for this population.  

                 Acute RfD (females 13-49) =  = 0.5 mg/kg/day

Chronic Reference Dose (cRfD) 

Studies Selected:  A 2-year carcinogenicity study in mice and a 1-year chronic oral study in dogs (co-critical studies) were selected to establish the cRfD.  The 2-year 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 were 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 dryness 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 the 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 Carcinogenicity Study in Mice 	
MRID Nos:  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-year 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 brown 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-Year Chronic Oral Toxicity Study in Dogs	
MRID Nos:  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/Endpoint/Uncertainty Factors:  A 1-year 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 4.9 mg/kg/day in females (a 10 fold higher dose).  A second 2-year chronic feeding study in rats (MRIDs 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 males; 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 study was not chosen for risk assessment.   

Dermal Exposure (Short-, Intermediate-Term) 
Studies Selected:  21-Day Dermal Toxicity Study in Rats, In Vivo Dermal Penetration Study in Rats, and In Vitro Dermal Penetration Study in Human and Rat Skin
MRID Nos:  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, the 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 from 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 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 (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 were 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.

             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
Commodity
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
0.05

 [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.

                                       

              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 (20°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
                                      162
                                      512

Vapor Pressure (25°C) 
1.73 x 10[-7] mm Hg
(2.3 x 10[-5] Pa)
LSS 2000_1973_2LS_rev
Dissociation Constant (pKa)
Average pKa = 7.22 in 50% ethanol/water (v/v)
MRID 42208401
Octanol/Water Partition Coefficient (KOW)
3,630
(Log Kow = 3.56)
MRID 42208401
UV/Visible Absorption Spectrum
                                      pH
                                  λmax (nm)
PMRA Regulatory Note REG2003-12

                                       5
                                       7
                                    >10
                                      238
                                   239, 342
                                 260, 343, 482

  
	

                     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 Database 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 might have included review by the Human Studies Review Board.  Descriptions 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.

  Appendix E:  Structures of Fluazinam Metabolites and Degradates of Concern

Table E.1.  Structures of Fluazinam Metabolites and Degradates of Concern
Compound Common Name
Structure

Fluazinam
                                       
                                       
                                       

AMGT

Plant Metabolite
                                       
                                       
                                       

AMPA

Livestock Metabolite
Drinking Water Degradate

                                       
                                       
                                       

DAPA

Livestock Metabolite
Drinking Water Degradate

                                       
                                       

CAPA

Drinking Water Degradate

                                       
                                       
                                       

DCPA

Drinking Water Degradate

                                       
                                       
                                       

HYPA

Drinking Water Degradate

                                       
                                       
                                       

                                  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, the toxicity and exposure databases for fluazinam are complete.  Therefore, the new use aggregate 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 proposed 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 treated 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 with 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 health 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 health 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 required 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 systemic 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 equivalent 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 label 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 residue 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 assumptions used for DFR studies, is presented in Z. Figueroa (D397723, 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
                                  Omega 500F
                          (40% ai; 4.17 lb a.i./gal)
                      Dry Bean & Succulent 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)
                                       
                                   Bushberry
                             Groundboom, airblast
                                     0.65
                                  6 (7 days)
                                       
                                    Carrots
                        Groundboom, aerial, chemigation
                                     0.52
                                  4 (7 days)
                                       
                                    Lettuce
                        Groundboom, aerial chemigation
                                     0.78
                                   1 (none)
                                       
                                    Onions
                        Groundboom, aerial, chemigation
                                     0.52
                                  6 (7 days)
                                       
                                    Apples
                         Aerial, chemigation, airblast
                                     0.45
                                  10 (7 days)
                                       
                                    Ginseng
                                  Groundboom
                                     0.78
                                  4 (7 days)
                                       
                                    Peanuts
                                  Groundboom
                                     0.78
                                  2 (21 days)
                                       
                                   Potatoes
                        Groundboom, aerial chemigation
                                     0.26
                                  7 (7 days)
                                   CO 070003
                                  Omega 500F
                                   Potatoes
                                  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 (backpack, manually-pressurized handwand, and mechanically-pressurized handgun sprayers)
                                     0.70
                                 12 (14 days)

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 developed 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,
::	Mixer/Loader/Applicator for Mechanically-Pressurized Handgun Sprayer,
::	Mixer/Loader/Applicator for Backpack Sprayer, and
::	Mixer/Loader/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 exposure 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 are 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-term exposures are not expected.

Table F.2 presents the short-term dermal and inhalation risk estimates for occupational handlers.  The 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., chemical-resistant gloves, double layer clothing with chemical-resistant hat) and assuming use of engineering controls (i.e., enclosed cockpit) for aerial applications.  Based on the risk estimates shown below, no additional PPE or other mitigation is needed on registered labels.  

