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.