 Table F.2.  Short-Term Occupational Handler Exposure and Risk Estimates for Fluazinam Registered Uses.
                               Exposure Scenario
                                Crop or Target
                             Dermal Unit Exposure 
                                (μg/lb ai)[1]
                    Inhalation Unit Exposure (μg/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
                                      840
                                       
                                   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)
                                 0.44 lb ai/A
                                      80
                                    0.0968
                                      250
                                   0.0000964
                                      500
                                       
                                Carrots, Onions
                                      220
                                  (Baseline)
                                     0.219
                                (No respirator)
                                 0.52 lb ai/A
                                      80
                                    0.1140
                                      210
                                   0.000114
                                      420
                                       
                                   Bushberry
                                      220
                                  (Baseline)
                                     0.219
                                (No respirator)
                                 0.65 lb ai/A
                                      80
                                    0.1430
                                      170
                                   0.000143
                                      340
                                       
                               Ginseng, Peanuts,
                            Lettuce (Head and Leaf)
                                      220
                                  (Baseline)
                                     0.219
                                (No respirator)
                                 0.78 lb ai/A
                                      80 
                                    0.1710
                                      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
                                      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 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
                                  Applicator
                      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)
                                 0.44 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 
                                    0.0613
                                      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
                                    (AHETF)
                                   Potatoes
                                       5
                   (Engineering Controls - Enclosed cockpit)
                                     0.068
                   (Engineering Controls - Enclosed cockpit)
                                 0.26 lb ai/A
                                      350
                                    0.00569
                                     4,300
                                   0.0000774
                                      620
                                       
                                    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
                                   0.000233
                                      210
                       Sprays for 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
                                       
                                   Bushberry
                                     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
                                    0.0250
                                      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, Golf Course
                                     8260
                                  (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 Areas
                                    100000
                                  (Baseline)
                                      30
                                  (Baseline)
                               0.0175 lb ai/gal
                                    5 gals
                                     0.109
                                      220
                                   0.0000328
                                     1,500
              Mechanically-pressurized Handgun Sprayer (Liquids)
                                    (ORETF)
                              Turf, Golf Courses
                                  (Broadcast)
                                     1140
                                  (Baseline)
                                      1.9
                                  (Baseline)
                                 0.70 lb ai/A
                                      5 A
                                     0.050
                                      490
                                   0.0000831
                                      580
              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 Policy #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 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 (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] Inhalation MOE = Inhalation NOAEL (0.048 mg/kg/day)/ Inhalation Dose (mg/kg/day); LOC = 30.

Occupational Post-Application Exposure and Risk Estimates

Post-Application Inhalation 

Based on the Agency's current practices, a quantitative non-cancer occupational post-application inhalation exposure assessment for the existing uses is not being performed for fluazinam at this time; handler inhalation exposure estimates are considered to be protective of occupational post-application inhalation exposure scenarios.  If new policies or procedures are put into place, the Agency might revisit the need for a quantitative occupational post-application inhalation exposure assessment for fluazinam.

Post-Application Dermal 

Short- and intermediate-term dermal 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 presented 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 studies 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 were available based on information about the study conditions, region of use, use pattern, etc. (M. Collantes, 03/18/2008, D349315).  Therefore, the peanut DFR data were used as a surrogate to assess dermal post-application exposure resulting from application of fluazinam on ginseng, Brassica (cole) leafy vegetables, succulent edible podded and dry beans, carrots, bushberries, 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 based on the registered labels (EPA Reg. No. #71512-1 and EPA Reg. No. #71512-20).  Residue values were adjusted by application rate, when applicable.  

Post-application Exposure and Risk Estimates  -  Agricultural Crops

A summary of the post-application exposure and risk estimates for the registered agricultural uses is provided in Table F.3.  

 Table 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 Maintenance, 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 μg/cm[2] is based on predicted day 0 residue value calculated from chemical-specific data (MRID No. 45584201) and then adjusted by application rate.  Dislodgeable Foliar Residue (DFR) from Potatoes = 0.429 μg/cm[2] is based on predicted day 0 residue value calculated from chemical-specific data (MRID No. 45584202) and then adjusted by application rate.  Dislodgeable Foliar Residue (DFR) from Apples = 0.0471 μg/cm[2]  is based on predicted day 0 residue value calculated from chemical-specific data (MRID No. 45584203) and then adjusted by application rate.  
2. Daily Dermal Dose = [DFR (ug/cm[2]) x TC x 0.001 mg/ug x 8 hrs/day]  BW (80 kg).
3. MOE = NOAEL (24.4 mg/kg/day) / Daily Dermal Dose.  

Short- and intermediate-term post-application risk estimates were not a concern on day 0 (i.e., 12 hours following application) for most activities.  Based on HED's post-application exposure calculations, the following crops reached a dermal MOE of 100 within 48 hours of application, 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 (cole) leafy vegetables resulted in an 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 fluazinam technical material.  Fluazinam is classified as Toxicity Category I for eye irritation.  Under the Worker Protection Standard for Agricultural Pesticides, active ingredients 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[(R)] 500F label is appropriate to protect agricultural workers from post-application exposures to fluazinam. 

Dermal Post-application 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 post-application dermal exposure estimate resulted in an 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, turf grasses on golf courses 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 label is considered to be appropriate.